Topoisomerase I Inhibitors Show Promise Against Difficult-to-Treat CNS Tumors

DURHAM, North Carolina— Topoisomerase I inhibitors have shown promising activity in difficult-to-treat tumors of the central nervous system (CNS), according to Henry S. Friedman, MD. In studies of camptothecins, both irinotecan (Camptosar) and topotecan (Hycamtin) showed "prodigious activity" in slowing tumor growth and causing tumor regression in subcutaneous xenografts of human gliomas, Dr. Friedman told those attending the Vanderbilt University Symposium. Dr. Friedman is Jones B. Powell, Jr., Professor of Neuro-Oncology at Duke University Medical Center in Durham, North Carolina.

"In studies of intracranial glioma xenografts, median survival increased by 29% to 39% with topotecan, 114% with irinotecan, and by 48% with 9-aminocamptothecin (9-AC)," Dr. Friedman reported. "In intracranial medulloblastoma xenografts, median survival increased by 25% with 9-AC and by 73% with irinotecan."

These preclinical studies led in 1998 to a phase II trial of irinotecan in 60 patients with recurrent malignant glioma. Patients were treated with irinotecan 125 mg/m² weekly x 4, with 2 weeks’ rest between cycles. Physical examinations and magnetic resonance imaging (MRI) studies were performed every cycle.

"In these 60 patients there were 9 partial responses, 4 minimal responses, and 13 patients with stable disease," Dr. Friedman said. "We thought there should have been a higher response rate. When we examined the data more closely, we found that patients on the anticonvulsants carbamazepine (Tegretol), phenobarbital, or gabapentin (Neurontin) actually had irinotecan (SN-38) plasma levels about 25% of expected, so most of these patients were being underdosed. An estimated irinotecan dose of 410 mg/m²/week x 4 with a 2-week break would be needed for most patients on these anticonvulsants, although there is considerable interpatient variability."

Combined with Carmustine

Irinotecan has also been combined with chloroethylating agents such as carmustine in malignant glioma. Dr. Friedman said that a phase II trial of irinotecan plus carmustine in patients with recurrent malignant glioma showed that carmustine should be given first to achieve optimal effect from the regimen.

In this trial, the carmustine dose was 100 mg/m² on day 1. Irinotecan was administered at 125 mg/m² in patients not on anticonvulsants and 225 mg/m² in patients on anticonvulsants, given on days 1, 8, 15, 22 and skipping days 29 and 36. The combination significantly increased activity over that seen with irinotecan alone.

Temozolomide (Temodar) has also been tested in combination with irinotecan for treating malignant glioma. Dr. Friedman said that a phase I trial will accrue patients into two strata, depending on whether the patient uses carbamazepine, hydantoin (Dilantin), or phenobarbital, or not.

Irinotecan will be given prior to temozolomide on day 1 of each cycle at 200 mg/m²/d x 5 days, every 6 weeks. Irinotecan will be given in 4 weekly administrations followed by a 2-week rest. Irinotecan doses will escalate from 40 to 125 mg/m²/wk.