The relationship between high-dose treatment and combination chemotherapy: the concept of summation dose intensity

The most important variables for the clinical use of antitumor agents (AAs) are dose and combination chemotherapy. The objectives of this study were to analyze the relationship between these two variables and to propose a unified conceptual framework for the construct and interpretation of clinical trials. Definitions and variables with respect to dose include potency, therapeutic index, standard dose, efficacy, relative efficacy, dose-limiting toxicity (DLT), dose rate, dose density, dose intensity, and fractional dose intensity. Our overarching concept, that is, summation dose intensity (SDI), was calculated in several ways, depending upon the nature of the data, and included the relative efficacy method, the unit regimen method, and the high dose method. The SDI concept was then applied to disease categories and strategies to determine its usefulness and effectiveness in integrating dose and combinations. The tumors and settings were: mustargen-vincristine-procarbazine-prednisone in Hodgkin's disease, combination chemotherapy for acute lymphocytic leukemia in children, metastatic breast cancer including dose and combinations, selected other solid tumors, alternating chemotherapy, and high dose studies in the leukemias and lymphomas. SDI was effective in integrating and quantifying dose and combination chemotherapy. For classical AAs, the implication of SDI for the construct and analysis of clinical trials was emphasized. In addition to new drug development, emphasis should be given to reducing or eliminating DLTs, such as those of the marrow, now and, in the future, those of the gastrointestinal tract toxicity and other DLTs. The above was derived from and applies to the classical AAs. Whether they will apply to, with appropriate adjustment, agents with significantly different dose-response curves, such as biotherapeutics and hormonal agents, remains to be determined.