title: Refining risk stratification for locoregional failure after chemoradiotherapy in human papillomavirus-associated oropharyngeal cancer.
abstract: BACKGROUND
  To determine whether the addition of molecular and imaging biomarkers to established clinical risk factors could help predict locoregional failure (LRF) after chemoradiation in human papillomavirus (HPV)-related (+) oropharyngeal cancer (OPC) and improve patient selection for locoregional treatment de-intensification.
  
  
  METHODS
  HPV status was determined for 198 consecutive patients with stage III/IV OPC treated with definitive chemoradiation from 5/2003 to 10/2010. The impact of pre-therapy epidermal growth factor receptor (EGFR) overexpression; imaging biomarkers including primary tumor and nodal maximum standardized uptake values on FDG-PET, gross tumor volumes, and matted nodes; and clinical factors on LRF (including residual disease at adjuvant neck dissection) was assessed.
  
  
  RESULTS
  Primary tumors were HPV+ in 184 patients and HPV-negative in 14. EGFR overexpression was related to HPV-negative status and was univariately associated with LRF in the overall population, but was neither retained in the multivariate model after adjustment for HPV status, nor associated with LRF in HPV+ patients. Similarly, imaging biomarkers were univariately associated with LRF, but correlated with T-stage and/or N-stage and did not remain predictive in HPV+ patients after adjustment for T4- and N3-stages, which were the only significant predictors of LRF on multivariate analysis. Among HPV+ patients with non-T4- or N3-stages, only minimal smoking was associated with decreased LRF.
  
  
  CONCLUSIONS
  The prognostic impact of EGFR overexpression and imaging biomarkers on LRF was predominantly related to their association with HPV-negative status and T- or N-stage, respectively. Among HPV+ OPC patients treated with uniform chemoradiation, only T4-stage, N3-stage, and smoking contributed to risk-stratification for LRF.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Vainshtein
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Spector
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: McHugh
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Ka Kit
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Walline
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, MI, United States.
authors.forename: Serena A
authors.initials: SA
authors.lastname: Byrd
authors.affiliation: Department of Otolaryngology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Komarck
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Mohannad
authors.initials: M
authors.lastname: Ibrahim
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Stenmark
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Prince
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Carol R
authors.initials: CR
authors.lastname: Bradford
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Wolf
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: McLean
authors.affiliation: Division of Hematology Oncology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, United States.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Worden
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Chepeha
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carey
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States. Electronic address: eisbruch@umich.edu.
authors.forename: Avraham
authors.initials: A
authors.lastname: Eisbruch
mesh_terms: D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy* / Q000821:virology; D027383:Papillomaviridae / Q000302:isolation & purification*; D018570:Risk Assessment; D016896:Treatment Outcome
keywords: EGFR; FDG-PET; HPV; Local-regional failure; Oropharyngeal cancer; Risk stratification