Background: 5-Fluorouracil (5-FU), as a single agent, produces a 15% response rate in advanced squamous cell carcinoma of the head and neck (SCCHN). N-phosphonacetyl-L-aspartate (PALA) inhibits pyrimidine biosynthesis and increases incorporation of 5-FU metabolites into ribonucleic acid (RNA). Recombinant alpha interferon-2b (rIFN-alpha-2b) may inhibit 5-FU clearance and blunt reflex rise in thymidylate synthetase, therefore enhancing inhibition of the target enzyme of 5-FU.
Methods: In an attempt to exploit their potential therapeutic synergy, we initiated a phase II trial combining PALA 250 mg/m2 by intravenous (IV) bolus day 1 with 5-FU 2600 mg/m2 24-hour IV infusion initiated 24 hours after PALA, followed by rIFNalpha-2b 10 million units (MU) by subcutaneous injection days 2, 3, and 4 in patients with advanced, measurable SCCHN incurable with surgery or radiotherapy. Treatment was repeated weekly; patients were assessed every 4-6 weeks. Pretreatment tumor specimens were analyzed for p53 mutations in exons 5-8 and for protein expression using the p53 polyclonal antibody CM-1.
Results: Nineteen patients were enrolled from November 1991 through February 1994. Median age was 59 years (range, 31-72 years). All had previously received definitive radiotherapy, and all but two had undergone surgical resection. Seven patients (37%) had received prior adjuvant chemotherapy. Median time from initial diagnosis to protocol enrollment was 17 months (range, 5 months to 10 years). Median performance status (PS) was 1. Primary tumor sites included oral cavity (8 patients), larynx (7 patients), oropharynx (3 patients), and hypopharynx (1 patient). The median serum transferrin was 241 (range, 141-333). Sixteen patients (84%) had sufficient pretreatment biopsy material for p53 analysis. Patients received a median of 6 weeks of treatment (range, 2-30 weeks). Six patients (32%) in the absence of disease progression failed to finish the first 6 weeks of treatment: 3 died of pulmonary insufficiency or pneumonia and 3 were removed from study during the first 6 weeks due to toxicity. Grade 2-3 flulike symptoms occurred in 17 patients (89%); grade > or = 3 fatigue occurred in 12 patients (63%), and grade > or = 2 stomatitis occurred in 5 (26%). Gastrointestional toxicity was minimal and myelosuppression mild. Of 13 evaluable patients, there were 2 partial responses (15%) lasting 3 months and 20 months; 5 patients with stable disease lasting 2, 2, 2.5, 3, and 4.5 months; and 6 with disease progression. For all 19 patients, the overall response rate was 11%, the median survival was 6 months and 1-year survival rate 26%. Lower transferrin values (< or =241) were associated with shortened median survival 2.5 vs 11 months). Increased p53 protein expression but not p53 mutations in pretreatment specimens also predicted inferior survival (median, 6 vs 11 months) after enrollment in study (p = .0124).
Conclusions: Biochemical modulation of 5-FU by rIFNalpha-2b and PALA does not enhance its efficacy in patients with advanced SCCHN whose disease has progressed after prior radiotherapy. Serum transferrin and p53 protein expression segregate outcome in this group of uniformly treated patients.