PROGRESS IN CANCER CHEMOPREVENTION - PERSPECTIVES ON AGENT SELECTION AND SHORT-TERM CLINICAL INTERVENTION TRIALS

The basic cancer-related chemical and biological sciences, pathology, and epidemiology have contributed to the understanding that anti-mutag enesis and antiproliferation are the important general mechanisms of c hemoprevention and to the development of antimutagenic and anti-prolif erative agents as potential chemopreventive drugs. These disciplines h ave also provided the biochemical and histopathological bases for iden tifying intermediate biomarkers that can be used as surrogate end poin ts for cancer incidence in clinical chemoprevention trials and for sel ecting cohorts for these trials. Particularly important as histologica l biomarkers of cancer are the cytonuclear morphological and densitome tric changes that define intraepithelial neoplasia (IEN). IEN changes are on the causal pathway to cancer. They may serve as target lesions in Phase II chemoprevention trials and as standards against which othe r earlier cellular and molecular biomarkers can be evaluated. Strategi es for the clinical evaluation of chemopreventive agents have been def ined for seven targets-colorectal, prostate, lung, breast, bladder, or al, and cervical cancers. Cohorts have been identified for short-term Phase II trials that investigate the effects of chemopreventive agents on IEN and on earlier biomarkers. Patients with adenomas serve as a c ohort for trials in colon. One cohort for Phase II trials in prostate is patients with early stage cancers scheduled for prostatectomy; anot her is patients with prostatic intraepithelial neoplasia (without pros tatic carcinoma). Patients treated for lung cancer are at high risk fo r bronchial dysplasia and second cancers; such patients are a cohort f or Phase II trials in lung cancer. Presurgical breast cancer patients and patients with ductal or lobular carcinoma in situ are cohorts for studies in breast. Patients with superficial bladder cancers (T(a)/T1 with or without carcinoma in situ) are cohorts for studies of chemopre vention in bladder, and patients with dysplastic oral leukoplakia are evaluated for chemoprevention of oral cancers. Cervical intraepithelia l neoplasia is a prototype IEN, and patients with cervical intraepithe lial neoplasia are a cohort for studies of cervical cancer.