Cancer Patients Who Get Better, Get Better

JCO coverA study published in the October 20 Journal of Clinical Oncology (Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with Cetuximab, Piessevaux H. et al, 31:3764-3775,2013) described “early tumor shrinkage” as a predictor of long-term survival in patients with metastatic colorectal cancer. These Belgian and German investigators re-analyzed two large clinical trials in colon cancer, CRYSTAL and OPUS, to evaluate the impact of early tumor shrinkage at eight weeks of therapy. Both studies were in patients with wild type (non-mutated) KRAS colon cancer who received chemotherapy with or without the monoclonal antibody Cetuximab.

They used a cutoff of 20 percent tumor shrinkage at eight weeks to separate “early responders” from “non-responders.” Early responders were found to have a significantly better survival. The accompanying editorial by Jeffrey Oxnard and Lawrence Schwartz (Response phenotype as a predictive biomarker to guide treatment with targeted therapies, J Clin Oncol 31:3739-3741, 2013) examined the implications of this study.

The measurement of tumor response has been a lynchpin of cancer therapeutics for decades. This was later refined under what is known as RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Despite this, there remained controversy regarding the impact of early response on long term survival. The current Piessevaux trial however, is only the most recent addition to a long history of studies that established the correlation between tumor shrinkage and survival. Earlier studies in colorectal, kidney, esophagus and lung cancers have all shown that early response correlates with superior outcomes.

What is gratifying in the accompanying editorial is the discussion of the “response phenotype” as a predictor of survival. Phenotype, defined as “the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment” reflects the totality of human biology not just its informatics (genotype). This renewed appreciation of tumor phenotype in oncology is important for it re-focuses on tumor biology over tumor genetics.

The  ex-vivo analysis of programmed cell death (EVA-PCD) that we utilize, is itself a phenotypic platform that measures actual cellular behavior, not gene profiles, to gauge drug sensitivity. We have previously shown that the measurement of chemotherapy effect on human tumor tissue predicts response, time to progression and survival. The current study used clinical response (early tumor shrinkage) to successfully measure the same.

This analysis of early response by Piessevaux is bringing our most sophisticated investigators back to what they should have known all along.
1. Responding patients do better than non-responding patients.
2. Early measurement of response is predictive of long term outcome.
3. These measurements can and should be done in the laboratory.

Taken together, the current study supports early tumor shrinkage and by inference, ex vivo analyses, as important predictors of patient response and survival.

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.

4 Responses to Cancer Patients Who Get Better, Get Better

  1. mpdonsimoni says:

    Robert it is better to be right than wrong albeit it takes time for some to acknowledge it

    Love

    Marie-Paule Donsimoni-Bupp +33 6 48 74 84 49 CET

    >

  2. Paul Battle PA-C says:

    Did they look at other parameters such as NK cell counts, nutritional status, stress levels, support systems. They may have responded better but it did not have anything to do with the drugs. Especially if they used the same protocol. What we should be looking at is what is different about the responders. Look at things like vitamin D levels, Cortisol levels, vitamin levels, stress levels, religous beliefs and passion, family support. Who really cares if the tumor shrinks more responsively then it is only logical those patients will do better. What has that taught us we could not figure with deductive reasoning.?

  3. The choice to use an option medicine cure for cancer requires courage in the outset. When you’re initial told you have cancer it can be like stepping into an elevator shaft – your entire life can feel like it’s going into free fall. And when you’re told by your oncologist or consulting surgeon and also you have to have surgery your first impulse might be “Let’s get done quickly so I can get on with life after cancer.” This was accurate of my partner. Even though she regularly used alternative medicine the lure of the immediate fix that surgery for her breast cancer appeared to provide was enticing.

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