title: Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer.
abstract: We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF).
  
  
  
  Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL).
  
  
  
  Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment.
  
  
  
  RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio athanassios.argiris@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: J E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Department of Medicine, Division of Hematology/Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Ohr
authors.affiliation: Department of Biostatistics.
authors.forename: W E
authors.initials: WE
authors.lastname: Gooding
authors.affiliation: Department of Medicine, Division of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh.
authors.forename: D E
authors.initials: DE
authors.lastname: Heron
authors.affiliation: Division of Otolaryngology, Department of Medicine, University of Pittsburgh, Pittsburgh.
authors.forename: U
authors.initials: U
authors.lastname: Duvvuri
authors.affiliation: Division of Radiation Oncology, Department of Medicine, Cooper University Healthcare, Camden.
authors.forename: G J
authors.initials: GJ
authors.lastname: Kubicek
authors.affiliation: Division of Biobehavioral Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Posluszny
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Hopital de la Pitie-Salpetriere, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Vassilakopoulou
authors.affiliation: Division of Otolaryngology, Department of Medicine, University of Pittsburgh, Pittsburgh.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Otolaryngology, Department of Medicine, University of California, San Francisco.
authors.forename: J R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Division of Otolaryngology, Department of Medicine, University of Pittsburgh, Pittsburgh.
authors.forename: J T
authors.initials: JT
authors.lastname: Johnson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, UH Case Medical Center, Cleveland.
authors.forename: M K
authors.initials: MK
authors.lastname: Gibson
authors.affiliation: Department of Medicine, Division of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh.
authors.forename: D A
authors.initials: DA
authors.lastname: Clump
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: J T
authors.initials: JT
authors.lastname: Flaherty
authors.affiliation: Division of Pathology, Department of Medicine, University of Pittsburgh, Pittsburgh, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Chiosea
authors.affiliation: Department of Medicine, Division of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh.
authors.forename: B
authors.initials: B
authors.lastname: Branstetter
authors.affiliation: Division of Otolaryngology, Department of Medicine, University of Pittsburgh, Pittsburgh.
authors.forename: R L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000009:adverse effects; D011788:Quality of Life; D000077195:Squamous Cell Carcinoma of Head and Neck; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068437:Pemetrexed; D000068258:Bevacizumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: bevacizumab; cetuximab; clinical trial; head and neck cancer; pemetrexed; radiation therapy