Topotecan Used in Aggressive Front-Line Therapy for SCLC

NEW YORK—A study of an aggressive front-line regimen for limited-stage small-cell lung cancer (SCLC) is proceeding in a community-based setting. The regimen consists of topotecan (Hycamtin), carboplatin (Paraplatin), and paclitaxel (Taxol) along with radiation therapy. Howard A. Burris III, MD, director of drug development, The Sarah Cannon Cancer Center, Nashville, described the study rationale and design at the Chemotherapy Foundation Symposium XIX (abstract 62).

The trial is being conducted via the Minnie Pearl Research Network, a consortium of community-based physicians throughout the Southeast. In 14 months, 78 of the projected 100 patients have been enrolled. "It’s clear," Dr. Burris said, "that the doctors are interested in pursuing this sort of aggressive therapy."

The rationale for the drug triplet, Dr. Burris said, stems from preclinical studies showing evidence of topotecan’s synergism with both taxanes and platinums. An inhibitor of topoisomerase I, topotecan has a half-life of 3 to 4 hours, "which is nice for combining with other drugs," he said. Its renal excretion differs from the hepatic metabolism of most cancer drugs, he added.

The protocol calls for paclitaxel at 135 mg/m², carboplatin to AUC 5, and topotecan at 0.75 mg/m². The topotecan dose, Dr. Burris noted, is half that generally used in other settings and is administered only on the first 3 days of the 21-day cycles. Thoracic radiation at 61.2 Gy is given concurrently with the chemotherapy in cycles 3 and 4. After completion of therapy, responders receive oral etoposide (VePesid).

Previous Phase II Study

The chemotherapy regimen is the same as that used in a prior phase II study completed by the Minnie Pearl Research Network, but the radiation dosage has been increased from 45 Gy. The prior study included patients with both extensive and limited-stage disease, but thoracic radiation was not given to those with advanced-stage disease. Follow-up for responders (and for stable limited-disease patients) included oral etoposide for three cycles and then, for complete responders, prophylactic cranial radiation.

Response rates were high, Dr. Burris noted, 93% in limited disease and 88% in extensive disease. "The encouraging thing for limited-stage patients is the high proportion of complete responders— 37%," he observed. "Adding on the oral etoposide did not seem to convert many patients to responders." Although three patients with limited disease did go on to have a complete response after etoposide, he indicated that this might have been an effect of time.

Median survival was 18 months for patients with limited disease and 9 months for those with extensive disease. The 1-year survival rate in the limited-disease group was 75% and the 2-year rate, 45%, "findings that we think are encouraging," Dr. Burris said.

Grade 4 neutropenic fever occurred in 6% of therapy courses and in 21% of patients. Topotecan, a myelosuppressive drug, "did not seem to add to the nonhematologic toxicity profile," he noted. The problems came in patients with a performance status of 2, he said, since seven of the eight treatment-related deaths occurred in this subset. "It’s clear that we need to eliminate that population from aggressive therapy in trials going forward," he said.

Extensive-Stage Disease

Dr. Burris and his associates also have a first-line study of a topotecan regimen underway in patients with extensive-stage SCLC. It compares a regimen of paclitaxel, carboplatin, and etoposide with paclitaxel-topotecan. The hope is that the paclitaxel-topotecan combination may be less toxic but still efficacious. Clinical data on combinations of topotecan with taxanes "are very encouraging," Dr. Burris concluded. "I think more work needs to be done in that direction."