Topotecan - A review of its efficacy in small cell lung cancer

Topotecan, a water soluble semisynthetic derivative of camptothecin, has de monstrated antineoplastic activity in a wide range of cell culture and xeno graft systems and is currently approved for second-line therapy in ovarian and small cell lung cancer (SCLC). The drug inhibits replication of rapidly dividing cells by disrupting the normal function of the nuclear enzyme top oisomerase I. The efficacy of topotecan is related to exposure time and the recommended regimen is 1.5 mg/m(2) as a 30-minute intravenous infusion, da ily for 5 days, repeated every 21 days. In phase II trials of topotecan in SCLC (usually with the 1.5 mg/m(2), 5 da y regimen) the overall response rate in refmetory patients (those who had r elapsed less than or equal to 90 days after first-line therapy) was low at 2 to 11%, whereas in sensitive patients (those relapsing greater than or eq ual to 90 days after first-line therapy) the overall response rate was 14 t o 37%. Topotecan was compared with combined cyclophosphamide/doxorubicin(ad riamycin)/vincristine (CAV) therapy in patients with relapsed, sensitive (r elapsed greater than or equal to 60 days after first-line therapy) SCLC. Th e response rates were 24.3% and 18.3% and, respectively, for the topotecan- and CAV-treated groups, and no significant differences were detected when primary efficacy endpoints (response rates and duration) were compared. How ever, the results of a symptom-specific questionnaire for SCLC did suggest that topotecan offend superior control of some symptoms. SCLC is usually treated with combinations of cytotoxic drugs, and topotecan is showing promise when partnered with paclitaxel and platinum compounds. The efficacy of an oral formulation of topotecan is also being investigated : preliminary results are encouraging and suggest similar efficacy to intra venous formulations, but with less frequent neutropenia. The tolerability a nd compliance advantages of oral topotecan may make this the route of choic e in the future. Noncumulative anaemia, neutropenia and thrombocytopenia are the dose-limiti ng adverse effects associated with topotecan. CAV and topstecan therapy had similar suppressive effects on neutrophils in patients with SCLC, but the incidences of grade 3 or 4 anaemia and grade 3 thrombocytopenia were signif icantly higher in topotecan-treated patients. Non-haematological adverse ev ents in SCLC patients treated with topotecan or CAV were similar and most w ere grade 1 or 2. Gastrointestinal disturbances were common in both groups, as were alopecia and fatigue. Conclusions: In a large randomised comparative study, topotecan was as effe ctive as CAV in treating relapsed SCLC. The response rate was modest and fu rther comparative and drug-combination studies are required to accurately p osition topotecan within the schedule of available drugs used to treat SCLC , particularly in relation to first-line therapy, However, recurrent SCLC i s extremely intractable to therapy and topotecan is a valuable extension to the limited range of treatment options for SCLC.