The Pot Calling the Kettle Black

The January issue of the Journal of the National Comprehensive Cancer Network features a point-counterpoint on the topic of the validity of chemosensitivity assays for drug selection in recurrent ovarian cancer. Having conducted a similar exercise with Maurie Markman, MD, as a part of a special symposium at the Society of Gynecologic Oncology in New Orleans in February 2003 — attended by hundreds of gynecologic oncologists — I was surprised on several levels.

First, (and perhaps, in this case, to his credit) Dr. Markman’s position hadn’t changed whatsoever in eight years — one could virtually excerpt his commentary, verbatim from the discussion that we had almost a decade ago. His references and scientific arguments strike me as no more convincing today than they did then, but at least they are consistent.

Second, that the authors arguing in the affirmative neglected to mention seminal influences in the field. Strikingly, Dr. Larry Wiesenthal, a pioneer and mentor, was never mentioned. Of all the modern-day investigators in this field, Dr. Wiesenthal’s contributions should certainly have been referenced. Despite this, these authors do repeatedly cite the marginal contributions of other platforms.

Third, these investigators who claim that there are no published prospective clinical correlations in ovarian cancer, appear to not read their own literature. In a paper that I authored with the chairman of the Gynecologic Oncology Group (Dr. Philip DiSaia) we provided unequivocal, statistically significant evidence in a blinded prospective analysis that assay sensitivity correlated with response (P = 0.035) and time to progression (P = 0.022). (Nagourney RA., Brewer, CA., Redecki S., et al. Gynecologic Oncology ADA 35-39. 2003.)

At least in our neck of the woods, that’s called significant.

What is perhaps the most surprising aspect of these articles is the sudden, newfound interest in this field on the part of these investigators. After a decade of efforts on my and other investigator’s parts to incorporate these methods into GOG trials fell upon deaf ears, it’s surprising to me that these arguments are finally being heard. Maybe my voice, or that of pioneers like Dr. Wiesenthal, has gotten louder? I hadn’t noticed.

In the scientific literature we use statistical tools like analysis of variance (ANOVA) to discern trends and explore new findings. When I examine these two manuscripts for new insights, I find that Dr Markman’s position, to his credit, hasn’t changed; that the statistical significance of our response and survival data also hasn’t changed; that the well documented scientific basis of our work hasn’t changed. But, I do identify one new correlate associated with this sudden enthusiasm for the field. A small (but potentially loud) line found at bottom of the first page “receives research support from…”

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

One Response to The Pot Calling the Kettle Black

  1. I wouldn’t expect Maurie Markman’s position to change in eight years. Those that are soulfully involved in clinical trials feel a subtle pull towards getting patients involved in those trials. Some researchers discourage patient empowerment so they can call the shots through these trials. They’ve even broaden their appeal by encompassing community hospital oncology practices.

    These researchers seem to have a readiness to believe that the clinical trial is more reasonable for the patient and that other options do not offer an advantage. Many of these researchers, supported by those
    specialty medical societies and other fraternal organizations, are often paid phenomenal amounts of money for enrolling patients in clinical trials, making financial gain the key motivation.

    The infamous 2004 ASCO tech assessment of cell culture assays stated that there was nothing wrong with the assays, it’s just that they should not be used outside the confines of a clinical trial setting.

    The same people who maintain that assay-directed therapy should not be used until proven in prospective, randomized clinical trials, are the same people whose entire careers are utterly dependent upon mega-trials funded by pharmaceutical comapnies (that, plus fees from speeches they give for these companies), are the same people who control the clinical trials system, the grant review study sections, and the journal editorial boards. Why else would they want this technology tested under the clinical trial setting?

    Opponents of cell culture assay testing can blow all the smoke screens they want, but the fact is that every single time advocates for cell culture assays have been given fair consideration by an impartial, non-ASCO adjudication, the decision has been made that this testing is a perfectly appropriate medical service, worthy of coverage on a non-investigational basis.

    It is only when ASCO or the insurance industry has been appointed itself as the judge/jury/prosecutor/defense rolled into one and not invited input from all “relevant” parties that the decisions have been unfavorable.

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