Endpoints for agents that slow tumor growth.

The endpoints of confirmed response and progression are widely used in oncology clinical trials. These endpoints originated at a time when agents used to treat cancer were primarily cytotoxic. Increasingly agents that are cytostatic are being investigated in combination with agents that are cytotoxic. Since tumor growth rates often depend on the volume of the tumor, combining cytotoxic agents that reduce tumor volume with cytostatic agents may mask the activity of the cytostatic agent. This paper explores the sensitivity of time to progression/progression free survival (TTP/PFS) as an endpoint for evaluating the efficacy of cytostatic drugs when combined with cytotoxic agents. Mathematical models of tumor growth are used to describe tumor growth over time. The models account for the impact of chemotherapy and an agent that slows tumor growth in the context of the Gompertzian growth kinetics. We use a clinical trial of an angiogenesis inhibitor in metastatic breast cancer as a motivating example. We demonstrate that the endpoint TTP/PFS may not be sensitive to the effects of active cytostatic agents when they are combined with chemotherapy, and measuring time to regrowth would be more sensitive to the activity of a cytostatic agent. We conclude that an active cytostatic agent may not appear effective when combined with chemotherapy and evaluated with TTP/PFS in a clinical trial.