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Reader Review of the Day: Benefit Cosmetics high beam

BellaSugar — Tue, 23 Dec 2008 07:00:58 -0800

Highlighters are great, so don't just save them for special occasions; use them everyday for that wide-awake glow.

So, for today's reader review, we're looking at Benefit Cosmetics high beam ($24), a brightening complexion enhancer. Reader A Million Suns is loving this product, calling it an ethereal glow in a bottle. Here's what she had to say:

"Just a few dots of this on my brow bones, inner corners of my eyes, and cheekbones made instantly makes me look fresher and gives me that ethereal glow. Plus it lasts forever because you don't need to use much of it each time."

Want to add your own two cents? Check out our product reviews section to share your thoughts.

Get a Healthy Glow: Highlighters

FabSugar — Thu, 24 Aug 2006 11:32:27 -0700

Ever wonder how celebrities all get that healthy, radiant glow? Most likely, it's because their makeup artist is using a face illuminator, like Benefit's High Beam and Moon Beam complexion highlighters. These products can be used as spot enhancers or blended all over your face for a glowing, sexy look. High Beam is a satiny pink shine, while women with olive or tan skin tones should opt for Moon Beam, which gives skin a more natural, golden-pink glow. Both cost $22 and are available here and here.

To learn how to use highlighters, read more

To apply highlighters such as Benefit's High Beam, use these simple tips:

First, be sure to pick the right color for your skin tone. Women with blue undertones should use a pinkish color like High Beam, and if your skin is more yellow, use a golden color.
With the nail polish-like brush, draw an X on the apple of each of cheek and beneath each brow.
Using your fingertips, blend the Xs in an upward and outward circular motion.
For an all-over dewy effect, try mixing just a dab of highlighter into your foundation or moisturizer.

Backstage Pass To LFW Spring 2010: Mattijis

BellaSugarUK — Mon, 21 Sep 2009 07:30:00 -0700

On Friday afternoon, the buzz backstage at the Mattijis van Bergen show all about a creating a fun loving, sexy and Summery feel. Hair was pulled back and teased in the front to create a kind of frizzy, wind-blown effect, whilst makeup was controlled yet luminous using toned down metallics. My pal, the friendly makeup artist Rachel Wood said,

"Because the designer is using copper and bronze jewellery, I wanted to complement the look and accent the eyes with that same colour scheme. The goal for this face was to create something ethereal, summery and light."

As Benefit Cosmetics was the official makeup sponsor of the show, all of the products used were theirs, and Jessica Nails used a light coloured nudey-pink shade on each of the models. To see more photos from backstage, and for a list of all of the colours that Rachel used to create this gorgeous makeup look, just read more.

View 8 Photos ›

FACE: Begin by blending Boi-ing (concealer), Erase Paste (brightening concealer) and a a little bit of Moon Beam (liquid highlighter) on the cheekbones, lips and brow bone to create a smooth canvas with a touch of luminescence.
EYES: Then, to create that perfect metallic colour on the eyes, Rachel mixed some One Hot Minute and Big Daddy Lust Dusters and blended it all over the lids of the eyes on top of Birthday Suit (an oyster cream shadow she used as a base). Next, she lined the eyes with Gilded Tequilla (a gold highlighter pencil that she used as eye liner), she added some High Brow white liner on the inside of the eyes and finished the look with a couple coats of Bad Gal Mascara.
CHEEKS: As a contour, Rachel lightly dusted Coralista Blush on the model's cheeks and left them bronzer-free.
LIPS: First, lips were prepped with Benetint Lip Balm and them she added a little bit of Moon Beam over the balm for an iridescent effect.

Photos Courtesy of Benefit

Prostate cancer

FitSugar — Wed, 08 Oct 2008 17:35:05 -0700

In This Report

Highlights
Introduction
Prognosis
Risk Factors
Symptoms
Conditions with Similar Sym...
Screening and Diagnosis
Tests to Determine Severity...
Treatment
Treatment Options by Stagin...
Treatment for Localized Pro...
Surgery
Radiation Treatments
Options if Treatments Fail...
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New Guidelines for Localized Prostate Cancer

In 2007, the American Urological Association (AUA) released updated guidelines for treatment of localized prostate cancer. The guidelines recommend that:

Patients should be classified as low, intermediate, or high risk, depending on their PSA levels, cancer stage, and tumor aggressiveness.
Doctors need to consider patients’ personal preferences and quality of life concerns as well as their clinical status.
Standard treatment options include active surveillance (watchful waiting), surgery, or radiation therapy. Initial androgen deprivation therapy (hormone therapy) is seldom recommended for localized prostate cancer.

New Guidelines for Androgen Deprivation Therapy

The American Society of Clinical Oncology (ASCO) 2007 guidelines recommend that doctors delay androgen deprivation therapy for advanced prostate cancer until patients develop symptoms. When treatment is started, ASCO recommends either removal of both testicles (orchiectomy) or luteinizing hormone releasing hormone (LHRH) drug treatment.
Androgen deprivation therapy can increase the risks for heart disease death and diabetes, according to a 2006 Journal of Clinical Oncology study.

Diagnosis

Experts do not recommend prostate specific antigen (PSA) tests for men over age 70, yet many of these men continue to receive unnecessary tests, indicates a 2006 Journal of the American Medical Association study.
A new investigational test for early prostate cancer antigen-2 (EPCA-2) may be more accurate than the PSA test and may eventually replace it, suggests a 2007 study in Urology.

Genetic Research

Researchers have identified a set of genetic variations that may account for about 68% of prostate cancer cases in African-American men. Scientists hope that further investigation of this chromosomal region may help in developing genetic tests for prostate cancer.

Introduction

Prostate cancer is a malignant tumor that arises in the prostate gland. As with any cancer, if it is advanced or left untreated in early stages, it can eventually spread through the blood and lymph fluid to other organs. Fortunately, prostate cancer tends to be slow growing compared to other cancers. As many as 90% of all prostate cancers remain dormant and clinically unimportant for decades. This high incidence of latent or incidental malignancy is unique to the prostate gland. Most older men eventually develop at least microscopic evidence of prostate cancer, but it often grows so slowly that, as one specialist has written, many men with prostate cancer "die with it, rather than from it."

The prostate gland is an organ that surrounds the urinary urethra in men. It secretes fluid which mixes with sperm to make semen.

Male hormones (androgens) play major roles in the development of prostate cancer. Some research, for example, reports a higher risk with increasing testosterone and a lower risk with increasing estrogen levels. Dihydrotestosterone (DHT) is the principal male hormone in the prostate gland. It affects the size of the prostate gland itself and may play a role in prostate cancer. Nevertheless, researchers have not yet fully clarified the specific mechanisms that may be important in the development of this disease. Most likely, genetic mutations affecting androgens trigger the process. Certain growth hormones, such as insulin-like growth factor-I, are unrelated to testosterone and may increase the risk for prostate cancer.

Description of the Prostate Gland

The prostate gland is located between the bladder and the rectum and wraps around the urethra (the tube that carries urine through the penis). It is basically composed of three different cell types:

Smooth muscle cells, which contract during sex and squeeze the fluid from the glandular cells into the urethra, where it mixes with sperm and other fluids to make semen
Glandular cells, which produce a milky fluid that liquefies semen
Stromal cells (which form the structure of the prostate)

The central area of the prostate that wraps around the urethra is called the transition zone. The entire prostate gland is surrounded by a dense, fibrous capsule.

Functions of the Prostate Gland

The prostate gland provides the following functions:

The glandular cells produce a milky fluid, and during sex the smooth muscles contract and squeeze this fluid into the urethra. Here, it mixes with sperm and other fluids to make semen.
The prostate gland also contains an enzyme, called 5 alpha-reductase, that converts testosterone to dihydrotestosterone, another male hormone that has a major impact on the prostate.

Changes During the Lifespan

The prostate gland undergoes many changes during the course of a man's life. At birth, the prostate is about the size of a pea. It grows only slightly until puberty, when it begins to enlarge rapidly, attaining normal adult size and shape, about that of a walnut, when a man reaches his early 20s. The gland generally remains stable until about the mid-forties, when, in most men, the prostate begins to enlarge again through a process of cell multiplication.

Click the icon to see an image of the male reproductive anatomy.

Prognosis

Prostate cancer is the most common male cancer in the U.S. Only lung cancer causes more cancer deaths in American men. The lifetime probability of developing prostate cancer is about 16%. Each year, approximately 218,890 men in the United States will be diagnosed with prostate cancer, and about 27,050 will die from the disease. According to the American Cancer Society, 5-year survival rates for all stages of prostate cancer have increased during the past 20 years from 67% to nearly 100%.

A survival rate indicates the percentage of patients who live a specific number of years after the cancer is diagnosed. For prostate cancer, the 10-year survival rate is 93% and the 15-year survival rate is 77%. After 15 years, survival rates stabilize. A 2006 study in the Journal of the American Medical Association found that men who are diagnosed with low-grade prostate cancers have a minimal risk of dying from prostate cancer up to 20 years after diagnosis. However, men diagnosed with more severe forms of prostate cancer have a higher risk of dying within 10 years.

Treatment of prostate cancer varies depending on the stage of the cancer (i.e., spread) and may include surgical removal, radiation, chemotherapy, hormonal manipulation or a combination of these treatments.

Because so many prostate tumors are low-grade and slow growing, survival rates are excellent when prostate cancer is detected in its early stages. Cure rates can be as high as 98% in some cases.

Click the icon to see an image of the pelvic lymph nodes.

Locally Advanced. If the disease is at the locally-advanced stage, in which it has spread beyond the prostate but only to nearby regions, it is more difficult to cure, but survival rates can be prolonged for years in many men. (When cancer has metastasized to the pelvic lymph nodes, the outlook is worse than if it has spread to other areas.)

Metastasized Cancer. If prostate cancer has spread to distant organs (metastasized), average survival time is 1 - 3 years, but some of these patients may live longer or die of other causes.

If cancer recurs after initial treatment for early-stage tumors, it is still potentially curable if it is contained within the prostate, although in most cases the cancer has spread. Hormone treatments for such recurring cancers can often prolong survival for years, although the cancer almost always returns again.

Risk Factors

The major risk factors for prostate cancer include genetic, dietary, and environmental factors that affect male hormones (androgens) and make a man more susceptible to this cancer.

Prostate cancer occurs almost exclusively in men over age 40 and most often after age 50. It is estimated that by age 70, about 65% of men have at least microscopic evidence of prostate cancers. Fortunately, the cancer is often very slow growing and older men with the cancer nearly always die of something else.

Heredity plays a role in some types of prostate cancers. Men with a family history of the disease have a higher risk of developing prostate cancer. Having one family member with prostate cancer doubles a man's own risk, and having three family members increases risk by 11-fold.

In 1998, scientists discovered a gene, located on chromosome 1, which may be involved in 1 in 500 cases of prostate cancer. They named this gene HPC1. (HPC stands for “hereditary prostate cancer.”) In 2005, scientists announced another major breakthrough in understanding the genetic components of prostate cancer. Research published in Science suggested that, in some cases, prostate cancer occurs when a specific set of genes merge. The genes are part of the ETS gene family and include ETV1, ETV4, and ERG.

In 2007, three separate studies published in Nature Genetics focused on DNA variations located on chromosome 8 in the 8q24 region. The research suggested that men who carry these genetic variations have a substantially increased risk of developing prostate cancer. The DNA variations may be associated with as many as 32% of prostate cancers in Caucasian men and 68% of prostate cancer cases in African-American men.

Doctors hope that future research will help develop genetic tests to identify men most at risk and, eventually, targeted drug therapy for prostate cancer.

A gene is a short segment of DNA which is interpreted by the body as a plan or template for building a specific protein. Genes reside within long strands of DNA which in turn make up the chromosomes.

African-American men have the world's highest risk for prostate cancer, more than 50% higher than the risk for Caucasian males. The disease is also more lethal among African-Americans. Men who live in Asia have lower risks for prostate cancer, but their risk increases if they move to North America. This indicates that there are unknown environmental or dietary factors that can alter a man's underlying genetic risk of developing this disease.

Socioeconomic Issues. The higher mortality rates in African-American men may be partly due to socioeconomic factors, such as lack of insurance, irregular screening and a late diagnosis, and unequal access to health care.

Dietary Factors. Dietary factors may play some small role in the higher risk in African-American men. This is suggested by the fact that prostate cancer is rare in many parts of Africa.

Biologic Factors. Evidence suggests that African-American and Asian men have certain genetic factors that may affect male hormones differently and may help account in part for the higher risk in the first group and the lower risk in the second.

Higher PSA Levels. African-American men also tend to have higher PSA levels than Caucasians. They are overdiagnosed with prostate cancer by 37% compared to 15% in Caucasians using PSA screening tests.

Chemicals. The relationship between prostate cancer and chemical exposure is controversial. Men whose work involves heavy labor and those exposed to certain metals and chemicals, including cadmium, dimethylformamide, and acrylonitrile, may be at higher risk for prostate cancer. Some studies have indicated that farmers might be at higher risk.

A 2001 study concluded that certain leisure activities may expose men to the same chemicals as those that pose a possible danger in the industrial setting. These chemicals included:

Home or furniture maintenance
Painting, stripping, or varnishing furniture
Activities that involved exposure to lubricating oils or greases, metal dust, or pesticides or garden sprays

Scientists think that specific genes that affect the body's response to viruses may be associated with certain types of prostate cancer. Some theories suggest that there may be a relationship between prostate cancer and infections, such as herpes virus, human papillomavirus, and cytomegalovirus. In 2006, scientists identified a new virus, XMRV, which is 30 times more common in men with prostate cancer who have a genetic mutation with the HPC1 gene. Scientists know that men who have the HPC1 genetic mutation are more likely to get prostate cancer. This new research suggests that the genetic mutation may make them more vulnerable to a virus that causes the cancer. Researchers will continue to investigate XMRV and other possible infectious causes of prostate cancer.

Obesity. Obesity may increase the risk for prostate cancer, particularly more aggressive forms of the disease. Obesity may also make prostate cancer more difficult to diagnose. A 2005 study found that overweight and obese men were more likely to be diagnosed with advanced prostate cancer and to die of the disease than normal-weight men.

Nonmelanoma Skin Cancers and Sunlight. Some studies report that patients with prostate cancer and a history of nonmelanoma skin may have a higher risk for a poorer outlook. Such skin cancers are highly associated with exposure to sunlight. However, sunlight triggers production of vitamin D in the body, which research indicates may help protect against prostate cancer. Prostate cancer rates are, in fact, lower in southern, sunny regions.

Vasectomy. Because testosterone levels remain higher for a longer period in men who had vasectomy, experts have theorized that such men have a greater chance for developing the cancer. While some studies have suggested a higher risk with vasectomy, other studies have reported no higher danger. A rigorous 2002 study from New Zealand, for example, which has the highest vasectomy rates in the world, found no increased risk of prostate cancer from the procedure, even 25 years after the operation. A 2002 study in California, in fact, reported a lower risk for prostate cancer in men who had had vasectomies. It is possible that the higher rates reported in earlier studies may have been due to earlier prostate screening in men who have had vasectomies. Indeed, one study reported that about 25% of doctors screened men with vasectomies earlier for prostate cancer than those without the operation. [See In-Depth Report #37: Vasectomy.]

Click the icon to see an illustrated series detailing a vasectomy.

Click the icon to see an animation on vasectomy.

A Western lifestyle is associated with prostate cancer, so obesity, high-meat intake, and dietary fats have been intensively studied. Results have been inconsistent, however. Certain factors, such as cancer-causing compounds in well-cooked meat or high-calorie intake, may help explain the associations between such dietary factors and cancer risk.

Click the icon to see an image on different types of weight gain.

Fats. Some studies have found an association between high fat-intake and prostate cancer. This association may be explained by other suspected dietary factors for prostate cancer, such as high-calorie diet, high meat intake, and calcium (found in dairy products), all of which are associated with fat intake. The effects of specific fatty acids (compounds that make up fats) may also help clarify the role of fats in prostate cancer. The omega-3 fatty acids in fish (EPA and DHA) and the omega-3 fatty acids found in certain vegetables (ALA) can all protect the heart, but they may have different effects on the prostate.

Marine Omega-3 Fatty Acids. Research indicates that docosahexanoic acid (DHA) and eicosapentaneoic acid (EPA), the omega-3 fatty acids found in fish, may be protective against prostate cancer. Some studies have reported a lower risk for prostate cancer in men who ate fish frequently (two or more times a week).
Alpha-Linolenic Acid. On the other hand, some research has indicated that alpha-linolenic acid (ALA), the omega-3 fatty acid found in certain plants and nuts (flaxseed, canola, walnuts), may increase the risk of prostate cancer. However, some studies suggest that flaxseed, a plant food that is also rich in omega-3 fatty acids, may help slow the growth of prostate tumors.

Meat and High-Temperature Cooking. Some evidence suggests that a high intake of red meat raises the risk for prostate cancer. Because red meat is high in saturated fat, such findings may explain the inconsistencies found in studies that simply look at fat content as a risk for prostate cancer. High-temperature cooking (grilling, broiling, or pan-frying) of meat or poultry has been specifically associated with increased risk for cancer in some studies. Over-cooking meat increases the amount of compounds called heterocyclic amines, which has been associated with cancerous changes in general and prostate cancer in particular, at least in some studies. Cooking meats in liquid does not appear to increase these compounds. As with all dietary studies, some have observed no association between high intake of well-cooked meat and prostate cancer.

Vegetarian Diet. Small studies suggest that a vegetarian diet may be protective. Specific foods may be especially helpful in reducing the risk of prostate cancer:

Whole grain cereals, seeds, and nuts have been associated with a lower risk for prostate cancer. Part of this protection may be due to their high fiber content. Fiber binds to sex steroids and is excreted, carrying the hormones with it. Whole grains also contain selenium, a trace mineral that may have some protective properties.
Many studies have reported a significantly lower risk for prostate cancer with high intake of cooked tomatoes, which are high in a beneficial plant chemical called lycopene. (However, other studies have not reported such protection.)
Soy may also be protective, which may partially explain the low rate of prostate cancer observed in Japanese men and vegetarians (who typically use soy as a protein replacement). Theoretically soy, which is a rich source of an estrogen-like plant compound, may inhibit hormones that promote prostate cancer. Laboratory studies are mixed on such effects, however.
Cruciferous vegetables (cauliflower and broccoli) may have cancer-fighting chemicals.
Boron-rich foods (nuts, red grapes, avocados, and dried fruits) may also be protective.
Green tea. Scientists have speculated that the antioxidants contained in green tea may help to inhibit prostate cancer growth. Investigators are researching the effects of both green tea and green tea extract supplements, but results to date have been inconclusive.

Dairy Products, Calcium, and Vitamin D. Studies have reported an association between consuming large amounts of dairy products and a modestly increased risk for prostate cancer. (Moderate intake has not been associated with a higher risk.) There is some evidence that calcium (contained in dairy products) may increase the risk for prostate cancer by reducing levels of the most active form of vitamin D (1,25 dihydroxyvitamin D). Many studies indicate that vitamin D may help protect against prostate cancer. Men should make sure they are getting enough vitamin D through sunlight exposure, food, or vitamin supplements.

Getting enough calcium to keep bones from thinning throughout a person's life may be made more difficult if that person has lactose intolerance or another reason, such as a tendency toward kidney stones, for avoiding calcium-rich food sources. Calcium deficiency also affects the heart and circulatory system, as well as the secretion of essential hormones. There are many ways to supplement calcium, including a growing number of fortified foods.

Click the icon to see an image of the benefits of vitamin D.

Click the icon to see an image of the sources of vitamin D.

There is some evidence that certain vitamin and mineral supplements (such as vitamin E and selenium) can protect against prostate cancer, and also some evidence that excessive use of supplements may increase risk. In a 2007 National Institutes of Health study, men who took multivitamin supplements more than seven times a week increased their risks for developing advanced prostate cancer and for dying from the disease. The risks were highest for men who had a family history of prostate cancer and for those who took individual supplements of selenium, beta-carotene, or zinc. However, using multivitamin supplements occasionally or once a day does not appear to increase prostate cancer risk.

The National Cancer Institute is conducting a large-scale clinical trial of more than 35,000 men to investigate whether selenium, vitamin E, or a combination of these two dietary supplements can help to prevent prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the largest prostate cancer prevention trial ever initiated.

Click the icon to see an image of the benefits of vitamin E.

Click the icon to see an image of the sources of vitamin E.

In general, a healthy diet with nutritious fruits and vegetables is the best way to meet your daily requirement of vitamins and minerals.

Alcohol consumption does not appear to be associated with increased prostate cancer risk. A recent study, however, suggested a linear trend between red wine consumption and reduced risk of prostate cancer. In a study of over 1,400 newly diagnosed middle-aged patients with prostate cancer, researchers found that each additional glass of red wine consumed per week reduced the relative risk of prostate cancer by 6%. Researchers theorize that the flavonoids contained in red wine may inhibit tumor cell growth. More research is needed to confirm these results.

Regular physical activity may help reduce the risk of prostate cancer and slow the progression of the disease. The beneficial effects of exercise may be particularly important for older men. A 2006 study found that men ages 65 and older who exercised vigorously for at least 3 hours weekly had a 70% lower risk of being diagnosed with advanced prostate cancer.

Finasteride (Proscar) is a drug used to shrink the prostate in men with benign prostatic hyperplasia (BPH). It blocks an enzyme that converts testosterone to dehydroepiandrosterone (DHEA), the form of the male hormone that stimulates the prostate. Researchers are investigating whether finasteride may help prevent prostate cancer. In the 2003 Prostate Cancer Prevention Trial (PCPT), more than 18,000 men were randomly assigned to receive either finasteride or placebo. The men took the pills daily for 7 years. Results, published in 2003 in the New England Journal of Medicine, indicated that men who took finasteride were 25% less likely to develop prostate cancer than men who took placebo. However, although the finasteride group had fewer prostate cancers overall, those that did develop were higher-grade and more aggressive. Men who took finasteride had more sexual problems, including episodes of erectile dysfunction, but were less likely to have urinary problems, such as incontinence. It is still unclear if finasteride is an appropriate preventive approach.

Frequent ejaculations from masturbation or sexual activity have been associated with a lower risk for prostate cancer. Some experts speculate that certain carcinogens may be concentrated in prostate fluid, so that frequent ejaculation helps eliminate them. Of note, risky sexual activity, such as with multiple partners, increases the risk for sexually transmitted disease, which in turn may increase the risk for prostate cancer.

There is some evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) offer some protection against prostate cancer. NSAIDs suppress chemicals in the body called COX-2, a protein that may cause prostate cancer cells to spread. Standard NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve). However, NSAIDs taken on a long-term basis can increase the risk for heart and gastrointestinal problems.

Symptoms

Prostate cancer usually causes no symptoms in the early stages. As the malignancy spreads, it may constrict the urethra and cause urinary problems.

Urine flows from the kidney through the ureters into the urinary bladder where it is temporarily stored. As the bladder becomes distended with urine, nerve impulses from the bladder signal the brain that it is full, giving the individual the urge to void. By voluntarily relaxing the sphincter muscle around the urethra, the bladder can be emptied of urine. Urine then flows out through the urethra.

Later-stage urinary symptoms typically include:

Weak urinary stream
Inability to urinate
Blood in the urine
Interruption of urinary stream (stopping and starting)
Frequent urination (especially at night)
Pain or burning during urination

Significant pain in one or more bones may indicate the occurrence of metastases (spread of disease). This chronic pain occurs most often in the spine and sometimes flares in the pelvis, the lower back, the hips, or the bones of the upper legs. It may be accompanied by significant weight loss.

Conditions with Similar Symptoms

In up to half of men in their 40s, the prostate begins to enlarge through a process of cell multiplication called benign prostatic hyperplasia (BPH). The symptoms of BPH can mirror late-stage prostate cancer because the enlarging inner portion of the prostate puts pressure on the urethra, which can potentially cause urinary problems. About 80% of men eventually develop enlarged prostates, but only some experience significant symptoms. BPH is a normal condition and is not life-threatening. [See In-Depth Report #71: Benign prostatic hyperplasia.]

Benign prostatic hypertrophy (BPH) is a non-cancerous enlargement of the prostate gland, commonly found in men over the age of 50.

Relationship to Prostate Cancer. Because the prostate enlargement in BPH is affected by testosterone, many men are concerned that it may be related to prostate cancer. Fortunately, current evidence indicates that it has no effect one way or the other. The two conditions develop in different parts of the prostate. BPH occurs in the inner zone of the prostate, while cancer tends to develop in the outer area. A 10-year study found no higher risk for prostate cancer in men with BPH.

Click the icon to see an animation about benign prostatic hypertrophy.

Prostatitis is an inflammation of the prostate, often caused by bacterial infections. Symptoms include urgency, frequency, and pain in urination, sometimes accompanied by fever or blood in the urine.

Screening and Diagnosis

The prostate specific antigen (PSA) blood test is widely used for screening men for prostate cancer. However, there is great uncertainty over whether regular screening has major benefits for most men. The most recent guidelines from the U.S. Preventive Services Task Force report that there is no conclusive evidence that routine prostate screening saves lives. Indeed, it may lead to invasive testing, and to treatments for many men who, considering the slow growth of the cancer, might derive no benefits from them. It is a difficult subject, and men must discuss all aspects carefully with their doctor.

A 2006 study in the Archives of Internal Medicine also suggested that screening tests for prostate cancer may not reduce men’s risk of death. The small study of 1,000 men found no differences in survival between men who had prostate specific antigen tests or digital rectal exams, and men who were not screened. Doctors should inform men of the uncertainty of prostate cancer tests so that patients understand the relative risks and benefits of screening

Standard Screening Tests for Early Detection. Two standard tests are used for early detection of prostate cancer:

Digital rectal examination (DRE). With the DRE, a doctor palpates the prostate in order to feel lumps or masses.
PSA test. The PSA blood test measures the level of a protein called prostate-specific antigen. It is able to detect early prostate cancer, although it has limitations.

If the digital rectal examination indicates the possible presence of cancer, regardless of the PSA results, a doctor may also obtain a visual image of the prostate through an ultrasound procedure called transrectal ultrasonography (TRUS). Only a biopsy, however, in which a tiny sample of prostate tissue is surgically removed, can actually confirm a diagnosis of prostate cancer.

Candidates for Annual Screening. Until major studies report on the survival benefits of prostate screening, expert groups recommend the following:

Men ages 50 - 70 should be offered annual screening. (Some experts believe that men whose PSA levels are under 1.0 and possibly under 2.0 may safely be screened only every 2 years thereafter.)
Men with a family history of prostate cancer and all African-American men should consider annual screening at about age 45.
Experts agree that PSA testing is inappropriate for men over age 70. PSA testing in this age group can cause more harm than good by leading to overly aggressive treatment. Despite this fact, many elderly men continue to receive unnecessary PSA tests.

The best age to start annual screening is under debate. Some experts advocate performing a first PSA test in all men aged 40 and then monitoring anyone whose PSA levels are over 0.60 ng/mL. They argue that such men are at high risk for developing prostate cancer within 25 years. A study presented at the 2007 meeting of the American Urological Association suggested that even a small increase in PSA in men age 44 - 50 may predict whether advanced prostate cancer will develop later in life.

Researchers are working on developing more accurate tests that, hopefully, will one day replace the PSA test. A promising test in development measures a protein called early prostate cancer antigen-2 (EPCA-2). A 2007 study suggested that the EPCA-2 test is highly accurate. It can distinguish between benign prostatic hyperplasia (BPH) and prostate cancer and can evaluate whether or not a man has prostate cancer, regardless of what his PSA levels indicate. Researchers hope that this test may eventually provide better diagnoses of prostate cancer, and help prevent men from receiving unnecessary biopsies.


	DRE alone	PSA alone and in Combination with DRE
Chance of Cancer	Only 20% of men with abnormal DREs have cancer. Unfortunately, 70% of prostate cancers detected with DRE alone have already spread beyond the prostate gland.	The odds of cancer with PSA readings are: 3 ng/mL or below indicates 2% or less chance of cancer. 3 - 10 ng/mL indicates about a 25% chance of cancer. 10 ng/mL and over indicates a very strong chance. Men with abnormal results from both DRE plus PSA tests have a 60% chance for cancer.
Risk of Missed Cancers with Normal Results	About 60% of men who have prostate cancer have normal DRE results.	Some evidence suggests that only performing biopsies at levels above 4.0 would miss over 80% of cancers present below that level in men under 60 years and 65% in older men. As a result, some experts recommend biopsies with PSA levels at 3.0 or below in young men. Still, cancer at low PSA levels is very uncommon, particularly in younger men.

About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities. The exam is quick and painless but some men find it embarrassing. It is not very accurate in detecting early cancers, but studies indicate that regular DREs still save lives.

Prostate Cancer is the most common cancer in men in the United States. Prostate cancer forms in the prostate gland, and can sometimes be felt on digital rectal examination. This is one of the purposes of the digital rectal exam.

Prostate specific antigen (PSA) is a protein produced in the prostate gland that keeps semen in liquid form. Prostate cancer cells appear to produce this protein in elevated quantities. Measuring PSA levels increases the chance for detecting the presence of cancer when it is microscopic. There are many unresolved questions surrounding PSA testing. The test is not accurate enough to either completely rule out or confirm the presence of cancer. Relying too much on the test may lead to unnecessary biopsies. Not relying on it enough may miss cancers. It is still unclear if PSA testing is actually saving lives.

Click the icon to see an image of a PSA blood test.

Indications for Biopsy. A biopsy is usually performed to confirm or rule out cancer after screening tests that report:

PSA level of 4.0 ng/mL or higher. Some evidence indicates that men with an initial test showing PSA levels above 4.0 should take a second PSA test several weeks afterward before having a biopsy, since many non-malignant factors can increase PSA levels. (Some experts urge biopsies even if PSA levels fall below 4.0 mg, particularly in men under 60, since lower levels do not necessarily rule out cancer.)
Abnormal digital rectal examination (DRE).

Men with abnormal results from both tests have a 60% chance of prostate cancer. The chances for cancer if only one test is abnormal are considerably lower. To further complicate matters, biopsies themselves may miss very small cancers detected by PSA levels alone.

Factors Affecting PSA Levels. A number of factors and noncancerous conditions can influence PSA levels:

Ethnicity. Normal levels in Caucasian males may be different from those for African-American or Asian men. For example, using PSA screening, one study suggested that 15% of Caucasians and 37% of African-Americans are overdiagnosed with prostate cancer based upon PSA results. Some experts believe that there should be different scales for determining risk among these groups, but there is still not enough information to determine a specific range for various ethnic groups.
Age. PSA levels tend to rise naturally with age, so an elevated level in a man who is 70 may be less serious than the same level in a younger man. Some experts believe that men older than 65 who have low PSA levels are at such low risk for prostate cancer that they may be able to forgo further testing.
Benign Prostatic Hyperplasia (BPH) and Its Treatments. Between 25 - 56% of patients with BPH have elevated PSA levels. Certain treatments for this condition can also elevate PSA.
Prostatitis. About half of men with elevated PSA levels but no signs of cancer on biopsy have signs of prostatitis as indicated by urine and prostate secretion tests. (Prostatitis simply means inflammation in the prostate. Inflammation is usually due to bacterial infection, but it can also be caused by nonbacterial factors.) In one study, screening for prostatitis increased the accuracy of the PSA test significantly and reduced the number of unnecessary biopsies.
Other Noncancerous Conditions. Other noncancerous conditions that can increase PSA levels include surgical procedures or drug treatments for BPH, acute urinary retention, digital rectal examinations, and prostate biopsies themselves.
Ejaculation. Ejaculation within 48 hours before testing can raise PSA levels.

Even with its limitation, the PSA test has increased the number of detectable early-stage and therefore treatable cancers. Because of the slow-growing nature of prostate cancer, however, it is not known whether all of these very early cancers will result in significant or life-threatening disease. It is possible that PSA screening could result in the detection of some possible cancers that would never have bothered the patient and would never have posed a threat to his life.

To improve the accuracy of the PSA tests, particularly when PSA levels have risen to an intermediate range of between 4 - 10 ng/mL, researchers are developing methods for measuring other factors. To date, no test has emerged as clearly superior to the PSA test.

Free PSA Test. A small amount of prostate specific antigen leaks out of the prostate into the bloodstream. There, PSA can circulate without binding to other proteins and is referred to as free PSA. It can also form chemical combinations with other proteins. If cancer is present, PSA is more likely to be bound, and so there is less free PSA in circulation. The free PSA blood test, then, is a ratio of free PSA to the total PSA (free PSA plus chemically bound PSA).

The following results are used to determine if an elevated PSA level could mean cancer:

A free-to-total PSA ratio of 20% or lower, plus total PSA levels of 4 - 10 ng/mL, are suggestive of prostate cancer. (Some experts use 25% as a cut-off, but studies suggest that using this cut-off would miss cancers in many African-American and older men.)
A free-to-total PSA level of more than 20% plus normal or even moderately elevated total PSA tend to indicate the presence of other, benign conditions, such as benign prostatic hyperplasia (but it still does not rule out cancer).

Some studies have reported that adding a test for free PSA may improve prostate cancer detection by roughly 40% and may also reduce the need for unnecessary biopsies. In addition, any cancers that the test misses would not develop into significant disease for many years, providing ample opportunity to identify them before they became serious. Not all studies support its advantages, however, compared to measuring total PSA alone, and to date there is no consensus among doctors for how it can be used.

Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating PSA that is bound to a molecule called alpha1-antichymotrypsin. It represents about 90% of the total PSA in men and is significantly higher in men with prostate cancer than in those with BPH. To date, studies have reported conflicting results on its benefits for diagnosing prostate cancer.

Transition Zone PSA Test. Some tests have been developed to measure the density of the PSA in the transition zone of the prostate gland. (The transition zone is the central area of the prostate that wraps around the urethra.) A major comparison study in 2002 reported more accurate results than with complexed PSA.

An ultrasound procedure called transrectal ultrasonography (TRUS) provides a visual image of the prostate and is used if the DRE indicates the presence of cancer. Ultrasound is not effective as a diagnostic tool by itself because it cannot differentiate very well between benign inflammations and cancer, but the procedure may help to confirm an uncertain preliminary diagnosis and is useful as a guide for needle biopsies. Ultrasound enhancements, such as Doppler imaging or computer modeling techniques called artificial neural networks (ANN), may increase the accuracy of TRUS.

Initial Biopsies. If preliminary tests raise the suspicion of cancer, doctors will perform a biopsy. Biopsy is used to diagnose prostate cancer, and is a very accurate method for predicting the severity of an existing cancer. However, biopsies can still miss cancers if they are very small.

Core Biopsy. The standard method is called a core biopsy, which uses a spring-loaded biopsy device inserted into the rectum. The device propels a needle into the prostate, obtaining a core of tissue, which is examined by pathologists.
Fine Needle Aspiration. A more recent procedure, called fine needle aspiration, is less painful and may be as accurate as a core biopsy if the sample obtained is sufficient for analysis and if it is analyzed by a skilled pathologist.

More than half of the men who have a biopsy experience discomfort and anxiety, with men under 60 reporting higher levels of discomfort than older men. Taking a sedative 1 - 2 hours before the procedure can help reduce distress. Complications of biopsy are low, but urinary tract infection, fever, or bleeding occurs in 0.1 - 4% of men.

Repeat Biopsies. Because a biopsy can miss very small cancer cells, sometimes three or even more biopsies are recommended if cancer is still suspected after negative results, such as when:

PSA levels are high. Two or more biopsies may be taken if a man has very high PSA levels and still has normal results on a biopsy. Even men with mildly elevated PSA (between 4 - 10 ng/mL) who test negative may be given a repeat biopsy. Cancer will be detected in about 10% of this group. Whether a third biopsy is useful in these men if they still test negative after a second biopsy is uncertain.
DRE results are abnormal.
Ultrasound results are abnormal.
The initial biopsy yields microscopic findings that are suspicious.
The initial biopsy detects precancerous cells known as high-grade prostatic intraepithelial neoplasia (PIN). No treatment is necessary with this finding, but these patients should be rechecked every 3 - 6 months for the next 2 years, and then annually.

Doctors may also perform a lymph node biopsy to see if the cancer has spread.

Tests to Determine Severity of Cancer

Once cancer is diagnosed, PSA levels may help to determine its extent. If PSA levels are less than 20 ng/mL, it is possible that the cancer has not spread to distant sites. PSA levels over 40 ng/mL are a strong indicator that cancer has metastasized (spread throughout the body). PSA levels are also monitored after treatments begin. Changes in the level can show if a treatment is working or if the cancer has come back.

Doctors also monitor how quickly PSA levels rise over time. This rate is called PSA velocity (PSAV). The PSAV is very helpful in determining when treatment should begin and which treatment should be used. A high rate of PSAV is considered to be 2 ng/mL a year. Recent research suggests that men with early-stage prostate cancer who have a slow PSAV are more likely to live longer than men with rapidly rising PSA levels.

A number of biological factors are being used or investigated as markers for cancer or its severity:

Chromosomal Sets. The number of chromosomal sets in the nucleus of the tumor's DNA, known as its ploidy, is an important marker for patients in late stages of prostate cancer. Tumors with the normal two sets of chromosomes, called diploid tumors, usually have a more favorable outcome than tumors that have four sets of chromosomes (tetraploid tumors) or have an abnormal number of individual chromosomes (aneuploid tumors).

Blood Vessel Density. The density of blood vessels in the tumor is an important indicator of outcome. The greater the density, the more likely the tumor is to be aggressive.

Serum Acid Phosphatase. High levels of this enzyme indicate a more aggressive disease and the need for intensive treatments.

Testosterone Levels. Higher total testosterone levels may increase the risk for metastasis. A 2000 study found an association with low free testosterone and more extensive prostate cancer, suggesting free testosterone could be a marker for aggressive disease. (Free testosterone, as with free PSA, is not chemically bound.)

Genetic Markers. Researchers have identified a genetic marker (EZH2), which may prove to be an important marker for aggressive prostate cancer. It may, in fact, prove to be a better predictor of outcome than the tumor grade, stage, or surgical margins. Other genes being studied are those that regulate tumor growth (p53, p27, bcl-2).

Other Markers. Other markers being investigated for predicting cancer progression include prostate-specific membrane antigen, prostatic acid phosphatase, and growth factors.

The ProstaScint is a scanning technique that uses tiny amounts of radioactive material with a monoclonal antibody that can attach specifically to prostate cancer cells. A special camera then can detect tumor cells that cannot be detected with other diagnostic tools. It may help doctors make better treatment decisions. The role of this test in the routine management of prostate cancer is still being defined.

If the biopsy indicates cancer, the doctor will order other tests to determine whether or how far the cancer has spread.

Bone Scans and X-Rays. Bone scans and x-rays may reveal whether the cancer has invaded the bones. To perform a bone scan, doctors inject low doses of a radioactive substance into the patient's vein, which accumulates in bones that have been damaged by cancer. A scanner then reveals how much of the radioactive material has accumulated. Arthritis and infections may also produce positive scans. Patients with PSA levels below 20 ng/mL are unlikely to have scans that show cancer in the bone.

A radiotracer is injected into a peripheral vein. As the radiotracer decays, gamma radiation is emitted and is detected by a Gamma camera. When the tracer has collected in the target organ the area is scanned. Radionuclide scans can detect abnormalities such as fractures, bone infections, arthritis, rickets, and tumors that have spread, among other diseases.

Computed Tomography and Magnetic Resonance Imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) scans can further pinpoint the location of cancer that has spread beyond the prostate. Advanced MRI techniques are showing promise for staging and planning treatments.

Click the icon to see an image of a CT scan.

Click the icon to see an image of a MRI.

Bone Metastasis Markers. Researchers are investigating chemical markers, such as amino-terminal propeptide of type I procollagen (PINP), as early indicators of bone metastasis.

Treatment

Because BPH rarely causes serious complications, men usually have a choice between treating it or opting for watchful waiting:

Watchful Waiting. Watchful waiting (also called active surveillance) involves lifestyle changes and an annual examination. Even when choosing watchful waiting, an initial examination is critical to rule out other disorders.
Treatment Options. The primary goals of treatment for BPH are to improve urinary flow and to reduce symptoms. Many options are available. They include drug therapies, minimally invasive procedures, and major surgery.

The choice between watchful waiting and treatment usually depends on a number of factors, such as urine flow rates, prostate size, and PSA levels. Men with BPH who develop symptoms at around age 50 are more likely to need treatment within their lifetimes than older men. Unfortunately, there is no current way to determine who specifically might be at risk for serious problems and need early treatment.

The development of the International Prostate Symptoms Score (IPSS) has made the evaluation of symptoms somewhat easier. This scoring service serves as a benchmark for determining severity. The decision to treat or not to treat is typically based on the guidelines described below, but the ultimate choice is often guided primarily by a man's perception of his own symptoms.

Mild, or No, Symptoms. Men with mild, or no, symptoms (IPSS scores of 7 or below) usually choose watchful waiting even if their prostates are enlarged. BPH eventually progresses to the point of needing treatment in about 15% of men with mild symptoms who wait.

Moderate Symptoms. The choice is most difficult for men with moderate symptoms (scores between 8 - 19) and may simply depend on a man's ability to tolerate them. Some studies have reported that up to 40% of men with moderate symptoms eventually seek treatment, and a quarter require surgery. In a small percentage of patients, symptoms improve.

Severe Symptoms. Men with severe symptoms (scores over 20) nearly always choose treatment, although if their prostate glands are small or normal-sized, symptoms may improve.

If a man opts for treatment, there are several choices. Most experts recommend a staged approach as follows:

Mild Symptoms. Medications are the best choice for men with mild symptoms who decide to have their condition treated. There are two standard choices: alpha-blockers and anti-androgens, nearly always finasteride (Proscar). Specific conditions determine the choice, although most men take an alpha-blocker. Men with mild symptoms who choose surgery only experience minor improvement afterward but face the same risks as patients with more severe symptoms.
Moderate-to-Severe Symptoms. Men with moderate-to-severe symptoms often respond to the same medications as men with mild symptoms. (Combinations of alpha-blockers and finasteride are under investigation.) Recent developments in drug therapy have reduced the number of surgical procedures needed and delayed their use. However, a quarter of men with moderate symptoms, and even more men with severe symptoms, eventually need surgery. If a man chooses surgery, there are many choices. Transurethral resection of the prostate (TURP) is the standard procedure, but less invasive procedures, particularly those using heat or lasers to destroy prostate tissue, are gaining prominence.

Click the icon to see an illustrated series detailing transurethral resection of the prostate surgery.

The most common reason for choosing surgery is obstruction of the bladder outlet, which causes urinary retention. Surgery is also typically a reasonable option when BPH is clearly related to one or more of the following conditions:

Recurrent urinary tract infection.
Hematuria (blood in the urine). Studies have suggested that when hematuria is left untreated, two-thirds of patients continue to bleed and one third require surgery. The drug finasteride may help some men with this condition and should probably be tried before surgery.
Bladder stones.
Kidney problems.
Some experts believe that surgery might benefit patients for whom an early diagnosis of prostate cancer is important. Unsuspected prostate cancer is detected during surgery in about 15% of cases.

The greatest improvements resulting from surgery are usually increased urinary flow and reduced urine retention. In one study, men who chose surgery reported more worry and depression before the procedure, but afterward they had less depression and anxiety than those who had chosen medication. Often, however, the benefits of surgery are not permanent.

Treatment Options by Staging and Grading

Stages indicate the extent of the cancer:

Stage I and stage II cancer are considered early stage. The cancer is localized and has not spread outside the prostate gland.
Stage III, locally advanced cancer, means that the cancer has spread into the seminal vesicles (glands at the base of the bladder, which are connected to the prostate gland and help produce semen).
Stage IV is advanced cancer. The cancer has spread to the lymph nodes and other tissues or organs.

Experts have devised treatments based on classification systems, including staging and tumor grade. However, there are no clear-cut answers on the best treatments for particular stages. In addition to staging, other factors must be considered. These factors include the patient’s age, overall health status, and personal preferences concerning side effects and quality of life. In addition to standard treatments, patients may also wish to consider enrolling in clinical trials of investigational treatments.

The U.S. National Cancer Institute recommends the following treatment options by cancer stage:

Tumors: T1a, N0, M0, G1, Stage A

Active surveillance
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
External beam radiation therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include high-intensity focused ultrasound

Click the icon to see an illustrated series detailing prostatectomy surgery.

Tumors: T1a - c, N0, M0, any G, Stage A2, B1, or B2

Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy after surgery
Active surveillance
External beam radiation therapy with or without hormone therapy
Implant radiation therapy (brachytherapy)
Clinical trial options include radiation therapy with or without hormone therapy; ultrasound-guided cryosurgery; hormone therapy followed by radical prostatectomy

Tumors: T3, N0, M0, any G, Stage C

External beam radiation with or without androgen deprivation therapy (hormone therapy)
Androgen deprivation therapy
Radical prostatectomy, usually with pelvic lymphadenectomy, with or without radiation therapy following surgery
Radiation therapy, androgen deprivation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Clinical trial options include ultrasound-guided cryosurgery

Click the icon to see an illustrated series detailing transurethral resection of the prostate.

Tumors: Any T, any N, any M, any G, Stage D1 - D2

Androgen deprivation therapy
External beam radiation therapy with or without androgen deprivation therapy
Radiation therapy or transurethral resection of the prostate (TURP) to relieve symptoms
Active surveillance
Clinical trial options include radical prostatectomy with surgery to remove both testicles (orchiectomy)

Treatment options are dependent on various factors, including prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations.

Patients whose cancer recurs locally after prostatectomy: Radiation therapy, androgen deprivation therapy.
Patients whose cancer recurs locally after radiation therapy: Androgen deprivation therapy, prostatectomy (very select patients).
Patients whose recurrent cancer has spread: See treatment options for stage IV.

Treatment for Localized Prostate Cancer

Choosing the best treatment for localized prostate cancer (T1 or T2) is generally based on the patient's age, the stage and grade of the cancer, overall health status, and the patient's personal preferences for the risks and benefits of each therapy.

Patients have three main options:

Active surveillance, also called watchful waiting, involves monitoring the tumor for cancer progression to determine if and when treatment should be started.
Surgery (radical prostatectomy) removes the prostate gland. The vessels that carry semen and surrounding tissue may also be removed. Studies indicate that compared to watchful waiting, radical prostatectomy may lower the risk of cancer recurrence and death, particularly for younger men with aggressive tumors.
Radiation therapy targets the tumor either externally (external beam radiation) or internally (implanted “seeds”).

In 2007, the American Urological Association (AUA) released guidelines for the treatment of localized prostate cancer. The guidelines recommend that patients should be classified as low, intermediate, or high risk. Doctors determine the risk category by using criteria such as PSA tests, tumor aggressiveness, and the clinical stage of the tumor.

Among the AUA’s treatment recommendations:

Compared with active surveillance, radical prostatectomy may lower the risk of cancer recurrence and death.
For men at intermediate and high risk, adding androgen deprivation therapy to external beam radiation may improve survival. A higher dose of external beam radiation also improves the odds for survival.
Initial (first-line) androgen deprivation therapy is seldom recommended for localized prostate cancer except for the relief of symptoms in patients with poor prognoses. Androgen deprivation therapy can increase the risks for diabetes and heart disease.
Patients with localized prostate cancer should have the opportunity to enroll in clinical trials investigating new types of therapy.

Conflicting Data on Survival Rates. To date, neither treatment nor active surveillance has emerged with a definitive survival advantage. Several studies from 2005 and 2006 suggested that treatment provides a survival advantage over watchful waiting for some men with early-stage prostate cancer. A 2005 New England Journal of Medicine study reported that men who had a radical prostatectomy before age 65 had a reduced risk of death from prostate cancer, death from other causes, localized cancer progression, and metastases than men who chose watchful waiting.

Similarly, research presented at the 2006 Prostate Cancer Symposium found in a study of nearly 50,000 men with early-stage prostate cancer that men who had radiation or surgical treatment had a 30% lower risk of death than men who were randomly assigned to watchful waiting. However, a 2005 Journal of the American Medical Association study advised against aggressive treatment for localized low-grade prostate cancer. The study found that men with low-grade prostate cancer had a small risk of cancer progression even after 20 years of watchful waiting or hormonal drug therapy

Imperfection of Classification System. The classification systems are not perfect. Even if tumors are rated in low stages and grades and are treated accordingly, undetected cancer cells may escape and spread beyond the prostate. Other factors, such as the man's age and medical condition, must be included in determining whether aggressive treatments or conservative measures are appropriate.

Specialty Bias. Patients should be aware that doctors may be biased to prefer a specific treatment depending on their specialty. For example, in one study the following treatments were favored for patients who were generally appropriate candidates for either surgery, radiation, or watchful waiting:

93% of urologists recommended radical prostatectomy.
72% of radiation oncologists recommended radiation. (And 82% thought that radical prostatectomy was overused.)
Virtually none of the doctors recommended watchful waiting for higher-risk disease. When in doubt, patients should always seek a second opinion to help them make this important choice.

Quality of Life. Surgery and radiation both have potentially distressing side effects, including the possibility of impotence, incontinence, or both. A man must weigh his own emotional responses to the possibility of these side effects versus the possible stress of watchful waiting.

In general, differences in quality of life after surgery or radiation treatment have to do with the specific effects of each type of treatment:

Radiotherapy generally causes more bowel problems than surgery, 30 - 35% versus 6 - 7%, according to a 2001 study. In a 2003 review, the risk for impotence from radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy.
Prostatectomy causes more urinary incontinence (39 - 49% versus 6 - 7% for radiotherapy patients) than radiotherapy. Risks for impotence range from 66% after nerve-sparing prostatectomy to 87% after cryotherapy. In spite of these adverse effects, a 2002 study reported no meaningful differences in well-being or quality of life during a 4-year period for men who chose surgery versus those who chose watchful waiting.
Active surveillance could lead to cancer growth that eventually obstructs the urinary tract (which can happen with the treatments as well). It may also impose an emotional burden on men who live with the possibility of progressive cancer and its difficult treatments. Some who decide to wait become what some doctors refer to as the "walking worried," men who are constantly concerned with their PSA levels. Because aggressive treatment reduces such anxiety, some studies reported that years after surgery, about 75% of men said they would chose it again, in spite of the significant side effects.

Watchful waiting involves lifestyle change and careful monitoring for cancer progression. Over the last several years, watchful waiting has evolved into a strategy called “active surveillance” or “delayed surgical intervention.” With this approach, patients have a digital rectal exam and PSA blood test every 6 - 12 months. If test results indicate cancer progression, then treatment options (surgery, radiation, drugs) are considered. Patients should exercise and eat healthy foods. Patients should report symptoms such as weight loss, pain, urinary problems, fatigue, or impotence to their doctors.

Candidates. Active surveillance may be most appropriate for the following patients:

Men in their late 70s and older. More aggressive therapies (surgery and radiation) are usually recommended for men in their 50s and younger. The choice for men in their 60s and early 70s is more problematic. The general recommendation is that aggressive therapy is suitable for those who have a life expectancy of more than 10 years and who have localized but mid- to high-grade tumors. The tumor grade may be the best guide for determining the risks in choosing watchful waiting.
Elderly men with early-stage (T0 - T2) low-grade tumors.
Men with low-to-moderate (3 - 13 ng/mL) PSA levels.

Some experts think that because prostate cancer grows so slowly, it is likely that older men will die from causes unrelated to the cancer. There is therefore little potential benefit from surgery or radiation, with both posing a risk for impotence and incontinence. However, some recent surveys suggest that more men are choosing treatment (especially surgery) over active surveillance. The choice is a difficult one. It is important that patients find a doctor who can provide them with all the necessary information so that they can make an informed decision.

In men whose cancer is confined to the prostate, surgical resection (radical prostatectomy) offers the potential for cure. Cure rates from initial surgery in men with localized cancer are about 70%, depending on tumor stage, tumor grade, and PSA levels. Research suggests that surgery provides long-term cancer control. Most patients can consider themselves disease-free if their PSA levels remain undetectable 10 years after surgery.

Candidates. Radical prostatectomy is a consideration for men who meet all of the following criteria:

In good health and with a life expectancy of 10 years or more. As average life expectancy in men has increased, more older men are becoming candidates for surgery. Complication rates are higher the older a man is, however.
The cancer has not spread beyond the prostate gland.
The cancer is potentially life threatening. (In general, a life-threatening tumor is indicated by volumes more than 0.2 cc and Gleason grade scores greater than 5.)

The procedure is more likely to cause incontinence (up to 50%) than radiation treatment but has fewer bowel complications. Impotence rates are about the same. Surgery for prostate cancer may be particularly difficult in men who have had transurethral resection of the prostate (TURP).

Radiation therapy (or radiotherapy) is administered as external beam radiation or as brachytherapy (radiation implants). It may be used as the sole primary treatment for localized prostate cancer; 5-year survival rates are similar to those of surgery.

Candidates. Radiation is considered for men with one or more of the following characteristics:

Being older and, particularly, having other medical problems.
Cancer has extended beyond the prostate capsule but has not spread to the lymph nodes or further.
Being a good surgical candidate, but having decided against an operation.

The risk for incontinence (less than 10%) is much lower than with surgery, although bowel problems occur in about a third of patients. Impotence rates are about the same.

Androgen Deprivation Therapy With Radiation. Hormonal (“androgen deprivation”) drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used. Hormone therapy can also be given at the same time or following radiation.

An important study published in 2004 in the Journal of the American Medical Association (JAMA) found that for men with localized prostate cancer, a 6-month course of androgen deprivation therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be given for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

A 2005 JAMA study suggested that PSA velocity (PSAV) may help doctors decide which patients should receive androgen deprivation drugs along with radiation therapy. PSAV lets doctors calculate how quickly a patient’s PSA level has risen. Researchers found that men who had at least a 2.0 ng/mL increase in PSA levels during the year before their cancer diagnosis had a high risk of dying after external beam radiation therapy, even though they had low-grade prostate cancer. The study suggests that men with this particular PSAV history should consider combining radiation therapy with androgen deprivation drugs.

Surgery

Radical prostatectomy is the surgical removal of the entire prostate gland along with the seminal vesicles (the vessels that carry semen) and surrounding tissue. The incision can be made in one of the following regions:

Retropubicly (through the abdomen and under the pubic bone, exposing the entire surface of the prostate).
Through the perineum (the skin between the scrotum and the anus).

The gland and other structures are then removed. The operation lasts 2 - 4 hours. Advanced surgical techniques, such as minilaparotomy and laparoscopy, are being developed for radical prostatectomy. These techniques use smaller incisions, are less invasive, and may cause fewer complications.

Click the icon to see an illustrated series detailing prostatectomy surgery.

Nerve-Sparing Techniques. Surgical procedures have been refined over the years, and many operations for localized low-grade prostate cancer now spare the nerves that control erection.

A bilateral nerve-sparing procedure saves the nerves on both sides of the sex organs.
A unilateral procedure saves nerves on only one side.

Nerve-sparing techniques can improve quality of life. The ability for sexual intercourse recovers in about a third of patients at 3 years and nearly 60% at 5 years after surgery. (Rates vary depending on certain factors, such as the patient's age -- the younger the better.) In cases where the tumor is bulky and undifferentiated, nerve-sparing techniques may not be appropriate.

Convalescence. Patients remain hospitalized for up to 2 weeks. A temporary catheter used to pass urine is kept in place when the patient is sent home and usually removed about 3 weeks after the operation. The convalescent period at home is about a month. In general, younger patients with early-stage cancers recover fastest and experience the fewest side effects.

Complication rates vary after radical prostatectomy and usually depend on the age of the patient and the experience of the surgeon and medical center. They can range from 4% in men in their 40s to 14% in men over age 70. Complication rates are 10 times higher in patients who have prostatectomy because of cancer recurrence after radiation treatment.

Complications include the usual risks of any surgery, such as blood clots, heart problems, infection, and bleeding. Complications specific to radical prostatectomy, (incontinence, impotence, and contracture of the bladder neck), are discussed below. The mortality rate is very low, about 0.4%.

Quality of life usually improves shortly after surgery, and recovery from certain complications, such as incontinence and sexual function, can continue to occur even over years.

Urinary Incontinence. Urinary incontinence is a common complication and a more distressing side effect of surgery for most men than sexual dysfunction. When the urinary catheter is first removed following surgery, nearly all patients lack control of urinary function and will leak urine for at least a few days and sometimes for months. Major medical centers report that continence returns within about 18 months for nearly all men younger than age 70 and in the great majority of men older than 70. The average time for return of continence in one center was just 1.5 months.

Click the icon to see an image of catheterization.

A number of approaches may help prevent or treat incontinence:

Nerve-sparing techniques can help prevent incontinence, although even in experienced centers, 8% of patients will have some postoperative incontinence, and this rate is much higher (up to 50%) in many community medical centers.
A procedure called endopelvic anterior urethral stitch (EAUS) used with prostatectomy appears to reduce urinary incontinence. In one small study, 75% of selected patients recovered continence in a month. The procedure requires a simple stitch at the front of the urethra.
Kegel exercises, contracting and relaxing the muscles used to shut off the urinary stream, strengthen the muscles on the pelvic floor and are reported to be very beneficial for many men.

If incontinence persists beyond a year, patients may require drug therapy or surgery. Collagen injections into the urethra, bladder neck suspension surgery, or a urinary sphincter implant may be helpful for men who have chronic incontinence. [See In-Depth Report #50: Urinary incontinence.]

Impotence. Studies suggest that about 40% of men have problems with erection after the procedure. In one study, however, more than 70% said they would have the procedure again. Nerve-sparing procedures are proving to be helpful in reducing impotence as well as incontinence.

Sildenafil (Viagra) may help restore potency on average in about a third of patients, but some men may do better than others. In one study, for example, 80% of younger men who were potent before surgery and had bilateral nerve sparing procedures responded to the drug. (Only 40% responded with only unilateral procedure.) Sildenafil is unlikely to be effective for men who had unilateral or no nerve sparing procedures. In those who respond, sildenafil may provide a benefit for years. Sildenafil may take 9 months or longer to become effective. Men who take it may benefit from alprostadil injections started right after surgery to preserve elasticity and help prevent scarring.

Early treatments with alprostadil injections may helpful in restoring erectile function in any case. This treatment maintains blood flow in the penis, and some research suggests that impotence after prostate surgery may be due in part to injury to these blood vessels. In one study, men administered injections every other night for 6 months. They then started taking sildenafil 3 months after surgery. At 6 months, 82% of these men achieved penetration compared to only 52% of men who took Viagra only. The vacuum pump may serve a similar purpose as the injections. [See In-Depth Report #15: Erectile dysfunction.]

Even when erectile function is preserved, men may experience other sexual problems:

Erections may not be as rigid as before the operation.
Orgasm and sexual sensation may be altered.
Patients who retain potency may suffer from retrograde ejaculation, also known as dry ejaculation. During ejaculation, semen travels backward into the bladder, causing infertility.

Fecal Incontinence. Radical prostatectomy can also cause fecal incontinence. The risk may actually be higher in men undergoing nerve-sparing procedures.

Contracture of the Bladder Neck. Another common postsurgical complication is contracture of the bladder neck at the point where it has been stitched to the remainder of the urethra. Contracture usually occurs within the first 3 months after the operation, causing a sharp decrease in urinary stream. The condition can be treated by dilation or surgery on the bladder neck, and rarely recurs.

Pelvic lymphadenectomy is the surgical removal of the pelvic lymph nodes. It is usually performed at the same time as prostatectomy. If the surgeon suspects that cancer has spread beyond the prostate, the surgeon will perform the lymphadenectomy as part of the operation. Some surgeons do this procedure as a matter of course when performing prostatectomy, since it has few complications and adds information on the state of the disease. The lymph nodes are removed through an incision in the lower part of the abdomen, using conventional surgery or laparoscopy, a less invasive variation. The nodes are immediately examined. If they show signs of cancer, metastasis has occurred. In such cases, the operation is usually stopped and the patient is offered radiation or hormone treatments.

Click the icon to see an image of the pelvic lymph nodes.

Transurethral resection of the prostate (TURP) involves removing a section of the prostate with a surgical instrument (resectoscope) that is inserted through the urethra. TURP may be used to control urinary symptoms in men who are not good candidates for curative therapy due to advanced age, health status, or other reasons. TURP is also used as a treatment for benign prostatic hyperplasia (BPH).

Cryosurgery is an alternative to standard prostatectomy. The goal of cryosurgery is destruction of the entire prostate gland and possibly surrounding tissue. Steel probes are inserted through the skin between the anus and the rectum and into the prostate. Liquid nitrogen is pumped through the probes to freeze all prostate cells, both healthy and cancerous. For success, cryosurgery requires a uniformly frozen area. The dead cells are absorbed and eliminated by the body. Patients can leave the hospital in 2 - 3 days.

Candidates. Cryosurgery may be considered for patients with:

Early stage local cancer
Cancer that has recurred after radiation treatments
Large primary tumors that the surgeon wishes to reduce
Possibly tumors that have spread beyond the prostate if they have not yet reached the lymph nodes

Strong predictors of treatment failure include:

A history of both hormonal and radiation treatments
Tumor grades 8 and above
PSA levels of more than 10 ng/mL

Complications. Complications are similar to those of standard prostatectomy, but incontinence rates are much lower. Impotence rates, however, are much higher. Nevertheless, 96% of patients report that they are satisfied with the results. Incontinence and other side effects may be higher in patients who have had previous radiation treatments. Other significant complications include scarring and narrowing of the urethra, and fistulas (abnormal passages from internal organs to the skin or between two internal organs).

Radiation Treatments

The two major radiation treatments are:

External beam radiation
Brachytherapy (internal radiation)

Both treatments have generally equal success rates. Research presented at the 2006 Prostate Cancer Symposium indicated that the two therapies work equally well for treating localized prostate cancer. In some cases, both techniques may be used in high-risk patients.

In external beam radiation therapy, a doctor focuses a beam of radiation directly on the tumor for 35 3-minute treatments given 5 times a week over 7 weeks. 3-D conformal techniques use computers and a three-dimensional image of the prostate to target the tumor precisely, using high-dose radiation beams. It poses a lower risk for inflammation. Men who have had transurethral resection of the prostate (TURP) or have a history of lower urinary tract symptoms may be particularly good candidates for 3D conformal techniques.

According to the 2007 American Urological Association guidelines for treatment of localized prostate cancer, patients considering external beam radiation should know that higher radiation doses may reduce the risk for cancer recurrence and improve survival outcome.

Brachytherapy is an outpatient technique that implants radioactive "seeds" directly into the prostate. Implants can be temporary or permanent. Temporary implants are usually accompanied by external beam radiation. This procedure requires more skill than external beam radiation therapy and, even with experienced doctors, the distribution of radioactive seeds is uneven in 15% of cases, increasing the risk for insufficient doses.

Computerized systems are being developed to help oncologists optimize seed placement and allow precise treatment for each patient and higher radiation doses. Eventually, it could improve tumor control, reduce side effects, and cut costs.

It is common for PSA levels to temporarily rise, or "bounce," following seed implantation without it being a signal for cancer recurrence. This effect can produce anxiety and can interfere with the diagnosis of true recurrence.

Candidates. Studies suggest that brachytherapy is useful for select patients, specifically those with prostate volumes less than 60 mL and who have early-stage prostate cancer (T1 or T2 tumors, a Gleason grade lower than 7, and PSA levels below 10 ng/mL). It may be beneficial in patients with inflammatory bowel disease or with cancer close to the bowel. Poorer candidates for brachytherapy include men who have had TURP and patients with advanced cancer, high-grade tumors, or very enlarged prostate glands.

The side effects of radiation therapy include most of those of surgery, but the risks for impotence and incontinence are considerably lower. A 2000 study concluded that adjuvant radiation therapy (given right after surgery) in moderate doses does not increase the risk for long-term urinary incontinence or sexual dysfunction beyond that of surgery alone.

Gastrointestinal Complications. Complications in the gastrointestinal are common. Short-term effects include nausea and loss of appetite. Diarrhea is a very common side effect and can last for the duration of therapy. It is usually treated with Lomotil. A few patients have diarrhea flare-ups for years afterwards. Less than 1% suffer more serious intestinal problems.

There is potential for injury to the rectum with brachytherapy. Ulcers in the rectum occur in more than 10% of patients, but the risk decreases with greater experience in the technique.

Urinary Problems. The risk for incontinence is about 7 - 20%. Patients treated with radiation may experience a painful, but usually temporary, urinary tract inflammation. About 10 - 15% of patients develop a long-term urgent and frequent need to void their bladder. Brachytherapy carries a lower risk for urinary incontinence.

Scarring and narrowing of the urinary tract (stricture) may occur, particularly in men who had TURP performed within a short time before radiation treatment. In such men, radiation treatments should be delayed by 4 - 6 weeks. If the prostate has been injured or damaged or the bladder is easily irritated, side effects with brachytherapy may actually be worse than with other procedures.

Impotence. In a 2003 review, the risk for impotence following radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy. Still, very few studies on brachytherapy have lasted more than 2 years, so more research is needed.

Sildenafil (Viagra) may help many men experiencing impotence following radiation therapy for local prostate cancer. Early use of both alprostadil injections and sildenafil may be even more effective. Other treatments may also be useful. [See In-Depth Report #15: Erectile dysfunction.]

Investigators are testing radiation treatments that use a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard proton radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions.

High-Intensity Focused Ultrasound (HIFU). Studies are reporting promising results with an intensive ultrasound procedure called transrectal high-intensity focused ultrasound (HIFU). It allows for very precise minimally invasive removal of tissue in local prostate cancers. It may eventually prove to be an alternative to radiation therapy. More research, with long-term follow up, is needed.

Radiofrequency. Radiofrequency is being used to heat and destroy the prostate. Early studies suggest that this is a promising approach.

Options if Treatments Fail

Rising PSA Levels. If prostate cancer has been eliminated, PSA levels should drop to 0.5 ng/mL or less after treatment. A sudden rise or persistently elevated PSA levels after treatment are often indications that prostate cancer persists:

If PSA levels are above 2.0 ng/mL, then cancer is most likely still present.
If PSA levels are between 0.5 - 2.0 ng/mL, the situation is less clear. One study indicated that measuring free PSA may help determine the status of the cancer in such patients. An average free PSA of 27% indicated that cancer had been eliminated, while an average of 15% meant that cancer was still present.

Note: It is common for PSA levels to temporarily rise following radiation seed implantation without signaling cancer recurrence.

Rising PSA levels do not necessarily mean that the cancer has spread or even that the cancer will recur during a man's lifetime. An actual cure is still possible if the cancer is localized within the prostate. In one study, 64% of patients with rising PSA levels after surgery still had cancer confined to the prostate. Indications of a poorer outlook in this study included:

Cancer penetration of the prostate capsule
Positive surgical margins (microscopic evidence of cancer cells at the very edge of the resected specimen)
Invasion of nearby vessels or lymph nodes

Still, among the men in the study, after 7 years only 3% of patients had died of prostate cancer. After 15 years, only 19% had evidence of recurrence. Other markers for persistent cancer are under investigation. For example blood tests that show low levels of acid phosphatase (ACP) before treatments may predict a higher chance for recurrence-free survival.

Treatment for recurring cancer is not always clear-cut. If the cancer recurs locally, cure may still be possible:

Surgery and androgen deprivation therapy may be considered for patients who were first treated with radiation.
For patients who were initially treated with surgery, radiation or androgen deprivation therapy are both options.

If the disease has already spread or if the doctor suspects that it may have spread, the patient is typically given androgen deprivation therapy. Chemotherapy drugs in combination with hormonal drugs are being investigated for patients who fail surgery or radiation.

A 2005 study in the Journal of the American Medical Association suggested three factors that may help doctors and patients decide if additional treatment is needed if cancer recurs after surgery:

How quickly PSA levels double after surgery (shorter time equals higher risk)
How quickly the cancer recurred after surgery (shorter time equals higher risk)
Gleason score (higher score suggests more aggressive tumors and greater risk)

Patients at high risk are more likely to die from the recurrent cancer and should be considered for additional treatments. Patients at low risk face a lower likelihood of death from prostate cancer and probably do not require more treatment. The study found that for patients at low risk, the time to death after cancer recurrence was very long, generally lasting more than 16 years.

Androgen Deprivation Therapy. Androgen deprivation therapy, also called androgen suppression therapy or hormone therapy, involves blocking the effect of male hormones such as testosterone through medical (drugs) or surgical castration. Androgen suppression therapy is not recommended as a first-line approach for most men with localized prostate cancer. It is usually given to patients with recurrent, progressive, or advanced prostate cancer. It may also be given for a relatively brief time in combination with external beam radiation.

Although androgen deprivation therapy slows the growth of most prostate cancers, it can have serious side effects. The American Society of Oncology’s (ASCO) 2007 guidelines do not recommend the early use of hormone therapy. However, ASCO does recommend that patients start therapy once they begin to experience cancer symptoms. Patients who defer therapy should have regular doctor visits every 3 - 6 months to monitor their condition.

Salvage Prostatectomy. Salvage prostatectomy is sometimes performed after unsuccessful radiation treatment if the cancer is still local. The odds of the procedure's success are only 10 - 64%. Many experts recommend against salvage prostatectomy in most cases of radiation failure. Severe complication rates for salvage prostatectomy are very high: 10 times that of men who have not had radiation. For example, incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures.

Salvage Cryosurgery. Salvage cryosurgery may be effective in certain patients who fail external beam radiotherapy. The best candidates are those with Stage II cancer or less and PSA levels below 10 ng/mL.

Adjuvant and Salvage Radiation. Radiation is proving to help patients who still show detectable levels of PSA after surgery (generally 2 ng/mL or less). It may even be useful years after surgery if PSA levels rise. Depending on timing, radiation after treatment failure is referred to as either:

Adjuvant radiation is radiation therapy performed within 6 months after radical prostatectomy. One area of controversy is whether to use adjuvant radiation after surgery on patients whose PSA levels are very low or undetectable but who have other test results that indicate the cancer is likely to spread. Patients with adverse findings and low PSA have to weigh the potential complications of radiation therapy against the odds of recurrence without it, which are about 20 - 30%. A small 2006 study found that adjuvant radiation worked much better than salvage radiation for men with advanced (stage III or IV) local prostate cancer. However, a 2007 study indicated that adjuvant radiation in men with advanced cancer may reduce the risk of cancer recurrence but does not improve length of survival.
Salvage radiation is radiation therapy more than 6 months after surgery. A 2004 study suggested that salvage radiation could be more beneficial than previously thought, even for men with aggressive prostate cancer. Researchers studied 501 men who had undergone radical prostatectomy (surgical removal of the prostate gland) and subsequently received radiation treatment for recurrent cancer (as indicated by rising PSA levels). Men with lower Gleason scores and lower PSA levels benefited the most from salvage radiation. However, even men with higher-grade cancers were able to delay metastatic cancer progression as long as they received radiation at an early stage while their PSA levels were relatively low (less than 2.0 ng/mL).

Other Treatments

Male hormones (called androgens), particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die.

Androgen deprivation therapy (also called androgen suppression therapy or hormone therapy) uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen) -- particularly testosterone and dihydrotestosterone -- that stimulate the growth of prostate cells. Androgen deprivation therapy is used for advanced and metastatic cancer and may be used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels). Side effects can include decreased bone density, decreased muscle mass, hot flashes, depression, fatigue, weight gain, enlarged breasts, and high cholesterol levels. Evidence also indicates that androgen deprivation therapy increases the risk for diabetes and death from heart disease.

There has been some debate about when androgen deprivation therapy should be initiated. In 2007, the American Society of Clinical Oncology (ASCO) published clinical guidelines for androgen deprivation therapy in patients with recurrent, progressive, or advanced prostate cancer. The guidelines recommend that hormone therapy should, in general, be delayed until patients begin to experience symptoms from their cancer. However, when therapy is deferred, patients should regularly visit their doctors every 3 - 6 months for careful monitoring of their condition.

ASCO recommends either removal of both testicles (bilateral orchiectomy) or injections with luteinizing hormone-releasing hormone (LHRH) as initial androgen deprivation treatments. Combining nonsteroidal antiandrogen drug therapy with orchiectomy or LHRH may also be considered.

Doctors vary widely on their opinions of androgen deprivation therapy. A 2006 study found that the decision to use hormonal therapy depends more on a patient’s urologist than on the patient’s tumor or other factors.

Androgen deprivation therapy includes:

Hormonal Drugs. The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormone (LH-RH) agonists.

Orchiectomy. Orchiectomy is the surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. Studies do not indicate that it significantly improves survival rates. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes. Combining orchiectomy with antiandrogen drug therapy adds a modest benefit.

The median survival rate after the operation is about 55% over a 40-month period. An estimated 25% of patients survive 5 years or more. Nevertheless, orchiectomy, although irreversible, may produce fewer adverse effects than hormonal drugs, and interestingly, many patients report significantly higher quality of life after orchiectomy than those who opt for hormonal treatment, particularly total androgen ablation. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis.

Many men can still achieve erection after orchiectomy, but there is almost always a decline in sexual drive. Men who cannot achieve erection may be candidates for a penile implant. Patients do not experience a reversal of sex characteristics; the voice does not change and body hair is not affected.

Androgen Deprivation Therapy Before or With Radiation. Hormonal drugs combined with radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these drugs long-term to improve outcomes. Hormonal drugs before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used.

An important study published in 2004 in the Journal of the American Medical Association found that for men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; the JAMA study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

Androgen Deprivation Therapy Before or After Surgery. Some studies suggest benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, although it is not clear yet if this approach has survival benefits. Hormonal treatment may be useful after surgery in men who have high-grade tumors or tumors that have invaded the semen-carrying vessels or lymph nodes. Such men have a risk for failure after surgery of 50 - 80%.

The primary drugs used for suppressing androgens are called luteinizing hormone-releasing hormones (LHRH) agonists. They include:

Leuprolide (Lupron, Leuprogel). Studies report that disease progression is prevented in 72% of men taking daily leuprolide and up to 89% of those taking monthly injections. Certain men, however, may not respond to injections. Drug delivery using implants is under investigation.
Goserelin (Zoladex). Partial responses of 60 - 80% have been reported. A controlled release formulation has been developed that increases the time between injections from 4 weeks to 3 months.
Buserelin.

LHRH drugs block the pituitary gland from producing hormones that stimulate testosterone production. Patients must have injections of LHRH agonists for the rest of their lives.

Testosterone and PSA Surges. Treatment with LHRH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. Leuprogel, a newer leuprolide, may pose a lower risk for this effect. Researchers are investigating other drugs, such as GnRH antagonists, that do not produce this surge.

LH-RH agonists can also cause PSA levels to rise temporarily. Administering flutamide, a drug known as an antiandrogen, for 2 weeks prior to LH-RH agonists may not only prevent PSA surge but also induce early declines in PSA levels.

Side Effects. Side effects include hot flashes and occasionally nipple and breast tenderness.

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary gland to release luteinizing hormone-releasing hormones (LHRH). GnRH antagonist drugs such as abarelix (Plenais) and histrelin (Vanta) block this action. They have two advantages over LHRH agonists:

They do not cause the same testosterone surge that can temporarily worsen cancer symptoms.
They seem to reduce testosterone levels more quickly.

Anti-androgens are drugs used to block the effects of testosterone. They are used alone or in maximal androgen blockage (MAB), in which they are combined with LHRH agonists or orchiectomy to completely block androgen hormones. Anti-androgens are either steroidal or nonsteroidal.

Nonsteroidal Anti-androgens. Nonsteroidal anti-androgen drugs include:

Flutamide (Eulexin, Drogenil). Flutamide has produced extended response in some patients. Side effects may include diarrhea and liver damage, which has been fatal in rare cases; liver function must be monitored closely.
Nilutamide (Nilandron). Nilutamide is associated with reversible interstitial pneumonitis, nausea, alcohol intolerance, and visual disturbances.
Bicalutamide (Casodex). Bicalutamide is effective and appears to have fewer severe side effects than other anti-androgens, including loss of sexual interest, osteoporosis, visual disturbance, and interstitial pneumonia. This drug is proving to have survival rates equal to those of maximal androgen blockage.

Steroidal Antiandrogens. Steroidal antiandrogens act like female hormones and include:

Megestrol uppresses androgen production, but incompletely, and is generally not used as initial therapy.
Cyproterone combined with estrogen may prevent the testosterone surge that occurs with LH-RH agonists.

Men often experience fatigue, loss of energy, and emotional distress from androgen suppression treatment. Hormonal therapy may significantly impair quality of life, particularly in men who had no symptoms beforehand and whose cancer has not metastasized. Common side effects of androgen suppression drugs include:

Osteoporosis, the loss of bone density. This risk is higher with orchiectomy than with androgen suppressants. Some androgen suppressants, such as bicalutamide, may cause less bone loss. The use of estrogens may actually be bone protective. A number of medications, especially bisphosphonates, are available to help prevent or reduce bone loss.
Diarrhea
Loss of muscle mass
Psychological disturbances
Fatigue
Loss of sexual drive and sexual dysfunction
Swelling of the breasts (gynecomastia)
Nausea and vomiting
Hair loss
Anemia

In addition, there is growing evidence that androgen deprivation therapy increases the risks for diabetes and heart disease.

Prostate cancer that does not respond to hormonal treatment is called hormone-resistant, or hormone-refractory, cancer. There are various drug treatments for hormone-resistant cancer:

Docetaxel and Other Chemotherapy. Chemotherapy drugs for prostate cancer include docetaxel (Taxotere), mitoxantrone (Novantrone), estramustine (Emcyt), and various platinum-based drugs, such as carboplatin. These drugs are often combined with other cancer drugs (such as 5-fluorouacil) or corticosteroids (such as prednisone).

Docetaxel-based drug regimens are emerging as the main chemotherapy treatment for hormone-refractory prostate cancer. In 2004, the FDA approved docetaxel injection in combination with prednisone for treatment of patients with hormone-resistant prostate cancer. Patients who received this drug combination survived on average 2.5 months longer than patients who received mitoxantrone and prednisone. Another 2004 clinical trial found that a docetaxel and estramustine combination worked better than mitoxantrone and prednisone for advanced resistant prostate cancer. Side effects can be serious and may include gastrointestinal problems (nausea, vomiting, or diarrhea), fatigue, low blood cell counts, and increased risk for blood clots.

Researchers are continuing to investigate docetaxel combinations and compare them to other chemotherapy regimens. A large 2006 study reported that docetaxel and prednisone worked better than mitoxantrone plus prednisone in improving quality of life, pain relief, and survival. Docetaxel is also being investigated in combination with vitamin D-related drugs. A 2006 trial found that men with advanced prostate cancer who took docetaxel plus high-dose vitamin D (calcitriol) lived about 8 months longer than men who received docetaxel and placebo. Calcitriol also appeared to protect against docetaxel’s side effects, especially gastrointestinal problems and blood clots.

Doctors are also studying other ways to help patients cope with docetaxel’s side effects. Research presented at the 2006 Prostate Cancer Symposium suggested that patients may be able to take periodic breaks from docetaxel treatment instead of having continuous therapy. In the study, patients with advanced prostate cancer were given the option of suspending docetaxel treatment if their PSA levels improved within a certain range. Researchers found that patients were able to take 16-week breaks and still show improvement once they resumed treatment. This approach may work best for patients who experienced a good initial response to docetaxel.

Bisphosphonates. These drugs prevent bone loss and reduce bone pain in metastasized cancers. They are of particular interest because they may inhibit prostate cancer cell growth in the bone. The bisphosphonates showing most promise in prostate cancer are newer drugs called nitrogen-containing bisphosphonates (pamidronate, zoledronic acid).

Immunotherapies. The prostate organ offers special possibilities for genetic therapies because it contains highly specific antigens (factors that the immune system can target). There are a number of approaches currently under investigation, including:

Genetically designed vaccines (Provenge, Gvaz, JBT 1001) inject factors into prostate cancer cells that trick the immune system into attacking the cancer cells.
Antisense therapy for prostate cancer blocks expression of a protein called BCL-2, which tends to be genetically overexpressed in some patients with androgen-independent prostate cancer. This protein prevents apoptosis (a natural process by which all cells, including cancer cells, self-destruct).
Monoclonal antibodies (MAbs) are genetically designed immune factors that target foreign compounds called antigens for attack by the immune system. Monoclonal antibodies are being designed to target prostate-specific antigens.

Angiogenesis Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis ). The spread of new blood vessels is controlled by compounds called growth factors, which may be important in cancer cell proliferation. Researchers are interested in drugs that turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In doing so, the drugs may be able to cut off cancer's life blood. Gefitinib (Iressa) and erlotinib (Tarceva) are angiogenesis inhibitors that target receptors of epidermal growth factors called tyrosine kinase. They are being used in lung cancer and are being investigated in a number of other cancers, include prostate cancer. Various drugs that inhibit angiogenesis in other ways (thalidomide, endostatin) are also under investigation.

Ketoconazole. Ketoconazole is an antifungal drug that blocks an enzyme that stimulates production of testosterone. It is effective in high doses but can have severe gastrointestinal effects, mainly nausea and anorexia. Long-term use can result in impotence, itchy skin, nail changes, and suppression of stress hormones. One center reported a consistent PSA response in more than 60% of patients who had failed other androgen deprivation treatments.

Aromatase Blockers. Aminoglutethimide (Cytadren) and similar drugs block aromatase, an enzyme important in estrogen production. Because the female hormone estrogen plays such a major role in the development of breast cancer, some experts think that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.

Atrasentan. Atrasentan is known as an ET(A)-receptor antagonist. It is showing promise in reducing bone loss and delaying progression of prostate cancer in men with advanced disease that no longer responds to hormone therapy. Side effects are relatively mild.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.prostatecancerfoundation.org -- Prostate Cancer Foundation
www.fightprostatecancer.org -- National Prostate Cancer Coalition
www.urologyhealth.org -- Urology Health
www.nccn.org -- National Comprehensive Cancer Network
www.cdc.gov/cancer/prostate -- CDC Cancer Prevention and Control
www.psa-rising.com -- PSA Rising: Prostate Cancer Survivor Info
www.ustoo.org -- Us Too! Prostate Cancer Education and Support
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):416-24.

Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007 May;39(5):631-7. Epub 2007 Apr 1.

Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007 May;39(5):638-44. Epub 2007 Apr 1.

Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006 Sep 20;24(27):4448-56.

Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J Natl Cancer Inst. 2007 May 16;99(10):754-64.

Leman ES, Cannon GW, Trock BJ, Sokoll LJ, Chan DW, Mangold L, et al. EPCA-2: a highly specific serum marker for prostate cancer. Urology. 2007 Apr;69(4):714-20.

Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007 Apr 20;25(12):1596-605. Epub 2007 Apr 2.

Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, et al. Guideline for the management of clinically localized prostate cancer: 2007update. J Urol. 2007 Jun;177(6):2106-31.

Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006 Nov 15;296(19):2329-35.

Walter LC, Bertenthal D, Lindquist K, Konety BR. PSA screening among elderly men with limited life expectancies. JAMA. 2006 Nov 15;296(19):2336-42.

Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May;39(5):645-9. Epub 2007 Apr 1.

Review Date:
6/27/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Brain tumors - primary

FitSugar — Wed, 08 Oct 2008 17:35:12 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Causes
Prognosis
Diagnosis
Common Brain Tumors
Treatment
Surgery
Radiotherapy
Chemotherapy
Other Treatments
Treatment of Complications...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Radiation Therapy Complications

Radiation therapy in children with cancer increases the risk of new brain and spinal cord tumors, suggests a study in the Journal of the National Cancer Institute. The risk appears to increase along with the radiation dosage. Children who receive radiotherapy before age 5 are especially at risk for second primary tumors.
Survivors of childhood brain tumors who received cranial radiotherapy as part of their treatment are at risk for later having a stroke, indicates a study in the Journal of Clinical Oncology. The average length of time from brain tumor diagnosis to post-treatment stroke was 14 years.

Radiation Therapy for Elderly Patients

Radiotherapy provides modest improvement in survival for elderly patients (age 70 years and older) with glioblastoma, with no detriment to quality of life or cognition function, according to a 2007 study in the Journal of the American Medical Association.

Temozolomide (Temodar)

The chemotherapy drug temozolomide (Temodar) has become an important and effective treatment for patients newly diagnosed with glioblastoma. However, not all patients respond equally well to this drug. A 2007 study in the journal Neurology suggests that a patient’s genotype may explain differences in response. Though genetic testing, researchers found that temozolomide works best in people who are missing a particular gene.

Investigational Treatments

Vorinostat (Zolinza), a cancer drug used for T-cell lymphoma, may help patients with recurrent glioblastoma multiforme, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin), a targeted therapy drug used for lung and colorectal cancers, may help prolong survival in patients with advanced glioma, indicates a 2007 study in Clinical Cancer Research. Another anti-angiogenesis drug, cediranib (Recentin), may help make glioblastomas more responsive to chemotherapy and radiotherapy, according to recent interim trial results.
Vitespen (Oncophage), an experimental vaccine for glioma, is showing promise in early clinical trials, suggests research presented at the 2007 meeting of the American Association of Neurological Surgeons.

Introduction

Brain tumors are composed of cells that exhibit unrestrained growth in the brain.

The major areas of the brain have one or more specific functions.

They can be benign (noncancerous, meaning that they do not spread elsewhere or invade surrounding tissue) or malignant (cancerous).

Cancerous brain tumors are further classified as either primary or secondary tumors. Primary tumors start in the brain, whereas secondary tumors spread to the brain from another site such as the breast or lung. (In this report, the term "brain tumor" will refer mainly to primary malignant tumors, unless otherwise specified.)

Benign tumors represent half of all primary brain tumors. Their cells look relatively normal, grow slowly, and do not spread (metastasize) to other sites in the body. Benign tumors can still be serious and even life-threatening if they are in vital areas in the brain where they exert pressure on sensitive nerve tissue or if they increase pressure within the brain. While some benign brain tumors may pose a health risk, including risk of disability and death, most are usually successfully treated with techniques such as surgery.

Click the icon to see an image of a primary brain tumor.

A secondary (metastatic) brain tumor occurs when cancer cells spread to the brain from a primary cancer in another part of the body. Secondary tumors are about three times more common than primary tumors of the brain. Usually, multiple tumors develop. Solitary metastasized brain cancers may occur but are less common. Most often, cancers that spread to the brain to cause secondary brain tumors originate in the lung, breast, kidney, or from melanomas in the skin.

A primary malignant brain tumor is one that originates in the brain itself. Although primary brain tumors often shed cancerous cells to other sites in the central nervous system (the brain or spine), they rarely spread to other parts of the body.

Brain tumors are generally named and classified according to the following:

The normal brain cells from which they originate, or
The location in which the cancer develops

The biologic diversity of these tumors, however, makes classification difficult, and some experts believe that more specific categories are needed.

About half of all primary brain tumors are known collectively as gliomas. They are cancerous forms of glial cells, the building-block cells of the connective, or supportive, tissue in the central nervous system. There are several glial cells types from which gliomas form. Their names are:

Astrocytomas are primary brain tumors derived from astrocytes, which are star-shaped glial cells. Normal astrocytes provide nutrients, support, and insulation for nerve cells and are one of the primary neurologic cells in the body. The malignant astrocytomas called glioblastomas account for 23% of brain tumors and are the most common ones.
Oligodendrogliomas develop from oligodendrocyte glial cells, which form the protective coatings around nerve cells. Although oligodendrogliomas were thought to represent about 5% of all gliomas, more recent evidence suggests they may comprise about 20% of gliomas. Pure oligodendrogliomas, however, are rare. In most cases they occur in mixed gliomas.
Ependymomas are derived from ependymal cells, which line the ventricles (fluid-filled cavities) in the lower part of the brain and the central canal of the spinal cord. They constitute about 6% of all primary tumors in the central nervous system. About 30% of these tumors occur in the spinal cord.
Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

It should be noted that gliomas may also contain cancer cells derived from brain cells other than glial cells.

Some brain tumors are categorized by their location in the brain. Such tumors often contain gliomas but are also frequently a mixture of different cell types.

Meningiomas. Meningiomas are usually benign tumors that develop in the membranes that cover the brain and spinal cord (the meninges).

Click the icon to see an image of the meninges.

They are not technically classified as brain tumors, but they have similar symptoms and develop within the brain. So in practical terms, they are considered brain tumors. In fact, meningiomas comprise 20% of all primary brain tumors. They occur more often in women than in men. Most grow very slowly, and the majority of people who have them never know they are present. Malignant forms called anaplastic meningiomas and hemangiopericytomas are less common and are difficult to remove surgically.

Cerebral Astrocytomas. Gliomas that develop inside the brain often occur in the cerebral hemispheres (the right and left sides of the brain). In such cases, they are referred to as cerebral astrocytomas. Gliomas sometimes occur in another part of the brain, called the cerebellum. The cerebellum is responsible for balance and coordination. In such cases, the term cerebellar astrocytoma is used.

Click the icon to see an image of the function of the left cerebral hemisphere.

Click the icon to see an image of the function of the right cerebral hemisphere.

Brain Stem Gliomas. Brain stem gliomas develop in the lowest portion of the brain. The brain stem connects the cerebrum (the higher centers of the brain) to the spinal cord. The brain stem is thought to be the primitive brain because it controls the most basic functions.

Click the icon to see an image of the function of the brainstem.

The brain stem consists of three primary parts:

The medulla regulates breathing, swallowing, blood pressure, and heart rate.
The pons links the cerebellum to the cerebrum.
The midbrain helps control vision and hearing.

Click the icon to see an image of the structures of the brain.

Medulloblastomas. Medulloblastomas are always located in the cerebellum, which is at the base and toward the back of the brain. They represent about 3% of all brain tumors.

Click the icon to see an image of the function of the cerebellum.

Pituitary Tumors. Pituitary tumors comprise about 10% of primary brain tumors and are often benign, slow-growing masses in the pituitary gland.

Click the icon to see an image of the pituitary gland.

Other Brain Tumor Locations. Optic nerve gliomas occur in the optic nerve, which is located behind the eye. Acoustic neuromas make up 7.5% of brain tumors.

Click the icon to see an image of the optic nerve.

Symptoms

Brain tumors produce a variety of symptoms, ranging from headache to stroke. They are great mimics of other neurologic disorders. Symptoms occur if the tumor directly damages the nerves in the brain or central nervous system or if its growth imposes pressure on the brain. Some gliomas develop gradually, and symptoms may be subtle for a long time, making an early diagnosis difficult.

Headache is probably the most common symptom of a brain tumor. It should be strongly emphasized, however, that everyone has headaches, and they rarely represent an underlying brain tumor. Headaches caused by brain tumors may vary depending on the location, and many different features.

Steady and worse upon waking in the morning and clears up within a few hours
Persistent non-migraine headache that occurs while sleeping and is also accompanied by at least one other symptom (such as vomiting or confusion)
May or may not be throbbing, depending on location of the tumor
Accompanied by double vision, weakness, or numbness
May worsen with coughing or exercise or with a change in body position
Sometimes accompanied by neck pain

Gastrointestinal symptoms, including nausea, are also common. Nausea and vomiting, in fact, often occur in children with brain tumors and in all people with brain stem cell tumors.

Seizures occur in between 15 - 95% of patients, depending on the location of the tumor.

Tumors are more likely to be localized and affect one area of the brain. In such cases they can cause partial seizures. In this case, a person does not lose consciousness but may experience confusion, jerking movements, tingling, or odd mental and emotional events.
Generalized seizures, which can cause loss of consciousness, are less common, since they are caused by disturbances of nerve cells in diffuse areas of the brain.

Sometimes the only symptoms are mental changes, which may include the following:

Memory loss
Impaired concentration
Problems with speech and reasoning
Increased sleep

Gradual loss of movement or sensation in an arm or leg
Unsteadiness
Unexpected visual disturbance (especially if it is associated with headache), including vision loss (usually of peripheral vision) in one or both eyes or double vision
Hearing loss with or without dizziness
Speech difficulty

Specific symptom syndromes may help identify the tumor. The following are some examples.

Symptoms of Brain Stem Gliomas. Sudden onset of symptoms that include vomiting (usually just after waking), a clumsy walk, muscle weakness on one side of the face, difficulty in swallowing, slurred or nasal speech, as well as impaired hearing or vision.

Symptoms of Glioblastoma Multiforme. Rapid onset and worsening of symptoms that include headaches, seizures, memory loss, and changes in behavior.

The below symptoms indicate an emergency condition and require immediate medical attention:

Pupil dilation
A fixed gaze
Paralysis on one or both sides of the body
Blindness or defective vision in one eye

Risk Factors

Nearly 360,000 people in the U.S. are living with brain cancer. Men are at higher risk than women for most brain tumors. Primary malignant brain tumors are still uncommon and represent only 1.3% of all cancers diagnosed in the United States and 2.4% of all deaths due to cancer.

Primary brain cancers are rare, occurring in slightly more than 11 people per 100,000 per year. There has been some evidence of a growing incidence of brain cancer among the elderly since the 1980s. The increase, however, is most likely due to the rise in incidence of non-Hodgkin's lymphomas -- which can occur in the brain. When this malignancy is eliminated, any increase in other tumors is not significant.

The average age of diagnosis for brain tumors is 57, and about 90% of primary brain tumors occur in adults. These tumors can develop at all ages, usually peaking in two age groups.

In adults, ages 55 - 65
In children, ages 3 - 12

Risk Factors in Children. Tumors in the central nervous system are now the most common primary cancers in children, but they are still rare. An estimated 3,110 benign or malignant brain tumors are expected to be diagnosed in children each year. Brain tumors in children are more likely to occur in the cerebellum, the midbrain, or the optic nerve.

The incidence has increased over the past years, but there is some evidence that this increase is only due to better diagnostic procedures. The mortality rate has actually decreased. Researchers have attempted to uncover risk factors for childhood brain cancer. There may be some association between a higher risk and the following conditions:

Children treated with radiation to the head for leukemia and who have a specific genetic defect may face a high risk for brain cancer. (It should be noted that for children without this defect, the risk is very small.)
Having parents with specific cancers. (According to one study, having parents with nervous system cancers, colon cancer, or cancer in the salivary glands increased the risk of specific brain tumors in their children.)

Click the icon to see an illustrated series detailing colon cancer surgery.

The risk for primary brain tumors in Caucasians is higher -- as much as twofold depending on type -- than in African-Americans.

Radiation Exposure. People who receive radiation therapy to the head during cancer treatment have an increased risk of developing brain tumors 10 - 15 years later. Workers in the nuclear industry are also at increased risk.

There is no evidence that electromagnetic field exposure from power lines or household appliances poses any risk. Several recent epidemiological studies, including a 2006 study in the British Medical Journal, found that cell phones, cordless phones, and wireless devices are also safe and do not increase the risk for gliomas.

Chemical and Metals in Brain Tumors. High exposure to numerous metals and chemicals have been associated with brain tumors:

Industrial chemicals, including vinyl chloride and petroleum products
Lead, arsenic, or mercury exposure
Exposure to pesticides. A major study of pesticides is underway, but results are not in yet. A 2003 study indicated that parental exposure to pesticides or herbicides did not appear to be important in increasing risk for brain cancer in their children.

Brain cancer is uncommon, and, over the course of their lifetime, many people are exposed to these chemicals, many of which are very common. To date, there has been no clear evidence that implicates any specific industrial chemical or metal.

One study reported a higher risk for brain cancers in patients who had undergone organ transplantations. Researchers believed that the drugs used to suppress the immune response after the procedures may increase the risk.

One study reported lower risks for brain cancers in individuals with allergies and autoimmune diseases (such as type 1 diabetes). Autoimmune diseases were also associated with a lower risk for meningiomas. The cause of this possible association remains unknown.

Studies have also found an association between lower risk for gliomas and a history of infection with varicella zoster, the virus that causes chicken pox and shingles.

Click the icon to see an image of the chicken pox.

Causes

Only 5 - 10% of primary brain tumors are associated with genetic disorders. These inherited conditions and associated genes include:

Von Recklinghausen disease, also called neurofibromatosis 1 (NF1 gene) and neurofibromatosis 2 (NF2 gene)
Turcot's syndrome (APC gene)
Gorlin syndrome, also called basal cell naevus syndrome (PTCH gene)
Tuberous sclerosis (TSC1 and TSC2 genes)
Li-Fraumeni syndrome (TP53 gene)

Certain types of brain tumors are specifically linked with these genetic conditions. For example, neurofibromatosis 1 is associated with about 15% of cases of pilocytic astrocytomas, the most common type of childhood glioma. Neurofibromatosis results from defects in the tumor suppressor genes NF1 and NF2. Li-Fraumeni syndrome results from mutations in the tumor suppressor gene TP53. These mutations affect the production of tumor suppressor protein p53.

Tumor suppressor genes regulate cell division and help repair DNA damage. When mutations that affect protein encoding occur, unregulated cell division and growth can lead to the development of a tumor. Tumor suppressor genes are sometimes described as being in a tug-of-war with cancer-causing genes called oncogenes. Oncogenes derive from mutations or overexpressions of proto-oncogenes. Proto-oncogenes encode for proteins that regulate cell growth and differentiation. When proto-oncogenes become oncogenes, normal cells start to grow uncontrollably. Cancer can occur when tumor suppressor genes are turned off, or when oncogenes are turned on.

Many different oncogenes are involved in cancer. Growth factors are a particularly important type of oncogene associated with brain tumors. Growth factors attach to receptors (connectors) that stimulate cell growth. Epidermal growth factor receptor (EGFR) has been shown to play a role in high-grade brain tumors such as glioblastoma multiforme. In 2007, scientists identified insulin-like growth factor binding protein (IGFBP2) with an oncogene that may be associated with the development of astrocytoma and oligodendroglioma.

Knowing the molecular origin of a brain tumor may help determine the treatment course, both for standard chemotherapy and "targeted therapy" biologic drugs. For example, patients with tumors marked by high EGFR proliferation may benefit from treatment with the EGFR kinase inhibitor drugs gefitinib (Iressa) or erlotinib (Tarceva).

Most genetic abnormalities that cause brain tumors are not inherited but occur as a result of environmental or other factors that affect genetic materials (DNA) in the cells. Researchers are studying various environmental factors (viruses, hormones, chemicals, radiation) that may trigger the genetic disruptions that lead to brain tumors in susceptible individuals. They are also working to identify the specific genes that are affected by these environmental triggers. For example, in a 2007 study, scientists proposed that genetic susceptibility may explain why some people develop meningioma, a rare type of brain tumor, following exposure to ionizing radiation. Future investigations will hopefully identify the specific genes involved and help determine which people would potentially be most at risk.

Prognosis

About 13,100 people die from cancerous brain tumors each year. Recent advances in surgical and radiation treatments have significantly extended average survival times and can reduce the size and progression of malignant gliomas. In general, survival rates are highest in younger people and lowest in the elderly.


Age	Survival Rates
0 - 19 years	63.1%
20 - 44 years	50.4%
45 - 64 years	14.2%
Over 65	4.9%
Data From: 2002 - 2003 Primary Brain Tumors in the United States Statistical Report. Fact Sheet (1973- 1999 data). Brain Tumor Registry of the United States www.cbtrus.org/factsheet/factsheet.html.

In general, studies are reporting that patients who survive the first 2 years after a diagnosis of a brain tumor have at least a 70% chance of surviving for at least 5 years. The best recent progress has been made for:

Medulloblastomas in both children and adults. Long-term survival rates are now about 60% in children after treatment for medulloblastomas, the most common malignant brain tumor in this age group. (New treatments, however, may significantly improve these rates.)
Nonmalignant astrocytomas and oligodendrogliomas in adults.

Unfortunately, the majority of primary brain tumors, notably anaplastic astrocytomas and glioblastoma multiforme, are only rarely curable.

The specific effects of tumors on the brain can cause seizures, mental changes, and mood, personality, and emotional changes. Such effects can be devastating to the patient and the caregivers. Numerous treatments are available that help alleviate these complications, and patients and family members should discuss these with their doctors.

Diagnosis

A neurological exam is usually the first test given when a patient complains of symptoms that suggest a brain tumor. The exam includes checking eye movements, hearing, sensation, muscle movement, sense of smell, and balance and coordination. The doctor will also test mental state and memory.

X-rays of the skull were once standard diagnostic tools but are now performed only when more advanced procedures are not available. Advanced imaging techniques have dramatically improved the diagnosis of brain tumors in recent years.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) is the gold standard for diagnosing a brain tumor. It does not use radiation and provides pictures from various angles that can enable doctors to construct a three-dimensional image of the tumor. It gives a clear picture of tumors near bones, smaller tumors, brainstem tumors, and low-grade tumors. MRI is also useful during surgery to show tumor bulk, for accurately mapping the brain and for detecting response to therapy.

An MRI (magnetic resonance imaging) of the brain creates a detailed image of the complex structures in the brain. An MRI creates a three-dimensional picture of the brain, which allows doctors to more precisely locate problems such as tumors or aneurysms.

A variant called magnetic resonance spectroscopy (MRS) is capable of providing information on the activity of the brain using magnetic resonance imaging. MRS is proving to be accurate for distinguishing dead (necrotic) tissue caused by previous radiation treatments from recurring tumor cells in the brain, a difficult diagnostic issue.

Computed Tomography. Computed tomography (CT) uses a sophisticated x-ray machine and a computer to create a detailed picture of the body's tissues and structures. It is not as accurate as an MRI and does not detect about half of low-grade gliomas. It is useful in certain situations, however. Often, doctors will inject the patient with an iodine dye, called contrast material, to make it easier to see abnormal tissues. A CT scan helps locate the tumor and can sometimes help determine its type. It can also help detect swelling, bleeding, and associated conditions. In addition, computed tomography is used to check the effectiveness of treatments and watch for tumor recurrence.

Click the icon to see an image of a CT scan of the brain.

Positron Emission Tomography. Positron emission tomography (PET) provides a picture of the brain's activity rather than its structure by tracking substances that have been labeled with a radioactive tracer. As with magnetic resonance spectroscopy (MRS), it is also able to distinguish between recurrent tumor cells from dead cells or scar tissue, although MRS is more widely available. PET is not routinely used for diagnosis, but it may supplement MRIs to help determine tumor grade after a diagnosis. Data from PET may also help improve the accuracy of newer radiosurgery techniques.

Other Imaging Techniques. Numerous other advanced imaging techniques may be used for specific purposes, if available or under investigation.

Single photon emission tomography (SPECT) is similar to PET but is not as effective in distinguishing tumor cells from destroyed tissue after treatments.
Magnetoencephalography (MEG) scans measure the magnetic fields created by nerve cells as they produce electrical currents.
Cerebral angiography involves x-rays of blood vessels in the brain. A long, thin tube (catheter) is threaded through blood vessels from a distant site to the brain, and a radiopaque substance (a substance that is impenetrable to x-rays) is injected through it. The role of angiography in glioma is usually limited to planning surgical removal of a tumor suspected of having a large blood supply.
Radionuclide brain scintigraphy uses a radioactive substance that is administered and absorbed by capillaries in the tumor, which are then viewed using imaging techniques.
Digital holography, a new technique that provides full three-dimensional mapping, is under investigation.

A lumbar puncture is used to obtain a sample of spinal fluid, which is examined for the presence of tumor cells. A computed tomography (CT) scan or magnetic resonance imaging (MRI) should generally be performed before a lumbar procedure to be sure that the procedure will be safe.

Click the icon to see an image of a lumbar puncture.

A biopsy is a surgical procedure in which a small sample of tissue is taken from the suspected tumor and examined under a microscope for malignancy. The results of the biopsy also provide information on the cancer cell type.

In some cases, such as brain stem gliomas, a biopsy might be too hazardous because removing any healthy tissue from this area can affect vital functions. In such cases, diagnosis must rely on less invasive and possibly less accurate measures. Of promise is the stereotactic technique (also called stereotaxy), which uses computers to provide three-dimensional views of very small areas. This may allow precise biopsies of cancer cells without affecting healthy brain tissue. Expertise in this technique is extremely important, however, and the technique is not widely available.

The survival rates in people with brain tumors depend on many different variables:

Whether the tumor is malignant or benign
Cancer cell type and location (location affects whether the tumor can be removed surgically or not)
The tendency to spread and the growth rate (tumor grade)
Patient's age
Patient's ability to function
Duration of symptoms

The outlook is poorer in the very youngest and very oldest patients, although younger patients who survive 2 years after diagnosis have a much better outlook than older patients.

Grading Tumors. Malignant primary brain tumors are classified according to tumor grade. Grade I is the least cancerous, and Grades IV and V are the most dangerous. Grading a tumor attempts to predict its tendency to spread and its growth rate. It is based on the appearance of the tumor cells as seen under a microscope.

Lower-grade (I and II) tumor cells are well defined and almost normal-shaped. (Some primary low-grade brain tumors are curable by surgery alone, and some are curable by surgery and radiotherapy. Low-grade tumors tend to have the most favorable survival rates and high-grade the least. However, this is not always the case. For example, some low-grade II gliomas are at very high risk for progression.)
Higher-grade (III and IV) tumor cells are abnormally shaped and are more diffuse, which indicates more aggressive behavior. (High-grade brain tumors usually require surgery, radiotherapy, chemotherapy, and possibly investigational treatments.)
In tumors that contain a mixture of different-grade cells, the tumor is graded using the highest-grade cells in the mixture, even when there are very few of them.

Biologic Markers. Elevated levels of certain cancer-associated molecules or compounds may be correlated with prognosis. For example, evidence of genetically mutated p53 indicates a poorer prognosis in younger patients with glioblastoma multiforme.

Elevations of epidermal growth factors (EGF) or vascular endothelial growth factors (VEGF) suggest aggressive tumors. High levels of the receptor for EGF (EGFR), in fact, are found in 70% of glioblastoma specimens.

Genetic Profiles of Cancer Cells. Analyses that identify genetic types may soon help clinicians determine if patients with specific brain tumor cells might respond better to one treatment than another. For example, specific genetic profiles of oligodendrogliomas can help predict how patients respond to nitrosourea alkylating drugs such as carmustine. Genetic variation tests are also being used to determine how patients may respond to epidermal growth factor receptor (EGFR) kinase inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa).

A genetic profile can also help give doctors a better idea of a patient’s prognosis and survival. In a 2006 study of patients with anaplastic oligodendroglioma, the status of specific chromosomal deletions within tumors was a better predictor of survival than which kind of treatment patients received. In fact, the researchers suggested that gliomas be classified according to chromosomal deletion status, and recommended that chromosomal testing be a regular part of diagnosis and treatment decisions.

Common Brain Tumors


GENERAL DESCRIPTION OF ASTROCYTOMAS: Derived from star-shaped glial cells called astrocytes.

Low-Grade (Usually I) Astrocytomas. Pilocytic gliomas.	Pilocytic gliomas occur mostly in children. Tumors are well differentiated. Cells are relatively normal and rarely metastasize. They grow relatively slowly. Pilocytic astrocytomas have the highest 5-year survival rates (greater than 70%). However, even well differentiated astrocytomas are life threatening if they are inaccessible.	Cancer may sometimes be completely removed through surgery, particularly if it occurs in the cerebellum. For recurrence or residual tumors, reoperation, radiotherapy, or chemotherapy may be given, depending on the circumstances. Repeat surgery for cerebellar astrocytoma is often very successful. For those who fail radiotherapy and chemotherapy, investigative drugs are used.
Low-Grade (II) Astrocytomas. Fibrillary, protoplasmic, and protoplasmic astrocytomas. Some pleomorphic xanthoastrocytomas.	Tumors are well differentiated. Cells are relatively normal and less malignant than those in higher grades. They grow relatively slowly but can spread. Survival rates average 5 years, but people can survive for a decade or more. Pleomorphic xanthoastrocytomas have a relatively favorable prognosis, but can recur and demonstrate aggressive clinical behavior. Low-grade astrocytomas generally occur in young adulthood, with a peak incidence in 30s and 40s.	Surgery, if possible, plus radiotherapy. Surgery alone in certain children, if possible. Trials on postoperative radiotherapy include the following: radiotherapy with or without chemotherapy; low-versus-high radiotherapy doses (studies suggest results are the same and high-dose causes more side effects); deferring radiotherapy until tumor progresses and symptoms occur. (A major study confirmed earlier ones that suggest that this approach has the same 5-year survival benefits -- about 65% -- as immediate postoperative radiotherapy.)
Malignant (High-grade III and IV) Astrocytomas. Anaplastic astrocytoma (gemistocytic and some pleomorphic xanthoastrocytomas). Usually mid-grade (III).	Tumors grow more rapidly than lower grades and infiltrate other nearby healthy cells. Not well-differentiated. Five-year survival rates are about 30%. Recurrence is common.	Treatment same for all high-grade malignant astrocytomas. Surgery, with removal of as much of tumor as possible followed by radiotherapy, with or without chemotherapy. The addition of chemotherapy, particularly being able to take more than 6 cycles, appears to improve survival rates. Carmustine (BCNU) most effective drug at this time. Other drugs and treatment sequences are under investigation. For example, temozolomide is showing promise for many patients, including the elderly. Topotecan may also be useful with other drugs or with radiation. For recurring gliomas, surgery with placement of wafers that release carmustine (Gliadel wafers) is the only proven beneficial therapy to date. Combinations, such as procarbazine and carmustine, provide benefits for recurrent anaplastic astrocytomas. Single drugs may be less toxic and as helpful for other recurrent gliomas. Temozolomide has been approved in Europe for high-grade recurrent gliomas and is proving to be beneficial. Other trials include the following: drugs that block small molecules involved in tumor growth; radioimmunotherapy using monoclonal antibodies; advanced radiotherapy techniques; intraarterial chemotherapy.
High-grade (IV and V). Glioblastoma (notably glioblastoma multiforme or GBM).	Very rapidly growing tumors that spread quickly. Represents about 25% of all primary brain tumors. Most common in older adults (over age 55) and affect more men than women. Recurrences are common in patients who achieve long-term survival.


GENERAL DESCRIPTION OF EPENDYMOMAS: Derived from cells that line the ventricles (fluid-filled brain cavities) and spinal cord central canal. Do not usually spread into normal brain tissue. Can block exits for cerebrospinal fluid and cause hydrocephalus. They constitute about 4% of all central nervous system tumors in adults and 10% of these tumors in children. About 30% of ependymomas develop in the spinal column.

Low-grade (I). Myxopapillary ependymoma (found in the spine). Subependymoma (found in one of the ventricles).	No or very slow growth. In addition to grade, risk is also based on location of the tumor. Tumors on the spinal cord are more accessible than those in the fourth ventricle or in the middle of the lower back portion of the brain.	Can often be removed and cured with surgery, particularly those on spinal cord. Radiation may be needed. Chemotherapy (avoid radiation, if possible) in children under age 6).
Low-grade (II). Papillary, cellular, and clear cell ependymomas.	Slow growth. Usually affect adults.	Surgery alone or followed by radiotherapy. For those who fail radiotherapy, possible use of nitrosourea-based chemotherapies or investigative drugs.
Grade III. Anaplastic ependymomas.	Spreads to the spinal fluid.	Surgery followed by radiotherapy to brain and spinal cord. Possible shunt.
Grade IV. Primitive neuroecto-dermal tumor (PNET). Composed of malignant forms of early, undeveloped nerve cells called neuroblasts. (This malignancy is also referred to as neuroblastoma.)	Very rare, but more common in children. Primitive nerve cells that grow very rapidly. Usually occur in cerebellum.	Surgery followed by radiotherapy to brain and spinal cord. Chemotherapy in young children. Investigative high-dose chemotherapy with stem cell rescue for children with relapsed cancer.


DESCRIPTION OF OLIGODENDROGLIOMAS: They develop from oligodendrocyte glial cells. These cells form the protective coatings around nerve cells. Pure cell types are rare. Most often occur in mixed gliomas. Categorized as either low- or high-grade. Most are low-grade II.

Low-grade: Low grade difficult to tell from astrocytomas, although they are usually calcified. Very likely to bleed. Usually spread along nerve pathways of the brain and spine and rarely outside this area. In spite of difficulty in removing surgically, in some patients survival can be 30 - 40 years. Usually have better prognosis than astrocytomas of equal grade. Occur mostly in middle-aged adults, although there is also a small peak of incidence in children.	Treatment usually delayed until progression causes symptoms. Surgery to remove whole tumor. Radiotherapy often follows in all adults over age 40 or in anyone in which tumor cannot be completely removed. Solid evidence is lacking on this approach, however, and there is some debate on its benefits. Trials using chemotherapy after radiation are promising. Two-thirds of patients respond to PCV (combination of procarbazine, lomustine and vincristine.) Sustained remissions averaging 16 years often achieved. Pure oligodendrogliomas respond better than mixed gliomas. Temozolomide is showing promise as second-line treatment. Others under investigation. Trials of additional chemotherapy for less well-differentiated tumors or for residual tumors after surgery.
High-grade. Anaplastic oligodendrogliomas.	Immediate treatment. Surgery to remove the whole tumor, if possible. Radiation typically follows surgery. Chemotherapy treatments either before or with radiation. Standard drugs are limited. Experts recommend trying investigative drugs. Temozolomide and retinoic acid may be useful. Possible additional drugs include melphalan, thiotepa, carboplatin, cisplatin, and etoposide. (Numerous biologic markers may help identify specific oligodendrogliomas that will respond better or worse to specific treatments.)


GENERAL DESCRIPTION OF MIXED GLIOMAS: Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

Grade determined by the highest-grade cell present in the tumor.	Same as for oligodendroglioma.



Meningiomas	They are found in the membranes around the brain and spinal column. They are usually benign and rarely invasive. In such cases, long-term outlook is very favorable. (Malignant forms, anaplastic meningiomas, and hemangiopericytomas are uncommon and occur in about 2% of cases.)	Usually watchful waiting. Aggressive surgery the treatment of choice, if possible, although 20% recur after 10 years. Malignant forms and those at the base of the skull difficult to impossible to remove surgically. Stereotactic radiosurgery or fractionated external beam radiotherapy showing promising results for some patients.
Cerebellar astrocytomas (located in cerebellum)	Located in the cerebellum. Usually low-grade, but depends on cell type. If surgical removal is complete, up to 90% survival rates. More common in children than adults.	Surgery primary treatment. Radiotherapy if removal is incomplete.
Brain Stem Gliomas	About 60 - 70% of brain stem tumors are diffuse, which are likely to spread and have a rapid onset of symptoms. Focal tumors tend to be solid or cyst-like. They generally develop gradually. Occurs in both children and young adults.	Radiation is usual treatment. Tumors in this area are rarely removed surgically since the nerve tissue in this area is responsible for vital life functions. Slow-growing tumors may only require watchful waiting. Trials using advanced radiotherapy techniques, gene therapy, immunotherapy, and other experimental drugs.
Medulloblastomas	Occurs in cerebellum (the lower portion of the brain), brainstem, and spinal cord. Usually fast-growing aggressive cells. Most common brain tumors in children and young people, causing between 15 - 20% of brain tumors. With aggressive therapy, in children 5-year survival rates between 60 - 80%. In patients who survive for 2 years after diagnosis, long-term survival rate is nearly 80%.	Treatment is usually surgery and radiotherapy followed by chemotherapy. A 2005 study found that a combination chemotherapy regimen may replace radiation for very young children. A 2006 study suggested that radiation and chemotherapy doses should be adjusted based on disease severity.
Optic Tract Gliomas	Spread along the optic nerve. Usually slow growing. Most often in children under age 10. Children with these tumors often have vision and hormonal problems.	Usually surgery if one eye is involved. Possible chemotherapy or radiation.

Treatment

The approach for treating brain tumors is to reduce the tumor as much as possible using surgery, radiation treatment (also called radiotherapy), chemotherapy, or investigative procedures. Such treatments are used alone or, more commonly, in combinations. With some very slow-growing cancers, such as those that occur in the midbrain or optic nerve pathway, patients may be closely observed and not treated until the tumor shows signs of growth. The intensity, combination, and sequence of these treatments depends on the glioma subtype, its size and location, and patient age, health status, and medical history.

Recent advances in surgical and radiation treatments have significantly extended average survival times compared to those of standard therapy. Investigative treatments, such as monoclonal antibodies, are also showing promise. Patients or their caretakers should discuss all options thoroughly with a specialist in brain cancer. Different specialists may be needed to help manage symptoms.

Because of the low-cure rates of most malignant brain tumors, support for the patients and their families is a critical component of treatment and management. In response to one survey of patients with gliomas, experts made several recommendations to help both patients and caregivers:

Any physical impairment that could benefit from home equipment or physical therapy should be identified and treated.
Patients should discuss emotional as well as physical issues with their doctors. Depression, for instance, can be medically treated. Caregivers should also seek help for the inevitable stress, depression, and tension arising from their difficult role.
Relaxation techniques, meditation, and spiritual resources can be extremely helpful. Support groups are beneficial, but experts recommend separate groups for patients and their families.

Surgery

Surgery is usually the first step in treating most brain tumors. In some cases, however, such as most brain stem gliomas, it may be too dangerous to perform surgery. The object of most brain tumor surgeries is to remove or reduce as much of its bulk as possible. By reducing the size, other therapies, particularly radiotherapy, can be more effective. (Although there have been significant advances in brain surgeries, some experts argue that in high-grade gliomas extensive surgery may not improve survival rates at all and patients are best served by radiation therapy.)

The standard procedure is called craniotomy.

The neurosurgeon removes a piece of skull bone to expose the area of brain over the tumor.
The tumor is located and then removed.

Click the icon to see an illustrated series detailing craniotomy surgery.

There are various surgical options for breaking down and removing the tumor. They include:

Standard surgical procedures
Laser microsurgery (which produces great heat and vaporizes tumor cells)
Ultrasonic aspiration (which uses ultrasound to break the glioma tumor into small pieces, which are then suctioned out)

Relatively benign, grade I gliomas may be treated only by surgery. Some controversy exists over whether surgery for low-grade astrocytomas improves survival, although insufficient research has been conducted to prove its benefits for these gliomas. Most malignant tumors require additional treatments, including repeat surgery.

The surgeon's skill in removing the tumor as completely as possible is critical to survival. No one should be shy about asking the surgeon the number of similar procedures they have performed. (Asking for complication rates may not be useful, since a very experienced surgeon might operate on many high-risk patients.)

In most cancers outside the brain, surgical removal of a tumor usually involves taking out surrounding healthy tissue to be sure all cancer cells are gone. In the brain, however, removing healthy nearby nerve tissue can be as disastrous for the patient as the cancer itself. Special techniques have been developed to allow maximum removal of tumors while protecting healthy brain cells.

Stereotaxy. Stereotaxy has become a useful adjunct to both surgery (stereotactic surgery) and radiotherapy (stereotactic radiotherapy).

Cortical Localization. Cortical localization, or stimulation, uses a probe that passes a tiny electrical current to delicately stimulate a specific area of the brain. This produces a visible response of the body part (such as a twitch in a leg), which the stimulated region of the brain controls. The surgeon then knows to avoid those areas during the operation.

Image-Guided Surgery. Image guided surgery uses a three-dimensional picture of the patient's brain derived from computed tomography (CT) or magnetic resonance imaging (MRI) scans. An advanced technique called high-field interventional MR imaging (iMRI) is particularly accurate in identifying the tumor, but it is not widely available. The image, with various views of the brain, is displayed on a monitor in the operating room. During surgery, as the surgeon's instrument touches a part of the brain, a camera sends the image to a computer, which calculates the position of the surgical tool and displays it in its proper location on the 3-D image. The surgeon then can look at the monitor and see what structures to avoid.

Magnetic-Tipped Catheters. Neurosurgeons are investigating a technique in which external magnetic fields direct a magnet-tipped flexible catheter to the tumor site through a path that avoids harming certain important areas of the brain.

Heparin. Heparin, a blood-thinning drug, should be given at the time of surgery to help prevent blood clots.

Radiotherapy

Radiotherapy plays a central role in the treatment of most brain tumors, whether benign or malignant.

Radiotherapy after Surgery. Even when it appears that the entire tumor has been surgically removed, microscopic cancer cells often remain in the surrounding brain tissue. Radiation targets the residual tumor with the goal of reducing its size or stopping its progression. If the entire tumor cannot be removed safely, postoperative radiotherapy is often recommended. Even some benign gliomas may require radiation, since they may be life-threatening if their growth is not controlled.

Radiotherapy When Surgery Is not Appropriate. Radiotherapy may be used instead of surgery for inaccessible tumors or for tumors that have properties that are particularly responsive to radiotherapy.

Radiotherapy and Chemotherapy (Radiochemotherapy). Combining chemotherapy with radiotherapy is beneficial in some patients with high-grade tumors.

Various radiation treatments are now available.

Conventional radiotherapy uses external beams aimed directly at the tumor and is usually recommended for large or infiltrating tumors. It begins about a week after surgery and continues 5 days per week for 6 weeks. Older adults tend to have a more limited response to external-beam radiation therapy than younger people. According to a 2007 study in the New England Journal of Medicine, radiotherapy leads to a modest improvement in survival in elderly patients (70 years or older) with glioblastoma, and causes few negative impacts on quality of life or cognition.

For tumors that are highly localized, the radiation therapist has a choice of other radiation treatments:

Brachytherapy (also called interstitial radiation) uses radioactive "seeds" implanted directly in the tumor site. It is used as a booster to external beam radiation for patients with malignant astrocytoma. Brachytherapy appears to prolong survival in some aggressive gliomas. It may also be a safe and effective treatment for some children.
Intensity-modulated radiation therapy (IMRT) uses high-dose radiation beams that conform to the three-dimensional shape of the tumor.
Hyperfractionated radiation uses many small radiation doses to deliver a high total dosage of radiation.
A balloon catheter (GliaSite) that delivers radiation to the tumor cavity after surgery is showing promise.

Stereotactic radiosurgery has been developed to allow highly targeted radiation to be delivered directly to the small tumors while avoiding healthy brain tissue. The term radiosurgery is used because the destruction is so precise that it acts almost like a surgical knife. Some studies suggest that stereotactic radiosurgery improves survival, even in patients with the highly aggressive glioblastoma multiforme brain cancer. The procedure is being tested to boost standard radiotherapy.

Benefits of Stereotaxy. There are numerous benefits for stereotaxy:

Stereotaxy allows precisely focused, high-dose beams to be delivered to gliomas less than 1.25 inch in diameter.
Investigators have found that stereotactic radiosurgery can help them reach small tumors located deep in the brain that were previously considered inoperable.
Sometimes with stereotaxy only a single treatment may be needed.
Unlike traditional radiotherapy, stereotactic radiotherapy can be repeated, so it is useful for recurrent tumors when a patient has already received standard radiation treatments.
Combining stereotaxy with techniques that gauge speech and other mental functions in patients who are awake during the procedure can allow removal of brain tissue with a lower risk for complications in areas that affect such functioning.

The Planning Procedure. Stereotactic radiosurgery usually begins with a series of steps designed to plan the radiation target:

First, the patient is given a local anesthetic. In the standard operation, the patient's head must be totally immobilized by screwing a device known as a stereotactic frame into the patient's skull. (The frame procedure is effective only on brain tumors that have regular margins.) The frame is removed as soon as the whole procedure has been completed (about 3 - 4 hours).
A three-dimensional map, usually using magnetic resonance imaging (MRI) scans, is made of the patient's brain.
A computer program calculates dosage levels and specific areas for radiation targeting.

Advanced imaging techniques are now allowing frameless stereotaxy, which eliminates the frame and may be effective on more tumors. For example, high-field interventional MR imaging (iMRI) uses a guidance system based on cruise-missile technology to calculate the slightest variations in movements of the head and the location of the tumor relative to these movements. These calculations are then used to target the radiation beams directly on the tumor, even if the patient's head is moving slightly.

Delivery of Radiation Beams. Once the preliminary planning stage has been completed, treatment begins. Several advanced machines, such as the gamma knife, adapted linear accelerator (LINAC), and cyclotron, are being used with stereotaxy and can deliver very focused beams of radiation. Actual treatment takes 10 minutes to 1 hour.

The gamma knife uses gamma rays that are sent from multiple points to converge at a single point on the tumor. Although each gamma-ray beam is very low dosage, when the beams converge, the intensity and destructive power is very high. The gamma knife is limited to very small tumors and so is generally useful as a booster after standard radiation, surgery, chemotherapy, or combinations.
The linear accelerator (LINAC) produces photons (positively-charged atomic particles) in patterns that are matched to the tumor shape. The patient is positioned on a bed that can be moved to allow flexible positioning. It allows treatment over multiple sessions of small doses (fractionated stereotactic radiotherapy), instead of a single session. This means that larger tumors can be treated.
The cyclotron is basically an atom smasher, which produces protons that can be directed toward the tumor. As part of this procedure, some researchers are using boron neutron capture therapy (BNCT). BNCT employs intravenous administration of a boron compound, which is picked up more selectively by tumor cells than by normal brain tissue. The cyclotron delivers a single dose of radiation that triggers the release of high-energy particles from the boron to destroy nearby tumor cells. The cyclotron is available only in a very few locations, and there have been few trials to date.

Researchers are studying drugs that may be used along with radiation to increase the effectiveness of the treatment.

Radioprotectors. Drugs such as amifosistine (Ethyol) may protect healthy cells during radiation.

Radiosensitizers. Drugs such as fluorouracil (5-FU) and cisplatin (Platinol) may help make cancerous cells more sensitive to radiation.

Common Side Effects. Side effects of radiotherapy may vary depending on the tumor type and radiation treatment. Side effects may include hair loss, fatigue, and nausea and vomiting. Skin irritation and sensitivity may develop in the areas being treated. To prevent further irritation, avoid scratching or rubbing, avoid direct sunlight and heating pads, and do not attempt to treat the symptoms yourself. (Ask your doctor or radiation therapist for advice.) Brain swelling (edema) is another common radiotherapy side effect, which can sometimes cause an increase in brain tumor symptoms. Edema can be treated with steroids.

Tissue Injury. Radiation necrosis (total destruction of nearby healthy tissue) occurs in about 25% of patients treated with intensive radiation. Radiation necrosis can cause brain swelling and reduction in mental functions. The condition is treated with steroids. If steroids prove ineffective, surgery may be required to remove the damaged tissue.

New Tumors. Radiation therapy for childhood cancer is the most important risk factor for developing new brain and spinal column tumors, according to a 2006 study. The risk appears greatest for children who received radiation therapy before age 5. Researchers found that the risk of second primary tumors increased in relation to the radiation dose used to treat the first cancer.

Stroke. Survivors of childhood brain tumors who were treated with high doses of cranial radiation (especially doses greater than 50Gy) may be at increased risk of having a stroke later in life. In a study of nearly 2,000 brain tumor survivors, the average length of time from cancer diagnosis to stroke was 14 years.

Chemotherapy

Chemotherapy involves the use of drugs to kill or alter cancer cells. Chemotherapy is not an effective initial treatment for low-grade brain tumors, mostly because standard drugs cannot pass through the blood-brain barrier, the functional system that protects the brain by preventing certain molecules from reaching the central nervous system. In addition, not all types of brain tumors respond to chemotherapy. In general, chemotherapy for brain tumors is usually administered following surgery or radiation therapy.

The type of drug determines how it is administered. "Systemic delivery" drugs, which pass to the brain from the bloodstream, may be given by mouth, injected into a vein through an IV, or injected into an artery or a muscle. "Local delivery" drugs are placed within or around the brain tumor.

Scientists are working on several approaches to overcome the blood-brain barrier. Newer delivery methods include:

Interstitial chemotherapy uses disc-shaped polymer wafers (known as Gliadel wafers) soaked with carmustine, the standard chemotherapeutic drug for brain cancer. The surgeon implants the wafer directly into the surgical cavity after a tumor is removed.
Intrathecal chemotherapy delivers chemotherapeutic drugs directly into the spinal fluid.
Intraarterial chemotherapy delivers high-dose chemotherapy into arteries in the brain using tiny catheters. In one study, this approach was used within 2 weeks of radiotherapy in patients with high-grade astrocytomas, and the survival rates for glioblastoma multiforme tripled (20 months) compared to those who had chemotherapy and radiation at the same time.
Convection-enhanced delivery (CED) involves placing catheters into the brain tumor or nearby brain tissue to deliver slowly and continuously a cancer drug over several days.

Many different drugs, and drug combinations, are used for chemotherapy. Standard ones include:

Temozolomide (Temodar). Temozolomide, the first new drug approved for brain tumors in several decades, is taken by mouth as a pill. Temozolomide was first approved in 1999 for adult patients with anaplastic astrocytoma that did not respond to other treatments. In 2005, it was approved for use during and after radiation therapy for patients newly diagnosed with glioblastoma multiforme. The current first-line treatment for patients with glioblastoma is combined radiotherapy and temozolomide, followed by monthly doses of temozolomide after radiation treatment ends. A 2005 study, published in the New England Journal of Medicine, reported that adults with newly diagnosed glioblastoma who received temozolomide during and after radiation therapy had a higher rate of 2-year survival than patients who received radiation alone. A 2007 study in Neurology suggested that temozolomide works best for patients who are missing a particular gene (1p/19q). Temozolomide’s side effects are relatively minor, but may include constipation, nausea and vomiting, fatigue, and headache.

Carmustine (BCNU, BiCNU). Carmustine is used to treat many types of brain tumors, including glioblastoma, medulloblastoma, and astrocytoma. Carmustine is usually administered into the vein by IV. It can also be delivered through a wafer implant (Gliadel), which is surgically placed into the brain cavity after tumor removal. If carmustine is administered intravenously, side effects may include nausea and vomiting, fatigue, respiratory problems, and lung scarring (pulmonary fibrosis). Intravenous carmustine may cause bone marrow impairment, which results in decreased production of blood cells (a condition called myelosuppression). If carmustine is delivered through a wafer, side effects may include seizures, brain swelling, and infection within the brain cavity.

PCV Drug Regimen. PCV is an abbreviation for a chemotherapy regimen that combines procarbazine (Matulane), lomustine (CCNU), and vincristine (Oncovin). PCV is commonly used to treat oligodendrogliomas and oligoastrocytomas. The drugs may also be used alone or in other combinations. Procarbazine and lomustine are taken by mouth. Vincristine is given by either injection or IV. These drugs can cause significant side effects, including a drop in blood cell counts, nausea and vomiting, constipation, fatigue, and mouth sores. Procarbazine can cause high blood pressure when taken with foods high in tyramine. Patients should avoid foods such as beer, red wine, cheese, chocolate, processed meat, yogurt, and certain fruits and vegetables.

Platinum-Based Drugs. Cisplatin (Platinol) and carboplatin (Paraplatin) are standard cancer drugs that are sometimes used to treat glioma, medulloblastoma, and other types of brain tumors. These drugs are delivered by IV. In addition to nausea and vomiting, carboplatin can cause hair loss, and cisplatin can cause muscle weakness.

Patients with brain tumors, especially tumors that are in advanced stages, should consider enrolling in clinical trials. Many clinical trials are conducted through academic medical centers. Some promising areas of drug research include:

Other Chemotherapy Drugs. Researchers are investigating whether drugs used to treat other types of cancer may have benefits for brain tumors. These drugs include tamoxifen (Nolvadex) and paclitaxel (Taxol), which are used to treat breast cancer; topotecan (Hycamtin), which is used to treat ovarian and lung cancers; and vorinostat (Zolinza), which is approved for treatment of cutaneous T-cell lymphoma. Research presented at the 2007 meeting of the American Society of Clinical Oncology indicated that vorinostat may help patients with glioblastoma multiforme. Irinotecan (Campath) is another cancer drug that is being studied in combination treatment.

Molecular Targeted Therapy Drugs. One of the most promising developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotypes.

Promising targeted therapies for brain tumors include:

Anti-angiogenesis drugs block molecules involved with the growth of blood vessels that feed the tumor (a process called "angiogenesis," which is particularly important in the growth of glioblastomas.) These drugs starve tumors of vital nutrients and oxygen. Bevacizumab (Avastin) is being studied in combination with irinotecan for treatment of recurrent malignant gliomas. Bevacizumab targets vascular endothelial growth factor (VEGF), a specific angiogenesis growth factor. Cediranib (Recentin, AZD2171) is another VEGF inhibitor. In 2007 clinical trials, cediranib appeared to help make recurrent glioblastomas more responsive to chemotherapy and radiation treatment.
Tyrosine kinase inhibitor drugs block proteins involved in tumor cell growth and production. Drugs that specifically target epidermal growth factor receptors (EGFR) are a type of tyrosine kinase inhibitor of special interest in brain tumor research. These drugs include erlotinib (Tarceva), imatinib (Gleevac), and gefitinib (Iressa).
Farnesyl protein transferase inhibitors, such as tipifarnib (Zarnestra) and lonafarnib (Sarasar), are drugs that target a protein involved in the functioning of the cancer-causing Ras protein. Lonafarnib is being studied in combination with temozolomide, and tipifarnib in combination with radiation therapy.
MTOR inhibitors target other enzymes involved in cell growth and replication. Everolimus (RAD-001) is being studied for glioblastoma multiforme and astrocytoma. Everolimus is related to rapamycin (Siroliumus) and tacrolimus (Prograf), which are also being investigated for brain tumor treatment. These drugs are commonly used to suppress the immune system to prevent rejection after organ transplantation.

Other Treatments

Researchers are testing several drugs that target specific mechanisms associated with brain cancer. Combinations of some of these drugs, with or without standard chemotherapy and radiotherapy, may prove to be more effective than the use of any one treatment. It should be noted that none of these drugs at this time are producing cures, although some are improving survival.

Immunotherapy aims at using modalities that boost the patient's own immune system's ability to seek out and destroy cancerous cells.

Radioimmunotherapy with Monoclonal Antibodies. Radioimmunotherapy is showing special promise as a treatment approach to brain tumors. It typically uses monoclonal antibodies (MAbs), genetically engineered drugs designed to work against a specific target. MAbs are bound with radioactive substances and delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the surface of certain cells in the tumor. Once they do so, the radioactive substances destroy the cell. The approach is essentially mini-radiation therapy without the damage or severe side effects of standard radiation treatments. Numerous different radioimmunotherapies are being investigated, and trials of some are reporting improved survival rates in high-grade gliomas. Some doctors believe this approach could prove to be the most effective therapy against these cancers.

Interleukins. Interleukins are natural proteins created by the immune system. Certain tumor cells carry receptors for specific interleukins, which are being investigated for a possible therapeutic role. For example, some drugs combine an interleukin with a drug that is toxic to cancer cells. The interleukin locks onto the receptor on the cancer cell, and the toxic chemical enters the tumor with the intent to kill it. Some interleukins are also being investigated alone for their own tumor-cell killing properties.

Tumor Vaccines. Tumor vaccines are being created, in which tumor cells are removed from the patient and inactivated. When the tumor cells are transferred back to the patient, they are harmless but can elicit a powerful immunologic response against the tumor. Vitespan (Oncophage) is a tumor vaccine that is showing promise against recurrent high-grade glioma, according to preliminary results from early trials presented at the 2007 annual meeting of the American Association of Neurological Surgeons.

Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis). Such drugs, when effective, would starve tumors of vital nutrients and oxygen. Angiogenesis is particularly important in the growth of glioblastomas, the most malignant brain tumors. Of particular promise are drugs that inhibit enzymes called tyrosine kinase, farnesyl protein transferase, and matrix metalloproteinase, which play critical roles in angiogenesis.

Farnesyl Protein Transferase Inhibitors. Farnesyl protein transferase inhibitors, such as tipifarnib, also called R115777 (Zarnestra) and lonafarnib (Sarasar), are drugs in a new class that block a mutated gene called the Ras gene, which is responsible for about 30% of cancers. Lonafarnib is in early trials in combination with temozolomide. Tipifarnib is also currently in early trials and may prove to be effective.

Tyrosine Kinase Inhibitors. Drugs that target growth factor receptors, such as tyrosine kinase, interfere with the pathway leading to angiogenesis. Some tyrosine kinase inhibitors -- including erlotinib (Tarceva), imatinib (Gleevac), gefitinib (Iressa), and others -- are being investigated in early trials for brain tumor treatment. Side effects include rash, diarrhea, nausea and vomiting. Some of these drugs may reduce white blood cell count or cause liver damage. Researchers are trying to identify biomarkers that could help predict which patients would best respond to tyrosine kinase inhibitor therapy.

Matrix metalloproteinase Inhibitors. Matrix metalloproteinase is an important enzyme in angiogenesis. Inhibitors of these enzymes, including marimastat, metastat, and prinomastat, are in early trials. Marimastat has been studied and has shown some benefits in early trials for patients with recurrent glioblastoma and anaplastic gliomas, particularly in combination with temozolomide.

Phophoinositide 3-Kinse (Pi3K) Inhibitors. Rapamycin and its analog (CCI-779) inhibit Pi3K, an enzyme involved in cell growth. Early trials using CCI-779 are underway. (Another rapamycin analog, everolimus, has different effects but is also being studied for its actions in inhibiting cell growth.)

Other Drugs that Block Angiogenesis. Thalidomide was one of the first drugs used to inhibit angiogenesis and has undergone several trials. There is some evidence that it may work more effectively for metastasized brain tumors than primary tumors. Other drugs in early trials with various effects on tumor growth include suramin, cilengitide, semaxanib, PTK787, and atrasentan.

Retinoids. Retinoids are vitamin A derivatives and act as differentiating drugs in cancer treatments. That is, they can convert immature, dividing tumor cells into mature cells, stopping tumor growth. Studies suggest that they have little benefits as single drugs. Combination with radiotherapy and other drugs may hold promise.

Inactivated Viruses. Investigators are finding that certain genetically inactivated viruses, such as the poliovirus or herpes virus, may prove to be valuable fighters of brain cancers. Such viruses can enter cells and destroy them but do not pose any danger for infection. For example, one specially designed herpes virus targets the enzyme thymidine kinase (an enzyme that promotes tumor growth). Some researchers believe that a combination of this virus with retinoids may be effective with few serious side effects. Other viruses are being investigated. A drug based on this model is years away, however.

Immunotoxins. Drugs called immunotoxins use natural toxins to kill malignant brain cells.

Drugs that use diphtheria toxins, including TransMID-107R and DAB(389)EGF), are the first immunotoxins to show some promise. Clinical trials are investigating them for gliomas and metastatic brain cancers. Other toxins under investigation include irofulven (a mushroom toxin) and chlorotoxin (a substance derived from scorpions).

Taurolidine. Taurolidine is a unique drug that prevents tumor formation and growth in animals. An early clinical trial in patients with high-grade gliomas is under way.

Protein-Blocking Drug. Another development is the discovery of a protein called BEHAB (Brain-Enriched Hyaluronan Binding Protein). BEHAB is produced only by invasive glioma tumor cells, not by normal brain tissue or noninvasive tumor cells. Breakdown of BEHAB releases a substance called HABD (hyaluronan-binding domain), which appears to give glioma cells the ability to invade other areas of the brain. Both BEHAB and HABD represent potential targets for new therapies.

Chemotherapy destroys not only cancer cells but also healthy cells, including special blood cells in the bone marrow called stem cells. Stem cells are immature cells from which all blood cells develop. Transplantation procedures using bone marrow or stem cells allow high-dose chemotherapy to be administered while protecting blood cells. The procedures are being tested for patients with recurrent brain tumors, such as medulloblastoma, primitive neuroectodermal tumors, and germ cell tumors. A 2003 study reported long-term survival in some patients who underwent this procedure

Photodynamic therapy uses a special drug (Photofrin) that is absorbed by the tumor and causes the cancer cells to become fluorescent when a laser is directed at them. It is being investigated in trials in combination with other treatments. A 2003 study reported encouraging results, notably in patients with recurring glioblastoma multiforme. In the study, more than half of these patients survived for at least a year.

Treatment of Complications

Some tumors, particularly medulloblastomas, interfere with the flow of cerebrospinal fluid and cause hydrocephalus (accumulation of fluid in the skull). This causes a build-up fluid in the ventricles (the cavities) in the brain. Symptoms include nausea and vomiting, severe headaches, lethargy, difficulty staying awake, seizures, visual impairment, irritability, and tiredness.

The ventricles of the brain are hollow chambers filled with cerebrospinal fluid (CSF), which supports the tissues of the brain.

Corticosteroids (commonly called steroids) such as dexamethasone (Decadron), prednisolone, and prednisone are used to treat hydrocephalus. Side effects include high blood pressure, mood swings, increased risk of infection, stronger appetite, facial swelling, and fluid retention.

Human corticotropin-releasing factor (hCRF), a naturally occurring neurohormone, appears to possess substantial anti-swelling properties and thus has been proposed as an alternative to corticosteroids in brain edema, with potentially fewer side effects. A hCRF drug called Xerecept is currently in clinical trials.

A shunt procedure may be performed to drain fluid. Shunts are flexible tubes used to reroute and drain the fluid.

Seizures are common in brain tumor cases, with younger patients having higher risks than older ones. Anti-epileptic medications, such as carbamazepine or phenobarbital, may treat seizures and are helpful in preventing recurrence. These drugs are not useful in preventing a first seizure, however, and they should not be used routinely to treat patients with newly diagnosed brain tumors. Anti-seizure medications should be used only for patients who are experiencing seizures. Despite these guidelines, a 2005 study in the Journal of the American Medical Association reported that nearly 90% of patients with newly diagnosed malignant glioma are treated with anti-epileptic drugs, although only 32% of the patients actually have seizures. Anti-seizure medications can interact with some of the chemotherapies used to treat brain cancers, including paclitaxel, irinotecan, interferon, and retinoic acid. Patients should discuss these interactions with their doctors.

Antidepressants are very useful for treating the emotional side effects of this disease. However, according to a 2005 Journal of the American Medical Association study, only 8% of patients with malignant gliomas receive antidepressant medication even though over 90% report depressive symptoms. Support groups can also have great benefit for both patients and families.

Resources

www.abta.org -- American Brain Tumor Association
www.cbtf.org -- Children's Brain Tumor Foundation
www.virtualtrials.com -- Musella Foundation for Brain Tumor Research and Information
www.braintumor.org -- National Brain Tumor Foundation
www.neurosurgery.org -- American Association of Neurologic Surgeons
www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.asco.org -- American Society for Clinical Oncology
www.cancer.gov/clinicaltrials -- Find clinical trials
www.radiologyinfo.org -- RadiologyInfo
www.plwc.org -- People Living with CAncer

References

Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006 Nov 20;24(33):5277-82. Epub 2006 Nov 6.

Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11736-41. Epub 2007 Jul 2.

Flint-Richter P, Sadetzki S. Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol. 2007 May;8(5):403-10.

Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F, et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology. 2007 May 22;68(21):1831-6.

Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35.

Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, et al. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 2007 Feb 1;67(3):890-900.

Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA,et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9.

Review Date:
11/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Non-small cell lung cancer

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Research News:

About 3,000 nonsmokers die each year of lung cancer resulting from exposure to secondhand smoke, according to a 2006 Surgeon General report.
Advexin, a genetic therapy that contains the p53 tumor-suppressor gene, is showing promise. A 2006 study in Japan found that out of 13 patients with advanced NSCLC receiving Advexin, 10 had stabilized. Advexin is in Phase II clinical trials for NSCLC.
Studies are finding that NSCLC tumors in people who never smoked have a much higher rate of epithelial growth-factor receptor (EGFR) mutations. EGFR helps new blood vessels grow to feed tumors. This discovery may help tailor future treatments to specific patient populations. It also helps explain why some newer treatments seem effective mostly in patients who never smoked.

Treatment News:

Video-assisted thoracic surgery (VATS) is a new, less-invasive surgical technique that uses a thin tube containing a miniature camera and surgical instruments. Though the procedure is not appropriate in all cases, it offers significant advantages, especially in older or frail patients, in the treatment of early stage non-small cell lung cancer (NSCLC).
Bevacizumab, a monoclonal antibody, was approved in October 2006 as a first-line treatment (in combination with carboplatin and paclitaxel) for inoperable, locally advanced, metastatic, or recurrent non-squamous, non-small cell lung cancer.
Gefitinib (Iressa), a drug that targets EGFR, proved disappointing in final clinical trials. However, erlotinib (Tarceva), a drug that targets a different part of the EGFR molecule, has shown benefits. Erlotinib is now approved as a second-line chemotherapy to treat patients with locally advanced or metastatic NSCLC after a previous course of chemotherapy failed.

Introduction

Although lung cancer accounts for only 13% of all cancers, it is among the most lethal, accounting for over 28% of all cancer deaths. It is more deadly than colon, breast, and prostate cancers combined. An estimated 160,390 people will die from lung cancer in 2007. Death rates have been declining in men over the past decade, and they have now stabilized in women.

The lungs are two spongy organs surrounded by a thin moist membrane called the pleura. Each lung is composed of smooth, shiny lobes: the right lung has three lobes, and the left has two. About 90% of the lung is filled with air; only 10% is solid tissue.

Air is carried from the trachea (the windpipe) into the lung through flexible airways called bronchi.
Like the branches of a tree, the bronchi in turn divide into over a million smaller airways called bronchioles.
The bronchioles lead to grape-like clusters of microscopic sacs called alveoli.
In each adult lung, there are about 300 million of these tiny alveoli. A thin membrane makes up the alveoli sacs. Oxygen and carbon dioxide pass through this membrane to and from capillaries.
Capillaries, the smallest of our blood vessels, carry blood throughout the body.

The major features of the lungs include the bronchi, the bronchioles, and the alveoli. The alveoli are the microscopic blood vessel-lined sacks in which oxygen and carbon dioxide gas are exchanged.

Lung cancer develops when genetic mutations (changes) occur in a normal cell within the lung. As a result, the cell becomes abnormal in shape and behavior, and reproduces endlessly. The abnormal cells form a tumor that, if not surgically removed, invades neighboring blood vessels and lymph nodes and spreads to nearby sites. Eventually, the cancer can spread (metastasize) to locations throughout the body.

The two major categories of lung cancer are small cell lung cancer and non-small cell lung cancer. Most lung cancers are non-small cell cancer, the subject of this report. Less common cancers of the lung are known as carcinoids, cylindromas, and certain sarcomas (cancer in soft tissues).

Some experts believe all primary lung cancers come from a single common malignant (cancerous) stem cell that, as it copies itself, can develop into any one of these cancer types in different individuals.

In addition, cancers in the lung may have spread from other primary sites, such as the breast, thyroid, or colon. In these cases, doctors name the cancer after its original location; for example, "breast cancer with lung metastases."

Non-small cell lung cancers are categorized into three types: squamous cell carcinoma (also called epidermoid carcinoma), adenocarcinoma, and large cell carcinoma. These separate types are grouped together because, in early stages before the cancers have spread, they all can be treated surgically.

Squamous Cell Carcinoma. Squamous cells are formed from reserve cells, which are round cells that replace injured or damaged cells in the lining (the epithelium) of the bronchi, the major airways. Tumors formed from squamous cells are usually found in the center of the lung, either in a major lobe or in one of the main airway branches. They may grow to large sizes and form cavities in the lungs.

Click the icon to see an image of squamous cell carcinoma.

When squamous cell cancer metastasizes, it may travel to the bone, adrenal glands, liver, small intestine, and brain.

Squamous cell carcinoma is nearly always caused by smoking and used to be the most common cancer. It still makes up 25 - 40% of all lung cancers.

Adenocarcinoma. Adenocarcinomas usually arise from the mucus-producing cells in the lung. About two-thirds of adenocarcinomas develop in the outer regions of the lung, while one-third develop in the center of the lung. In 1965, 12% of lung cancers were adenocarcinomas. They are now estimated to account for 30 - 50% of all lung cancers and are the most common lung cancers in many countries. They are also the most common lung cancers in women. In fact, a 2000 European study showed that nearly 34% of the women with lung cancer under investigation had adenocarcinoma, compared to 26.4% who had squamous cell carcinoma, and 22.3% with small cell lung cancer. Adenocarcinoma is also increasing dramatically in men. Until recently, adenocarcinoma was only weakly linked to smoking. Experts now suggest, however, that the dramatic increase in recent decades in this lung cancer type may be due to low-tar, filtered cigarettes. People who smoke them draw tiny particles deeper into the lungs, thereby possibly increasing the risk for adenocarcinoma.

The course of this cancer varies widely. Most often, it develops slowly and causes few or no symptoms until it is far advanced. In some cases, however, it can be extremely aggressive and rapidly fatal. In 50% of cases in which this cancer spreads, it spreads only to the brain. Other common locations it spreads to include the other lung, the liver, the adrenal glands, and bone.

Click the icon to see an image of adenocarcinoma.

Bronchoalveolar Lung Cancer. Bronchoalveolar lung cancer is actually a subtype of adenocarcinoma. It develops as a layer of column-like cells on the lung and spreads through the airways, causing great volumes of sputum. This cancer also is increasing in incidence.

Large Cell Carcinoma. Large cell carcinoma, which makes up about 10 - 20% of lung cancers, includes cancers that cannot be identified under the microscope as squamous cell cancers or adenocarcinomas.

Click the icon to see an image of large cell carcinoma.

Small cell lung cancer may, like squamous cells, be derived from reserve cells or other cells in the epithelium. It causes 15 - 25% of all lung cancers; without chemotherapy, it is very aggressive and usually rapidly fatal. It requires a different treatment approach from non-small cell lung cancer, so it is not discussed in this report.

Click the icon to see an image of small cell carcinoma.

Causes

Cigarette Smoke. Smoking causes 87% of lung cancer deaths, accounting for 30% of all cancer deaths. Cigarettes, nicotine, or both may contribute to lung cancer in one or more of the following ways:

In general, chronic exposure to nicotine may cause an acceleration of coronary artery disease, peptic ulcer disease, reproductive disturbances, esophageal reflux, hypertension, fetal illnesses and death, and delayed wound healing.

The smoke is the most dangerous component of the cigarette. Chemicals formed during smoking trigger genetic mutations that lead to cancer. When people inhale cigarette smoke, they bring into their lungs tar that includes over 4,000 chemicals, some of which are carcinogenic (cancer-causing). Other inhaled chemicals in cigarette smoke that may increase the risk for cancer include cyanide, benzene, formaldehyde, methanol (wood alcohol), acetylene (the fuel used in torches), and ammonia. Smoke also contains nitrogen oxide and carbon monoxide, both of which are harmful gases.
Nicotine itself may be a hazard. A 2000 laboratory study suggested that the human body might be converting inhaled nicotine into a chemical called aminoketone, which has been linked to the formation of tobacco-related lung cancer. A 2001 study reported that nicotine triggered new blood vessel growth, which could, in theory, promote growth of any existing tumors. A study published in 2005 found that nicotine was responsible for disabling a gene that induces the death of cancer cells in lung tumors. Whether or not these studies apply to long-term use of nicotine replacement products (such as patches), or to cigarette smoking, is still unclear. The studies should certainly not discourage people from using nicotine replacement methods for quitting. However, these studies may indicate that people should not use these devices on a long-term basis.

Radon. Radon is a gas produced naturally by the breakdown of uranium. It is often present in the soil and in water and can seep into any dwelling. Radon may be responsible for between 10% and 14% of lung cancer deaths, making it, after smoking, the second leading cause of this cancer.

Other Contributors. Toxic particles leading to precancerous changes in the lung are also found in marijuana. In one study, 53.8% of cigarette smokers, 66.7% of marijuana smokers, and all of those subjects who smoked both substances showed evidence of precancerous changes in the lungs.

There is considerable debate over the lung cancer risk posed by depleted uranium used in military weapons (such as in the Gulf and Balkan conflicts). A 2001 study estimated that it would cause an additional 8 deaths from lung cancer out of every 10,000 people or soldiers who were highly exposed to this substance. The study was based on a mathematical model, however, and the issue is not settled.

Other lung carcinogens include asbestos, arsenic, certain petrochemicals (materials made from crude oil or natural gas), and other airborne (carried through the air) byproducts of various mining and manufacturing processes.

Click the icon to see an image of the tobacco plant.

Genetic mutations that cause cancer generally occur in two types of genes:

Tumor-suppressor genes, which prevent cells from endlessly copying themselves
Proto-oncogenes, which encourage cells to keep making copies of themselves [when a proto-oncogene changes (becomes mutated), it is then called an oncogene]

Damage to either type of gene can cause a mutation that results in an uncontrolled division of cells. This uncontrolled division forms tumors.

It is unlikely that a single specific abnormality causes all lung cancer. It probably takes a variety of mutations to start the devastating chain of events leading to cancer. The following mutations are among those under investigation:

BPDE-caused mutations: The chemical BPDE, a byproduct of tobacco smoke, is involved with a number of genetic mutations, including those to an oncogene called K-ras and to three tumor-suppressor genes known as p53, PPP2R1B, and p16. When normal, the tumor-suppressor genes are involved in cell repair and healthy copying of the cell. When they are damaged or blocked, out of control cell production can occur, leading to cancer. About 10% of the population may carry a gene that protects against lung cancer, by reducing levels of BPDE.
Chemotherapy resistance genes: Tumors that contain the p53 mutation may also be more resistant to chemotherapy.
Rb Mutations: Another important contributor to lung cancer is a genetically defective protein called retinoblastoma (Rb), which is associated with very aggressive tumors. Low levels of the normal Rb gene may sometimes predict aggressive cancer, especially in patients with small cell lung cancer.
Mutations to the FHIT gene: Another potentially important mutation may be an abnormality in the FHIT gene. This mutation causes the cells lining the lung to become more vulnerable to the effects of tobacco smoke and other carcinogens.

Symptoms

Lung cancer is unlikely to produce symptoms until the disease is advanced. When symptoms develop, they may result from the lung tumor itself, from its effects on tissues outside the lung, or from the spread of malignant cells to other organs.

Early symptoms may include the following:

Frequent bouts of pneumonia, or pneumonia that does not clear up in a normal period of time
Coughing (particularly coughing up blood)
Weight loss
Fever
Shortness of breath
Chest pain

Later-stage symptoms include the following:

Shortness of breath: This common symptom is the result of cancer that has spread in the lung and the pleura, the membrane covering the lung.
Superior vena cava syndrome: In some cases, tumor growth or spreading of the cancer presses against the superior vena cava, a large vein that returns blood from the upper part of the body to the heart. When this happens, a condition called superior vena cava syndrome may occur, leading to obvious swelling in the arms and face.
Trouble swallowing: The esophagus is the pipe that takes food from the mouth to the stomach. The cancer may spread to or press against the esophagus, interfering with swallowing and nutrition.
Hoarseness: Cancer can damage the nerves that control the voice box, causing hoarseness.
Pancoast syndrome: Damage to the brachial plexus, a group of nerves branching from the neck, can cause pain, weakness, or numbness in the arm or hand (Pancoast syndrome).
Bronchoalveolar lung cancer may produce very large amounts of mucus.
Hypercalcemia: Some lung cancers produce substances that remove calcium from bone and release it into the bloodstream, causing a condition called hypercalcemia. Patients with this disorder can experience nausea, vomiting, constipation, weakness, and fatigue.

Other lung cancers (usually small cell cancer) cause the body to retain water, lowering the blood's sodium levels. This condition, called hyponatremia, can produce confusion, weakness, and even seizures.

Risk Factors

Before cigarettes became popular in the beginning of the 20th century, lung cancer was rare. In 2007, lung cancer is expected to strike up to 213,380 Americans, and about 160,390 are expected to die from it.The disease usually occurs in people over 50 years old. Men have a significantly greater incidence of lung cancer compared to women. On the encouraging side, the rate of lung cancer in men has been declining significantly over the past decade. While lung cancer rates have been increasing dramatically in women (by 600% from 1950 to 2000), they now appear to be stabilizing.

Smoking appears to be the primary risk factor in 85 - 90% of lung cancers. About 15% of all people who smoke develop lung cancer. The risk depends on the duration of the addiction and the number of pack years. (One pack year equals the number of packs of cigarettes smoked per day, multiplied by the number of years that the person has smoked.) Genetic damage in the lung occurs in nearly all chronic smokers, even if cancer has not developed.

An elevated risk for lung cancer can persist for more than 20 years after quitting smoking, although the risk drops significantly even in the first year after quitting. And, there are benefits to quitting smoking even for people who are well into middle age.


Quitting Age	Percentage
30	2%
40	3%
50	6%
60	10%

Second-Hand Smoke. The Environmental Protection Agency has classified second-hand smoke as a carcinogen (cancer-causing chemical). Exposure to second-hand tobacco smoke increases the risk of lung cancer in the nonsmoker by about 20 - 30%. A 2006 Surgeon General report found that about 3,000 nonsmokers die each year of lung cancer resulting from exposure to secondhand smoke.

There may be some ethnic differences in lung cancer risk. For example, African-Americans face a risk that is two to four times higher than that in Caucasians, regardless of smoking status. It is not clear what factors are responsible for this higher risk. Some African-Americans appear to have a genetic vulnerability to the harmful chemicals in cigarette smoke.

In China, an estimated one third of all young male smokers will eventually die because of tobacco-related illnesses. Their risk for lung cancer, however, is much less than it is for chronic lung disease, the opposite of the Western trend. A 2001 study reported that the lower rate of lung cancer among Chinese people might be due to a slow rate of clearing nicotine, which results in smoking fewer cigarettes.

People with High Exposure to Radon. Studies have shown that radon raises the risk of lung cancer in underground miners by 40%. It is unclear whether the results of these studies would apply to people exposed to radon in their homes One study suggests that people with intense or prolonged exposure to radon in their homes do indeed face the same risk as miners exposed to similar levels of radon. A cumulative long-term exposure to radon and smoking also increases the danger. Most people move an average of 10 or 11 times over their lifetime, so the risk of developing lung cancer through radon exposure is very low in most individuals, even for those who lived for awhile in areas with high radon levels. People with homes that have high radon levels and those who sleep or spend many hours to days in basements with detectable but moderate levels should consider taking protective measures.

Workers Highly Exposed to Carcinogens. An estimated 9,000 - 10,000 men and 900 - 1,900 women develop lung cancer each year because of occupational exposure to carcinogens. More than half of these cases are attributable to past exposure to asbestos, which has long been known to be a risk factor for mesothelioma (cancer of the pleura, the lining around the lung) and can increase the risk of lung cancer in smokers. With better protective measures, these rates are expected to fall in the future.

Other chemicals that put workers at risk for lung cancer include:

Arsenic (insecticide and herbicide sprayers, tanners, oil refinery workers)
Chloromethyl methyl ether (workers exposed to certain polymers, water repellents, or products using chloride and formaldehyde)
Chromium compounds (workers using certain alloys, paints, pigments, and preservatives)
Depleted uranium (soldiers exposed to weapons during battlefield conditions)
Crystalline silica

By contrast, agricultural workers seem to have a lower lung cancer rate, despite their possible occupational exposures to risky chemicals. While this rate has traditionally been attributed to good health habits, including low tobacco use, a 2000 study suggests that agricultural workers' exposure to endotoxin may be responsible. Endotoxin is a component of common bacteria found in soil and animals and may have cancer-preventing effects on the immune system.

Exposure to Smoke from Grills. Grilling and high-heat frying emit chemicals called heterocyclic amines, which are known to be carcinogenic. A 2000 study of Chinese women found that smokers who stir-fried meat daily and inhaled cooking fumes had a higher risk of lung cancer than did those who stir-fried meat less frequently. No higher risk was found among nonsmokers.

Air Pollution. Although any risk from air pollution is very small, it nevertheless may be a contributor to those lung cancers not obviously related to smoking. Some studies, including a major analysis of vital statistics in 2002, have found an association between increased risk for lung cancer and long-term exposure to very small particulates, especially sulfates, present in polluted air. The risk, if any, is very small.

A family history of lung cancer may play a role in increasing susceptibility to this disease. In one study, people who had parents or siblings with respiratory tract cancers had a 30% higher risk for lung cancer, compared to people without a family history. Women with mothers or sisters with lung cancer had triple the risk. A higher risk occurred in both smokers and nonsmokers. There was no association between a history of other cancers and lung cancer. Both genetic factors and secondhand smoke appeared to contribute to the danger in these individuals.

Smokers with emphysema or chronic inflammatory lung diseases, such as asthma, are at increased risk for lung cancer. Both smokers and nonsmokers whose lungs are scarred from recurrent lung diseases, such as pneumonia or tuberculosis, are also at increased risk, particularly for bronchoalveolar lung cancer.

Lifestyle Changes

Quitting improves lung function almost immediately. Some evidence suggests that the benefits for the lungs are even more significant for women who quit than for men. It should be noted, however, that it can take 20 years or longer, particularly in heavy smokers, for the lungs to be restored to a fully healthy condition in which the risk for lung cancer is as low as for nonsmokers. Quitting is extremely difficult. No one should be discouraged if they relapse. Everyone should keep trying to quit. With continued efforts, many people succeed.

The many methods of quitting smoking include counseling and support groups, nicotine patches, gums and sprays, and incremental reduction.

At this time perhaps the most effective method for quitting is a combination of the following:

Nicotine replacement products that reduce withdrawal symptoms and cravings.
The antidepressants bupropion (Zyban) or nortriptyline (Pamelor, Aventyl), which reduce emotional effects and cravings associated with withdrawal, and improve abstinence rates.
Professional counseling or support organizations that may be effective, in addition to the medication, in helping people maintain abstinence.

[See In-Depth Report #41: Smoking.]

While people are in the process of quitting (and afterwards), they should maintain as healthy a lifestyle as possible.

Phytochemicals. Some data suggest that diets rich in fresh fruits and vegetables may be protective against lung cancer in both smokers and non-smokers. Some studies have reported protection from specific plant chemicals (phytochemicals), such as the following:

Isothiocyanates. These chemicals are found in cruciferous vegetables (broccoli, cauliflower, and Brussels sprouts). They may help block the effects of carcinogens in smoke, suppress tumor growth, and inhibit growth-promoting steroid hormones.
Flavonoids. Major sources are apples, grapefruit, onions, red wine, and tea. In one study on flavonoids, apple eaters had the lowest cancer risk, 68% less than those who ate fruit infrequently. In another, those who ate relatively more onions, apples, and white grapefruit had less than half the lung cancer risk as people who ate relatively small amounts of these foods. Flavonoids are also found in soybeans, berries, broccoli, carrots, citrus fruits, eggplant, peppers, squash, and tomatoes. Specific flavonoids in dark chocolate may be protective against lung cancer (but not other cancers).
Lycopene. Lycopene is found in tomatoes, which have been associated with a lower risk for lung cancer. Cooking the tomatoes appears to increase the potency of lycopene.
Cryptoxanthin. Some studies suggest that eating foods rich in cryptoxanthin, a yellow-orange pigment, reduces the risk for lung cancer. Foods with high amounts of cryptoxanthin include pumpkin, corn, papaya, red bell peppers, tangerines, oranges, and peaches. More research is needed in this area, however.
Isoflavones. Isoflavones, found in soy beans and flax seed, behave like estrogen in some ways and not in others. Some evidence suggests the genistein (a type of isoflavone) in soy may have properties that are protective against lung cancer.

Click the icon to see an image of phytochemicals.

Note: Studies on these chemicals are not consistent. It is unlikely that individual phytochemicals offer protection, but rather that the benefits come from a collection of vitamins and plant chemicals contained in fruits and vegetables. Fruit, especially, appears to be protective.

Fats and Oils. Some studies have indicated that diets high in animal fats increase the risk for lung cancer. Others have suggested some protection from cod liver oil, which contains omega-3 fatty acids (found in fatty fish), omega-6 fatty acids (found in flax and in soybean and canola oils), and monounsaturated oils (found in olive and canola oils). Of interest was a 2002 study reporting that women who had a high intake of cheese had a lower risk of lung cancer. Despite these intriguing pieces of information, the ability of these substances to protect against lung cancer remains controversial, and discontinuation of smoking remains the best advice.

Click the icon to see an image of fats and oils.

Vitamin Supplements. Even with a healthful diet, smoking reduces the levels of a number of vitamins, importantly vitamin C. There is no evidence, however, to support any protection from antioxidant supplements, including vitamins E, A, or beta carotene.

In fact, evidence is now suggesting that high doses of vitamin C, vitamin E, and beta carotene supplements may have harmful effects. A 2000 study, for example, reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E. The strongest studies to date on negative effects of antioxidant supplements have reported an increase in lung cancer and overall mortality rates among smokers who took beta carotene supplements. In determining reasons for this disturbing effect, one animal study suggested that beta carotene increased enzymes in the lungs that actually promote cancerous changes. In other words, antioxidants may actually be harmful in people who already harbor cancer cells. This is particularly important information for smokers, who may carry precancerous or cancerous cells for years prior to developing the disease. The best way of achieving healthy levels of important nutrients is from healthy foods.

Click the icon to see the benefits of vitamin A.

Click the icon to see dietary sources of vitamin A.

Trace Element Supplements. Trace elements may be important in cancer risk and prevention.

Selenium appears to inhibit cell production and may have other anti-cancer properties. A few studies have reported some protection with selenium. However, a major 2002 analysis supports previous work, indicating that taking selenium helps only people who are deficient to begin with.

Click the icon to see the benefits of selenium.

Zinc may prove to be more important than selenium. Some research suggests that zinc may help protect smokers by blocking cadmium. Smokers have higher levels of cadmium in their body, and there may be a link between cadmium and a higher risk for lung cancer. Some laboratory studies have indicated that zinc might help protect against tumor progression. There is no evidence that taking zinc supplements will reduce the risk for lung cancer, however.

A 2003 study reported a lower risk in lung cancer in men and women who were physically active. Both moderate and intensive exercises were associated with protection.

People concerned about radon in their home or area can purchase a test approved by the Environmental Protection Agency. Methods for removing radon include installing a soil suction system. It should be noted, however, that home prevention measures rarely reduce radon levels to zero. Simply sleeping by an open window reduces the risk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors (coxibs) both block cyclooxygenase (COX) enzymes. NSAIDs block COX-1 and 2, and coxibs selectively block COX-2. Evidence now strongly suggests that the COX-2 enzyme plays a role in blood vessel growth (angiogenesis) that can feed lung cancers.

NSAIDs. NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn, Naprelan, Anaprox). These agents inhibit COX-2, but they also target another COX enzyme. Studies are now reporting an association between regular use of aspirin or other NSAIDs and a reduced risk for non-small cell lung cancer.

COX-2 Inhibitors. The COX-2 inhibitors are more recent forms of NSAIDs. Currently, only celecoxib (Celebrex) is still on the market. Rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market due to their high risk of causing strokes and heart attacks. Because they target the COX-2 enzyme specifically, researchers are focusing on these drugs for a possible role in treating lung cancer and preventing recurrence.

Diagnostic Tests

Chest X-Rays. In a small percentage of cases, a routine chest x-ray reveals the first signs of lung cancer. Usually, however, symptoms of existing lung cancer, such as coughing, chest pain, and blood in the sputum, will lead to a chest x-ray. If non-small cell lung cancer is present, chest x-rays may show lesions (damaged or abnormal tissue) in the center of the lung, cavities formed by squamous cell carcinoma, or lace-like pattern of cells spreading through the lungs. By the time lung cancer is diagnosed by chest x-rays, however, it has often spread so far that it cannot be surgically cured. Four major studies found no survival benefits in early detection from chest x-rays and sputum screening. Regular screening for lung cancer using x-rays is therefore not currently recommended.

Computed Tomography. Computed tomography (CT), particularly the specific technique called low-dose spiral (or helical) CT, is more effective than x-rays for detecting cancer in patients with suspected lung cancer. It is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Surgeons also use CT scans to evaluate patients before lung surgery.

CT stands for computerized tomography. In this procedure, a thin x-ray beam is rotated around the area of the body to be visualized. Using very complicated mathematical processes called algorithms, the computer is able to generate a 3-D image of a section through the body. CT scans are very detailed.

The use of helical CT for early screening is still controversial. Studies of CT scans in smokers suggest that early screening will detect about 2% of lung cancers, most of these in early stages. In the studies, 62 - 82% of the patients with stage 1A cancer (when the tumor has not spread yet) were still alive at 5 years. Neither study, however, was controlled (compared with other groups, such as non-smokers). The survival figures were likely to be higher than in actual practice.

Click the icon to see an image of a CT scan of the chest.

Evidence regarding the survival benefits of early detection is not clear. Many experts are highly opposed to widespread screening for lung cancer. Some evidence, for example, suggests that lung cancer cells in non-small cell lung cancer are often very aggressive at microscopic levels (before a tumor is formed). If this were true, the cancer would be highly likely to have already spread, long before it was visible with CT scans. Moreover, some studies have found no association between tumor size at the time of diagnosis and survival times. On the other hand, some suspicious areas detected by CT scans may actually be innocent, and these patients might be more likely to die from aggressive treatments than from the disorder itself.

It should also be noted that about 98% of suspicious areas seen on CT scans turn out to be benign. Even after rescreening, many scans will show suspicious areas that turn out to be harmless but will require invasive and expensive biopsies. Additional experience with CT scans, however, may allow experts to better determine which abnormalities are likely to be benign.

High-risk individuals who are still interested in early screening with CT scans should ask their doctor about available clinical trials.

Computed tomography is the standard imaging procedure for determining if and where the cancer has spread (metastasized). Other imaging tests, however, may be useful for staging and tracking lung cancers (staging means finding out how advanced the cancer is).

Positron Emission Tomography. Positron emission tomography (PET), specifically a technique known as FDG/PET, is the most accurate noninvasive test for detecting early lung cancer. It is also the best imaging technique for staging lung cancers, not only those located in the lungs, but also those that have spread, particularly into the space between the two lungs (the mediastinum). With this imaging test, the patient is first injected with a specially formulated liquid sugar (called FDG), and then viewed with a machine that records energy given off by tumor cells.

PET is expensive and not widely available. However, its supporters suggest that it may prevent many unnecessary surgeries by identifying patients whose cancer has advanced past the stage at which surgery is helpful. There is some evidence that FDG/PET scan can detect a metabolic (processing) response to treatments that may help predict the outlook for the patient.

Scintigraphy. Scintigraphy is an imaging procedure in which patients are administered low-level radioactive agents that bind to cancer cells, which then can be tracked by special cameras to reveal the cancer cells' location and intensity. Agents selected are those that can best bind successfully with specific tumor types. For example, a 2001 study of the binding agent 111In-DOTA-LAN demonstrated excellent results in identifying non-small cell lung tumors. This study further suggests the possibility of using such highly-targeted binding agents as lung cancer treatments.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI), an imaging procedure that uses radio wave energy, is frequently used instead of CT scanning to locate brain and bone metastases that can be associated with lung cancer.

Biopsies of lung tissue are needed to confirm lung cancer. This requires invasive procedures that may vary from simple needle aspiration to chest surgery.

Needle Aspiration. Sometimes, a biopsy specimen is obtained by inserting a needle between the ribs, and then guiding it with the use of computed tomography scans, ultrasound, or fluoroscopy (a device allowing an x-ray view). Specific techniques include transbronchial or transthoracic needle aspiration (TBNA or TTNA) or endoscopic ultrasound-guided needle aspiration (EUS-NA). Their use depends on how much of the area can be observed with less invasive imaging methods. There is a 5 -10% risk for bleeding or collapsed lung with needle aspiration.

Thoracoscopy. Thoracoscopy is usually very effective for diagnosing cancer in the outer areas of the lungs, or those involving the pleura (membrane surrounding the lungs). This is a surgical procedure that uses a fiber-optic tube to view the area:

The procedure requires general anesthesia.
The surgeon passes surgical instruments and a fiber-optic tube through a small incision in the chest. The tube has a camera in it, which allows the surgeon to look at the lungs on a video screen.

Bronchoscopy. To locate cancer that develops in the central areas and major airways of the lung (usually squamous or small cell cancer), bronchoscopy is typically performed. The procedure is done as follows:

The patient is given a local anesthetic, supplementary oxygen, and sedatives.
The doctor inserts a bronchoscope, a hollow flexible tube often containing a fiber-optic light source, into the lower respiratory tract through the nose or mouth.
The tube acts like a telescope into the body, allowing the doctor to see the windpipe and major airways. In a procedure called fluorescence bronchoscopy, the doctor injects the patient with a drug that makes cancer tissue appear red when exposed to laser light from the bronchoscope.
The surgeon removes specimens for biopsy, ideally combining techniques to include cutting tissue, brushings, and a washing process called bronchoalveolar lavage (BAL). BAL involves injecting saline through the bronchoscope into the lung and then immediately suctioning the fluid back through the hollow tube of the bronchoscope; the fluid is then analyzed in the laboratory. Both brushing and washing procedures may be very valuable additions.

Advances in this procedure, such as laser-induced fluorescence endoscopic bronchoscopy, may improve early detection of cancer.

Bronchoscopy is usually very safe, but complications can occur; they include allergic reactions to the sedatives or anesthetics, asthma attacks in susceptible patients, and bleeding. Fever may follow the procedure.

Click the icon to see an image of bronchoscopy procedure.

Click the icon to see an image of a bronchoscope.

Mediastinoscopy. Mediastinoscopy uses a tube inserted between the lungs to locate the appropriate areas for biopsy. It is performed if the physician suspects that cancer has spread to nearby lymph nodes but has not yet metastasized.

Sputum Analysis for Presence of Cancer Cells. Some experts are now recommending an analysis of coughed-up sputum as a useful and cost-effective measure for identifying cancer cells, particularly those located in central areas of the lung. However, although sputum analysis appears to be as accurate as any other screening test currently conducted, it may miss cancers such as adenocarcinoma, which form in mucus-producing cells typically in the outer portion of the lungs. If a sputum analysis does not show cancer cells, but other signs of lung cancer are present, including blood in the sputum and suspicious areas on x-rays, other tests are performed.

Biomarkers. Biologic markers, called biomarkers, are high levels of substances that are released by tumors and indicate the presence of specific cancers. Biomarkers can be found in sputum, blood, and tissue samples. They can include enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some biomarkers may prove to reveal the presence of cancer cells before they are evident on CT scans or other imaging tests. For example, genetic mutations, notably K-ras and p53, can now be detected in cells found in sputum, or cells taken during bronchoscopy. Such mutations occur only with cancerous changes and may enable early detection. Other markers that prove to be important for predicting aggressive cancers are high levels of matrix metalloproteinase (MMP9) and vascular endothelial growth factor (VEGF), which are compounds involved with angiogenesis (the process in which blood vessels serving the tumor develop).

As part of the doctor's initial examination, patients may have a pulmonary function test to evaluate lung health and capacity. In addition, since the heart and lungs are often involved in complications following lung cancer surgery, the doctor may be especially interested in taking a complete history of those systems in patients who might need surgery.

Staging Systems

Tests to Determine Cancer Stage. After diagnosing non-small cell lung cancer, the doctor makes treatment choices by determining the cancer's stage (how large the tumor is and how far the cancer has spread). To stage the cancer and determine other aspects of the disease, a number of tests are conducted:

The cancer cells are examined microscopically for size, shape, and other configurations.
Computer tomography (CT), magnetic resonance imaging (MRI), or both, are used to scan the lung and perhaps other locations, such as the liver, upper abdomen, and brain, to determine the extent of the disease.

Physical Examination. A detailed physical examination of the whole body is very important to identify or rule out the spread of cancer to other areas, and to determine the general condition of the patient. For example, questions about dizziness or headaches can help the doctor determine if the cancer has spread to the brain, while bone or joint pain might suggest that the cancer has spread to the bone. The doctor will also look for head and neck symptoms that might reveal the presence of other tumors. Also, according to a 2000 review, the patient's weight loss and ability to function are two very important factors for predicting survival following treatment. Patients who are mobile and have lost less than 10% of their pre-treatment weight tend to have better survival rates.

In lung cancer, the stage of the disease at the time of diagnosis is a major factor in determining how to treat the cancer, and how long the patient can expect to live. In general, survival is longest for patients with very early-stage disease and shortest for patients with very advanced disease that has spread to several regions of the body. Staging is based on the results of physical and surgical examinations, and laboratory and imaging tests, including biopsies.

To determine the stage, medical professionals first categorize each tumor by size and by how far it has extended. This identification method is called the TNM system.

The TNM categories then determine the stage (numbered 0 to IV), indicating how advanced the cancer is.

TNM stands for Tumor, regional lymph Nodes, and Metastasis (cancer spread beyond the original tumor).

T refers to the size and extension of the tumor itself. In TX and T0, the tumor is indicated by cancer cells in sputum or lung samples but cannot be seen. Tis: Carcinoma in situ. The cells are cancerous, but the tumor does not show evidence of spreading. In T1, the tumor is 3 cm or less in size, is still contained in the lung or the membrane covering the lung, and has not reached the main airway.

In T2, the tumor has one or more of the following features:

It is greater than 3 cm
It involves the main airway
It is 2 cm or more away from the ridge (the carina) at the lowest part of the windpipe
It has invaded the pleura
It is associated with collapsed lung tissue (atelectasis) or swelling that blocks part (but not all) of the lung

In T3, a tumor of any size has directly invaded any of the following:

Chest wall
Diaphragm
The membrane covering organs and structures in the chest
The outer wall of the membrane around the heart (pericardium)

In addition, one or more of the following conditions are present:

The tumor is in the main airway, less than 2 cm away from the carina, but is not in the trachea (windpipe).
The tumor is associated with a collapsed lung or swelling that blocks the entire lung.

In T4, the tumor has invaded any of the following:

The area between the lungs (mediastinum)
The heart
The great vessels (the blood vessels that carry blood from the heart)
Carina, trachea, or esophagus
Main portion of the spine

In addition, one or both of the following occurs: separate tumors are present in the same lobe; the tumor is accompanied by an increased amount of fluid between the pleural membrane and the lung.

N followed by a number from 0 to 3 refers to whether the cancer has reached regional (in the area of tumor) lymph nodes. In stage N0, the regional lymph nodes are still cancer-free.

In N1, the cancer has spread to the nearest lymph nodes around the airways, to the hilum (a central zone in the lung where blood and lymph vessels enter), or both. The tumor has extended directly into lymph nodes within the lung. In N2, the cancer has spread to lymph nodes in the middle of the chest that are still next to the affected lung, to the nodes below the carina, or to both regions.

In N3 the cancer has spread to lymph nodes in the middle of the chest that are next to the opposite lung, to the hilum in the opposite lung, to lymph nodes in nearby or opposite muscle tissue, or to lymph nodes above the collar bone.

M Stages refer to metastasis. In M0, metastasis has not occurred.

In M1 distant metastasis has occurred. This includes the presence of a separate tumor in a different lobe.

Staging factors are used to help determine treatment and outlook. The following suggest a more aggressive disease:

The presence of respiratory symptoms
A tumor larger than 3 cm
High numbers of blood vessels in the tumor

Researchers are always looking for more accurate ways to determine a treatment and outlook for lung cancer. For example, some research involves specific biomarkers and related blood vessel development within tumors. These markers might eventually help determine how aggressive a cancer is likely to be, and what the best treatment approach is.

If the cancer is still localized, surgery can produce 5-year survival rates of up to 75% in stage I patients and up to 50% in stage II patients. Unfortunately, very few patients are diagnosed at such early stages. In locally advanced stages, the standard treatment is concurrent radiation and chemotherapy. However, even with this approach average survival times are less than 2 years. Even if an initial tumor has been surgically removed or irradiated, cancer recurrence rates are very high. The risk for recurrence is lower in smokers who quit after treatment.

On an encouraging note, advances in therapies for later stage lung cancer are now offering some hope for improving survival. Still at this time, the mortality rate for lung cancer is still extremely high, and reports of improved response or survival rates using drugs or combinations of therapies do not mean cures. Ultimately, the patient must weigh a diminished quality of life using aggressive treatments against a chance for a modestly prolonged life.

Surgical Procedures

Surgery is performed in the following circumstances:

The surgical removal of an entire lobe or parts of a lung is the primary treatment for eligible patients in early stages of cancer. Recurrence is high after surgery, although the new tumor is often operable.
Some patients with stage IIIA cancer may also benefit from surgery. The intent at this stage is to extend survival time, rather than cure the disease.
Surgery is not out of the question in rare cases of metastasis when the cancer appears in a single operable location, such as the brain.

Unfortunately, lung surgery may be too risky for patients with other lung diseases or serious medical conditions, and because lung cancers tend to occur in smokers over 50, such health problems are likely to be present. Long-term survival rates appear to be better in patients treated at hospitals that perform large numbers of lung cancer surgeries, and when surgeries are performed by thoracic surgeons, who specialize in chest procedures.

The type of surgery depends on the amount of lung or other tissue that needs to be removed.

Wedge Resection or Segmentectomy. Wedge resection and segmentectomy remove only a small part of the lung; consequently, they preserve almost normal breathing function after the operation.

Lobectomy. Removal of one of the lobes of the lung is called lobectomy. The patient's lung function must be adequate before undergoing this procedure. The operation carries an overall mortality rate of 3 - 5%, with older patients having the highest risk.

Click the icon to see an illustrated series detailing surgery to remove diseased lobes of the lung.

Pneumonectomy. Pneumonectomy removes the entire lung. The procedure itself carries a mortality rate of 5 - 8%, with the oldest patients having the greatest risk. In such patients, recurrence almost always occurs.

Surgical advances are allowing a wider range of options, including minimal surgeries for early cancers and surgeries that relieve cancer symptoms in late stages of the disease.

Thoracoscopy. Thoracoscopy, also known as video-assisted thoracic surgery (VATS), is a less-invasive technique that employs a thin tube containing a miniature camera and surgical instruments. It requires much smaller incisions than open surgery and speeds recovery to the point that patients are up within hours. Though the procedure is not appropriate in all cases, it offers significant advantages, especially in older or frail patients. The death and complication rates following VATS are lower than those following conventional surgeries. Pain is reduced, and patients are released from the hospital quicker. Several studies found that the 5-year survival and recurrence rates in patients with stage I NSCLC treated with VATS were comparable to those in patients treated with traditional open chest surgeries.

Laser Surgery. Laser surgeries allow removal of minimal amounts of lung tissue and are proving useful for improving symptoms in stage II and IIIA patients. They may also be beneficial in treating cancers that have spread to the throat, obstructing it.

Photodynamic Therapy. Photodynamic therapy uses bronchoscopy and special laser light beams combined with a light-sensitive drug, called porfimer sodium (Photofrin), to kill cancer cells. The most common side effect is sun sensitivity. Serious side effects include bleeding in the lungs. Photodynamic therapy may be considered for patients in early-stage disease who are not candidates for other surgical procedures. It may also be used to reduce symptoms in late-stage disease.

Cryosurgery. Cryosurgery uses a probe chilled to below freezing to destroy the tumor cells on contact and is being investigated in combination with radiation therapy. It may also be an alternative in early stage cancer for patients who cannot have surgery.

Electric Cauterization. Electric cauterization, the use of electricity to produce heat that destroys tissue, is also under investigation as a treatment for early-stage disease.

Back Surgery. Spinal cord compression is a common cause of pain in patients with advanced lung cancer. Because such patients can live for a year or longer, some research indicates that back surgery followed by radiation therapy can significantly improve the quality of life for many of these patients.

Radiation Treatments

In addition to surgery, radiation is the other primary treatment for early-stage lung cancer. Doctors are also studying the benefits of radiation treatment in advanced lung cancer.

Radical Radiation in Early-Stage Cancer. Radical radiation is used as the sole procedure in stage I and some stage II patients who have adequate lung function but, for medical or other reasons, cannot be treated with surgery. In these cases, the 5-year survival rate is about 20%, and the cancer is likely to recur. Survival rates may be higher or lower, depending on the tumor size. In general, treatment with radiation therapy alone shows less benefit with larger tumors. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. Nevertheless, a recent study confirmed earlier results that show that radiation therapy by itself is as effective as surgery in patients who are unable or unwilling to have surgery for early stage non-small cell lung cancer.

Combined Treatments for Improving Survival in Advanced Cancer. Radiation is also being investigated in various combinations with chemotherapy, surgery, or both. At this time, concurrent radiation treatment plus platinum-based chemotherapy may extend survival times in advanced lung cancer. Other combinations are showing promise.

Palliative Radiation. Doctors use palliative radiation to shrink tumors and reduce pain and symptoms. Palliative radiation is appropriate for patients with advanced disease and poor lung functions, or in those with metastasized cancer. In up to 85% of patients with advanced disease, palliative radiation therapy helps relieve pain, shortness of breath, the superior vena cava syndrome, coughing up blood, and symptoms caused by brain metastases. Radiation, in these cases, is not generally used with the intention of reducing mortality rates, although it may increase survival in some patients, such as those with excellent lung function whose tumors are small.

Delaying radiation therapy until symptoms develop does not appear to reduce survival times or impair quality of life compared to starting it right away, in patients with minimal or no symptoms.

Radiation Therapy in Metastasis to the Brain. Radiation is the primary treatment when cancer has spread to the brain unless the cancer is small enough to be treated surgically. When radiation is used, a technique called stereotactic radiosurgery may be used to deliver powerful, highly targeted radiation to specific areas in the brain. Some trials are investigating using radiation to the head to prevent metastasis to the brain.

The goal of radiation treatment is to administer doses as high as possible to kill as many cancer cells as possible, without destroying surrounding healthy tissues or causing a dangerous reaction. Doctors may try different procedures for the same patient. The exact radiation procedure depends on the site of the cancer or how far it has spread:

External-Beam Radiation. External-beam radiation therapy focuses a beam of radiation directly on the tumor. It is generally used for metastasized cancer.
Brachytherapy. Brachytherapy involved the implantation of radioactive seeds through thin tubes directly into the cancer sites. Brachytherapy may be used for lung cancers that have spread to the throat and caused obstruction. High-dose-rate brachytherapy may also have some value for patients with inoperable tumors in the central region of the lung.

Hyperfractionated radiotherapy gives smaller than standard doses a number of times a day (usually two or three). This allows doctors to use a higher cumulative dose over the whole course of treatment. It is not as useful as therapy by itself, but should be combined with chemotherapy to have any survival benefits.

Hyperfractionated Accelerated Radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART) administers multiple doses per day but uses standard doses. This allows the total dose of radiation to be administered over a shorter time period than the standard 6 weeks. CHART is proving to extend survival rates of patients with localized cancer over that of standard radiotherapy or non-accelerated hyperfractionated radiation. It can cause severe swallowing problems. A modification in which treatment is suspended for 2 days out of 7 may help reduce this effect.

Three-dimensional (3-D) conformal radiotherapy delivers external-beam radiation designed to closely match the specific targeted organs or tissues. This allows significantly higher doses to attack the cancer while reducing the risk to healthy cells. In a 2003 report, 3-year survival rates in stage IIIA patients were nearly 60%, and nearly half the patients experienced no side effects.

Stereotactic body radiotherapy, an advance on conformal radiation, uses a body frame and an abdominal press to immobilize the patient's body and limit breath movement. This allows a more accurate delivery of high-energy radiation. The technique is still investigational.

Radiation can have significant side effects when used as part of intensive treatments, such as hyperfractionated radiotherapy or radiotherapy in combination with chemotherapy. Among the most serious problems is severe inflammation in the esophagus (esophagitis) or the lungs (pneumonitis). Infection is also a danger.

The use of targeted approaches, such as conformal radiotherapy, may help reduce these complications. Investigators are also studying drugs, notably amifostine, which appear to help reduce throat and lung inflammation caused by radiation, without reducing its cancer-fighting effects.

Treatment Options by Stages

In the occult stage (TX, N0, M0), cancer cells are found in a sample of a patient's coughed-up sputum, but no cancer cells have yet been detected in the lung.

Treatment Options. Surgical removal of the tumor, if one can be located, allows identification of its stage and often results in cure.

Stage 0 or carcinoma in situ (Tis, N0, M0) are noninvasive cancers and only a few layers of cancer cells are detected within one local area. The cancer has not grown through to the top lining in the lung and can be surgically removed. There is a high risk for development of a second tumor, however.

Treatment Options:

Surgery, often a limited procedure, where only part of a lobe is removed from the lung.
In patients who cannot be treated surgically, consider photodynamic therapy, cryotherapy, or brachytherapy.

In stage I, the cancer has reached higher layers of the lung but has not spread into the lymph nodes or beyond the lung.

General Treatment Options. The primary treatment is surgery, such as lobectomy (removal of a whole lobe), if possible. Patients with poor lung function should undergo partial lobectomy, if possible. Radiation treatments may be appropriate and beneficial for patients who cannot have surgery. It is not clear if early-stage lung cancer patients, who have radiation or chemotherapy in addition to surgery, have higher survival rates. A 2002 analysis suggested that the use of radiotherapy after surgery in patients whose tumors had been completely removed might be associated with reduced survival rates. An analysis of studies using chemotherapy in addition to surgery or radiotherapy, however, indicated benefits in survival. The overall 5-year survival rates for early stage-cancer are in the range of 30 - 50%. Patients should consider clinical trials for prevention of recurring (returning) cancer after the initial treatment. The risk for recurrence is highest in patients who continue to smoke.

Stage IA (T1, N0, M0). The 5-year survival rates for stage IA patients after successful treatment can be as high as 80%. Treatment options are:
- Lobectomy or sometimes pneumonectomy (removal of one lung)
- Wedge or segment removal, particularly in patients with poor lung function who cannot withstand lobectomy
- Radiation in selected patients whose condition is inoperable (for example, frail patients with T1 tumors); 5-year survival rates can be equal to those with surgery, between 32 - 60%
- Clinical trials of adjuvant chemotherapy following surgery

Stage 1B (T2, N0, M0). Stage IB survival rates after treatment can be better than 60%. Treatment options are:
- Lobectomy or sometimes pneumonectomy; wedge or segment removal, particularly patients with poor lung function
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before surgery (induction therapy; studies are promising)
- Clinical trials for radiation treatments in selected patients whose condition is inoperable
- Clinical trials of chemotherapy before, after, or during radiation treatments

In stage II the cancer cells have spread to nearby lymph nodes.

General Treatment Options. Surgery, usually removal of a lobe (lobectomy) or one lung (pneumonectomy), is the treatment of choice. Five-year survival rates associated with stage II surgery can vary. A 2000 review of existing research places the numbers as high as 40 - 50%, but notes that they can drop to 25% and below if the cancer has spread beyond the immediate lymph nodes.

Patients whose cancer is inoperable may consider radiation treatments. In patients who can complete treatment, 5-year survival rates average 20 - 30%, with higher rates for stage IIA. Patients should consider clinical trials for prevention of recurring cancer after primary treatment. To date, however, supplementing surgical treatment with radiation or chemotherapy does not appear to prolong survival rates.

Stage IIA (T1, N1, M0). Survival rates can be as high as 60%. Treatment options are:
- Surgery
- Radiation
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before, after, or during radiation treatments
- Clinical trials of chemotherapy to reduce tumor size before surgery (induction therapy)
Stage IIB (T2, N1, M0) or (T3, N0, M0). Survival rates can be over 40%. Treatment options are:
- Surgery
- Radiation
- Clinical trials of chemotherapy following surgery
- Clinical trials of chemotherapy before surgery (induction therapy)
- Clinical trials of chemotherapy before, after, or given at the same time as radiation treatments

In stage III, the cancer cells have spread beyond the lung to the chest wall, diaphragm, or further lymph nodes, such as those in the neck.

General Treatment Options. Generally, the treatment of choice for stage III tumors is radiation and sometimes surgery, chemotherapy, or combinations of all three.

Combination approaches may be significantly more effective than single treatments. For example, of particular interest is a treatment approach that starts with chemotherapy and radiation, given at the same time, followed by surgery. In one study, 5-year survival in stage III patients treated this way was nearly 50%.

Stage IIIA (T1, N2, M0) or (T2, N2, M0) or (T3, N1, M0) or (T3, N2, M0).
- Surgery, if the tumor and affected lymph nodes can be completely removed. Consider platinum-based chemotherapy or radiation therapy after surgery.
- Radiation treatment plus platinum-based chemotherapy, given at the same time, is an option for those in otherwise good health. This regimen should be followed by surgery, if possible.
- Consider clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation.
- Consider other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs.
Stage IIIB (Any T, N3, M0) or (T4, Any N, M0). Some patients may consider surgery if there is no lymph node involvement (T4, N0), and tumor can be removed. Surgery is not an option for other patients with stage IIIB cancer. Treatment options are:
- Radiation alone, usually for symptom control; it may improve survival in certain patients, such as those with lymph node involvement above the collar bone
- Chemotherapy alone
- Concurrent (given at the same time) cisplatin-based chemotherapy plus radiation, sometimes followed by surgery if possible
- Clinical trials using induction chemotherapy alone to shrink tumors, which may then be treated with surgery or radiation
- Clinical trials using advanced radiation techniques, including continuous hyperfractionated accelerated radiation, or 3-D conformal radiation
- Other clinical trials, including those of various combination treatments, preventive radiation therapy to the brain, and new second-line drugs

In stage IV (any T, any N, M1), the cancer has spread (metastasized) to other parts of the body.

Treatment Options are:

Combination of two- or three-drug chemotherapies that include platinum-based drugs and newer agents; the best patient candidates are those in otherwise good health, who have a limited number of distant metastasized sites. Chemotherapy is not recommended for patients who are too ill
External-beam radiation for symptom relief
Paclitaxel or gemcitabine as a single medication
Other clinical trials
If metastasized cancer involves only one or two areas in the brain, it may respond to surgery followed by radiation to the brain

Recurring or additional new tumors occur, usually in the lung again, in half of treated patients. Research shows that a single tumor in the lung is more often a new tumor that, in many cases, may be operable.

Treatment Options are:

Radiation for symptom control
Chemotherapy with or without bevacisumab (Avastin)
If the cancer spread to only one site in the brain, it may respond to surgery, followed by whole-brain radiation. Extended disease-free survival is possible. If the brain tumor is not operable, it is treated with radiation. Even if cancer returns in the brain (in 50% of cases), treating it again is possible in many patients, if the disease has not spread elsewhere
Laser therapy or interstitial radiation for tumors inside the airways
Stereotactic radiosurgery (in a few selected patients)

Chemotherapy Treatments

Chemotherapy is the use of drugs given by mouth or by injection to destroy cancer cells that may have spread beyond the tumor. Until recently, there has been some doubt about the effectiveness of chemotherapy for lung cancer. A major 2002 analysis of 52 trials supported its use, particularly with platinum-based regimens, and with the use of supportive care.

Chemotherapy in early stages: Chemotherapy is proving to be beneficial in many patients as an additional (adjuvant) treatment with surgery or radiation.
Chemotherapy in advanced disease: Chemotherapy may be used as first-line treatment in patients with inoperable or metastasized lung cancer. It is typically used in late stages to reduce symptoms and, in some cases, extend survival. Since 2006, the combination of bevacizumab (Avastin, a monoclonal antibody) and platinum-based chemotherapy is also a first line treatment choice for such patients, if the cancer is the non-squamous type

Powerful platinum compounds, either cisplatin (Platinol) or carboplatin (Paraplatin), are the basis for most chemotherapy regimens. Two-drug combinations, with one drug being a platinum-based agent, are currently the preferred regimens. Reasonable combinations include paclitaxel (Taxol) and carboplatin or cisplatin. This regimen can also include gemcitabine, docetaxel, or vinblastine or its derivative (vindesine or vinorelbine). There does not seem to be any significant differences in effectiveness among them. Gemcitabine and vinorelbine combination might be a good option for patients who cannot tolerate platinum compounds. Chemotherapy for lung cancer may have reached its peak. Still, investigative chemotherapeutic drugs may yet improve response. Many experts are pinning their hope on agents called biologic response modifiers, such as gefitinib (Iressa) or LY900003 (Affinitak). To date, however, they have not achieved better results than standard platinum-based chemotherapies. Gefitinib (Iressa), a second-line therapy for non-small cell lung cancer (NSCLC), is now available only for a limited group of patients. These patients have benefited from gefitinib in the past, or they are enrolled in a clinical study with the drug. While this medicine initially showed great promise in clinical trials, results from a newer study failed to show that it prolonged survival in advanced lung cancer patients who failed other treatments.

If you are currently taking gefitinib, do not stop taking it without talking to your doctor.

Erlotinib (Tarceva) is in the same medication class as gefitinib. It is approved for patients with locally advanced or metastatic NSCLC, who have failed one type of chemotherapy treatment in the past (it is a second-line treatment). Unlike gefitinib, erlotinib shows survival and progression-free benefits compared to placebo. However, it should not be combined with platinum-based chemotherapy.

Chemotherapy treatments are usually performed in an outpatient setting and in regular cycles for several months. How many chemotherapy cycles to administer in late-stage cancers, the timing of those cycles, and the sequences of the drugs are still matters of investigation. For instance, research suggests that a three- or four-course cycle may achieve the same survival times and better quality of life than the standard of six or more course cycles. Changing even one day in a drug sequence can sometimes significantly affect outcome. Such fine-tuning of chemotherapy regimens is likely to have the most effect on patients with advanced-stage disease, which requires more tailored treatment than early-stage disease.

Treatment for lung cancer depends on the type of cancer and the stage of the disease. Chemotherapy is a form of treatment for lung cancer that may cure, shrink, or keep the cancer from spreading.

Side effects of chemotherapy treatments are common, and they are more severe with higher doses. Side effects increase over the course of treatment. Some trials suggest that they can be reduced by giving the drugs for shorter durations, without loss of cancer-killing effects. Common side effects include the following:

Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression
Nausea and vomiting: Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these two side effects. Serotonin antagonists work well in nearly all patients given moderate drugs, and in most patients who take drugs that are more powerful. In one study, a combination of dexamethasone (a steroid) with ondansetron, taken within 24 hours of chemotherapy, achieved either a major or complete reduction in nausea and vomiting.
Anemia: Anemia, an abnormally low number of red blood cells, is common in lung cancer. Treatments include transfusions or injections of erythropoietin, an agent that causes more red blood cell production. Erythropoietin is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp), which requires fewer injections. These agents improve well-being and quality of life. Trials are in progress to determine if they may have survival benefits as well.

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days per month.

Serious complications of chemotherapy can also occur and may vary depending on the specific drugs. They include the following:

Increased chance for infection from suppression of the immune system.
Severe drops in white blood cells (neutropenia): Certain chemotherapy drugs, such as taxanes, pose a higher risk for this complication than other drugs. White blood cell count can improve with the addition of a type of drug called granulocyte colony-stimulating factor (filgrastim and lenograstim).
Liver and kidney damage: Amifostine (Ethyol) reduces the risk for kidney damage in patients taking repeated regimens of cisplatin-based therapy. It is also a radioprotector; that is, it helps prevent severe effects in the esophagus from radiotherapy, with or without chemotherapy.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based agents: A simple skin test is under investigation that may identify people with a potential allergic response.

Second-line chemotherapy is used for patients whose cancers have recurred after first-line chemotherapy. Some experts believe that the longer survival rates for advanced lung cancer seen for the past 5 years may be due to these drugs. Because platinum-based agents are most often used first, they are not beneficial for second-line therapy. The following are commonly used second-line agents.

Docetaxel (Taxotere). Docetaxel is the drug of choice at this time for cancers that do not respond to initial chemotherapy. Studies have reported that it achieves longer survival times than supportive care alone. It is usually given every 21 days. This regimen causes more side effects than pemetrexed, the newer major second-line drug. Weekly doses of docetaxel are effective and less toxic than the 3-week schedule. It is not clear if survival rates are comparable to those of pemetrexed with that schedule, however.

Pemetrexed (Alimta). Pemetrexed, known as an anti-folate, is another promising new agent for second-line therapy and possibly for first-line treatment as well. The drug targets a number of enzymes that play a role in how cancer cells increase. Some research suggests that it is as effective as docetaxel. Pemetrexed does have some serious toxic effects, but they can be significantly reduced with folic acid and vitamin B12 supplements. It is then less toxic than docetaxel, when docetaxel is given every 21 days, but not when it is given weekly.

Gefitinib (Iressa) and Other Tyrosine Kinase Inhibitors. Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis). Compounds called growth factors, which may be important in cancer cell production, control the growth of these new blood vessels. Researchers, then, are interested in medications that literally turn off these growth factors or their receptors, such as epidermal growth factor receptor (EGFR). In so doing, the agents may be able to cut off cancer's lifeblood. Gefitinib and erlotinib are angiogenesis inhibitors that target receptors of an epidermal growth factor called tyrosine kinase. Interestingly, studies are finding that NSCLC tumors in people who have never smoked have a much higher rate of EGFR mutations. This helps to explain why gefitinib and erlotinib are more effective in treating NSCLC in people who have never smoked.

Gefitinib (Iressa) was approved in 2003 as a second-line therapy for non-small cell lung cancer. Many patients report significant improvement in symptoms and quality of life, and the drug initially showed great promise. In one study, gefitinib reduced tumor size by 50% in about 10% of the patients. However, recent large-scale clinical trial results have failed to confirm any survival advantage for most patients. At this time, gefitinib is available only for patients who have benefited from it in the past.
Erlotinib (Tarceva) was approved as a single agent second-line therapy in November 2004. Study results show that the drug prolonged survival by several more months than placebo (6.7 versus 4.7 months). Erlotinib is administered orally and has very low toxicity (rash and diarrhea are common).

Chemotherapy Following Surgery (Adjuvant Chemotherapy). Chemotherapy is being evaluated in combination with surgery, radiation therapy, or both. Fairly strong evidence is now supporting the use of platinum-based chemotherapy as adjuvant treatment after surgery in patients with lung cancers in stages Ib-IIIa, with some research indicating a 5% improvement in five-year survival rates. Not all studies confirm survival benefits, however, and trials are ongoing.

Chemotherapy before Surgery (Induction Chemotherapy). Some researchers are testing induction chemotherapy, which is used to shrink potentially operable tumors before surgery. Studies have been mixed in reporting any survival benefits in patients with advanced lung cancer.

Combined and Multi-Modal Therapy. In stage III cancers, investigators are researching very intensive treatments that use two or more combinations of chemotherapy, radiation, and surgery.

For example, radiation plus chemotherapy may be helpful in patients whose tumors are surgically removable.

In inoperable lung cancer, combining radiation with chemotherapy is proving to extend the time to recurrence, the overall duration of survival, or both, compared to radiation alone. Evidence also suggests that giving radiation treatments at the same time as chemotherapy (instead of in separate cycles) improves 5-year survival rates, compared to a sequential approach (separate cycles following each other). Chemotherapy and radiation treatments given at the same time are more toxic, however.

Other approaches use even more intensive multi-modal therapy. For example, some trials use radiation therapy with chemotherapy, followed by surgery. Patients are then sometimes given additional chemotherapy or radiation. In other promising regimens, patents are given concurrent radiation and chemotherapy followed by chemotherapy alone. Such approaches are very toxic but appear to improve survival in selected patients.

Severe inflammation in the esophagus is the most common severe side effect of the radiation and chemotherapy combination. There is also a very high risk of serious infections, including pneumonia, herpes zoster, and cytomegalovirus. Long-term antibiotic therapy may be needed.

Although patients over 70 may suffer more from toxic effects than younger patients, studies now suggest that they can achieve survival rates with combined treatments that are equal to those in younger patients.

There are many painkilling medications available. Research shows that aggressive pain relief can help patients manage cancer treatment symptoms (in addition to pain) better. For example, a 2001 study suggested that reducing pain in elderly cancer patients markedly lowered their fatigue levels, and improved other symptoms as well.

Opioids are the most potent painkillers. The correct use of these strong medications is very important for reaching acceptable pain relief, and preventing a toxic response. For example, the long-lasting version of oxycodone (OxyContin) must be swallowed whole; chewing, inhaling, or injecting it can create a deadly overdose.

Investigative Agents

According to a 2001 article, of the nearly 500 cancer drugs currently in development, 58 of them (about 13%) are aimed at fighting lung cancer. Only the number of breast cancer drugs exceeded that percentage. Unfortunately, none to date have shown any real benefit in terms of patient survival. However, some drugs are showing promise, and at this time, these agents are the best hope for improving lung cancer survival rates.

Monoclonal antibodies (MAbs) are genetically designed immune factors. MAbs mark foreign compounds called antigens for attack by the immune system. Trastuzumab (Herceptin) and cetuximab (Erbitux) are MAbs under investigation for lung cancer. Bevacizumab (Avastin) was approved in October 2006 as a first-line treatment (in combination with carboplatin and paclitaxel) for inoperable, locally advanced, metastatic, or recurrent non-squamous, non-small cell lung cancer.

All three of these MAbs block epidermal growth factor. These agents are of particular interest for patients who have cancers that produce too much of the protein called HER2. These agents show great promise in combination with chemotherapies and newer drugs, such as the tyrosine kinase inhibitors. For example, the disease-free survival time in patients with advanced NSCLC is longer when adding bevacizumab to platinum-based chemotherapy.

Antisense oligonucleotides are drugs being used to block molecules that result in too many cells that cause cancers. LY900003 (Affinitak), for example, targets an enzyme called PKC-alpha, which promotes tumor growth. Early studies with Affinitak showed some promising results. However, a 2003 study found no difference in survival when patients received Affinitak in combination with platinum-based chemotherapy, compared to patients receiving chemotherapy alone.

Genasense (G3139, oblimersen) blocks Bcl-2. Bcl-2 is a protein that is expressed in abnormally high amounts in some cancers. This antisense drug is also under investigation.

Advexin, a genetic therapy that contains the p53 tumor-suppressor gene, is showing promise. In one early study, 60% of patients experienced partial or total tumor shrinkage when the agent was used in combination with radiation therapy. A 2006 study in Japan found that out of 13 patients with advanced NSCLC receiving Advexin, 10 had stabilized. Three of the stabilized patients remained stable for over 9 months. One patient had a partial response to Advexin. The only side effect of the multiple doses given was a passing fever that disappeared within 24 hours. Advexin is in Phase II clinical trials for NSCLC.

Vaccines use inactivated genetic materials from cancer cells, such as defective p53 or ras genes, to cause a highly targeted immune response to attack the cancer.

Retinoids are vitamin A-like antioxidant chemicals that help repair cell damage and appear to support growth of lung cells. A number of retinoid-like agents (retinal palmitate, TAC-101, 23-cis-retinoic acid, N-acetyl-cysteine) are being studied for the treatment or prevention of lung cancer.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.cancercare.org -- Cancer Care
www.lungusa.org -- The American Lung Association
www.asco.org -- American Society of Clinical Oncology
www.alcase.org -- Alliance for Lung Cancer
www.lungcancer.org -- Joint project of Cancer Care and the Oncology Nursing Society
www.nccn.org -- National Comprehensive Cancer Network
www.lungcanceronline.org -- Lung cancer information
www.epa.gov/iaq/radon -- National radon information
www.clinicaltrials.gov -- Find clinical trials
www.cancer.gov/clinicaltrials -- Find clinical trials

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Review Date:
8/3/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Cervical cancer

FitSugar — Wed, 08 Oct 2008 17:34:57 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Prognosis
Symptoms
Prevention
Diagnosis
Treatment for Cervical Intr...
Treatment for Cervical Canc...
Treatment for Invasive Cerv...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Human Papilloma Virus (HPV) Prevalence

About 25% of women age 14 - 59 are infected with the human papilloma virus (HPV), indicates a 2007 study in the Journal of the American Medical Association (JAMA). HPV prevalence is highest (45%) among women age 20 - 24. HPV is the main cause of cervical cancer.

Immunization Guidelines

In 2006, the FDA approved the first vaccine to prevent cervical cancer. Gardasil protects against human papilloma virus (HPV) 16 and 18, the strains most likely to cause cervical cancer, and HPV 6 and 11, the strains most likely to cause genital warts. In 2007, several expert groups released immunization guidelines for the cervical cancer vaccine. Guidelines from the U.S. Centers for Disease Control’s Advisory Committee on Immunization Practices recommend:

Routine vaccination for girls age 11 - 12 with a vaccine series of 3 doses. Girls as young as 9 years old may be vaccinated at their doctors’ discretion.
Catch-up vaccination for girls and women age 13 - 26 who have not been previously vaccinated or who have missed doses.

Vaccine Effectiveness

The vaccine prevents human papilloma virus (HPV) infection caused by four HPV strains but cannot treat pre-existing HPV infection, confirms a 2007 JAMA study
The vaccine is nearly 100% effective in preventing cervical cancer and genital warts when it is administered before females become sexually active, indicate several 2007 studies.

HPV and Throat Cancer

Human papilloma virus (HPV) 16 increases the risk of oropharyngeal cancers of the throat, tonsils, and back of the tongue, according to several 2007 studies. HPV can be transmitted during oral sex, causing infection in the mouth. (However, not all people who engage in oral sex or who have oral HPV infection will develop throat cancer. The virus usually goes away on its own.) Previously, alcohol and tobacco use were considered the main risk factors for oropharyngeal cancer.

Introduction

The cervix is the lower third portion of the uterus (womb). It serves as a neck to connect the uterus to the vagina. The opening of the cervix, called the os, remains small and narrow, except during childbirth when it widens to allow a baby to pass from the uterus into the vagina.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Cervical cancer develops in the thin layer of cells called the epithelium, which cover the cervix. Cells found in the this tissue have different shapes:

Squamous cells (flat and scaly). Most cervical cancer arises from changes in the squamous cells of the epithelium (squamous cell carcinoma).
Columnar cells (column-like). These cells line the cervical glands and cancers here are known as adenocarcinomas.
In rare cases, cancer can occur in cells that form the supportive tissue around the cervix (the stroma).

Cervical cancer usually begins slowly with precancerous abnormalities, and even if cancer develops, it generally progresses very gradually. Cervical cancer is the most preventable type of cancer and is very treatable in its early stages. Regular Pap tests and human papilloma virus (HPV) screening can help detect this disease early.

Dysplasia. Dysplasia is a term that refers to a precancerous condition. It may become cancerous, but not always. In the case of cervical cancer, dysplasia indicates that the layer of cells that covers the cervix (squamous epithelial cells) are abnormal in size and shape and are beginning to grow.

Cervical Intraepithelial Neoplasia. Dysplastic changes seen on a Pap smear may indicate the presence of cervical intraepithelial neoplasia (CIN). This means precancerous changes are found within the lining of the cervix. The changes are categorized according to severity: CIN I, CIN II, and CIN III.

With CIN I, there are mild abnormalities that rarely develop into cervical cancer. This condition may progress if untreated but often goes away without treatment.
In CIN II, the lesions often appear more aggressive under the microscope and may turn into cancer unless treated.
CIN III is the most aggressive form of dysplasia. If not removed, there is a high chance that it will turn into invasive cancer. CIN III includes carcinoma in situ (CIS). CIS is an early stage of non-invasive cancer -- the cells are confined within the tissue where they grew and have not yet invaded surrounding tissue. However since CIS can progress to invasive cancer, this condition should be treated as soon as possible.

Click the icon to see an image of cervical dysplasia.

The cells of the epithelium rest on a very thin layer called the basement membrane. Invasive cervical cancer occurs when cancer cells in the epithelium cross this membrane and invade the stroma, the underlying supportive tissue of the cervix.

In later stages, the original cancer may spread to areas surrounding the uterus and cervix or near organs such as the bladder or rectum. It may also spread to distant sites in the body through the bloodstream or the lymph nodes.

Causes

The human papillomavirus (HPV) has been detected in virtually all invasive cervical cancers and has been confirmed as the major cause of this cancer.

How HPV Is Transmitted. HPV is spread primarily by having sex with an infected partner. Most sexually active young women become infected with this virus, but only 10% remain infected for more than 5 years. Only those infected for longer than 5 years have a higher risk (about 50% above normal). Other factors are then needed to trigger the disease.

How HPV Contributes to Cervical Cancer. Researchers believe that most cervical cancers develop when various aggressive genetic HPV strains activate certain oncogenes (cancer-causing genes). Oncogenes called E6 and E7 are particularly important because they interfere with certain protective proteins, such as p53 and pRb, respectively. Under normal conditions, these proteins limit cell growth. Once they are blocked, cell growth can run rampant, leading to tumor development and cancer.

HPV Genetic Types. More than 30 genetic variants of human papillomaviruses can be passed through sexual contact form one person to another. The severity, however, varies widely according to genetic type. (Women initially infected by one type of HPV are still at risk for infection from other types.)

In women with cervical intraepithelial neoplasia I , the HPV viruses that are present are often types 6 and 11, which are low risk. Other low-risk HPV genetic types are 40, 42, 43, 44, 54, 61, 70, 72, and 81. These viral types often produce genital warts (condylomata) that rarely lead to cancer. (These warts usually affect the woman's genitals, the vagina, and vulva, rather than the cervix.)

Of the high-risk types, HPV types 16 and 18 have long been known to be particularly dangerous. These two genetic types and six others (31, 33, 35, 45, 52, and 58) account for 95% of HPV-related cervical cancers. Other high-risk types are 39, 51, 56, 59, 68, 73, and 82. All are associated with moderate cervical intraepithelial neoplasia II and cervical intraepithelial neoplasia III. Types 26, 53, and 66 are also considered high-risk.

In 2007, several studies indicated that HPV-16 infection in the mouth is associated with increased risk for oropharyngeal cancer. (Oropharyngeal cancer develops in the throat, just behind the mouth. It includes the base of the tongue, soft palate, tonsils, and side and back walls of the throat.) Prior to this research, alcohol and tobacco were thought to be the main risk factors for this type of cancer. According to the studies, oral sex (both fellatio and cunnilingus) significantly increases the risk of HPV-16 transmission and, therefore, the risk of developing oropharyngeal cancer. While the risk of HPV-16 causing oropharyngeal cancer is lower than the risk of it causing cervical cancer, experts think that the HPV vaccine may help reduce the incidence of throat, tonsil, and tongue cancers, as well as cervical cancer.

High-risk types of HPV have also been associated with an increased risk for other cancers, including other genital and lung cancers. The high-risk viruses generally produce flat and nearly invisible growths, compared to the usually harmless warts caused by low-risk HPV viruses.

Herpes viruses. Certain herpes viruses, including herpes simplex virus 6, 2, 7, and cytomegalovirus, have been detected in women with cervical cancer. herpes simplex virus 6 is under particular suspicion for playing a role in activating the papilloma virus gene. The presence of these very common viruses, however, may simply be coincidental, and they may serve no purpose other than being bystanders.

Chlamydia Trachomatis. Studies are finding an especially strong association between the incidence of Chlamydiatrachomatis, a sexually transmitted infection, and HPV. (Chlamydia trachomatis should not be confused with Chlamydia pneumoniae, a common cause of mild pneumonia in young adults. Chlamydia pneumonia e is not associated with cervical cancer.)

Other Sexually Transmitted Diseases. Other sexually transmitted diseases that have been associated with cervical cancer include HIV and gonorrhea. These infections, however, also may only be markers of increased sexual activity and may not themselves cause cancer.

Risk Factors

According to the American Cancer Society, about 11,150 new cases of invasive cervical cancer will be diagnosed in the U.S. in 2007. However, the number of new cervical cancer cases has been declining steadily over the past decades. Fifty percent of cervical cancer diagnoses occur in women ages 35 - 55, and slightly more than 20% occur in women over 65 years of age.

Some women (15%) develop cervical cancer before the age of 30. Although cervical cancer is rare in women under age 20, cancer rates in younger women are on the rise. Many young women are infected with multiple types of human papillomavirus, which can increase their risk of getting cervical cancer. Young women with early abnormal changes who do not have regular examinations are at high risk for localized cancer by the time they are age 40, and for invasive cancer by age 50.

Although it is the most preventable type of cancer, cervical cancer is ranked as the second most common cause of female death. Each year it kills an estimated 3,700 women in the U.S. and nearly 300,000 women worldwide.

In the United States, cervical cancer mortality rates plunged by 74% from 1955 - 1992 thanks to increased screening and early detection with the Pap test.

Although the rate of cervical cancer has declined in both Caucasian and African-American women over the past decades, it remains much more prevalent in African-Americans -- whose death rates are twice as high as Caucasian women. Hispanic American women have more than twice the risk of invasive cervical cancer as Caucasian women, also due to a lower rate of screening.

These differences, however, are almost certainly due to social and economic differences. Numerous studies report that high poverty levels are linked with low screening rates. In addition, lack of health insurance, limited transportation, and language difficulties hinder a poor woman’s access to screening services. Researchers are investigating programs that provide screening and treatment for women with abnormal Pap smears in a single visit.

The human papilloma virus (HPV) is the primary cause of cervical cancer. According to a 2007 study in the Journal of the American Medical Association, about 1 in 4 U.S. females ages 14 - 59 are infected with HPV. The prevalence of HPV is highest (45%) in women age 20 - 24.

The risk for cervical cancer in infected women appears to be highest in those infected with HPV for more than 6 months. In most people, the virus goes away within a year. However, it persists in about 10% of infected women.

High Sexual Activity. In adults, the most important risk factor for HPV is sexual activity with an infected person. Women most at risk for cervical cancer are those with a history of multiple sexual partners, sexual intercourse at 17 years or younger, or both. A woman who has never been sexually active has a very low risk for developing cervical cancer. Sexual activity with multiple partners increases the likelihood of many infections in addition to human papilloma virus.

Douching. Women who douche on a weekly basis are more likely to contract cervical cancer than those who do not. Douching may destroy the natural antiviral substances normally present in the vagina, making women more susceptible to HPV.

Pessaries. Use of a pessary (a ring-shaped plastic device that keeps the vagina and uterus from collapsing) increases the risk of chronic inflammation and viral infection at the insertion site and therefore may increase the risk for cervical cancer.

Risk Factors for HPV in Children and Infants. HPV also can occur in children and even newborns. The virus may also be transmitted by an infected mother. In children, HPV is usually the harmless form that cause skin warts.

In one analysis, 15 - 20% of women with cervical cancer had at least one close relative with the disease. Two studies have also reported that in families with cervical cancer there have also been higher rates of other human papilloma virus-related and smoking-associated cancers. Inherited factors in such cases most likely cause changes in the immune system that make such people more susceptible to human papilloma virus or other viruses.

Several studies, including a major analysis, have reported a strong association between cervical cancer and long-term use of oral contraception (OC). Women who have taken OCs for more than 10 years have a much higher risk of human papilloma virus (HPV) infection (up to four times higher) than those who do not use OCs. (Women taking OCs for fewer than 5 years have no significantly higher risk.) The reasons for this risk from OC use are not entirely clear. Women who use OCs may be less likely to use a diaphragm, condoms, or other methods that offer some protection against sexual transmitted diseases, including HPV. Some researchers also suggest that the hormones in OCs might help the virus enter the genetic material of cervical cells.

Studies indicate that having many children increases the risk for developing cervical cancer, particularly in women with human papilloma virus.

Smoking is associated with a higher risk for precancerous changes (dysplasia) in the cervix and for progression to invasive cervical cancer. Smoking may cause human papilloma virus (HPV) to grow faster and increase its likelihood of causing cancer. According to a 2006 study, women smokers who have HPV-16 are 14 times more likely to develop cervical pre-invasive cancer than smokers who do not have the virus. By contrast, non-smokers with HPV-16 were only 6 times more likely to develop cancer than those who were not infected.

Secondhand smoke is also linked to increased risk for cervical cancer tumors. It is not clear if this association is due to cigarette smoke’s direct cancer-causing effects or general damage to the immune system. Cigarette smokers are also deficient in folate, a B vitamin. Folate deficiency may play a role in the development of dysplasia.

Diethylstilbestrol. From 1938 - 1971, diethylstilbestrol, an estrogen-related drug, was widely prescribed to pregnant women to help prevent miscarriages. The daughters of these women face a higher risk for cervical cancer, genital tract abnormalities, and miscarriage.

Environmental Chemicals. Long-term exposure to certain types of agricultural and industrial chemicals may increase the risk for cervical cancer.

Prognosis

The following are some examples of the time it takes for early stages of cervical dysplasia to progress to the next stage:

Only about 1% of untreated mild cervical dysplasia (CIN I) cases progress to severe dysplasia or cancer each year.
In women with untreated moderate dysplasia (CIN II), 16% will progress to the next stage in 2 years, while 25% will progress after 5 years.
Most untreated pre-invasive cancer will develop into invasive cancer over a period of 10 - 12 years.

Over the past 30 years, the death rate from cervical cancer has declined significantly. In general, 71% of women with invasive cervical cancer survive for 5 years or more. African-American women tend to have poorer 5-year survival rates than Caucasian women, although survival rates have significantly increased in African-American women in recent years.

The outlook for specific women varies depending on different factors:

In women who receive treatment when cervical cancer is still local, the cure rate is about 90%. Experts say universal screening could essentially reduce the cervical cancer death rate to zero. Still, only 12 - 15% of women have routine Pap smears. As a result, only 55% of Caucasian women and 44% of African-American women are diagnosed at early stages.
If the cancer cells have spread beyond the cervix, the average 5-year survival rates may drop to 50% and below, depending on how much it has spread and the type of cancer cell.

Identifying what type of human papilloma virus (HPV) a woman has may help determine outlook and the severity of cervical cancer. For example, HPV-18 and HPV-16 are associated with severe cases. HPV-16 has also been linked to a rare form of cervical and uterine cancers.

Other biochemical markers in the body may also help predict outcome and treatment. For example, women with cervical cancer who have high levels of an enzyme called cyclooxygenase (COX-2) may need more aggressive treatments than those with low levels.

The treatments for advanced cervical cancer also add to the emotional burden in premenopausal women, because they nearly always prevent future childbearing.

Symptoms

Most women with dysplasia or pre-invasive cancer have no symptoms. Screening tests, therefore, are very important.

When the cancer becomes invasive, unusual bleeding can occur. Bleeding may stop and start again between regular periods or there may be bleeding after menopause. Unexpected bleeding can also occur after intercourse or a pelvic exam. Periods sometimes last longer or are heavier than usual. Increased vaginal discharge may be noticeable as well. Pelvic pain can occur, but it is not common.

These symptoms are not exclusive to cervical cancer. Sexually transmitted diseases, for instance, can cause similar symptoms.

Prevention

The best way to prevent cervical cancer is to avoid getting infected with human papilloma virus (HPV). Because HPV is sexually transmitted, practicing safe sex and limiting the number of sexual partners can help reduce risk. A vaccine can protect against the major cancer-causing HPV strains. Regular Pap tests remain the most effective way of preventing the development of invasive cervical cancer.

In 2006, the FDA approved the first human papilloma virus (HPV) vaccine to prevent cervical cancer. Gardasil has been tested in more than 12,000 uninfected girls and women in 13 countries. Studies show it provides nearly 100% protection against HPV-16 and HPV-18, the viruses that cause 70% of cases of cervical cancer. Gardasil also protects against HPV-6 and HPV-11, which cause 90% of cases of genital warts.

Gardasil is approved for girls and women ages 9 - 26. Current immunization guidelines recommend:

Routine vaccination for girls ages 11 - 12 years. The vaccine should be administered in 3 doses, with the second and third doses administered 2 and 6 months after the first dose. The HPV vaccine can be given at the same time as other vaccines.
Girls as young as age 9 can receive the vaccine at their doctors’ discretion.
Girls and women ages 13 - 26 who have not been previously immunized or who have not completed the full vaccine series should get vaccinated to catch up on missed doses. [The U.S. Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend catch-up doses for ages 13 - 26. The American Cancer Society (ACS) recommends catch-up for ages 13 - 18. The ACS suggests that women ages 19 - 26 discuss with their doctors the relative risks and benefits of vaccination.]
Women should not get the vaccine during pregnancy.

The HPV vaccine can only prevent -- not treat -- HPV infection, genital warts, and cervical cancer. Because the vaccine cannot protect females who are already infected with HPV, doctors recommend that girls get vaccinated before they become sexually active. Several 2007 studies indicated that the vaccine is nearly 100% effective in preventing cervical cancer and genital warts when given prior to HPV exposure. However, young women who are sexually active may still derive some benefit from the vaccine, at least for protection against any of the four HPV strains that they have not yet acquired.

The FDA is considering approving another type of cervical cancer vaccine (Cervarix). Cervarix protects against HPV-16 and HPV-18, as well as the cancer-causing strains HPV-31 and HPV-45. It does not protect against genital warts.

The FDA is not yet sure how long Gardasil’s protection lasts or when patients may need a booster shot. A 2006 study of the Cervarix vaccine found that protection lasted for at least 4.5 years.

These vaccines do not protect against all types of cancer-causing HPV. The FDA still recommends that women receive annual screening to detect any early signs of cervical cancer. For girls and women who have been sexually active before they receive the vaccine, screening still provides the best protection against cervical cancer.

Use of barrier contraceptives such as condoms is associated with a reduced risk of cervical cancer, even in women already infected with human papilloma virus (HPV). HPV can exist outside the area protected by the male condom, so this method is not foolproof in preventing an initial infection. However, a 2006 New England Journal of Medicine study found that when men used condoms every time they had sexual intercourse, their female partners had less than half the rate of HPV infection as women whose partners used condoms less than 5% of the time. The female condom is becoming increasingly popular in developing countries. It may prove to be particularly effective against sexually transmitted diseases in these regions.

A 2002 study reported that men who are circumcised have a lower risk for carrying human papilloma virus (HPV) and therefore reduce the risk for cervical cancer in their female partners.

Some studies have suggested possible protective benefits against cervical cancer from certain vitamins.

High blood levels of vitamins E and C have been linked with lower rates of some cancers, including cervical cancers.

Although vitamin E is a fat-soluble vitamin, there are no known toxic effects of megadoses.

Click the icon to see sources of food which contain vitamin E.

Click the icon to see the benefits of vitamin C.

Click the icon to see sources of food which contain vitamin C.

Folic acid, a B vitamin, prevents birth defects and may also lower the risk for development of dysplasia (precancerous changes) leading to cervical cancer. It is not clear how strong this association is, or why this would occur. Some evidence points to its actions in reducing levels of homocysteine, a compound associated with a higher risk of cervical cancer.

There is no definitive evidence, however, that taking vitamins can prevent any cancer. Eating healthy foods rich in such vitamins and other important nutrients is, in any case, the best approach for overall good health.

Diagnosis

The changes that lead to cervical cancer develop slowly. Screening tests performed during regular gynecologic examinations can detect early changes.

Every year in the U.S. about 50 million women have a Papanicolaou test (the Pap smear). Use of the Pap smear has reduced the annual death rate from cervical cancer from 26,000 in 1941 to 3,700 in 2005.

Forty percent of women who have a Pap smear fail to follow-up for retesting and treatment. Most cases of cervical cancer occur in women who have not had regular Pap tests.

The Procedure. The most accurate test results are obtained 12 - 14 days after menstruation begins. Women should not douche or have intercourse within 48 hours of the test. Douches and spermicidal creams may clean out abnormal cells and interfere with the results of a Pap smear. (In general, douching is not recommended at all.) A Pap smear is usually painless, although some women may have some discomfort.

The test is done in a doctor's office. The woman removes her clothes from the waist down and puts on a medical gown. She lies on her back on the examination table, bends her knees, and puts her feet in supports (called stirrups) at the end of the table.
A doctor inserts a metal device into her vagina to widen it.
Using a spatula, brush, or both, the doctor gently scrapes the surface of the cervix, and sometimes the upper vagina, to gather living cells. The doctor will also obtain cells from inside the cervical canal. Such cells include squamous and glandular cells and those that lie higher up in the cervical canal (known as the endocervix). Using both a brush and spatula helps gather better samples to detect the presence of cancer.
The cells are preserved, stained for microscopic viewing, and then analyzed under a microscope by a specialist known as a cytopathologist.

A Pap test is a simple, relatively inexpensive procedure that can easily detect cancerous or precancerous conditions.

Reliability and Accuracy. Over the course of a lifetime of regular screening, a woman faces a 40% chance of being told her Pap smear is abnormal. The Pap smear is not, however, a perfectly reliable measure of a woman's risk for cervical cancer.

In general, about 10% of Pap smears have abnormal results, but only about 0.1% of the women who have these results actually have cancer. In most cases, abnormal cells are low grade and not likely to progress to cancer or are due to benign conditions, including natural cell changes after menopause.

No test is 100% accurate, and it is possible for the Pap smear to miss the presence of cancer. However, if abnormal cells are missed on one test they are likely to be spotted during the next one without a significant danger.

Newer, thin-layer liquid based tests (ThinPrep, SurePath) use the original cervical sample, which is rinsed in a special solution to thin the mucus (rather then dried). The result is a clear, clean sample that may be able to accurately reveal abnormal cells. The fluid can also be examined for evidence of human papilloma virus (HPV) and other early abnormalities. Some -- but not all -- studies have found this test to be more accurate than the standard Pap smear. A rigorous 2006 review of 56 studies found that liquid-based tests were no more accurate than conventional Pap smears.

The U.S. Preventive Service Task Force (USPST), the American Cancer Society (ACS), and the American College of Obstetricians and Gynecologists (ACOG) have all released guidelines for cervical cancer screening. ACOG and ACS have established separate screening criteria for women below and above 30 years of age. Although there are some small differences between these three sets of guidelines, they generally make similar recommendations as summarized below:

Recommendations for Initial Screening. Women should begin to undergo Pap tests within 3 years of onset of sexual activity or at age 21 (whichever comes first).

Women with no history of sexual activity should still have Pap smears. They are at low risk for squamous cell carcinoma, but adenocarcinoma (cancer that occurs in cervical glands) can occur, although this is very uncommon.

Women Up to Age 30. Women under age 30 should receive annual screening with the conventional Pap smear. The American Cancer Society (ACS) offers the alternative of screening every 2 years using the newer liquid-based testing. HPV testing is not recommended for this age group because HPV infections in women under age 30 tend to resolve on their own.

Women Age 30 and Over. Women in this age group who have received three consecutive negative (normal) annual Pap tests have two screening options:

Screening with standard or liquid-based Pap tests every 2 - 3 years. Women in high-risk groups (DES exposure, HIV infection, weakened immune system, or previous diagnosis of cervical cancer) should continue to receive annual tests.
Screening with Pap test plus HPV DNA test. If a woman tests negative on both of these tests, then she can be rescreened no more frequently than once every 3 years. If one of the tests is positive, she will need to be screened more frequently.

Elderly Women. In its 2003 guidelines, the U.S. Preventive Service Task Force recommended against routine screening in women over age 65 with low or no risk factors. (The ACS recommends stopping at age 70, while the American College of Obstetricians and Gynecologists declines to set an upper age limit.) Such women have had at least three previous normal screenings and have had no abnormal results for at least 10 years. According to the guidelines, older women should be screened if they have not been screened before or if there is a possibility that they have not been screened (for example, if the woman is from a country that does not do routine screening). However, a 2006 study of more than 15,000 postmenopausal women recommended continued screening for elderly women who are sexually active but not monogamous. (Women in the study had a uterus.) The researchers note that about 25% of new cervical cancer cases, and 41% of cervical cancer deaths, occur among women 65 years and older.

After a Hysterectomy. The 2003 guidelines recommend against routine screening for women who have undergone a total hysterectomy for benign causes. Women who have had a hysterectomy that preserves the cervix (called a supracervical hysterectomy) should continue with Pap screening.

If Pap smear results are normal for 3 consecutive years, most expert groups recommend a Pap test every 2 - 3 years thereafter in most women over 30 years of age. (The American Cancer Society suggests that such women wait until they are 30 before extending the interval to 3 years.)

Both the American Cancer Society and the American College of Obstetricians and Gynecologists recommend that annual screening should continue in women in high-risk categories. High risk categories may include the following, depending on the medical group:

Women who have had multiple sexual partners or whose male sexual partners have had multiple partners.
Women who engaged in sexual activity at a young age.
Women whose male sexual partners have had other sexual partners with cervical cancer.
Women with current or prior HPV infection.
Women who are HIV-positive or who are immunosuppressed.
Women with a history of sexually transmitted diseases.
Smokers and substance or drug abusers.
Women who have a history of cervical dysplasia or cervical, endometrial, vaginal, or vulvar cancer.
Women in lower socioeconomic groups, particularly if they have not been able to obtain regular gynecologic screening and care.

Any abnormal result, even a mild abnormality, requires follow-up visits and additional tests. The extent of these tests depends on the degree of abnormalities.

New tests and methods have been developed to improve the accuracy of the Pap smear in detecting cancer cells. For example, there are several computerized Pap test systems (FocalPoint, PAPNET) that are used to rescreen the original smear. These systems are either used to detect abnormal samples that may have been missed by manual review methods or are used in place of a human cytotechnologist. According to the U.S. Preventive Services Task Force (USPSTF), there is not yet enough evidence to know whether or not computerized methods are superior to conventional Pap testing.

There are tests for identifying the high-risk types of human papilloma virus (HPV) that are known to cause cervical cancer. The presence of these types is a strong predictor of high-grade aggressive abnormalities or cancer itself. Testing for HPV does not replace the Pap smear, but when used adjunctively with the Pap test this screening combination may help to more accurately detect cervical cell abnormalities than either test alone.

In 2003, the FDA approved the Hybrid Capture 2 (HC2) HPV DNA test for use with the Pap test for cervical cancer screening in women over 30 years of age. The HPV DNA test can identify 13 types of the high-risk HPV that are most frequently implicated in the development of cervical cancer. At this time, the test is recommended as an adjunct to the Pap test but not as the sole method for primary screening.

Other screening tests are being investigated for use in combination with the Pap smear for improving accuracy. For example, combinations with human papilloma virus (HPV) DNA tests or cervicography may prove to be more effective for detecting cervical intraepithelial neoplasia I and II dysplasia (potentially invasive cells) than Pap smears alone.

Cervicography. Cervicography uses a photograph of the cervical region (a cervigram), which is then highly magnified and examined. It may prove to be a useful companion to a Pap test, particularly in high-risk younger women. It is painless, easy to use, provides documentation of the area, and is highly sensitive to abnormal changes. (It also, however, picks up abnormalities that are not cancerous.)

Acid Test. A diluted solution of acetic acid (similar to vinegar) is applied to the cervix. When viewed through a special green lens, this solution makes abnormal cells look white, whereas normal cells appear pink. Skilled doctors may also be able to spot abnormal blood vessel patterns indicative of cancer areas on the cervix. This is an inexpensive and simple test.

Fluorescence Spectroscopy. Small noninvasive probes that can be swept across the surface of the cervix to detect cancer are showing promise as an effective screening tool for cervical cancer. One probe emits a laser light. The head of the probe catches the return signals from the woman's cervical cells and compares them with a computer library of cancer cells. In one comparison test, fluorescent spectroscopy was more accurate than the Pap smear but not as effective as other screening methods.

Other Investigative Tests. Experts are working on an antibody-based method for improving the identification of true cancerous cells in a cervical smear, which could significantly reduce the need for expensive and distressing tests in women who do not actually have cancer. In addition, they are looking for biologic markers to improve diagnosis, such as specific proteins that indicate the presence of cancer cells.

The cells viewed in a cervical smear sample are classified on a scale representing the spectrum of cell changes from normal to cancerous. The smear is first characterized as either "normal" or "abnormal."

Once abnormal cells are identified, the doctor must decide whether the patient needs only repeat Pap smears, a test for the human papilloma virus (HPV) virus, or colposcopy (a procedure used to magnify the cervix and permit detection of lesions for biopsy). To help the doctor make the decision, the abnormal cells are divided into categories, depending on the degree of abnormality. These classifications are based on the 2001 Bethesda System (TBS), which is formulated to standardize the reporting of Pap test results.

Atypical Squamous Cells. Atypical squamous cells (ASC) are mildly abnormal cells on the surface of the cervix. They may simply represent inflammation. Over 80% of these cells normalize, but unfortunately, between 5 - 17% of these women have a chance for having cervical intraepithelial neoplasia II and III dysplasia (potentially invasive cells). Researchers have further categorized atypical squamous cells as the following:

ASCUS. These atypical squamous cells of undetermined significance are the lowest risk abnormal cells. Women with these cells should be tested for human papillomavirus infection (HPV). If results indicate they are infected with HPV, they should receive colposcopy, a more invasive diagnostic procedure, to determine if the condition is actually at a more aggressive stage. If they do not have HPV they are simply monitored with repeat Pap smears.
ASC-H. This category refers to the presence of atypical squamous cells, but a doctor cannot exclude possible high-grade squamous intraepithelial lesions. Such women have a 24 - 94% chance of having cervical intraepithelial neoplasia II and III. All are referred for colposcopy.

Among those with atypical squamous cells, immunosuppressed women and those with high-risk human papilloma virus infections are at higher risk for cervical intraepithelial neoplasia II and III and should always be given colposcopy. Postmenopausal women with normal immune systems have a lower risk than younger women. It should be strongly noted, however, that actual risk for cervical cancer in general in women with atypical squamous cells is only 0.1 - 0.2%.

Low Grade Squamous Intraepithelial Lesions. Low-grade squamous intraepithelial lesions (LSIL) are typically associated with human papilloma virus changes, with or without early dysplasia. Between 15 - 30% of women with LGIL, however, may have cervical intraepithelial neoplasia II or III on biopsy. Women with LSIL are either monitored with repeat Pap smears or given colposcopy. Doctors recommending colposcopy argue that these are high-risk women who risk delaying a diagnosis of cancer using only repeat Pap smears.

High-Grade Squamous Intraepithelial Lesions. High-grade squamous intraepithelial lesions (HSIL) are associated with moderate dysplasia and other cervical intraepithelial neoplasia II or III. Such women are always referred to colposcopy for biopsy. Even if colposcopy results report only cervical intraepithelial neoplasia I, over a third of these women are likely to have cervical intraepithelial neoplasia II or III. Experts, therefore, recommend a careful review of the tests in such cases. Pregnancy poses a problem since it increases the chance in HSIL for both normal and abnormal results. In nonpregnant women, particularly when fertility is not an issue, immediate treatment with loop electrosurgical excision procedure may be appropriate.

Atypical Glandular Cells. Atypical glandular cells are uncommon, but pose a higher risk for cancerous changes than atypical squamous cells or low-grade squamous intraepithelial lesions. Between 9 - 54% have some cervical intraepithelial neoplasia, 0 - 8% have pre-invasive cancer, and 1 - 9% have invasive cancer. Doctors recommend that the next step should be a colposcopy (rather than a repeat Pap smear).

The Pap smear shows only the presence of abnormal cells. It is useful simply as a screening test that identifies women who may have preinvasive or early cancerous changes. For a definitive diagnosis, the next step is usually colposcopy, during which the cervix is visualized under low power magnification. The surgeon takes samples of suspicious cells for biopsies. A biopsy will determine the stage of the precancerous growth or whether invasive cancer is present.

The Procedure. Colposcopy can be performed in a doctor's office without anesthesia in 10 - 15 minutes. It causes about as much discomfort as mild menstrual cramps:

First, using a speculum to keep the vagina open, the doctor aims a light at the cervix.
The doctor then looks through the eyepiece of a special microscope, known as a colposcope, to view the cervix. (Some colposcopies include a TV attachment that transmits the picture to a nearby monitor for easier viewing.)
A biopsy (a sampling of the tissue) is taken of suspicious areas, of the endocervical canal (the inner part of the cervix and uterus), and any abnormal-looking areas. This may cause cramping or pinching.

Click the icon to see an image of a colposcopy-directed biopsy.

After the colposcopy, the woman may have a brownish discharge from an iron solution called Monsel's solution, which the doctor applies to prevent bleeding. The doctor usually advises sexual abstinence for 1 - 2 weeks.

Follow-Up Procedures. Women with evidence of cervical intraepithelial neoplasia (CIN) or cervical cancer require treatment. Women with biopsies that show low-grade abnormal cells (LGSIL), but whose cervix is otherwise normal, are generally given follow-up colposcopies.

Treatment for Cervical Intraepithelial Neoplasia and Pre-invasive Cancer

Treatment of cervical intraepithelial neoplasia (CIN), including pre-invasive cancer, depends on the type and extent of abnormal changes. Some of the treatments for CIN are also used for early-stage cancer.

CIN I often goes away on its own. Careful follow up is required to make certain that the Pap smear and colposcopic exam return to normal.
CIN II or CIN III may turn into invasive cancer if the suspicious area is not removed. This is often done using an outpatient technique called loop electrosurgical excision procedure (LEEP). [See next section.]
If doctors cannot see extensive areas of CIN II or III with colposcopy or if they sthese areas pread into the mucous membrane in the cervical canal, a more aggressive procedure called conization (cone biopsy) may be required.

The cold cone biopsy is a surgical procedure that requires general anesthesia. It is performed when there are severe precancerous changes in the cervix.

Treatment for Adenocarcinoma. An adenocarcinoma is cancer inside tissue that looks like or functions as a gland. (A gland is a group of cells that secretes a substance to be used by or removed from the body.) Adenocarcinomas tend to be more aggressive than the more common pre-invasive cancer, which grows in the lining of tissue (mucous membrane). Some evidence suggests that adenocarcinomas develop in numerous sites rather than a single location. Hysterectomy is generally recommended. For women who wish to retain fertility, a docotor may perform a cone biopsy, although this procedure sometimes causes sterility and it does not always remove all adenocarcinomas.

Follow-Up. Patients treated for CIN need to be monitored. Testing for human papilloma virus (HPV) may prove to be useful in determining whether repeat colposcopies may or may not be needed. One study strongly suggested that if both HPV and Pap smear tests are normal on two consecutive visits, treatment most likley was successful. If either the HPV or Pap smear is abnormal, it may be reasonable to consider another colposcopy.

Loop electrosurgical excision procedure (LEEP), also called large loop excision of the transformation zone (LLETZ), uses a high frequency electrical current to cut away diseased tissue.

A local anesthetic is applied to the cervix, and a wire loop is inserted into the vagina.
A button-sized slice of tissue is removed from the cervix for examination.
A deeper slice is used to evaluate the endocervical canal.

The procedure is done in one office visit. Extensive and deep sections of damaged tissue can be effectively removed in this visit. Disease can be cured in one treatment. When used for dysplasia, it appears to be as effective as more invasive procedures.

The only downside of LEEP may be its simplicity. Doctors may be tempted to use it for more serious conditions best treated by a procedure called conization. It also may impair the ability to detect hidden invasive cancer. Patients should be monitored closely if the biopsies on the cervical tissue removed by LEEP suggest that the cells may become invasive.

LLETZ is becoming increasingly popular as a treatment for cervical intraepithelial neoplasia. However, women of child-bearing age should be aware that it may later cause pregnancy problems, such as preterm delivery and low birth weight. Women who have this procedure may also be more likely to break their water too early (premature rupture of membranes).

Conization is a surgical procedure that removes suspicious sections of cells covering an abnormally large area, or those extending into the cervical canal. Conization is preferred over Loop electrosurgical excision procedure (LEEP) or large loop excision of the transformation zone (LLETZ) for lesions that are so big they require a larger biopsy for their complete removal. As in LEEP, patients should be monitored closely if patients are infected with human papilloma virus (HPV) virus or the biopsies on the cervical tissue removed show aggressive-grade cells.

The surgery can be performed under general anesthesia in the operating room with either traditional surgical instruments or lasers.

A technique called frozen section examination (FSE) freezes the margins of the area being removed. Studies suggest that FSE allows immediate and precise evaluation of areas that may harbor invasive cancer cells, and may be an important addition to this procedure in women with high-grade cervical intraepithelial neoplasia.

With conization, the ability to become pregnant can be preserved in many (but not all) cases. In women who do become pregnant, some studies have indicated that this procedure increases the risk for low-birth weight infants, so careful prenatal care is essential. Conization can also increase the risk for preterm delivery and Cesarean section. Patients who have this treatment must have follow-up evaluations.

Cryosurgery is not usually feasible for large abnormal areas. The procedure removes abnormal, but noncancerous, tissue by freezing it. Cryosurgery can be performed in a doctor's office in 15 minutes without medication.

The vagina is opened with a speculum and a probe transmits gas (either nitrous oxide or carbon dioxide), which freezes the surface of the cervix.
The gas is applied for 3 minutes or until ice crystals form on the targeted tissue.
After waiting 3 minutes, freezing can be repeated for another 3 minutes.

Click the icon to see an image of cervical cryosurgery.

Side effects from this procedure include cramping, sometimes painful, for a few hours or days and a heavy, watery discharge for 2 - 4 weeks. The discharge can be irritating, have a bad odor, and may be blood-tinged. Symptoms that may indicate serious complications are fever and chills, heavy clotted bleeding, or extreme pain in the abdomen or back.

The patient may have a temporary change in menstrual periods. The menstrual periods may be heavier or lighter, or come later or earlier. Tampons, douching, bathing, swimming, and intercourse should be avoided for several weeks after cryosurgery to prevent infection.

Patients who have this treatment must be willing to commit to regular follow-up examinations.

Treatment for Cervical Cancer

In contrast to cervical intraepithelial neoplasia, cervical cancer represents true invasion of cells beyond the epithelium into surrounding tissue. Cervical cancer may be detected in a biopsy performed during colposcopy for an abnormal Pap smear, or it may be visible to the naked eye when the doctor performs a speculum exam.

Imaging Tests to Determine Extent of Tumor Spread. If a biopsy detects invasive cancer, the patient will need additional tests to find out how far the cancer has spread. How fart the cancer has spread determines whether the cancer is operable.

An abdominal computed tomography (CT) scan is commonly used to check for spread of the disease to lymph nodes and areas around the pelvic area.

In computed tomography (CT), a thin x-ray beam rotates around the area of the body. Using very complicated mathematical processes called algorithms, a computer is generates a 3-D image of a section of the body.

Other procedures may be used to find out if cancer has spread to areas around the uterus. X-ray images are taken of the bladder and urinary system (known as intravenous pyelography, or IVP) or of the lower intestinal tract (known as a barium enema).

Click the icon to see an image of intravenous pyelography.

Click the icon to see an image of a barium enema.

If these tests detect cancer in any of these surrounding sites, the patient will need more tests :

Cystoscopy is performed to examine and take tissue from the bladder for biopsy.

Click the icon to see an image of cystoscopy.

Sigmoidoscopy is used to evaluate the rectum. (In this procedure and a cystoscopy, a tube with a lighting device is inserted to view internal areas.)

Click the icon to see an image of sigmoidoscopy.

Magnetic resonance imaging (MRI) is a sensitive and noninvasive procedure that is occasionally useful for finding tumors in the tissues surrounding the uterus.

Click the icon to see an image of a MRI.

Sentinel Node Biopsy. One technique is called a sentinel node biopsy. It has been used in patients with breast cancer to help determine if cancer has spread beyond the lymph nodes. It is now being investigated for patients with early cervical cancer and may be helpful in determining which patients need to have lymph nodes removed in their pelvic area:

The procedure uses an injection of a tiny amount of a blue dye, into the tumor site.
These substances then flow via the lymphatic system into the sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If these nodes do not show signs of cancer, the rest of the lymph nodes may be cancer-free, making further removal of lymph nodes unnecessary.

After making a diagnosis, the doctor will classify the stage of the cancer according to how far the disease has spread into the lining of the cervix, throughout the cervix, or beyond. Doctors use these classifications to determine treatment and outlook.

Patients who have been diagnosed with cervical cancer need to know the normal treatments for their particular stage, so they may compare their doctor's suggestions with these norms.

Stage 0 is pre-invasive cancerconfirmed by biopsy and confined to the first layer of cervical tissue (the epithelium). Treatment options include loop electrosurgical excision procedure (LEEP), laser therapy, conization, and cryotherapy.

Stage I is invasive cancer, but the tumor is confined to the cervix. This stage is further categorized as IA and IB.

Stage IA. Five-year survival rates for stage IA can be 95% or more.

In stage IA1 cancer cells are microscopic, there is minimal invasion (less than 3 mm) into the supportive tissue around the cervix (the stroma), and the horizontal extent of the tumor is less than 7 mm. Treatment is usually a simple hysterectomy. Conization is sometimes possible for women who want to remain fertile and who have a nonaggressive tumor that has spread less than 3 mm, with no lymph or blood vessel involvement. Trachelectomy has been investigated for women who want to preserve fertility. More research is needed.
In stage IA2 there is deeper invasion (greater than 3 mm but less than 5 mm) and the horizontal extent of the tumor is less than 7 mm. Radical hysterectomy with surgical lymph node removal (lymphadenectomy) is a common treatment.

Note on Stage IA2 through IIA: Postoperative concurrent radiation and platinum-based chemotherapy may be considered for stages IA2 through IIA tumors if the following high risk features are found at the time of primary surgery: lymph node involvement, cancerous cells found in the margins of the tumor, and involvement of the parametrium.

Stage IB and Locally Advanced Cancer. Five-year survival rates for stage IB can be 80 - 90% with either radiation or surgery. Survival rates are lower if the cancer has spread to the lymph nodes.

In stage IB1 the tumor is typically visible (not usually microscopic), and the diameter may be up to 4 cm. Radical hysterectomy with pelvic lymph node removal (lymphadenectomy) is the recommended treatment. Primary radiation can be used instead of surgery in patients who eitehr are poor surgical candidates or do not plan on being sexually active.
In stage IB2 the tumor is more than 4 cm and considered "bulky." Relapse rates after surgery are higher than in stage 1B1. Primary treatment with radiation therapy with concurrent platinum-based chemotherapy is reasonable. Some women in stage IB may receive combinations of radiation and surgery, although the benefits of such combinations are unclear for most women, particularly given a higher risk for severe side effects.

Note on Locally Advanced Cervical Cancer: Stages IB2 through IVA are often referred to collectively as locally advanced cancer and are frequently treated similarly. Standard treatment includes radiotherapy with concurrent platinum-based chemotherapy. Experimental approaches for some women with locally advanced cervical cancer use radiation therapy with hyperthermia (high heat often provided by ultrasound) and neoadjuvant (preoperative) chemotherapy and radical surgery. More research is necessary.

Stage II invasive cancer has spread beyond the cervix, but it has not spread to the pelvic side wall. This stage is further categorized as IIA and IIB.

Stage IIA. Cure rates for stage IIA can be as high as 75 - 80% with either radiation or radical hysterectomy. Survival rates are lower if cancer has spread to the lymph nodes. In stage IIA, cancer has spread to the upper two thirds of the vagina but not to the parametrium (the connective tissue between the pelvic floor and upper part of the cervix). Radical hysterectomy with pelvic lymph node removal (lymphadenectomy) is the recommended treatment. Primary radiation can be used instead of surgery in patients who eitehr are poor surgical candidates or do not plan on being sexually active. If the tumor is bulky, however, primary treatment with radiation therapy with concurrent platinum-based chemotherapy is reasonable. Some women in stage IB may receive combinations of radiation and surgery.

Stage IIB. For stage IIB 5-year survival rates are about 60%. In stage IIB the cancer has spread to the parametrium. Recommended treatment is radiation therapy with concurrent cisplatin-based chemotherapy.

In stage III, the cancer is invasive, extending to the lower third of the vagina (stage IIIA) or to the side walls of the pelvis (stage IIIB). The kidney may be affected. Recommended treatment is radiation therapy with concurrent cisplatin-based chemotherapy. Five-year survival rates are about 40%.

In stage IV, invasive cancer has spread beyond the pelvis or to the mucosal lining of the bladder or rectum. Five-year survival rates are less than 20%.

Stage IV. In stage IVA, the cancer has spread to the inner lining of the bladder or rectum. Recommended treatment is radiation therapy with concurrent cisplatin-based chemotherapy.

Stage IVB. In stage IVB, the cancer has spread beyond the pelvis. Recommended treatment is radiation therapy to relieve symptoms and chemotherapy (usually cisplatin or carboplatin combined with other drugs such as topotecan). Platinum-based chemotherapy yields short-lived response in 20% of patients. Clinical trial participation is reasonable.

Cervical cancer may recur locally in the lymph nodes near the cervix, it may spread to distant sites, such as the lung or bones, or it may appear both locally and in distant locations.

Recommended treatment is pelvic exenteration if cancer has spread to only local areas. (This involves removal of the cervix, uterus, vagina, and perhaps the bladder, lower colon, or rectum. It is an aggressive surgical approach that may lead to cure in a small percentage of patients with recurrent cervical cancer.) Radiotherapy is another option if it is technically possible -- generally if patients did not have it previously. If cancer has spread, platinum-based chemotherapy is reasonable. Other drugs may be useful under certain circumstances.

Only 1% of cervical cancers occur during pregnancy or shortly afterwards. To diagnose the condition, a cervical biopsy, in which a small amount of tissue is removed for diagnosis, can be performed anytime during the pregnancy. However, a cone biopsy, which removes larger amounts of tissue, is typically delayed until after the first trimester to reduce the risk of abortion. Treatment options may be as follows:

If the abnormality is diagnosed as dysplasia or even pre-invasive cancer, treatment is sometimes delayed until a few weeks after the mother gives birth, and vaginal delivery may still be possible. The pregnant woman should discuss the risks and benefits of this approach, however, with her doctor.
If early-stage cancer is diagnosed in the late second or third trimester, a woman may sometimes be able to delay treatment until the baby is delivered. A Cesarean section is the preferred delivery method. The cancer treatment of choice is started shortly afterward.
More locally advanced invasive cancer is nearly always treated, particularly if is diagnosed within the first 20 weeks of the pregnancy.

Treatment for Invasive Cervical Cancer

Radiation therapy and surgery are about equally effective as a single option for treating very small cervical cancers in their earliest stages. Survival rates in the appropriate patients can be about 85 - 90%. Factors influencing the choice between radiation therapy and surgery in women with invasive cancer include the patient's age and health and the amount of cancer. Both surgery and radiation therapy eliminate the possibility of having children in premenopausal women.

Although treatments for cervical cancer have several potentially severe side effects, they are usually well-tolerated. Women undergoing any of these treatments should feel free to seek support groups and counseling, which can be as important for their outlook as medical therapies.

Surgery. Surgery almost always involves a hysterectomy, an operation that removes the uterus and sometimes other areas in the pelvic region as well. It does not, however, usually impair sexual activity.

In general, surgery is the better choice when small cancers are confined to the cervix in women who wish to remain sexually active.

Radiation. Radiation treatments to the pelvis often inhibit ovarian function. Early menopause often occurs. Radiation also may cause vaginal scarring. Treatments are available that may reduce these problems, and women should not be shy about discussing them with their doctor. Radiation therapy is usually the choice under the following circumstances:

Cancers have spread beyond the cervix to the pelvis, lower vagina, and urinary tract.
When certain tumor features indicate a high risk for recurrence after surgery.

Important studies now strongly suggest that radiation along with chemotherapy can improve survival rates improve in patients with stages IB to IVA compared to radiation alone. The benefits are greatest in stages I and II.

In the early stages of cervical cancer, surgery is often the preferred primary treatment approach since it preserves normal sexual function. Some patients desiring fertility who have early stage I cancer may be candidates for cervical cone biopsy.

Hysterectomy. A hysterectomy attempts to eliminate the cancerous tissue by removing the uterus. There are several variations of this operation, depending on the location of the tumor. In women of childbearing age, the ovaries can usually be left intact. Although a woman who has a hysterectomy but retains her ovaries cannot bear children, she will not go into premature menopause. (Studies indicate that leaving the ovaries intact is safe for most women and does not pose any greater risk for cervical cancer recurrence.)

A simple hysterectomy involves the removal of the uterus and the cervix, but leaves the parametrium (tissue surrounding the uterus) and vagina intact. Lymph nodes in the pelvis are not usually removed.

Click the icon to see an illustrated series detailing a hysterectomy.

A radical hysterectomy removes not only the uterus and the cervix but also the parametrium, the supporting ligaments, the upper vagina, and some or all of the local lymph nodes (a procedure called lymphadenectomy).

If the cancerous tumor recurs within the pelvis after primary treatment, the patient may need a more extreme procedure called a pelvic exenteration, which combines radical hysterectomy with removal of the bladder and rectum. (In such cases, plastic surgery may be needed afterward to recreate an artificial vagina.) Patients undergoing this procedure are physically and psychologically screened in advance to determine whether it is an appropriate choice. The success rate for pelvic exenteration in halting the progression of the disease is about 25 - 45%.

Any form of hysterectomy is major surgery and requires at least a 3 - 5 day hospital stay. Although hysterectomy typically uses a wide abdominal incision, less invasive techniques that allow shorter recovery time may be possible for some women with early stage cancers if performed by experienced surgeons.

Side effects include difficulty emptying the bladder or bowels and a painful lower abdomen. Urinary tract infections are very common. Complications include fistulas (abnormal channels within the pelvis, which in this case are a result of surgery), bladder dysfunction, and cysts.

Normal activity, including intercourse, can be resumed in about 4 - 8 weeks. Once the uterus is removed, menstruation will cease. If the ovaries are removed, the symptoms of menopause will begin. These symptoms are likely to be more severe in surgical menopause than in natural menopause. The pateint should discuss the benefits and risks of hormone replacement therapy with her doctor.

Trachelectomy. An experimental procedure called trachelectomy is being investigated for preserving fertility in certain women in early-stage cervical cancer, but it is highly controversial and appropriate in only about 5% of patients. In the procedure, only the cancerous portion of the cervix is removed, while the uterus and the rest of the cervix are left intact. The cervix is closed with a suture.

The procedure is primarily performed outside the U.S., and few American surgeons are skilled in this surgery at this time. Throughout the world, in fact, only about a few hundred of these procedures have been performed to date. Larger and longer-term studies are needed to confirm its long-term safety.

Radiation therapy is an alternative approach for early stage cervical cancer. Radiation with concurrent cisplatin-based chemotherapy is now the standard treatment for locally advanced cervical cancer. Radiation therapy uses high-energy rays aimed at the body from an outside machine (external beam radiation) and radioactive materials placed inside the body against the cervix (intracavitary radiation).

External beam radiation is given first and aimed at the lymph nodes along the pelvic wall. It usually involves a short period of direct-radiation 5 days a week for about 6 weeks in an outpatient setting.
Intracavitary radiation (also called brachytherapy) follows and is designed to deliver high doses of radiation to the local tumor area. Radioactive material, typically cesium-137, is encapsulated in both gold and platinum. These capsules are inserted in a long stainless steel tube called a tandem, which is inserted in the uterus. and in small stainless steel cylinders, called colpostats, which are placed against the cervix as close to the cancerous cells as possible. Commonly, two or more radiation treatments are administered for about 35 hours each time. Radiation implants may also be inserted directly into the tumor using a needle.

In order to be effective, radiation therapy must be powerful enough to destroy the cancer cells' capacity to grow and divide. This means that normal cells are also affected, which may cause significant side effects. Fortunately, healthy cells usually recover quickly from the damage, whereas abnormal cells do not.

Advanced methods that target radiation more precisely and limit the damage to healthy tissue are now available. They include 3-D conformal radiation and intensity-modulated radiation therapy (IMRT):

3-D conformal techniques use computers and a three-dimensional image of the cervix to provide precise targeting of the tumor using multiple high-dose radiation beams.
IMRT also uses 3-D techniques and employs very thin and precise beam at various intensities.

Side Effects. Side effects of radiation therapy include fatigue, redness or dryness in the treated area, diarrhea, frequent or uncomfortable urination, and vaginal dryness, itching, or burning. After treatment, side effects usually disappear.

Long-Term Complications. Complications include proctitis (inflammation of the rectum) and cystitis (inflammation of the bladder). Bowel obstruction is an uncommon complication. Radiation therapy may also cause vaginal scarring, sexual difficulties, and premature menopause in younger women. Occasionally an abnormal tunnel between the bladder and the vagina, known as a vesicovaginal fistula, will develop and may require surgery.

Click the icon to see an image of the female anatomy.

Investigative temporary silicone implants or a noninvasive device called the belly board may protect the small intestine during radiation therapy and help reduce complications.

Radiation itself may increase the risk for later development of cancer in the area surrounding the treated tissue. Although newer more precise radiotherapy approaches should reduce this risk, there is some concern that IMRT may double the incidence of secondary cancers over time compared to 3-D conformal techniques. This is of particular concern in younger patients.

Radiation and Hyperthermia. Investigators are studying hyperthermia (use of high heat often provided by ultrasound) in combinations with radiation therapy. This approach has shown some promise in achieving significant response rates in small studies. Comparison studies are important to determine if this approach would be as beneficial with radiation therapy as concurrent chemotherapy.

Chemotherapy uses cell-killing drugs called cytotoxic drugs to destroy widespread cancer cells that have spread from the primary tumor and can no longer be treated with surgery or radiation.

For many years, chemotherapy was only used to reduce symptoms in women with very advanced disease. Today, platinum-based chemotherapy drugs (see below) are being used in many situations for cervical cancer, such as:

In combination with radiation therapy to improve survival rates in certain women, including some with locally advanced cancer.
In some women with locally advanced cancer to reduce tumors to the point where the cancer may be operable.
When cancer has spread (metastasized), mostly to reduce symptoms such as pain.

Platinum-Based Drugs. Platinum-based drugs cisplatin and carboplatin are often used for treating various stages of cervical cancer. These drugs are usually used in combination with radiation therapy or other chemotherapy drugs. In 2006, the FDA approved a combination of cisplatin and topotecan (another type of chemotherapy drug) for treatment of late-stage cervical cancer in women who are unlikely to be helped by surgery or radiation therapy. Women with stage IVB cervical cancer who received the combination treatment survived around 3 months longer (9.5 months versus 6.5 months) than women who received only cisplatin.

Other drugs. Other drugs, mostly used in combinations, have also been investigated with some promise. They include epirubicin, irinotecan, paclitaxel, bleomycin, mitomycin, vinorelbine, gemcitabine, and doxifluridine.

Administration. Chemotherapy may be given by mouth or as an injection. This may be done at a medical center, doctor's office, or even a patient's home. Some patients receiving chemotherapy may need to remain in the hospital for several days so the effects of the drugs can be monitored. The drugs are often given in cycles with a period of rest following a period of treatment, to allow recovery from the side effects.

Side Effects. Chemotherapy affects all fast-growing cells, including healthy ones. So, side effects are inevitable. Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs.
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Anemia
Depression

Complications. Serious short- and long-term complications can also occur and may vary, depending on the specific drugs used. They include:

Increased chance for infection. Chemotherapy suppresses the immune system.
Severe drop in white blood cell count (neutropenia). Certain drugs, such as taxanes, pose a higher risk for this than other chemotherapeutic drugs. White blood cell count may be improved with the addition of a type of drug called granulocyte colony-stimulating factor (either filgrastim or lenograstim).
Liver and kidney damage.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based drugs. (A simple skin test that may identify people with a potential allergic response is under investigation .)
Menstrual abnormalities. These are common. Premature menopause occurs in about 30% of women, particularly in those over 40.
Secondary cancers such as leukemia (rare).
Problems in concentration, motor function, and memory, which may be long-term. Between a quarter and a third of women report such problems. This may be due to a drop in estrogen levels after treatments.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.acog.org -- American College of Obstetricians and Gynecologists
www.ashastd.org -- American Social Health Association
www.arhp.org -- Association of Reproductive Health Professionals
www.nccc-online.org -- National Cervical Cancer Coalition
www.cervicalcancercampaign.org -- Cervical Cancer Public Education Campaign
www.fda.gov/womens/getthefacts/hpv.html -- FDA HPV Fact Sheet
www.thegcf.org -- Gynecologic Cancer Foundation
www.wcn.org -- Women's Cancer Network
www.plwc.org -- People Living with Cancer
www.gothpv.net -- HPV Support Site

References

Ault KA; Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007 Jun 2;369(9576):1861-8.

Committee on Infectious Diseases. Prevention of human papillomavirus infection: provisional recommendations for immunization of girls and women with quadrivalent human papillomavirus vaccine. Pediatrics. 2007 Sep;120(3):666-8.

Davey E, d'Assuncao J, Irwig L, Macaskill P, Chan SF, Richards A, et al. Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study. BMJ. 2007 Jul 7;335(7609):31. Epub 2007 Jun 29.

D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007 May 10;356(19):1944-56.

Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007 Feb 28;297(:813-9.FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007 May 10;356(19):1915-27.

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007 May 10;356(19):1928-43.

Gunnell AS, Tran TN, Torrang A, Dickman PW, Sparen P, Palmgren J, et al. Synergy between cigarette smoking and human papillomavirus type 16 in cervical cancer in situ development. Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2141-7. Epub 2006 Oct 20.

Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among youngwomen with preexisting infection: a randomized trial. JAMA. 2007 Aug 15;298(7):743-53.

Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Quadrivalent human papillomavirus vaccine: Recommendations of the AdvisoryCommittee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007 Mar 23;56(RR-2):1-24.

Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ. 2007 Jul 7;335(7609):28. Epub 2007 May 21.

Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007 Jan-Feb;57(1):7-28.

Sturgis EM, Cinciripini PM. Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer. 2007 Aug 27; [Epub ahead of print]Weller SC, Stanberry LR. Estimating the population prevalence of HPV. JAMA. 2007 Feb 28;297(:876-8.

Review Date:
9/1/2006
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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Colon and rectal cancers

FitSugar — Wed, 08 Oct 2008 17:35:05 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Dietary Factors
Prevention
Diagnosis
Staging
Prognosis
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HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In September 2006, the Food and Drug Administration approved panitumumab (Vectibix) for the treatment of patients with colorectal cancer that has spread to other parts of the body following chemotherapy. Like cetuximab (Ertibux), panitumumab targets the epidermal growth factor receptor (EGFR) on cancer cells. Panitumumab is the first new colorectal cancer drug approved since 2004. The FDA granted accelerated approval to panitumumab based on a clinical trial of patients with metastatic cancer. The average time to disease progression or death was 96 days in patients treated with panitumumab compared to 60 days in patients who received standard care.

Diet and Colorectal Cancer Recurrence

Evidence indicates that diet plays a role in colorectal cancer prevention. Now, a 2007 study in the Journal of the American Medical Association (JAMA) suggests that dietary factors also affect the risk of cancer recurrence. Patients with stage III colorectal cancer who ate lots of red meat, refined grains, and sweets had a higher risk of cancer recurrence and death than patients whose diets were high in fruits and vegetables, poultry, and fish.

Folic Acid No Good for Prevention?

Many experts have long believed that folic acid supplements may help protect against colorectal cancer. But according to a 2007 JAMA study, high-dose folic acid supplements may not prevent colorectal cancer and may actually increase the risk for adenomatous polyp formation. Adenomatous polyps are benign colorectal tumors that can potentially become cancerous. In the study, patients who took folic acid supplements had a greater risk of developing new, more numerous, and larger adenomatous polyps than patients who did not take the supplements.

NSAIDS Not Recommended for Colorectal Cancer Prevention

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer in people who are at average risk for this disease. Several recent studies have indicated that aspirin, and NSAIDs such as celecoxib (Celebrex), can help prevent colorectal cancer. But the USPSTF notes that the risks of these drugs outweigh the benefits. Long-term daily use of NSAIDs increases the risk for gastrointestinal bleeding, kidney function problems, and heart attack and stroke.

Introduction

Cancers of the colon and rectum, often referred to collectively as colorectal cancer, are life-threatening tumors that develop in the large intestine.

More than 80% of colorectal tumors evolve from adenomatous polyps. These gland-like growths develop on the mucous membrane that lines the large intestine. They are usually either:

Tubular polyps, which protrude mushroom-like
Villous adenomas, which are flat and spreading and are more apt to become malignant (cancerous)

Polyps are very common and almost always benign. Their numbers increase with age. Polyps are found in about 25% of people by age 50, and 50% of people by age 75. Fewer than 1% of polyps under 1 centimeter (slightly less than half an inch) become cancerous. About 10% of larger polyps become cancerous within 10 years, and about 25% of these larger polyps become cancerous after 20 years. Certain inherited polyps can become cancerous more rapidly.

Digestion takes place in the gastrointestinal (GI) tract, essentially a long tube that extends from the mouth to the anus. It is a complex organ system that first carries food from the mouth down the esophagus to the stomach. Food then travels through the small and large intestines before being excreted through the rectum and out the anus.

The esophagus, stomach, large and small intestine -- aided by the liver, gallbladder, and pancreas -- convert the nutritive components of food into energy and break down the non-nutritive components into waste to be excreted.

The esophagus is a narrow muscular tube, about 9 1/2 inches long that begins below the tongue and ends at the stomach.

In the stomach, acids and stomach motion break food down into particles small enough so that the small intestine can absorb nutrients.

Click the icon to see an image of stomach anatomy.

The small intestine, despite its name, is the longest part of the gastrointestinal tract, extending for about 20 feet. Food passes from the stomach through its three parts: first the duodenum, then the jejunum, and finally the ileum. Most of the digestive process occurs in the small intestine.

Click the icon to see an image of small intestine anatomy.

Undigested material, such as plant fiber, is passed next to the large intestine, mostly in liquid form. The large intestine is wider than the small intestine but only about 6 feet long. It is the final portion of the digestive tract and includes the cecum, the appendix, the colon, and the rectum, which extends to the anus.

Cecum and Appendix. The cecum and the appendix are located in the lower-right quadrant of the abdomen.

Colon. The colon absorbs excess water and salts into the blood. The remaining waste matter is converted to feces through bacterial action. The colon is divided into four major sections.

Click the icon to see an image of large intestine anatomy.

The first section, the ascending colon, extends upward from the cecum on the right side of the abdomen.
The second section, the transverse colon, crosses the upper abdomen to the left side.
The third section extends downward on the left side of the abdomen toward the pelvis and is called the descending colon.
The final section is the sigmoid colon.

Rectum and Anus. Feces are stored in the descending and sigmoid colon until they are passed through the rectum and anus. The rectum extends through the pelvis from the end of the sigmoid colon to the anus.

Causes

In most cases of colon or rectal cancers, the cause or causes are unknown. Defects in genes that normally protect against cancer play the major role in causing polyp cells to continuously spread and become cancerous. Some of these cases are caused by inherited genetic defects, and such patients usually have family histories of colorectal cancer. Most of the genetic mutations involved in colon cancers, however, appear to arise spontaneously (no strong family history) rather than being inherited. In such cases, environmental or other factors trigger genetic changes in the intestine that lead to cancer.

About 6% of cases of colon cancer are due to inherited factors.

APC Gene and Familial Adenomatous Polyposis (FAP). When the adenomatous polyposis coli (APC) gene is normal, it helps suppress tumor growth. In its defective form, it permits high levels of the protein beta-catenin to accumulate, which accelerates cell growth leading to polyps. Various genetic mutations that affect the APC gene directly or indirectly have been identified:

Familial adenomatous polyposis (FAP) is a rare and serious disorder in which the patient inherits an adenomatous polyposis coli (APC) mutation from either parent. It occurs in about 1 in 8,000 people. During early adulthood, hundreds to thousands of polyps grow in the colon. FAP causes less than 1% of all cases of colorectal cancer, but if untreated, virtually everyone who inherits this condition develops cancer before the age of 40. Many of the deaths attributed to FAP can be prevented with early and aggressive surgical treatment.
Non-inherited mutations of the APC gene have been detected in nearly all patients with spontaneous colon cancers.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, accounts for at least half of colorectal cancers that run in families. (However, only 3% or less of all colorectal cancers are due to this problem). About 50 - 80% of people who inherit the abnormal gene will develop colon cancer. HNPCC tends to develop in the right side of the colon, often in young individuals. (Left-sided cancers can still occur as well.)

People who inherit HNPCC and other defects are prone to other cancers, including uterine and ovarian cancers, as well as cancers of the small intestine and kidney system (very rare). HNPCC is highly associated with genes containing an abnormality called microsatellite instability (MSI), which is a sign of defective DNA repair. Testing tumors for MSI in people with newly diagnosed colon cancer who also have a family history of the disease may prove to be an effective method for identifying patients with hereditary nonpolyposis colorectal cancer. Tests are being developed that can detect the actual HNPCC genetic abnormality (mutation) that was inherited from a father or mother. The two most commonly affected genes are MSH2 and MLH1.

Cyclooxygenases and Prostaglandins. Cyclooxygenase 1 and 2 (COX-1 and COX-2) are enzymes involved in the production of prostaglandins, substances produced by the body that cause inflammation, widen and narrow blood vessels, control muscle contractions, and inhibit hormones that regulate fat metabolism. COX-2, but not COX-1, appears to play a role in the development and spread of colorectal tumors. COX-2 increases the levels of prostaglandin E2 (PGE2), which, in turn, stimulates factors that inhibit apoptosis, the natural process whereby all cells, including cancerous ones, self-destruct. It also activates interleukin-6 (IL-6), a factor in the immune system that is associated with cancer cell invasion.

C-Reactive Protein (CRP). CRP is another indicator of inflammation. In a 2004 study published in the Journal of the American Medical Association, elevated CRP levels predicted the development of colon -- but not rectal -- cancer.

Bile Acid Salts. Deoxycholic acid, which is found in the fat-digesting bile salts released by the gallbladder, appears to have carcinogenic properties. Its effects are now believed to play a role in some cases of colon cancer. Levels of the acid can rise as a result of high-fat diets or certain diseases.

Growth Factors. Chronically higher circulating levels of growth factors, including insulin-like growth factor, have been associated with colorectal cancer.

Inflammatory bowel diseases include Crohn's disease and ulcerative colitis. These chronic disorders cause persistent injuries in the intestinal tract that can, in some cases, produce cancerous changes.

Symptoms

It is possible to have colon or rectal cancer without symptoms. Many patients are free of symptoms until their tumors are quite advanced.

Weight loss and changes in bowel movements are general symptoms for colon cancer, but these symptoms also occur in many other diseases.

Blood in the stools is a common sign of many intestinal cancers. It may appear red if it is fresh or black if it is old. It should be reported to a doctor immediately, even though it is often caused by conditions other than cancer, including:

Hemorrhoids
Minor tears around the rectal or anal areas
Diverticulosis

In addition, stool can change color by:

Eating certain red foods, such as beets or red licorice (red)
Taking iron supplements and medications that have bismuth subsalicylate, most commonly Pepto-Bismol (black)

Nevertheless, blood in the stools is an abnormal finding that should never be ignored. Always report it to your doctor for further advice.

Symptoms of colorectal cancer vary widely depending on the location of the cancer within the large intestine.

Tumors in the Cecum and Ascending Colon (Right Colon). The waste matter in the first portion of the colon is in liquid or semi-liquid form. Tumors that develop here do not change bowel habits or stool formation, but they may cause intermittent or chronic bleeding. Although the stools look normal, patients may develop symptoms of anemia from iron deficiency. Such symptoms include weakness, fatigue, heart palpitations, shortness of breath, and exercise intolerance.

Tumors in the Transverse Colon. As waste material passes across the upper quadrants of the abdomen (the transverse colon), the intestine absorbs water, and the waste matter becomes more solid. In addition to bleeding, tumors here may cause cramps, gas, partial or complete obstruction, and even perforation of the bowel. Anemia can also occur.

Tumors in the Descending Colon and Rectum (Left Colon). When tumors partially block the lower intestine, thin, pencil-shaped stools may form. Bowel habits can change. Tumors in the rectum and lowest part of the intestine can cause pain and a feeling of fullness. Defecation may be painful, or patients may feel the urge to defecate but nothing happens. Bleeding from these locations may be brisk and bright red or maroon, but cancer is often detected before symptoms of chronic anemia develop.

Risk Factors

Colorectal cancer is the third most common cancer in the U.S., with Americans facing a lifetime chance of 5.5 - 6% for this cancer. In 2007, colorectal cancer was expected to cause 153,760 new cases and 52,180 deaths in the United States. About 73% of cancers occur in the colon and 27% in the rectum.

The lifetime risk of cancer of the colon or rectum is 5.9% for men and 5.5% for women.

Colorectal cancer risk increases with age. More than 90% of these cancers occur in people over age 50. The rate of colorectal cancer in patients under 20 years is less than 1 in 100,000 per year. At age 50 about 1 in 2,000 people per year will develop colorectal cancer. After age 65, this rate increases to almost 3 in 1,000.

African-Americans have the highest risk of being diagnosed with, and dying from, colorectal cancer. Among Caucasians, Jews of Eastern European (Ashkenazi) descent have an elevated rate of colorectal cancer. Asian Americans/Pacific Islanders, Hispanics/Latinos, and American Indians/Alaska Natives have a lower risk than Caucasians.

About 20 - 25% of colorectal cancers occur among people with a family history of the disease. (Seventy-five percent of cases are due to other causes.) People who have more than one first-degree relative (sibling or parent) with the disease are especially at high risk. The risk is even higher if the relative was diagnosed with colorectal cancer before the age of 60.

About 5 - 10% of patients with colorectal cancer have an inherited genetic abnormality that causes the disease. Genetic mutations associated with colorectal cancer include familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

The risks for colon cancer are far higher in industrialized nations than less developed countries. A Western lifestyle, being sedentary, smoking, and having excess weight have all been associated with increased risk for colorectal cancer. (However, about 75% of cases occur without a known predisposing factor.)

Dietary Factors. Eating a lot of red meat increases the risk for colorectal cancer. Other types of animal protein (low-fat dairy products, fish, poultry) may decrease the risk of developing polyps and colorectal cancer. Studies on fruits, vegetables, and fiber are mixed. Some evidence suggests that diets very low in fruits and vegetables may increase the risk. In any case, eating a variety of fruits and vegetables should be part of a healthy diet.

A 2007 study in the Journal of the American Medical Association suggested that diet may play a role in colorectal cancer recurrence, as well as prevention. The study evaluated patients with stage III colon cancer who had been treated with surgery and chemotherapy. Patients who ate diets high in red and processed meats, refined grains, and sweets had a higher risk of cancer recurrence and poorer survival than patients whose diets were high in fruits and vegetables, poultry, and fish.

Alcohol and Smoking. Alcohol use and smoking increase the risk for colorectal cancer. Patients who smoke and drink may also be diagnosed with colorectal cancer at a younger age than non-drinkers and non-smokers. Several studies suggest that women who smoke are at especially high risk of developing colorectal cancer.

Obesity. There is a demonstrated link between body mass and colon cancer risk for both men and women. The Centers for Disease Control and Prevention has reported that the risk of colon cancer rises as body mass index increases. Obesity has been associated biologically with higher circulating levels of insulin and a hormone called insulin-like growth factor. Chronically high levels of these substances may increase colorectal cancer risk.

Physical Inactivity. More than 50 studies from around the world suggest that physical activity helps prevent colon cancer. In contrast, exercise does not protect against rectal cancer.

Crohn's disease and ulcerative colitis are chronic afflictions of the large intestine known as inflammatory bowel diseases (IBD). Both have been linked to increased risk for colorectal cancer. (Patients with ulcerative colitis have a higher risk than those with Crohn's disease.) Family histories are helpful in determining risk associated with inflammatory bowel disease. Some studies suggest the following:

Patients with IBD who have a family history of colorectal cancer face up to a five-fold risk of colon cancer themselves.
Individuals without IBD who have relatives who suffered from both IBD and colorectal cancer may face a higher risk for developing colorectal cancer themselves.
Individuals without IBD but with a family history of IBD and no colon cancer most likely face no higher risk for cancer themselves.

Crohn's disease, also called regional enteritis, is a chronic inflammation of the intestines that is usually confined to the terminal portion of the small intestine, the ileum. Ulcerative colitis is a similar inflammation of the colon, or large intestine. These and other inflammatory bowel diseases have been linked with an increased risk of colorectal cancer.

Polyps. Polyps are tissue growths, usually benign, that develop in the color or rectum, most often in patients over 50 years of age. When pathologists examine polyps removed from the colon, they classify them as either hyperplastic or adenomatous. Both types are benign, but some adenomas will become malignant. As a preventive measure, polyps should be removed (polypectomy).

Ureterosigmoidostomy. People who have had ureterosigmoidostomy, a surgical procedure to correct a birth defect in the bladder or to treat some bladder cancers, may develop tumors near the site of the defect, which is chronically exposed to urine and feces. Such patients have a 5 - 10% chance of developing colon cancer 15 - 30 years after the operation.

Diabetes. Many studies have identified an association between type 2 diabetes and colon cancer. Both diseases share common risk factors of obesity and physical inactivity, but diabetes itself is a risk factor for colorectal cancer. Both men and women who have diabetes are at risk.

Heart Disease. Coronary artery disease (CAD) increases the risk for colorectal cancer. Both CAD and colorectal cancer share important risk factors, including smoking, high fat diet, sedentary lifestyle, and obesity.

Dietary Factors

Some, but not all, studies have suggested that a high intake of fruits and vegetables can lower the risk for colorectal cancer. One study, for example, reported that these foods do not prevent polyps from forming but may help prevent them from becoming cancerous.

Phytochemicals. Many studies have demonstrated the cancer-fighting effects of plant chemicals called phytochemicals. Fruits and vegetables that contain phytochemicals can often be identified by colors:

Dark green (broccoli, spinach, kale, collard greens, mustard greens). These vegetables contain chemicals called isothiocyanates, which have been associated with a lower risk for cancer in general.
Red (red pepper, tomatoes, watermelon, raspberries, pink grapefruit). Lycopene is a chemical found in these foods that may have strong cancer-protective properties. Cooking tomatoes appears to increase their benefits.
Yellow-orange (carrots, pumpkin, sweet potatoes, oranges, tangerines). The colors in these foods are due to carotenoids. Carotenoids have been associated with health protection, although they may not have much effect on colon cancer itself.
Blue-black (many berries). Dark berries appear to have potent antioxidant chemicals that may be protective against cancer.

Organosulfurs are important food chemicals that are part of the allium family. Studies have reported health benefits from foods containing them. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots. A review of 300 studies concluded that people who eat raw or cooked garlic regularly experience about two-thirds the risk of colorectal cancer as people who eat little or none. Another analysis, however, found the available evidence about garlic to be inconclusive. Garlic supplements, in any case, do not appear to be protective.

Fiber. Studies have been mixed on whether fiber (found in fruits, vegetables, and whole grains) protects the colon from cancer. For example, three major studies in 2002 and 2003 reported no difference in the development of colorectal polyps or cancer recurrence with high intake of fiber. On the other hand, results of the 2003 European Prospective Investigation into Cancer and Nutrition (EPIC) -- the largest study ever conducted on the role of diet in the development of cancer -- suggested that fiber is protective regardless of its source. However, in the study, the greatest benefits were observed for the left side of the colon and the least for the rectum. In any case, fiber, which is only found in plant products, may be beneficial for the heart and have other health advantages.

The role of fats in inflammatory bowel disease is complex and not fully known. A 2006 study from the Women’s Health Initiative found that a low-fat diet did not help reduce the risk for colorectal cancer. However, the study did not distinguish between types of fat.

Monounsaturated fats (olive, peanut, canola oils; avocados, nuts) and omega-3 polyunsaturated fats (fish, flaxseed oil, walnuts) are the healthiest types of fats.
Saturated fats (red meat, butter, high-fat dairy products) and trans-fats (hydrogenated fat found in snack foods, fried foods, commercial baked goods) are unhealthy types of fats.

Dietary guidelines recommend that adults limit the total fat in their diet to 25 - 35% of total daily calories. Saturated fat intake should be less than 7%, and trans fats less than 1%, of total daily calories. (Patients with heart disease or diabetes may need to limit unhealthy fat in their diet even further.) Most fats should come from polyunsaturated and monounsaturated fat sources.

[See In-Depth Report #43: Heart healthy diet; and #42: Diabetes diet.]

Evidence strongly suggests that red meat raises the risk for colon cancer development, and perhaps also recurrence. Red meat contains dietary iron, which has been associated with a higher risk for colon cancer.

High-temperature cooking (grilling, broiling, or pan-frying) has been specifically associated with increased risk for colon polyps and colon cancer. Overcooking meat increases the amount of carcinogens called heterocyclic amines, which has been associated with cancerous changes.

Milk, Lactose, and Probiotics. In one study, adults who drank the most milk had the lowest risk for colon cancer. A 2004 study published in the Journal of the National Cancer Institute supported this conclusion. In this review of 10 epidemiologic studies that included more than 500,000 people, those who consumed more milk and calcium had a lower risk of developing colorectal cancer. Milk contains not only calcium but also other compounds, such as lactose, that may help protect against colon cancer.

Yogurt specifically has been associated with a lower risk for colon cancer if it contains live active bacterial cultures, such as Lactobacillus acidophilus, that are called probiotics. These "friendly bacteria" appear to protect the colon from cancerous changes. (Acidophilus and other probiotic capsules are also available in health food stores.)

Calcium. Calcium, which is found in dairy products, is associated with colon cancer protection. Many studies have shown a possible protective effect from either high-calcium diets or calcium supplements. However, a 2006 study from the Women’s Health Initiative found that calcium and vitamin D supplements do not reduce women’s colorectal cancer risk. Many doctors still recommend that postmenopausal women take these supplements for bone health.

Obesity has been associated with colon cancer. In some studies of people under 67 years old, the amounts of fat and protein were less important than the total number of calories consumed: the higher the energy intake, the greater the risk for developing colon cancer. In older adults, high calorie intake did not make any significant difference. Other studies have indicated that eating too much sugar may increase the risk for colon cancer.

Studies conducted in several countries have found that drinking four or more cups of coffee a day is associated with a lower risk for colorectal cancer. Green tea may have also beneficial properties, but more research is needed in both of these areas.

Folate and B Vitamins. For years, many doctors have believed that the B vitamin folate (called folic acid) may help protect against colorectal cancer, particularly for people who are genetically predisposed to this disease. Folate is found in beans, citrus fruits, and green vegetables, but some studies have indicated that the greatest protective benefits come from taking supplements.

However, an important study published in 2007 in the Journal of the American Medical Association challenged this assumption. The study suggested that high-dose folic acid supplements do not prevent colorectal cancer, and may actually increase the risk for developing certain types of colorectal tumors. The study evaluated over 1,000 men and women who had a recent history of non-cancerous colorectal polyps. (Adenomatous polyps, also called colorectal ademomas, are the most common type of polyp found in colorectal cancer screenings.) The results indicated that patients who took 1 mg/day of folic acid supplements were more likely to develop new adenomatous polyps than patients who did not take supplements. Patients in the folic acid supplement group were also more likely to have advanced adenomas and more numerous adenomas.

Adenomatous polyps are benign tumors, but they can potentially develop into cancerous tumors. Researchers are continuing to investigate the role that folic acid plays in colorectal cancer risk and prevention. It is possible that folic acid may help prevent the initial appearance of adenomatous polyps, but increase the risk for additional polyp formation once they have begun to occur.

Antioxidant Supplements. Antioxidants are chemicals that help eliminate harmful particles called oxygen-free radicals that have been associated with cancerous changes. Some studies have associated supplements of the antioxidants selenium and vitamins A, C, D, and E with lower colon cancer risk, but most studies have found no protective effect.

Prevention

Studies indicate that daily exercise is one of the best ways to reduce the risk of colorectal cancer. The more vigorous the activity, the greater the benefit, but even moderate exercise (walking, stair-climbing) can help reduce colorectal cancer risk. The American Cancer Society (ACS) recommends that people engage in at least moderate exercise for 30 minutes or more at least 5 days a week. The ACS also notes that 45 minutes or more of moderate-to-vigorous activity at least 5 days a week may help further reduce cancer risk.

Some studies also suggest that regular exercise may be beneficial for patients who have been diagnosed with colorectal cancer. Two 2006 studies indicated that exercise may reduce the risk of colorectal cancer recurrence and death for patients with stage I - III cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very common pain relievers that are available over-the-counter and by prescription. They include aspirin, ibuprofen (Motrin), naproxen (Aleve), and the COX-2 inhibitor celecoxib (Celebrex). Several studies have reported that NSAIDs help reduce the risk of colorectal cancer. However, regular use of NSAIDs, even in low doses, can increase the risk of gastrointestinal bleeding and stomach ulcers. Long-term use of NSAIDs can also increase the risk for heart attack and stroke, especially in people who have a history of heart disease. Several 2006 and 2007 studies in the New England Journal of Medicine reported that celecoxib prevented precancerous polyps, but the drug more than doubled patients’ risk for heart attack and other cardiovascular events.

A 2005 Nurse’s Health Study found that aspirin, but not other NSAIDs, does provide protection against colorectal cancer. However, the risk was only reduced for women who took 2 aspirin a day for more than 10 years. In addition, this dose level greatly increases the risk for gastrointestinal bleeding. Furthermore, a 2007 study in the New England Journal of Medicine suggested that aspirin’s protective effects may only apply to some types of colorectal cancer tumors. Another 2007 study, published in the Lancet, indicated that long-term daily use of aspirin can protect against polyps and colorectal cancer, but experts agree that aspirin’s risks do not outweigh its benefits for most people. (Some people who are at high risk for developing colorectal cancer may benefit from aspirin therapy.)

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and other NSAIDs to prevent colorectal cancer in people at average risk for this disease. (This recommendation does not apply to people who have a family history of colorectal cancer or who are at high risk for developing colorectal cancer due to other risk factors.) Long-term use of NSAIDs can increase the risk for gastrointestinal bleeding, kidney function problems, and heart problems. Aspirin can also increase the risk for hemorrhagic stroke. Due to these risks, the American Cancer Society and other professional associations also recommend against the use of NSAIDs or other types of medications for colorectal cancer prevention.

Medications containing 5-aminosalicylate (5-ASA) are sometimes given to patients with ulcerative colitis to help control inflammation. These drugs, which include sulfasalazine and mesalamine, are chemically related to aspirin. A 2005 review of clinical trials found that patients with ulcerative colitis who used 5-ASA were 49% less likely to develop colorectal cancer than patients who did not use these drugs

Some studies have suggested that cholesterol-lowering statin drugs may help reduce colorectal cancer risk. A 2006 study in the Journal of the National Cancer Institute did not find any protective benefit for statins.

Estrogen has been associated with a lower risk for colon cancer, perhaps because of specific enzymes that prevent cell proliferation. Drugs containing estrogen, then, may help high-risk women:

There is some evidence that hormone replacement therapy (HRT) reduces the risk of colon cancer in postmenopausal women. It carries other risks, however, including a higher risk for breast and uterine cancer and blood clots. A 2004 New England Journal of Medicine study found that while short-term use of estrogen plus progestin reduced the risk of developing colon cancer, combination HRT users who were diagnosed with the disease had more advanced forms of the cancer. Older women who are at higher risk for colon cancer might discuss risks and benefits of HRT with their doctor.
Oral contraceptives may reduce younger women's risk of colon cancer. Duration of use does not seem to be associated with decreased risk, but protection appears stronger for women who have more recently used oral contraceptives.

Diagnosis

Colon and rectal cancers are diagnosed using the screening tests discussed below. These tests can detect precancerous polyps and colorectal cancers at stages early enough for complete removal and cure.

Unfortunately, only 30 - 40% of adults over 50 years old (mostly in the upper socioeconomic group) have regular screening tests that could detect a cancer early enough for curative treatment. A survey reported that many people are not screened because they are too embarrassed. Those who had already had the tests were willing to have them again if they saved one additional day of their lives.

There is some debate about what is the best screening method. Current screening guidelines offer several different options for patients. Doctors agree that not enough people are screened and that these tests, if adopted with the same regularity as such screening tests as Pap smears, would save many lives. It is especially important for anyone at increased risk or with symptoms, such as rectal bleeding or ulcerative colitis, to have testing at an earlier age.

There is also debate about when people should stop being screened. A 2006 study in the Journal of the American Medical Association indicated that screening provides little benefit for elderly people, especially because colorectal cancers grow very slowly. The researchers suggest that doctors should carefully consider the risks versus benefits of screening patients age 80 and older.

Individuals should discuss with their doctors the risks and benefits of all screening procedures. Some controversy exists over how often people without risk factors for cancer should be screened and which detection method should be used for them.

Guidelines for Adults Age 50 and Over with Average Risk. The following are the five screening options recommended for people age 50 and over who have no symptoms and no family history of colon cancer:

Fecal occult blood test (FOBT) or fecal immunochemical test (FIT) every year
Flexible sigmoidoscopy every 5 years
FOBT or FIT every year plus sigmoidoscopy every 5 years
Double-contrast barium enema every 5 years
Colonoscopy every 10 years

Choosing between Colonoscopy and Sigmoidoscopy. The choice between colonoscopy and sigmoidoscopy for routine screening for older adults with average risk is an area of intense debate. The issues are as follows:

Sigmoidoscopy is less costly, less invasive, quicker, and safer than colonoscopy. Although it allows inspection of only the left side of the colon, any abnormal findings from sigmoidoscopy trigger a full colonoscopy. Therefore, experts estimate that sigmoidoscopy can detect 80% of all significant problems.
Colonoscopy is more sensitive than any other current screening method for detecting colon cancer. It can find 75 - 90% of colorectal cancers. If the goal were to reduce the number of cancer cases, regardless of cost, colonoscopy would be the preferred approach. Colonoscopy, however, is more expensive than sigmoidoscopy and has a slightly higher risk for complications (bowel tears or bleeding when a polyp is removed).

There are 3 basic tests for colon cancer: a stool test (to check for blood), sigmoidoscopy (inspection of the lower colon), and colonoscopy (inspection of the entire colon). All 3 are effective in catching cancers in the early stages, when treatment is most beneficial.

Screening, particularly with colonoscopy, in increased- and high-risk populations can save lives. The most important risk factors are a family history of colorectal cancer and personal history of colorectal cancer, polyps, or chronic inflammatory bowel disease. People with these risk factors should be screened before age 50 and may need more frequent screenings.

Guidelines for Increased-Risk Groups. Anyone with first-degree relatives diagnosed with colon cancer younger than 60, or with two relatives who have been diagnosed with colon cancer at any age, should consider beginning the standard screening regimen with a colonoscopy every 5 years, beginning at age 40 or 10 years before the youngest case in the family (whichever is earlier).

Men of African descent are also considered to be at increased risk for colon cancer and should discuss similar screening guidelines with their doctors.

Guidelines for High-Risk Groups. The following guidelines may be useful for specific high-risk groups.

People who have the mutated hereditary nonpolyposis colorectal cancer gene (MSH2 or MLH-). Frequent colonoscopy (for instance, every 1 - 2 years) beginning in their early 20s. (Regular screening for other cancers, such as uterine cancer, is also reasonable.)
People who have the mutated familial adenomatous polyposis (FAP) gene. Frequent screening with endoscopy (flexible sigmoidoscopy or colonoscopy) beginning in early puberty. Genetic testing is now recommended for family members of people with known FAP.
People with predisposing intestinal problems, such as widespread and active ulcerative colitis or Crohn's disease. Annual screening with colonoscopy with biopsies of suspicious areas.

Guidelines for Follow-Up After Detection of Precancerous Polyps. Patients who have had a previous examination in which polyps were detected (and removed) should have a repeat colonoscopy 1 - 3 years later, depending on the size, number, and type of polyps removed.

The digital rectal examination is used to detect tumors in the rectum, lower intestine, and prostate gland. The doctor inserts a lubricated-gloved finger into the patient's rectum and feels for lumps or other abnormalities. The exam is quick and painless but embarrassing for some. Fewer than 10% of colon cancers develop within the region that can be evaluated by a DRE, so it is not useful as a sole screening test.

Blood in bowel movements is not always visible, in which case it is called occult (hidden) blood. Fecal occult blood tests (FOBTs) are used to detect this hidden blood. The most common FOBT method is called the guaiac-based test. The patient is asked to supply up to six stool specimens in a specially prepared package. A small quantity of feces is smeared on specially treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.

Accuracy. FOBTs can miss more than 75% of advanced cancers. Nevertheless, large studies have indicated that this simple test, performed annually, saves lives and may reduce the risk of dying from colon cancer by 15 - 33%. The following factors may affect its accuracy:

The levels of iron in the blood can affect results. Patients should not take iron supplements or eat red meats several days before the test.
Certain raw fruits and vegetables that contain the chemical peroxidase (cauliflower, horseradish, radishes, melons, and turnips) can cause a positive test reaction even if no blood is present.
Aspirin and NSAIDs are anticoagulants that can cause minor bleeding. They should not be taken for a week before the test. However, a 2005 study suggested that the prescription anticoagulant warfarin does not affect FOBT results.
Vitamin C and foods rich in this vitamin may cause a false negative reaction and should be avoided a few days before the test.
Bleeding from other causes, such as menstruation, hemorrhoids, gingivitis, or urinary infections, can produce blood in the stools and affect results.

Even if none of these conditions is present, a test that shows hidden blood does not necessarily mean that cancer is present. About 20 - 30% of people with occult blood have noncancerous polyps or other conditions, such as gastritis, and only 5 - 10% actually have cancer. Any abnormal result, however, requires further testing, such as colonoscopy.

Lack of Compliance. Compliance is a major problem. Patients are asked to perform the tests at home and send the test cards to the laboratory. Only 35 - 50% of patients actually follow through. Occult-blood tests that give results at home are available but are extremely inaccurate. In one large study, these tests failed to detect advanced cancer in about 62% of cases, although they may detect some early cancers.

If a digital rectal exam (DRE) or fecal occult blood test (FOBT) shows signs of trouble, several methods to visualize the colon are available. They include colonoscopy, sigmoidoscopy, and double-contrast barium enema. They have the following similarities and differences:

Sigmoidoscopy can only view the rectum and the left side of the colon, while colonoscopy and barium enemas allow a view of the entire large intestine.
Both flexible sigmoidoscopy and colonoscopy involve snaking a fiber optic tube through regions of the rectum and colon to view the walls of the intestine. The tube contains a tiny camera that transmits the image to a video screen. The use of an ultrasound (sound wave) scanner is proving to enhance viewing quality. Barium enemas simply use x-rays.
During either sigmoidoscopy or colonoscopy, the doctor is able to remove polyps or other abnormalities revealed by these procedures with surgical instruments inserted through the tube. It is not possible to remove polyps with a barium enema, which is not invasive.

Sigmoidoscopy. Sigmoidoscopy examines the rectum and the lower two feet of the colon. It cannot, however, detect the roughly half of cancers that occur in the right colon. Right-sided cancers are more common in older people.

The procedure uses a flexible fiber optic tube (it is thus referred to as flexible sigmoidoscopy) that contains a tiny camera and surgical instruments.
It lasts about 10 minutes and may be mildly uncomfortable, but it is not painful and is generally very safe. In one study, 70% of patients reported that the procedure was far less unpleasant than they had expected.

This procedure has been found to reduce the risk of fatal cancers in the rectal and sigmoid area by 60%. If polyps are detected, a colonoscopy is then used.

Colonoscopy. Colonoscopy is the most accurate testing method and can reduce cancer incidence by up to 90%. It is clearly indicated for anyone with an increased risk for colorectal cancer, including those with a personal or family history of the disease. As with sigmoidoscopy, a colonoscopy uses a flexible tube, but it is snaked through the entire large intestine.

For about a day before the procedure the patient eats nothing and drinks a laxative solution that cleans out the colon. The taste of the solution is unpleasant, although it has improved in recent years.
The procedure typically uses a sedative that produces a "twilight" sleep and often makes the procedure more comfortable than sigmoidoscopy.
Air may be introduced into the intestine to widen it and allow the tube to navigate curves. A colonoscopy avoids the risk of radiation associated with a barium enema, but it is important to note that even a colonoscopy does not detect all cancers.

Complications are rare, but include the following:

Hyponatremia. Hyponatremia is a low concentration of sodium in the blood. The complication may be caused by the effects of bowel cleaning before the procedure that can result in water retention and reductions in sodium. When severe, it can cause temporary neurological symptoms, such as confusion, lethargy, unsteadiness, and slurred speech. Researchers suggest that sodium concentrations be measured in patients who develop such symptoms after colonoscopy.
Bowel perforation (very low risk, about 2 in 1,000 procedures). The risk for bowel perforation is greater with colonoscopy than flexible sigmoidoscopy.
Bleeding at the site of biopsy or polyp removal.

Overall, colonoscopy is a safe procedure. However, according to a 2006 study in the Annals of Internal Medicine, serious complications occur in about 5 of every 1,000 colonoscopies. Most of these complications occurred when a biopsy or polyp removal was performed. (The risk for complications without biopsy or polyp removal is about 1 in every 1,000 colonoscopies.) This study looked at colonoscopies in general, including those that are done to diagnose the causes of a patient's symptoms. The risk may be lower for colonoscopies performed solely to screen for colorectal cancer.

Barium Enema. The double-contrast barium enema, which uses an x-ray image, is the less expensive alternative for viewing the entire colon. It is not as accurate as colonoscopy, and if any polyps or abnormalities are revealed on x-ray, a colonoscopy is then required to remove suspicious tissue, so it is now recommended much less often than in the past.

The barium enema is a valuable diagnostic tool that helps detect abnormalities in the large intestine (colon). The barium enema, along with colonoscopy, remains the standard in the diagnosis of colon cancer, ulcerative colitis, and other diseases of the colon.

Screening for familial adenomatous polyposis. Genetic screening for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) is now available and may be recommended for high-risk patients. The test for FAP detects a mutation in the adenomatous polyposis coli in up to 90% of people who carry it. Testing for HNPCC mutation is somewhat more complex.

Screening for insulin-like growth factor. A gene that regulates insulin-like growth factor (IGF-2) is functional during fetal development and then becomes inactive. Some evidence now suggests that people who have IGF-2 in adulthood have a higher risk for colon cancer. Blood tests for detecting IGF-2, then, may be helpful in identifying patients who should have more intensive screening. Currently, however, this is only used as a research tool.

Stool DNA Testing. A promising technique for colorectal cancer screening is the detection of altered DNA in cancer cells that have shed from the colon and are excreted in the stool. Such tests may prove to detect both inherited and noninherited genetic mutations. This may become a widely used tool in the future. However, larger clinical studies are needed.

Virtual Colonoscopy. A promising experimental technique called virtual colonoscopy allows three-dimensional imaging of the colon without using invasive instruments. As with standard colonoscopy, the patient takes a laxative first to clear out the intestine. The procedure itself involves pumping air into the colon and scanning the intestine using computed tomography (CT). It is very safe and takes about only 10 minutes. The procedure is similar in accuracy to conventional colonoscopy for detection of larger polyps (6 mm or more in diameter) and is also potentially less expensive. Colonoscopy is required, however, if suspicious areas are found, which may occur frequently with the CT procedure, since it erroneously identifies a high number of nonexistent polyps.

A study published in April 2004 in the Journal of the American Medical Association compared results of standard colonoscopy versus virtual colonoscopy in over 600 patients at nine major medical centers. Virtual colonoscopy had much lower rates of successfully finding polyps than standard colonoscopy. Virtual colonoscopy detected polyps of at least 6 mm in 39% of patients and polyps of at least 10 mm in 55% of patients. By contrast, standard colonoscopy detected 99% of polyps of at least 6 mm, and 100% of polyps of at least 10 mm. In addition, accuracy rates varied widely among the different hospitals. The authors advised that until more improvement in training and technique is achieved, virtual colonoscopy "is not yet ready for widespread clinical application."

Magnetic Resonance Colonography. Magnetic resonance colonography (MRC) is another non-invasive technique for visualizing the colon. The patient receives an enema containing a contrast substance, and then magnetic resonance images are taken. MRC is fast, comfortable, and less invasive than colonoscopy. Currently, however, there is a poor detection rate for flat tumors and for polyp tumors less than 10 mm in diameter.

Staging

A diagnosis of cancer will lead to staging and other tests to help determine the outlook and the appropriate treatments.

The large intestine is a long hollow organ lined with mucous membrane (mucosa). Muscle layers wrap around the entire length and help move food material through to the rectum.

Unlike many other cancers, the size of the tumor is not a major factor in determining the outcome of colorectal cancer. Of greater importance is how far the cancer has spread. To determine this, doctors will assign a stage to the tumor. There are several methods for staging. The older system, known as Dukes', categorizes four basic stages: A, B, C, and D. A more recent system refers to these stages as I, II, III, and IV but divides the categories slightly differently. The term "5-year survival" means that patients have lived at least 5 years since diagnosis. Most patients who live 5 years without a recurrence are considered to be cured of their disease.


Stage	Condition	5-Year Survival
A or I	Tumor superficially involves the inner lining of the intestine.	More than 90%
B or II	Tumor has penetrated through the muscle wall of the intestine but has not reached the lymph nodes.	70 - 85%
C or III	Lymph nodes are involved.	65% or below
D or IV	Tumor has spread to other organs (metastasized), usually the liver first.	5 - 9%

Click the icon to see an image of the stages of cancer.

Researchers are continually seeking to identify tumor markers, substances (usually found in blood samples) that will assist in the diagnosis of cancer and in monitoring effects of treatment.

Carcinoembryonic Antigen. High blood levels of a protein called carcinoembryonic antigen (CEA) sometimes indicate the presence of colon cancer. Unfortunately, it is also elevated in other cancers and in some noncancerous conditions. CEA is not effective as a screening tool for healthy people, but might eventually be helpful for patients with cancer.

An advanced diagnostic technique called polymerase chain reaction (PCR) can detect genetic evidence of CEA. One study indicated that when these microscopic footprints of colon cancer are detected in the lymph nodes of patients with Stage II cancer (whose lymph nodes otherwise appear to be not involved with cancer), the outlook is similar to that of patients with Stage III cancer. Patients without this so-called micrometastasis have a very favorable prognosis. Further research is needed, however, before PCR can be used in widespread practice.
In patients with a history of, or active, colon cancer, follow-up measuring of blood CEA levels may be helpful in detecting recurrence of the cancer and effectiveness of treatments.

Defective P53 Gene. The presence of a defective p53 gene is a marker for very poor prognosis in patients with advanced colon cancer. In its normal state, the gene is important for regulation of cell growth. Testing for this abnormality, however, is not widely done because it is not clear how to use this information.

Other Tumor Markers. Other tumor markers under investigation include a protein called GLUT1, cancer antigen 19-9 (CA 19-9), matrix metalloproteinase-9 (MMP-9) RNA, HER-2/neu oncoprotein, transforming growth factor beta-1 (TGF-beta-1), and CD44.

Click the icon to see an image of drawing blood for culture.

A technique known as a sentinel node biopsy is increasingly performed by experienced surgeons in selected patients. This procedure is used to determine if cancer has spread beyond the nodes, possibly reducing the need for complete axillary lymphadenectomies. It involves the following:

The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
The tracer or dye then flows via the lymphatic system into the so-called sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If they do not show any signs of cancer, it is highly likely that the remainder of the lymph nodes will be cancer free, and further surgery becomes unnecessary.

It is still not known if the sentinel node biopsy has any survival advantages compared to the standard procedures with lymph nodes removal. However, one study indicated that careful and complete removal of potentially cancerous lymph nodes is still very important for improving survival in patients with Stage II and III colorectal cancer.

Whole-body imaging scans that combine positron emission tomography (PET) and computed tomography (CT) may be helpful in accurately staging colorectal cancer, according to preliminary research published in 2006 in the Journal of the American Medical Association.

Prognosis

Survival rates for colorectal cancer have been rising in recent years. The 5-year survival rate is as high as 90% for cancer that has not spread to the lymph nodes (localized cancer). When cancer has spread to lymph nodes and other parts of the body, survival rates drop to 65% and below. Because many cancers are detected at later stages, the overall survival rate is currently about 60%. African-Americans and other minorities tend to have lower survival rates than Caucasians. Studies suggest, however, these higher mortality rates are largely due to less access to optimal health care, including appropriate surgical care and aggressive treatments.

In most cases, age is not a factor in treatment success. Good survival rates are achieved in the elderly as well as in young people. Chances for survival are less in Stage II cancers if the intestine is obstructed or perforated. If cancer has spread to lymph nodes (Stage III), the outlook is better if three or fewer lymph nodes are involved. Treatment can prolong life even when cancer has spread.

Surgery

Surgical removal of the tumor ("resection") along with any affected surrounding tissue is the standard initial treatment for potentially curable colorectal cancers (cancers that have not spread beyond the colon or lymph nodes). Drug and radiation therapy are often used for advanced cancers and are continuously being tested with surgery in different combinations and sequences.

Although choosing a qualified surgeon is critical, choosing a hospital experienced in procedures is also important. The more often colon cancer surgery is performed at a given hospital, the lower the mortality rate at that hospital is likely to be.

Unless cancer is very advanced, most tumors are removed by an operation known as colectomy:

Colectomy involves removing the cancerous part of the colon and nearby lymph nodes.
The surgeon then reconnects the intestine.
If the surgeon cannot reconnect the intestine, usually because of infection or obstruction, the surgeon will perform a colostomy. The need for colostomies is higher after surgery for rectal cancer. In most cases of colon cancer, colostomies are not needed. [See "Colostomy" below.]

Click the icon to see an illustrated series detailing colon cancer treatment.

The Surgical Approach. The standard technique for a colectomy is open, invasive surgery. Laparoscopy, sometimes called “keyhole surgery,” is a less invasive method. Laparoscopy is still considered an investigational technique for treating colon cancer, but it is gaining more acceptance and showing good results in clinical trials.

Open Surgery:

Open surgery uses a wide incision to open the patient's abdomen. The surgeon then performs the procedures with standard surgical instruments. This is the usual method for performing colectomy.

Laparoscopy:

Laparoscopy uses a few small incisions through which the surgeon passes a fiber optic tube (laparoscope) containing a small camera or tiny instruments. It is generally used for early colon cancer (for tumors less than 2 centimeters or for well-defined tumors less than 3 centimeters).
A 2004 New England Journal of Medicine study found that patients who received laparoscopic colectomy had similar rates of surgical complications, cancer recurrence, and survival as those who received traditional open surgery. However, the patients who had laparoscopy recovered faster and did not need as many narcotic painkillers.
Several 2005 studies indicated that laparoscopy works as well as conventional surgery for treatment of colon cancer. However, laparoscopy does not appear to be as effective for rectal cancer.

Click the icon to see an image detailing pelvic laparoscopy.

Click the icon to see an illustrated series detailing a resection of the large intestine.

Other Investigational Measures. Researchers are testing expandable metal tube-like devices called stents to keep the intestine open. Stents may be used before a procedure to allow bowel cleansing or for long-term use to keep open colons that can't be operated on.

A colostomy is performed in order to bypass or remove the lower colon and rectum. The procedure generally involves creating a passage, called a stoma, through the abdominal wall that is connected to the colon. The feces pass through this passage and are eliminated. Patients must learn how to care for the stoma and keep the area sanitary.

A colostomy usually will have one opening (single-barreled), or there may be two loops opening through the skin (double-barreled).

Usually the colostomy is temporary and can be reversed by a second operation after about 3 - 6 months. It the rectum and sphincter muscles in the rectum need to be removed, the colostomy is permanent. Permanent colostomies are more common when the cancerous regions are within 2 - 3 centimeters of the anus. Fortunately, surgical advances and knowledge of the extent of safe margins are reducing the need for permanent colostomies.

Click the icon to see an illustrated series detailing a colostomy procedure.

Managing Permanent Colostomies. In cases where the colostomy is permanent, the patient must wear a colostomy pouch, which sticks to the skin using a special glue. Pouches are available as one- or two-piece systems. The one-piece system is simpler, but the two piece system allows replacement of the pouch without removing the tape.

For best results, the pouch should be emptied when about one-third full. It should be replaced 1 - 2 times a week, depending on signs of leakage (itching or burning of the skin near the stoma). The pouches are odor proof.

Surgical treatments for cancer in the rectum are complex since they involve muscles and tissue that are critical for urinary and sexual function.

Local Excision or Polypectomy for Early Stages. In order to preserve the function of the anal sphincter and prevent the need for colostomy, Stage I and Stage II tumors may be removed by local excision, sometimes followed by chemotherapy and radiation. In this procedure, the tumor is cut out without removal of a major section of rectum. In some cases cancer recurs, but a second operation may be possible. Another treatment for early-stage rectal cancer, called electrocoagulation, destroys tumors using a high frequency electric current. It is being tested in clinical trials.

Radical Resection. In about a third of cases of rectal cancer, the cancer occurs in the lower part of the rectum, where between 70 - 80% of cancers have spread beyond the rectal wall. These patients need a radical resection, in which surrounding structures, including the sphincter muscles that control bowel movements, must often be removed.

The use of chemotherapy and radiation prior to surgery may prevent the need for permanent colostomy in some patients. This is an active area of clinical research, and trials are under way to address this issue. Another technique, called coloanal anastomosis, reconstructs the area to avoid the need for colostomy, and may be appropriate in some patients.

Total Mesorectal Excision. Total mesorectal excision (TME) involves dissection and removal of the entire cancerous area of the rectum along with surrounding fatty regions where the lymph nodes are located (the mesorectum). When successful, TME preserves the sphincter muscle, reducing the need for a permanent colostomy. Increasing use of this procedure is resulting in lower recurrence rates, lower levels of impotence and incontinence, and better overall survival rates compared to other resection techniques. Some experts now recommend it as a first choice for certain patients with locally advanced rectal cancer.

Combining chemotherapy and radiation either before or after TME is yielding promising long-term results and a low risk for local recurrence. There are many questions, however, and it is not clear which approach is better for specific patients.

Side effects of colon surgery include:

Sexual dysfunction. This is of particular concern. In general, colostomy does not usually affect sexual function. However, wide rectal surgery can cause short- or long-term sexual dysfunction. Sildenafil (Viagra) may help men who experience this after surgery.
Irregular bowel movements.
Gas and flatulence. Pouching filters are available to reduce gas. Certain foods produce more gas than others -- usually within 6 - 8 hours after ingestion for colostomy patients. They include beans, oat bran, most fruit, and certain vegetables (cabbage, cauliflower, Brussels sprouts, broccoli, and asparagus). To prevent swallowing air, patients should avoid sipping through straws, chewing gum, and chewing with their mouths open.
Diarrhea.
Bladder complications.
Sense of urinary urgency.
Fecal incontinence. Patients with rectal surgery have a higher risk for bowel dysfunction than those who had a colostomy.
Complications in or around the stoma. These can occur early after surgery to many years after the procedure. They include skin infection or breakdown, hernias, narrowing of the stoma, bleeding, and collapse.

There are no dietary restrictions, although many patients avoid foods that can produce gas. Everyone should drink plenty of fluids and get sufficient fiber.

The potential side effects of sexual and bowel dysfunction for colorectal surgical patients can be devastating, although many patients do very well and live normal productive lives. Positive emotions play a strong role in recovery. Patients who are depressed should discuss with a doctor all aspects of treatment that affect the quality of life, and consider seeking support groups.

Medications

Chemotherapy uses drugs that kill cancer cells throughout the body. There are two situations in which chemotherapy is used:

The adjuvant setting. Adjuvant refers to the use of chemotherapy after surgery in patients with Stage III tumors and selected patients with high-risk Stage II tumors (disease that is potentially curable). The goal of this therapy is to eliminate any cancer cells that surgery may have missed, thereby preventing recurrence and increasing the chance of cure. Patients of all ages, including the elderly, can benefit.
In metastatic disease. In patients with metastatic disease (where the cancer has spread to other parts of the body) the goal of chemotherapy is to shrink tumors, improve symptoms and quality of life, and lengthen life.

In the adjuvant setting, there are some differences in chemotherapy treatments between colon and rectal cancers:

Chemotherapy for Stage II is considered standard care for Stage II rectal cancer but is under debate for colon cancer.
Chemotherapy is standard for patients with Stage III colon cancer. Chemotherapy is also standard for patients with Stage III rectal cancer but is used in combination with radiation.

Chemotherapy for Stage II Colon Cancer. Adjuvant chemotherapy for Stage II colon cancer is controversial. Such patients tend to have a good outcome after surgery, and the positive effects of chemotherapy have been difficult to demonstrate. To date, the survival advantage of adjuvant chemotherapy in this group has been reported to be only in the range of 2%. However, better trials are still needed to confirm or refute the benefits in specific patient groups.

Although not yet known with certainty, some data suggest that certain patients with Stage II cancer may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include patients with cancers that have:

Obstructed the bowel
Perforated the wall of the colon
Adhered to structures outside the intestine

Advanced diagnostic techniques are under investigation for helping to select appropriate candidates for adjuvant therapy. None of these methods, however, are ready to be used routinely to help make treatment decisions. The decision whether to pursue chemotherapy for Stage II disease should be made after careful discussion between the patient and their oncologist, especially after features, such as bowel perforation or obstruction, are taken into account.

Chemotherapy for Stage III Colon Cancer. Since the early 1990s, adjuvant chemotherapy with 5-FU and leucovorin has been the standard of care for Stage III colon cancer. In recent years, the FOLFOX (5-FU, leucovorin, oxaliplatin) regimen has also been used for chemotherapy following surgery. Numerous trials have shown that adjuvant chemotherapy in this setting reduces the absolute risk of death from colon cancer by about one-third and improves survival by 10%. Clinical trials are also investigating combinations of other drugs.

Chemotherapy for Advanced Colorectal Cancer. Chemotherapy is either given directly into the arteries of the liver or intravenously (through a vein) with 5-FU and leucovorin. Oxaliplatin is sometimes added, but recent evidence suggests that the targeted therapy biologic drug bevacizumab may be a better addition. Other alternative chemotherapy choices are capecitabine, or irinotecan combined with cetuximab. Radiation therapy may be used in place of chemotherapy or in combination with it. Studies indicate that chemotherapy offers only a modest improvement in survival, but may help reduce symptoms.

Seven drugs are currently approved for colorectal cancer chemotherapy:

5-fluorouracil (5-FU, Adrucil), which is often given in combination with leucovorin (Wellcovorin). Leucovorin is a vitamin that helps boost the effectiveness of 5-FU.
Capecitabine (Xeloda)
Oxaliplatin (Eloxatin)
Irinotecan (Camptosar)
Bevacizumab (Avastin)
Cetuximab (Erbitux)
Panitumumab (Vectibix)

Capecitabine is a pill form of 5-FU. The other drugs are administered intravenously. Many of these drugs are given in combination with each other. Common chemotherapy combination regimens include:

5-FU / LV (5-FU and leucovorin)
FOLFOX (5-FU with leucovorin and oxaliplatin)
FOLFORI (5-FU with leucovorin and irinotecan)
IFL (Irinotecan, 5-FU, leucovorin)
XELOX (Capecitabine and oxaliplatin)

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Because cancer cells grow and divide rapidly, anticancer drugs work by killing fast-growing cells. This means that healthy cells that multiply quickly can also be affected. The fast-growing normal cells most likely to be affected are blood cells forming in the bone marrow, and cells in the digestive tract, reproductive system, and hair follicles. Nausea and vomiting is a very common side effect, but drugs such as ondansetron (Zofran) can help provide relief. In general, side effects are nearly always temporary, and medications can help manage them. Most patients are able to continue with normal activities for all but perhaps 1 - 2 days a month.

5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil, either alone or with leucovorin (5-FU/LV), is the standard treatment for patients with high-risk colon cancer (Stage III or select patients with Stage II tumors). Leucovorin, also called folinic acid, is a form of the B vitamin folic acid, which helps increase 5-FU’s effectiveness. Patients are given a series of cycles that usually continue for at least 6 months.

There are many different ways of giving 5-FU, including intravenously over several hours once a week, intravenously daily for 5 consecutive days every month, or as continuous infusion with a portable pump.

The side effects can be quite different, depending on the way 5-FU is given, and women may be more susceptible than men. In one analysis, 53% of women and 40% of men experienced severe side effects, while response rates and survival were similar for both sexes. Many patients, however, tolerate 5-FU with leucovorin well, with manageable side effects. The most common side effects include nausea and vomiting, diarrhea, loss of appetite, hair loss, swelling of hands and feet, rashes, and mouth sores.

Irinotecan. Irinotecan (Camptosar) blocks an enzyme essential for cell division. Irinotecan can be given alone or in combination with 5-FU and leucovorin. This combination therapy (irinotecan plus 5-FU/LV) is also referred to as the "Salz regimen," or IFL. When it was approved in the mid 1990s, irinotecan was the first new drug developed for colon cancer in over 30 years. Studies have shown that irinotecan combined with 5-fluorouracil and leucovorin (5-FU/LV) significantly delays the time at which tumors progress and improves survival in metastatic cancer compared to 5-FU/LV alone. While the survival advantage is small, the combination has become the standard of care for metastatic cancer. Of concern, however, are studies that have reported an increased risk of death from toxic effects with the use of the three-drug combination. These deaths appeared to be related to blood-clotting complications. Doctors should carefully monitor dosages. Diarrhea is a common side effect of irinotecan.

Capecitabine. Capecitabine (Xeloda), an oral form of 5-FU, was approved in 2001 as a treatment for metastatic colorectal cancer. It is the only pill approved for colorectal cancer. A major 2005 study, published in the New England Journal of Medicine, found that capecitabine works as well as the standard 5-FU/LV regimen and causes significantly fewer side effects. The study involved patients with Stage III colon cancer who had undergone surgical removal of the tumor. In 2005, capecitabine was approved for postsurgical treatment of patients with Dukes’ C colon cancer. Capecitabine is also showing promise in combination with radiation therapy for rectal cancers.

Oxaliplatin. Oxaliplatin (Eloxatin) is related to cisplatin, a widely used platinum-based chemotherapy drug. Oxaliplatin is used in combination with 5-FU and leucovorin. (This triple combination therapy is called the FOLFOX regimen.) Oxaliplatin was first approved in 2002 for use in combination with 5-FU and leucovorin as a second-line treatment for cancer that has progressed after initial therapy.

Since 2002, oxaliplatin has received additional approvals as a first-line treatment for advanced colorectal cancer, and as a post-surgical treatment for patients who have undergone tumor resection.

Oxaliplatin can cause pain and tingling sensations in the hands and feet (neuropathy) that is worsened by exposure to cold. Recent research suggests that adding xaliproden (Xaprila) to the FOLFOX regimen may help reduce the frequency of neuropathy without interfering with the benefits of chemotherapy. Xaliproden is a drug used to treat the neurological disease amyotrophic lateral sclerosis (also known as Lou Gehrig's disease).

Bevacizumab. Bevacizumab (Avastin) was approved in February 2004 as a first-line treatment for patients with metastatic colorectal cancer (advanced cancer that has spread in the body). It is used in combination with IFL (irinotecan, 5-FU, leucovorin). Bevacizumab is a genetically engineered monoclonal antibody that targets and inhibits vascular endothelial growth factor (VEGF), a protein that regulates angiogenesis (the development of new blood vessels that feed a tumor's blood supply). It is the first anti-angiogenic therapy approved for the treatment of colorectal cancer.

In a study of 800 patients with metastatic colorectal cancer, bevacizumab administered intravenously along with IFL extended survival by about 5 months longer than IFL alone. Common side effects of bevacizumab include nosebleeds, fatigue, diarrhea, and high blood pressure. Less common side effects include stroke, heart attacks, angina, and formation of holes in the colon and stomach (gastrointestinal perforation).

Cetuximab. Cetuximab (Erbitux) was approved in February 2004 for the treatment of metastatic colorectal cancer. This monoclonal antibody drug targets epidermal growth factor receptor (EGFR), a protein required by cancer cells in order to proliferate. It can be used either in combination with irinotecan or alone for patients who have not responded to irinotecan. Studies of the cetuximab-irinotecan combination suggest it can help in tumor shrinkage. It has a modest effect on survival, prolonging patients’ lives by about an additional month.

Panitumumab. Panitumumab (Vectibix) was approved in September 2006 for treatment of colorectal cancer that has metastasized following standard chemotherapy. Like cetuximab, panitumumab is a monoclonal antibody drug that targets EGFR. In clinical trials, panitumumab helped delay disease progression and prolong survival by about 3 months. About 8% of patients experienced tumor shrinkage. Common side effects of this drug include skin rash, fatigue, abdominal pain, nausea, and diarrhea or constipation. Serious side effects include pulmonary fibrosis, severe skin rash, and skin reactions at the infusion site.

One of the most promising recent developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotype. In the future, diagnostic tests may help doctors identify which patients are more likely to respond successfully to specific drugs.

Biologic therapies use the body's immune system to attack the cancer (immunotherapy). These drugs are derived from biological sources and include vaccines, monoclonal antibodies (MAbs), and gene therapies. Many targeted therapies are classified as biologics. Bevacizumab (Avastin), cetixumab (Erbitux), and panitumumab (Vectibix) are currently the three biologic drugs approved for colorectal cancer treatment, but many other drugs are in development.

Targeted therapies involve many different types of drugs and molecular pathways. These include:

Angiogenesis Inhibitors. Anti-angiogenesis drugs inhibit the formation of new blood vessels that supply tumors with the blood, oxygen, and nutrients vital to tumor growth. Angiogenesis inhibitors, such as the monoclonal antibody bevacizumab (Avastin), target vascular endothelial growth factor (VEGF). Cediranib (Recentin), formerly AZD2171, is a new angiogenesis inhibitor that is in Phase III clinical trials for treatment of colorectal cancer.

Tumor Growth Factor Inhibitors. Tumor growth factors, such as epidermal growth factor, stimulate cell growth. Cetixumab (Erbitux) and panitumumab (Vectibix) are the two currently approved colorectal cancer drugs that target the epidermal growth factor receptor (EGFR). Nimotuzumab (TheraCIM) is currently being studied in combination with irinotecan in Phase III trials.

Tyrosine Kinase Inhibitors. Tyrosine kinase is an enzyme associated with EGFR that is involved with the signaling mechanisms that prompt cell growth. The EGFR/tyrosine kinase inhibitor erlotinib (Tarceva), which is approved for the treatment of pancreatic and lung cancers, is being investigated as an adjuvant treatment for metastatic colorectal cancer. Sunitinib (Sutent), which is approved for renal cell carcinoma, is another tyrosine kinase inhibitor in Phase III trials for colorectal cancer.

Radiation Treatment

Radiation therapy uses x-rays to kill cancer cells that might remain after an operation or to shrink large tumors before an operation so that they can be removed surgically. The object of radiation therapy is to damage the tumor as much as possible without harming surrounding tissues. Radiation may be administered in the following ways:

Externally by an x-ray machine (external beam radiation).
By passing radioactive pellets through thin plastic tubes inserted into the intestine.
By implanting tiny radiation seeds directly into the tumor (brachytherapy).
Computer imaging techniques providing 3-dimensional pictures of the cancerous area are allowing precise targeting of radiation to the tumor.

Postoperative radiation treatment combined with chemotherapy is common practice for patients with rectal cancer in Stages II and III. Such patients are at risk of recurrence both at the site of their original tumor and elsewhere in the body. Although there can be significant long-term side effects, the combination of 5-FU and radiation is still considered standard after surgery.

The standard procedure in the U.S. is to apply radiation after surgery (postoperative). Pre-operative chemotherapy and radiation, however, are sometimes used to preserve sphincter-muscle function and reduce the chance that a patient will need a colostomy. Furthermore, some studies suggest that the use of radiation before surgery reduces the likelihood of recurrences and may slightly prolong survival in some patients with rectal cancer. (It has no additional advantages, however, if the subsequent surgery does not completely remove the cancerous regions.) Studies comparing preoperative and postoperative chemotherapy and radiation are currently under way.

Radiation therapy can also be used during surgery (a procedure called intra-operative radiotherapy). It allows the surgeon to move healthy tissue out of the path of the radiation beam.

Short-term side effects of radiation include:

Diarrhea
Skin irritation around the anus
Incontinence
Fatigue
Bowel movement problems

Longer-term complications may include:

Incontinence
Hip and pelvic fractures
Diarrhea
Increased risk for bowel obstruction

Follow-up Testing

The American Society of Clinical Oncology (ASCO) sets guidelines for follow-up testing to detect recurring cancer after the completion of treatment. The following guidelines are based on ASCO’s 2005 updated recommendations.

Most colorectal cancer recurrences happen within 3 years after surgery. American Society of Clinical Oncology recommends that a colorectal cancer patient sees their doctor for a physical examination every 3 - 6 months for the first 3 years, every 6 months for the fourth and fifth years, and at the doctor's and patient's discretion during subsequent years.

Patients should have a colonoscopy 3 years after surgery. If the results are normal, patients should then receive a colonoscopy every 5 years. Some patients with hereditary types of colorectal cancer may need more frequent screenings.

A flexible sigmoidoscopy is recommended every 6 months for 5 years for patients with Stage II or III rectal cancer who did not receive radiation therapy.

Carcinoembryonic antigen (CEA) levels should be measured every 3 months after surgery for 3 years in patients with Stage II or III cancer. High CEA levels in the blood may indicate that the cancer has spread to other parts of the body.

Patients at high risk for cancer recurrence should receive an annual computerized tomography (CT) scan for the first 3 years after treatment. The CT scan can help determine if cancer has spread to the lungs or liver. Patients who have had rectal cancer, and did not have radiation therapy, should receive a pelvic CT scan. The scan is not recommended for most lower-risk patients with Stage I or II colorectal cancer.

American Society of Clinical Oncology does not recommend other follow-up blood tests such as complete blood count, liver function tests, fecal occult blood tests. There appears to be no additional benefit for these tests.

Treatment for Metastasized Colorectal Cancer

The liver is the most frequent site for colorectal cancers to spread (metastasized). Here, treatments may slow the spread of cancer and even prolong survival. Cure is very rare.

When cancer has spread, surgery to remove or bypass obstructions in the intestine may be performed. In these circumstances, surgery is considered palliative in that it may improve symptoms but will not lead to cure. In rare cases, metastatic colon cancer may be cured with surgical removal of tumors in areas to which the cancer has spread, such as the liver, ovaries, and lung. The liver is the most common site of spread. Only selected patients may be eligible for such surgery, but in these patients, 5-year survival has been 25% or higher.

Chemotherapy may help improve symptoms and possibly prolong survival in metastasized colorectal cancers. Several investigational drugs are being tested. Doctors are also testing chemotherapy administered directly into the liver -- a treatment called hepatic arterial infusion (HAI). A 2006 study found that hepatic arterial infusion improves survival and quality of life for patients whose cancer has spread to the liver. The study indicated that HAI works better for these patients than chemotherapy delivered intravenously.

Other investigative techniques used to destroy liver tumors include:

Cryosurgery. This approach freezes the tumor or surrounding tissue.
Embolization. Embolization employs a catheter to deliver substances into the liver that block blood vessels and therefore starve the tumor. Chemotherapy is often administered during this procedure.
Radiation.

For end-stage cancer, hospice care is a compassionate option.

Resources

www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.oncolink.org -- OncoLink cancer information
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.nccn.org -- National Comprehensive Cancer Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007 May 24;356(21):2131-42.

Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9.

Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA AspirinTrial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidencefrom randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13.

Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 2007 Jul 26;357(4):360-9.

Levin TR, Zhao W, Conell C, Seeff LC, Manninen DL, Shapiro JA, Schulman J. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med. 2006 Dec 19;145(12):880-6.

Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007 Aug 15;298(7):754-64.

U.S. Preventive Services Task Force. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2007 Mar 6;146(5):361-4.

Veit-Haibach P, Kuehle CA, Beyer T, Stergar H, Kuehl H, Schmidt J, et al. Diagnostic accuracy of colorectal cancer staging with whole-body PET/CT colonography. JAMA. 2006 Dec 6;296(21):2590-600.

Review Date:
9/8/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Breast cancer

FitSugar — Wed, 08 Oct 2008 17:34:59 -0700

In This Report

Highlights
Introduction
Risk Factors
Prevention and Lifestyle Fa...
Symptoms
Diagnosis
Prognosis
Treatment
Surgery
Radiation
Medications
Chemotherapy
Hormone Therapy
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In September 2007, Evista (raloxifene) was approved for prevention of breast cancer in postmenopausal women with osteoporosis, and postmenopausal women at high risk for invasive breast cancer. Raloxifene and tamoxifen are the only two drugs approved for breast cancer prevention in high-risk women.
In March 2007, lapatinib (Tykerb) was approved in combination with capecitabine (Xeloda) for treatment of advanced HER2-positive breast cancer.
In November 2006, trastuzumab (Herceptin) was approved for treatment of early-stage HER2-positive breast cancer. Trastuzumab is also approved for advanced HER2-positive breast cancer.

Screening

The American College of Physicians’ 2007 guidelines recommend that women with a low risk for breast cancer talk to their doctor before starting to have mammogram screening at age 40. Other associations, including the American Cancer Society, continue to recommend annual mammograms for women age 40 and older.
Women at high risk for breast cancer should have an MRI scan along with their annual mammogram, according to 2007 guidelines from the American Cancer Society.
For women who have been diagnosed with cancer in one breast, an MRI can help detect tumors in the other breast, indicates a 2007 study in the New England Journal of Medicine.

Post-Treatment Guidelines

The American Society of Clinical Oncology (ASCO)’s 2006 post-treatment guidelines recommend regular physical exams, breast self-exam, mammograms, and genetic counseling. Know how to recognize the signs of breast cancer recurrence. ASCO does not recommend blood and imaging tests for routine recurrence screening.

Hormone Replacement Therapy (HRT) and Breast Cancer Risk

Fewer women are using HRT, which may explain why new cases of breast cancer among postmenopausal women have declined, suggests a recent New England Journal of Medicine study.

Aromatase Inhibitors

Drug treatment with aromatase inhibitors is improving survival in women with hormone-sensitive advanced breast cancer, suggest recent studies. Switching from tamoxifen to an aromatase inhibitor may help improve the odds for survival.

Introduction

Breast cancers are potentially life-threatening malignancies that develop in one or both breasts. The structure of the female breast is important in understanding this cancer:

The interior of the female breast consists mostly of fatty and fibrous connective tissues.
It is divided into about 20 sections called lobes.
Each lobe is further subdivided into a collection of lobules, structures that contain small milk-producing glands.
These glands secrete milk into a complex system of tiny ducts. The ducts carry the milk through the breast and converge in a collecting chamber located just below the nipple.
Breast cancer is either noninvasive (referred to as in situ, confined to the site of origin) or invasive (spreading).

The female breast is either of two mammary glands (organs of milk secretion) on the chest.

Noninvasive breast cancers include:

Ductal carcinoma in situ (also called intraductal carcinoma or DCIS). DCIS consist of cancer cells in the lining of the duct. DCIS is a non-invasive, early cancer, but if left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer.
Lobular carcinoma in situ, or LCIS. Although noninvasive, lobular carcinoma in situ is a marker for an increased risk of invasive cancer in both breasts. (Some experts prefer to call this condition lobular neoplasia rather than refer to it as a cancer.) According to a 2001 report, for patients with LCIS the risk for developing invasive cancer in the same breast is about 18% -- and 14% in the other breast -- after 20 years. These invasive cancers can be either lobular or ductal.

At the time of diagnosis of these early cancers (DCIS and LCIS), there is no evidence of invasion.

Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancers include the following:

Infiltrating ductal carcinoma. This is invasive breast cancer that penetrates the wall of a duct. It comprises between 70 - 80% of all breast cancer cases.
Infiltrating lobular carcinoma. This invasive cancer has spread through the wall of a lobule. It accounts for 10 - 15% of all breast cancers. It may sometimes appear in both breasts, sometimes in several separate locations.

Click the icon to see an image of the breast.

There are other less common breast cancers that are not discussed in this report.

Risk Factors

About 12 - 13% of women develop breast cancer in their lifetime. Experts estimate that about 178,480 women will be newly diagnosed with invasive breast cancer in the United States in 2007. Another 2,030 men will be diagnosed with breast cancer during the year. Although breast cancer in men is rare, the incidence has been increasing, and men are diagnosed at a later stage than women. An estimated 40,460 women and 450 men will die from breast cancer in 2007. The earlier breast cancer is diagnosed, the earlier the opportunity for treatment. According to the American Cancer Society, over 2 million women who have been treated for breast cancer are alive today.

Age is a major identifiable risk factor. More than 80% of breast cancer cases occur in women over age 50, and especially in women over age 65. The odds by age are as follows:

From ages 30 - 39, a woman’s chance for being diagnosed with breast cancer is 1 in 233
Ages 40 - 49, the odds are 1 in 69
Ages 50 - 59, the odds are 1 in 38
Ages 60 - 69, the odds are 1 in 27
Ages 70 - 79, the odds are 1 in 11
After age 80, the odds are 1 in 8

Breast cancer is more prevalent among Jewish women of Eastern European (Ashkenazi) descent. Meanwhile, African-American women tend to get breast cancer at an earlier age than Caucasians. Although African-American women have lower overall rates of breast cancer, they represent the highest proportion of women who are diagnosed with the disease before age 45. Comparative studies of breast cancer rates among sub-Saharan Africans suggest a genetic component, as African women are diagnosed most frequently between ages 35 - 45.

The mortality rate in African-Americans is twice that of Caucasians, although it is declining. Social and economic factors make it less likely that African-American women will be screened, so they are more likely to be diagnosed at a later stage. They are also less likely to have access to effective treatments. However, there also appears to be a biological basis for African-American women’s poorer prognosis. According to research presented at the 2007 Breast Cancer Symposium, African-American women are more likely to have estrogen receptor-negative tumors, a type of breast cancer that is more difficult to treat.

An estimated 10% of all women with breast cancer have a very strong family history of the disease. Inherited forms of breast cancer often appear in young women under the age of 50. In such families, some members may also be at higher risk for ovarian cancer. These mutations can be inherited from either a mother or father.

Prior to menopause, a mass on the ovary that is smaller than 2 centimeters is probably a follicle cyst that will go away on its own. However, if the growth is larger and doesn't go away over the course of a few menstrual cycles, then it may need to be removed.

BRCA Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are responsible for 30 - 50% of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers. According to some studies, the risk each gene carries is:

Between 25 - 35% of BRCA1 carriers develop breast cancer by age 70.
Between 35 - 50% of BRCA2 carriers develop the disease. BRCA2 genes also increase the lifetime risk of breast cancer in men.

These mutations are present in only about 0.5% of the overall population. However, certain ethnic groups -- such as Jewish women of Eastern European (Ashkenazi) descent -- have a higher prevalence (2.5%) of BRCA gene mutations. BRCA gene mutations are also seen in some African-American and Hispanic women.

Screening Guidelines for BRCA Genes. In 2005, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines for BRCA testing. While women at high risk should be tested, the USPSTF does not recommend routine genetic counseling or testing for BRCA genes in low-risk women (no family history of BRCA 1 or 2 genetic mutations).

ESR Genes. Genetic variations in estrogen receptor genes (ESRs) may increase the risk for some women but offer protection to others. Mutations in the ESR1 and ESR2 genes may be associated with breast cancer susceptibility for Ashkenazi women over age 50 years.

Other Genetic Factors. Mutations in the tumor suppressor gene p53 are more common in the breast cancer tumors of African-American women than in Caucasian women. Researchers have also identified other defective genes that contribute to breast cancer, such as NOEY2 (which is inherited from the father), CHEK2, and ATM, a mutant gene for the rare disorder ataxia-telangiectasia. (The disease itself is rare, but 1% of the population carries a single copy -- enough to increase the risk for breast cancer.) Cowden's syndrome is an inherited disorder caused by a defective PTEN gene that is associated with a higher risk of breast cancer.

Not all genetic mutations are inherited. In 2007, scientists announced they had located a genetic mutation found in as many as 30 - 40% of breast cancers. The IKBKE mutation appears to occur during the course of a women’s lifetime. It causes overproduction of a kinase protein (IKK-epsilon) that fuels cell growth and tumor development. By identifying this genetic mutation, scientists hope they can develop drugs that will target and block IKK-epsilon production.

Because growth of breast tissue is highly sensitive to estrogens, the more estrogen a woman is exposed to over her lifetime, the higher her risk for breast cancer.

Duration of Estrogen Exposure. Early age at menarche (first menstrual period) or later age at menopause may slightly increase a women’s risk for breast cancer.

Pregnancy. Women who have never had children or who had their first child after age 30 may have a slightly increased breast cancer risk. Having children at an early age, and having multiple pregnancies, reduces breast cancer risk.

Although a few studies have suggested a slightly increased risk for breast cancer in women who have had abortions, the weight of evidence does not support an association between abortion and breast cancer. A large-scale 2007 study found that neither induced abortions nor spontaneous abortions (miscarriages) increases breast cancer risk. However, interrupting a pregnancy does reduce the protective features of a full-term pregnancy.

Studies have been mixed on whether breast-feeding decreases breast cancer risk. Breast-feeding reduces a woman’s total number of menstrual cycles, and thereby estrogen exposure, which may account for its possible protective effects. Some studies suggest that the longer a woman breast-feeds, the lower her risk.

Oral Contraception. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer. Some studies have found no evidence that oral contraceptive use increases the risk for breast cancer, even in women who have taken birth control pills for 15 years or more or had taken them at young ages. In contrast, other studies have reported a slightly higher risk in women who are current or recent users and in women who take them for more than 4 years before a first full-term pregnancy.

Hormone Replacement Therapy. Many studies have reported a higher risk for breast cancer in postmenopausal women who take hormone replacement therapy (HRT) that contains both estrogen and progestin. A combination of estrogen and testosterone also increases breast cancer risk. A 2005 study suggested that HRT with no or low progestin is safer than standard estrogen-progestin combination therapy.

Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take estrogen for 10 - 15 years or more do have an increased risk, especially women who are already at higher risk for breast cancer. In addition, HRT increases breast cancer density, making mammograms more difficult to read. This can cause cancer to be diagnosed at a later stage. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.

As further evidence of the association between HRT and breast cancer, a 2007 New England Journal of Medicine study noted that breast cancer rates have fallen as HRT use has declined. The decline in rates occurred among women over the age of 50 and was particularly associated with cancers that were estrogen receptor-positive. This type of cancer requires estrogen for growth. Experts think that postmenopausal women’s discontinuation of estrogen-containing HRT may explain the decrease in rates of new cases of estrogen receptor-positive cancer.

A 2007 position statement from the North American Menopause Society recommends that women who are at risk for breast cancer should avoid hormone therapy and try other options to manage menopausal symptoms such as hot flashes. At this time, most experts recommend that women use HRT only for short-term relief of menopausal symptoms. [See In-Depth Report #40: Menopause.]

Infertility and Infertility Treatments. There has been concern that infertility treatments using the drug clomiphene may increase the risk for breast cancer. A reassuring 2006 study indicated that ovulation induction with clomiphene does not increase breast cancer risk, and may actually decrease it. (Clomphine is related to tamoxifen, a drug that is used for breast cancer prevention in high-risk women.) The study also suggested that women who are infertile because of ovulatory dysfunction have a 25% lower risk for breast cancer than fertile women.

Abnormalities or Breast Conditions Suggesting a Higher Risk. Certain factors and breast conditions may increase the risk for breast cancer:

Dense breast tissue is associated with a higher risk for breast cancer. Studies suggest that women with highly dense tissue have 2 - 6 times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density. In addition, dense breasts make mammograms more difficult to read, which increases the likelihood of missing early signs of cancer.
Benign proliferative breast disease, or unusual cell growth known as atypical hyperplasia, is a significant risk factor for breast cancer.

Some common benign breast abnormalities that pose few or no risks include the following:

Cysts. These mostly occur in women in their middle-to-late reproductive years and can be eliminated simply by aspirating fluid from them.

Click the icon to see an image of cysts in the breast.

Fibroadenoma. These are solid benign lumps that occur in women ages 15 - 30.
Breast abscesses during breast-feeding.

Click the icon to see an image of a breast abscess.

Nipple discharge. Discharge from the nipple is worrisome to patients, but is unlikely to be a sign of cancer. Unexplained discharge still warrants evaluation, however.

Click the icon to see an image of nipple discharge.

Mastalgia. This is breast pain that occurs in association with, or independently from, the menstrual cycle. About 8 - 10% of women experience moderate-to-severe breast pain associated with their menstrual cycle. In general, breast pain does not need assessment unless it is severe and prolonged.

The following physical characteristics have been associated with increased risk:

Obesity increases the risk for all types of estrogen receptor-positive breast cancers. Women who gain weight after menopause are most at risk. (On a positive note, losing weight after menopause decreases breast cancer risk.) In postmenopausal women, estrogen is produced in fat tissue. High amounts of fatty tissue increase levels of estrogen in the body, leading to faster growth of estrogen-sensitive cancers.
Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to be at greater risk for breast cancer.
Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth. In one study, regardless of their actual height, women who reached their full height at age 13 or younger had a higher risk than those who attained maximum height at age 18, reflecting higher estrogen levels at an earlier age.

Exposure to Estrogen-like Industrial Chemicals. Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (DDT and its metabolites, such as dieldrin) and pyrethroids (permethrin), but at this time evidence of any causal association is very weak.

Exposure to Diethylstilbestrol. Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. Recent studies also suggest a slightly increased risk for their daughters (commonly called "DES daughters"), who were exposed to the drug when their mothers took it during pregnancy.

Radiation Exposure. Heavy exposure to radiation is a significant risk factor for breast cancer. Girls who received high-dose radiation therapy face an increased risk for breast cancer in adulthood. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations.

Researchers theorize that viruses may be involved in some types of breast cancers. A study of breast cancer samples taken from Tunisian women in North Africa found similarities with a virus known to cause breast cancer in mice. The samples were compared with those taken from women living in other global regions. The researchers suggested that a human breast cancer virus may be more prevalent in specific parts of the world.

Prevention and Lifestyle Factors

Evidence indicates that regular exercise, particularly vigorous exercise, may offer some modest protection against breast cancer. Exercise can help reduce body fat, which in turn lowers levels of cancer-promoting hormones such as estrogen. In fact, a 2006 study suggested that physical activity may help women reduce the risk for developing estrogen receptor-positive tumors.

Exercise can also help women who have been diagnosed with breast cancer. Studies indicate that both aerobic and weight training exercises benefit the body and the mind, and improve quality of life for breast cancer survivors. Even moderate exercise can help improve survival. A 2005 study in the Journal of the American Medical Association reported survival benefits for women diagnosed with breast cancer who walked 3 – 5 hours per week at an average pace. The American Cancer Society recommends engaging in 45 - 60 minutes of physical activity at least 5 days a week. A recent study indicated that diet and exercise can reduce the risk of breast cancer recurrence.

Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.

Despite much research on the association between diet and breast cancer, there is still little consensus. The best advice is to eat a well-balanced diet and avoid focusing on one "cancer-fighting" food. The American Cancer Society’s dietary guidelines for cancer prevention recommend that people:

Choose foods and amounts that promote a healthy weight.
Eat 5 or more servings of fruits and vegetables each day.
Choose whole grains instead of refined grain products.
Limit consumption of processed and red meat.
Women should limit alcohol consumption to 1 drink per day (women at high risk for breast cancer should consider not drinking alcohol at all).

For breast cancer survivors, the American Cancer Society recommends diets that include lots of fruits and vegetables, low amounts of saturated fat (from meat and high-fat dairy products), moderation in soy foods, and moderate or no alcohol consumption.

Here are results from recent studies evaluating diet and breast cancer, for preventing both the development of cancer and its recurrence:

Fats. Research is still mixed on the role that fats, and which specific types of fats, play in breast cancer risk and prevention. Several studies have indicated that red meat, which is high in saturated fat, may increase breast cancer risk when eaten in large quantities on a daily basis. (Red meat is also high in iron, which in itself may increase breast cancer risk.) According to results from the 2006 Women’s Health Initiative study of dietary fat and breast cancer, experts cannot yet definitely say that a low-fat diet will help prevent breast cancer. However, the study suggested that women who normally eat a very high-fat diet may benefit by reducing their fat intake. In the study, the low-fat diet reduced blood estrogen levels by 15%. The low-fat diet also appeared to reduce the risk for developing progesterone receptor-negative tumors.

Fruits and Vegetables. Fruits and vegetables are important sources of antioxidants, which may help protect against the tissue damage linked to increased cancer risk. Antioxidants include vitamin C, vitamin E, and carotenoids such as beta-carotene and lycopene. Richly colored fruits and vegetables -- not supplements -- are the best sources for these nutrients. These fiber-rich foods are an essential part of a healthy diet. However, it is not clear whether fruits and vegetables can specifically prevent breast cancer development or recurrence. According to a 2007 study of women with early-stage breast cancer, a low-fat diet very high in vegetables, fruit, and fiber does not work any better in preventing breast cancer recurrence than the standard 5 servings a day of fruits and vegetables. (However, a combination of diet and exercise may help.)

Calcium and Vitamin D. Eating lots of foods rich in calcium and vitamin D (such as yogurt and milk) may modestly reduce the risk of breast cancer for premenopausal -- but not postmenopausal -- women, according to a 2007 study. Low-fat or non-fat dairy products are a healthier choice than high-fat ones.

Click the icon to see an image of vitamin D sources.

Soy. Soy is an excellent low-fat protein alternative to meat. Soy contains phytoestrogens, which are estrogen-like plant chemicals. In particular, soy contains a type of phytoestrogen called isoflavones. Because many soy foods (such as tofu) are eaten in Asian countries where women tend to have a lower incidence of breast cancer, research has focused on whether soy may have a protective effect. To date, the evidence does not indicate that soy foods or supplements can reduce breast cancer risk. In addition, some studies suggest that high intakes of soy may actually increase the risk of estrogen-responsive cancers such as breast cancer. Some animal studies have suggested that the isoflavone compound genistein may reduce the protective properties of tamoxifen, a drug used to prevent breast cancer in high-risk women. The American Cancer Society recommends that women with breast cancer eat only moderate amounts of soy foods and avoid taking dietary supplements that contain high amounts of isoflavones.

Click the icon to see an image of phytochemicals.

Lifestyle Factors. Premenopausal women at higher risk, usually because of family history, should take as many preventive measures as possible, starting at an early age. The following lifestyle choices may be beneficial:

Exercising and eating healthily is the first essential rule.
High-risk premenopausal women may choose alternatives to oral contraceptives and, if feasible, consider having children early in their life.
High-risk postmenopausal women may want to forego hormone replacement therapy.
Any woman at high risk for breast cancer should consider avoiding alcohol or drinking it very sparingly.

In spite of some rumors published in the popular press, antiperspirants or use of deodorants after shaving have not been linked with any higher risk for breast cancer.

Tamoxifen and Raloxifene. Drugs known as selective estrogen-receptor modulators (SERMs) act like estrogen in some tissues but behave like estrogen blockers (anti-estrogens) in others. Two SERMs -- tamoxifen (Nolvadex) and raloxifene (Evista) -- are approved for breast cancer prevention for high-risk women. Tamoxifen and raloxifene are not recommended as prevention for women at low risk for breast cancer or its recurrence. Women at high risk for breast cancer should discuss with their doctors the risks and benefits of SERMs.

Tamoxifen (Nolvadex) is the most studied of these drugs. It is currently used to treat breast cancer and was the first drug approved for prevention. Evidence strongly suggests that it halves the risk for estrogen receptor-positive cancers in high-risk women, including those with BRCA2 mutations (although possibly not BRCA1). It also helps prevent recurrence in women who have been treated for breast cancers. However, it has no protective effects against estrogen receptor-negative (hormone-insensitive) cancers.

Tamoxifen can increase the risk for uterine (endometrial) cancers. It can also increase the risk for blood clots, strokes, and endometriosis. Less serious side effects include hot flashes and vaginal discharge.

Raloxifene (Evista) was approved in 2007 for prevention of breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for invasive breast cancer. Raloxifene was previously approved for prevention and treatment of osteoporosis in postmenopausal women. One of raloxifene’s main benefits is that it has a lower risk than tamoxifen of causing uterine cancer. However, raloxifene also has some serious risks.

According to the prescribing information from the Food and Drug Administration (FDA), raloxifene can increase the risk of blood clots. Women with a history of blood clots in the legs, lungs, or eyes should not take this medicine. Although studies indicate raloxifene does not increase the risk of stroke, it can increase the risk of dying from a stroke. Women with a history of stroke or current risk factors for stroke should discuss with their doctors whether raloxifene is an appropriate choice. Less serious side effects of raloxifene include hot flashes, leg cramps, swelling of the legs and feet, flu-like symptoms, joint pain, and sweating. Raloxifene can cause birth defects and is approved only for postmenopausal women. It should not be taken with the cholesterol-lowering drug cholestyramine (Questran) or with estrogens.

The FDA based its approval of raloxifene on results from several major studies. The comparison trial Study of Tamoxifen and Raloxifene (STAR), published in 2006 in the Journal of the American Medical Association, indicated that raloxifene works as well as tamoxifen in reducing the risk of invasive breast cancer, and has a lower risk of causing blood clots. However, the Raloxifene Use for the Heart (RUTH) trial, published in 2006 in the New England Journal of Medicine, suggested that raloxifene carries its own risks for blood clots and fatal strokes and may not be a safe choice for women at high risk of heart disease.

Investigational Drugs for Breast Cancer Prevention.

Aromatase inhibitors. Aromatase inhibitors such as anastrazole (Armidex), letrozole (Femara), and exemestane (Aromasin) are effective treatments for hormone-receptor positive breast cancer. Like tamoxifen, they are also being investigated for protection in high-risk women. However, these drugs may decrease bone mineral density and cognitive function, and increase the risk for falls.
Retinoids. Analogues of vitamin A called retinoids are being studied for protection against breast cancer. One retinoid, fenretinide, appears to offer some protection against a second breast cancer in previously diagnosed, premenopausal women (but not in postmenopausal women). It can cause birth defects and should not be used during pregnancy.

Symptoms

Breast cancers in their early stages are usually painless. Often the first symptom is the discovery of a hard lump. Fifty percent of such masses are found in the upper outer quarter of the breast. The lump may make the affected breast appear elevated or asymmetric. The nipple may be retracted or scaly. Sometimes the skin of the breast is dimpled like the skin of an orange. In some cases there is a bloody or clear discharge from the nipple. Many cancers, however, produce no symptoms and cannot be felt on examination. They can be detected only with a mammogram.

Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture, and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.

Diagnosis

Breast Examination by a Health Professional. Early detection of breast cancer significantly reduces the risk of death. Women ages 20 - 49 should have a physical examination by a health professional every 1 - 2 years. Those over age 50 should be examined annually. A breast exam by a health professional can find 10 - 25% of breast cancers that are missed by mammograms. Between 6 - 46% of the lumps detected by examination are malignant. (The yield is lowest in younger women and highest in older women.)

Self-Examinations. Woman have been encouraged to perform a self-examination each month, but well-conducted studies in 2002 reported no difference in mortality rates between women who were intensively instructed in self-examination and those who were not. This does not mean women should stop attempting self-examinations, but they should not replace the annual examination done by a health professional, which evidence suggests is beneficial.

1. Pick a time of the month that is easy to remember and perform self-examination at that time each month. The breast has normal patterns of thickness and lumpiness that change within a monthly period, and a consistently scheduled examination will help differentiate between what is normal from abnormal.

2. Stand in front of a mirror. Breasts should be basically the same size (one may be slightly larger than the other). Check for changes or redness in the nipple area. Look for changes in the appearance of the skin. With hands on the hips, push the pelvis forward and pull the shoulders back and observe the breasts for irregularities. Repeat the observation with hands behind the head. Move each arm and shoulder forward.

3. Lie down on the back with a rolled towel under one shoulder. Apply lotion or bath oil over the breast area.

The finger action should be as follows: Using the 2nd, 3rd, and 4th finger pads (not tips) held together, make dime-sized circles. Press lightly first to feel the breast area, then press harder using a circular motion.

Using this motion, start from the collarbone and move downward to underneath the breast. Shift the fingers slightly over, slightly overlapping the previously checked region, and work upward back to the collarbone. Repeat this up-and-down examination until the entire breast area has been examined. Be sure to cover the entire area from the collarbone to the bottom of the breast area and from the middle of the chest to the armpits. Move the towel under the other shoulder and repeat the procedure.

Examine the nipple area, by gently lifting and squeezing it and checking for discharge.

4. Repeat step 3 in an upright position. (The shower is the best place for this, using plenty of soap.)

Note: A lump can be any size or shape and can move around or remain fixed. Of special concern are specific or unusual lumps that appear to be different from the normal varying thicknesses in the breast.

Click the icon to see an image of a breast self-exam.

Current Recommendations for Screening. Mammograms are very effective low-radiation screening methods for breast cancer. At this time, the U.S. Preventive Services Task Force recommends screening mammograms, with or without breast examination, every 1 - 2 years for all women over age 40.

Guidelines from the American College of Physicians (ACP), however, debate whether women with a low risk for breast cancer should begin mammogram screening at age 40. The 2007 guidelines, instead, recommend that women in their 40s ask their doctor when they should begin having the test. In contrast, the American Cancer Society and the U.S. National Cancer Institute continue to endorse annual screening for women age 40 and older.

The ACP's guidelines have created controversy within the medical community. Supporters of the guidelines believe that these new recommendations reflect some of the risks involved in screening younger women. These risks include radiation exposure and unnecessary biopsies. Mammographies in younger women produce a relatively high rate of false-positive results (when the test falsely indicates breast cancer). Scientists are working on new technologies to improve mammography's accuracy, but more work is needed. For example, a 2007 New England Journal of Medicine study reported that computer-aided detection software, which is used to help radiologists interpret mammograms, may instead make readings less accurate.

Opponents of the ACP guidelines argue that mammograms help catch tumors while they are in their earliest and most treatable stages, and that the most deadly types of breast cancer tend to occur in women in their 40s.

In addition, according to a review in the American Cancer Society's journal, mammography rates have declined since 2000. In fact, while many experts believe that the recent decline in new cases of breast cancer is partially due to reduced use of hormone replacement therapy, other experts are concerned that fewer cases of breast cancer are being detected because fewer mammographies are being performed.

After age 50, all guidelines recommend annual screenings. The older a women gets, the greater her risk for developing breast cancer. (Women over age 65 account for most new cases of breast cancer.) Women with risk factors for breast cancer, including a close family member with the disease, should consider having annual mammograms starting 10 years earlier than the age at which the relative was diagnosed.

Click the icon to see an image of a mammogram.

Magnetic Resonance Imaging and Ultrasound. Magnetic resonance imaging (MRI) and ultrasound techniques can detect very small tumors (less than half an inch). However, they are expensive and time-consuming procedures. Nevertheless, some doctors believe they are important in identifying small tumors missed on mammography in women who are receiving lumpectomy or breast-conserving surgeries. Such findings would allow the surgeons to remove the optimal amount of abnormal tissue. Ultrasound may also be particularly important for women with dense breast tissue who show signs of breast cancer.

In a report published in 2007, the American Cancer Society recommended that high-risk women have an MRI of their breast with their annual mammogram, including those who have:

A BRCA1 or BRCA2 mutation
A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
A lifetime risk of breast cancer that has been scored at 20 - 25% or greater
Had radiation to the chest between ages 10 - 30
Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these genetic syndromes based on a history in a first-degree relative

For women who have had cancer diagnosed in one breast, MRIs can also be very helpful for detecting hidden tumors in the other breast. A landmark 2007 study in the New England Journal of Medicine reported that MRI scans of women who were diagnosed with cancer in one breast detected over 90% of cancers in the other breast that had been previously missed by mammography or clinical breast exam. Currently, few women who are diagnosed with cancer in one breast are offered an MRI of the other breast. Some experts advocate MRIs for all women newly diagnosed with breast cancer; others oppose this view. MRI scans may be most useful for younger women with breast cancer who have dense breast tissue that may obscure tumors from mammography readings. MRIs are less likely to be helpful for older women with early tumors in one breast and clear mammography readings in the other.

It is very important that women have MRIs at qualified centers that perform many of these procedures each year. MRI is a complicated procedure and requires special equipment and experienced radiologists. MRI facilities should also be able to offer biopsies when suspicious findings are detected.

Scintimammography. In scintimammography, a radioactive chemical is injected into the circulatory system, which is then selectively taken up by the tumor and revealed on mammograms. This method is very accurate in detecting the presence or absence of breast cancer, and some doctors hope that it might eventually reduce the number of unnecessary invasive biopsies. It is used for women who have had abnormal mammograms or for women who have dense breast tissue. It is not used for regular screening or as an alternative to mammography.

A definitive diagnosis of breast cancer can be made only by a biopsy (a microscopic examination of a tissue sample of the suspicious area).

When a lump can be felt and is suspicious for cancer on mammography, an excisional biopsy may be recommended. This biopsy is a surgical procedure for removing the suspicious tissue and typically requires general anesthetic.

Click the icon to see an image of breast biopsy.

A core biopsy involves a small incision and the insertion of a spring-loaded hollow needle that removes several samples. The patient only requires local anesthetic.
A wire localization biopsy may be performed if mammography detects abnormalities but there is no lump. With this procedure, using mammography as a guide, the doctor inserts a small wire hook through a hollow needle and into the suspicious tissue. The needle is withdrawn, and the hook is used by the surgeon to locate and remove the lesion. The patient may receive local or general anesthetic.
A new vacuum-assisted device may be useful for some biopsies. This uses a single probe through which a vacuum is used to draw out tissue. It allows several samples to be taken without having to remove and re-insert the probe.

Final analysis of the breast tissue may take several days.

If breast cancer has been determined, the next diagnostic step is to find out how far it has spread. To do this, the doctor performs a procedure called an axillary lymphadenectomy, which partially or completely removes the lymph nodes in the armpit beside the affected breast (called axillary lymph nodes). It may require a hospital stay of 1 - 2 days.

Click the icon to see an image of the axillary lymph nodes.

Once the lymph nodes are removed, they are analyzed to determine whether subsequent treatment needs to be more or less aggressive:

If no cancer is found in the lymph nodes, the condition is referred to as node negative breast cancer. The chances are good that the cancer has not spread and is still local.
If cancer cells are present in the lymph nodes, the cancer is called node positive. Their presence increases the possibility that the cancer has spread microscopically to other areas of the body. In such cases, however, it is still not known if the cancer has metastasized beyond the lymph nodes or, if so, to what extent. The doctor may perform further tests to see if the cancer has spread to the bone (bone scan), lungs (x-ray or CT scan) or brain (MRI or CT scan).

Side effects of the procedure include increased risk for infection and pain, swelling in the arm from fluid build-up, and impaired sensation and restricted movement in the affected arm. Patients might ask their doctor about the availability of physical therapy or upper-body exercises after treatment. In two studies, such programs resulted in quicker recovery and no fluid build-up in the arm.

A technique known as a sentinel node biopsy is a less invasive alternative to axillary lymph node dissection. This procedure can help determine if cancer has spread beyond the nodes. If the doctor finds no evidence of cancer, the patient may not need to have a complete axillary lymphadenectomy.

Click the icon to see an image of a sentinel node biopsy.

Sentinel node biopsy involves:

The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
The tracer or dye then flows through the lymphatic system into the sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If they do not show any signs of cancer, it is highly likely that the remaining lymph nodes will be cancer free, making further surgery unnecessary.

Patients who have a sentinel node biopsy tend to have better arm function and a shorter hospital stay than those who have an axillary node biopsy. The American Society of Clinical Oncology's 2005 guidelines recommend sentinel node biopsy instead of axillary lymph node dissection for women with early stage breast cancer who do not have nodes that can be felt during a physical exam. It is still not known if the sentinel node biopsy has any survival advantages compared to standard lymph node removal procedures.

Women often have to wait several days for results of sentinel node biopsies to learn whether they will require another surgery to remove additional lymph nodes. In 2007, the Food and Drug Administration approved the GeneSearch BLN Assay to help speed sentinel node biopsy testing. This molecular-based lab test can detect within 40 minutes whether cancer has spread to nearby lymph nodes. Because the test delivers rapid results while the patient is still on the operating table, it may help spare women the discomforts of a second surgical procedure and help them get treatment earlier.

Prognosis

In the U.S., about 40,460 women will die from breast cancer this year, making it the second most lethal cancer in women. (Lung cancer is the leading cancer killer in women.) The good news is that early detection and new treatments have improved survival rates. The 5-year survival rate for women diagnosed with cancer is 80%. About 88% of women diagnosed with breast cancer will survive at least 10 years. Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.

Several factors are used to determine successful treatment and the possibility for a cure. They include:

The location of the tumor and how far it has spread
Whether the tumor is hormone receptor-positive or -negative
Genetic factors
Tumor size and shape
Rate of cell division
Biologic markers

The good news is that women are living longer with breast cancer, and at this time more than 2 million American women are survivors. Due to better treatment options, from 1990 - 2003, breast cancer mortality rates declined by 24%. However, survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.

Recurrences of cancer usually develop within 5 years of treatment. However, 25% of recurrences and half of new cancers in the opposite breast occur after 5 years. One study suggested that the risk factors for a first breast cancer do not necessarily place a woman at any higher risk for recurrence. (Women with a first cancer, however, do have a higher risk for a new cancer in the opposite breast. The outlook for such new cancers is independent from those of the first one.)

The location of the tumor is a major factor in outlook:

If the cancer is ductal carcinoma in situ (DCIS) or has not spread to the lymph nodes (is node-negative), the 5-year survival rates with treatment are up to 98%. However, cancer recurs in 9 - 30% of women with node-negative cancers. Recurrence is a potentially life-threatening problem, even if the disease relapses locally in the same breast. In one study of DCIS patients with locally invasive recurrence, 8-year mortality rates were only 12%.
If the lymph nodes contain cancer cells (are node positive) then survival rates fall. If the tumor is larger than 5 cm or there is widespread involvement in the lymph nodes, the cancer is sometimes referred to as locally advanced. In such cases, the survival rate drops to about 75% and below.
If the cancer has spread (metastasized) to other sites (most often the lung, liver, and bone), the average survival time is about 2 years (with some patients living for many years). New drug therapies, particularly aromatase inhibitors, have helped prolong survival for women with metastatic cancer.

The location of the tumor within the breast is an important predictor. Tumors that develop toward the outside of the breast tend to be less serious than those that occur more toward the middle of the breast.

Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.

Hormone receptor-positive cancer is also called "hormone sensitive" because it responds to hormone therapy such as tamoxifen or aromatose inhibitors. Hormone receptor-negative tumors are referred to as "hormone insensitive" or "hormone resistant."

Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) A 2007 study in the Journal of Clinical Oncology indicated that recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical tamoxifen therapy.

Determining a "genetic signature" for a tumor may prove to be a very powerful predictor of the aggressive nature of a breast cancer. Researchers have focused on 70 genes whose activity patterns may help make such predictions. In 2007, the Food and Drug Administration approved MammaPrint, a DNA microarray diagnostic test that profiles these 70 genes. The molecular test may help predict how likely it is that breast cancer will recur within 5 - 10 years. However, the accuracy of the test depends on a woman’s risk. It is more accurate when predicting a low risk for recurrence than a high risk.

The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations offer a survival advantage. Others suggest that they make no difference or even worsen prognosis. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively.

Researchers are investigating numerous substances in tumor cells that may indicate whether or not a cancer is likely to spread. Such chemical markers may help doctors determine treatments, and some may even prove to be targets for future drugs. The following are only a few of the more well-researched markers.

HER2. The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2:

Immunohistochemistry (IHC)
Fluorescence in-situ hybridization (FISH)

Some doctors think that FISH is a more accurate test than IHC. According to 2006 HER2 testing guidelines from the American Society of Clinical Oncology and the College of American Pathologists, either test may be used as long as it is performed by an accredited laboratory. Tests that are not clearly positive or negative should be repeated. Treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) may help women who test positive for HER2.

Angiogenesis Factors. Angiogenesis is the growth of new blood vessels. High levels of angiogenesis factors indicate that the tumor is developing its own supply of blood vessels, which enable the tumor to send colonies of cancer cells into the bloodstream and spread to other parts of the body. Specific angiogenesis factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), may turn out to be important markers for determining treatment and prognosis. The monoclonal antibody bevacizumab (Avastin) targets VEGF. The drug is showing promise in clinical trials for prolonging progression-free survival in women with metastatic breast cancer.

Others. Many other markers are being investigated, including p53, cathepsin-D, protein c-erbB-2, bcl-2, Ki-67, telomerase, thymidylate synthase, CA 15-3, and carcinogenic embryonic antigen (CEA). The American Society of Clinical Oncology (ASCO) cautions, however, that the value of many of these factors has not yet been confirmed.

Tumor Size and Shape. Large tumors pose a higher risk than small tumors. Undifferentiated tumors, which have indistinct margins, are more dangerous than those with well-defined margins.

Rate of Cell Division. The more rapidly a tumor grows, the more dangerous it is. Several tests measure aspects of cancer cell division and may eventually prove to predict the disease. For example, the mitotic index (MI) is a measurement of the rate at which cells divide. The higher the MI, the more aggressive the cancer. Another test measures cells at a certain phase of their division.

Recent evidence has not supported early reports of survival benefits for women with metastatic breast cancer who engage in support groups. However, some studies have suggested that psychotherapy, group support, or both may relieve pain and reduce stress, particularly in women who are suffering emotionally.

Stress has been ruled out as a risk factor either for breast cancer itself or for its recurrence.

Treatment

The three major treatments of breast cancer are surgery, radiation, and drug therapy. No one treatment fits every patient, and combination therapy is usually required. The choice is determined by many factors, including the age of the patient, menopausal status, the kind of cancer (ductal vs. lobular), its stage, and whether or not the tumor contains hormone-receptors.

Breast cancer treatments are defined as local or systemic:

Local Treatment. Surgery and radiation are considered local therapies because they directly treat the tumor, breast, lymph nodes, or other specific regions. Surgery is usually the standard initial treatment.
Systemic Treatment. Drug treatment is called systemic therapy, because it affects the whole body.

Any or all of these therapies may be used separately or, most often, in different combinations. For example, radiation alone or with chemotherapy or hormone therapy may be beneficial before surgery, if the tumor is large or not easily removed at prevention. Surgery followed by radiation and hormone therapy is usually recommended for women with early-stage, hormone-sensitive cancer. There are numerous clinical trials investigating new treatments and treatment combinations. Patients, especially those with advanced stages of cancer, may wish to consider enrolling in a clinical trial.

Treatment strategies depend in part on the stage of the cancer.

Stage 0 (Carcinoma in Situ). Stage 0 breast cancer is considered non-invasive (‘in situ"), meaning that the cancer is still confined within breast ducts or lobules and has not yet spread to surrounding tissues. Stage 0 cancer is classified as either:

Ductal carcinoma in situ (DCIS). These are cancer cells in the lining of a duct that have not invaded the surrounding breast tissue.
Lobular carcinoma in situ (LCIS). These are cancer cells in the lobules of the breast. LCIS rarely develops into invasive breast cancer, but having it in one breast increases the risk of developing cancer in the other breast.

Treatment options for DCIS include:

Breast-conserving surgery and radiation therapy (followed by hormone therapy for women with hormone-sensitive cancer)
Total mastectomy (followed by hormone therapy for women with hormone-sensitive cancer)
Breast-conserving surgery without radiation therapy

Treatment options for LCIS include:

Regular exams and mammograms to monitor any potential changes (observation treatment)
Hormone therapy to prevent development of breast cancer (for women with hormone-sensitive cancer)
Mastectomy of both breasts was previously used as treatment, but is now rarely recommended

Stage I and II (Early-Stage Invasive). In stage I cancer, cancer cells have not spread beyond the breast, and the tumor is no more than 2 cm (about 3/4 of an inch) across.

Stage II cancer is classified as either stage IIA or stage IIb.

In stage IIA cancer the tumor is either:

No more than 2 centimeters and has spread to the underarm lymph nodes (axillary lymph nodes)
Between 2 - 5 centimeters and has not spread to the underarm lymph nodes

Treatment options for stage I and stage II breast cancer may include:

Breast-conserving surgery (such as lumpectomy) followed by radiation therapy
Modified radical mastectomy with or without breast reconstruction
Post-surgical therapy (adjuvant therapy), including radiation of lymph nodes, chemotherapy, or hormone therapy
Trastuzumab (Herceptin) given along with or following adjuvant chemotherapy for women with HER2-positive cancer

Stage III (Locally Advanced). Stage III breast cancer is classified into several sub-categories: Stage IIIA, stage IIIB, and stage IIIC (operable or inoperable).

In stage IIIA breast cancer, the tumor is usually confined to the underarm lymph nodes. Treatment options for stage IIIA breast cancer are the same as those for stages I and II.

In stage IIIB breast cancer, the tumor has spread to either:

Tissues near the breast (including the skin or chest wall)
Lymph nodes within the breast or under the arm

Stage IIIB treatment options may include:

Chemotherapy, and possibly hormone therapy (sometimes in combination with chemotherapy)
Chemotherapy followed by surgery (breast-conserving surgery or total mastectomy) with lymph node dissection followed by radiation therapy and possibly more chemotherapy or hormone therapy
Clinical trials

Stage IIIC breast cancer is classified as either operable or inoperable.

In operable stage IIIC, the cancer may be found in:

10 or more of the underarm lymph nodes
Lymph nodes beneath the collarbone and near the neck on the same side of the body as the affected breast
Lymph nodes within the breast as well as underarm lymph nodes

Treatment options for operable stage III breast cancer are the same as those for stage I and II breast cancers.

In inoperable stage III breast cancer, the cancer has spread to lymph nodes above the collarbone and near the neck on the same side of the body as the affected breast. Treatment options are the same as those for stage IIIB.

Stage IV (Advanced Cancer). In stage IV, the cancer has spread (metastasized) from the breast to other parts of the body. In about 75% of cases, the cancer has spread to the bone. The cancer at this stage is considered to be chronic and incurable, and the usefulness of treatments is limited. The goals of treatment for stage IV cancer are to stabilize the disease and slow its progression, as well as to reduce pain and discomfort.

Treatment options for stage IV cancer include:

Surgery or radiation for any localized tumors in the breast. A 2006 study indicated that surgical removal of the primary tumor immediately after metastatic cancer diagnosis can dramatically improve survival.
Chemotherapy, hormone therapy, or both. Targeted therapy with trastuzumab (Herceptin) or lapatinib (Tykerb) should be considered for women with HER2-positive cancer.
Cancer that has spread to the brain may require radiation and high-dose steroids.
Cancer that has spread to the bone may be helped by radiation or bisphosphonate drugs. Such treatments can relieve pain and help prevent bone fractures.
Clinical trials of new drugs or drug combinations, or experimental treatments such as high-dose chemotherapy with stem cell transplant.

In 2006, the American Society of Clinical Oncology (ASCO) released updated guidelines on follow-up care for patients who have been treated for breast cancer. ASCO recommends:

Visit your doctor every 3 - 6 months for the first 3 years after your first cancer treatment, every 6 - 12 months during the fourth and fifth year, and once a year thereafter.
Have a mammogram 1 year after the mammogram that diagnosed your cancer (but no earlier than 6 months after radiation therapy), and every 6 - 12 months thereafter.
Perform a breast self-exam every month (however, this is no substitute for a mammogram).
See your gynecologist regularly (women taking tamoxifen should be sure to report any vaginal bleeding).
A year after diagnosis, you can either continue to see your oncologist or transfer your care to your primary care physician.
If you are on hormone therapy, discuss with your oncologist how often to schedule follow-up visits for re-evaluation of your treatment.

ASCO does not recommend the use of laboratory blood tests (complete blood counts, carcinoembryonic antigen) or imaging tests (bone scans, chest x-rays, liver ultrasound, FDG-PET scan, CT scan) for routine breast cancer follow-up.

Genetic counseling may be helpful if you have:

Ashkenazi Jewish heritage
Personal or family history of ovarian cancer
Personal or family history of cancer in both breasts
Any first-degree female relative (mother, sister, daughter) diagnosed with breast cancer before age 50
Two or more first-degree or second-degree (grandparent, aunt, uncle) diagnosed with breast cancer
History of breast cancer in a male relative

Pregnancy after Breast Cancer Treatment. There are no definite recommendations on how long a woman should wait to become pregnant after breast cancer treatment. Because of the connection between estrogen levels and breast cancer cell growth, some experts recommend delaying pregnancy until 2 years after treatment in order to reduce the risk of cancer recurrence and improve odds for survival. However, a 2007 study indicated that conceiving 6 months after treatment does not negatively affect survival. Discuss with your doctor your risk for recurrence, and when it may be safe to attempt pregnancy.

Recurrent breast cancer is considered to be an advanced cancer. In such cases, the disease has come back in spite of the initial treatment. Most recurrences appear within the first 2 - 3 years after treatment, but breast cancer can recur many years later. Treatment options are based on the stage at which the cancer reappears, whether or not the tumor is hormone responsive, and the age of the patient. Between 10 - 20% of recurring cancers are local. Most recurrent cancers are metastatic. All patients with recurring cancer are candidates for clinical trials.

Because most breast cancer recurrences are discovered by patients in between doctor visits, it is important to notify your doctor if you experience any of the following symptoms. These symptoms may be signs of breast cancer recurrence:

New lumps in the breast
Bone pain
Chest pain
Abdominal pain
Shortness of breath or difficulty breathing
Persistent headaches or coughing
Rash on breast
Nipple discharge

Surgery

Surgery forms a part of nearly every patient's treatment for breast cancer. The initial surgical intervention is often a lumpectomy, the removal of the tumor itself. In the past, mastectomy (the removal of the breast) was the standard treatment for nearly all breast cancers. Now, many patients with early-stage cancers can choose breast-conserving treatment, or lumpectomy followed by radiation, with or without chemotherapy.

For invasive breast cancer, studies indicate that lumpectomy or partial mastectomy combined with radiation therapy works as well as a modified radical mastectomy.

Breast-conserving procedures are now appropriate and as successful as mastectomy in most women with early stage breast cancer. All women should discuss these options fully with their doctor. Recurrence rates with conservative surgery are highest in women under age 45. Some women choose mastectomy over breast-conserving treatment even if the latter is appropriate because it gives them a greater sense of security and allows them to avoid radiation therapy.

Lumpectomy. Lumpectomy is the removal of the tumor, often along with lymph nodes in the armpit. It serves as an opportunity for biopsy, a diagnostic tool, and a primary treatment for small local breast tumors. If invasive cancer is found, the doctor will decide to proceed with breast radiation therapy, to remove additional tissue (should the margins of the specimen show signs of cancer), or to perform a mastectomy. Lumpectomy followed by radiation therapy is appropriate and as effective as mastectomy in most women with Stage I or II breast cancers.

Click the icon to see an illustrated series detailing breast lump removal surgery.

Breast-Conserving Surgery (Quadrantectomy). Breast-conserving surgery (sometimes referred to as quadrantectomy) removes the cancer and a large area of breast tissue, occasionally including some of the lining over the chest muscles. It is less invasive than a full mastectomy, but the cosmetic results are less satisfactory than with a lumpectomy. Excellent studies have found that breast-conserving surgeries plus postoperative radiotherapy offer the same survival rates as radical mastectomy in women with early breast cancer. A new technology called partial breast radiation (MammoSite), approved by the Food and Drug Administration in 2002, confines radiation to the tumor site rather than delivering it to the whole breast, and reduces treatment time from 5 weeks to 5 days in women who undergo breast conserving surgery.

Surgery to remove the breast (mastectomy) is important for women with operable breast cancer who are not candidates for breast conserving surgeries. There are different variations on the procedure:

A total mastectomy involves removal of the whole breast and sometimes lymph nodes under the armpit.
A radical mastectomy removes the breast, chest muscles, all of the lymph nodes under the arm, and some additional fat and skin. (A modified radical mastectomy removes the entire breast and armpit lymph nodes, with the underlying chest wall muscle.) A 25-year study supported other research that observed no survival advantages from radical mastectomy compared to the less invasive mastectomies for the great majority of patients. It is rarely used anymore except when cancer is very advanced.

Click the icon to see an illustrated series detailing mastectomy surgery.

Complications and Side Effects of Surgery. Short-term pain and tenderness occur in the area of the procedure, and pain relievers may be necessary.

The most frequent complication of extensive lymph node removal is edema, or swelling, of the arm, which is usually mild and rarely painful but does increase the risk for infection. The likelihood of edema can be lessened by removing only some of the lymph nodes instead of all of them.

Infrequent complications include poor wound healing, bleeding, or a reaction to the anesthesia.

After mastectomy and lymph node removal, women may experience numbness, tingling, and difficulty in extending the arm fully. These effects can last for months or years afterward.

After a mastectomy, some women choose a breast prosthesis or opt for breast reconstruction, which can be performed during the mastectomy itself, if desired. Several studies have indicated that women who take advantage of cosmetic surgery after breast cancer have a better sense of well-being and a higher quality of life than women who do not choose reconstructive surgery. The breast is reshaped using a saline implant or, for a more cosmetic result, a muscle flap is taken from elsewhere in the body. Muscle flap procedures are more complicated, however, and blood transfusions may be required. (It should be noted that implants, including silicone implants, do not appear to put a woman at risk for breast cancer recurrence.) If the nipple is removed, it is rebuilt from other body tissues and color is applied using tattoo techniques. It is nearly impossible to rebuild a breast that is identical to its partner, and additional operations may be necessary to achieve a desirable effect.

Click the icon to see an illustrated series detailing breast reconstruction surgery.

Numerous studies are investigating minimally invasive techniques that use lasers, deep-freezing of cancer cells (cryosurgery), high-intensity ultrasound, and other experimental approaches to kill cancer cells and reduce severe complications of surgery. Radiofrequency ablation, for example, is an approach that uses an electrode inserted into the tumor. It emits radio waves that produce enough heat to destroy cancer cells. Early trials are promising. These procedures, however, are not considered standard at the present time.

Radiation

Radiation therapy uses high-energy x-rays to kill cancer cells or to shrink the size of a tumor in the breast or surrounding tissue. It is used for several weeks following lumpectomy or partial mastectomy, and sometimes after full mastectomy. Radiation therapy can help reduce the chance of breast cancer recurrence in the breast and chest wall. Radiation is also important in advanced stages of cancer for relief of symptoms and to slow progression. Research shows that radiation therapy is helpful for women of all ages, including those over age 65.

Radiation is generally administered in the following ways:

External Beam Radiation. This type of radiation is administered 4 - 6 weeks after surgery and delivered externally by an x-ray machine that targets radiation to the whole breast. It may be delivered to the chest wall in high-risk patients (large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about 6 weeks. A follow-up boost of radiation therapy in patients with lumpectomies appears to reduce the risk for recurrence.

Brachytherapy. Less commonly, radiation is delivered in implants (called brachytherapy). Implants are most often used as a radiation boost after whole breast radiation. Studies suggest they improve survival in patients at high risk for local recurrence. Some evidence suggests that implants alone can reduce treatment time and may be as effective as external beam radiation in some patients with early stage breast cancer. A new technology for breast brachytherapy (MammoSite) was approved in 2002. The technique provides 5-year local tumor control rates similar to those of whole-breast radiation for selected patients, with much shorter treatment time and good cosmetic results.

Investigators are also testing other approaches to radiation treatment. One uses a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard photon radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions. Such an approach may improve the coverage of breast cancers while reducing the toxic effects to the heart and lungs.

Side effects of radiation include:

Fatigue is very common and increases with subsequent treatments, but most women are able to continue with normal activities. Exercise may be helpful.
Nausea and lack of appetite may develop and worsen as treatment progresses.
Skin changes and burns can occur on the breast skin. Using a cream that contains a corticosteroid, such as mometasone furoate (MMF), may be helpful. After repeated sessions, the skin may become moist and "weepy." Exposing the treated skin to air as much as possible helps healing. (Washing the affected skin with soap and water does not seem to be harmful and in one study was associated with a lower risk for this side effect.)
Uncommonly, the breast may change color, size, or become permanently firm.
Rarely, the nearest arm may swell and develop impaired mobility or even paralysis.

Future complications include:

Radiation to the left breast may increase the long-term risk for developing heart disease and heart attacks.
There is a very small risk (less than 1%) of lung irritation and scarring.
Some studies have reported a higher risk for future cancer in the opposite breast in younger women who have been given radiation to the chest wall.
Radiation therapy can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.

Current advanced imaging techniques use precise radiation that reduces exposure. These newer techniques are likely to reduce the risks for heart disease and other serious complications.

Medications

The most important advances in the cure of breast cancer have come through the use of drug therapy, also called systemic therapy. Surgery and radiation therapy are effective for treating tumors confined to the breast but not for cancer cells that have spread or are at risk of spreading. In such cases, drug therapy is needed.

Drug treatments for breast cancer include:

Chemotherapy. Chemotherapy drugs are "cytotoxic" (cell-killing) drugs. They are given orally or by injection. They work systemically by killing cancer cells throughout the body. (Unfortunately, they also kill normal cells, which accounts for many of their side effects.) Chemotherapy is always used for advanced breast cancer, but may also be used to treat types of early-stage breast cancer.
Hormone Therapy. The goal of hormone therapy is to prevent estrogen from stimulating breast cancer cells. It is recommended for women whose breast cancers are hormone-receptor positive (either estrogen or progesterone), regardless of the size of the tumor and whether or not it has spread to the lymph nodes. Like chemotherapy, hormone therapy works systemically.
Targeted Therapy. Newer biologic drugs target specific proteins involved in cancer. Because they do not work as systemically as chemotherapy or hormone therapy drugs, they tend to cause fewer widespread side effects. Currently, the monoclonal antibody trastuzumab (Herceptin) and the kinase inhibitor lapatinib (Tykerb) are the two targeted therapies approved for breast cancer. These drugs target the HER2/neu protein and are used to treat HER2-positive breast cancers. Bevacizumab (Avastatin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein involved in tumor blood vessel formation (angiogenesis). It is being studied in clinical trials for treatment of metastatic breast cancer.

Drug therapy may be used as:

Primary therapy for patients for whom surgery or radiation therapy is not appropriate.
Neoadjuvant therapy (before surgery or radiation) to shrink tumors to a size that can be treated with local therapy.
Adjuvant therapy (following surgery or radiation) to reduce the risk of cancer recurrence.

For metastatic cancer, drugs are used not to cure but to improve quality of life and prolong survival.

Chemotherapy

Chemotherapy needs to be tailored to the type of cancer involved. Women require different treatments depending on whether the tumor is node-negative or -positive, hormone receptor-positive or -negative, or HER2-positive or -negative. Different treatment approaches are also used for early-stage cancer and advanced cancer.

A 2006 study in the Journal of the American Medical Association indicated that women with hormone receptor-negative cancers respond better to chemotherapy than women with hormone receptor-positive cancer. However, some women with hormone receptor-positive cancer do benefit from chemotherapy, as well as from hormone therapy.

Adjuvant chemotherapy is administered following surgery and before radiation therapy. A 2007 study in the Journal of Clinical Oncology suggested that women with early-stage breast cancer can safely wait for up to 12 weeks after surgery before beginning chemotherapy. However, delaying chemotherapy until more than 12 weeks after surgery significantly increases the risk for breast cancer recurrence and can reduce the odds for survival by as much as 60%.

Many different types of chemotherapy drugs are used to treat breast cancer. Common types of chemotherapy drug classes include:

Anthracyclines include doxorubicin (Adriamycin) and epirubicin (Ellence). Anthracycline-based combination regimens are often used to treat early-stage breast cancer, as well as advanced cancer.
Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). Two 2003 studies suggested that taxane-based therapy is particularly helpful for node-positive breast cancer. A newer formulation of paclitaxel (Abraxane) is used as a secondary treatment for advanced breast cancer.
Platinum-based drugs include oxaliplatin (Eloxatin) and carboplatin (Paraplatin). These drugs may be used in combination regiments for advanced cancer or for cancers associated with BRCA genes.

Some of the abbreviations used for chemotherapy drug combinations (regimens) refer to drug classes rather than drug names. For example, regimens that contain an anthracycline drug (such as doxorubicin) use the letter "A," and regimens that contain a taxane drug (such as docetaxel) use the letter "T." Cyclophosphamide (Cytoxan), fluorouracil (5-FU), and methotrexate (MTX) are standard cancer drugs used in many breast cancer chemotherapy regimens.

Chemotherapy regimens usually consist of 4 - 6 cycles of treatment given over 3 - 6 months. Common chemotherapy regimens for early-stage breast cancer include:

AC (Doxorubicin and cyclophosphamide)
AC followed by T (Doxorubicin and cylophosphamide followed by paclitaxel)
CAF (Cyclophosphamide, doxorubicin, and 5-FU)
CMF (Cyclophosphamide, methotrexate, and 5-FU)
TAC (Docetaxel, doxorubicin, and cyclophosphamide)

Trastuzumab (Herceptin). Trastuzumab is a monoclonal antibody that targets the HER2 protein on cancer cells. HER2-positive cancers account for 15 - 25% of early-stage breast cancer and are associated with more aggressive disease. Younger women tend to be most affected. In November 2006, the Food and Drug Administration approved trastuzumab for treatment of HER2-positive, early-stage breast cancer (cancer confined to the breasts or lymph nodes that has been surgically removed). Trastuzumab is given along with other chemotherapy drugs following lumpectomy or mastectomy. Research indicates that trastuzumab can help prevent cancer recurrence and death among women with early-stage breast cancer, but it increases the risk of heart problems. Trastuzumab can cause heart failure. Women who have heart failure or weak heart muscle (cardiomyopathy) should not use this drug. Women who take trastuzumab need to have regular heart monitoring, especially if they have already have heart problems.

Patients who develop metastatic disease (cancer that spreads throughout the body) are generally not curable. New advances in drug therapies, however, can help shrink tumors, prolong survival, and improve quality of life.

Chemotherapy regimens for advanced cancer may use a single drug or a combination of drugs. Many chemotherapy regimens used for early-stage breast cancer are also used for advanced breast cancer. Some specific combinations for advanced cancer include:

Gemcitabine and paclitaxel. In 2004, the Food and Drug Administration approved the antimetabolite drug gemcitabine (Gemzar) for use in combination with paclitaxel (Taxol) as a first-line treatment option for women with metastatic breast cancer.
Capecitabine (Xeloda) and docetaxel (Taxotere). Capecitabine is an oral drug that is chemically related to 5-FU. It is also being studied in combination with many other drugs.

Numerous chemotherapy drugs and drug combinations are being tested in clinical trials. Patients with advanced breast cancer may also receive other types of drug treatments. Bisphosphonate drugs, such as zoledronic acid (Zometa) and pamidronate (Aredia), are important supportive drugs for preventing fractures and reducing pain in people whose cancer has spread to the bones.

Two targeted therapy drugs are approved for the treatment of HER2-positive advanced breast cancer

Trastuzumab (Herceptin) was approved in 1998 for treatment of metastatic breast cancer. It is used in adjuvant chemotherapy, along with drugs such as paclitaxel.
Lapatinib (Tykerb) was approved in March 2007 for patients who have not been helped by other cancer drugs, including an anthracycline, a taxane, or trastuzumab. Lapatinib is used in combination with capecitabine (Xeloda). Research suggests it may have fewer risks for heart problems than trastuzumab.

Promising new treatments for advanced breast cancer include:

Ixabepilone (BMS-247550). Ixabepilone is the first of a new class of cancer drugs called epothilones. It is showing encouraging results when combined with capecitabine, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin). Bevacizumab is a targeted therapy anti-angiogenesis drug approved for treatment of colorectal and lung cancers. It is being studied in combination with various chemotherapy drugs for treatment of advanced cancer.

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting. Aprepitant (Emend), a new drug for preventing chemotherapy-caused nausea and vomiting, was approved in 2006.
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. They include the following:

Anemia. The erythropoietins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production and can help reduce or prevent anemia, resulting in significant improvement in quality of life. Aranesp persists longer in the blood than epoetin alfa and may therefore require fewer injections.
Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection.
Liver and kidney damage.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based drugs.
Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women, particularly in those over 40. A natural hormone medication called a gonadotropin-releasing hormone analogue, which puts women in a temporary pre-pubescent state during chemotherapy, may preserve fertility in some women. Women may also wish to consider embryo cryopreservation -- the harvesting of eggs, followed by in vitro fertilization and freezing of embryos for later use. The American Society of Clinical Oncology recommends that women being treated for cancer see a reproductive specialist to discuss all available fertility preservation options.
Sexual dysfunction.
Rarely, secondary cancers such as leukemia.
A quarter to a third of women report problems in concentration, motor function, and memory, which can be long-term. In one study, women were having these symptoms 2 years after treatment, although by 4 years they had resolved.
Heart problems. Trastuzumab (Herceptin) may increase the risk for heart failure, particularly in women with pre-existing risk factors. Cumulative doses of anthracyclines (doxorubicin, epirubicin) can also damage heart muscles over time and increase the risk for heart failure.
Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in taxol than taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.

High-dose chemotherapy along with peripheral-blood stem cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs.

Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells.

Despite the initial enthusiasm over the use of high-dose therapy for treatment of high risk breast cancer, this approach can no longer be generally recommended and should not be used outside of a clinical trial setting. The results of several randomized studies have failed to show a convincing advantage for the use of high-dose therapy. Nevertheless, some experts believe this approach can still be useful in selected patients, and studies continue. In general, however, transplantation has a limited role in breast cancer management, and its use should be restricted to clinical trials.

Hormone Therapy

Hormone therapy works by blocking estrogen that causes cell proliferation. It is used only for patients with hormone receptor-positive tumors. Different types of hormone therapy work in different ways by:

Blocking estrogen receptors in cancer cells (Tamoxifen)
Suppressing estrogen production in the body (Aromatase inhibitors)
Destroying ovaries, which produce estrogen (Ovarian ablation)

Tamoxifen was the first widely used hormonal therapy drug, but it has been replaced by aromatase inhibitors for some women. Aromatase inhibitors are used only to treat postmenopausal women. Tamoxifen is mainly used as adjuvant therapy for premenopausal women with hormone-sensitive breast cancer.

Tamoxifen (Nolvadex) has been the standard hormonal drug used for breast cancer. It belongs to a class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Because SERMs block estrogen’s effects on cancer cells, they are sometimes referred to as "anti-estrogen" drugs.

Tamoxifen is used for all cancer stages in women of all ages with hormone receptor-positive cancers. In addition, it is used to prevent breast cancer in high-risk women. Another SERM drug, toremifene (Fareston), is an option for women with advanced cancer, but this drug is rarely used in the United States. A third drug, fulvestrant (Faslodex), works in a similar anti-estrogen way to tamoxifen but belongs to a different drug class. Fulvestrant is approved only for postmenopausal women with hormone-sensitive advanced breast cancer in which tamoxifen or aromatase inhibitors no longer work.

To prevent cancer recurrence, women should take tamoxifen for 5 years following surgery and radiation. Tamoxifen is an effective cancer treatment, but it can cause unpleasant side effects and has small (less than 1%) but serious risks for blood clots and uterine (endometrial) cancer. Immediately report any signs of vaginal bleeding to the doctor, as this may be a symptom of uterine cancer.

Less serious, but discomforting, side effects include hot flashes and mood swings. According to a 2007 study, nearly 25% of women stop taking tamoxifen within 1 year because of these symptoms. By 3.5 years, over 33% stop treatment. Taking tamoxifen for fewer than 5 years, however, increases the risk for cancer recurrence and death. Talk with your doctor about antidepressants or other therapies that may help you cope with tamoxifen’s side effects.

Many doctors now recommend that postmenopausal women switch to an aromatase inhibitor after 2 - 3 years of tamoxifen therapy. Several 2007 studies indicated that switching from tamoxifen to an aromatase inhibitor significantly improves survival rates and reduces the risk of death from breast cancer as well as other causes.

Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.

Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. Aromatase inhibitors work differently than tamoxifen. Tamoxifen interferes with tumors’ ability to use estrogen by blocking their estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body.

Because these drugs cannot stop the ovaries of premenopausal women from producing estrogen, they are recommended only for postmenopausal women.

There are currently three aromatase inhibitors approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women:

Anastrazole (Armidex) for treatment after surgery
Exemestane (Aromasin) for women who have taken tamoxifen for 2 - 3 years
Letrozole (Femara) for treatment after surgery or for women who have completed 5 years of tamoxifen therapy

All of these drugs are also approved for women with advanced (metastatic) hormone-sensitive breast cancer. Studies indicate that the introduction of aromatase inhibitors has helped greatly in prolonging survival for women with advanced cancer.

Compared to tamoxifen, aromatase inhibitors are less likely to cause blood clots and uterine cancer. However, these drugs are more likely to cause osteoporosis, which can lead to bone loss and fractures. In general, recent studies indicate that aromatase inhibitors are better than tamoxifen in improving survival and reducing the risk of cancer recurrence. Unfortunately, like tamoxifen, they can cause hot flashes, as well as joint pain.

Ovarian ablation literally shuts down estrogen production from the ovaries. Medications can accomplish ovarian ablation. Destroying the ovaries with surgery or radiation can also shut down estrogen production. (Osteoporosis is one serious side effect of this approach, but several therapies are available to help prevent bone loss.)

Chemical Ovarian Ablation. Drug treatment (non-chemotherapy drugs) to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, therefore stopping ovulation and estrogen production.

Studies suggest that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who take standard chemotherapy. They also experience fewer serious side effects. A major analysis of four trials using LHRH agonists plus tamoxifen suggested that this combination should be the standard for patients with advanced breast cancers that are hormone-receptor positive, although this is an area of controversy. (Chemotherapy is still more effective in women with estrogen-negative tumors.)

Ovariectomy. Ovariectomy, the removal of the ovaries, has modestly improved breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility and can have a major negative emotional impact on younger patients.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.oncolink.org -- Oncolink
www.womenshealth.gov -- National Women's Health Information Center
www.nccn.org -- National Comprehensive Cancer Network
www.plwc.org -- People Living With Cancer
www.cancer.gov/clinicaltrials -- Find clinical trials
www.breastcancer.org -- Find clinical trials

References

Bardia A, Hartmann LC, Vachon CM, Vierkant RA, Wang AH, Olson JE, et al. Recreational physical activity and risk of postmenopausal breast cancer based on hormone receptor status. Arch Intern Med. 2006 Dec 11-25;166(22):2478-83.

Barron TI, Connolly R, Bennett K, Feely J, Kennedy MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer. 2007 Mar 1;109(5):832-9.

Boccardo F, Rubagotti A, Aldrighetti D, Buzzi F, Cruciani G, Farris A, et al. Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer. 2007 Mar 15;109(6):1060-7.

Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15;129(6):1065-79.

Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36.

Breen N, A Cronin K, Meissner HI, Taplin SH, Tangka FK, Tiro JA, et al. Reported drop in mammography : is this cause for concern? Cancer. 2007 Jun 15;109(12):2405-9.

Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007 Jul 23;110(5):973-979 [Epub ahead of print]

Cho E, Chen WY, Hunter DJ, Stampfer MJ, Colditz GA, Hankinson SE, et al. Red meat intake and risk of breast cancer among premenopausal women. Arch Intern Med. 2006 Nov 13;166(20):2253-9.

Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70.

Fenton JJ, Taplin SH, Carney PA, Abraham L, Sickles EA, D'Orsi C, et al. Influence of computer-aided detection on performance of screening mammography. N Engl J Med. 2007 Apr 5;356(14):1399-409.

Geiger AM, Thwin SS, Lash TL, Buist DS, Prout MN, Wei F, et al. Recurrences and second primary breast cancers in older women with initial early-stage disease. Cancer. 2007 Mar 1;109(5):966-74.

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43.

Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ. 2007 Jan 27;334(7586):194. Epub 2006 Dec 8.

Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol. 2007 May 1;25(13):1683-90. Epub 2007 Apr 2.

Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006 Oct;81(10):1290-302.

Kerlikowske K, Miglioretti DL, Buist DS, Walker R, Carney PA; National Cancer Institute-Sponsored Breast Cancer Surveillance Consortium. Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst. 2007 Sep 5;99(17):1335-9. Epub 2007 Aug 14.

Khatcheressian JL, Wolff AC, Smith TJ, Grunfeld E, Muss HB, Vogel VG, et al.American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7. Epub 2006 Oct 10.

Lehman CD, Gatsonis C, Kuhl CK, Hendrick RE, Pisano ED, Hanna L, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007 Mar 29;356(13):1295-303. Epub 2007 Mar 28.

Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med. 2007 May 28;167(10):1050-9.

Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2006 Oct 20;24(30):4888-94. Epub 2006 Oct 2.

Michels KB, Xue F, Colditz GA, Willett WC. Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study. Arch Intern Med. 2007 Apr 23;167(:814-20.

Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet. 2006 Dec 9;368(9552):2053-60.

North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause. 2007 Mar-Apr;14(2):168-82.

Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2.

Pierce JP, Natarajan L, Caan BJ, Parker BA, Greenberg ER, Flatt SW, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007 Jul 18;298(3):289-98.

Qaseem A, Snow V, Sherif K, Aronson M, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007 Apr 3;146(7):511-5.

Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19;356(16):1670-4.

Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89.

Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36.

Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med. 2006 Dec 11-25;166(22):2484-9.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007 Jan 1;25(1):118-45. Epub 2006 Dec 11.

Review Date:
1/26/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (11/01/07).

A.D.A.M. Copyright

adam.com

Coronary artery disease

FitSugar — Wed, 08 Oct 2008 17:35:07 -0700

In This Report

Highlights
Introduction
Prognosis
Risk Factors
Diagnosis
Managing Heart Disease
Anti-Clotting Medications...
Other Medications
Surgery
Coronary Artery Bypass Graf...
Angioplasty and Stents
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Angioplasty Versus Drugs

Angioplasty works no better than drug therapy (high blood pressure, cholesterol, anti-platelet, and other medication) in preventing heart attack and stroke in patients with stable coronary artery disease (CAD), according to an important New England Journal of Medicine study. Experts still recommend angioplasty for patients with unstable or severe CAD.

Stents

Stents coated with drugs may have a slightly higher risk of causing blood clots than bare metal stents, according to FDA meetings held in late 2006. Researchers still need to conduct more research before reaching final conclusions.
Drug-coated stents work well when they are used for patients with specific types of heart conditions, indicate several studies published in the New England Journal of Medicine. However, problems may develop when these stents are used for “off-label” purposes. Experts are also concerned that both bare metal and drug-coated stents may be used too frequently.
Patients who receive a drug-coated stent must take both aspirin and an anti-platelet thienopyridine drug (usually clopidogrel) for at least 1 year after the stent is inserted, advises an important statement from the American Heart Association. Patients who cannot take a thienopyridine drug should receive a bare metal stent instead of a drug-coated stent.

Anti-Bleeding Drugs for Coronary Artery Bypass Graft (CAGB)

Aprotinin (Trasylol), a drug used to control bleeding during CABG, is more dangerous than other types of anti-bleeding drugs, according to a 2007 study in the Journal of the American Medical Association. Many experts now recommend against its use.

Diagnosis

Blood tests for biomarkers do not provide much more predictive information than standard disease risk factors, suggest several recent studies. In a 2006 study published in the New England Journal of Medicine, researchers found that risk factors such as high blood pressure, high cholesterol, and diabetes are still the best methods for predicting the likelihood of heart disease and heart-related death.

Introduction

The heart is the human body's hardest working organ. Throughout life it continuously pumps blood enriched with oxygen and vital nutrients through a network of arteries to all parts of the body's tissues.

The external structures of the heart include the ventricles, atria, arteries, and veins. Arteries carry blood away from the heart while veins carry blood into the heart. The vessels colored blue indicate the transport of blood with relatively low content of oxygen and high content of carbon dioxide. The vessels colored red indicate the transport of blood with relatively high content of oxygen and low content of carbon dioxide.

In order to perform the difficult task of pumping blood to the rest of the body, the heart muscle itself needs a plentiful supply of oxygen-rich blood, which is provided through a network of coronary arteries. These arteries carry oxygen-rich blood to the heart's muscular walls (the myocardium).

Click the icon to see an image of the anterior heart arteries.

If blood flow to the myocardium is interrupted, an injury known as an infarct occurs. This is also known as myocardial infarction or, more commonly, a heart attack.

Click the icon to see an animation about coronary artery disease.

Coronary artery disease is the end result of a complex process called atherosclerosis (commonly called "hardening of the arteries"). This causes blockage of arteries (ischemia ) and prevents oxygen-rich blood from reaching the heart. There are many steps in the process leading to atherosclerosis, some not fully understood.

Click the icon to see an image of atherosclerosis.

Increasingly, however, researchers are studying the interactions between cholesterol and processes known as oxidation and the inflammatory response.

Cholesterol and Lipoproteins. The story begins with cholesterol and sphere-shaped bodies called lipoproteins that transport cholesterol.

Cholesterol is a white, crystalline substance that is found in all animal cells and in animal-based foods. It is critical for many functions, but under certain conditions cholesterol can have harmful effects.
The lipoproteins that transport cholesterol are referred to by their size. The most commonly known are low-density lipoproteins (LDL) and high density lipoproteins (HDL). LDL is often referred to as the "bad" cholesterol and HDL as the "good" cholesterol.

Click the icon to see an image of cholesterol inside an artery.

Oxidation. The damaging process called oxidation is an important trigger in the atherosclerosis story.

Oxidation is a chemical process in the body caused by the release of unstable particles known as oxygen-free radicals. It is one of the normal processes in the body, but under certain conditions (such as exposure to cigarette smoke or other environment stresses) these free radicals are overproduced.
In excess amounts, they can be very dangerous, causing damaging inflammation and even affecting genetic material in cells.
In heart disease, free radicals are released in artery linings and oxidize low-density lipoproteins (LDL). The oxidized LDL is the basis for cholesterol build-up on the artery walls and damage leading to heart disease.

Inflammatory Response. For the arteries to harden there must be a persistent reaction in the body that causes ongoing harm. Researchers now believe that this reaction is an immune process known as the inflammatory response. The following is one theory about how the inflammatory response contributes to heart disease:

The injuries to the arteries during oxidation signal the immune system to release white blood cells (particularly those called neutrophils and macrophages) at the site. These factors initiate the inflammatory response.
Macrophages literally "eat" foreign debris, in this case oxidized LDL cholesterol.
The process converts LDL cholesterol into foamy material that attaches to the smooth muscle cells of the arteries. The cholesterol becomes mushy and accumulates on artery walls.
Over time the cholesterol dries and forms a hard plaque, which causes further injury to the walls of the arteries.
In response to this additional harm, the immune system releases other factors called cytokines. These are powerful inflammatory molecules that attract more white blood cells and perpetuate the whole cycle, causing persistent injury to the arteries.

Click the icon to see an image of atherosclerosis.

Evidence is growing that the inflammatory response may be present not only in local plaques in single arteries but also throughout the arteries leading to the heart.

Blockage in the Arteries. Eventually these calcified (hardened) arteries become narrower (a condition known as stenosis).

As this narrowing and hardening process continues, blood flow slows and prevents sufficient oxygen-rich blood from reaching the heart.
Such oxygen deprivation in vital cells is called ischemia. When it affects the coronary arteries, it causes injury to the tissues of the heart.
Injured inner vessel walls also fail to produce enough nitric oxide, a substance critical for maintaining blood vessel elasticity. (Nitric oxide has complex effects and may increase inflammation in the arteries.)
These narrow and inelastic arteries not only slow down blood flow but also become vulnerable to injury and tears.

Click the icon to see an image of coronary artery blockage

The End Result: Heart Attack. Heart attack can occur as a result of one or two effects of atherosclerosis.

(1) If the artery becomes completely blocked and ischemia becomes so extensive that oxygen-bearing tissues around the heart die.

(2) If the plaque itself develops fissures or tears. Blood platelets adhere to the site to seal off the plaque, and a blood clot (thrombus) forms. A heart attack can then occur if the formed blood clot completely blocks the passage of oxygen-rich blood to the heart.

Click the icon to see an image of the developmental process of atherosclerosis.

Angina is the primary symptom of coronary artery disease and, in severe cases, of a heart attack. It is typically experienced as chest pain and occurs when the heart muscle does not get as much blood (hence as much oxygen) as it needs for a given level of work (ischemia). Angina is usually referred to as one of two states:

Click the icon to see an image about angina.

Stable Angina (which is predictable)
Unstable Angina (which is less predictable and a sign of a more serious situation)

Angina itself is not a disease. Much evidence indicates that onset of angina less than 48 hours before a heart attack may be protective, possibly by conditioning the heart to resist the damage resulting from the attack. Angina may be experienced in different ways and can be mild, moderate, or severe.

Click the icon to see an image of angina.

Specific factors are typically considered in determining whether symptoms indicate angina:

Quality of the pain. Angina pain is typically described by patients as squeezing, heavy, suffocating, or griplike. It is rarely described as stabbing or burning. Changing one's position or breathing in and out does not affect the pain. The intensity of the pain does not always relate to the severity of the medical problem. Some people may feel a crushing pain from mild ischemia, while others might experience only mild discomfort from severe ischemia. In some cases, the patient experiences shortness of breath, fatigue, or palpitations instead of pain. In others, the ischemia is entirely asymptomatic ("silent ischemia").
Duration. A typical angina attack lasts minutes. If it is more fleeting or lasts for hours, it is probably not angina.
Location. Pain is usually in the chest under the breast bone. It often radiates to the neck, jaw, or left shoulder and arm. Less commonly, patients report symptoms that radiate to the right arm or back.
Triggers of Angina. Angina is usually triggered by physical exertion, emotional stress, or exposure to cold.
Factors that Relieve Angina. Angina is usually relieved by rest or by taking nitroglycerine under the tongue.

Stable Angina. Stable angina is predictable chest pain. Although less serious than unstable angina, it can be extremely painful. It is usually relieved by rest and responds well to medical treatment (typically nitroglycerin). Any event that increases oxygen demand can cause an angina attack. Some typical triggers include:

Exercise
Cold weather
Emotional tension
Large meals

Angina attacks can occur at any time during the day, but most occur between 6 a.m. and noon.

Unstable Angina and Acute Coronary Syndrome. Unstable angina is a much more serious situation and is often an intermediate stage between stable angina and a heart attack, in which an artery leading to the heart (a coronary artery) becomes completely blocked. A patient is usually diagnosed with unstable angina under one or more of the following conditions:

Pain awakens a patient or occurs during rest.
A patient who has never experienced angina has severe or moderate pain during mild exertion (walking two level blocks or climbing one flight of stairs).
Stable angina has progressed in severity and frequency within a 2-month period, and medications are less effective in relieving its pain.

Unstable angina is now usually discussed as part of a condition called acute coronary syndrome (ACS). ACS also includes people with a condition called NSTEMI (non ST-segment elevation myocardial infarction) -- also referred to as non-Q wave heart attack. With NSTEMI, the blood tests suggest a developing heart attack. These conditions are less severe than heart attacks but may develop into full-blown attacks without aggressive treatment. [See In-Depth Report #12: Heart attack and acute coronary syndrome.]

Prinzmetal's Angina. A third type of angina, called variant or Prinzmetal's angina, is caused by a spasm of a coronary artery. It almost always occurs when the patient is at rest. About two-thirds of people with it have severe atherosclerosis in at least one major blood vessel. Irregular heartbeats are common, but the pain is generally relieved immediately with standard treatment.

Click the icon to see an image of a coronary artery spasm.

Silent Ischemia. Some people with severe coronary artery disease do not experience angina pain. This condition is known as silent ischemia, which some experts attribute to abnormal processing of heart pain by the brain. This is a dangerous condition because patients have no warning signs of heart disease. Some studies suggest that people with silent ischemia experience higher complication and mortality rates than those with angina pain. (Angina pain may actually protect the heart by conditioning it before a heart attack.)

Syndrome X. Syndrome X is a condition that occurs when patients have atypical angina chest pain. Their electrocardiograms are abnormal during a stress test, but they have no signs of blocked arteries. It is more likely to occur in women. Although it unclear what causes this condition, imaging tests suggest that Syndrome X may also be caused by ischemia, as is angina.

Prognosis

According to a 2007 report, nearly 16 million Americans have coronary artery disease. In the U.S., coronary artery disease is the leading killer of both men and women. In 2004, nearly 500,000 people died because of CAD. On the positive side, heart attack mortality rates have been declining. Half of men and 63% of women who die of heart disease do not have angina or other warning symptoms prior to their fatal attacks. Although at this time no tests can reliably predict whether a heart attack will occur, experts estimate that up to 30% of fatal attacks and many follow-up surgeries could be avoided with healthy lifestyle changes and by sticking to medical treatments. Two-thirds of patients who have suffered a first heart attack, however, do not take the necessary steps to prevent another.

The following syndromes suggest different degrees of severity among patients with heart disease.

Stable Angina. This condition can usually be managed with lifestyle measures and medications, such as low-dose aspirin. The more severe the angina, however, the greater the chance for progressing to a more serious condition.

Acute Coronary Syndromes (ACS). ACS includes severe and sudden heart conditions that require aggressive treatment but have not developed into a full-blown heart attack. ACS refers to either unstable angina or NSTEMI (non ST-segment elevation myocardial infarction). NSTEMI is also known as non Q-wave myocardial infarction.

Angina is a specific type of pain in the chest caused by inadequate blood flow through the blood vessels (coronary vessels) of the heart muscle (myocardium).

Unstable angina is potentially serious and chest pain is persistent, but blood tests do not show markers for heart attack.
With NSTEMI, the blood tests suggest a developing heart attack, but, most likely, injury in the arteries is less serious than with a full-blown heart attack.

Most discussions of the treatment of unstable angina now refer to acute coronary syndrome. Doctors use the presence of a number of factors to help predict which ACS patients are most at risk for developing a heart attack.

First, patients are categorized by whether they have a history of heart disease or risk factors for heart disease (such as diabetes, high blood pressure, peripheral artery disease) or other complicating conditions (such as lung disease, heart failure). The doctor also evaluates the severity of the angina. Other factors that pose a high risk for ACS include:

Age 65 years or older
Evidence of severe heart tissue injury
Having a lighter weight
Having a history of severe chronic angina
Having abnormal lung sounds called rales (a bubbling or crackling sound) on examination
ST-segment deviation
Having either very slow or very fast heat beats
Having very low blood pressure

Heart Attack. A full-blown heart attack occurs with severe damage to the heart, which blocks oxygen.

ANYONE WHO BELIEVES THEY ARE HAVING A HEART ATTACK SHOULD IMMEDIATELY CALL THE EMERGENCY MEDICAL SYSTEM (911 IN THE UNITED STATES).

People with known heart disease and any unusual chest pain or other symptoms of heart attack that do not clear up with medications should go to the hospital. The degree of pain and the specific symptoms before a heart attack vary greatly among individuals. Symptoms can be abrupt, gradual, or intermittent.

Chest Pain. People with heart disease or risk factors should be concerned about any chest pain, usually precipitated by exercise or stress, that interrupts normal activities and does not clear up after resting or taking angina medications. Chest symptoms might be experienced as follows:

Pain is typically felt as a crushing weight against the chest, accompanied by profuse sweating. The pain may radiate to the left shoulder and arm, the neck or jaw, and even infrequently to the right arm. The arm may be tingling or numb.
Some people may have only a tingling sensation or a sense of fullness, squeezing, or pressure in the chest.
In some patients with a history of heart disease, chest pain is mild. Such patients may have experienced unexplained fatigue, depression, and ill health within a month of a heart attack. Although chest pain is the classic symptom, it occurs in only about half of patients with a heart attack.

Other Common Symptoms.

Nausea, vomiting, and cold sweats
A feeling of indigestion or heartburn
Fainting
A great fear of impending death, a phenomena known as angor animi

Atypical Symptoms. Some studies suggest that nearly half of patients with heart attack do not have chest pain as the primary symptom. Common atypical symptoms of a heart attack include:

Shortness of breath
Cardiac arrest
Dizziness, weakness, and fainting
Abdominal pain

Patients most likely to have atypical symptoms are women and the very elderly (although they can certainly have classic heart attack symptoms as well).

In one study, 52% of elderly people with acute coronary syndrome had atypical symptoms that included shortness of breath, nausea, profuse sweating, pain in the arms, and fainting. Such symptoms were more likely to occur in people with personal or family history of heart disease.
Before a heart attack, women are more likely than men to be nauseous and experience pain high in the abdomen or chest. Their first symptom may be extreme fatigue after physical activity rather than chest pain. Chest pain in women is also more likely to be caused by non-heart problems than in men.

Symptoms That Are Less Likely to Indicate a Heart Attack. The following symptoms are less likely to be due to a heart attack:

Sharp pain brought on by lung movements or coughing
Pain that is mainly or only in the middle or lower abdomen
Pain that can be pinpointed with the top of one finger
Pain that can be reproduced by moving or pressing on the chest wall or arms
Pain that is constant and lasts for hours (although no one should wait hours if they suspect they are having a heart attack)
Pain that is very brief and lasts for a few seconds
Pain that spreads to the legs

However, the presence of these symptoms does not always rule out a serious heart event.

Chest pain is a very common symptom in the emergency room, but heart problems account for only 10 - 33% of all episodes.

The most common causes of chest pain are muscular and bone problems. Problems affecting the ribs and chest muscles include injured muscles, fractures, arthritis, spasms, and infections.

Other causes of chest pain include:

Anxiety attacks
Gastrointestinal disorders (gallstone attacks, peptic ulcer disease, hiatal hernia, heartburn)
Asthma
Spasm in the coronary artery
Abnormalities of the heart muscle
Rupture of the aorta
Collapsed lung
Acute inflammation of the heart
Blood clot in the lung
High thyroid levels (hyperthyroidism)
Anemia
Vasculitis (a group of disorders that cause inflammation of the blood vessels)
Exposure to high altitudes (rare)

Individuals who experience symptoms of a heart attack should take the following actions:

For angina patients, take one nitroglycerin dose either as an under-the-tongue tablet or in spray form at the onset of symptoms. Take another dose every 5 minutes up to three doses or when the pain is relieved, whichever comes first.
Call 911 or the local emergency number. This should be the first action taken if angina patients continue to experience chest pain after taking the full three doses of nitroglycerin. However, only 20% of heart attacks occur in patients with long-standing angina. Therefore, anyone who has heart disease or risk factors for it and experiences heart attack symptoms should contact emergency services.
The patient should chew an aspirin (250 - 500 mg) and be sure that emergency health providers are informed of this so an additional dose is not given.
Patients with chest pain should go immediately to the nearest emergency room, preferably traveling by ambulance. They should not drive themselves.

Click the icon to see an image about heart attack symptoms.

Click the icon to see another image about heart attack symptoms.

Risk Factors

Over 13 million Americans have had angina, a heart attack, or both. Each year, about 1.2 million people will experience a serious heart event. About 25% of all Americans have one or more risk factors for heart disease. Most risk factors for heart disease are related to lifestyle and environmental factors.

Over the past decades, heart disease rates declined in both men and women as they quit smoking and improved dietary habits. This rate, however, has stabilized in recent years, most likely because of the dramatic increase in obesity in the U.S. and other industrialized nations. There have also been minimal changes in other risk factors, including smoking, sedentary behavior, and blood pressure control. Some risk factors cannot be changed, including age, gender, and genetics. Nevertheless, their effects can still be modified with healthy lifestyle changes.

Heart disease may be prevented with a healthy diet and regular exercise, and by quitting smoking if you smoke. Follow your health care provider's recommendations for the treatment and prevention of heart disease.

The American Heart Association guidelines for preventing heart disease recommend:

Improve Cholesterol. People with at least two risk factors and a 10-year risk for heart disease or stroke of more than 20% should aim for LDL levels of less than 100 mg/dl. Statins are now used in more cases.

Keep Blood Pressure Low. People in normal health should have a blood pressure reading of 120/80 mm Hg or less. According to the latest guidelines, blood pressure readings of 120/80 are considered normal, readings of 140/90 or higher indicate hypertension, and readings in between the two are called pre-hypertension. Patients with diabetes or chronic kidney disease should maintain blood pressure readings of 130/80 mm Hg or less, while others should be no higher than 140/90 mm Hg.

Exercise. Everyone in normal health should engage in at least moderate physical activity for a minimum of 30 minutes on most, if not all, days of the week.

Healthy Diet. Everyone should aim for a diet that contains a healthy balance of fruits, vegetables, grains, fish, nuts, legumes, poultry, lean meat, and low-fat dairy items. Avoid saturated fats and trans-fatty acids.

Quit Smoking. Also avoid exposure to secondhand smoke.

Maintain Weight. People should aim for a BMI index of 18.5 - 24.9.

Taking Aspirin. People whose risk for heart disease within 10 years is 10% or more should take a low-dose aspirin every day, unless they have medical reasons to avoid aspirin.

Control Diabetes. People with diabetes should aim for fast blood glucose levels of less than 110 mg/dl and hemoglobin A1C or less than 7%.

Control Atrial Fibrillation. People with atrial fibrillation should use anticoagulants to reduce the risk for blood clots.

Age. About 85% of people who die from heart disease are over the age of 65.

Gender. Coronary artery disease and heart attacks are much more common in middle-aged men. Women have, on average, 10 - 15 more years of heart disease-free life than do men, but as women age, they catch up to men. Women, in fact, are more likely to have angina than men. Younger women with heart disease often do not have the same symptoms as their male counterparts and may be less likely to be diagnosed correctly. They are also more likely than men to die after a heart attack.

In 2007, the American Heart Association issued updated guidelines focusing on prevention of heart disease in women. The new guidelines recommend:

Healthy diet (fresh fruits and vegetables, low-fat dairy products, salt and saturated fat restrictions, alcohol moderation)
Eating oily fish (such as salmon) at least twice a week. Women with existing heart disease should consider taking fish oil supplements of 850 – 1,000 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DPA).
Increased physical activity (60 – 90 minutes, preferably 7 days a week)
Quitting smoking
Low-dose aspirin therapy for all women age 65 years and older who can safely take aspirin. High-risk women may require 75 – 325 mg / day; lower-risk women may benefit from 81 mg a day or 100 mg every other day.

Genetic Factors. Genetics are involved in increasing the likelihood of developing important risk factors such as diabetes and high blood pressure. For example, one genetic variant called apolipoprotein E4 (ApoE4) affects cholesterol levels, particularly those associated with heart disease.

Ethnicity. African-American women face the highest risk for death from heart disease, and their rate of heart attacks is increasing. (Mortality rates in men do not differ much by race.) Native American men have a lower risk for heart disease than Caucasian men, and Hispanics have the lowest risk for heart disease of all major American population groups.

African-Americans face a number of biologic and social dangers to their hearts.

They have a higher prevalence of diabetes and hypertension than do Caucasians.
They tend to have poorer diets, higher stress levels, and less access to health care.
All African-Americans risk discrimination in obtaining optimal treatments, but women may be at particular risk for unequal treatment. In one study in which female actors portrayed heart patients, African-American women were 60% less likely to receive aggressive (and expensive) diagnostic tests than African-American men or any Caucasians, even though they presented with similar symptoms.
While African-Americans comprise 13% of the U.S. population, African-Americans have comprised only 2 - 9% of subjects in most major research trials, so knowledge about their specific risks is limited.
Some African-Americans with coronary artery disease appear to have a genetic trait that increases the danger of triglycerides, which may be particularly hazardous for women.

Click the icon to see an image about ethnicity and heart disease risks.

Cholesterol. In spite of its bad press, cholesterol is an essential nutrient necessary for many cellular functions. However, when certain cholesterol levels rise in the blood, they can have dangerous consequences, depending on the type of cholesterol. Low-density lipoprotein (LDL) cholesterol is the "bad" cholesterol responsible for many heart problems. Triglycerides are another type of lipid (fat molecule) that can be bad for the heart. High-density lipoprotein (HDL) cholesterol is the "good" cholesterol that helps protect against heart disease. Doctors test for a "total cholesterol" profile that includes measurements for LDL, HDL, and triglycerides. The ratio of these lipids can affect heart disease risk.

For example, according to one study, men with total cholesterol levels over 240 mg/dl have a risk that is two to four times higher than men whose cholesterol is below 200. A number of studies have demonstrated that reducing LDL and total cholesterol levels and boosting high-density lipoprotein (HDL) levels can improve survival and prevent heart attacks in people with and without heart disease.

It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated by the Friedewald formula: LDL=TC-HDL-TG/5. (LDL=low-density lipoprotein; TC= total cholesterol; HDL=high-density lipoprotein; TG=triglycerides.)

Click the icon to see an image about serum cholesterol.

Cholesterol Goals. In 2004, the National Cholesterol Education Program updated its clinical practice guidelines. The new recommendations set lower treatment goals for LDL levels based on a patient's risk factors for heart disease.

These risk factors include:

Having a first-degree female relative diagnosed with heart disease before age 65 or a first-degree male relative diagnosed before age 55
Being male and over age 45 or female and over age 55
Cigarette smoking
Diabetes
High blood pressure
Metabolic syndrome (risk factors associated with obesity such as low HDL levels and high triglycerides

Having two or more of these risk factors indicates a greater than 20% chance of having a heart attack within 10 years.


Risk Level	Goal (d/L)	Optimal Goal(d/L)
Very High Risk	70	70
High Risk	100	70
Moderate Risk	130	100
Low Risk	160	130

LDL cholesterol, together with other risk factors for heart disease, is the best determinant for whether cholesterol therapy is needed and whether it is working properly. In particular, the new guidelines emphasize lower LDL levels and earlier treatment for people with coronary artery disease, or other forms of atherosclerosis, and diabetes.


Total Cholesterol Goals	LDL Goals	HDL Goals	Triglyceride Goals
Less than 200 mg/dL is desirable. Between 200 and 239 is borderline. Over 240 is high.	70 mg/dL or less is the new goal for very high-risk patients (recent heart attack; current active or unstable cardiovascular or cerebrovascular disease; or two multiple risk factors as defined above.) Below 100 mg/dl is optimal for everyone. It should be the goal for high-risk people including those with existing heart disease, diabetes, or two or more risk factors for heart disease; 70 mg/dL is an optimal goal for these individuals. 130 mg/dl or below for people with two or more risk factors; 100 mg/dL is the optimal goal. 160 mg/dl or less for people at less risk (one or zero risk factors); 130 mg/dL is the optimal goal. Anything over 160 is high with levels over 190 being very high. LDL levels over 190 require medication even with no other cardiac risk factors present.	Levels above 40 mg/dL are desirable; levels above 60 mg/DL are optimal.	Below 150 mg/dL is normal. 150-199 is borderline high. 200-499 is high. Over 500 is very high.
*Risk factors for heart disease include a family history of early heart problems before age 55 for men, before age 65 for women, smoking, high blood pressure, diabetes, being older (over 45 for men and 55 for women), and having HDL levels below 35 mg/dl. People with two or more of these risk factors may have a 10-year risk of heart attack that exceeds 20%, and may therefore need to aim for LDL levels of 100 mg/dL or below.

Other Lipids. Elevated levels of other fatty molecules (lipids) are also now thought to be important indicators of heart disease risk. Studies are finding an elevated risk for angina and first heart attacks in people with elevated levels of lipoprotein(a), or lp(a). This lipoprotein falls somewhere in density between HDL and LDL and may have some properties that increase the risk for blood clots. Some experts suggest, however, that high levels of lp(a) may merely be markers of late-stage atherosclerosis, not a cause.

[See In-Depth Report #23: Cholesterol; and In-Depth Report #43: Heart-healthy diet.]

High blood pressure, or hypertension, has long been a proven cause of coronary artery disease. Blood pressure is categorized as normal, prehypertensive, and hypertensive (which is further divided as Stage 1 or 2 according to severity). High blood pressure is generally considered to be a blood pressure reading greater than or equal to 140 mm Hg (systolic) or greater than or equal to 90 mm Hg (diastolic). Blood pressure readings in the prehypertension category (120 - 139 systolic or 80 - 89 diastolic) indicate an increased risk for developing hypertension. [See Table Blood Pressure Ranges.]

A normal blood pressure reading is 120/80 mm Hg or lower. Most people with high blood pressure should aim for a goal of below 140/90 mm Hg. Patients with certain health problems should aim lower (blood pressure in patients with kidney disease, heart failure, or diabetes should be equal to or lower than 130/80 mm Hg.)

Click the icon to see an image about hypertension.


Blood Pressure Category	Ranges for Most Adults (systolic/diastolic)
Normal Blood Pressure (systolic/diastolic)	Systolic below 120 mm Hg Diastolic below 80 mm Hg
Prehypertension (Formerly Classified as Normal to High-Normal Blood Pressure)	Systolic 120 to 139 mm Hg Diastolic 80 to 89 mm Hg (NOTE: 139/89 or below should be the minimum goal for everyone. People with diabetes or chronic kidney disease should strive for 130/80 or less.)
Mild Hypertension (Stage 1)	Systolic 140 to 159 mm Hg Diastolic 90 to 99 mm Hg
Moderate-to-Severe Hypertension (Stage 2)	Systolic over 160 mm Hg and/or Diastolic over 100 mm Hg
Note: If one of the measurements is in a higher category than the other, the higher measurement is usually used to determine the stage. For example, if systolic pressure is 165 (Stage 2) and diastolic is 92 (Stage 1), the patient would still be diagnosed with Stage 2 hypertension. A high systolic pressure should be a major focus of concern in most adults.

American obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels are usually high while HDL (beneficial cholesterol) levels tend to be low, both risk factors for heart disease. Obesity has other effects (hypertension, increase in inflammation) that pose major risks to the heart.

Click the icon to see an image of childhood obesity.

Obesity is particularly hazardous when it is one of the components of the metabolic syndrome. This syndrome is diagnosed when three of the following are present: abdominal obesity, low HDL cholesterol, high triglyceride levels, high blood pressure, and insulin resistance. Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. A 2002 study estimated that 24% of the population now has this condition. Obesity is highly linked with type 2 diabetes, and diabetes itself poses a significant risk for high cholesterol levels and heart disease.

Some obese patients with coronary artery disease may consider having bariatric surgery (stomach bypass) to lose excess weight. The weight lost after surgery can help improve blood pressure, cholesterol, blood sugar and other factors associated with CAD. A 2005 study reported that bariatric surgery is safe for patients with CAD who cannot lose weight with diet and exercise, which should always be tried first.

[See In-Depth Report #53: Weight control and diet.]

People who are sedentary are almost twice as likely to suffer heart attacks as are people who exercise regularly. Exercise has a number of effects that benefit the heart and circulation, including:

Improving cholesterol and lipid levels
Reducing inflammation in the arteries
Assisting weight loss programs
Helping to keep blood vessels flexible and open

Studies continue to show that physical activity and avoiding high-fat foods are the two most successful means of reaching and maintaining heart healthy levels of fitness and weight.

Experts have been attempting to define how much exercise is needed to produce heart benefits. In 2002, a well-conducted study on overweight adults confirmed previous research that reported beneficial changes in cholesterol and lipid levels even when people performed low amounts of moderate or high intensity exercise (walking or jogging 12 miles a week). However, more intense exercise is required to significantly change cholesterol levels, notably by increasing HDL (the so-called good cholesterol). Overweight people who have trouble losing pounds can still achieve considerable heart benefits by exercising. Resistance (weight) training has also been associated with heart protection. Exercises that train and strengthen the chest muscles may prove to be very important for patients with angina.

Click the icon to see an image about exercise.

Click the icon to see an image about hypertension and lifestyle changes.

Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise, which can be particularly helpful for older people.

Sudden strenuous exercise (such as snow shoveling and mowing lawns) puts many people at risk for angina and heart attack. Activities that involve raising the arms above the head may also be risky. Patients with angina should never exercise shortly after eating. People with risk factors for heart disease should seek medical clearance and a detailed exercise prescription. And all people, including healthy individuals, should listen carefully to their bodies for signs of distress as they exercise. [See In-Depth Report #29: Exercise.]

Heart disease and stroke are the leading causes of death in people with diabetes. People with diabetes are at risk for the following heart-risk conditions, and the more of these conditions they have, the worse the outlook.

High blood pressure (hypertension). Up to 75% of cardiovascular problems in people with diabetes may be due to hypertension.
Very unhealthy cholesterol and lipid balances (high triglyceride levels and lower HDL).
Blood clotting problems.
Impaired nerve function (neuropathy), which can also damage the heart. Some experts estimate that the mortality rates from neuropathy-related heart conditions range from 15 - 53%.

People with both diabetes and heart disease may have a higher risk for silent ischemia, a condition in which people have blocked arteries but do not experience the angina, the chest pain that signals heart disease. [See In-Depth Report #9: Diabetes - type 1; or In-Depth Report #60: Diabetes - type 2.]

Peripheral artery disease (PAD) occurs when atherosclerosis affects the extremities, particularly the feet and legs. The major risk factors for heart disease and stroke are also the most important risk factors for PAD. (The combination of such conditions with PAD also produces more severe forms of heart or circulatory disease.) Although signs of heart disease are detected in only 20 - 40% of patients with PAD after an initial diagnosis, studies suggest that when intense heart-diagnostics tests are performed, such as angiography or thallium stress tests, co-existing heart disease is detected in up to 90% of all PAD patients. [See In-Depth Report #102: Peripheral artery disease.]

Smokers in their 30s and 40s have a heart-attack rate that is five times higher than their nonsmoking peers. Cigarette smoking may be directly responsible for at least 20% of all deaths from heart disease, or about 120,000 deaths annually. Smoking cigars may increase the risk of early death from heart disease, although evidence is much stronger for cigarette smoking. Although heavy cigarette smokers are at greatest risk, a 2002 study suggested that people who smoke as few as three cigarettes a day are at higher risk for blood vessel abnormalities that endanger the heart. Regular exposure to passive smoke also increases the risk of heart disease in nonsmokers. [See In-Depth Report #41: Smoking.]

Eating habits can be protective or dangerous to the heart. Avoiding saturated fats and trans-fatty acids is particularly important for controlling cholesterol.

Diet plays an important role in the health of the heart. In 2006, the American Heart Association (AHA) issued revised diet and lifestyle recommendations. The current guidelines recommend:

Balance calorie intake and physical activity to achieve or maintain a healthy body weight. (Controlling weight, quitting smoking, and exercising regularly are essential companions of any diet program. Try to get at least 30 minutes, and preferably 60 – 90 minutes, of daily exercise.)
Consume a diet rich in a variety of vegetables and fruits. Vegetables and fruits that are deeply colored (spinach, carrots, peaches, berries) are especially recommended as they have the highest micronutrient content.
Choose whole-grain, high-fiber foods. These include fruits, vegetables, and legumes (beans). Good whole grain choices include whole wheat, oats/oatmeal, rye, barley, brown rice, buckwheat, bulgur, millet, and quinoa.
Consume fish, especially oily fish, at least twice a week (about 8 ounces/week). Oily fish such as salmon, mackerel, and sardines are rich in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Consumption of these fatty acids is linked to reduced risk of sudden death and death from coronary artery disease.
Limit daily intake of saturated fat (found mostly in animal products) to less than 7% of total calories, trans fat (found in hydrogenated fats, commercially baked products, and many fast foods) to less than 1% of total calories, and cholesterol (found in eggs, dairy products, meat, poultry, fish, shellfish) to less than 300 mg per day. Choose lean meats and vegetable alternatives (such as soy). Select fat-free and low-fat dairy products. Grill, bake, or broil fish, meat, and skinless poultry.
Use little or no salt in your foods. Reducing salt can lower blood pressure and decrease the risk of heart disease and heart failure.
Cut down on beverages and foods that contain added sugars (corn syrups, sucrose, glucose, fructose, maltrose, dextrose, concentrated fruit juice, honey.)
If you consume alcohol, do so in moderation. The AHA recommends limiting alcohol to no more than 2 drinks per day for men and 1 drink per day for women.

[See In-Depth Report #43: Heart-healthy diet.]

Stress. The effects of mental stress on heart disease are controversial. Stress can affect the heart when it activates the sympathetic nervous system (the automatic part of the nervous system that affects many organs, including the heart). Some studies suggest an association between acute stress and a higher risk for serious cardiac events, such as heart rhythm abnormalities and heart attacks, in people with heart disease. However, not all studies report strong evidence that stress has any effect on the heart, particularly in people without any history of heart disease. [See In-Depth Report #31: Stress.]

Depression. Depression increases the severity of heart attack and may even worsen a patient's response to medication for heart disease. Although people with heart disease may become depressed, this does not explain entirely the link between the two problems. Data suggest that depression itself may be a risk factor for heart disease as well as its increased severity.

A number of studies indicate that depression has biologic effects on the heart, including blood clotting and heart rate. One study, for example, reported an association between depression and a greater risk for death from heart problems even in people without a history of heart disease. Even mild depression, which includes feelings of hopelessness experienced over many years, may harm the heart. A 2007 study suggested that depressive symptoms (fatigue, loss of appetite) may be a sign of thickening arteries, the early stage of coronary artery disease. [See In-Depth Report #8: Depression.]

Benefits of Moderate Drinking. Several studies have found heart protection from moderate intake of alcohol (one or two glasses a day). Moderate alcohol consumption can help boost HDL levels. Alcohol may also prevent blood clots and inflammation. Although red wine is most often cited for healthful properties, any type of alcoholic beverage appears to have similar benefit.

Adverse Effects of Heavy Drinking. By contrast, heavy drinking harms the heart. In fact, heart disease is the leading cause of death in alcoholics. Evidence suggests that people who consume more than three drinks a day have abnormal blood clotting factors. Heavy alcohol consumption can raise blood pressure, and binge drinking may increase the risk for hemorrhagic stroke (caused by bleeding in the brain). Large doses of alcohol can trigger irregular heartbeats, which can be dangerous in people with existing heart disease.

Pregnant women and people who can't drink moderately should not drink at all.

Homocysteine and Vitamin B Deficiencies. Deficiencies in the B vitamins folate (known also as folic acid), B6, and B12 have been associated with a higher risk for heart disease in some studies. Such deficiencies produce higher blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease, stroke, and heart failure. Researchers have been studying whether vitamin B supplements can reduce homocysteine levels and, consequently, heart disease risks.

Several major 2006 studies indicated that while B vitamin supplements do help lower homocysteine levels, they have no effect on heart disease outcomes. The studies, published in the New England Journal of Medicine, examined patients who had either recently had a heart attack or suffered from diabetes or heart disease. Results showed a similar number of heart attacks and strokes among patients who took B vitamins and those who received placebo. Some experts think that homocysteine may be a marker for heart disease rather than a cause of it.

Click the icon to see the benefits of vitamin B.

Click the icon to see the food sources of vitamin B.

C-Reactive Protein. C-reactive protein is a product of the inflammatory process. Evidence increasingly suggests that high levels may predict future heart disease. It is not known if the protein plays any causal role or whether it is simply a marker for other factors in the disease process.

C. pneumoniae and Other Infectious Organisms. Some microorganisms and viruses have been under suspicion for triggering the inflammation and damage in the arteries that contribute to heart disease. The strongest evidence to date supports a possible role from Chlamydia (C.) pneumoniae (a non-bacterial organism that causes mild pneumonia in young adults). C. pneumoniae has been detected in plaques in the arteries of patients with heart disease. In some studies, evidence of previous infection has been associated with a higher risk for heart events.

Other studies also suggest that cytomegalovirus (CMV), a common virus, may have similar effects. Many people, however, have been infected with these organisms, and no clear association has been found with any of these infections.(H. pylori, the bacteria that causes peptic ulcers, has also been studied for heart effects, but evidence is very weak on any link.)

Erectile Dysfunction. Recent research suggests that erectile dysfunction may be a warning sign of coronary artery disease, even in men who are not considered at risk for the condition. Some studies indicate that men with erectile dysfunction have higher levels of C-reactive protein and more symptoms of atherosclerosis than men without erectile problems.

Periodontal Disease. A number of studies support an association between periodontal disease and cardiovascular disorders. According to a 2003 major analysis, periodontal (gum) disease is associated with a 20% higher risk for ischemic stroke and heart disease. (The added risk may be even higher in adults under 65.) Recent evidence is pointing to the inflammatory response as the common element.

Click the icon to see an image of gum disease.

Anemia. Anemia has adverse effects on the heart and increases the severity of cardiac conditions, including heart failure and heart attacks. A 2002 study suggested that anemia may even be a risk factor for heart disease itself. Blood transfusions after a heart attack improve survival rates in elderly patients who are anemic.

Iron Overload. An inherited disease called hemochromatosis, in which the intestinal tract absorbs too much iron from food, has been associated with atherosclerosis and heart attack. About 10% of Caucasians carry the gene for this condition. There is no strong evidence that excess iron levels in people without hemochromatosis can contribute to heart disease.

Sleep Apnea. Obstructive sleep apnea is a condition in which tissues in the upper throat collapse at intervals during sleep, thereby blocking the passage of air. It has been strongly associated with high blood pressure and obesity, but is also associated with heart disease and heart attacks, regardless of these risk factors. Some evidence suggests that obstructive apneas cause an increase in stiffness and inflammation in the arteries.

Some inborn or natural conditions are not risk factors themselves but have been associated with a higher incidence of heart disease or its consequences:

Factors Before Birth and In Infancy. Low weight at birth and in the womb has been associated with later heart disease in a few studies. Some suggest, however, that this may just reflect poor nutrition in the mother, which appears to affect life-long risk.

Seasonal Differences. More deaths from heart disease occur in December and January, and the fewest in the summertime. Although lower temperatures and snow shoveling may play a role in some cases, more winter deaths have been reported even in warm regions. Holiday stress or fewer daylight hours have been suggested as other reasons for these higher winter rates.

Physical Characteristics. Male pattern baldness, hair in the ear canals, and creased earlobes are associated with a higher risk for heart disease in Caucasian males.

Click the icon to see an image of an ear lobe crease.

Diagnosis

Many tests can diagnose possible heart disease. The choice of which (and how many) tests to perform depends on the patient's risk factors, history of heart problems, and current symptoms. Usually the tests begin with the simplest and may progress to more complicated ones.

Doctors routinely check for high blood pressure and unhealthy cholesterol levels in all older adults. Specific tests are also important in people who may have risk factors or symptoms of diabetes. Doctors may also test for homocysteine, the protein albumin, and blood clotting factors, especially fibrinogen.

An electrocardiogram (ECG) measures and records the electrical activity of the heart. Between 25 - 50% of people who suffer from angina or have silent ischemia, however, have normal ECG readings. The waves measured by the ECG correspond to the contraction and relaxation pattern of the different parts of the heart. Specific waves seen on an ECG are named with letters:

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

P. The P wave is associated with the contractions of the atria (the two chambers in the heart that receive blood from outside).
QRS. The QRS is a series of waves associated with ventricular contractions. (The ventricles are the two major pumping chambers in the heart.)
T and U. These waves follow the ventricular contractions.

The most important wave patterns in diagnosing and determining treatment for heart disease and heart attack are called ST elevations and Q waves.

A depressed or horizontal ST wave suggests some blockage and the presence of a heart disease, even if there is no angina present. (This finding, however, is not very accurate, particularly in women, and can occur without heart problems).
ST elevations and Q waves are the most important wave patterns in diagnosing and determining treatment for a heart attack. They suggest that an artery to the heart is blocked, and that the full thickness of the heart muscle is damaged. ST segment elevations do not always mean the patient has a heart attack. And, some heart attack patients do not have elevated ST segments. Other factors are important in making a diagnosis.

The primary value of exercise stress tests is not to detect coronary artery disease but to help determine the severity and predict the outcome of an existing heart condition. It is considered for the following people:

Patients with possible or probable angina and low or intermediate risk for adverse heart events.
Selected adults who do not have symptoms of heart disease but are at moderate risk to high risk for developing heart disease (a 10 - 20% chance within 10 years). Moreover, heart blockage without angina (silent ischemia) may suggest a more severe condition, at least in men.

Basic Procedure. A stress test (exercise tolerance test) monitors the patient's heart rhythms, blood pressure, and clinical status. It can tell how well the heart handles work and if parts of the heart have decreased blood supply. A typical stress test involves:

The patient walks on a treadmill or rides a stationary bicycle. Exercise continues until the heart is beating at least 85% of its maximum rate, until symptoms of heart trouble occur (changes in blood pressure, heart rhythm abnormalities, angina, fatigue), or the patient simply wants to stop.
For patients who cannot exercise, the doctor may administer dobutamine or arbutamine, which are drugs that simulate the stress of exercise.
An ECG is used to monitor heart rhythms during a stress test. (An echocardiogram or more advanced imaging technique may also be used to visualize the actions of the heart and blood flow.)

More than 25% of patients stop exercising before they reach their own maximum limits because of fear of a heart event. Patients should be reassured that the activities performed in the test under the guidance of a professional are safe.

Interpreting Results. To accurately assess heart problems, experts look at a number of findings derived from the ECG and other tools during exercise. They include:

Exercise capacity. This is a measure of a person's capacity to reach certain metabolic rates.
Heart rate and ST waves. On ECGs, doctors specifically look for abnormalities in part of the wave tracing called an ST segment. A certain type of ST segment depression may suggest the presence of heart disease. However, gender, drugs and other medical conditions can affect the ST segment. Using a measurement that adjusts the ST segment to heart rate improves accuracy.
Dukes Treadmill Score. This important score uses the number of minutes a patient can exercise and other factors that are present in patients with exercise-limiting angina.
Heart rate recovery.
Chronotropic index. This is the percentage of the heart-rate reserve that is used during the exercise. A result of 80% or less suggests a significant risk for serious heart problems in most patients.
Changes in systolic blood pressure.

Using these and other measures, doctors can determine risk fairly accurately, particularly for men of any age with chronic stable angina. The test has limitations, however, and some are significant. For example, a 2002 study indicated that in patients with suspected unstable angina the chances for a future adverse heart event remain high even if the exercise test shows low risk. In addition, for many reasons, the test is less accurate in women, and an echocardiogram may be a more accurate procedure for them. About 10% of patients, particularly younger people, will have false positive test results. In such cases, test results indicate abnormalities when there are no heart problems.

An echocardiogram is a noninvasive test that uses ultrasound images of the heart. This test is more expensive than an ECG, but it can be very valuable, particularly when used with a stress test, to detect the location and extent of heart muscle damage. It appears to be more accurate for women than ECG stress tests, but at this time it is not routinely recommended as a replacement for most women.

Computed tomography (CT) scans used alone or with ECG may be used to detect calcium deposits on the arterial walls, which are strong indicators of current and future coronary artery disease. The presence of calcium does not always signify narrowing of the arteries. But, the absence of calcification in the arteries indicates the patient has no risk for heart disease.

Advanced CT techniques are improving accuracy:

Click the icon to see an image of a CT scan.

Electron Beam Computed Tomography. Electron beam computed tomography (EBCT) is a CT technique that scans the heart so quickly that the motion of the heart appears frozen. This procedure identifies calcification and stratifies cardiac risk accurately.
Multidetector Computed Tomography. Another CT technique called multidetector computed tomography (MDCT) is able to take pictures of the entire heart in 1 millimeter slices in the time it takes for a patient to hold one breath. A 2006 study indicated that MDCT tends to have a high “false-positive” rate (indicating disease when it is not actually there), but for some patients the test may be helpful in ruling out coronary artery disease.

Some expert groups recommend CT scans in selected patients who have an intermediate risk (10 - 20% chance of heart disease within 10 years). For some of these patients, EBCT may be preferred over exercise stress testing, but most experts recommend a stress test as the main diagnostic tool. In general, the use of these expensive imaging tests is probably not very helpful for people at low or high risk. (For people with high risk, the additional information from these tests would not add much value.) More research is needed to determine the benefits of CT scanning in specific individuals.

Radionuclide procedures use imaging techniques and computer analyses to plot and detect the passage of radioactive tracers through the region of the heart. Such tracing elements are typically given intravenously. Radionuclide imaging is useful for diagnosing and determining:

Severity of unstable angina when less expensive diagnostic approaches are unavailable or unreliable
Severity of chronic coronary artery disease
Success of surgeries for coronary artery disease.
Whether a heart attack has occurred

Various imaging techniques may be used with radionuclide procedures, including:

Planar scintigraphy uses a special overhead camera and is the oldest scanning technique.
Single-photon emission computed tomography (SPECT) uses a camera that rotates around the patient and takes pictures of "slices" of the heart. It is more accurate than planar imaging in precisely locating problems in the arteries.
Positron-emission tomographic (PET) scanners employ multiple rings that surround the patients, which detect and record atomic particles (photons) that are emitted by the tracer elements (such as radioactive oxygen, nitrogen, or carbon). It is more expensive and less widely available than SPECT.

Myocardial Perfusion (Blood Flow) Imaging Test (also called the Thallium Stress Test). This radionuclide test is typically used with an exercise stress test to determine blood flow to the heart muscles. It is a reliable measure of severe heart events. It may be useful in determining the need for angiography if CT scans have detected calcification in the arteries. About a minute before the patient is ready to stop exercising, the doctor administers a radioactive tracer into the intravenous line. (Tracers include thallium, technetium, or sestamibi.) Immediately afterwards, the patient lies down for a heart scan, usually with a planar scintigraphy or with SPECT. If the scan detects damage, more images are taken 3 or 4 hours later. Damage due to a prior heart attack will persist when the heart scan is repeated. Injury caused by angina, however, will have resolved by that time.

Radionuclide Angiography. This is a technique for visualizing the chambers and major blood vessels of the heart. It uses an injected radioactive tracer and can be performed during exercise, at rest, or with use of stress-inducing drugs. It is an excellent test for assessing the heart's pumping action and for determining the severity of coronary artery disease. It is an alternative to echocardiograms in certain situations.

Click the icon to see an internal view of the heart.

Magnetic Resonance Angiography (MRA). MRA is a very promising noninvasive imaging technique that can provide three-dimensional images of the major arteries to the heart and identify disease with high accuracy. Experts believe this approach will eventually be a good alternative to angiography.

Click the icon to see an image of a MRI.

Angiography is an invasive test. It is used for patients who show strong evidence for severe obstruction on stress and other tests, and for patients with acute coronary syndrome.

A narrow tube is inserted into an artery, usually in the leg or arm, and then threaded up through the body to the coronary arteries.
A dye is injected into the tube, and an x-ray records the flow of dye through the arteries.
This process provides a map of the coronary circulation, revealing any blocked areas.

Click the icon to see an image of dye in the coronary artery.

Major complications include stroke, heart attacks, and kidney damage. These risks are very low (about 0.1%), however, if the procedure is done in an experienced medical center (one that performs at least 300 of these operations every year). Allergic reactions can also occur. The procedure is expensive, and between 10 - 30% of patients who have this procedure have normal results.

When heart cells become damaged, they release different enzymes and other molecules into the bloodstream. Elevated levels of such markers of heart damage in the blood or urine may help predict a heart attack in patients with severe chest pain and help determine treatment. Some of these factors include:

Troponins. The proteins cardiac troponin T and I are released when the heart muscle is damaged. Both are proving to be among the best diagnostic indications of heart attacks. They help to identify many individuals with ACS who might otherwise be misdiagnosed.
Creatine kinase myocardial band (CK-MB). CK-MB has been a standard marker, but the MB fraction is not as accurate as troponin levels, since elevated levels can appear in people without heart injury.
Myoglobin. Myoglobin is a protein found in heart muscles. It is released early in the injured heart, and it may be useful in combination with CK-MB and the troponins.
Newer biomarkers, including C-reactive protein (CRP), homocysteine, B-type natriuretic peptide (BNP), urinary albumin, and fibrinogen.

Several 2006 studies that evaluated how well biomarkers predict risk of heart events concluded that they do not provide much more useful information than standard risk factors (high blood pressure, unhealthy cholesterol levels, diabetes). At this time, most experts feel that these standard disease risk factors provide the best predictors of the likelihood of developing coronary artery disease, heart attack, or stroke.

Managing Heart Disease

The approach for managing any degree of coronary artery disease involves lifestyle changes. Depending on severity and individual conditions, patients may need one or more medications, surgery, or both.

Healthy diet, regular exercise and quitting smoking if you are a smoker may prevent heart disease. Follow your health care provider's recommendations for treatment and prevention of heart disease.

Experts have come up with a mnemonic device (ABCDE) for remembering 10 factors that are fundamental for management of stable angina and coronary artery disease:

A. Aspirin and anti-angina drugs

B. Blood pressure and beta-blockers

C. Cholesterol-lowering drugs (typically statins) and cigarettes (stopping)

D. Diet and diabetes control

E. Exercise and education

Unstable angina is now usually classified with non-Q myocardial infarction as acute coronary syndrome (ACS) in professional discussions of treatments. ACS usually requires more aggressive treatments, including surgery. [ACS is more fully discussed in In-Depth Report #12: Heart attack and acute coronary syndrome.]

Click the icon to see an image about angina.

Anti-Clotting Medications

Anti-clotting drugs that inhibit or break up blood clots are used at every stage of heart disease. They are generally classified as either antiplatelets or anticoagulants. All anti-clotting therapies carry the risk of bleeding, which can lead to dangerous situations, including stroke.

A thrombus is a blood clot that forms in a vessel and remains there. An embolism is a clot that travels from the site where it formed to another location in the body. Thrombi or emboli can lodge in a blood vessel and block the flow of blood in that location depriving tissues of normal blood flow and oxygen. This can result in damage, destruction (infarction), or even death of the tissues (necrosis) in that area.

Antiplatelet Drugs. These drugs prevent formation of blood platelets. Platelets are very small disc-shaped blood cells that are important for blood clotting.

Aspirin. Aspirin is an antiplatelet. It is the most common anti-clotting drug. Nearly anyone with existing heart disease or at risk for it is advised to take a low-dose aspirin every day.
Thienopyridines. Clopidogrel (Plavix) and ticlopidine (Ticlid) are thienopyridines, another type of anti-platelet drug.
Glycoprotein IIb/IIIa Inhibitors. These powerful blood-thinning drugs include abciximab (ReoPro, Centocor), eptifibatide (Integrilin), tirofiban (Aggrastat), and lamifiban. They are administered intravenously in the hospital and are used after angioplasty surgery and stent placement.

Click the icon to see an image about blood.

Anticoagulants. Anticoagulants help thin blood and include:

Heparin
Warfarin (Coumadin)
Direct thrombin inhibitors

Aspirin. Aspirin is known as a nonsteroidal anti-inflammatory drug (NSAID). It stops blood platelets, which are major clotting factors, from sticking together to form a blood clot. A daily low-dose aspirin (75 - 325 mg) is usually the first choice for preventing heart disease in high-risk individuals. Aspirin can prevent by 25 – 50% the risk of heart attacks and death in people with existing heart disease and a history of heart attack. It also reduces the risk for stroke. According to a 2006 review, aspirin works equally well for both men and women.

Click the icon to see an image about stomach ulcers.

Side effects from prolonged use of aspirin may include stomach ulcers and bleeding. (There may be a slight increased risk for bleeding-related strokes, which are very uncommon, however. Furthermore, this risk may be outweighed by protection against the more common type of stroke, which is caused by artery blockage.)

Clopidogreland Ticlopidine. Clopidogrel (Plavix) and ticlopidine (Ticlide) are anti-platelet drugs known as thienopyridines. When taken with aspirin, these drugs can significantly reduce the risk for heart attack and stroke in patients with acute coronary syndrome (unstable angina or early signs of heart attack). The combination of aspirin and a thienopyridine is essential for patients who have a drug-eluting stent. According to a 2007 American Heart Association advisory, patients who have a drug-eluting stent must take both aspirin and a thienopyridine for at least 1 year after the stent is inserted. Many experts recommend clopidogrel instead of ticlopidine because ticlopidine has been associated with dangerous blood disorders, particularly thrombocytopenia.

Clopidogrel is also recommended for patients who are undergoing angioplasty. For patients having coronary bypass surgery, it should be withheld for at least 5 -7 days prior to surgery because of a significant bleeding risk. Researchers are investigating whether clopidogrel and aspirin together are better than aspirin alone in reducing the risks following coronary bypass surgery. A 2006 study suggested that for some patients with heart disease, clopidogrel plus aspirin does not work better than aspirin alone for preventing a first heart attack or stroke.

Click the icon to see an image of the developmental process of atherosclerosis.

Click the icon to see an image about atherosclerosis.

Anticoagulants are drugs that prevent or delay blood coagulation and the formation of blood clots. Heparin has been the standard anticoagulant, but a number of drugs are now available that are proving to be better choices in many cases.

Standard (Unfractionated) Heparin. The heparin referred to as unfractionated heparin has been the standard for years and is used alone or in combination with aspirin for managing unstable angina. It is no longer the recommended first choice, however, for this patient group. It must be intravenously administered and monitored with frequent blood tests. The major complication is thrombocytopenia (a severe drop in platelets). This condition is extremely serious and can become life-threatening, particularly with bleeding in various body tissues. Alternatives include low-molecular weight heparin and direct thrombin inhibitors.

Low-Molecular Weight Heparin. Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep) are drugs known as low-molecular weight heparins (LMWHs). Many doctors now recommend these drugs over standard heparin for patients with unstable angina (unless bypass surgery is being planned). They have similar rates of survival, recurring angina, and bleeding as standard heparin. However, they pose lower risks for heart attack, repeat angioplasties, and thrombocytopenia. They require injections but do not require the ongoing monitoring that standard heparin does. Patients may even be able to self-administer LMWHs as people with diabetes do insulin.

Warfarin. Warfarin (Coumadin) is an oral anticoagulant. It prevents clots by inhibiting vitamin K. Warfarin is used with aspirin after a heart attack to prevent another one and to prevent blood clots in patients with atrial fibrillation. Warfarin is also proving to be more effective than aspirin for preventing heart attacks in patients with acute coronary syndromes. Warfarin therapy poses a dangerous risk for bleeding and blood coagulation must be monitored with frequent blood tests.

Direct Thrombin Inhibitors (DTIs). Direct thrombin inhibitors are a more recent group of anti-coagulants. The first DTI was hirudin, a natural substance derived from the saliva of leeches. New forms include argatroban (Novastan), bivalirudin (Angiomax), danaparoid (Orgaran), lepirudin (Refludan), desirudin (Revasc), and ximelagatran (Exanta). Many of these drugs are used along with warfarin and may be good options for patients who develop thrombocytopenia with heparin use. DTIs may prove to be superior to standard heparin for patients with acute coronary syndrome.

Other Medications

Nitrates have been used in the treatment of angina for over 100 years. These drugs release nitric oxide, thereby relaxing the smooth muscles in blood vessels. Many nitrate preparations are available. The most commonly used are nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. Nitrates can be absorbed from the gastrointestinal tract (oral tablet), skin (ointment or patch), or from under the tongue (sublingual tablet or spray).

Rapid Acting Nitrates. Rapid-acting nitrates are used to treat acute attacks. Nitroglycerin is the most widely used drug for this purpose. It can be administered under the tongue (sublingually or as a spray) or pocketed between the upper lip and gum (buccally) and can relieve angina within minutes. The procedure for taking nitroglycerin during an attack is as follows:

At the onset of an angina attack, the patient administers one sublingual or buccal tablet or one metered dose of the spray.
If the pain is not relieved within 5 minutes the patient takes a second dose; a third can be taken after another 5 minutes if symptoms persist.
If pain continues after a total of three doses in 15 minutes, the patient should go immediately to the nearest emergency room.

Nitroglycerin is very volatile so its potency can be easily lost. Patients should take the following precautions:

Keep no more than 100 tablets on hand, stored in their original container.
When first opened, the cotton filler should be discarded, and the cap screwed on tightly immediately after each use.
A supply should always be kept close at hand in case of an attack, with the rest kept in a cool dry place.

Intermediate to Long-Term Nitrates. Sublingual tablets of isosorbide dinitrate have a somewhat slower onset of action than nitroglycerin and are useful for preventing exercise angina. Ointments, patches, and oral tablets are used for longer-term prevention of angina attacks:

Transdermal patches are applied in the morning to any hair- or injury-free area on the chest, back, stomach, thigh, or upper arm. Hands should be washed after each patch or ointment application, and sites of application should be rotated to avoid skin irritation.
Nitroglycerin ointment is applied by measuring out an even amount on an applicator paper and then placing, not rubbing or massaging, it on the chest, stomach, or thigh. Any ointment that remains from the previous application should be removed.

Long-acting forms may lose their effectiveness over time, so doctors generally schedule nitrate-free breaks to prevent tolerance. Some concern exists that nitrate-free periods might increase the risk for angina and adverse heart events. One large study, however, found no increased danger when patients used a nitroglycerine patch with scheduled breaks. The use of high blood pressure drugs known as ACE inhibitors may help prevent tolerance to nitrates.

Side Effects. Nitrates have many side effects, some of which can be serious.

Common side effects of nitrates include headaches, dizziness, nausea and vomiting, blurred vision, fast heartbeat, sweating, and flushing on the face and neck. Low blood pressure and dizziness can be relieved by lying down with the legs elevated. These effects are significantly worsened by alcohol, beta-blockers, calcium channel blockers, sildenafil (Viagra), and certain antidepressants. The doctor may prescribe medicines to lessen these side effects. Patients should contact their doctor if these side effects are persistent or severe.

Serious side effects requiring immediate medical help include fever, joint or chest pain, sore throat, skin rash (especially on the face), unusual bleeding or bruising, weight gain, and swelling of the ankles.

Withdrawal. Withdrawal from nitrates should be gradual. Abrupt termination may cause angina attacks.

Beta-blockers are useful for preventing angina attacks and reducing high blood pressure. They reduce the heart's oxygen demand by slowing the heart rate and lowering blood pressure. They are recognized for reducing deaths from heart disease and from heart surgeries, including angiography and coronary bypass. Beta-blockers are the drugs of choice for older patients with stable angina and may also be beneficial for people with silent ischemia. They are, however, less useful for the treatment of Prinzmetal’s angina. Beta-blockers are often prescribed along with other drugs such as nitrates, calcium channel blockers, or statins. A 2006 study suggested that beta-blockers and statins may help stabilize coronary artery disease and prevent the development of heart attacks.

Specific Beta-blockers. Beta-blockers include propranolol (Inderal), carvedilol (Coreg), bisoprolol (Zebeta), acebutolol (Sectral), atenolol (Tenormin), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol-XL), and esmolol (Brevibloc). A nasal spray form of propranolol appears to be very helpful in reducing exercise-induced angina attacks.

Side Effects. Beta-blocker side effects include fatigue, lethargy, vivid dreams and nightmares, depression, memory loss, and dizziness. They can lower HDL (“good”) cholesterol. Beta blockers are categorized as non-selective or selective. Non-selective beta blockers such as carvedilol and propranolol can narrow bronchial airways. These beta-blockers should not be used by patients with asthma, emphysema, or chronic bronchitis.

Patients should never abruptly stop taking these drugs. The sudden withdrawal of beta-blockers can rapidly increase heart rate and blood pressure. The doctor may advise a patient to slowly decrease the dose before stopping completely.

Calcium channel blockers reduce heart rate and slightly dilate the blood vessels of the heart, thereby decreasing oxygen demand and increasing oxygen supply. They also reduce blood pressure. CCBs vary chemically, however, and although some are helpful, others may even be dangerous for certain patients with angina.

Click the icon to see an image of the anterior heart arteries.

Long-acting nifedipine (Adalat, Procardia) and nisoldipine (Sular) and newer CCBs, such as amlodipine (Norvasc) and nicardipine (Cardene), may be beneficial for some patients with angina. They can be considered alone for patients who cannot tolerate beta-blockers, but may provide the best results when used in combination with a beta-blocker. Studies suggest that they reduce the need for repeat angioplasties. Their effects on other outcomes, including mortality rates and heart attack, are less clear.
Short-acting CCBs, including short-acting forms of verapamil, diltiazem, nifedipine, and nicardipine, are helpful for many patients with Prinzmetal's angina. However, short-acting forms of certain CCBs, such as nifedipine and nisoldipine, have been associated with severe and even dangerous side effects, including an increase in heart attacks and sudden death in some patients with unstable angina. They also increase the risk for adverse effects in patients with stable angina. Short-acting CCBs are, therefore, not used for stable or unstable angina.

There is no strong evidence that any calcium channel blockers improve survival rates. Overdose can cause dangerously low blood pressure and slow heart beats. Patients with heart failure have a higher risk for death with these drugs and should not take them. No one taking any calcium channel blocker should withdraw abruptly because such action could dangerously increase the risk of high blood pressure. Note: Grapefruit and Seville oranges boost the effects of CCBs, sometimes to toxic levels. (Regular oranges do not appear to pose any hazard.)

Angiotensin converting enzyme (ACE) inhibitors are important heart-protective drugs, particularly for people with diabetes and high blood pressure. They reduce the production of angiotensin, a chemical that causes arteries to narrow, and so are commonly used to lower blood pressure. They may also reduce risk for heart attack, stroke, complications of diabetes, and death in patients at high risk for heart disease.

ACE inhibitors include captopril (Capoten), ramipril (Altace), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), perindopril (Aceon), and lisinopril (Prinivil, Zestril).

Side Effects. Side effects of ACE inhibitors are uncommon but may include an irritating cough, excessive drops in blood pressure, and allergic reactions. In the past, doctors sometimes avoided giving aspirin to patients who were taking ACE inhibitors because the combination was believed to cause kidney problems. But, a 2005 study of patients with both coronary artery disease and heart failure found that taking aspirin and ACE inhibitord together is safe. The researchers also noted that taking aspirin with an ACE inhibitor can significantly reduce the risk of death for older patients with CAD and heart failure. [See In-Depth Report #14: High blood pressure.]

In 2004, the National Cholesterol Education Program issued updated recommendations on how to control cholesterol levels. These guidelines emphasize that patients should lower their LDL (“bad”) cholesterol and recommend that more people take LDL-lowering medication. Lowering LDL cholesterol and raising HDL (“good”) cholesterol can significantly reduce the risks of heart disease. Several different types of drugs (statins, bile-acid binding resins, niacin, and fibrates) are used to treat cholesterol. [See In-Depth Report #23: Cholesterol.]

Statins are the most important of these drugs. Brands include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). A major analysis of over 200 studies found that statins reduced the risk for heart problems by 60% and stroke by 17%. A 2005 review found that the more that statins lower LDL, the more they reduce CAD and other heart disease risks.

An important 2006 study found that aggressive treatment with statins may have the potential to reverse coronary artery disease. In the study, rosuvastatin reduced fatty plaque in the arteries in addition to improving LDL and HDL cholesterol levels. However, a follow-up 2007 study of rosuvastatin indicated that while the drug slowed the rate of atherosclerotic progression, it did not reverse heart disease. Future studies will continue to investigate this issue.

Side effects of statins may include stomach upset, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The main safety concern with statins is an uncommon condition called myopathy, which can cause muscle and joint pain and possible muscle damage. Doctors will immediately stop statin therapy if myopathy occurs. Patients should talk to their doctor about any unusual muscle discomfort or weakness, or if their urine becomes brown-colored. Statins can also affect the liver, particularly at higher doses, so patients taking these drugs should receive regular liver function tests.

Click the icon to see an image of cholesterol.

Influenza Vaccinations (Flu Shots). Evidence suggests influenza vaccinations help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two-thirds of at risk people are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.

Antibiotics. Researchers have investigated antibiotics for treating patients with heart disease and past infection of the bacteria Chlamydia pneumoniae. Results from several recent large-scale clinical trials suggest that antibiotic treatment provides no benefit in preventing heart attack or other cardiac events in patients with coronary artery disease. In addition, a 2006 study indicated that short-term treatment with the antibiotic clarithromycin may increase the risk for death in patients with coronary artery disease. While it is still possible that C. pneumoniae may play a role in triggering inflammatory responses associated with ACS, antibiotic therapy is no longer considered appropriate for treatment or prevention of heart disease.

Ranolazine (Ranexa) was approved in 2006 for treatment of chronic angina. It is recommended for patients who have not responded to other angina drugs. Ranolazine is taken in combination with amlodipine, beta blockers, or nitrates. The drug appears to work better in men than in women

Gene Therapy and Angiogenesis. Proteins known as growth factors are being investigated for their ability to grow new blood vessels for supplying oxygen to the heart. After promising small trials, two large studies of genetically engineered forms of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF [GenerX]) failed to detect any benefits. Studies on therapies that actually genetically encode these proteins are underway.

Testosterone Supplements. Some trials using testosterone supplements or patches have reported improved exercise-induced blood flow in the coronary arteries and improvement in angina in some cases. Supplements of this male hormone, however, may increase the risk for prostate cancer. Experts suggest that testosterone be used only in older men with significant deficiencies in testosterone.

Selective Estrogen-Receptor Modulators (SERMs). Selective estrogen-receptor modulators (SERMs), including raloxifene (Evista), have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. Raloxifene may have some heart benefits, although it poses a risk for deep vein blood clots, which may have long-term implications for patients with heart problems. A major study is underway to determine its effects on the heart.

Surgery

Surgery is usually recommended for patients who have:

Unstable angina that does not respond promptly to medical treatment
Severe recurrent episodes of angina that last more than 20 minutes
Acute coronary syndrome
Severe coronary artery disease (severe angina, multi-artery involvement, evidence of ischemia), particularly if abnormalities are evident in the left ventricle of the heart, the main pumping chamber

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Researchers have been investigating whether surgery offers any advantages if used as an early treatment for mild angina. A major analysis in 2003 reported that the use of angioplasty in patients with mild heart blockage did not reduce the risk for heart attack or death over the long term. A landmark 2007 study found that angioplasty was no better than drug therapy for preventing heart attack and stroke in patients with stable coronary artery disease. (For more information, see Angioplasty and Stents.)

Two effective surgical procedures for heart patients are:

Coronary artery bypass grafting (commonly called bypass or CABG)
Percutaneous coronary intervention (commonly called angioplasty or PCI), usually with coronary artery stent placement

Click the icon to see an image about bypass grafting.

Each of these procedures is described below.

Studies have generally reported similar survival rates with either procedure. There are some differences, however, and decision often depends on individual conditions. Patients considering surgery should discuss all options and risks with their doctor. No surgical procedure cures coronary artery disease, and patients must continue to rigorously maintain a healthy lifestyle and any necessary medications. For some patients, lifestyle changes and medications may be able to control the disease without surgery or angioplasty.

Considerations for Choosing Angioplasty with Stent Placement. Angioplasty has the following advantages for most patients. It is:

Less invasive than bypass. (Although a minimally invasive variation of bypass surgery may reduce this distinction.)
Less expensive than bypass. (Although the postoperative need for more medications and the high risk for repeat procedures to reopen the artery may reduce the long-term difference in cost between the two procedures.)
Life-saving emergency procedure for many patients with heart attacks. (The use of bypass after a heart attack has much higher mortality rates than when it is used electively and its use is controversial in heart attack patients.)

It has the following disadvantages:

The blood vessels can close up again (restenosis) so that patients require additional procedures. (New blood thinning drugs, coronary stent coatings, and radiation treatments may help to significantly reduce restenosis rates. However, there is also some indication that stents, especially drug-eluting stents, may increase the risk for blood clots.)
It is not as appropriate as bypass for many patients with angina (people with diabetes, elderly patients, or those with multi-vessel blockage). Increasingly, however, angioplasty is proving to be as safe and as effective as bypass in many high-risk patients. Patients should be sure to discuss with their doctors the relevant risks and benefits of angioplasty and bypass.

Considerations for Choosing Bypass. Bypass is usually the appropriate procedure in patients with high-risk conditions, such as:

Multi-vessel blockage. (In one report comparing surgery to angioplasty in patients with two or three blocked vessels, the mortality rate 1 year after bypass was 0.8% and after angioplasty was 2.5%. About 80% of patients in the study were men.)
Diabetes. (Bypass produces significantly higher survival rates in these patients. Some experts believe angioplasty should rarely, if ever, be used in this population.)
Being elderly.
Certain structural features, such as a left main artery narrowed by 50% or more or a very long diseased portion of the artery.

Considerations for Women. Studies have reported higher mortality rates in women than in men after any heart surgery. Some experts theorize that on average women may be older and sicker when they have a heart operation. A 2002 study, however, suggested that when women with acute coronary syndromes are given the same aggressive and early treatment as men are, their survival rates are equal or even better.

In addition to angioplasty and bypass procedures, a number of other procedures are available or under investigation for coronary artery disease. They include:

Atherectomy
Myocardial Laser Revascularization
Enhanced External Counterpulsation (EECP)

Coronary Artery Bypass Graft Surgery

Coronary artery bypass graft surgery (CABG) is a good alternative to angioplasty for many patients, but it is very invasive. The surgery involves the following processes:

Click the icon to see an animation about CABG.

The chest is opened, and the blood is rerouted through a lung-heart machine.
The heart is stopped during the procedure.
Large blood vessels supply the grafts, which are used to reroute the blood. The blood vessel grafts are transplanted in front of and beyond the blocked arteries, so the blood flows through the new vessels around the blockage.
The standard grafts now use arteries taken from the chest wall. Studies are reporting that with such grafts arteries remain open in 90% of cases after 15 years.
In general, patients with triple bypass procedures stay in the hospital for 5 days. Those with one-vessel bypass may be able to go home in 3 days.

Click the icon to see an illustrated series detailing a heart bypass surgery.

In spite of the invasive nature of this procedure, elective bypass procedures produce better long-term survival rates than angioplasty, particularly in patients with diabetes and multi-vessel blockage. Overall mortality rates after this procedure range from 1% to slightly over 2%. The risk for stroke or heart attack after a bypass operation ranges from 1.3 - 5%. Finding a surgeon who performs at least 100 of the procedures a year helps reduce the risk for complications.

Blood clots may form in the new graft, closing it up or narrowing the treated vessel over time. Therapy with aspirin and other anti-clotting drugs help keep the graft open and working properly. For long-term prevention of closure, as well as for slowing progression of atherosclerosis, aggressive treatment with cholesterol-lowering drugs may be more beneficial than standard anti-clotting drugs.

Bleeding is also a potential complication of CABG. Anti-bleeding (also called hemorrhage-sparing) drugs are sometimes used to limit blood loss in patients who undergo this surgery. In 2006, concerns were raised about one of these drugs, aprotinin (Trasylol). Data suggested that aprotinin seriously increased the risks for kidney failure, heart failure, and stroke.

An important study, published in 2007 in the Journal of the American Medical Association, compared aprotinin with two anti-fibrinolytic drugs, aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron), which are also used to control blood loss. The study of nearly 4,000 patients who had CABG found that over a 5-year period, the death rate for patients who took aprotinin was 21%, and patients had a 48% increased risk of dying. By comparison, the death rate was 16% for aminocaproic acid, 15% for tranexamic acid, and 13% for no anti-bleeding drug. Because aprotinin is more expensive as well as potentially more dangerous than other anti-bleeding drugs, experts are now recommending against its use in CABG.

Minimally invasive bypass (also called buttonhole or keyhole bypass) surgeries are exciting advances in basic bypass surgery. Studies indicate good success of these procedures for patients with disease in single vessels. They are also being investigated for multiple vessels.

One variation of minimally invasive bypass uses a four-inch incision. The surgeon works on the front of the heart while it is beating slowly. To date, there have been no differences in cardiac events or later mental complications between this so-called off-pump procedure and the standard bypass procedure.
In another variation, the heart is stopped, and the patient is put on a machine that reroutes the blood through a device that keeps it oxygenated. Fiberoptic scopes and instruments are passed through a number of finger-sized incisions. The surgeon works on all sides of the heart, guided by a video image from a tiny camera inserted through a 4-inch incision.
Some advanced heart centers now use robotic systems, which allow the surgeon to perform extremely delicate maneuvers on tiny vessels through pencil-size incisions. They are not yet used for the whole bypass process.

Eventually, minimally invasive bypass procedures may prove to be less expensive, require a shorter hospital stay, and have fewer complications than conventional coronary artery bypass surgery -- or even angioplasty. At this time, however, they are experimental procedures, performed in only a few medical centers for select candidates. Long term-success rates are unknown.

Angioplasty and Stents

Percutaneous coronary intervention (PCI), also called angioplasty, involves procedures such as percutaneous transluminal coronary angioplasty (PTCA) that help open the blocked artery.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

A typical angioplasty procedure follows these steps:

The cardiologist threads a narrow catheter (a tube) containing a catheter into the blocked vessel.
The doctor opens the blocked vessel using balloon angioplasty, in which the surgeon passes a tiny deflated balloon through the catheter to the vessel.
The balloon is inflated to compress the plaque against the walls of the artery, flattening it out so that blood can once again flow through the blood vessel freely.
In order to keep the artery open afterwards, surgeons use a device called a coronary stent, an expandable metal mesh tube that is implanted during angioplasty at the site of the blockage. (In some cases, a stent may be used as the initial opening device instead of balloon angioplasty.)
Once in place, the stent pushes against the wall of the artery to keep it open.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

Complications occur in about 10% of patients (about 80% within the first day). Outcomes are better in hospital settings with experienced teams and backup.

Click the icon to see an illustrated series detailing coronary artery balloon angioplasty surgery.

The most important long-term complication is reclosure (restenosis), which can lead to heart attack if not treated with a repeat procedure. Stenting and other advances have helped significantly in preventing reclosure and reducing heart attack rates. Nevertheless, a repeat procedure is still needed to restore the opening in 10 - 15% of procedures that use stents.

PCI (angioplasty) has been proven to help reduce the frequency of angina attacks. It is commonly recommended for patients who have critically blocked arteries or have already had a recent, acute heart attack. PCI can also help improve survival and prevent heart attacks in patients with acute coronary syndrome (ACS). However, doctors have been uncertain about angioplasty’s benefits for survival and heart attack prevention in lower-risk patients with stable coronary artery disease.

In 2007, a landmark study was published in the New England Journal of Medicine and presented at the 2007 meeting of the American College of Cardiology. The COURAGE study found that PCI works no better than standard heart medication (drugs to control blood pressure, lower cholesterol, and prevent blood clots) in preventing heart attack, stroke, and hospitalization in patients with stable coronary artery disease. Based on this study’s findings, experts are now recommending angioplasty only for patients who have severe heart disease. For patients with stable heart disease, drug therapy may be sufficient enough treatment and allow them to safely defer having surgery.

Angioplasty is less invasive than bypass surgery, requiring only one night in the hospital. Recuperation takes about a week. Chest pain after the procedure is very common and usually due to problems other than ischemia. Mild chest pain is even more common when a stent is used, possibly because the artery is stretched.

Reclosure of the artery during or shortly after angioplasty often occurs. A number of anti-clotting drugs are used to help prevent this.

Aspirin and the anti-platelet drug clopidogrel (Plavix) are often used to prevent reclosure during the procedure.
A high dose of the anticoagulant heparin is typically given before the operation.
Intravenous glycoprotein IIb/IIIa inhibitors, powerful drugs that block platelets, also prevent reclosure after stenting in many high-risk patients, and evidence now strongly suggests that they reduce rates of heart attack and death. Eptifibatide (Integrilin) and tirofiban (Aggrastat) are the standard drugs used during angioplasty. They may be most effective if administered during angioplasty, rather than beforehand.

All of these drugs pose a risk for bleeding complications.

Narrowing or reclosing of the artery (restenosis) can occur within a year of angioplasty or even longer in 15 - 60% of angioplasty patients. Coronary stents, anti-clotting drugs, and other advances have reduced these events significantly, but have not eliminated the problem. Theories for the cause of restenosis include:

The release of oxidants (damaging unstable particles) at the surgical site may cause injury and activate immune factors that produce cellular overgrowth in smooth muscles of the blood vessels.
Other activities, including scarring, may remodel and narrow the blood vessels. (This is most likely the reason for restenosis in patients with stents.)

Symptoms of restenosis include chest pain on exertion. (Heart attacks, however, do not usually occur with such events.) The narrowing of the artery in this case is not due to blood clots, so anti-clotting drugs are not useful. Restenosis usually requires a repeat operation. A number of approaches, mostly investigative, have been developed to prevent restenosis after angioplasty.

Drug-Coated Stents. Stents coated with the drugs sirolimus (Rapamune) or paclitaxel (Taxol) have been increasingly used in the last several years. Drug-eluting stents (as they are also called) can help prevent restenosis. However, because drug-eluting stents reduce arterial tissue growth, they can increase the risks of blood clots. In late 2006, the FDA held several meetings to discuss the increased risks of blood clots associated with drug-eluting stents. The committees found that drug-eluting stents do appear to have a small increased risk of blood clots compared to bare metal stents, but not enough research has been conducted to fully determine their risks for heart attack and death.

Five studies published in the New England Journal of Medicine in March 2007 indicated that drug-eluting stents are safe and effective for patients with coronary artery disease when they are used for FDA-approved indications. Problems have arisen when these stents are used for “off-label” purposes in patients with more complicated health problems. There is still some concern as to whether all stents (both bare metal and drug eluting) are used too frequently for patients who may be better served by drugs or bypass surgery.

In February 2007, the American Heart Association and other professional organization issued an extremely important joint advisory statement. The statement advises that all patients who have drug-eluting stents must continue to take aspirin and clopidogrel (or, rarely, ticlopidine) for at least 1 year after the stent is inserted to reduce the risk of blood clots. Clopidogrel and ticlopidine are thienopyridine drugs that, like aspirin, help prevent blood platelets from clumping together. It is very important that patients who have drug-eluting stents take both aspirin and a thienopyridine drug. If for some reason patients cannot take a thienopyridine drug, they should receive a bare metal stent instead of a drug-eluting stent.

Coronary Artery Brachytherapy. Radiation treatment called coronary artery brachytherapy (Gamma One, Beta-Cath) can slow the cell growth in the arteries that causes restenosis. With this approach, any blockage in the stent is first removed, and a tube with an inflatable balloon is inserted. The surgeon then implants a temporary device that delivers radiation. Brachytherapy has shown excellent results in preventing restenosis and significantly reducing heart events and improving survival. Brachytherapy is also showing promise in preventing restenosis in stented artery grafts that were put in place after bypass surgery and later failed. However, several 2006 studies in the Journal of the American Medical Association indicated that drug-coated stents may work better than brachytherapy in preventing restenosis in failed stents. In these studies, the drug-coated stents were inserted inside the original bare metal stents.

Medications. A number of medications are being studied for prevention of restenosis, although benefits to date have been modest. Other drugs under investigation include statins, various anti-clotting drugs, and B vitamins.

Other Procedures. Other procedures under investigation to keep the arteries open use ultrasound, "soft" x-rays, and cryotherapy (very low temperatures).

Other Treatments

Transmyocardial laser revascularization (TMLR) applies laser energy directly to areas in the heart where blockage has occurred, creating 10 - 50 tiny channels. TMLR is recommended for patients with severe angina who have not responded to surgical bypass or angioplasty procedures. TMLR is not suitable for patients who have severely damaged heart muscles. A variant called percutaneous transmyocardial laser revascularization uses a small laser (a holmium YAG laser), which is smaller than the device used in TMLR and does not require open chest surgery and a general anesthetic.

Patients report improved symptoms and exercise tolerance. Both procedures carry risks for serious complications, however, including some that can be life-threatening. It is not clear if either TMLR procedure improves survival, and, in one study, the quality of life afterwards was less than with standard heart surgeries.

A noninvasive technique called enhanced external counterpulsation (EECP) has been used successfully by over a million people in China. The technique uses an air pump that inflates and deflates pressurized cuffs around the legs, causing blood to be pushed into the heart.

EECP may help patients with angina who have not had pain relief from nitrate drugs and who do not qualify as candidates for bypass or angioplasty. In different studies, it has relieved angina in over 75% of patients who used it and reduced the need for medication. The benefits persist, and there is some evidence that it produces actual cellular changes that benefit the heart. In 2002, the FDA approved EECP for the treatment of heart failure but some insurance companies still consider its use “experimental” and will not pay for it. EECP is not recommended for patients with arrhythmia, serious heart valve problems, or peripheral artery disease.

Atherectomy procedures clear the narrowed arteries by using an approach called debulking. All of these procedures use a catheter (a thin tube) that is inserted into an artery (usually in the groin) and threaded up to the blockage. Devices are inserted through the tube to remove the plaque. They include:

Rotational atherectomy, which uses a tiny cutter spinning at 2,500 rpm
Extractional atherectomy, which "shaves" the plaque
Directional atherectomy, which slices the plaques

Although they are successful in opening arteries, they offer no advantages over standard angioplasty and are used only for special cases.

Resources

www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
www.americanheart.org -- American Heart Association
www.acc.org -- American College of Cardiology

References

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Review Date:
4/16/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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