title: Benefit of chemotherapy as part of treatment for HPV DNA-positive but p16-negative squamous cell carcinoma of the oropharynx.
abstract: BACKGROUND
  To determine (a) the cause of an improvement in survival from oropharyngeal squamous cell carcinoma (OSCC) in South East Scotland and (b) whether this improvement was human papillomavirus (HPV) and p16 subtype-dependent.
  
  
  METHODS
  Clinicopathological characteristics and outcome data for patients referred with OSCC from 1999 to 2001 (Cohort-1) and 2003 to 2005 (Cohort-2) were obtained. Molecular HPV detection and immunohistochemistry for p16 were performed from paraffin blocks.
  
  
  RESULTS
  Cohort-1 and Cohort-2 contained 118 and 136 patients, respectively. Kaplan-Meier analysis revealed significantly improved survival in Cohort-2 (P<0.0001). Sub-classification according to HPV and p16 status revealed no improvement in survival in Class-I (HPV-ve/p16-ve; 47 patients) or Class-III (HPV+ve/p16+ve; 77 patients). However in Class-II (HPV+ve/p16-ve; 56 patients) an increase in 5-year cause-specific survival from 36% in Cohort-1 to 73% in Cohort-2 was detected (P=0.0001).Proportional hazards analysis of 217 patients treated radically demonstrated that significant variables were p16 (P<0.0001), N stage (P=0.0006) and cohort (P=0.0024). Removing cohort from the variables offered to the model showed that, whereas p16 (P<0.0001) and N stage (P=0.0016) remain significant, chemotherapy (P=0.0163) and T stage (P=0.0139) are now significant. This suggests that much of the cohort effect is due to the higher use of chemotherapy in the second cohort.
  
  
  CONCLUSIONS
  These data suggest that HPV+ve/p16-ve patients constitute a separate subclass of OSCC who may particularly benefit from chemotherapy. They imply that p16 status cannot be considered a surrogate for HPV status, and those trials to de-escalate treatment in HPV+ve OSCC should take p16 status into account.
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK. Elizabeth.Junor@luht.scot.nhs.uk
authors.forename: E
authors.initials: E
authors.lastname: Junor
authors.forename: G
authors.initials: G
authors.lastname: Kerr
authors.forename: A
authors.initials: A
authors.lastname: Oniscu
authors.forename: S
authors.initials: S
authors.lastname: Campbell
authors.forename: I
authors.initials: I
authors.lastname: Kouzeli
authors.forename: C
authors.initials: C
authors.lastname: Gourley
authors.forename: K
authors.initials: K
authors.lastname: Cuschieri
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015331:Cohort Studies; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D012008:Recurrence; D012907:Smoking; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D004279:DNA, Viral