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 antimutagenesis and antiproliferation are the important general mechanisms of chemoprevention and to the development of antimutagenic and anti-proliferative agents as potential chemopreventive drugs. These disciplines have also provided the biochemical and histopathological bases for identifying intermediate biomarkers that can be used as surrogate end points for cancer incidence in clinical chemoprevention trials and for selecting cohorts for these trials. Particularly important as histological biomarkers of cancer are the cytonuclear morphological and densitometric 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 other earlier cellular and molecular biomarkers can be evaluated. Strategies for the clinical evaluation of chemopreventive agents have been defined for seven targets--colorectal, prostate, lung, breast, bladder, oral, 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 cohort for trials in colon. One cohort for Phase II trials in prostate is patients with early stage cancers scheduled for prostatectomy; another is patients with prostatic intraepithelial neoplasia (without prostatic carcinoma). Patients treated for lung cancer are at high risk for bronchial dysplasia and second cancers; such patients are a cohort for 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 (Ta/T1 with or without carcinoma in situ) are cohorts for studies of chemoprevention in bladder, and patients with dysplastic oral leukoplakia are evaluated for chemoprevention of oral cancers. Cervical intraepithelial neoplasia is a prototype IEN, and patients with cervical intraepithelial neoplasia are a cohort for studies of cervical cancer.
Kelloff
G J
GJ
Chemoprevention Investigational Drug Unit, National Cancer Institute, Bethesda, Maryland 20892.
Boone
C W
CW
Steele
V E
VE
Crowell
J A
JA
Lubet
R
R
Sigman
C C
CC
D000236:Adenoma / Q000453:epidemiology / Q000517:prevention & control; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D002986:Clinical Trials as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D005260:Female; D006801:Humans; D008297:Male; D009062:Mouth Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D009369:Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D012107:Research Design; D014481:United States / Q000453:epidemiology; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000517:prevention & control; D014594:Uterine Neoplasms / Q000453:epidemiology / Q000517:prevention & control
D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor