Is It Ethical to Deny Cancer Patients Functional Analyses?

The ethical standards that govern human experimentation have become an important topic of discussion. Clinical trials are conducted to resolve medical questions while protecting the rights and well-being of the participants. Human subject committees known as Institutional Review Boards (IRB’s) not only confront questions of protocol design and patient protection but also the appropriateness of the questions to be answered. The Belmont Report (1979) defined three fundamental principles i) respect for persons, ii) beneficence and iii) justice. These have been incorporated into regulatory guidelines codified in the code of federal regulations like 45 CFR 46.111. One historical experience offers an interesting perspective upon contemporary oncologic practice.

With advances in cardiac surgery in the1970s and 1980s, in both valvular and coronary artery bypass, an alarming amount of post-operative bleeding was being observed. To address this complication an enzyme inhibitor named Aprotinin was developed by Bayer pharmaceuticals. The drug works by preventing the body from breaking down blood clots (thrombolysis). This is critical for the prevention of postoperative bleeding. Concerns regarding its safety led to Aprotinin’s temporary withdrawal from the market, but those have been resolved and the drug is again available.

After Aprotinin’s introduction, clinical trials were conducted to test its efficacy. Initial results were highly favorable as the drug consistently reduced post-op bleeding. By December 1991, 455 patients had been evaluated providing strong statistical evidence that Aprotinin reduced bleeding by more than 70 percent. Despite this, trialists continued to accrue patients to Aprotinin versus “no treatment” studies. By December 1992, more than 2,000 patients had been accrued and by October of 1994, the number had increased to more than 3,800 patients. Yet the 75 percent risk reduction remained entirely unchanged. Thus, 3,400 patients at untold cost and hardship were subjected to the risk of bleeding to address a question that had long since been resolved.

In a 2005  analysis, Dean Fergusson et al, decried that it should have been evident to anyone who cared to review the literature that Aprotinin’s efficacy had been established. Further accrual to clinical trials beyond 1991 only exposed patients to unwarranted risk of bleeding, and had no possible chance of further establishing the clinical utility of the intervention. This stands as a striking lack of consideration for patient well-being. Fergusson’s review raises further questions about the ethics of conducting studies to prove already proven points. With this as a backdrop, it is instructive to examine functional profiling for the prediction of response to chemotherapy.

Beginning in 1997, a cumulative meta-analysis of 34 clinical trials (1,280 patients), which correlated drug response with clinical outcome was reported. Drug sensitive patients had a significantly higher objective response rate of 81 percent over the response rate of 13 percent for those found drug resistant (P < 0.0000001). This was met by the ASCO/Blue Cross-Blue Shield Technology Assessment published in Journal of Clinical Oncology (Schrag, D et al J Clin Oncol, 2004) that cried for further clinical trials. A subsequent meta-analysis correlated the outcome of 1929 patients with leukemia and lymphoma against laboratory results and again showed significantly superior outcomes for assay directed therapy (P <0.001) (Bosanquet AG, Proc. Amer Soc Hematology, 2007). In response, a second ASCO Guideline paper was published in 2011. (Burstein H et al J Clin Oncol, 2011) Although the authors were forced to concede the importance of the field, they concluded that “participation in clinical trials evaluating these technologies remains a priority.” Most recently we conducted a cumulative meta-analysis of 2581 treated patients that established that patients who receive laboratory “sensitive” drugs are 2.04 fold more likely to respond (p < 0.001) and 1.4 fold more likely to survive one year or more (p <0.02) (Apfel C. Proc Am Soc Clin Oncol 2013).

Slide Detail-smallEach successive meta-analysis has concluded, beyond a shadow of a doubt, that human tumor functional analyses (e.g. EVA-PCD) identify effective drugs and eliminate ineffective drugs better than any other tool at the disposal of cancer physicians today. Not unlike those investigators who continued to accrue patients to trials testing Aprotinin, long after the result were in, oncologists today continue to clamor for trials to prove something which, to the dispassionate observer, is already patently obvious. If we now pose the question “Is it ethical to deny patients functional analyses to select chemotherapy?” the answer is a resounding No!

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.

2 Responses to Is It Ethical to Deny Cancer Patients Functional Analyses?

  1. So, in each successive meta-analysis, it certainly does prove the principle of human tumor functional analyses in exactly the way nay-sayers have demanded. At some point you have to ask yourself, given all of the evidence that exists in support of functional profiling for the prediction of response to chemotherapy in so many tumor types, is it reasonable to think that this is an anomaly? Of course not! However, one of the reasons medical oncologists don’t like in vitro chemosensitivity tests is that it may be in direct competition with the randomized controlled clinical trial paradigm.

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