Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non‐small cell lung cancer

The authors treated 32 patients with Stage IIIB or IV non‐small cell lung cancer (NSCLC) with an outpatient regimen of edatrexate (10‐ethyl‐10‐deaza‐aminopterin) (10‐EdAM) on days 1 and 8, cyclophosphamide on day 1, and cisplatin on day 1, repeated every 3 weeks with dose modification. The 22 men and 10 women (median age, 57 years of age) had no prior chemotherapy and a Zubrod performance status less than or equal to 2. A schedule with initial doses of 80 mg/m², 800 mg/m², and 80 mg/m², respectively, yielded a 47% major response rate with two complete responses (95% confidence interval [CI], 25% to 70%), but it also yielded significant stomatitis and myelosuppression. A schedule with reduced starting doses (70 mg/ m², 700 mg/m², and 70 mg/m²) was better tolerated, but dropped the major response rate to 27% with no complete responses (95% CI, 11% to 52%). Median survival time was 39 weeks for all 30 evaluable patients without a significant difference between the treatment groups (which were comparable in patient characteristics). Major response, however, was associated with longer survival time than minor response or no change (P = 0.024) or progressive disease (P = 0.001) (median survival times, 55, 39, and 27 weeks, respectively). When the doses delivered were compared, patients treated with the reduced dose schedule received less mean 10‐EdAM per course (P = 0.01), although the doses of cyclophosphamide and cisplatin were comparable to the original dose schedule for the second course and thereafter. These results suggest that this three‐drug regimen may have synergistic antitumor effects, with a steep dose‐response relationship, particularly with 10‐EdAM. With amelioration of the dose‐limiting stomatitis of 10‐EdAM, it seems possible to maximize the antitumor effects of this regimen.