Methotrexate and 5-fluorouracil in sequence in squamous head and neck cancer.

5-Fluorouracil (5-FU), when preceded by methotrexate (MTX), results in synergistic tumor cell kill both in vitro and in vivo in mice. Since MTX concentrations 10 microM or greater maximize the synergy in vitro, we administered sequential MTX-5-FU as follows: MTX 125-250 mg/m2 i.v. followed 1 hr later by 5-FU 600 mg/m2 i.v. Leucovorin (LV) rescue 10 mg/m2 i.v. was given at hr 24, then 10 mg/m2 p.o. every 6 hr for 5 doses. One-hour and 24-hr serum MTX levels were monitored and 24-hr serum creatinine levels obtained. A weekly schedule was adhered to where possible, although most patients had at least one course delayed during the first month of treatment because of toxicity. Maintenance was every 2 wk. Since our initial report (Proc Am Soc Clin Oncol 21:473, 1980), a total of 35 squamous cell head and neck cancer patients, 12 with de novo and 23 with recurrent or metastatic disease, have been treated. Overall response rate is 71%, 65% in recurrent patients, 83% in de novo patients. Complete response rate was 11%. Median response duration for recurrent patients was 3.6 mo. With all deaths scored as disease-related and a minimum follow-up of 18 mo in all patients, a median survival of 11.5 mo for the 23 recurrent and 12 mo for the de novo patients was seen. Pretreatment performance status affected survival with Eastern Cooperative Oncology Group (ECOG) 0-1 patients living significantly longer than bedridden patients (p less than 0.001). Toxicity was either hematologic or gastrointestinal, with diarrhea, the limiting toxicity, accounting for the one drug-related death. The MTX/5-FU combination sequence may provide significant long-lasting palliation in patients with recurrent squamous head and neck cancer.