White Coat Underground

Why does plausibility matter? Because bad medicine kills

Posted by PalMD on September 9, 2009
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ResearchBlogging.orgIn the latest conversation about placebos, Steve Silberman got a number of things just right, including these converse statements:

Anthracyclines don’t require an oncologist with a genial bedside manner to slow the growth of tumors.

…the placebo response has limits. It can ease the discomfort of chemotherapy, but it won’t stop the growth of tumors.

Placebo, if it exists as a utile clinical entity (and I’m still not convinced) cannot cure cancer—but chemotherapy can, no matter what hand waving and chanting may or may not accompany it. This goes directly to the concept of “plausibility”. Let me explain.

One of the criticisms of evidence-based medicine, the system of evidence and trials we use to determine what does and does not work, is that it often fails to take into account the plausibility of an intervention. This is what Dr. Harriet Hall calls “tooth fairy science”. A very well-designed trial may, with great statistical significance and reproducibility, determine the average reimbursement for a bicuspid, the average age of children visited by the fairy, the most common perfume worn by the Winged One—but if you fail to examine the assumption that the tooth fairy actually exists, you’ve wasted a lot of time and effort.

When the same thing happens in human medicine, people can die.

The reasons for not bothering to test implausible medical claims are twofold: positive results are statistically likely to be false positives (cf Bayes Theorem), and subjecting people to implausible treatments is dangerous and unethical. Enter the Gonzalez Trial.

The definitive blog posts on the topic are a Science-based Medicine. If you want some depth, go there and read Dr. Atwood’s work. What I’m going to give you is a summary of the topic, and the results of a recent study.

The Gonzalez regimen is a proposed therapy for pancreatic cancer.  For some reason, NCCAM decided to put this regimen head-to-head with standard chemotherapy.  Our gold standard therapy for pancreatic cancer is not great.  Stage IV pancreatic cancer has a five-year survival rate of 1.8%.  Reading the NCCAM summary of the Gonzalez regimen is like watching COPS—you’re horrified, but you just can’t turn away.  There are many problems, but the most fundamental is the complete implausibility.  It is based on a long-discredited hypothesis about cancer that erroneously connects embryonic trophoblast cells with pancreatic development (don’t ask, you’ll just get a headache).  The regimen relies on various forms of detoxification:

Two major concepts underlie use of the Gonzalez regimen in cancer treatment. The first concept is that the pancreas, like the liver, is an organ that performs a detoxification function and that pancreatic enzymes help the body eliminate toxins and help normal cells repair damaged cells.[2] The second concept is that cancer and most other human illness are related to physiological imbalances created by environmental toxins either consumed in food or contacted in the environment.

Cancer is fundamentally a genetic disease.  What Dr. Gonzalez may or may not understand is that there is a difference between what causes cancers, and what cancers actually are.  Sometimes cancers can be caused by toxic substances.  For example, certain chemicals can cause changes to a cell’s DNA that effectively render it cancerous.  This is not reversible.  As the cell divides, it produces more cancer cells.  The only way to get rid of them is to surgically excise them or kill them with various types of cytotoxic or radiation therapy.  If you have a cancer that was caused by an environmental toxin, it’s too late to remove the toxin—the damage is done.

This is only one of the many reasons that the Gonzalez regimen is implausible, but the fact that it is not even plausible makes it a very foolish thing to study clinically.  Aside from the clinical and ethical considerations, the fact that it is so implausible means that any positive results of a clinical study are likely due to chance or bias and not an effect of the regimen.

But in this study, there were no positive results.  Of the 55 unfortunate people who were ultimately enrolled in the study,  most patients did not live very long—pancreatic cancer is a lousy disease.  But the patients in the Gonzalez group lived on average 4.7 months, while those in the chemo group lived on average 14 months.  But, you may ask, if the chemo patients lived 9 months longer, might they not have suffered 9 months longer?

No.  Quality of life, including pain, was significantly worse in the Gonzalez group. 

This study will likely go down in history as one of the least ethical clinical studies ever conducted.  It took patients with a bad disease and compared an effective science-based therapy with a completely implausible fake therapy.  There was never any good justification for doing this study, and it reflects poorly not just on the investigators but on all of NCCAM.

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Chabot JA, Tsai WY, Fine RL, Chen C, Kumah CK, Antman KA, & Grann VR (2009). Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PMID: 19687327

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Comments

  1. #1 Dianne
    September 9, 2009

    Actually, unless I’m misreading the abstract (I’m tired and am not at work so can’t get full text), 9.7 months was the difference between median survival for patients taking chemo and those taking the Gonzales regimen. Median survival for chemotherapy was 14 months. So I think you may have actually underestimated the efficacy of chemo (which is admittedly still poor in pancreatic cancer.) This was not a randomized trial: patients were offered the choice of Gonzales regimen versus chemo, which arguably makes it less unethical but does call into question whether the groups were different through self-selection. Nonetheless, it’s clear that the Gonzales regimen produced no miracles and was generally a flop. I wonder whether any naturopaths will abandon the treatment based on these results.

  2. #2 Militant Agnostic
    September 10, 2009

    I wonder whether any naturopaths will abandon the treatment based on these results.

    As Calvin said when Hobbes inquired about whether he gotten hi mother’s permission for something.

    Questions I know the answer to, I don’t need to ask.

  3. #3 Donna B.
    September 10, 2009

    Pancreatic cancer is my next great fear for my husband. He has now been diagnosed with three primary cancers and type II diabetes. Colon cancer, prostate cancer, and bladder cancer diagnoses have naturally led us to ask “where next?”

    His background is unique in that his military service exposed him to both Agent Orange and above ground nuclear tests. I can’t interest him in applying for VA benefits based on any of the above, but it’s likely that his military service contributes to the variety of cancers and other disease he has.

  4. #4 PalMD
    September 10, 2009

    @Dianne
    Correcting now, thanks

  5. #5 DrYak
    September 15, 2009

    That is pretty unpleasant trial – big pharma isn’t the only ones that get to conduct unethical trials. How did this get through ethical review in the first place?

    And, because I happen to work on the trophoblast and have the all-to-human fascination with train-wrecks, I just have to ask about this:
    It is based on a long-discredited hypothesis about cancer that erroneously connects embryonic trophoblast cells with pancreatic development (don’t ask, you’ll just get a headache).

  6. #6 PalMD
    September 15, 2009

    Just remember, you asked for it:

    A key concept underlying the original use of pancreatic enzymes for cancer treatment is the trophoblastic theory of cancer.[8] When a human egg is fertilized by sperm, the early cell divisions produce a small ball of cells, which give rise to the blastocyst (preimplantation embryo). The blastocyst possesses a surrounding layer of cells known as the trophoectoderm, which is made of individual cells called trophoblasts. Responsible for protecting the developing blastocyst and for mediating its attachment to the wall of the uterus, trophoblasts create the placenta. During the process of attaching the blastocyst to the uterine wall, trophoblasts express invasive qualities similar to those found in cancer cells. Trophoblasts, however, cease their invasive activity once the placenta is in place and functioning and then differentiate into other cell types.[8]

    When Scottish embryologist Dr. John Beard [6] first observed the invasive activity of trophoblasts in 1902, he speculated on the similarities between these cells and cancer cells. In addition, he observed that trophoblast invasiveness begins to decline at about the same time that the pancreas in the developing fetus begins to function. He also theorized that maternal pancreatic enzymes might play a role in containing trophoblastic invasiveness in the uterus. These considerations led to his proposal that cancer cells, like trophoblasts, arise from primordial germ cells. Dr. Beard also thought that some of these primordial cells—carrying latent capacities for invading tissues—could escape and spread throughout the body of the developing fetus. He thought it was possible that pancreatic enzymes modulated the degree of trophoblastic invasiveness in the uterus, he suggested that these same enzymes play a role in either limiting or eliminating cancerous cells elsewhere in the body.[6] Reviewed in [8] Dr. Beard worked before the advent of molecular biology and human genetics. Although unable to experimentally establish that pancreatic enzymes had anticancer effects, he published papers and a book about his theory between 1902 and 1911. Other scientists of the time raised significant objections to the trophoblastic theory of cancer, and it was never broadly accepted. Reviewed in [9]

    From here; http://www.cancer.gov/cancertopics/pdq/cam/gonzalez/healthprofessional/allpages#Section_25

  7. #7 DrYak
    September 16, 2009

    Ok, what might have been an interesting idea in 1902 or so, but, with light of decades and decades of research and fundamental shifts in our understanding of development has been shown to be fatally flawed is used as the basis of a full-scale clinical trial for terminally ill patients?

    With obvious, basic errors like:
    As Dr. Beard had before him, Dr. Kelley also asserted that trophoblasts and cancer cells have a common origin in primordial germ cells.
    and the insanity of thinking that
    Ingestion of 25 g to 40 g of porcine lyophilized pancreas product daily, in capsule form, taken away from meals and spread evenly throughout the day will have any effect, or even be taken up into the bloodstream. How does this escape being a serious breach of medical ethics with the origionators and participants in the trial being in front of the boards for malpractice?

    Just in case anyone has any misconceptions – trophoblast and primary germ cells (PGC) do NOT in any way have the same origen except in as much as they are both derived from a fertilized egg.

  8. #8 DrYak
    September 16, 2009

    The most amusing flaw in this quackery is that pigs don’t actually have an invasive placenta, hence pig trophoblast cells are non-invasive. How then does porcine pancreatic extract stop invasiveness of human cancers?

    The mind, she boggles…

  9. #9 PalMD
    September 16, 2009

    So, did it give you a headache?

  10. #10 daedalus2u
    September 17, 2009

    Dr Yak, you are hopelessly mired in logical thinking and unable to embrace the other ways of thinking that CAM teaches. You need to think outside the box that facts and logic have confined you to.

    Of course pig trophoblast cells are non-invasive. Something about pigs is obviously 100% completely effective at preventing them from being invasive, duh. Maybe pig pancreatic enzymes are not enough. There are hundreds of other pig parts that have not been tested enough.

    If Gonzalez was using pig pancreatic enzymes and the pancreatic cancer got worse, that simply shows that it is some other part of the pig that is effective, and should be expected to be even more effective because in pigs it has to counter the pro-invasive properties of the pig pancreatic enzymes.