Cisplatin, 5‐fluorouracil, and high‐dose oral leucovorin for advanced head and neck cancer

Abstract

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.

Candidate's Thesis: Polymer Chemotherapy for Head and Neck Cancer

“…It is synergistic with cisplatin in vivo and in vitro and is a cell‐cycle–selective radiosensitizer, inducing the accumulation of cells in the G 2 /M phase of the cell cycle. 22 Furthermore, the four agents used in the present study are known for their synergistic anticancer potential, 2,16–18 thus opening the door for possible combination polymer chemotherapy.…”

“…They have been used successfully in a variety of solid tumors including ovarian and testicular carcinomas, bladder transitional cell carcinomas, small cell lung carcinomas, and head and neck malignancies. 17 The clinical applicability of cisplatin is limited by its systemic toxicity, including gastrointestinal tract, otic, and renal system toxicity, and peripheral neuropathy.…”

“…Methotrexate is clinically effective against a large number of malignancies including leukemias, choriocarcinoma, mycosis fungoides, lung carcinoma, osteogenic sarcoma and SCCs of the head and neck. 16–18 It is a folate antagonist that kills cells during the S phase of the cell cycle and has a potentially synergistic effect with cisplatin and 5‐FU. 18 The clinical applicability of MTX is limited by its systemic toxicity, which is mostly gastrointestinal tract (anorexia, weight loss, bloody diarrhea) and bone marrow related (leukopenia, erythropenia, and thrombocytopenia).…”

Cisplatin, Fluorouracil, and Leucovorin: Increased Toxicity Without Improved Response in Squamous Cell Head and Neck Cancer

“…Median survival in one study was 6.5 months. 30 The median duration of response in a study by Loeffler et al12 was still shorter (3.8 months).…”

“…Chemotherapy included cisplatin (100 mg/m2) on day 1 by short intravenous infusion; fluorouracil (800 mg/m2) on days 1 through 5 by continuous infusion; and leucovorin (100 mg) every 4 hours by mouth for 30 doses. The PFL combination was administered every 21 days.…”