…can be found here, at the Cancer Research Blog Carnival.
Archive for Cancer
PRELUDE: THE PROBLEM WITH SCREENING
If there’s one aspect of science-based medicine (SBM) that makes it hard, particularly for practitioners, it’s SBM’s continual requirement that we adjust what we do based on new information from science and clinical trials. It’s not easy for patients, either. To lay people, SBM’s greatest strength, its continual improvement and evolution as new evidence becomes available, can appear to be inconsistency, and that seeming inconsistency is all too often an opening for quackery. Even when there isn’t an opening for quackery, it can cause a lot of confusion; some physicians are often resistant to changing their practice. It’s not for nothing that there’s an old joke in medical circles that no outdated medical practice completely dies until a new generation of physicians comes up through the ranks and the older physicians who believe in the practice either retire or die. There’s some truth in that. As I’ve said before, SBM is messy. In particular, the process of applying new science as the data become available to a problem that’s already as complicated as screening asymptomatic people for a disease in order to intervene earlier and, hopefully, save lives can be fraught with confusion and difficulties.
Certainly one of the most contentious issues in medicine over the last few years has been the issue of screening for various cancers. The main cancers that we most commonly subject populations to routine mass screening for include prostate, colon, cervical, and breast cancer. Because I’m a breast cancer surgeon, I most frequently have to deal with breast cancer screening, which means, in essence, screening with mammography. The reason is that mammography is inexpensive, well-tested, and, in general, very effective.
Or so we thought. Last week, yet another piece of evidence to muddle the picture was published in the New England Journal of Medicine (NEJM) and hit the news media in outlets such as the New York Times (Mammograms’ Value in Cancer Fight at Issue).
A critical aspect of both evidence-based medicine (EBM) and science-based medicine (SBM) is the randomized clinical trial. Ideally, particularly for conditions with a large subjective component in symptomatology, the trial should be randomized, double-blind, and placebo-controlled. As Kimball Atwood pointed out just last week, in EBM, scientific prior probability tends to be discounted while in SBM it is not, particularly for therapies that are wildly improbable strictly on the basis of basic science, but for both the randomized clinical trial remains, in essence, where the “rubber hits the road,” so to speak. Indeed, when the prior probability of a therapy working based on preclinical basic science investigations appears high, EBM and SBM should be (and are, for the most part) more or less indistinguishable.
The ethics of clinical trials, however, demand a characteristic known as clinical equipoise. Stated briefly, for purposes of clinical trials, clinical equipoise demands that at the time a clinical trial is being carried out there be a state of genuine scientific uncertainty in the medical community over which of the drugs or treatments being tested is more efficacious and safer. One reason (among many) why the Gonzalez trial was completely unethical was a lack of clinical equipose. (Lack of adequate informed consent was another.) Lack of clinical equipoise is also the reason why a prospective randomized, double-blind, placebo-controlled clinical trial testing an unvaccinated group versus a vaccinated control group to determine whether vaccines cause autism would be completely unethical. Such a trial would egregiously violate the principle of clinical equipoise because the unvaccinated group would be left unprotected against potentially life-threatening vaccine-preventable diseases, and that is completely unacceptable from an ethical perspective. Consequently, we have had to rely on on the accumulation of data from less rigorous trial designs to demonstrate that there is no correlation between vaccines and autism. Even so, the accumulated weight of such evidence is enough, and for some questions that is the best we can do because scientific rigor sometimes conflicts with human subjects research ethics. This is an extreme example of lack of clinical equipoise, but it illustrates the point. If we know (or have good scientific reason to suspect) that one treatment is better than another, it is unethical to randomize patients to the arm that receives what is, based on what is known at the time of the trial, likely to be an inferior treatment.
Sometimes, however, the question of whether clinical equipoise exists in a clinical trial is not so obvious as it is for trials proposed by cranks. This situation sometimes crops up in clinical trials for cancer. I was reminded of this issue by a front page story in the New York Times yesterday, New Drugs Stir Debate on Basic Rules of Clinical Trials. In it, reporter Amy Harmon uses a classic human interest story to highlight the issue of clinical equipoise in a clinical trial for a new drug for melanoma that shows great promise. In brief, it is the story of two cousins, one of whom is receiving the new “wonder drug” (whether it is truly a wonder drug or not remains to be seen) in a clinical trial and one of whom is receiving the current standard of care for stage IV melanoma, which, to put it bluntly, sucks in that it has very little effect in prolonging life:
Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 2
NB: If you haven’t yet read Part 1 of this blog, please do so now; Part 2 will not summarize it.
At the end of Part 1, I wrote:
We do not need formal statistics or a new, randomized trial with a larger sample size to justify dismissing the Gonzalez regimen.
In his editorial for the JCO, Mark Levine made a different argument:
Can it be concluded that [the] study proves that enzyme therapy is markedly inferior? On the basis of the study design, my answer is no. It is not possible to make a silk purse out of a sow’s ear.
That conclusion may be correct in the EBM sense, but it misses the crucial point of why the trial was (ostensibly) done: to determine, once and for all, whether there was anything to the near-miraculous claims that proponents had made for a highly implausible “detoxification” regimen for cancer of the pancreas. Gonzalez himself had admitted at the trial’s inception that nothing short of an outcome matching the hype would do:
DR. GONZALEZ: It’s set up as a survival study. We’re looking at survival.
SPEAKER: Do you have an idea of what you’re looking for?
DR. GONZALEZ: Well, Jeff [Jeffrey White, the director of the Office of Cancer Complementary and Alternative Medicine at the NCI—KA] and I were just talking a couple weeks ago. You know, to get any kind of data that would be beyond criticism is—-always be criticism, but at least three times.
You would want in the successful group to be three times — the median to be three times out from the lesser successful groups.
So, for example, if the average survival with chemo, which we suspect will be 5 months, you would want my therapy to be at least — the median survival to be at least 15, 16, 17 months, as it was in the pilot study.
We’re looking for a median survival three times out from the chemo group to be significant.
Recall that the median survival in the Gonzalez arm eventually turned out to be 4.3 months.
Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1
Background: the distinction between EBM and SBM
An important theme on the Science-Based Medicine blog, and the very reason for its name, has been its emphasis on examining all the evidence—not merely the results of clinical trials—for various claims, particularly for those that are implausible. We’ve discussed the distinction between Science-Based Medicine (SBM) and the more limited Evidence-Based Medicine (EBM) several times, for example here (I began my own discussion here and added a bit of formality here, here, and here). Let me summarize by quoting John Ioannidis:
…the probability that a research finding is indeed true depends on the prior probability of it being true (before doing the study), the statistical power of the study, and the level of statistical significance.
EBM, in a nutshell, ignores prior probability† (unless there is no other available evidence) and falls for the “p-value fallacy”; SBM does not. Please don’t bicker about this if you haven’t read the links above and some of their own references, particularly the EBM Levels of Evidence scheme and two articles by Steven Goodman (here and here). Also, note that it is not necessary to agree with Ioannidis that “most published research findings are false” to agree with his assertion, quoted above, about what determines the probability that a research finding is true.
The distinction between SBM and EBM has important implications for medical practice ethics, research ethics, human subject protections, allocation of scarce resources, epistemology in health care, public perceptions of medical knowledge and of the health professions, and more. EBM, as practiced in the 20 years of its formal existence, is poorly equipped to evaluate implausible claims because it fails to acknowledge that even if scientific plausibility is not sufficient to establish the validity of a new treatment, it is necessary for doing so.
Thus, in their recent foray into applying the tools of EBM to implausible health claims, government and academic investigators have made at least two, serious mistakes: first, they have subjected unwary subjects to dangerous but unnecessary trials in a quest for “evidence,” failing to realize that definitive evidence already exists; second, they have been largely incapable of pronouncing ineffective methods ineffective. At best, even after conducting predictably disconfirming trials of vanishingly unlikely claims, they have declared such methods merely “unproven,” almost always urging “further research.” That may be the proper EBM response, but it is a far cry from the reality. As I opined a couple of years ago, the founders of the EBM movement apparently “never saw ‘CAM’ coming.”
Given that it’s a holiday and I debated whether or not I even wanted to post anything today, I think I’ll keep things light and uncharacteristically brief today. After all, not every post can be like last week’s epic on Avastin or the week before’s epic on peer review. That’s a lot of work, and it is a holiday, after all. Besides, sometimes a perverse mood overtakes me, and I feel the need to go slumming.
Bring on Mike Adams.
Mike Adams, as regular readers may know, runs the website NaturalNews.com from deep in the jungles of Ecuador. His website is a one-stop shop, a repository if you will, of virtually every quackery known to humankind, all slathered with a heaping, helping of unrelenting hostility to science-based medicine and science in general. True, Mike Adams is not as big as, say, Joe Mercola, whose website, as far as I can tell, appears to draw more traffic than NaturalNews.com, but what Adams lacks in fame he makes up for in sheer crazy. If you don’t believe me, check out his latest hip-hop video Vaccine Zombie:
Personally, if I had anything to do with the Michael Jackson estate, I’d be suing for copyright infringement. Still, grudgingly, I have to admit that the animation is pretty good, although when Mike Adams raps, “‘Cause livin’ without a brain ain’t half bad,” I don’t think he realizes that he is apparently living proof of that. In fact, so full of crazy is Mike Adams, that there has even been disagreement among SBM bloggers over whether we should lower ourselves to deal with some of his loonier stuff. Guess which side I took?
The reason I argue that, even at the risk of wrestling the proverbial pig in mud, we should not shy away from taking on some of Mike Adams’ lunacy from time to time is because he illustrates certain aspects of the mindset that allows unscientific so-called “alternative” medicine to remain popular. Sometimes, articles on Adams’ website bring up the question of whether Adams really believes the utter nonsense he lays down or whether he is simply a scammer, much like Kevin Trudeau is a scammer, and doesn’t believe a word of it but has such contempt for his followers that he thinks nothing of lying to them to sell them whatever nostrums he’s hawking on his website. You’ll see what I mean in a minute. I hope.
On Friday, Adams decided to attack “America’s doctor” and a promoter of woo whom we have from time to time taken on here at SBM, Dr. Mehmet Oz because, of all things, Dr. Oz apparently underwent colonoscopy and was found to have a precancerous polyp. That this might have happened to him is not at all surprising given that Dr. Oz recently turned 50 and current guidelines recommend commencing screening by colonoscopy at age 50. Indeed, I’m only a couple of years from needing to submit to the same screening myself. In any case, Adams decided to write one of his patented screeds, entitled, Dr. Oz colon polyps raises question of “spontaneous disease” without cause. In it, he inadvertently reveals a lot about alt-med thinking, making it worth a brief discussion.
Adams starts out:
One of the most frustrating aspects of taking care of cancer patients is that in general, with only a few specific exceptions, we do not have good curative therapies for patients with stage IV cancer, particularly solid tumors. Consequently, patients with stage IV disease are viewed as “incurable” because, the vast majority of the time, they are incurable. Over the years, we have thrown everything but the kitchen sink at patients with stage IV disease, largely with dissapointing results. That’s not to say that the few specific exceptions to which I alluded are not a reason for hope. After all, patients with colorectal cancer and liver metastases used to have a median survival of around 6 months, but these days, with newer chemotherapeutic regimens like FOLFOX plus Avastin, median survival has more than tripled. While expecting to live less than two years is cold comfort to cancer patients with this particular clinical situation, the prognosis is far better than it was.
Of course, I specifically mentioned Avastin because it’s been in the news a lot recently with respect to my area of clinical specialty, breast cancer. Specifically, beginning in July there started appearing a spate of stories about the FDA considering revoking the approval of Avastin for advanced breast cancer based on recent studies that demonstrate that it does not prolong survival in these patients. Many lay people and patients find this reconsideration of Avastin to be quite puzzling, given that the drug was granted accelerated approval in 2008 and has since gone on to be used fairly widely. Given that the case of Avastin in breast cancer is rapidly becoming a classic case study of how messy science-based medicine can be when practiced in the public eye and debated among pharmaceutical companies, the government, and patient advocacy groups.
One of the main topics that we’ve covered here on this blog over the last couple of years is the relatively rapid, seemingly relentless infiltration of pseudoscience into what should be bastions of science-based medicine (SBM), namely medical schools and academic medical centers promoted by academics who should, but apparently don’t, know better. From the very beginning, we’ve written numerous posts about this infiltration and how it has been facilitated by a variety of factors, including changes in the culture of medical academia and our own culture in general, not to mention a dedicated cadre of ideologues such as the Bravewell Collaboration, whose purpose is to blur the lines between science and pseudoscience and promote the “integration” of quackery into science-based medicine. Certainly promoters of what Dr. Robert W. Donnell termed “quackademic medicine” wouldn’t put it that way, but I would. Indeed, promoters of quackademic medicine scored a major victory last month, when a credulous piece of tripe about acupuncture passing as a review article managed to find its way into the New England Journal Medicine, a misstep that was promptly skewered by Mark Crislip, Steve Novella, and myself. It’s rare for more than two of us to write about the same topic, but it was earned by a mistake as dire as the editors of the NEJM allowing rank pseudoscience to sully its normally science-based pages.
Today, I want to riff a bit on one aspect of this phenomenon. As a cancer surgeon, I’ve dedicated myself to treating patients with cancer and then subspecialized even further, dedicating myself to the surgical treatment of breast cancer. Consequently, the interface of so-called “complementary and alternative medicine” (CAM) in the treatment of cancer both interests and appalls me. The reason for my horror at the application of CAM to cancer patients, as you might expect, is that cancer is a disease that is highly feared and can be highly deadly, depending upon the specific kind of cancer. Cancer patients deserve nothing less than the best science-based evidence that we have to offer, free of pseudoscience. Yet in even the most highly respected cancer centers, such as M.D. Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, there are departments or divisions of what is increasingly called “integrative oncology.” The claim behind “integrative oncology” is that it is “integrating the best of science-based and ‘alternative’ medicine,” but in reality all too often it is “integrating” quackery with science-based medicine. I have yet to hear an explanation of how “integrating” pseudoscience or nonscience into science-based oncology benefits cancer patients, but, then, that’s probably just the nasty old reductionist in me. Let’s find out.
On the heels of Scott Gavura’s superb post yesterday on dietary supplement regulation in the US and Canada, I bring you one of the most egregious and obscene product cases I have seen in 15 years of teaching on botanical and non-botanical products: Miracle Mineral Solution. Please accept my apologies in advance for not having a scholarly post for you today – this is just too unbelievable not to share with Science-Based Medicine readers.
On July 30, the FDA released this warning:
FDA NEWS RELEASE
For Immediate Release: July 30, 2010
Media Inquiries: Elaine Gansz Bobo, 301-796-7567, [email protected]
Consumer Inquiries: 888-INFO-FDA
FDA Warns Consumers of Serious Harm from Drinking Miracle Mineral Solution (MMS)
Product contains industrial strength bleach
The U.S. Food and Drug Administration is warning consumers not to take Miracle Mineral Solution, an oral liquid also known as “Miracle Mineral Supplement” or “MMS.” The product, when used as directed, produces an industrial bleach that can cause serious harm to health.
The FDA has received several reports of health injuries from consumers using this product, including severe nausea, vomiting, and life-threatening low blood pressure from dehydration.
Consumers who have MMS should stop using it immediately and throw it away.
MMS is distributed on Internet sites and online auctions by multiple independent distributors. Although the products share the MMS name, the look of the labeling may vary.
The product instructs consumers to mix the 28 percent sodium chlorite solution with an acid such as citrus juice. This mixture produces chlorine dioxide, a potent bleach used for stripping textiles and industrial water treatment. High oral doses of this bleach, such as those recommended in the labeling, can cause nausea, vomiting, diarrhea, and symptoms of severe dehydration.
MMS claims to treat multiple unrelated diseases, including HIV, hepatitis, the H1N1 flu virus, common colds, acne, cancer, and other conditions. The FDA is not aware of any research that MMS is effective in treating any of these conditions. MMS also poses a significant health risk to consumers who may choose to use this product for self-treatment instead of seeking FDA-approved treatments for these conditions.
The FDA continues to investigate and may pursue civil or criminal enforcement actions as appropriate to protect the public from this potentially dangerous product.
The FDA advises consumers who have experienced any negative side effects from MMS to consult a health care professional as soon as possible and to discard the product. Consumers and health care professionals should report adverse events to the FDA’s MedWatch program at 800-FDA-1088 or online at www.fda.gov/medwatch/report.htm.
Over a year ago I wrote about The China Study, a book by T. Colin Campbell and his son based on a huge epidemiologic study of diet and health done in China. The book’s major thesis is that we could prevent or cure most disease (heart disease, cancer, diabetes, autoimmune diseases, bone, kidney, eye and other diseases) by eating a whole foods plant-based diet, drastically reducing our protein intake, and avoiding meat and dairy products entirely.
I noticed a number of things in the book that bothered me. I found evidence of sloppy citations, cherry-picked references, omission of data that contradicted the thesis, and recommendations that went beyond the data. I concluded:
He marshals a lot of evidence, but is it sufficient to support his recommendation that everyone give up animal protein entirely, including dairy products? I don’t think so.
The China Study involved 367 variables and 8,000 correlations. I said I would leave it to others to comment on the study design and the statistical analysis, and now someone has done just that. Denise Minger devoted a month and a half to examining the raw data to see how closely Campbell’s claims aligned with the data he drew from; she found many weaknesses and errors. (more…)