Re: Cancer Chemoprevention: Progress and Promise RESPONSE

Re: Cancer Chemoprevention: Progress and Promise The commentary by Lippman et al. (1) provides a useful review of the topic by organizing a massive amount of in- formation in an organized way. How- ever, because this review will be widely read and referenced, there are two gen- eral points made by the authors that could be challenged. The authors define two of the four criteria for identifying a “definitive” chemoprevention trial as “primary end point of cancer incidence” and “large scale (n 艌 1000) with the Journal of the National Cancer Institute, Vol. 91, No. 6, March 17, 1999 definitive sample size and duration based on anticipated event rates in the intervention arm (treatment effect) and placebo arm.” One major goal of chemoprevention research is to determine the protective effect of an agent while placing as few participants as possible at risk. One straightforward way to accomplish this goal is to understand the process of the disease (carcinogenesis) sufficiently to conduct trials with markers that predis- pose to or predict the final end point of cancer. In general, most histologically identifiable precancers (e.g., cervical in- traepithelial neoplasia, Barrett’s esopha- gus, adenoma polyps, actinic kerotoses, and dysplastic nevi) evolve to cancer with a sufficiently predictable frequency to conclude that their reversal or sup- pression can be used to predict cancer development and to assess the value of a chemoprevention agent. There are, in fact, as the authors note, several studies (2–6) that have addressed the effective- ness of chemoprevention in this manner. The medical community accepts hyper- tension and cholesterol as surrogate “preneoplasias” of cardiovascular dis- ease risk and their modulation as indica- tive of a favorable or unfavorable drug effect. Modulation of the pathobiology of precancers is as valid a marker of carcinogenesis as is the end point of can- cer. Undoubtedly, advances in our un- derstanding of carcinogenesis will allow us to identify and develop new agents by the modulation of a biochemical event earlier in the carcinogenic process and this should be a major goal of chemo- prevention research. Large numbers may provide comfort to the investigator that a definitive result has been obtained. However, there are many instances in medicine when large numbers were not required to make the point, i.e., where the underlying cause CORRESPONDENCE 563