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Archive for Clinical Trials

The Trial to Assess Chelation Therapy: Equivocal as Predicted

The ill-advised, NIH-sponsored Trial to Assess Chelation Therapy (TACT) is finally over. 839 human subjects were randomized to receive Na2EDTA infusions; 869 were randomized to receive placebo infusions. The results were announced at this weekend’s American Heart Association meeting in Los Angeles. In summary, the TACT authors report a slight advantage for chelation over placebo in the “primary composite endpoint,” a combination of five separate outcomes: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina:

 

Although that result may seem intriguing, it becomes less so when the data are examined more carefully. First, it barely achieved the pre-ordained level of statistical significance, which was P=.036. Second, none of the individual components of the composite endpoint achieved statistical significance, and most of the absolute difference was in coronary revascularization–which is puzzling:

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Posted in: Clinical Trials, Health Fraud, Medical Ethics, Politics and Regulation, Science and Medicine

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NIH funds training in behavioral intervention to slow progression of cancer by improving the immune system

Editor’s note: Because of Dr. Gorski’s appearance at CSICon over the weekend, he will be taking this Monday off. Fortunately, Dr. Coyne will more than ably substitute. Enjoy!

 

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NIH is funding free training in the delivery of the Cancer to Health (C2H) intervention package, billed as “the first evidence-based behavioral intervention designed to patients newly diagnosed with cancer that is available for specialty training.” The announcement for the training claims that C2H “yielded robust and enduring gains, including reductions in patients’ emotional distress, improvements in social support, treatment adherence (chemotherapy), health behaviors (diet, smoking), and symptoms and functional status, and reduced risk for cancer recurrence.” Is this really an “empirically supported treatment” and does it reduce risk of cancer recurrence?

Apparently the NIH peer review committee thought there was sufficient evidence fund this R25 training grant. Let’s look at the level of evidence for this intervention, an exercise that will highlight some of the pseudoscience and heavy-handed professional politics in promoting psychoneuroimmunological (PNI) interventions.

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Posted in: Clinical Trials, Science and Medicine

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The Placebo Gene?

A study recently published in PLOS one (Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome) purports to have found a gene variant that correlates strongly with a placebo response in irritable bowel syndrome (IBS). The study is small and preliminary, but the results are interesting and do raise important questions about placebo responses.

Researchers are increasingly trying to tease apart the various components of “the placebo effect.” In reality we should use the term “placebo effects” as it is demonstrably multifactorial. “The placebo effect” really refers to whatever is measured in the placebo arm of a clinical trial – everything other than a physiological response to an active intervention. Within that measured response there are many potential factors that would cause an outcome from a fake treatment to be different from no treatment at all. These include statistical effects like regression to the mean and the natural course of symptoms and illness, reporting bias on the part of the subject, and a non-specific response to the therapeutic interaction with the practitioner.

It is also critical to realize that placebo responses vary greatly depending on the disease or symptom that is being treated and the outcome that is being measured. Placebo response is greatest for subjective symptoms of conditions that are known to be modified by things like mood and attention, while it is virtually non-existent for objective outcomes in pathological conditions. So there is a substantial placebo response for pain and nausea, but nothing significant for cancer survival.

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Posted in: Clinical Trials

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Chinese Systematic Reviews of Acupuncture

I’ll begin with the possibly shocking admission that I’m a strong supporter of the collection of ideas and techniques known as evidence-based medicine (EBM). I’m even the current President of the Evidence-Based Veterinary Medicine Association (EBVMA). This may seem a bit heretical in this context, since EBM  takes a lot of heat in this blog. But as Dr. Atwood has said, “we at SBM are in total agreement…that EBM “should not be without consideration of prior probability, laws of physics, or plain common sense,” and that SBM and EBM should not only be mutually inclusive, they should be synonymous.” So I have hope that by emphasizing the distinction between SBM and EBM and the limitations of EBM, we can engender the kind of changes in approach needed to address those limitations and eliminate the need for the distinction. One way of doing this is to critically evaluate the misuses of EBM in support of alternative therapies.

One of the highest levels of evidence in the hierarchy of evidence-based medicine is the systematic review. Unlike narrative reviews, in which an author selects those studies they consider relevant and then summarizes what they think the studies mean, which is a process subject to a high risk of bias, a systematic review identifies randomized controlled clinical trials according to an explicit and objective set of criteria established ahead of time. Predetermined criteria are also used to grade the studies evaluated by quality so any relationship between how well studies are conducted and the results can be identified. Done well, a systematic review gives a good sense of the balance of the evidence for a specific medical question.

Unfortunately, poorly done systematic reviews can create an strong but inaccurate impression that there is high-level, high-quality evidence in favor of a hypothesis when there really isn’t. Reviews of acupuncture research illustrate this quite well.

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Posted in: Acupuncture, Clinical Trials

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Mouse “avatars”: New predictors of response to chemotherapy?

Over the years, I’ve written a lot about “personalized medicine, mainly in the context of how the breakthroughs in genomic medicine and data pouring in from the Cancer Genome Atlas is providing the raw information necessary for developing truly personalized cancer therapy. The problem, of course, is analyzing it and figuring out how to apply it. Another problem, of course, is developing the necessary targeted drugs to attack the pathways that are identified as being dysregulated in cancer cells. Oh, and there’s that pesky evolution of resistance to antitumor therapies. Indeed, most recently, the Cancer Genome Atlas is bearing fruit in breast cancer (a study that I’ve been meaning to blog about).

One problem with modeling the pathways based on next generation sequencing data and expression profiling is testing whether therapies predicted to work from these analyses actually do work without actually testing potentially toxic drugs on patients. Cell culture is notoriously unreliable as a predictor. However, there is another way that’s intriguing. Unfortunately, as intriguing as it is, it has numerous problems, and, unfortunately, it’s being prematurely marketed to patients. Although I had heard of this technique as a research tool before, I learned about its marketing to patients when I came across an article by Andrew Pollack in the New York Times entitled Seeking Cures, Patients Enlist Mice Stand-Ins. Basically, it’s about a trend in science and among patients to use custom, “personalized’ mouse xenograft models in order to do “personalized” therapy:
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Posted in: Basic Science, Cancer, Clinical Trials, Diagnostic tests & procedures

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News flash! Doctors aren’t all compliant pharma drones!

There’s an oft-quoted saying that’s become a bit of a cliché among skeptics that goes something like this: There are two kinds of medicine: medicine that’s been proven scientifically to work, and medicine that hasn’t. This is then often followed up with a rhetorical question and its answer: What do call “alternative medicine” that’s been proven to work? Medicine. Of course, being the kind of guy that I am, I have to make it a bit more complicated than that while driving home in essence the same message. In my hands, the way this argument goes is that the whole concept of “alternative” medicine is a false dichotomy. There is no such thing. In reality, there are three kinds of medicine: Medicine that has been shown to efficacious and safe (i.e., shown to work); medicine that has not yet been shown to work (i.e., that is unproven); and medicine that has been shown not to work (i.e., that is disproven). So-called “complementary and alternative medicine” (CAM or, its newer, shinier name, “integrative medicine”) consists almost completely of the latter two categories.

Part of the reason why this saying and its variants have become so commonplace among those of us who support science-based medicine is that they strike at a common truth about medicine, both science-based and “alternative.” That common truth is what we here at SBM have been arguing since the very inception of this blog, namely that there must be one science-based standard of evidence for all treatments, be they “alternative” or the latest creation of big pharma. That point informs everything I write here and everything my blogging parters in crime write about too. What that means is a single, clear set of standards for evaluating medical evidence, in which clinical evidence is coupled to basic science and scientific plausibility. Indeed, one of our main complaints against CAM and its supporters has been how they invoke a double standard, in which they expect their therapies to be accepted as “working” on the basis of a much lower standard of evidence. Indeed, when they see high quality clinical trials demonstrating that, for example, acupuncture doesn’t work, they will frequently advocate the use of “pragmatic” trials, lower quality trials of “real world effectiveness” that do not adequately control for placebo effects. It’s putting the cart before the horse.
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Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

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Is shameless self-promotion of your science a good idea?

As part of my ongoing effort to make sure that I never run out of blogging material, I subscribe to a number of quack e-mail newsletters. In fact, sometimes I think I’ve probably overdone it. Every day, I get several notices and pleas from various wretched hives of scum and quackery, such as NaturalNews.com, Mercola.com, and various antivaccine websites. I think of it as my way of keeping my finger on the pulse of the antiscience and pseudoscience wing of medicine, but I must admit that I don’t really read them all, but they do allow me to know what the quacks are selling and what new arguments they’re coming up with without actually going to each of their websites. I can then judge by the headlines and the blurbs included in the e-mails whether I think it’s worth it to go to the website itself and, of course, whether the topic might represent fodder for a good blog post. I will admit that not all the sites I monitor are as loony as the Health Ranger’s. In fact, I monitor the blogs and websites of the National Center for Complementary and Alternative Medicine (NCCAM), various naturopath organizations, and the like in order to learn of the “respectable” arguments being used to tout various nostrums.
Sometimes—albeit rarely—I even learn about some interesting new science.

One of the most common themes (besides antivaccine hysteria, claims that diet can prevent 95% of all cancers, etc.) tends to be one of a variety of pitches for various “cures” of serious diseases like cancer and heart disease that “they” don’t want you to know about; i.e., the Kevin Trudeau gambit. Who this “they” is can range from doctors to pharmaceutical companies to universities to the government, but the central message is that someone out there doesn’t want you to know The Truth. A variation of this sort of appeal is the claim that there is a promising new therapy, a cure even, usually natural, that is languishing somewhere because it can’t be patented, because pharmaceutical companies would lose money if it were ever validated and brought into clinical use, or because it goes against current medical dogma. It doesn’t even have to be natural. After all, dichloroacetate (DCA) is not exactly “natural.” After it was shown to have promise in animal models, a pesticide salesman named Jim Tassano sold DCA bought from chemical companies to desperate cancer patients from a website that claimed to be selling it only for pets with cancer, a ruse that fooled no one. Yet the “natural treatment” crowd embraced it whole-heartedly because it looked as though sellers of DCA were sticking it to The Man.
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Posted in: Basic Science, Cancer, Clinical Trials

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Alternative medicine use and breast cancer (2012 update)

[Editor's note: It's a holiday here in the U.S.; consequently, here is a "rerun" from my other super not-so-secret other blog. It's not a complete rerun. I've tweaked it a bit. If you don't read my other blog, it's new to you. If you do, it's partially new to you. See you all next week with brand spankin' new material. It also (Ih hope) complement's Scott's excellent post from Thursday discussing the same issue and the same paper, but from a different perspective.]

As a cancer surgeon specializing in breast cancer, I have a particularly intense dislike reserved for cancer quacks, which I have a hard time containing at times when I see instances of such quackery applied to women with breast cancer. I make no apologies. These women are, after all, the type of patients I spend all my clinical time taking care of and to whose disease my research has been directed for the last 13 years or so. That’s why I keep revisiting the topic time and time again. Unfortunately, over the years, when it comes to this topic there’s been a depressing amount of blogging material. Indeed, Scott Gavura took a bite out of this particularly rotten apple just a few days ago. Even though he handled the discussion quite well, I thought it would be worthwhile for a breast cancer clinician to take a look. Our perspectives are, after all, different, and this is an issue that, from my perpective, almost can’t be discussed too often.

One question that comes up again and again is, “What’s the harm?” Basically, this question boils down to asking what, specifically, is the downside of choosing quackery over science-based medicine. In the case of breast cancer, the answer is: plenty. The price of foregoing effective therapy can be death; that almost goes without saying. In fact, it can be a horrific and painful death. It is, after all, cancer that we’re talking about. Aside from that, however, the question frequently comes up just how much a woman decreases her odds of survival by avoiding conventional therapy and choosing quackery. It’s actually a pretty hard question to answer. The reason is simple. It’s a very difficult topic to study because we as physicians have ethics. We can’t do a randomized trial assigning women to treatment or no treatment, treatment or quacke treatment, and then see which group lives longer and by how much. If a person can’t see how unethical that would be without my having to explain it, that person is probably beyond explanations. (As an aside, I can’t help but point out that a randomized trial of not vaccinating versus vaccinating is unethical for exactly the same reason; physicians can’t knowingly assign subjects to a group where he knows they will suffer harm. There has to be clinical equipoise.) There’s no doubt that foregoing effective treatment causes great harm.
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Posted in: Cancer, Clinical Trials, Health Fraud

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Related by coincidence only? University and medical journal press releases versus journal articles

There are certain topics in Science-Based Medicine (or, in this case, considering the difference between SBM and quackery) that keep recurring over and over. One of these, which is of particular interest to me because I am a cancer surgeon specializing in breast cancer, is the issue of alternative medicine use for cancer therapy. Yesterday, I posted a link to an interview that I did for Uprising Radio that aired on KPFK 90.7 Los Angeles. My original intent was to do a followup post about how that interview came about and to discuss the Gerson therapy, a particularly pernicious and persistent form of quackery. However, it occurred to me as I began to write the article that it would be better to wait a week. The reason is that part of how this interview came about involved three movies, one of which I’ve seen and reviewed before, two of which I have not. In other words, there appears to be a concerted effort to promote the Gerson therapy more than ever before, and it seems to be bearing fruit. In order to give you, our readers, the best discussion possible, I felt it was essential to watch the other two movies. So discussion of the Gerson protocol will have to wait a week or two.

In the meantime, there’s something else that’s been eating me. Whether it’s confirmation bias or something else, whenever something’s been bugging me it’s usually not long before I find a paper or online source to discuss it. In this case, it’s the issue of why scientific studies are reported so badly in the press. It’s a common theme, one that’s popped upon SBM time and time again. Why are medical and scientific studies reported so badly in the lay press? Some would argue that it has something to do with the decline of old-fashioned dead tree media. With content all moving online and newspapers, magazines, and other media are struggling to find a way to provide content (which Internet users have come to expect to be free online) and still make a profit. The result has been the decline of specialized journalists, such as science and medical writers. That’s too easy of an answer, though. As is usually the case, things are a bit more complicated. More importantly, we in academia need to take our share of the blame. A few months ago, Lisa Schwartz and colleagues (the same Lisa Schwartz who with Steven Woloshin at Dartmouth University co-authored an editorial criticizing the Susan G. Komen Foundation for having used an inappropriate measure in one of its ads) actually attempted to look at how much we as an academic community might be responsible for bad reporting of new scientific findings by examining the relationship between the quality of press releases issued by medical journals to describe research findings by their physicians and scientists and the subsequent media reports of those very same findings. The CliffsNotes version of their findings is that we have a problem in academia, and our hands are not entirely clean of the taint of misleading and exaggerated reporting. The version as reported by Schwartz et al in their article published in BMJ entitled Influence of medical journal press releases on the quality of associated newspaper coverage: retrospective cohort study. It’s an article I can’t believe I missed when it came out earlier this year.
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Posted in: Clinical Trials, Medical Academia, Science and the Media

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The perils and pitfalls of “patient-driven” clinical research

Dying of cancer can be a horrible way to go, but as a cancer specialist I sometimes forget that there are diseases that are equally, if not more, horrible. One that always comes to mind is amyotropic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease. It is a motor neuron disease whose clinical course is characterized by progressive weakness, muscle atrophy and spasticity, with ultimate progression to respiratory muscles leading to difficulty breathing and speaking (dysarthria) and to the muscles controlling swallowing. The rate of clinical course is variable, often beginning with muscle twitching in an arm or a leg or slurring of speech. Ultimately, however, ALS progresses to the loss of ability to move, speak, eat, or breathe. The most common cause of death is from respiratory failure, usually within three to five years after diagnosis, although there is the occasional outlier with a less malignant form of the disease with a slower course of progression who can live a long time, such as Steven Hawking.

In other words, ALS is a lot like cancer in some ways. It is a progressive, fatal disease that usually kills within a few years at most. On the other hand, it is different from cancer in that, at least for many cancers we actually do have effective treatments that prolong life, in some cases indefinitely. In contrast the most effective treatment we currently have for ALS is a drug (riluzole) that is not particularly effective—it prolongs life by months—and can be best described as better than nothing, but not by a whole lot. So it is not surprising that ALS patients, like cancer patients, become desperate and willing to try anything. This is completely understandable, but sometimes this desperation leads to activities that are far more likely to do harm than good. I was reminded of this when I came across a post in the antivaccine propaganda blog, Age of Autism, referring to an article in The Scientist entitled Medical Mavericks. The fortuitous posting of this story, which was apparently designed to try to show that it’s not as crazy as critics have said to be treating autistic children with “Miracle Mineral Solution” (MMS) (which is a bleach) given that the introduction explicitly mentioned Kerri Rivera and the patient described in the article used sodium chlorite to treat his ALS, provided me the opening to discuss a group whose existence and advocacy brings up a complex tangle of issues that boil down to questions of how far patient autonomy should be allowed to go. I’m referring to a company, PatientsLikeMe, which describes itself thusly:
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Posted in: Cancer, Clinical Trials, Neuroscience/Mental Health

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