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

Abstract

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.

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

“…In breast cancer, activity of between 34 and 41% was seen in 2 trials involving 73 patients (Table 8), [168,169]. By combining edatrexate with various other cytotoxic drugs response rates of up to 47% are achievable (Table 9, [178][179][180]). Although an edatrexate, cisplatin, vinblastine, doxorubicin combination was highly active [180], 3 treatment related deaths occurred and patients experienced deterioration in quality of life.…”

New Antifolates: Pharmacology and Clinical Applications

“…The major dose-limiting toxicities of high-dose EdAM have been stomatitis, skin rash and elevated liver transaminases. EdAM is also undergoing clinical testing in combination with other active agents, including carboplatin [80][81][82], cisplatin [83][84][85], cyclophosphamide [83], doxorubicin [85,86], mitomycin and vinblastine [87], ifosfamide [84], and paclitaxel [88,89]. Many of these combination regimens combine EdAM with leucovorin rescue [80,84,90] or oral cryotherapy [81,82] in an attempt to decrease the incidence of stomatitis.…”