Cisplatin, 5-fluorouracil, and high-dose oral leucovorin for advanced head and neck cancer.
Both cisplatin and leucovorin may increase the activity of 5-fluorouracil (5-FU) by increasing the intracellular concentration of reduced folates. Therefore, a Phase I study was conducted in patients with recurrent or metastatic head and neck cancer in which high doses of oral leucovorin were added to the combination of cisplatin and 5-FU. Patients received intravenous cisplatin 100 mg/m2 on day 1, followed by a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days. Leucovorin 50 mg/m2 orally was administered from the start of the cisplatin infusion and then every 6 hours throughout the 5-FU infusion. The dose of 5-FU was increased to 800 mg/m2/day and 1 g/m2/day according to observed toxicity. In a second phase of the study, the dose of leucovorin was increased to 50 mg/m2 orally every 4 hours. Twenty-five patients were registered: 23 had recurrent head and neck cancer after extensive treatment; two had newly diagnosed metastatic disease. The maximum tolerated dose of 5-FU was 800 mg/m2/day with leucovorin administered every 6 hours. Toxicities at that level included mild-to-moderate myelosuppression. Mucositis in the previously irradiated field prevented the further increase of the 5-FU dose to 1 g/m2/day. Identical toxicities were observed when administering 5-FU at 800 mg/m2/day with 50 mg/m2 of leucovorin every 4 hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who had previously received cisplatin and 5-FU as induction chemotherapy). Eight patients did not respond. The median survival for all 25 patients was 6.5 months. It was concluded that the combination of cisplatin, 5-FU, and leucovorin is active in the treatment of recurrent head and neck cancer. The maximum tolerated dose of 5-FU in previously treated patients is 800 mg/m2/day, with mucositis being the dose-limiting toxicity. Further investigation of this regimen as neoadjuvant chemotherapy in previously untreated patients with locally advanced head and neck cancer is in progress.
Department of Medicine, University of Chicago, Illinois.
E E
EE
Vokes
R L
RL
Schilsky
R R
RR
Weichselbaum
A
A
Guaspari
C M
CM
Guarnieri
S M
SM
Whaling
W R
WR
Panje
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local
D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil