INTERVENTION WITH THE HYPOXIC TUMOR-CELL SENSITIZER ETANIDAZOLE IN THE COMBINED-MODALITY TREATMENT OF LIMITED STAGE SMALL-CELL LUNG-CANCER - A ONE-INSTITUTION STUDY

Purpose: We report the toxicity, patterns of failure and survival of a cohort of patients with limited disease (LD) small-cell lung cancer ( SCLC) treated with combined radiation and chemotherapy. During the cou rse of thoracic irradiation, we added intravenous (i.v.) etanidazole ( SR-2508, a third-generation 2-nitroimidazole) as a hypoxic cell sensit izer in an attempt to reduce the primary local failure rate and improv e survival. Methods and Materials: Between July 1988 and August 1990, 30 consecutive patients with limited disease SCLC were enrolled and tr eated on a Phase II protocol receiving a standard combination chemothe rapy regimen utilizing i.v. cisplatin 25 mg/m(2)/day x 3 days, i.v. et oposide 100 mg/m(2)/day x 3 days alternating with intravenous cyclopho sphamide 1000 mg/m(2)/day, intravenous doxorubicin 15 mg/m(2), and int ravenous vincristine 2 mg (CAV) to a total of six cycles every 3 weeks . Radiotherapy and etanidazole were started after the first cycle of c hemotherapy. Etanidazole was administered intravenously at a dose of 2 g/m(2) three times per week for a total of 30 g/m(2) during the cours e of thoracic radiation that delivered 50.00 Gy tumor dose in 25 fract ions in an overall time of 6 weeks. Results: The overall response rate of the primary lesion in the thorax was 96% (CR + PR), with 64% compl ete responses. The median time to treatment failure was 18 months. Of the patients that have relapsed, only 18% failed in the thorax (alone or concomitant with other sites). This is a marked improvement compare d to the 40-50% rate reported in the literature. The 2-year crude surv ival was 46%. The 3- and 5-year crude survival rate with no evidence o f disease was 33 and 30%, respectively. We have observed a 10% increas e in the incidence of transient etanidazole related peripheral neuropa thies compared to previous etanidazole studies not utilizing systemic chemotherapy. There was no increased incidence of radiation esophagiti s, pulmonary toxicity, or nephro-or myelotoxicity over and above what has been routinely observed with this radio/chemotherapy regimen. Ther e were no treatment related deaths. Conclusion: The moderate increase in etanidazole-related transient peripheral neuropathies could have be en related to the concomitant use of etanidazole with vincristine and cisplatin. Although the almost 50% improvement in the incidence of tum or failure rate in the thorax in this small group of patients did not correlate with an equal marked improvement in their survival, the 5-ye ar survival outcome in our series is at least equal or better than the best reports in the literature of larger clinical trials. We believe there is sufficient data from this study, particularly the improvement of local tumor control, to warrant a large randomized controlled clin ical trial, using the most current systemic chemotherapy with concomit ant thoracic irradiation with or without the most effective available hypoxic cell cytotoxic/sensitizer. (C) 1998 Elsevier Science Inc.