Cytostatic anticancer drug development.

Abstract

This review focuses on clinical trials and the approval process in order to understand the discrepancy between vibrant science and the continuing failure of mechanism-based anticancer drugs. CLINICAL TRIALS: Mechanistic trials in cancer require at least three elements: the assurance of tumor definition, knowledge of the natural history, and earlier intervention. Histologic identity is not a reliable surrogate of the functional nature or a predictor of the natural history. cDNA arrays and computational models have promise in improving diagnosis and prediction, and thereby making tailored therapy possible. The latter requires: the incorporation of initial and earlier rational combination therapy, dynamic models of disease progression, and methods to discourage the emergence of resistance. For cytostatics, and in early cancer, a delay in progression may represent a better index of survival than tumor shrinkage. APPROVAL PROCESS: Since mechanistic similarities may outweigh therapeutic predictions based on organ-and histology-defined cancer, there is a need for a revised process that would allow for tailored treatment and initial combination therapy to improve safety, efficacy, and circumvent resistance. CONCLUSION: In order to translate the major and immediate potential of cytostatic drugs, clinical trials and the approval process may need to shift to a mechanism-based framework.