Adding the chemotherapy drug topotecan to a standard first-line chemotherapy regimen in women with advanced ovarian cancer offers no benefit, according to the final results of an international phase III clinical trial published in the August 2 Journal of the National Cancer Institute. Patients who received topotecan also had higher grade hematological side effects such as low platelet and red blood cell levels.

Combined with similarly disappointing findings in other phase III trials assessing different chemotherapy regimens, these results suggest that standard cytotoxic chemotherapy drugs have run their course in ovarian cancer.

"Certainly we have pushed the available agents very far," said Dr. Edward Trimble of NCI's Division of Cancer Treatment and Diagnosis. "It's unclear where we go next with chemotherapy."

Dr. Trimble did stress that, in the appropriate patients, intraperitoneal delivery of chemotherapy has now proven to have a substantial benefit.

Ovarian cancer continues to be a highly fatal disease. Even patients who respond to initial treatments often have disease recurrence and die. In response, several large phase III trials have tested adding different chemotherapy drugs - including doxorubicin, gemcitabine, and epirubicin - to the currently recommended first-line therapy of paclitaxel and carboplatin. But, explained this most recent study's lead author, Dr. Jacobus Pfisterer of the Universtitatsklinikum Schleswig-Holstein in Kiel, Germany, none have demonstrated improvements in overall or progression-free survival compared with the standard regimen alone.

The current trial, led by French and German clinical trial groups, involved more than 1,300 women with previously untreated advanced ovarian cancer. Participants were randomized to the standard first-line therapy of six cycles of paclitaxel and carboplatin with or without four cycles of topotecan. The overall and progression-free survival rates were effectively the same.

In an accompanying editorial, Dr. William P. McGuire from the Weinberg Cancer Institute in Baltimore, argued that it was time to abandon testing new chemotherapy regimens in clinical trials and, instead, "use all our valuable patient resources to evaluate whether ovarian cancer responds to the targeted therapies as other solid tumors have."

A number of phase II clinical trials, and at least one phase III trial, are testing different targeted therapies in patients with ovarian cancer. Most of these trials involve anti-angiogenic agents.

There also is a randomized phase III trial pitting the trio of carboplatin, paclitaxel, and the anti-angiogenic agent bevacizumab (Avastin) against carboplatin and paclitaxel alone in women with advanced ovarian cancer.

According to Dr. Robert F. Ozols, senior vice president of Fox Chase Cancer Center in Philadelphia, bevacizumab has promise in this setting.

"What's striking is that bevacizumab has had activity as a single agent in ovarian cancer, whereas in other tumor types it has had very little activity [when used alone]," he said.

Although targeted therapies should be aggressively pursued, Dr. Ozols added, some investigational cytotoxic agents may yet have value against ovarian cancer.

"We still don't know whether some of the newer agents may have a benefit," he said. "I wouldn't abandon cytotoxic drugs just yet."

By Carmen Phillips