Lack of Blindness

I want to raise another issue that is little discussed, but may influence clinical trial results. Once upon a time, most clinical trials were what is called ‘double-blinded' and placebo-controlled - i.e., neither the patients nor their physicians knew who was getting the drug under evaluation. But, for various reasons, double blinding has become less frequent in clinical trials of oncologic drugs. The National Institutes of Health's clinicaltrials.gov Web site presently lists over 16,000 cancer treatment clinical trials. Yet only 1,165 of these are also placebo-controlled and double-blind. The FLEX study was not one of these.

In the FLEX study, one group of patients was randomly assigned to receive chemotherapy with a combination of two standard anticancer drugs, cisplatin and vinorelbine, while the other group was given cisplatin and vinorelbine plus the additional drug, Erbitux. This random assignment created two very different psychological pathways. One group of patients knew they were getting the added, and potentially more promising, agent. The other group consisted of patients who were only given the standard chemo treatment. This divergence may be reflected in the somewhat better results seen in the treatment group.

At the same time, the oncologists monitoring the trial also knew who was getting the experimental treatment and who was not. For a variety of reasons, not least the simple hope of being able to provide something more effective, oncologists have an interest in seeing the experimental group do better than those in the standard treatment group. In addition, the sponsoring company has a strong vested interest in seeing a positive outcome. And of course a positive finding and a high-profile publication will advance everyone's careers. Finally, while I am not suggesting any ethical impropriety or deliberate attempt to control the outcome, there are certainly ways in which doctors and nurses can unconsciously enhance the care of the patients in one group over those in another, thereby influencing the course of the disease.

So, in order to believe in the relevance of the FLEX results to the general population, you must accept the proposition that changes in doctors' and patients' consciousness has no significant bearing on the outcome of the trial. If you accept the basic idea that psychological factors can influence survival, you then have to pose the question: To what degree do mood, attitude, intention, etc. influence survival? Could it result in one week of extra life? Two weeks? Or even five weeks?

Some work has been done on this question. Dr. Hermann Faller and colleagues, in Würzburg, Germany, showed that "active coping and hope were associated with longer survival" while emotional distress, depression and depressive coping were associated with shorter survival (Faller 1997). These researchers looked particularly at patients with lung cancer. "Both coping and emotional distress had a statistically independent effect on survival among patients with lung cancer," they wrote (Faller 1999). In a 10-year review of results with lung cancer, they again found that "a depressive coping style…was linked with shorter survival" (Faller 2002). The relative risk was 1.91, which means that depressed patients' risk of dying was nearly double that of non-depressed patients.

Dr. Kirk W. Brown and colleagues, of the University of Rochester, NY, drew similar conclusions. In a study of more than 200 cancer patients, they showed that "depressive symptomology was the most consistent psychological predictor of shortened survival time" (Brown 2003). So depression influences survival - a proposition that is both common sense and good science.

I would love to see a study of the effect that either inclusion or, conversely, exclusion from the more promising arm of a clinical trial has on patients' survival. It is probable that being excluded from the active treatment arm does indeed predispose to depression in some individuals, and that this in turn may influence their survival. Such a study might throw an interesting light on the reasons for increased survival in some non-blinded clinical trials, especially when difference between the two arms is small, as it was in the FLEX trial recently reported at ASCO.

THE WAR ON CANCER by GUY FAGUET, MD

Two years ago in this newsletter I reviewed an important book, The War On Cancer: An Anatomy of Failure; A Blueprint for the Future, by Guy Faguet, MD.

To read my review please click or go to:
http://www.cancerdecisions.com/040206.html

The paperback edition of the book has just been published and is now available at www.Amazon.com. You can access it by clicking here.

--Ralph W. Moss, Ph.D.