Editorial
“Blinded” Is Right
The New England Journal,
the Miss Manners of medical practice, recently published two studies
which shattered the sacred cow of blinded, randomized controlled trials.
Tackling one of the most prevalent myths of the medical
trade, authors Arthur J. Hartz, MD, PhD and Kjell Benson, BA 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, MPH 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 worshipped 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 100 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 3,868 observational studies, the authors
narrowed the list to 19 similar studies in which there was 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, MD, 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 1,248
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
2%. Only two patients (0.16%) 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.
Patrick McGrady
CANHELP
3111 Paradise Bay Road
Port Ludlow, Washington 98365 USA
360-437-2291
Website
[Periodically, CANHELP will publish on its
website signed opinions on the subject of cancer. Our readers are welcome
to submit their thoughts for inclusion in this department.]
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