Cytostatic anticancer drug development

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.

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.

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.

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.