Unexpected toxicity of combined modality therapy for small cell carcinoma of the lung a southwest oncology group study

Combination chemotherapy with cyclophosphamide, vincristine, methotrexate and Adriamycin was delivered to 35 patients with small-cell carcinoma of the lung (28 with extenstive and 7 with limited disease), including elective administration of intrathecal methotrexate. Whole-brain irradiation (3000 rad in 10 fractions) was then administered, with concomitant systemic cyclophosphamide and methotrexate for patients with extensive disease. Those with limited disease received concomitant chest irradiation without chemotherapy. Maintenance therapy then involved cyclophosphamide 750 mg/m² day 1, and methotrexate 30 mg/m²days 1 and 8, every 3 weeks. In only 2 patients reinduction was carried out at 24 weeks with the original chemotherapy. Myelosuppression was severe; there were at least 2 drug-related deaths from this cause in the induction period, and 15 febrile episodes with leukopenia. Stomatitis was more frequent and more severe in "maintenance" than in "induction" courses, especially the first maintenance course which was given with concomitant whole-brain irradiation. In addition, 13 episodes of unusual toxicity occurred in close temporal relation to systemic methotrexate administration, usually associated with stomatitis, in patients who were on maintenance therapy. These included 3 episodes of loss of consciousness, 4 of generalized erythroderma, 2 of "flu"-like syndrome, and I each of the following: fatal, bilateral interstitial pneumonia; reversible, eosinophilic pleural effusion; acute myocardial infarction; and renal compromise with hematuria. As a result of this unexpected and protean toxicity, the pilot study was discontinued. However, at this time seven patients (4 with extensive and 3 with limited disease) remain in complete remission.