Clinical trials for the evaluation of cancer therapy

One of the great advances of the last 50 years has been the introduction of prospective randomized controlled trials into clinical medicine. Those efforts apply the scientific method to clinical problem solving and provide the mechanism for obtaining answers to important clinical and biologic questions that can be obtained in no other way. When properly employed, clinical trials supply definitive information relative to the worth of therapies prior to their widespread use on populations as a whole. They are sophisticated endeavors requiring the interactions of clinicians, investigators, and statisticians as equal partners in a common effort that requires discipline as rigid as that of a laboratory experiment. There are three types or phases of clinical trials conducted on cancer patients; each is directed toward supplying answers to different questions. Phase I trials determine safe dose levels and/or schedules of drugs in humans. They may be aimed at using known drugs in combinations heretofore not tried or at determining the tolerably toxic dose of drugs that have shown benefit in animal models. Efficacy is not a defined goal of Phase I trials. Utilizing schedules and dosages and incorporating limitations discovered in Phase I trials, studies are next conducted that are aimed at determining therapeutic efficacy; i.e., Phase II trials. They are performed on patients of the same tumor type and measurable disease (usually Stage IV). In neither Phase I or II trials is randomization a feature. With demonstration of at least some efficacy in a Phase II trial, a therapy becomes a candidate for full-scale testing and comparison with a currently "standard" therapy in a Phase III trial. This report presents an overview of some of Stages I and II cancer. Comments will be made relative to their rationale, design, conduct, and statistical requirements, as well as ethical considerations, with the hope that more of the current generation of physicians will become aware of their importance and will be stimulated to participate in such endeavors. This overview is not meant for the statistician or for the sophisticate who is well versed in the vast literature that is accumulating in this area. Comments are primarily based upon experiences derived from the clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) for a quarter of a century. Where appropriate, breast cancer will serve as a model for the discussion.