Randomized clinical trials and other approaches in clinical research

Phase III randomized clinical trials have greatly contributed to our understanding of the pathobiology of neoplastic disease and, particularly, to therapeutic progress. However, randomized Phase III studies are no better than or are critically dependent on Phase I and Phase II studies for positive therapeutic leads that are compelling enough to test in the Phase III arena. The variables involved in the series of randomized trials that led to the curative treatment of acute lymphocytic leukemia also resulted in an understanding of the principles of cancer therapy in therapeutic research. These principles, when applied to Hodgkin's disease in non-Hodgkin's lymphoma, testis cancer, childhood solid tumors, and others, resulted in a substantial cure rate for those diseases. However, for the adult epithelial common solid tumors, a second strategy, adjuvant chemotherapy, was required This has resulted in a 20% reduction in mortality in patients with node positive and node negative breast cancer. Tamoxifen has been similarly effective in patients with postmenopausal breast cancer. In colon cancer, adjuvant chemotherapy with fluorouracil plus levamisole has decreased mortality to a comparable degree. New agents, modulations, combination chemotherapy, and biotherapeutics are being addressed to the adjuvant situation which has proven effective in a variety of neoplastic diseases. A third strategy is neoadjuvant chemotherapy. This involves the use of chemotherapy first for patients with solid tumors, designed to down-stage the primary tumor thus making it more susceptible to less radical surgery and to organ- or limb-sparing procedures in osteogenetic sarcoma and in head and neck cancer. For example, neoadjuvant chemotherapy has not resulted in an increased survival as compared with the appropriate control but has allowed for important quality-of-life contributions, such as limb-sparing and radical surgery-sparing procedures. In addition to new agents and combination chemotherapy, dose is a critical variable. This is most evident clinically in the transplantation arena. Comparative studies recently completed, for example, in patients with adjuvant breast cancer and with acute leukemia indicate that dose is a significant factor in tumor control.