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February 16, 2005

Trends in the Risks and Benefits to Patients With Cancer in Phase 1 Clinical Trials—Reply

JAMA. 2005;293(7):795. doi:10.1001/jama.293.7.795-b

In Reply: The question raised by Dr Ross regarding stable disease rates as a surrogate for clinical benefit is a valid one: anticancer agents with mechanisms of action that are not cytotoxic may produce clinical benefit by delaying tumor progression without effectively shrinking tumors. For these agents, stable disease rates or time to tumor progression (TTP) may represent more appropriate surrogates for clinical benefit than rates of objective response such as tumor shrinkage. However, stable disease and TTP can be reliably evaluated only with randomized trials. The measure of these end points may be influenced by the underlying biology of the tumor, the frequency of imaging studies, and potential investigator bias in the timing of imaging studies, as well as the interpretation of clinical data. A slow-growing tumor may appear to be of stable size for several months in a phase 1 trial; without concurrent controls it is impossible to determine if the stability of the tumor relates to its underlying biology or to the effects of the agent under study. Because of these limitations, stable disease rates and TTP were not uniformly reported in the types of trials we analyzed, and the Food and Drug Administration has been hesitant to grant approvals based on these end points outside of randomized trials.