The New England Journal of Medicine, the Miss Manners of medical practice, recently published two studies which shattered the sacred cow of blinded, randomized controlled trials (NEJM, July 22,2000-Vol.342, No.25).
 
    Tackling one of the most prevalent myths of the medical trade, authors Arthur J. Hartz, M.D., Ph.D. and Kjell Benson, B.A. found "little evidence that estimates of treatment effects in observational studies reported after 1984 are either consistently larger than or qualitatively different from those obtained in randomized, controlled trials."  The second study, by John Concato, MD., M.P.H. came to the same conclusion.  And while these studies deal with cardiovascular and other diseases, the implications for cancer, I think, are similar.

    Predictably an attempt was made to stanch the bleeding.  The articles were followed by a critical review that impugned the landmark findings.  You don't trash sacred dogma without meeting resistance.

    For as long as I can remember, academicians and doctors of high estate and low sensibility, have worshiped at the altar of the Randomized Double-Blind Controlled Trial.  Cancer patients tend to steer clear of them, despite the warm invitation of researchers whose livelihoods depend on them.  Only two out of one hundred patients volunteer. 

    Panic and confusion are frequent fellow travelers with a diagnosis of cancer. Many doctors discourage their patients from exploring other options.  Hospitals and clinics usually do not discuss alternatives because their incomes are dependent upon the amount of chemotherapy they can prescribe.  One mediocre oncologist, fired for incompetence, was rehired later because whatever the diagnosis, as one hospital official put it: "He could always come up with an expensive chemotherapy protocol." 

    In a randomized, controlled trial, usually there is only a  50/50 chance of getting the desired experimental treatment.  It is chance, not the patient, which decides whether one is assigned to the experimental arm or the placebo arm of a trial.  Once one surrenders one's choices to a drug company the die is cast.   The transformation of a human being into a guinea pig is an ominous process. 

    The advantages of non randomized trials are many.  They're hugely cheaper.  Quicker. And they may be tried on a greater variety of patients.  And if the results are almost always the same, where did the tenet of randomized trial superiority come from?  The Journal's authors point out that studies of the 60s and 70s were lacking in the improved methodology of the 80s and 90s, among which more reliable statistics and choice of data.

    Exploring some 3868 observational studies, the authors narrowed the list to 19 similar studies in which there were both a randomized trial and an "observational" study.  In only two of them was there a discrepancy in interpretation of the magnitude of treatment effects.  

    Europeans often regard the double-blind, randomized, controlled trial as an unethical practice.  I remember the Robert Janker Klinik medical director, Dr.  Wolfgang Scheef, being grief-stricken at the outcome of a particular randomized controlled trial of his discovery, Mesna, a rescue agent for an entire class of drugs such as Cytoxan and ifosfamide.  Three young soldiers with testicular cancer, who were randomized to the placebo arm of the study, died from ifosfamide's toxicity.  The experiment was deemed a success and the results were published in the NCI journal Cancer Treatment Reports.

    Scheef felt personally responsible for the fatalities.

    "There was no need for such a trial," he complained.  "Mesna had never failed among the hundreds of patients on whom it had been tried heretofore.  You do not need a comparison other than the historical controls for something as obvious as this."  Previously, ifosfamide was thought a most dangerous drug.  With Mesna, it no longer kills."

    The traditional problem with these drugs was the urinary tract problems.  The chemotherapy attacked the kidney, the bladder, and the urethra.  Ifosfamide was temporarily  withdrawn from marketing by its manufacturer, Asta Werke, after 14 South African patients died of drug-induced cystitis and hematuria.

    I scarcely ever suggest that cancer patients resort to experimental trials because they rarely produce a positive outcome for the patient.

    Maurie Markman, M.D., formerly of Sloan-Kettering Memorial Hospital, reported in a 1985 article in CA -- A Cancer Journal for Clinicians, that in a series of Phase I clinical trials on 1248 patients coordinated by the National Cancer Institute, "the complete plus partial response rate (a 50% or greater decrease in the product of the perpendicular diameters of measurable tumor masses) was only two percent.  Only two patients (0.16 percent) achieved a complete remission..."

    Where were the benefits for the patients?  Where were the benefits for "posterity?"  Well, at least the drug companies got to find out a little more about their products and create another step forward along the tortuous path of FDA approval.  I don't know of any of the current "approved" chemotherapy treatments for cancer that are totally safe or convincingly curative.  But they have a long paper trial.

    And, in this world of scientific propriety, that's what counts.  Never mind what happens to the patients.
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