HOUSTON—Inconsistent but largely negative results have limited progress of clinical trials of chemoprevention for cervical cancer, but investigators remain optimistic that lessons learned from the trials to date eventually will lead to better results.
Speaking here at the recent 2nd International Conference on Cervical Cancer, cancer prevention expert Frank Meyskens, MD, Director of the Chao Family Comprehensive Cancer Center and Professor of Medicine & Biological Chemistry at the University of California, Irvine, explained that the chemoprevention experience in cervical cancer has mirrored that of other fields of oncology.
Multiple studies have produced largely negative results, he said, including four trials with beta-carotene, two with folic acid, one with ascorbic acid, and one with the synthetic retinoid 4-HPR.
The lone positive results came from a 1994 evaluation of topical trans-retinoic acid in women with moderate cervical intraepithelial neoplasia (CIN-2), a study led by Dr. Meyskens.
The chemopreventive potential of I-3-C will be further evaluated in a prospective, placebo-controlled GOG trial in patients with CIN-3.
“Clearly, we have a long way to go,” said Dr. Meyskens, a member of OT's Editorial Board, who cochaired (with Terri L. Corneilson, MD, PhD) a session on chemoprevention and biomarkers. “We need to learn more about the disease process and which stages of the disease are amenable to chemoprevention. We also need to know more about potential biomarkers of cervical cancer to guide the development of more effective chemoprevention strategies.”
Three studies reviewed at the conference, which was cosponsored by The University of Texas M. D. Anderson Cancer Center, Johns Hopkins University School of Medicine, and the National Cancer Institute, reflected the most recent clinical experience with chemopreventive strategies for cervical cancer. A small study of the phytoestrogen indole-3-carbinol (I-3-C) produced statistically significant regression compared with placebo in 27 patients with CIN-2 and CIN-3.
Multiple chemoprevention studies have produced largely negative results in cervical cancer, including four trials with beta-carotene, two with folic acid, one with ascorbic acid, and one with 4-HPR.
The rationale for the study came from observations that I-3-C retards cancer growth in animal models and that increased consumption of I-3-C (found in cruciferous vegetables) is associated with a reduced risk of certain types of cancer. Moreover, I-3-C has been identified as the specific compound associated with anticancer effects, said Maria C. Bell, MD, Clinical Associate Professor of Medicine at the University of South Dakota in Sioux Falls.
Moreover, she added, I-3-C alters estrogen metabolic pathways and promotes optimal estrogen metabolism. A final rationale came from preclinical evidence linking estrogen metabolism to human papillomavirus (HPV)-induced tumors, which were inhibited by treatment with I-3-C.
Women enrolled in the trial, conducted while Dr. Bell was at Louisiana State University in New Orleans, were randomized to receive placebo or I-3-C at a dose of 200 or 400 mg/day for four weeks. Colposcopy was performed at baseline and then every four weeks, and each women had a biopsy at baseline and 12 weeks.
Loop electrosurgical excision procedure (LEEP) was performed in the event of persistent dysplasia, and HPV and urinary estrogen metabolites were assessed, including 16-alpha hydroxyestrone, which is elevated in HPV infection and CIN.
Seven of 10 placebo patients were HPV positive, as were seven of eight patients in the 200-mg I-3-C group and eight of nine in the 400-mg group.
At the 12-week biopsy no patient randomized to placebo showed evidence of CIN regression, whereas four of eight patients in the low-dose I-3-C group and four of nine in the high-dose group exhibited complete regression. HPV status did not correlate with response, but the 2/16-alpha hydroxyestrone ratio changed in a dose-dependent fashion. No patient reported any treatment-related toxicity.
“Some patients in the placebo group experienced regression, but no one had complete regression,” Dr. Bell said. “When we looked at overall regression, more occurred in the high-dose group than in the patients who received the lower dose of I-3-C.”
The chemopreventive potential of I-3-C will be further evaluated in a prospective, placebo-controlled trial conducted under the auspices of the Gynecologic Oncology Group, she added. The trial will be limited to patients who have CIN-3, and the same two doses of I-3-C will be used.
9-Cis Retinoic Acid
In another presentation at the meeting, Ronald D. Alvarez, MD, Professor of Obstetrics and Gynecology at the University of Alabama at Birmingham, reported a randomized placebo-controlled trial that found that the pan-retinoid receptor agonist 9-cis retinoic acid (9-CRA), which had demonstrated potent chemopreventive activity in preclinical models, had no significant effect on CIN regression in a trial of 114 patients with CIN-2/3.
Patients were randomized to receive placebo or 9-CRA at 25 or 50 mg/day and followed for 12 weeks. At the end of the trial, all patients had loop excision procedures, and pretreatment histology was compared with loop specimens.
Nearly identical rates of CIN regression occurred in the three treatment groups: 32% with placebo and the lower dose of 9-CRA and 36% with the higher dose of 9-CRA. Some progression occurred in the patients, but no cancers developed. Subgroup analysis revealed a trend favoring higher efficacy for 9-CRA in patients with CIN-2.
“The placebo group had a high rate of regression, emphasizing the importance of having a placebo group in these trials,” Dr. Alvarez said. “The early enthusiasm for 9-cis retinoic acid was generated by non-placebo-controlled studies.”
The investigators continue to evaluate data on surrogate endpoint biomarkers to determine whether 9-CRA at the doses used in the study had any modulating effects on molecular and cellular processes involved in neoplastic transformation, he added.
In another presentation, Michele Follen, MD, a gynecologic oncologist at the University of Texas M. D. Anderson Cancer Center, reported that a randomized trial of 4-HPR (also called fenretinide) was terminated prematurely when an interim analysis revealed worse outcomes in patients on active treatment.
The agent appeared to be a good candidate for a chemopreventive strategy in cervical cancer because it induces apoptosis though non-retinoic acid-receptor mechanisms and has a low toxicity, she explained.
The study involved 39 patients with biopsy-confirmed CIN-2/3 and negative endocervical curettage. The patients were randomized to receive placebo or 4-HPR at a dose of 200 mg/day for 27 days, followed by a three-day drug holiday.
Treatment continued for six months, and follow-up was to 12 months. Patients whose disease progressed had unblinding of their therapy, and placebo-treated patients who progressed could cross over to 4-HPR.
An interim analysis showed significantly worse outcomes for one of the treatment groups at 12 months, and the trial was halted. When the code was broken, the data showed worse outcomes at six and 12 months in the 4-HPR group.
Six-month response rates were 25 percent for 4-HPR and 44 percent for placebo, and 12-month response rates were 20 percent for 4-HPR and 50 percent for placebo. The difference achieved statistical significance at 12 months.
Analysis of 4-HPR continues on surrogate endpoint biomarkers, and future plans may include clinical evaluation in a secondary prevention environment and evaluation of topical 4-HPR.
Because 4-HPR has shown significant anti-cancer activity in the laboratory, the trials results came as a surprise, said Dr. Follen. One possible explanation for the findings is that the 4-HPR dose used in the trial was too low, an issue that is being evaluated in the laboratory.
Investigators are not yet ready to give up on the agent, she added, and future plans might include clinical evaluation in a secondary prevention environment and evaluation of topical 4-HPR. Analysis continues on surrogate endpoint biomarkers.