title: Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer.
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.
  
  
  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.
  
  
  CONCLUSIONS
  The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine.
authors.forename: M V
authors.initials: MV
authors.lastname: Karamouzis
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Radiation Oncology.
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine.
authors.forename: A
authors.initials: A
authors.lastname: Kotsakis
authors.affiliation: University of Pittsburgh Cancer Institute; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine.
authors.forename: M K
authors.initials: MK
authors.lastname: Gibson
authors.affiliation: Department of Otolaryngology.
authors.forename: S Y
authors.initials: SY
authors.lastname: Lai
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Otolaryngology.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology; Department of Radiology, University of Pittsburgh School of Medicine.
authors.forename: B F
authors.initials: BF
authors.lastname: Branstetter
authors.affiliation: University of Pittsburgh Cancer Institute.
authors.forename: Y
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: University of Pittsburgh Cancer Institute; Division of Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine.
authors.forename: M
authors.initials: M
authors.lastname: Romkes
authors.affiliation: Department of Otolaryngology; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Otolaryngology.
authors.forename: J R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Otolaryngology; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Otolaryngology.
authors.forename: J T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: University of Pittsburgh Cancer Institute; Department of Radiation Oncology.
authors.forename: D E
authors.initials: DE
authors.lastname: Heron
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D000068818:Cetuximab; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000532:radiotherapy; D000068437:Pemetrexed; D011110:Polymorphism, Genetic; D000077195:Squamous Cell Carcinoma of Head and Neck; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D000068818:Cetuximab