Thalidomide aids topotecan efficacy in ovarian ca

OB/GYN News, May 15, 2006 by Doug Brunk

PALM SPRINGS, CALIF. -- Combining thalidomide with topotecan for the treatment of recurrent ovarian cancer significantly increased the response to therapy and the duration of progression-free survival without added toxicity, according to a multicenter, randomized trial presented at the annual meeting of the Society of Gynecologic Oncologists.

"We've identified a new concept in the treatment of ovarian cancer," Dr. Levi S. Downs Jr. said in an interview. "That is, combining biologic agents with chemotherapy appears to work in this disease."

In what he said is the first trial of its kind to involve thalidomide, Dr. Downs and his associates at seven sites enrolled 69 women with recurrent ovarian cancer, as documented by examination, imaging study, or elevated level of CA-125, between April 2001 and July 2005, said Dr. Downs, of the division of gynecologic oncology at the University of Minnesota, Minneapolis.

Study participants had received one or two prior platinum-based chemotherapy regimens.

The researchers randomized 30 women to receive topotecan 1.25 mg/m2 on days 1-5 of a 21-day cycle and 39 women to receive the same topotecan regimen plus thalidomide 200 mg/day, which was increased to 800 mg/day as tolerated.

There were no differences between the two groups in toxic effects, including fatigue, constipation, peripheral neuropathy, and deep vein thrombosis.

The median dose of thalidomide in the topotecan plus thalidomide group was 200 mg/day.

The overall response rate in the topotecan-alone group was 21%, compared with 47% in the topotecan-plus-thalidomide group, a statistically significant difference.

The median progression-free survival was 4 months for the topotecan-alone group, compared with 6 months for the topotecan-plus-thalidomide group, also a statistically significant difference.

Researchers noted a trend toward improved overall survival in the topotecan-plus-thalidomide group, but the difference between the two groups did not reach statistical significance (a median of 15 months in the topotecan-alone group vs. 19 months in the topotecan-plus-thalidomide group).

At the meeting, Dr. Scott McMeekin, a gynecologic oncologist with the University of Oklahoma Health Sciences Center, Oklahoma City, called the study results "provocative" but took issue with the trial design. "On the surface it looks like a phase III randomized trial, but it uses a phase II end point of response rate," he explained. "Small numbers of patients using response rate as an end point suggests that this is more like a randomized phase II study, in which case it's more difficult to compare outcomes or end points between two treatment arms."

Dr. Downs, who said that lack of funding resulted in the trial being 11 patients short of the enrollment goal, remained optimistic about the study results. "We're trying to figure out why this [combination of agents] worked," said Dr. Downs, who also directs the University of Minnesota's Women's Health Center. "If we can identify that, it may help us to make better analogues. Next is to determine if the analogues of thalidomide that are available now have the same relationship with topotecan. There are new drugs in the pipeline that we are going to be looking at in this same setting and with this combination."

He hypothesized that thalidomide may fight tumors by inhibiting the tumor's ability to generate new blood vessels. "We also know that thalidomide has an immune stimulatory mechanism," he added. "It might be improving the patient's full immune system's response to new cancers that are growing."

Celgene Corp., which makes thalidomide, partially funded the trial; Dr. Downs said that he has no financial interest in the company.

BY DOUG BRUNK

San Diego Bureau