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Do over one in five breast cancers detected by mammography alone really spontaneously regress?

ResearchBlogging.orgIt figures.

Last Wednesday, right before the four-day Thanksgiving holiday weekend, as I was far more interested in preparing to have family over the next day than in what was going on in the medical news or the blogs, the results of a most fascinating study hit the news. In Medscape, the title of the news report was Mammography Study Suggests Some Breast Cancer May Spontaneously Regress; on WebMD, the story ran under the title Can Breast Cancer Disappear?; on Medical News Today, Mammograms May Identify Cancers That Would Otherwise Just Regress by Drs. Per-Henrik Zahl, Jan Maehlen, and H. Gilbert Welch. Not surprisingly, the study found its way out of the medical news and into mainstream media outlets as well, given how provocative the findings seemingly are. From the Medscape report on this study:

A mammography study from Norway has come up with the controversial proposal that one fifth of breast cancer detected on screening may spontaneously regress. But there is no easy way to verify whether this is the case, say experts.

The study was published in the November 24 issue of the Archives of Internal Medicine. It found that the cumulative incidence of invasive breast cancer in a cohort of women, aged 50 to 64 years, who received 3 mammograms over 6 years was 22% higher than in a control group of age-matched women who received only 1 mammogram at the end of a 6-year period.

In their review of possible explanations for the difference in the breast cancer rates between the 2 groups — which had similar risk factors for breast cancer — the researchers write that the “natural course for some screen-detected breast cancers may be to spontaneously regress.”

“I anticipate that many clinicians will react negatively to the possibility of spontaneous regression, said coauthor Jan Maehlen, MD, PhD, professor of pathology at the Ulleval University Hospital, in Oslo, Norway, in an interview with Medscape Oncology.

Before I discuss the study itself, let me briefly discuss why clinicians may have a bit of a problem with the implications of this study, if they accurately reflect the biology of breast cancer.
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Posted in: Cancer, Clinical Trials, Diagnostic tests & procedures, Science and the Media

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The “Gonzalez Trial” for Pancreatic Cancer: Outcome Revealed

A Review

Dr. Lipson’s “detoxification” post on Thanksgiving Day and Dr. Gorski’s recent post about “Gerson Therapy” were timely, because last weekend I noticed something that I should have noticed months ago. Before delivering the punch line, let me remind you, Dear Reader, of the nature of the topic. The regimen advocated by Nicholas Gonzalez is a variation of a “detoxification” treatment for cancer that has been around, in one form or another, for more than 50 years (“Gerson Therapy” is another example).† Here is the National Cancer Institute’s (NCI) description:

Patients receive pancreatic enzymes orally every 4 hours and at meals daily on days 1-16, followed by 5 days of rest. Patients receive magnesium citrate and Papaya Plus with the pancreatic enzymes. Additionally, patients receive nutritional supplementation with vitamins, minerals, trace elements, and animal glandular products 4 times per day on days 1-16, followed by 5 days of rest. Courses repeat every 21 days until death despite relapse. Patients consume a moderate vegetarian metabolizer diet during the course of therapy, which excludes red meat, poultry, and white sugar. Coffee enemas are performed twice a day, along with skin brushing daily, skin cleansing once a week with castor oil during the first 6 months of therapy, and a salt and soda bath each week. Patients also undergo a complete liver flush and a clean sweep and purge on a rotating basis each month during the 5 days of rest.

As unlikely as it may seem, in 1999 American taxpayers began paying for people with cancer of the pancreas to be subjected to that regimen, in a trial sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) and the NCI, conducted under the auspices of Columbia University. Gonzalez provided the treatments. A few months ago I presented a multi-part treatise on the “Gonzalez regimen” and the trial. It demonstrated that all evidence, from basic science to clinical, including the case series that supposedly provided the justification for the trial, had failed to support any real promise (the case series had previously been considered by reader Dr. Peter Moran, who also found them wanting).

It showed that the impetus for the trial, as has been true for other regrettable trials of implausible health claims, can be traced not to science but to the reactionary politics of anti-intellectual populism: initially to Laetrile and to the “Harkinites,” and more recently to the Honorable Dan Burton (R-IN). It reported that there were major problems with the Gonzalez trial from the outset, and that for at least one subject the regimen was more torture than therapy. It reported that for unclear reasons the trial had come to a halt a couple of years ago, and that it appeared that there would never be a report of its findings.

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Posted in: Cancer, Clinical Trials, Medical Academia, Medical Ethics, Politics and Regulation

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NCCAM: the not-even-wrong agency

The National Center for Complementary and Alternative Medicine (NCCAM) is a government agency tasked with (among other things), “[exploring] complementary and alternative healing practices in the context of rigorous science.” In this space we have talked about NCCAM quite a bit, but I have to admit that I don’t think about them very much. The other day, though, I was reading though JAMA and I came across a study funded by the agency. The study, which showed that Ginkgo does not prevent Alzheimer’s-type dementia, was pretty good, so I cruised on over to NCCAM’s website to see what else they’ve been up to.

A quick glance at NCCAM’s front page:

    “Ginkgo Evaluation of Memory (GEM) Study Fails To Show Benefit in Preventing Dementia in the Elderly”
    “CAM and Hepatitis C: A Focus on Herbal Supplements ‘No CAM treatment has yet been proven effective for treating hepatitis C or its complications.’”
    “Selenium and Vitamin E in Prostate Cancer Prevention Study, ‘selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer.’”

It seems that NCCAM is finding out something we already strongly suspected:  improbable medical claims are usually wrong.  Since that’s not how they see things,  and since I don’t believe that there is such a thing as alternative medicine, I was curious how they defined CAM.

CAM is a group of diverse medical and health care systems, practices, and products that are not presently considered to be part of conventional medicine. Conventional medicine is medicine as practiced by holders of M.D. (medical doctor) or D.O. (doctor of osteopathy) degrees and by their allied health professionals, such as physical therapists, psychologists, and registered nurses. Some health care providers practice both CAM and conventional medicine. While some scientific evidence exists regarding some CAM therapies, for most there are key questions that are yet to be answered through well-designed scientific studies–questions such as whether these therapies are safe and whether they work for the diseases or medical conditions for which they are used.

The list of what is considered to be CAM changes continually, as those therapies that are proven to be safe and effective become adopted into conventional health care and as new approaches to health care emerge. emphasis mine, ed.

The list of NCCAM studies appears to fall into three broad categories.

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Posted in: Clinical Trials, Politics and Regulation, Science and Medicine

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On the dangers of using valid placebo controls in clinical trials of acupuncture

ResearchBlogging.orgI don’t recall if I’ve ever mentioned this before on this blog, but there was a time when I was less skeptical of acupuncture than I am now. It’s true. Don’t get me wrong, though. I never for a minute considered that the whole rigamarole about “unblocking” or “redirecting” the flow of that mystical life force known as qi had anything to do with whether or not acupuncture did or did not have efficacy treating disease or other conditions. That was clearly a holdover from the pre-scientific medicine times in which most beliefs about the causes of disease involved either the wrath of the gods or vitalism, the latter of which is, when you come right down to it, the philosophical basis upon which many “complementary and alternative” (CAM) modalities are based, especially the so-called “energy healing” modalities, such as reiki, therapeutic touch, and, of course, acupuncture.

However, because unlike so many other “energy healing” methods, acupuncture involved an actual physical action upon the body, namely the insertion of thin needles into the skin to specified depths, it did not seem to me entirely unreasonable that there might be some sort of physiological effect that might produce a therapeutic result. At least, that’s what I used to think until I actually started paying attention to the scientific literature on acupuncture. That’s when I started to realize that “there’s no ‘there’ there,” if you know what I mean. Horribly designed studies with either no controls or utterly inadequate controls tend to be the norm in the acupuncture “literature” (if you can call it that). Moreover, acupuncture was touted as having value for conditions and procedures for which there is no plausible (or even mildly plausible) physiological mechanism by which it could be reasonably postulated to have an effect. Arthritis, allergies, headache, back pain, gastroesophageal reflux disease (GERD), Parkinson’s disease, post-operative nausea, hot flashes in breast cancer patients caused by the anti-estrogen drugs they have to take, infertility, it doesn’t matter. Seemingly acupuncture can do it all; it’s the Swiss Army knife of CAM therapies. Moreover, the “explanations” given to explain “how acupuncture works” seemed increasingly less plausible to me. Most of these explanations involve counterirritation or the release of opioids, and I’ve had an increasingly hard time believing that, even if these mechanisms are at play, they could have anything other than nonspecific effects, with no mechanism to explain how acupuncture could possibly do all things attributed to it. One rule of medical skepticism is that you should be very skeptical of modalities that are touted to be useful for a wide variety of medical conditions that have very different pathophysiology. Indeed, a funny thing happens when rigorous placebo controls are introduced, and that’s sometimes the placebo control does better than the “true” acupuncture; i.e., the evidence for acupuncture, taken in its totality, is completely compatible with placebo effect.

As Harriet Hall put it in her excellent analysis of a study purporting to show that acupuncture is useful for GERD:

This study falls into the category of what I call Tooth Fairy science. You could measure how much money the Tooth Fairy leaves under the pillow, whether she leaves more cash for the first or last tooth, whether the payoff is greater if you leave the tooth in a plastic baggie versus wrapped in Kleenex. You can get all kinds of good data that is reproducible and statistically significant. Yes, you have learned something. But you haven’t learned what you think you’ve learned, because you haven’t bothered to establish whether the Tooth Fairy really exists.

One area that acupuncturists keep needling away at is infertility. Somehow, in the CAM community it’s become conventional wisdom that acupuncture can somehow increase the chance of success for couples undergoing in vitro fertilization (IVF). Indeed, early this year I wrote about a meta-analysis that concluded that acupuncture did actually increase the success rate of IVF and why it did not show what its authors thought it showed. Tooth fairy science, indeed.

Now comes yet another study being publicized in the media that examines once again the question of whether sticking needles into women before they undergo IVF can increase their chances of conceiving. I could not help but be extremely amused by the title given to the ScienceDaily story about it: Placebo Acupuncture Is Associated With Higher Pregnancy Rate After IVF Than Real Acupuncture. You have to love a headline like that, and opening paragraphs like this:
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Posted in: Acupuncture, Clinical Trials, Medical Academia, Science and the Media

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Vitamin Cocktail with a Meme Twist (Supplement my gimlet with a dash of dissonance)

A trail of recent reports is trying to tell us something. But are we listening, and are “they” listening? If so, does it mean the same to “them” as it does to us?

The report trail is telling us that multiple vitamins fail as preventatives against cardiovascular disease, cancer, or even for anything other than for dietary vitamin deficiency. And that is what we were saying in the first place – forty and more years ago.

Here is a partial list of these recent reports –  followed by an odd turn

Vitamins E and C were ineffective in preventing `cardiovascular disease in men. Sesso HD, Buring JE, Christen WG et al. JAMA, 2008;300 (Physicians’ Health Study II, mong 14,641 male physicians. [...] The study participants were randomized to receive 400 IU of vitamin E every other day or a placebo and 500 mg of vitamin C daily or a placebo.

B Vitamins (B12, B6, folate) May Not Reduce Cardiovascular Events For Coronary Artery Disease Patients Ebbing M, et al, JAMA 2008, Aug 20 — In a large clinical trial involving patients with coronary artery disease, use of B vitamins B6, B12, folate was not effective for preventing death or cardiovascular events. Patients were randomly assigned to one of four groups receiving a daily oral dose of one of the following treatments: folic acid, 0.8mg, plus vitamin B12 , 0.4mg, plus vitamin B6 , 40mg (n= 772); folic acid plus vitamin B12 (n = 772); vitamin B6 alone (n = 772); or placebo (n = 780).The study was stopped early because of concerns among the participants about preliminary results from another similar Norwegian study suggesting no benefits from the treatment and an increased risk of cancer from the B vitamins. Daily supplementation combination that included folic acid and vitamin B6 and B12 had no significant effect on the overall risk of cancer, including breast cancer, among women at high risk of cardiovascular disease. Zhang M et al, JAMA 2008 Nov. 5.

Certain Vitamin Supplements May Increase Lung Cancer Risk, Especially In Smokers. November 11, 2008, from American Thoracic Society. March of the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Selenium and vitamin E supplements, taken either alone or together, did not prevent prostate cancer; these results came from initial, independent review of study data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), funded by the National Cancer Institute. (publication  Feb. 1 in the Journal of Clinical Oncology.)

These reports, along with those showing inefficacy of vitamin E in CV prevention and others, all in recent months, dovetail on more reported over the past decade. Now for the dissonance. A popular Web portal posted a brief questionnaire following one of last week’s reports. It asked readers to answer if they took vitamins regularly, infrequently, or not at all.
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Posted in: Cancer, Clinical Trials, Health Fraud, Herbs & Supplements, Nutrition, Politics and Regulation

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Statins Are Better on JUPITER

Over 26 million Americans are taking statin drugs. Some people think they should be available over-the-counter without a prescription, and it has even been facetiously suggested that they should be added to our drinking water. The protective effect of statins in cardiovascular disease and in high-risk patients with high cholesterol levels is well established. But what about people with no heart disease and normal cholesterol levels – can they benefit too?

The New England Journal of Medicine has pre-released an important new study on statins online prior to its planned publication date of November 20, 2008. It is certain to stir up a lot of controversy, and the International Network of Cholesterol Skeptics will not be happy, because it contradicts some of their favorite arguments. They have claimed that statins do more harm than good, that reducing cholesterol levels is harmful to health, that the benefits of statins and/or cholesterol lowering do not extend to women and the elderly, and that studies showing benefits of statins are meaningless because they do not show reduction of overall mortality. This study indicates otherwise. (more…)

Posted in: Clinical Trials, Pharmaceuticals

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When Further Research Is NOT Warranted: The “Wisdom of Crowds” Fallacy

Most scientific research studies have at least one thing in common: the conclusion section ends with, “further research is warranted.” I’d say it’s about as common as the “talk to your doctor” disclaimer in TV ads for pharmaceutical products. And in a way, they both serve the same purpose. They’re a “CYA” move.

What does “further research is warranted” mean in plain English? I think it can be roughly translated: “My research study is not of the size or scope to fully explain all the phenomena described in this article. Therefore, draw conclusions beyond the data and study methods at your own risk. And yeah, my work is important and cool – so people should study it further.”

Of course, the first two sentences are reasonable – we should always remember not to draw conclusions beyond the information provided by the data we’ve collected (even though that’s about as challenging as getting a beagle not to eat a table scrap in an empty room). The real problem is the third sentence. Is the research promising enough to require further investment? How are we to know if further research is indeed warranted? I would argue that it should not be based solely on the subjective opinions of the researchers nor the popularity of the research topic to the general public. (more…)

Posted in: Clinical Trials, Science and Medicine

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Interpreting the Medical Literature

The science in science-based medicine includes all of science, but relies most heavily on the biomedical literature – published studies that collectively represent our scientific medical knowledge. The scientific basis of medicine is only as good as this body of knowledge and the manner in which it is interpreted and put into practice.

We often discuss on this blog how to evaluate individual studies- the need for blinding, randomization, the importance of study size to meaningful statistical analysis, and other features that distinguish a reliable study from a worthless one. This is important, but only half of the equation. We also at times discuss the medical literature as it relates to a specific medical question or set of related questions – does homeopathy work or are statins beneficial for cholesterol reduction, for example. This requires not only the ability to judge individual studies, but a higher order analysis of the overall pattern of evidence among all relevant studies. Failure to do this, by focusing only on individual studies, results in the failure to see the forest for the trees.

It is this higher order analysis that I wish to discuss in this entry.

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Posted in: Clinical Trials, Science and Medicine

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Getting It On with Homeopathy

I have more thoughts on the homeopathy matter than fit in follow-up notes, so here goes.

First, David Gorski recalls the 1994 Pediatrics report on childhood diarrhea treated with tailored homeopathic remedies for each patient. There is more to the story than has been written. I am certain much of this will get back to the authors, but others may benefit from knowing how this group of homeopaths operate.

I recall the paper well, because it was the first journal report that I deconstructed and published (Pediatrics, Oct 1995) as a regular article. I think it was the first time the journal had published a formal rebuttal outside the Letters section. The head of pediatric pharmacy at Valley Medical Center, San Jose, brought the paper to me and asked what I thought if it. Bill London of National Council against Health Fraud and I spent six months discussing it and working over the details.

The paper had so many flaws, that one letter could not contain them. It had five or six end points, several arithmetical errors, graphs with missing data, only one end point reached consensus signficance (barely.)

Each case received a remedy tailored to the age, condition, duration of symptoms, appearance and odor of the stool, the recall of the parent or relative about stool frequency (which depended on how often the child’s diapers were changed, and a number of other qualities, typical of a homeopathic approach to diagnosis. The remedies given were not based on etiology, but based on personal observations, We saw that the remedy was chosen at a snapshot in time, depending on all those factors which varied from hour to hour. So the remedies depended on the time at which the child was brought in for examination and were unchanged throughout the duration of illness. That made no sense at all. Besides, the specific remedies had no data behind them for proof of efficacy, and were chosen on basis of charts and computer references.

One could hardly find anything about the paper that would lend credibility to its conclusion that suggested homeopathy “worked“ better than placebo. The results in our opinion demonstrated nothing more than the variations in the clinical trial system (noise.)
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Posted in: Clinical Trials, Homeopathy, Science and Medicine

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Massage for AIDS

ResearchBlogging.orgI recently learned of a study entitled “Dominican Children with HIV not Receiving Antiretrovirals: Massage Therapy Influences their Behavior and Development.” It disturbed me, and I couldn’t get it out of my head. They’re massaging these kids but letting them die of AIDS? I went back and read the complete article, and it left me even more disturbed.

They studied 48 Dominican children ages 2-8 with untreated HIV/AIDS, randomizing them to receive twice weekly sessions of either massage or play therapy for 12 weeks. The abstract said that those in the massage group improved in self-help abilities and communication, and that children over the age of 6 showed a decrease in depressive/anxious behaviors and negative thoughts. That’s what the abstract said. The text revealed a more complex story. (more…)

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