Why Most Randomized Phase II Cervical Cancer Chemoprevention Trials are Uninformative: Lessons for the Future
Authors: M. Follen, F. L. Meyskens, E. N. Atkinson, D. Schottenfeld
Journal: JNCI Journal of the National Cancer Institute (2001)

COMMENTARY Why Most Randomized Phase II Cervical Cancer Chemoprevention Trials are Uninformative: Lessons for the Future Michele Follen, Frank L. Meyskens, Jr., E. Neely Atkinson, David Schottenfeld According to the worldwide cancer incidence database main- tained by the World Health Organization, cervical cancer is the third most common malignancy in women worldwide, exceeded in incidence only by breast and colorectal cancers (1). Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical and histopathologic model of carcinogenesis. Human papillomavirus (HPV) is the major etiologic agent in cervical cancer. The cervix is easily accessible for examination, and colposcopy provides a visual model of angiogenesis and tumor development, making the cer- vix a good model for preventive interventions (2). The precursor lesions to cervical cancer are squamous intra- epithelial lesions (SILs) or cervical intraepithelial neoplasia (CIN). SILs are used in the cytologic classification, and CINs are used in the histopathologic classification. Several chemopreven- tion trials have been conducted in women with SIL/CIN by use of retinoids, micronutrients, ␣-difluoromethylornithine, and in- dole-3-carbinol. Although the results of phase I/IIa studies have appeared to be promising, the phase IIb/III studies have usually been negative (3–13) (Table 1). 1 The failure of the phase IIb/III studies to demonstrate an effect may be due to several factors not being adequately considered in the design of these trials. Advances in the design and implementation of clinical trials have been made over the last decade. Factors that need to be considered in the design of cervical chemoprevention trials are as follows: the natural history of the disease in the absence of any intervention, the optimal range of anticipated clinical re- sponse to the randomly assigned intervention, and the validity and predictiveness of the primary (histologic regression) and secondary (surrogate endpoint biomarker modulation) outcome measures (14–16). The likelihood that phase II cervical chemo- prevention trials will be uninformative can be minimized with careful attention to critical features of study design: enrollment of a sufficient number of patients to permit the study to reveal differences in response rates; careful selection of the type and dose of chemopreventive agent, based on results from preclinical studies and phase I and IIa clinical trials; accurate classification of patients’ disease status, both at enrollment and at study end; and selection of appropriate primary and secondary outcome measures. To ensure that cervical cancer chemoprevention trials have appropriate statistical power, the natural history of the disease must be taken into account. Patton wrote an extensive review of the natural history of SIL/CIN in the 1950s [reviewed in (17,18)], and two recent reviews of the natural history of SIL/CIN have also been reported (17,18). Estimated rates of regression of CIN vary widely, both within each CIN grade and among stud- ies. The regression rate decreases as the CIN grade increases, but estimates of spontaneous regression based on randomized trials vary from 27% to 66%, depending on the study and the entry criteria (Table 1). Apparent spontaneous regression of CIN has been observed from the natural history studies, from 57% re- gression of CIN1 and 43% regression of CIN2 to 32% regression of CIN3 (18). Thus, with the exception of the studies by Mey- skens et al. (3), de Vet et al. (8), and Childers et al. (13), many of the published phase IIb trials did not have sufficient power to detect a clinically significant difference in response rate. The dose and duration of medications used in chemopreven- tion trials should be selected on the basis of results from phase I/IIa trials, which are, unfortunately, rarely performed before phase IIb/III trials in the cervix. Phase I/IIa trials preceded the trials of Meyskens et al. (3), Romney et al. (4,5), and Keefe et al. (6,7) but not de Vet et al. (8), Fairley et al. (9), Mackerras et al. (10), Butterworth et al. (11,12), or Childers et al. (13). As such, the dose of medication used may have been inactive. A phase I/IIa trial is an opportunity to carefully examine toxicity, tissue drug levels, and modulation of surrogate endpoint biomarkers. It is important that selection of the dose and duration of medication for a cervical chemoprevention trial be based on a trial in the cervix, not taken from another organ where tissue drug levels and biomarker modulation may not be the same. Eligibility for cervical chemoprevention trials should be as- certained on the basis of colposcopically directed biopsy (15). The standard of clinical care is to perform colposcopically di- rected biopsies in patients in whom Pap smears are abnormal. Since the “gold standard” (or criterion standard) used for treat- ment is the colposcopically directed biopsy, this same standard should hold for chemoprevention trials. There are several met- rics used to compare the performance of clinical tests, such as sensitivity, specificity, positive and negative predictive values, receiver operating characteristic (ROC) curve analysis, and the area under the ROC curve. Tests may perform differently in screening populations, in which the disease prevalence is low, and in diagnostic or follow-up populations, in which the disease prevalence is high. Fahey et al. (19) conducted a meta-analysis Affiliations of authors: M. Follen (Department of Gynecologic Oncology), E. N. Atkinson (Department of Biomathematics), The University of Texas M. D. Anderson Cancer Center, Houston; F. L. Meyskens, Jr., Chao Family Compre- hensive Cancer Center, University of California-Irvine; D. Schottenfeld, Depart- ment of Epidemiology, The University of Michigan, School of Public Health I, Ann Arbor. Correspondence to: Michele Follen, M.D., Ph.D., Department of Gynecologic Oncology, Biomedical Engineering Center, Box 193, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: mfollen@mdanderson.org). See “Notes” following “References.” © Oxford University Press Journal of the National Cancer Institute, Vol. 93, No. 17, September 5, 2001 COMMENTARY 1293