Nuove prospettive nel trattamento del microcitoma del polomone: Ruolo del topotecan

In spite of the high response rate achievable by combination chemotherapy, the prognosis of Small Cell Lung Cancer patients remains very poor, with a 5-year survival probability not exceeding 10% in the whole population. Any combinations of the old drugs, even at very high doses, failed to translate into substantial improvement of the outcome; therefore, it is mandatory to design new therapeutical approaches based on the use of new molecules with original mechanisms of action. Topotecan is a semisynthetic analog of camptothecin, an alkaloid derived from the oriental tree Camptotheca acuminata, which exerts its cytotoxic effects through the inhibition of the nuclear enzyme topoisomerase I. Several schedules have been tested in the phase I setting, but the short-term daily administration for five days every 3 weeks has initially shown the best therapeutical index, and thus has been recommended for phase II trials. In an ECOG phase II study topotecan at the dose of 2.0 mg/m² d 1-5 every 3 weeks with G-CSF support has given a 39% overall response rate, with a 10-month median survival in chemo-naive patients with extensive disease. THree large phase II studies tested the antitumor activity of topotecan alone at the dose of 1.5 mg/m² d 1-5 q 3 weeks in pretreated SCLC patients. The EORTC trial gave the beset results in terms of response rate. An overall 21.7% activity rate was observed (response rate was 6.4% in refractory and 37.8% in sensitive patients), with a median survival of 5.4 months in the whole population. The North-American and the EUropean trials gave less impressive results as for response rate (11% and 10% respectively), but the median survival times were similar to those reported in the EORTC study (26.6 and 25.7 weeks, respectively). In the pooled analysis of the results of these 3 studies the activity rate of topotecan in the subset of sensitive patients was 18% with a median survival rate of 30 weeks. The role of topotecan in the treatment of SCLC patients relapsed ≤ 2 months after completion of front-line treatment was confirmed by the results of a phase III study comparing topotecan as a single-agent tot he CAV regimen. (25% vs 15%), and both time to progression and overall survival were not significantly different in the two arms. Topotecan alone has not shown a relevant therapeutical activity in truly refractory pretreated patients, as suggested by the results of the EORTC, European and North-American trials, and as confirmed by the data of the MD Anderson Cancer Center study involving only this subset of patients (11% overall response rate). On the basis of these data it seems advisable to evaluate the role of topotecan in the front-line therapy in combination with other antitumor agents. Cisplatin, VP16, paclitaxel have shown an in vitro strong positive interaction with topotecan. Phase I studies evaluating the combination of topotecan with these drugs have been conducted. A combination of topotecan at the dose of 1.0 mg/m² d 1-5 with paclitaxel 135 mg/m² in a 24 h infusion has been tested in 18 chemo-naive extensive SCLC patients with promising results (92% overall response rate and 1-year median survival). In view of the very high hematological toxicity produced by the topotecan- including combinations, resulting in quiet low dose intensities of the drugs employed, further efforts should be made to optimize the modality of administration of this very promising drug.