Phase II study of carboplatin and edatrexate (10-EdAM) with leucovorin rescue for patients with recurrent squamous cell carcinoma of the head and neck.

Recurrent squamous cell carcinoma of the head and neck is poorly responsive to chemotherapy in most patients; therefore, the development of new approaches is essential. Edatrexate is a new antifolate with improved preclinical antitumor activity when compared to methotrexate. The purpose of this study was to define the feasibility and efficacy of combining edatrexate with another active single agent, carboplatin in chemotherapy-naive recurrent disease. Carboplatin was given as an outpatient on day 1 at a dosage based on the formula: Dose (mg/m2) = (0.091) (creatinine clearance) (body surface area) (desired percentage change in platelet count) + 86. Edatrexate (80 mg/m2) was given on days 1, 8, and 15 of a 21 day cycle. Calcium leucovorin 15 mg was given orally every 6 h for 4 doses after edatrexate. Of the 26 patients entered on the study, 1 was invaluable for toxicity or response and 3 patients were evaluable for toxicity only. Grade 3 or 4 neutropenia occurred in 2 patients each, and grade 3 or 4 thrombocytopenia occurred in 2 and 4 patients, respectively. Grade 3 stomatitis occurred in only two patients. Overall, major responses occurred in 2 of 22 evaluable patients (9%). The combination of carboplatin and edatrexate was not superior to the results expected with either agent alone.

Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin.

Acute myocardial infarction was observed in two patients receiving standard intravenous doses of 5-fluorouracil (5-FU)-based chemotherapy. Therefore, the authors prospectively assessed the thrombogenicity of this agent by studying ten patients, six with head and neck cancer and four with gastrointestinal malignancies, receiving 5-FU (1 g/m2/day) as a constant intravenous infusion over a 4-day or 5-day period. The six patients with head and neck cancer also received a single dose of 100 mg/m2 of cisplatin on day 1. Blood samples were obtained preinfusion, 24 hours into the infusion, and postinfusion. Samples were assayed for fibrinopeptide A (FpA) by enzyme-linked immunoassay, for protein C activity (PCa) using a chromogenic substrate (Spectrozyme PCa), and protein C (PCag) and free protein S antigen (PSag) by electroimmunoassay. No patient experienced a thrombotic event. A significant increase was observed in FpA levels during the infusion which returned toward baseline at the conclusion of the infusion. After infusion of 5-FU, the PCa value was significantly lower than the PCag (37 +/- 17 versus 69 +/- 24%; P less than 0.002). No effect on protein S was observed. The changes in the patients receiving 5-FU alone were comparable to those who also received CDDP. The authors conclude that during the infusion of 5-FU, the rise in FpA activation and reduction in PCa as compared to PCag are compatible with activation of coagulation.