A Argiris1, M V Karamouzis2, R Smith3, A Kotsakis2, M K Gibson4, S Y Lai5, S Kim6, B F Branstetter7, Y Shuai8, M Romkes9, L Wang10, J R Grandis6, R L Ferris11, J T Johnson6, D E Heron3. 1. University of Pittsburgh Cancer Institute; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine; Department of Otolaryngology. Electronic address: argirisae@upmc.edu. 2. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine. 3. University of Pittsburgh Cancer Institute; Department of Radiation Oncology. 4. University of Pittsburgh Cancer Institute; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine. 5. Department of Otolaryngology. 6. University of Pittsburgh Cancer Institute; Department of Otolaryngology. 7. Department of Otolaryngology; Department of Radiology, University of Pittsburgh School of Medicine. 8. University of Pittsburgh Cancer Institute. 9. University of Pittsburgh Cancer Institute; Division of Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine. 10. Department of Otolaryngology; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, USA. 11. University of Pittsburgh Cancer Institute; Department of Otolaryngology; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
Abstract
BACKGROUND: We studied the combination of pemetrexed, a multi-targeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. PATIENTS AND METHODS: Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. RESULTS: Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. CONCLUSION: The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.
BACKGROUND: We studied the combination of pemetrexed, a multi-targeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. PATIENTS AND METHODS: Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. RESULTS: Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. CONCLUSION: The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.
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