Non-Cross-Resistant Agents for Ovarian Cancer

BOCA RATON, Fla--Topotecan (Hycamtin) and other non-cross-resistantdrugs appear to be good salvage therapy for patients with recurrent ovariancancer, Robert F. Ozols, PhD, said at the annual meeting of the Networkfor Oncology Communication and Research.

He noted that oncologists are "very good at getting people intoa clinical complete remission," using cytoreductive surgery and standardfirst-line regimens of cisplatin (Platinol) or carboplatin (Para-platin)plus paclitaxel (Taxol). "But the problem is that most of these patientswill recur," said Dr. Ozols, senior vice president of medical science,Fox Chase Cancer Center.

For those who recur with drug-sensitive disease, there is no need toswitch to non-cross-resistant agents, he said. For patients who recur withdrug-resistant or drug-refractory disease, a number of newer non-cross-resistantdrugs are available.

These include the topoisomerase I inhibitor topotecan (Hycamtin), oraletoposide (VePesid), gemcitabine (Gemzar), vinorelbine (Navelbine), andliposomal doxorubicin (Doxil), along with two older drugs, hexamethymela-mine(Hexalen) and ifosfamide (Ifex).

In a European trial, Dr. Ozols said, patients with recurrent ovariancancer who did not receive paclitaxel up-front were randomized to receivetopotecan or paclitaxel. The results showed a response rate of 23% fortopotecan versus 14% for paclitaxel, response duration of 32 weeks versus20 weeks, and time to progression of 23 weeks versus 14 weeks.

"Of course," Dr. Ozols said, "all you can really concludefrom this type of study is that topotecan is an active agent in recurrentdisease." The study is irrelevant to today's practice, he said, since"everyone starts off with a first-line treatment of paclitaxel."

As a second-line treatment, topotecan is usually given at the FDA-approveddosing schedule of 1.5 mg/m² qd × 5 every 3 weeks. Thedose-limiting toxicity in phase I trials was hematologic, primarily neutro-penia.However, Dr. Ozols said that the hematologic problems are both predictableand manageable.

"And since there is no evidence that a higher dose equals a higherresponse," he said, "you can back off early if there are signsof hematologic toxicity." He even suggests starting with a lower doseif patients have had extensive therapy, and decreasing the dose at thefirst signs of even mild hematologic toxicity.

The future direction of topotecan use, he said, involves giving it atdifferent schedules, combining it with other agents, and giving it as partof initial therapy.

Dr. Ozols also described a Gynecologic Oncology Group trial of oraletoposide in 70 patients with recurrent ovarian cancer. Platinum-resistantpatients had an overall 27% response rate with oral etoposide and platinum-sensitivepatients had a 34% response rate.

Gemcitabine, which is approved for use in pancreatic cancer, is currentlybeing studied in Europe where it is showing a 19% response rate in platinum-resistanttumors. There is also evidence of a possible in vitro synergy between gem-citabineand cisplatin.

Results are expected soon for studies in recurrent ovarian cancer ofliposomal doxorubicin and the vinca alkaloid vinorelbine, he added.

While there are many trials going on and many agents now available,there is no drug of choice in second-line treatment, Dr. Ozols said. Sothe criteria for selecting second-line therapy lies in three areas--patientpreference, toxicity profile, and oral versus IV.

He recommends selecting a drug and evaluating the patient after twocourses of treatment. "If the drug is not working, then try anotheragent," he said. "The worst we can do is administer a drug thatis not effective."