Evidence That Drugs in Multiple Combinations Have Materially Advanced the Treatment of Human Malignancies

Abstract

Is combination chemotherapy superior to single drug therapy in the treatment of cancer? The straightforwardness of this question, implicit in the title of this talk, belies its complexity. Lacking a simple explanation of cancer, I must dissect the query and my rejoinders into the many ramifications of treatment-its purpose, its phases, and its results-cognizant that no one conclusion, affirmative or negative, will of itself suffice. In the most general sense, combinations of therapies, whether drugs and/or other modalities, will always play an important role in the management of diseases for which there exists no single specific and totally effective treatment. When one treats patients with certain cancers, rheumatoid arthritis, hypertension, diabetes mellitus, or tuberculosis, to mention just a few examples, one is frequently unable to control the total disease process by any single means, and a cure is often unobtainable. Single agents may suffice during parts of the illness, but from time to time multiple agents are invaluable. In each instance the identification of a single, totally effective treatment would quickly render the combination obsolete, as has occurred with many bacterial infections and a handful of neoplasms. In other morbid conditions, for example, multiple sclerosis, infectious hepatitis, and most disseminated cancers, no therapy is known to definitely and specifically alter the natural course of the illness, and in these situations com binations have been equally unimpressive. These examples outline some of the indications for com bination therapy: (a) the illness does not regularly respond to any single form of treatment, but (b) it can be modified partially by at least two modalities of therapy. Combination chemotherapy has most frequently been explored in the treatment of leukemia, but it has also provided benefit in certain solid tumors. Evaluation of therapy in solid tumors, similar to comparative studies of leukemia chemo therapy, has been hampered in many studies by: (a) lack of sufficient suitable patients, (b) inability to determine the full extent of disease, (c) difficulty in establishing criteria of response, and (d) uncontrolled variation in dosage and spacing of therapeutic agents (such as radiation therapy). Despite the aforementioned handicaps, the use of combinations of drugs with or without radiation therapy has provided sufficient data in certain malignancies other than leukemia either to suggest or to prove the superiority of combined therapy versus single agents. In most instances, the duration of a complete objective response or tumor-free interval has been used as the criterion of effectiveness; however, in some studies, survival time has