[Phased clinical trials in cancer chemotherapy]

A major objective of phase I trials is to determine the toxicity of a new anticancer drugs. However phase I trials should be conducted with therapeutic intent. After the starting dose has been chosen, MTD should be reached safely and efficiently by dose escalation based on the animal toxicologic data and dose-relationship of toxicity observed in patients under the study, and there is no established scheme for dose escalation. Retreatments and reentries at increasing dose in the same patient may be useful for determining the cumulative toxicity and predicting antitumor activity. A flow of clinical trials recently introduced by the NCI is cited as a new concept of screening of the antitumor activity of new anticancer drugs in phase II trials. Prognostic factors that may affect the antitumor activity should be taken into consideration in phase II trials. In the conduct of phase III trials, there are many difficulties with historical controls, and comparative study should be performed in a controlled randomized fashion with stratification of patients who are categorized by known prognostic factors. In phase IV trials, long-term follow-up of patients is required to demonstrate advantage in survival rates and to monitor late-onset toxicity. The advantages and disadvantages of single-center and multicenter clinical trials are also discussed.