Wednesday, April 11, 2012

HCV News Ticker- EASL 2012-Hepatitis C Drug Abstracts Leak Ahead of EASL Confab

More Hep C Drug Abstracts Leak Ahead of EASL Confab
By Adam Feuerstein
On Tuesday, an investor who asked to remain anonymous emailed me three research abstracts involving hepatitis C drug data from Gilead Sciences and Bristol-Myers Squibb(BMY). All of the abstracts were supposed to be embargoed and therefore not publicly available, according to EASL rules.
One of these abstracts, titled "Electron: Once Daily PSI-7977 Plus RBV in HCV GT1/2/3" is the subject of intense investor interest because it will help assess the efficacy of Gilead's most important hepatitis C drug, acquired through the $11 billion acquisition of Pharmasset.
EASL officials confirmed the authenticity of the leaked research abstracts via email but requested that specific information contained in the abstracts not be disclosed. I'm abiding by EASL's request because the leaked abstracts are not much more than placeholders containing early, incomplete and previously announced data that will only be updated at the EASL meeting April 18-22.
The embargoed abstract for Gilead's Electron study, for example....

Continue Reading at The Street.....

 NATAP Updates

New DAA FDA Guidance March 2012 - (04/10/12)
Medivir Announces Final Results from TMC435 Phase IIb ASPIRE (C206) Study - (04/10/12)
DAA Update - (04/10/12)


The high comorbidity burden of the hepatitis C virus infected population in the United States
Karly S Louie, Samantha St. Laurent, Ulla M Forssen, Linda M Mundy and Jeanne M Pimenta
BMC Infectious Diseases 2012, 12:86 doi:10.1186/1471-2334-12-86
Published: 11 April 2012
Abstract (provisional)

Chronic hepatitis C (HCV) disease can be complicated with comorbid conditions that may impact treatment eligibility and outcomes. The aim of the study was to systematically review comorbidities and symptoms in an HCV infected population, specifically assessing comorbidities associated with HCV anti-viral treatment and disease, as well as comparing comorbidities between an HCV infected and uninfected control population.

This was a retrospective cohort study within a United States medical claims database among patients with chronic HCV designed to estimate the two-year period prevalence of comorbidities. Patients with two HCV diagnosis codes, 24 months of continuous health insurance coverage, and full medical and pharmacy benefits were included.

Among a chronic HCV cohort of 7411 patients, at least one comorbid condition was seen in almost all patients (>99%) during the study period. HCV-infected patients reported almost double the number of comorbidities compared to uninfected controls. Of the 25 most common comorbidities, the majority of the comorbidities (n = 22) were known to be associated with either HCV antiviral treatment or disease. The five most frequent comorbidities were liver disease [other] (37.5%), connective tissue disease (37.5%), abdominal pain (36.1%), upper respiratory infections (35.6%), and lower respiratory disease (33.7%). Three notable comorbidities not known to be associated with antiviral treatment or disease were benign neoplasms (24.3%), genitourinary symptoms & ill-defined conditions (14.8%), and viral infections (13.8%).

This US medically insured HCV population is highly comorbid. Effective strategies to manage these comorbidities are necessary to allow wider access to HCV treatment and reduce the future burden of HCV disease and its manifestations.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.  

Stem Cells

UCLA researcher explores the risk and rewards of stem cell products
The brave new world of stem cell research dangles the exciting potential for a host of leading-edge treatments that may one day help cure debilitating diseases such as Alzheimer's and Parkinson's, maladies that today cannot be treated with modern medicine.

However, not much thought has been given to how those products might be regulated and how issues of legal liability may be addressed in a way that encourages scientific innovation but also protects the patients for whom these treatments might provide great relief.

Now, a lawyer from the UCLA School of Law and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has developed a road map that could help guide researchers, stem cell product manufacturers, treating physicians and patients through the complex maze of imagining, creating and developing stem cell products and using them to treat disease.

"Stem cell research and its eventual applications hold enormous promise, but they also carry some significant risks," said Stephen R. Munzer, a distinguished professor of law and author of the article. "Our understanding of the number and gravity of those risks right now is incomplete and uncertain. Developing a plan now that details how to deal with such issues as stem cell product liability is important, because we need to think carefully and rationally about how to address these issues before the market is flooded with products."

Munzer's work appears April 11, 2012 in the Boston University Journal of Science and Technology Law.

In the article, Munzer offers suggestions on how stem cell products might be classified in the future, examines how applying existing product liability rules to stem cell products is inadequate, details the economic considerations for a stem cell liability regime and offers his views of what the law should be on liability for stem cells.

"One thing I detect from the stem cell scientists I've spoken to is a certain amount of judicious caution," he said. "What they don't want is to have people rushing to get something approved by the FDA and then see it result in unanticipated, unforeseeable problems."

One of the byproducts of that judicious caution, both of risk of liability and potential risk to patients, Munzer said, has been scientists and biotech companies initially going after the so-called "low hanging fruit" of stem cell treatments, those projects that appear to have the least amount of risk and maximum benefit, such as treatments for retinal disease as opposed to organ regeneration.
In the article, Munzer also emphasizes the "ethics of risk," or having all those involved from the conception of an idea for a stem cell product to its eventual development and manufacture and administration, accountable for the risks they may be imposing on patients.

"The scientists who come up with the ideas for these products, the people who design them, the biotech companies that manufacture them and produce them in large numbers and the treating physicians who ultimately will be administering these treatments all have to be accountable, as well as the FDA, which is charged with regulating them," Munzer said.

Munzer likened the anticipation for potential stem cell products to the excitement created in the 1980s and 1990s over early gene therapies and what may have been a rush to test the therapies without adequately considering the risks. That potential for new treatments was temporarily derailed after an 18-year-old, Jesse Gelsinger, in a gene therapy trial died in 1999 as a result of the treatment.
"Existing blood products, growth factors, vaccines, we've got more understanding of how those things work and that is not true in the case of stem cells," Munzer said. "We want to create a strict liability regime that encourages innovation, but on the other hand does not encourage it so much that products are put on the market long before they should be."

Munzer suggests creating a social-insurance arrangement that would pool resources from everyone involved from the scientists to the manufacturers to the treating physician and the patients, contributing to a fund that could eventually be used to compensate those harmed by stem cell products during their testing. His proposal is similar to the National Vaccine Injury Compensation Program, a no fault alternative to the traditional tort system created in 1988 to ensure an adequate supply of vaccines, stabilize vaccine costs and establish and maintain an accessible and efficient forum for individuals found to be injured by certain vaccines.

Munzer also recommends limiting punitive damages in stem cells cases, but only if the product has been FDA approved and the FDA regulatory requirements have been strictly followed, the risks of the products have become more understood and predictable, and the FDA has gained sufficient experience in regulating the products.

Munzer's liability road map could be of value to courts, lawyers and regulatory bodies in navigating what is to come in stem cell product development. It also should be considered a dynamic document, he said, that responds to what is learned in the coming decades about the creation and development of stem cell products.

"It is important to address these issues this early with as much insight as we can bring to it, recognizing that there will be, as the years go on, more information and a better understanding of what we're doing," he said. "Starting to address this now instead of waiting five to 10 years is vital, as it will be much easier to prevent potential mishaps and messes from occurring than it will be to try to clean them up later."

Munzer's article attempts to tackle problems that are on or just beyond the horizon, and looks to what has happened in the past for guidance.

"The product liability claims regarding stem cell products will require the most exacting attention to their safety and effectiveness that is possible without imposing an undue burden on manufacturers," the study states. "No existing category offers a perfect legal model for stem cell products. However, we can tease out pertinent features of these categories for tort litigation to show what might work well for stem cell products. Definitive recommendations must wait for these products to appear on the market and for their risks and rewards to become better understood over the coming decades."

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA's Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at

In The News

From Reuters Health Information

HCV Treatment May Improve Insulin Resistance in Nondiabetics                   

By Will Boggs MD
NEW YORK (Reuters Health) Apr 09 - In nondiabetics with hepatitis C virus (HCV), insulin resistance (IR) may improve once the virus is treated - regardless of whether the treatment is successful, researchers say.

They pointed out in a recent paper that HCV infection is an independent risk factor for incident diabetes, particularly when other risk factors for diabetes are present. It may be, they suggest, "that individuals with higher degrees of IR may benefit from receipt of HCV therapy in an attempt to decrease their risk of clinical sequelae of IR."

"Host factors, especially obesity, play a great role in insulin resistance in the HCV population, similar to other populations, but HCV therapy appears to also decrease insulin resistance irrespective of sustained virologic response," Dr. Mandana Khalili from University of California San Francisco told Reuters Health in an email.

Dr. Khalili and colleagues used direct measurements of insulin sensitivity to evaluate the impact of insulin resistance on achieving a sustained virologic response (SVR) to HCV therapy -- and the impact of HCV eradication on insulin resistance. As a control group, they used patients with HCV who did not receive antivirals.

Fifty nondiabetic HCV patients ages 18 to 60 - including 23 on pegylated interferon and ribavirin -- participated in the study, as reported online March 7 in Diabetes Care. At baseline, rates of insulin resistance were statistically similar in patients who did and did not receive antivirals.
There were 14 SVRs, with significantly higher rates in patients with genotypes 2 and 3 (83%) than in those with genotype 1 (36%; p=0.03).

Host and viral factors were similar among patients who did and did not achieve SVR, and the odds of achieving SVR did not differ with the degree of insulin resistance before treatment, regardless of genotype.

Six months after HCV therapy ended, insulin resistance (as measured by steady state plasma glucose) improved among patients who received anti-HCV therapy - although wide confidence intervals, possibly related to the small sample size, meant the difference was not statistically significant.
Specifically, SSPG decreased by 36 mg/dL in those with SVR and by 28 mg/dL in those without SVR, compared with the untreated group.

On multivariate analysis, the improvement in insulin resistance did not differ significantly between patients who did and did not achieve SVR.

As expected, increasing BMI was associated with higher levels of insulin resistance and with higher fasting glucose levels. Interferon use was positively associated only with insulin resistance.
"The main purpose of this study was to evaluate the influence of insulin resistance on SVR as well as SVR on improvement of insulin resistance," the researchers note. "When using precise measurements of insulin resistance, insulin resistance did not appear to be substantially associated with achievement of SVR. Successful viral eradication did not appear to substantially influence insulin resistance when compared with HCV therapy that does not result in SVR."

They added, "Similar to other studies using the direct measurements of insulin resistance, our study is limited by small sample size, which may not have allowed for detection of other known host and viral factors that influence SVR."

"Any patient who is a candidate for HCV therapy should be considered for therapy, especially considering the more recent effective anti-HCV therapy regimens," Dr. Khalili said. "However, those who have known risk factors associated with insulin resistance, especially obesity, should address these factors (including weight loss) first, since they have a much higher impact on decrease in insulin resistance, but they should also be considered for HCV therapy."

"We are currently evaluating a large cohort of HCV patients to describe the distribution and variability of insulin resistance in an ethnically diverse HCV population," Dr. Khalili added.
"Further studies are necessary to determine if additional changes in insulin resistance occur after successful viral eradication beyond six months after discontinuation of HCV therapy," the investigators say.
Diabetes Care 2012.

Baby Boomers Facing Hepatitis Time Bomb
By Mark G Swain, MD, MSc, FRCPC

Professor of Medicine and Cal Wenzel Family Foundation Chair in Hepatology
Snyder Institute for Chronic Diseases
Head, Division of Gastroenterology, University of Calgary

Hepatitis C is a virus which was first identified in 1989. Very quickly it came to be appreciated that hepatitis C was a significant health issue, infecting roughly 250,000 Canadians; a five-fold higher number than are infected with HIV. Hepatitis C is mainly acquired through exposure to contaminated blood; through transfusions and through the use of intravenous drugs. In fact, after exposure to hepatitis C, even after one exposure, up to 85 per cent of people will keep the virus in their bodies for the rest of their lives. Hepatitis C lives in the liver where it multiplies, and as part of its’ life cycle, hepatitis C kills liver cells. In response to these dying liver cells the liver tries to heal itself with scar tissue, and in roughly 20 per cent of infected people after 2-3 decades of infection, the amount of scar tissue in the liver can get to the point where these individuals have developed cirrhosis of the liver. Many people believe that excessive alcohol intake is the cause of liver cirrhosis; however, there are in fact many causes of cirrhosis, with hepatitis C being an important cause of cirrhosis in Canada.
Typically people infected with hepatitis C have no symptoms, and so they do not suspect that they are infected. Over time they often forget that they have a risk factor for hepatitis C acquisition, and it is not until 20 or 30 years later that they are discovered to have hepatitis C infection, and in many instances have advanced liver scarring. This issue has been recently brought to light by the findings, in a large American study, of a significant increase in the incidence of hepatitis C infection amongst baby boomers (prevalence rate of 3 per cent of people within this age group). This finding in general reflects lifestyle choices made by individuals who lived during the 1960’s and 70’s, when experimentation with injection drugs occurred widely. Often this experimentation took the form of a single exposure, and was soon forgotten. However, it is becoming increasingly apparent that hepatitis C was acting in a stealth fashion, silently destroying the livers of many of these people. As a result of this, hepatitis C has now overtaken AIDS as a cause of death. Hepatitis C is currently the most common indication for liver transplantation in Canada; however, as a result of organ shortages up to 20 per cent of people with hepatitis C-related liver failure will die waiting for a liver transplant. In addition, hepatitis C-related cirrhosis leads to the development of liver cancer in up to 3 per cent of infected people per year.

Despite these concerning statistics, not all is doom and gloom for these baby boomers. Treatments for hepatitis C have made astounding breakthroughs through research over the past few years. Specifically, just recently Health Canada has approved 2 new therapies which, when combined with standard treatment protocols, can cure hepatitis C in up to 75 per cent of people infected with the most common type of hepatitis C in Canada. Unfortunately, these new therapies are very expensive, potentially limiting access to those infected and in need of treatment most. In Calgary we are fortunate to have a world leading Hepatitis Unit, located in the Snyder Institute of Chronic Disease at the University of Calgary, which has specialized expertise in the treatment of hepatitis C and its’ complications, providing those infected with leading edge hepatitis C care.

This column was written in response to a study from the US Centers for Disease Control and Prevention (CDC), published in the February 21 2012 issue of the Annals of Internal Medicine.
The research paper can be found here:

Chemo Brain: It is Real
Recently a colleague at work who had just returned from a getting a haircut mentioned to me that his hairdresser, who has lung cancer, was upset because her husband was very worried about her. The hairdresser explained that she had started having some memory problems - couldn't remember what she did yesterday or couldn't remember people's names. And she had started to tell her husband something and stopped in the middle of her story - not remembering what to say next. She too acknowledged being a little concerned and was seeing her doctor in 3 days, but she didn't know how to help her husband until then. I asked if she was receiving chemotherapy and was told yes, so I explained that she might have "chemo brain."

We've known for some time that radiation therapy to the brain can cause problems with thinking and memory. Now, we are learning that chemotherapy is linked to some of the same kinds of problems. Research has shown that some chemotherapy agents can cause certain kinds of changes in the brain. Though the brain usually recovers over time, the sometimes vague yet distressing mental changes cancer patients notice are real, not imagined. These changes can make people unable to go back to their school, work, or social activities, or make it so that it takes a lot of mental effort to do so. These changes affect everyday life for many people receiving cancer treatment.

Patients report the following symptoms:
  • Short-term memory lapse -- forgetting things that they usually have no trouble recalling
  • Trouble concentrating -- can't focus on what they're doing, have a short attention span, may "space out"
  • Trouble with word-finding, such as remembering names, not completing sentences, or not being able to think of a word
  • Trouble multi-tasking, like answering the phone while cooking, without losing track of one task
  • Taking longer to finish things-- slower thinking and processing
Doctors and researchers refer to these symptoms as a "mild cognitive impairment," but they're commonly called "chemo brain." For most people, chemo brain happens quickly and only lasts a short time. Others have long-term mental changes. Usually the changes that patients notice are very subtle, and others around them may not even notice any changes at all. Still, the people who are having problems are well aware of the differences in their thinking. Many people do not tell their cancer care team about this problem until it affects their everyday life.

What causes chemo brain?
Studies suggest that there may be more than one cause of chemo brain, especially for the short-term symptoms. Some people with cancer have very real brain problems even though they have not had chemotherapy. Still others notice problems when getting hormone treatments, such as estrogen blockers or androgen deprivation therapy. For some, problems start after surgery.
Along with chemotherapy, other health problems that might cause or worsen brain function include: the cancer itself; other drugs; patient age; stress; low blood counts; sleep problems; infection; depression; fatigue; hormone changes or hormone treatments; other illnesses, such as diabetes or high blood pressure; nutritional deficiencies; and anxiety or other emotional distress.
Most of these cause short-term problems, and get better as the underlying problem is treated or goes away. A few factors, such as depression, can cause long-lasting brain problems unless the cause is treated.

What can patients do about it?
So far, there is no way to prevent chemo brain while you are getting cancer treatment. For some people, treating their cancer will mean trouble with thinking, memory, planning, and word finding. If you are having symptoms, the first step is to discuss them with your cancer care team. They will consider what the underlying cause is, then help you identify some management strategies.
The following are steps that some patients have found helpful in managing their day-to-day living.
  • Write things down. Keep track of appointments and schedules, to-do lists, important dates, phone numbers and addresses.
  • Exercise your brain. Take a class, do word puzzles, or learn to do something new.
  • Exercise your body. Regular physical activity is good for your body; it improves your mood, makes you feel more alert, and helps you feel less tired.
  • Get enough rest and sleep.
  • Eat your veggies. Studies have shown that eating more vegetables can help you keep up your brain power.
  • Set up and follow routines. Put the things you often lose in the same place each time you're done with them. Try to keep the same daily schedule.
  • Give yourself permission to focus on one thing at a time.
  • Choose only those activities that are important to you and allow yourself plenty of time to complete tasks.
  • Consider use of relaxation techniques such as yoga or meditation.
  • Track your memory problems. Keep a diary of when you notice problems and the events that are going on at the time. Medicines taken, time of day, and where you are may help you figure out what affects your memory. Don't plan important tasks or events when your memory problems are worse.
  • Do not criticize yourself for not being able to remember. Accepting the problem will help you deal with it. Patients say that being able to laugh about things you can't control can help you cope. And remember, you probably notice your problems much more than others do.
Also, be sure to tell your family and friends what is going on with you. They will be relieved and will worry less. You are not crazy and you area not losing your mind. Chemo brain is real.

More research is needed

More research is needed so we can better understand chemo brain, but it is not easy to study. For example, researchers may use different tests to measure the problems with thinking and memory, so the results may not compare well with each other. Some people report changes that are so mild that their brain tests look normal and doctors don't have a good way to measure the changes.
There are also differences in when certain kinds of brain problems happen. Some researchers have tested brain function a few weeks after treatment, others months or even years later. If the problem only lasts a few weeks with no long-term changes, late testing can miss it. If the changes last more than a year but the testing stops after 6 months, no one knows how long they last. Another timing problem in studying chemo brain is that most studies didn't test the patients before treatment to compare to results after treatment.
In studies that did test before treatment, some people were seen to have brain function problems before treatment was even started. So it's possible that the cancer itself causes some of the problems, or that some other related problem (like anxiety about having cancer) caused brain function to decline. Studies are needed that test people before the treatment and then follow up to look for changes over time.
So, my colleague quickly called his hairdresser and said, "I want you to talk to this oncology nurse practitioner about your symptoms." And she agreed. I explained that her symptoms sounded like chemo brain. I could hear the relief in her voice. Of course she was planning to tell her doctor about her symptoms, but she was going home to tell her husband not to worry!
For more information about chemo brain and other chemotherapy side effects, , click here
Dr. Ades is director of cancer information for the American Cancer Society. Source

Researchers Find That Molecular Pair Controls Time-Keeping And Fat Metabolism
The 24-hour internal clock controls many aspects of human behavior and physiology, including sleep, blood pressure, and metabolism. Disruption in circadian rhythms leads to increased incidence of many diseases, including metabolic disease and cancer. Each cell of the body has its own internal timing mechanism, which is controlled by proteins that keep one another in check.

One of these proteins, called Rev-erb alpha, was thought to have a subordinate role because the clock runs fairly normally in its absence. New work, published in Genes and Development this month, from the lab of Mitchell Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine, University of Pennsylvania, found that a closely related protein called Rev-erb beta serves as a back-up for Rev-erb alpha. When both are not functioning, the cellular clock loses its time-keeping function.

The two Rev-erbs work together to control fat metabolism, and in their absence, the liver fills with fat. These findings establish the Rev-erbs as major regulators of both clock function and metabolism.
Lazar, postdoctoral fellow Anne Bugge, PhD, and the team knocked out Rev-erb alpha in mice and didn't see a large effect on the liver. When they knocked out both Rev-erb alpha and Rev-erb beta, they saw a loss of the rhythmic cycling of the clock protein Bmal 1's messenger RNA. They concluded that the Rev-erb system is an integral part of the human clock, not ancillary. 
Prior to this paper, the Lazar team discovered molecules that act as "shift workers" to maintain the daily rhythm of fat metabolism. When those molecules do not do their jobs, the liver also dramatically fills with fat. 

In normal mice, the team of molecules migrates to the genome of liver cells during the daytime. Rev-erb, one of the team members, delivers the molecular workers to thousands of specific locations in the liver genome, many of which are near genes involved in the production of fat. Another team member, histone deacetylase 3 (HDAC3), does construction work on the protein scaffold (the epigenome) surrounding the genome to dampen the activity of the fat-related genes.
During the night, the day shift molecules depart the liver genome, and fat production increases due to other regulatory molecules. The fat production is kept in check when the Rev-erb construction team returns to the genome the next day. However, if HDAC3 is absent, the cycles do not occur, and the liver fills with fat.

The absence of both Rev-erbs prevents HDAC3 from doing its job, since Rev-erbs serve as the shuttle delivering HDAC3 to target genes. Sure enough, fat accumulates in the liver to a much great extent when both Rev-erbs are missing compared to when one is still available. 
"This work shows that if we want to manipulate the human clock we would likely need to affect both Rev-erb alpha and Rev-erb beta," explains Lazar. "Circadian rhythm of metabolism is important because disruption of this rhythm leads to a fatty liver. This may explain, in part, why altered circadian rhythms in people who do shift work is associated with metabolic disorders."

Healthy You

Featured Article
UC Berkeley Wellness Letter, April 2012
April 2012  

Do You Really Need a Colonoscopy?
Other tests may be just as good and encourage more people to be tested

Screening for colorectal cancer—that is, cancers of the colon (large intestine) and rectum—is a proven lifesaver. This is partly due to the fact that this is one cancer which screening can actually prevent, since it can lead to the detection and removal of polyps, some of which may progress to cancer.

So why are anywhere from one-third to one-half of Americans over 50 not getting the recommended tests for colorectal cancer? One reason this screening rate lags behind those for some other cancers may be an overemphasis on colonoscopy as the screening test of choice in this country.

For years many experts, organizations and media spokespeople (such as Katie Couric) have promoted colonoscopy as the best colorectal screening test. As a result, it has become the most frequently used screening test for colorectal cancer in the U.S. Most doctors today do not even discuss alternatives with their patients.

Offering only colonoscopies discourages some people from getting tested, since they may dread the bowel-cleansing prep (clear liquid diet, strong laxatives and high fluid intake), are scared or embarrassed about the procedure itself, worry about potential complications and/or can’t afford its high price. Medicare and private insurance cover colonoscopy (and other screening tests), but that leaves out uninsured people, who are only half as likely to be screened for colorectal cancer as the insured.

Colonoscopy is a good test, though not perfect. You should know your other screening options as well. “Much more screening will be carried out if primary-care providers and the American public are not made to feel that screening tests other than colonoscopy are ineffective,” says Dr. James Allison, professor emeritus of medicine at the University of California, San Francisco, and a leading expert on colorectal cancer screening.

Colonoscopy: strengths and weaknesses
Colonoscopy examines the colon via a flexible scope that transmits the images to a video screen while the patient is sedated. The claim that it is the best screening option has been based on assumptions and expectations about what it can do—allow a doctor to examine the entire colon and rectum and remove polyps during the procedure. But colonoscopy’s superiority has never been proven in randomized controlled trials (the “gold standard”) comparing its effectiveness to other tests.

Other kinds of studies have suggested that colonoscopy (typically done every ten years if no cancer or polyps are found) doesn’t save more lives than sigmoidoscopy, which examines only the lower part of the colon and is usually done every five years. In some studies, sigmoidoscopy was combined with stool tests (see below). Two large randomized controlled studies comparing colonoscopy with stool tests are underway, but results won’t be available for years.

[Editor’s note: In February, shortly after this article went to press, a major study on colonoscopy was published in the New England Journal of Medicine. It confirmed that colonoscopy, by detecting and removing polyps, can prevent cancer and save lives. In fact, it cut the death rate from the disease by half. But the study was not a randomized controlled study, did not look at colonoscopy as a screening test for the general public, and didn’t compare it to stool tests or sigmoidoscopy. It included only people with polyps, some of which were detected by these other tests.]

One problem with colonoscopy is that it’s less effective in detecting polyps and cancer in the right side of the colon (the upper portion, including the ascending colon and cecum) than the left side. This is because many polyps and cancers in the right side are flat, pale and difficult to identify and remove completely. Also, bowel cleansing may be less complete in the right side of the colon, making detection more difficult there.

Other factors can also reduce colonoscopy’s accuracy. For instance, it tends to be less accurate when done comparatively quickly, by less experienced doctors (typically those who are not gastroenterologists) and/or when patients don’t prep adequately to empty the colon.

In addition, though colorectal cancer starts in certain adenomas and other polyps, the vast majority of polyps detected and removed (including most ademonas) are harmless. It’s estimated that 30 to 50 percent of Americans over 50 have or will develop adenomas, and that between 1 and 10 percent of these polyps will progress to cancer in 5 to 10 years.

Finally, colonoscopy poses a small—but not insignificant—risk of serious complications such as bleeding or colon perforation.

Sigmoidoscopy has some advantages over colonoscopy. It costs only a fraction as much, is quicker and can be done well by primary-care doctors. The prep is simpler, and sedation is usually not needed. But it too misses some cancers, especially since it can’t examine the upper portion of the colon. And if suspicious polyps are found, you’ll need a colonoscopy to remove them and check the upper colon.

Starting with stool
Not too long ago, annual stool tests were the primary way to screen for colorectal cancer in the U.S. In most countries they still are. Called fecal occult blood tests (FOBT), they detect hidden (“occult”) blood in stool, a possible sign of colorectal cancer. Your doctor gives you a kit to take home; you then provide one to three stool samples to be analyzed, depending on the type of FOBT. You’ll be referred for a colonoscopy if blood is detected.

The standard stool tests are called guaiac tests, named for the compound used on the test cards. The early versions have increasingly been replaced by more sensitive guaiac tests. However, they still often produce false-positive results because of blood that comes from something besides polyps or cancer; certain foods or medications (even vitamin C) can also throw off the results. And they miss some advanced polyps and cancers, especially those that don’t bleed or do so intermittently. That’s why screening should be done every year—repeated testing provides multiple opportunities to identify advanced polyps before they become malignant and early cancers before they become life-threatening.

A 2010 review paper in Gastroenterology concluded that annual highly sensitive FOBT is indeed effective at identifying colon cancer and reducing deaths from it. Because it is inexpensive, more people can afford FOBT, so it may save more lives than colonoscopy, according to some analyses. But FOBT is most effective only if people are compliant—take the test annually and do the follow-up tests when necessary.

A more advanced form of FOBT is the fecal immunochemical test (FIT), which is superior in several ways. For one thing, it requires only one stool sample. It is more accurate than standard FOBT because it identifies antigens in blood that may be in the stool, and it can’t be thrown off by food or medication. And it only detects blood originating in the colon or rectum. What’s more, the processing and reading of the test can be automated for quality assurance. Used primarily in Europe, Australia, Japan and Israel, FIT is being used more and more in the U.S., even though it is more expensive than standard stool tests.

Our advice
Everybody age 50 to 75 should be screened for colorectal cancer, whichever test they use. People at high risk—notably those with a family history, a known genetic risk, inflammatory bowel disease or certain other disorders—should start earlier.

Discuss the screening options with your doctor. Colonoscopy is not the only test—which is fortunate, since there aren’t enough skilled practitioners to screen all eligible people. Nor is it necessarily the best. All the tests have strengths and weaknesses, which you and your doctor need to weigh. Here are the options:

• Colonoscopy every 10 years, unless polyps have been found or you are at high risk, in which case more frequent testing will be needed. Despite that standard guideline, many people, especially those over 65, have colonoscopies repeated in less than seven years, even though there is no clear reason for them to repeat the exam that soon, according to a study in the Archives of Internal Medicine last year.

• Sigmoidoscopy every five years, along with stool tests (preferably FIT) every three years.

• Annual stool tests. Ask your doctor about FIT, or at least make sure you’re getting a highly sensitive FOBT.

• People at elevated risk or with a history of polyps and/or colon cancer should have colonoscopies—and perhaps FIT during the intervals.

Your doctor should consider your personal preferences. For instance, some people want to steer clear of colonoscopy because of its prep, invasiveness and/or cost. Others prefer colonoscopy because it usually needs to be done only once a decade rather than every year like stool tests, and it allows for the removal of polyps, if present. (It’s worth noting that some colon-cleansing preps and regimens are easier and still effective—we’ll discuss this in an upcoming issue.)

You can stop being screened after 75 if you’ve always had normal results and have no symptoms, and all screening should stop after age 85, according to federal guidelines. With increasing age, the benefits of screening decline, while the risks from sigmoidoscopy and especially colonoscopy increase.

Accompanying editorial by Dr. John Swartzberg:
Virtual reality

You may have heard of “virtual” (or CT) colonoscopy and wondered why we didn’t discuss it in our lead article. Many people are attracted to the idea because they dread the invasiveness of being “scoped.” With virtual colonoscopy, no colonoscope is inserted. Instead, the colon is visualized by a CT scan. It may sound like a great alternative, but it really isn’t.

Studies on virtual colonoscopy have had some promising results. One in the New England Journal of Medicine in 2008, for instance, found that the test is good at identifying larger polyps and cancer in people at average risk.

The advantages of virtual colonoscopy are obvious. No sedation is needed, the test is almost noninvasive (just a short tube is inserted in the rectum to inflate the colon), and there’s little or no risk of complications. So more people may be willing to undergo it.

But there are plenty of disadvantages as well. You still have to clean out your colon as you would before a regular colonoscopy. Moreover, the doctor can’t take a biopsy or remove polyps during the procedure. If polyps are found, a regular colonoscopy should be done to remove them (usually on another day, requiring another bowel prep). Virtual colonoscopy should be done every five years, rather than ten, because it may be less accurate. In particular, the test often misses smaller polyps. Medicare and most insurance plans won’t pay for it unless a conventional colonoscopy can’t be done for some reason.

Unlike regular colonoscopy, the virtual test can also detect suspicious growths outside the colon. That’s often promoted as a plus, but it probably isn’t. The overwhelming majority of such findings, sometimes called “incidentalomas,” are not cancer or are small cancers that will never cause harm. But their discovery leads to invasive procedures and, often, unnecessary treatments. And the key fact is, there’s no evidence that routine CT screening of other organs saves lives.

Another big drawback: Like any CT scan, virtual colonoscopy ex--poses you to radiation. That worries me because the test has to be repeated periodically, radiation exposure is cumulative, and Americans are already being exposed to increasing amounts of radiation from medical scans.

For these reasons, the U.S. Preventive Services Task Force, American College of Gastroenterology and American Cancer Society do not recommend virtual colonoscopy. We agree.

Ask the Experts
April 2012 Archive

Q: I take Tylenol PM to help me sleep. Are there any risks (such as liver damage) from taking it every day?

A: Yes. Such nighttime pain relievers contain a “first generation” antihistamine (usually diphenhydramine), which causes drowsiness. Unless you need a pain reliever, you’re better off skipping the Tylenol (acetaminophen) and just taking the antihistamine (such as Benadryl or a generic). That’s what’s in most OTC sleep aids (such as Sominex or Unisom).

Acetaminophen can indeed cause liver problems if taken in high doses and/or with alcohol. It’s easy to inadvertently get harmful amounts, since acetaminophen is found in many headache and cold/flu remedies and other over-the-counter drugs. It can also interact with certain other medications.

Nighttime pain relievers such as Advil PM and Motrin PM contain ibuprofen along with the antihistamine. Ibuprofen also has potential side effects, so don’t take it in a sleep aid unless you also need pain relief.

Moreover, antihistamines like diphenhydramine pose risks, especially for older people. They can reduce alertness, impair driving performance the next day (even if you don’t feel drowsy) and increase the risk of falls. They can also cause short-term memory problems. And in men who have an enlarged prostate, they can worsen urinary retention.

Tolerance to the antihistamine’s sedative effect can develop fairly quickly, so don’t take it for more than three or four nights in a row. If you need a sleep aid every night, you should talk to your doctor.

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