Topotecan Active as First-Line Combination Therapy for Advanced Non-Small-Cell Lung Cancer

A new study presented at the Ninth World Congresson Lung Cancer demonstrated that topotecan (Hycamtin) in combination with carboplatin (Paraplatin) is active as a first-linetreatment of advanced non-small-cell lung cancer. Topotecan is not currentlyapproved for the treatment of patients with non-small-cell lung cancer.

The noncomparative, multicenter study, conducted by L’HopitalArnaud de Villeneuve, in conjunction with SmithKline Beecham, evaluated theactivity of topotecan in combination with carboplatin in chemotherapy-naivepatients. Results from the investigation indicate that the combination producedan overall response rate of 14% in evaluable patients, with 49% achieving anarrest in tumor progression.

"These results indicate that topotecan is active in solidtumors other than ovarian and small-cell lung cancer," said Jean-LouisPujol, MD, L’Hôpital Arnaud de Villeneuve, Montpellier, France. "Theyalso underscore the fact that combination treatment with topotecan may offerpatients with non-small-cell lung cancer an additional therapeuticoption."

Activity of Topotecan

In this phase II trial, 47 chemotherapy-naive, non-small-celllung cancer patients were treated with IV topotecan 0.5 mg/m² daily for 5 days,with an area under the concentration-time curve (AUC) 5 dose of carboplatinadministered on the first day of treatment. The regimen was repeated every 21days. Patients received a median of four courses of treatment; reductions andescalations in the dose of topotecan were based on the incidence of toxicityand/or adverse events.

Of the 42 patients who were evaluable for efficacy, 14% achievedan objective response (one complete response, five partial responses). Stabledisease that lasted at least 56 days was reported in 36% of patients (n = 17).When the overall response and stable disease rates were combined, 49% ofpatients achieved an arrest in tumor progression. The median duration ofresponse was 16 weeks, with a median survival of 32.7 weeks.

"The study results are interesting in light of the EasternCooperative Oncology Group (ECOG) 1594 study comparing three front-line non-small-celllung cancer regimens to the standard of care that was presented at ASCO[American Society of Clinical Oncology] this spring [2000], where the mediansurvival across the four regimens ranged from 31 to 36 weeks," said Dr.Pujol.

Hematologic toxicities were the most frequent adverse events,but were reversible in most patients. The most common hematologic eventsincluded grade 3/4 anemia in 36% of patients, neutropenia in 53%, andthrombocytopenia in 58%. Nonhematologic events included asthenia in 11% ofpatients, dyspnea in 6%, and infection in 6%. These toxicities were mild ormoderate in severity and manageable with the usual methods of supportive care.

Additional Data

Additional presentations at the Ninth World Congress on LungCancer included a phase I/II study that evaluated the activity of oral topotecanin combination with either paclitaxel (Taxol) or cisplatin (Platinol) in thetreatment of chemotherapy-naive patients with non-small-cell lung cancer.According to data from the phase I trial, oral topotecan in combination withpaclitaxel produced an overall response rate of 12% (n = 33) in patients whowere evaluable for response. Further, 27% of the treated patients achievedstable disease lasting at least 56 days.

The investigators noted that it was premature to evaluatesurvival. Grade 3 and 4 hematologic toxicities included neutropenia and anemia,which were reported in 68% and 18% of patients, respectively. The most frequentgrade 3 and 4 nonhematologic toxicities included dyspnea (17%), nausea (12%),and vomiting (12%) at the maximum tolerated dose.

Phase II Study

In the phase II study of 50 patients, 28% (n = 14) of thosetreated with oral topotecan and cisplatin achieved a partial response, while 16%(n = 8) experienced disease stabilization that lasted more than 56 days. In thisstudy, the median survival was 35.4 weeks. The most common adverse eventsincluded grade 3/4 neutropenia, anemia, and thrombocytopenia in 70%, 48%, and46% of patients, respectively. All of the nonhematologic toxicities were mild ormoderate and manageable and included vomiting (27%), anorexia (20%), anddiarrhea (20%).

"These data illustrate that oral topotecan in combinationwith paclitaxel or cisplatin produces activity with acceptable tolerability andan acceptable androgen-receptor profile," said Professor Torben Palshof,MD, Arhus Kommunehospital, Copenhagen, Denmark. "These results, togetherwith those of the topotecan and carboplatin study, indicate that topotecan hasthe potential to provide patients with an additional therapeutic option.Further, the 56-day sustained disease stabilization observed in these trialsbodes well for the use of topotecan in this treatment population."

Studies assessing the safety and efficacy of oral topotecan invarious tumor types are currently ongoing.