Extending Platinum-Free Interval in Ovarian Cancer

NEW YORK—A trial is being launched to explore whether lengthening the platinum-free interval will affect recurrent ovarian cancer outcomes, William P. McGuire, MD, medical director, oncology, Franklin Square Hospital Center, Baltimore, announced at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

Data laying the theoretical basis for the project, Dr. McGuire said, include studies in which response rates rose with lengthened platinum-free intervals. If the platinum-free interval is less than 5 months, he noted, "there is a very low chance of response." If the interval is longer than 2 years, in at least one study, he said, the response rate was 59%, "not dissimilar from what you would expect if you were treating a chemonaïve patient." In contrast, when the interval was 6 to 12 months, the response rate was 27% and when the interval was 12 to 24 months, the response rate was 33%.

• Patients’ response to first-line platinum therapy, Dr. McGuire stressed, also affects second-line or salvage efforts. He defined four categories.

• Platinum-refractory patients, he noted, do not respond to primary therapy or have an incomplete response. For these patients, who usually die within 12 to 18 months, he recommended trials of investigational drugs.

• Platinum-resistant patients have a limited response to primary therapy and tumor recurrence within 6 months. These patients, too, he said, are not likely to benefit from a second round of platinum therapy.

• Platinum-sensitive patients have a complete response to primary therapy and do not have recurrent disease until at least 6 months after discontinuation of that treatment.

• Very-platinum-sensitive patients have a complete response to primary therapy and tumor recurrence 18 to 24 months after finishing the initial treatment course.

The majority of ovarian cancer patients, Dr. McGuire said, are platinum sensitive and have platinum-free intervals of 6 to 18 months before disease recurrence. Whether the platinum-free interval can be extended and improve survival remains unknown, he said.

"Does it make sense," he asked, "to withhold platinum therapy in that patient who has a 6 to 18 month platinum-free interval now that we have multiple drugs that have similar response rates to platinum in this patient population?"

The return of platinum sensitivity over time is not fully understood, he noted, "but we do know that a lot of platinum resistance is due to upregulation of excision repair enzymes, and, at least in vitro, if you take platinum out of the cell culture, those excision repair enzymes actually downregulate."

In platinum-sensitive patients with recurrent ovarian cancer, he observed, response rates with nonplatinum agents are comparable to those with platinums in the same setting. In a study by the Gynecologic Oncology Group in which the median platinum-free interval was 9.6 months, Dr. McGuire noted, the response rate to the standard dose of topotecan (Hycamtin) was 33%. "Alternate agents may, in fact, allow a further increase in the platinum-free interval," he said, "and may improve response to platinums later."

Some nonplatinum agents, however, carry a risk of cumulative toxicity, Dr. McGuire cautioned. Weekly doses of paclitaxel (Taxol) at 80 to 100 mg/m² have been associated with cumulative peripheral neurotoxicity in more than 25% of patients, he noted. Among the few agents that have not been shown to increase the adverse event profile, he noted, are topotecan and gemcitabine (Gemzar).

The new randomized trial, Dr. McGuire explained, was designed to explore whether extension of the platinum-free interval makes a clinical difference when relapses are diagnosed 6 to 18 months after completion of initial chemotherapy. It will enroll platinum-sensitive patients with recurrent disease. Patients in one arm of the study will receive carboplatin (Paraplatin) at AUC 6 every 3 weeks. Those in the other arm will be given topotecan at a dose of 1.25 mg/m² for 5 consecutive days.

"At the time of recurrence, there is crossover to the alternate regimen," Dr. McGuire said. The goal, he added, is to learn whether giving topotecan first will increase the response rate to carboplatin "by this artificial extension of the platinum-free interval."