Where’s the Proof? Clinical Trials and Cancer Testing

Numerous trials have been conducted to assess the predictive validity of the Rational Therapeutics Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) and similar platforms. However, we (and other investigators) are sometimes dismissed for lack of data supporting the validity of our methods.  Despite the unwillingness of the cooperative groups to formally test laboratory-directed therapy against standard protocol treatments, we have compiled a compelling collection of both retrospective and prospective correlative analyses that strongly support the clinical utility of these methodologies.

Two of the trials that I’ve reported prospectively compared the results of the EVA-PCD platform with objective response, time to progression and survival. The findings in breast cancer confirmed a significant correlation between drug sensitivity and progression-free survival in the evaluation of cisplatin plus gemcitabine (Nagourney et al, JCO 2000).

A second study conducted in ovarian cancer established the correlation between sensitivity and objective response, time to progression and overall survival (Nagourney et al, Gyn Onc 2003). More recently, a laboratory-directed protocol in NSCLC provided an objective response rate of 62 percent, statistically significantly superior to standard outcomes (p=0.003), with a median progression-free survival of 9.5 months and median overall survival of 22.3 months.

We and other investigators in the field have made it abundantly clear that we are very willing to participate in well-conducted formal studies. Amongst the organizations that have been approached to conduct such studies — NSABP, GOG, ECOG and CCG — have all been unwilling to undertake confirmatory studies. The costs of prospective clinical trials (now in the range of millions of dollars) remain a substantial hurdle for investigators in this field. Nonetheless, a fair test of these methodologies should be conducted.

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 Where’s the Proof? Clinical Trials and Cancer Testing

  1. Gregory D. Pawelski says:

    The Committee on Comparative Effectiveness Research Priorities should conduct a study to compare the effectiveness of various genetic and cell culture assay technologies for targeted as well as conventional cancer treatment.

    Back in April 2009, I submitted to the Committee on Comparative Effectiveness Research Priorities, who was conducting a study to recommend national priorities for comparative effectiveness research conducted or supported with funds from the American Recovery and Reinvestment Act of 2009, a specific priority via their survey tool.

    I asked that they compare the effectiveness of various genetic and cell culture assay technologies for targeted as well as conventional cancer treatments. The purpose of the study was to show what technologies work.

    The primary condition to be studied would be oncology and hematology. The types of interventions to be compared would be testing, monitoring and evaluation (e.g. lab, functional assessments), pharmacological treatments, and treatment pathways (e.g. chemotherapy selection).

    The types of research that would be most effective in providing the needed evidence would be synthesis of existing evidence (e.g. qualitative review, meta-analysis), primary research using existing health care databases, primary research using prospective data collection without randomization (e.g. observational study, registry), and primary research through a prospective randomized trial.

    Real-world studies are not being performed under real-world conditions. No one is publishing real-world studies, except private laboratories performing cell-based analysis, which can only do real-world studies, because their studies require fresh, viable specimen, which must be accessioned and tested in real-time under real-world conditions.

    Patient outcomes need to be reported in real-time, so patients and physicians can learn immediately if and how patients are benefiting from new diagnostics and therapies.

    It would be terrific to have a head to head comparision of molecular and cell culture technologies. I was hoping someone would pay attention to this. It never happened!

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