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“Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part II: Loose Ends)

Last week I discussed the dismal results of the “Gonzalez Trial” for cancer of the pancreas,* as reported in an article recently posted on the website of the Journal of Clinical Oncology. I promised that this week I’d discuss “troubling information, both stated and unstated [in the report],” and also some ethical issues. More has come to light in the past few days, including Nicholas Gonzalez’s own voluminous, angry response to the JCO article. I’ll comment upon that below, but first a brief review.

The trial was begun in 1999 under the auspices of Columbia University, after Rep. Dan Burton had pressured NCI Director Richard Klausner to fund it. It was originally conceived as a randomized, controlled trial comparing the “Gonzalez Regimen” to standard chemotherapy for cancer of the pancreas. In the first year, however, only 2 subjects had been accrued, purportedly because those seeking Gonzalez’s treatment were not willing to risk random assignment to the chemotherapy arm. In 2000, the protocol was changed to a “prospective, cohort study” to allow potential subjects to choose which treatment they would follow. Gonzalez himself was to provide the ‘enzyme’ treatments.

After that there was little public information about the trial for several years, other than a few determination letters from the Office of Human Research Protections and a frightening account of the experience of one subject treated by Gonzalez. By 2006 or so, those of us who pay attention to creeping pseudomedicine in the academy were wondering what had become of it. About a year ago we found out: the trial had been quietly “terminated” in 2005 after it met “pre-determined stopping criteria.” As explained here, that meant that the Gonzalez group had not fared well.

Four years after the trial’s ‘termination,’ the report was finally published: The Gonzalez cohort had not only fared much worse than the cohort that received chemotherapy, but it had fared worse than a comparable group of historical controls. Here, again, is the survival graph from the JCO paper:

Snapshot 2009-09-11 16-16-15

The Gonzalez group had also fared much worse in ‘quality of life’ scores, which included a measure of pain.

Now let’s read between the lines. Forgive me for taking shortcuts; I’m a little pressed for time. (more…)

Posted in: Clinical Trials, Health Fraud, Herbs & Supplements, Medical Academia, Medical Ethics, Science and Medicine, Science and the Media

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Tom Harkin, NCCAM, health care reform, and a cancer treatment that is worse than useless

ResearchBlogging.orgPRELUDE: SOME BAD NEWS FOR ADVOCATES OF SCIENCE-BASED MEDICINE

It was a bad week for science-based medicine. It was a good week (sort of) for science-based medcine.

First the bad.

There has been a development that anyone who supports science in medicine and opposes quackery will likely find disturbing. Do you remember Senator Tom Harkin (D-IA)? We’ve written about him extensively over the last several months on this blog. First of all, he is the man most responsible for the creation of that government-sanctioned, government-funded bastion of pseudoscience, the National Center for Complementary and Alternative Medicine. He’s also one of the men most responsible for the Dietary Supplement Health and Education Act (DSHEA) of 1994, which has done more to protect the supplement industry from making dubious health claims than any other piece of federal legislation. More recently, Harkin has made a name for himself in the health care reform debate currently ongoing by inviting advocates of “integrative” medicine (IM), which in essence integrates quackery and the pseudoscientific with scientific medicine, to Capitol Hill as a means of trying to persuade his fellow legislators to include a CAM/IM version of “wellness” care as part of any bill that might pass this fall. In essence, he is trying to hijack any health care reform bill to include government sanction of unscientific medicine. Meanwhile, he has been chastising NCCAM because it hasn’t “validated” enough “alternative medicine” for his taste. (Actually, it’s validated none, because virtually none of it is likely to be valid.)

This is the man who, according to reports, will almost certainly be taking over the chair of the Senate Committee on Health, Education, Labor, and Pensions (HELP) after the death of its former chair, Senator Edward Kennedy. This committee is among the most important for government health policy and will be in the thick of the final negotiations and battles over any health care reform that may arise from Congress this fall.

The existence of powerful supporters of pseudoscience in the highest eschelons of government has real consequences. As I’ve described before, NCCAM, being based entirely on studying highly–even ridiculously implausible–notions about disease and how to treat it, has resulted in the infiltration of quackery into academia, where ideas once rightly dismissed as quackery are respectfully given deference and studied as though they were anything other than Tooth Fairy science, a process that Dr. R. W. Donnell has amusingly termed “quackademic medicine.” One result was the expenditure of $30 million on an unethical, poorly designed, and corrupt trial of chelation therapy for cardiovascular disease. Another result was an even more unethical trial of an even more scientifically implausible remedy for a deadly cancer. Although the fact that the trial was even done is a horror, at least last week we finally found out the results, which had been suppressed for nearly four years, namely that this protocol is not just useless, but worse than useless. It’s a Pyrrhic victory for science-based medicine and cold comfort to patients with pancreatic cancer who may have continued to use this protocol during those four years, but at least we finally know.

Let’s take a look at the study. But first, a little background.
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Posted in: Cancer, Clinical Trials, Politics and Regulation

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“Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part I: Results)

ResearchBlogging.org

Review

One of the more bizarre and unpleasant “CAM” claims, but one taken very seriously at the NIH, at Columbia University, and on Capitol Hill, is the cancer “detoxification” regimen advocated by Dr. Nicholas Gonzalez:

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.

Veteran SBM readers will recall that in the spring of 2008 I posted a series of essays* about this regimen and about the trial that compared it to standard treatment for subjects with cancer of the pancreas. The NIH had funded the trial, to be conducted under the auspices of Columbia, after arm-twisting by Rep. Dan Burton [R-IN], a powerful champion of quackery, and much to the delight of the “Harkinites.”

In the fall of 2008 I posted an addendum based on a little-known determination letter that the Office for Human Research Protections (OHRP) had sent to Columbia during the previous June. The letter revealed that the trial had been terminated in October, 2005, due to “pre-determined stopping criteria.” This demonstrated that Gonzalez’s regimen must have been found to be substantially worse than the current standard of care for cancer of the pancreas, as ineffective as that standard may be. I urge readers who require a review or an introduction to the topic to read that posting, which also considered why no formal report of the trial had yet been made available.

Now, finally, the formal report has been published online by the Journal of Clinical Oncology (JCO):

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Posted in: Cancer, Clinical Trials, Health Fraud, Herbs & Supplements, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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“There must be a reason,” or how we support our own false beliefs

ResearchBlogging.orgFor a change of pace, I want to step back from medicine for this post, although, as you will see (I hope), the study I’m going to discuss has a great deal of relevance to the topics covered regularly on this blog. One of the most frustrating aspects of being a skeptic and championing science-based medicine is just how unyielding belief in pseudscience is. Whatever realm of science in which there is pseudoscience I wander into, I find beliefs that simply will not yield to science or reason. Whether it be creationism, quackery such as homeopathy, the anti-vaccine movement, the “9/11 Truth” movement, moon hoaxers, or any of a number of pseudoscientific movements and conspiracy theories, any skeptic who ventures into discussions of such a topic with believers will become very frustrated very fast. It takes a lot of tenacity to keep going back to the well to argue the same points over and over again and refute the same nonsense you’ve refuted over and over again. Many do not have sufficient stick-to-it-iveness, leading them to throw up their hands and withdraw from the fight.

Although some of us here have blamed this phenomenon on “cultishness” and, make no mistake, I do think that there is an element of that in many of these movement, particularly the anti-vaccine movements, cultishness alone can’t explain why people hold on so hard to beliefs that are clearly not supported by science or evidence, such as the belief that vaccines are responsible for an “autism epidemic.” Then last week, what should pop up in the newsfeeds that I regularly monitor but a rather interesting article in Science Daily entitled How We Support Our False Beliefs. It was a press release about a study1 that appeared a few months ago in Sociological Inquiry, and the the study was described thusly:
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Posted in: Clinical Trials, Politics and Regulation, Science and Medicine, Vaccines

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The perils and pitfalls of doing a “vaccinated versus unvaccinated” study

The anti-vaccine movement is nothing if not plastic. It “evolves” very rapidly in response to selective pressures applied to it in the form of science refuting its key beliefs. For instance, when multiple studies looking at the MMR vaccine and autism failed to confirm the myth that the MMR causes autism or “autistic enterocolitis,” most recently late last year, it was not a problem to the anti-vaccine movement. Neither was it a major problem to the movement when multiple studies similarly failed to find a link between mercury in the preservative thimerosal that used to be in most childhood vaccines and is no more (except the flu vaccine) and autism. No problem! Andrew Wakefield is alleged, based on strong evidence, to have falsified his data alleging a link between the MMR vaccine and “autistic enterocolitis”? Fuggedabouddit! The anti-vaccine movement simply pivoted neatly, de-emphasized points that the evidence was so clearly against that even they couldn’t spin it to a positive anymore, and found new bogeymen. These days, it’s the “toxins” (such as formaldehyde and the latest antivax bogeyman, squalene), and “too many too soon” (a gambit given seeming respectability by Dr. Bob Sears and Dr. Jay Gordon, apologists for and supplicants to the anti-vaccine movement both.

However, there is one trait of the anti-vaccine movement that, however its camouflaging plumage may evolve, never, ever changes. It is as immutable as believers say that God is. That trait is that, whatever other claims, the anti-vaccine movement makes, at its core it is always about the vaccines. Always. No matter how often science fails to find a link between vaccines and autism or vaccines and whatever other horreur du jour the anti-vaccine movement tries to pin on vaccines, no matter how many studies do not support the viewpoint that vaccines cause autism, no matter how much the anti-vaccine movement tries to deny and obfuscate by saying that it is not “anti-vaccine” but rather “pro-safe vaccine,” at its core the anti-vaccine movement is about fear and loathing of vaccines. Always. When inconvenient science doesn’t support their views, anti-vaccine activists either ignore the science, distort the science, or launch ad hominems against the people doing the science or citing the science. And, as I said before, the claims of the anti-vaccine movement evolve. Never again will the anti-vaccine movement make the horrific mistake of yoking itself to a hypothesis that is as easily testable as the hypothesis that mercury in vaccines causes autism. The claim that mercury in vaccines causes autism predicted that, if thimerosal were removed from vaccines or reduced to pre-”epidemic levels” of the early 1990s, then autism rates should plummet. Thimerosal was removed from nearly all childhood vaccines (the sole exception being some flu vaccines), reducing infant mercury exposure from vaccines to levels not seen since the 1980s; yet autism rates continue to rise. This is about as resounding a refutation of the hypothesis that mercury in vaccines is a major cause or contributor to autism that even the anti-vaccine movement has backed away from the pure claim, which has now evolved to unnamed “environmental toxins,” either in concert with mercury or with other nasty things, as being the Real One True Cause of Autism.

It’s evolution in action. These new claims are much “fitter” because they are much harder to falsify through scientific research, epidemiology, and clinical trials.
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Posted in: Clinical Trials, Medical Ethics, Public Health, Science and Medicine, Vaccines

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Needles in the skin cause changes in the brain, but acupuncture still doesn’t work

ResearchBlogging.orgI don’t recall if I’ve mentioned it on SBM before, but I went to the University of Michigan. In fact, I didn’t go there just for undergraduate studies or medical school, but rather for both, graduating with a B.S. in Chemistry with Honors in 1984 and from medical school in 1988. In my eight years in Ann Arbor, I came to love the place, and I still have an affinity for it, even though it’s been over 20 years since I last walked about the campus as a student, although I have been back from time to time for various functions, most recently to see Brian Deer speak last winter. True, I’m not fanatical about it, as some of my contemporaries and friends who attened U. of M. with me back in the 1980s (and, sadly, the string of losses to Ohio State and the definitively mediocre last season Michigan had last year make it very hard to be a Michigan football fan these days). However, I do have considerable affection for the place. It molded me, trained me in science, taught me medicine, and provided me the basis for everything I do professionally today.
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Posted in: Acupuncture, Clinical Trials, Medical Academia, Science and the Media

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Vertebroplasty for compression fractures due to osteoporosis: Placebo medicine

If there’s one thing we emphasize here on the Science-Based Medicine blog, it’s that the best medical care is based on science. In other words, we are far more for science-based medicine, than we are against against so-called “complementary and alternative medicine” (CAM). My perspective on the issue is that treatments not based on science need to be either subjected to scientific scrutiny if they have sufficient prior plausibility or strong clinical data suggesting efficacy or abandoned if they do not.

Unfortunately, even though the proportion of medical therapies not based on science is far lower than CAM advocates would like you to believe, there are still more treatments in “conventional” medicine that are insufficiently based on science or that have never been validated by proper randomized clinical trials than we as practitioners of science-based medicine would like. This is true for some because there are simply too few patients with a given disease; i.e., the disease is rare. Indeed, for some diseases, there will never be a definitive trial because they are just too uncommon. For others, it’s because of what I like to call medical fads, whereby a treatment appears effective anecdotally or in small uncontrolled trials and, due to the bandwagon effect, becomes widely adopted. Sometimes there is a financial incentive for such treatments to persist; sometimes it’s habit. Indeed, there’s an old saying that, for a treatment truly to disappear, the older generation of physicians has to retire or die off.

That is why I consider it worthwhile to write about a treatment that appears to be on the way to disappearing. At least, I hope that’s what’s going on. It’s also a cautionary tale about how the very same sorts of factors, such as placebo effects, reliance on anecdotal evidence, and regression to the mean, can bedevil those of us dedicated to SBM just as much as it does the investigation of CAM. It should serve as a warning to those of us who might feel a bit too smug about just how dedicated to SBM modern medicine is. Given that the technique in question is an invasive (although not a surgical technique), I also feel that it is my duty as the resident surgeon on SBM to tackle this topic. On the other hand, this case also demonstrates how SBM is, like the science upon which it is based, self-correcting. The question is: What will physicians do with the most recent information from very recently reported clinical trials that clearly show a very favored and lucrative treatment does not work better than a placebo?

Here’s the story that illustrates these issues, fresh from the New York Times this week:
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Posted in: Clinical Trials, Science and Medicine, Surgical Procedures

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Are one in three breast cancers really overdiagnosed and overtreated?

ResearchBlogging.orgScreening for disease is a real pain. I was reminded of this by the publication of a study in BMJ the very day of the Science-Based Medicine Conference a week and a half ago. Unfortunately, between The Amaz!ng Meeting and other activities, I was too busy to give this study the attention it deserved last Monday. Given the media coverage of the study, which in essence tried to paint mammography screening for breast cancer as being either useless or doing more harm than good, I thought it was imperative for me still to write about it. Better late than never, and I was further prodded by an article that was published late last week in the New York Times about screening for cancer.

If there’s one aspect of medicine that causes more confusion among the public and even among physicians, I’d be hard-pressed to come up with one more contentious than screening for disease, be it cancer, heart disease, or whatever. The reason is that any screening test is by definition looking for disease in an asymptomatic population, which is very different from looking for a cause of a patient’s symptoms. In the latter case, the patient is already being troubled by something that is bothering him. There may or may not be a cause in the form of a disease or syndrome that is responsible for the symptoms, but the very existence of the symptoms clues the physician in that there may be something going on that requires treatment. The doctor can then narrow down range of possibilities for what may be the cause of the patient’s symptoms by taking a careful history and physical examination (which will by themselves most often lead to the diagnosis). Diagnostic tests, be they blood tests, X-rays, or other tests, then tend to be more confirmatory of the suspected diagnosis than the main evidence supporting a diagnosis.
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Posted in: Cancer, Clinical Trials, Diagnostic tests & procedures, Public Health, Science and Medicine, Science and the Media

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The clinician-scientist: Wearing two hats

About a week ago, Tim Kreider wrote an excellent post about the differences between medical school training and scientific training. As the only other denizen of Science-Based Medicine who has experienced both worlds, that of a PhD and that of an MD, and as the one who two decades further along the path than Tim (give or take a couple of years), his musings reminded me of similar musings I’ve had over the years, as well as emphasizing yet again something I’ve said time and time again: Most physicians are not scientists. They are not trained like scientists; they are trained to apply scientific knowledge to the care of their patients. That’s what science-based medicine is, after all, applying science to the care of patients. Not dogma. Not tradition. Not knowledge of antiquity. Science.

Leave dogma, tradition, and “ancient knowledge” to practitioners of “alternative medicine.” That’s where they all belong. Whether you want to call it “alternative medicine,” “complementary and alternative medicine” (CAM), or “integrative” medicine (IM), it rarely changes and almost never abandons therapies that science finds to be no better than placebo, whereas scientific medicine is, as it should be, ever changing, ever improving. I’ll grant you that the process is often messy. There are often false starts and blind alleys, and physicians are all too often reluctant to change their practices in response to the latest scientific findings. We sometimes even joke that for some practices, it takes the supplanting of one generation of physicians with a new generation to get rid of some practices. But change does come when the science and evidence are there. Indeed, for example, in response to evidence that a bacterium, H. pylori, causes duodenal ulcers, medical practice changed in a mere decade, which is about as fast as anyone could do the science and clinical trials to show the validity of the new concept. Although CAM practitioners like to hold up the example of Barry Marshall and Robin Warren, the researchers who discovered that H. pylori causes most duodenal ulcers, as an example of how researchers with radical ideas are ostracized, but that story is largely a myth, as our very own Kim Atwood showed.

The application of science to medicine is a difficult thing. It takes basic scientists and clinicians, but the two of them exist in different worlds. Or so it often seems. That’s why some individuals seek to straddle both worlds. Tim is one such person. So am I. Unfortunately, most people don’t understand what we do very well. We wear two hats. In my case, I’m a surgeon, and I’m a scientist. In Tim’s case, he’s a scientist and a physician, but he doesn’t yet know what kind of physician he will end up being. At the risk of sounding somewhat arrogant, I believe that we, and others like us, represent an important element in bridging the gap between basic science and clinical science, in, essentially, building a more science-based medicine.
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Posted in: Basic Science, Clinical Trials, Medical Academia

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NIH Awards $30 Million Research Dollars To Convicted Felons: Cliff’s Notes Version

In case you’re coming late to this discussion (or have ADD), I’ve summarized Dr. Kimball Atwood’s terrific analysis of the ongoing clinical trial (TACT trial) in which convicted felons were awarded $30 million by the NIH.

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In one of the most unethical clinical trial debacles of our time, the NIH approved a research study (called the TACT Trial – Trial to Assess Chelation Therapy – a supposed treatment for arteriosclerosis) in which the treatment had no evidence for potential benefit, and clear evidence of potential harm – and even the risk of death. Amazingly, the researchers neglected to mention this risk in their informed consent document. The NIH awarded $30 million of our tax dollars to ~100 researchers to enroll 2000 patients in this risky study (ongoing from 2003-present). Even more astounding is the fact that several of the researchers have been disciplined for substandard practices by state medical boards; several have been involved in insurance fraud; at least 3 are convicted felons.

But wait, there’s more.

The treatment under investigation, IV injection of Na2EDTA, is specifically contraindicated for “generalized arteriosclerosis” by the FDA. There have been over 30 reported cases of accidental death caused by the administration of this drug – and prior to the TACT, 4 RCTs and several substudies of chelation for either CAD or PVD, involving 285 subjects, had been reported. None found chelation superior to placebo.

So, Why Was This Study Approved?

The NIH and the TACT principal investigator (PI) argued that there was a substantial demand for chelation, creating a “public health imperative” to perform a large trial as soon as possible. In reality, the number of people using the therapy was only a small fraction of what the PI reported.

It’s hard to know exactly what happened “behind the scenes” to pressure NIH to go forward with the study – however a few things are clear: 1) the National Heart, Lung, and Blood Institute (NHLBI) initially declined to approve the study based on lack of scientific merit 2) congressman Dan Burton and at least one of his staffers (Beth Clay) and a lobbyist (Bill Chatfield) worked tirelessly to get the study approved through a different institute – NCCAM 3) some of the evidence used to support the trial was falsified (The RFA cited several articles by Edward McDonagh, the chelationist who had previously admitted in a court of law to having falsified his data.) 4) The NIH Special Emphasis Panel that approved the TACT protocol included L. Terry Chappell, whom the protocol had named as a participant in the TACT.

All evidence seems to suggest that political meddling managed to trump science in this case – putting the lives of 2000 study subjects at risk, without any likely benefit to them or medicine.

A formal analysis of the sordid history and ethical violations of the TACT trial was published by the Medscape Journal of Medicine on May 13, 2008. Atwood et al. provide a rigorous, 9-part commentary with 326 references in review of the case. Congressman Burton’s staffer, Beth Clay, published what is essentially a character assassination of Dr. Atwood in response.

The NIH Writes TACT Investigators a Strongly Worded Letter

On May 27, 2009 the Office for Human Research Protections Committee sent a letter to the investigators of TACT, stating that they found, “multiple instances of substandard practices, insurance fraud, and felony activity on the part of the investigators.” The letter describes a list of irregularities and recommends various changes to the research protocol.

It is almost unheard of for a letter from the NIH to state that research study investigators are guilty of fraud and felony activity – but what I don’t understand is why they haven’t shut down the study. Perhaps this is their first step towards that goal? Let’s hope so.

Conclusion

The TACT trial has subjected 2000 unwary subjects and $30 million of public money to an unethical trial of a dubious treatment that, had it been accurately represented and judged by the usual criteria, would certainly have been disqualified. Political meddling in health and medical affairs is dangerous business, and must be opposed as strongly as possible. Congressmen like Tom Harkin and Dan Burton should not be allowed to push their political agendas and requests for publicly funded pseudoscience on the NIH. I can only hope that the new NIH director will have the courage to fend off demands for unethical trials from political appointees.

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

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