Research targets evolution of CIN

OB/GYN News, May 15, 2006 by Roxanne Nelson

LAS VEGAS -- Chemopreventive therapeutic agents may be able to alter the molecular changes that occur in the progression from preinvasive to invasive cervical disease, Dr. Janet S. Rader said at a meeting of the American Society for Colposcopy and Cervical Pathology.

"Chemoprevention for cervical cancer is a priority," said Dr. Rader, who is a professor of obstetrics and gynecology at Washington University in St. Louis. "There are no standard-of-care treatments now for cervical dysplasia, but there are several ongoing clinical trials."

In chemoprevention trials in the United States, researchers are examining the efficacy of a diverse array of agents including a topical immunomodulator, a cell-cycle inhibitor that can induce apoptosis, an amino-bisphosphonate, and celecoxib.

The cyclooxygenase-2 (COX-2) inhibitors are key enzymes in the conversion of arachidonic acid to prostaglandins, and the COX-2 isoform has been associated with inflammation and carcinogenesis.

Some data indicate an inverse relationship between the risk of cancer and the intake of COX-2 inhibitors.

Investigators in the Phase II Randomized Study of Celecoxib in Patients With Cervical Intraepithelial Neoplasia 3 are studying the efficacy of celecoxib in terms of achieving histologic complete or partial response, as well as its toxicity in these patients.

"Nonsurgical treatment for this disease is of benefit due to unknown effects of surgery on future pregnancy outcomes," said Dr. Rader. "The ongoing chemoprevention studies are open and accruing patients, and all are worth evaluating, including COX-2 inhibitors."

The goal of chemoprevention is to interrupt the sequence of events leading to malignancy by a chemical agent, thereby saving lives as well as ameliorating the heavy burden that cancer places on the health care system.

Cervical cancer has been given considerable attention by researchers, as the cervix has proved to be an ideal model for the study of chemoprevention in humans.

Strong evidence exists that normal cervical epithelium proceeds through a precancerous stage prior to the development of invasive cancer.

"Cervical dysplasia can be recognized early in its disease process and lends itself for close observation," said Dr. Rader.

Dr. Rader focused her presentation on secondary strategies, those that would target women with high-grade cervical intraepithelial neoplasia (CIN 3) to either induce a complete remission or a partial regression to a lower-grade neoplasia (CIN 1).

Secondary chemoprevention clinical trials are easier to orchestrate than primary prevention studies, because in the latter, larger populations are needed to show significance.

Past and ongoing trials have evaluated a large number of dietary, herbal, and pharmacologic agents for potential chemopreventive effects. But these agents are often cell-type and dose dependent, said Dr. Rader, and in vitro effects may not be reproduced in vivo.

There have been 11 large phase IIb/III clinical chemopreventive trials evaluating a number of agents. Only one trial, which evaluated the effectiveness and safety of interferon-[beta] in women with recurrent cervical human papillomavirus lesions, demonstrated efficacy.

But on subanalysis, Dr. Rader pointed out, some of the studies that reported negative results had, in fact, some positive results when analyzed in subpopulations.

More than 668 patients with CIN 1-3 have participated in 32 smaller trials that evaluated the efficacy of interferon-[alpha], -[beta], and -[gamma].

But many of these trials were too small to be adequately powered, interferon can be highly toxic, and the follow-up period wasn't sufficient to determine long-term effects.

A number of small trials have also evaluated agents such as beta carotene, retinoids, 5-fluorouracil cream, and in-dole-3-carbinol.

One of the problems in chemopreventive trials is waiting for an end point, said Dr. Rader. "We don't want to wait for a patient to get cancer, so we need to find other workable end points."

Aside from reliable surrogate biomarkers, other challenges include the high and variable natural regression rates, the effect of colposcopic biopsies, a sufficiently large sample size for statistical power, the teratogenicity of some of the agents used in women of childbearing potential, and dose and duration of treatment for effects on the cervix.

BY ROXANNE NELSON

Contributing Writer