title: Regional recurrence of oropharyngeal cancer after definitive radiotherapy: a case control study.
abstract: BACKGROUND
  Elective treatment of lymph nodes in oropharyngeal cancer (OPC) has impact on both regional recurrences (RR) and risk of late side effects. This study was performed to quantify the dose-dependent impact on RR and overall survival (OS) in a prospectively collected cohort of OPC from the ARTSCAN study with emphasis on elective treatment.
  
  
  METHODS
  ARTSCAN is a previously published prospective, randomized, multicentre study of altered radiotherapy (RT) fractionation in head and neck cancer. In ARTSCAN the elective treatment volume for node positive OPC varied significantly between centres due to local treatment principles. All patients with OPC in complete response after primary treatment were eligible for the present case-control study. Cases were patients with RR during five years follow-up. Patients with no recurrence were eligible as controls. Four controls per case were matched according to T- and N-stage. Mean (D mean) and median (D 50%) dose for the lymph node level (LNL) of RR in the cases and the corresponding LNL in the controls were analysed with conditional logistic regression. OS was estimated with the Kaplan-Meier method and evaluated by multivariate Cox regression analysis.
  
  
  RESULTS
  There was a dose-dependent risk reduction for D 50% in the interval that represented elective treatment (40-50 Gy) (OR = 0.18, p < 0.05) and a trend in the same dose interval for D mean (OR = 0.19, p = 0.07). OS rates at five years were 0.39 (0.24-0.65) for cases and 0.70 (0.62-0.81) for controls (p < 0.001). The Kaplan-Meier and the Cox regression analysis for cases categorised by delivered dose showed an inverse relationship between dose and survival. The cases with RR in a LNL outside planning target volume (PTV) (D mean < 40 Gy) had an OS rate comparable to that of all patients, and those with RR in a LNL in PTVelective (D mean 40-60 Gy) or PTVtumour (D mean >60 Gy) did significantly worse (p < 0.05). The same inverse relationship was also shown for a small subset of patient with known HPV-status, defined by over expression of p16 (p < 0.05).
  
  
  CONCLUSIONS
  There was a significant risk reduction for RR of elective treatment. However the OS for patients with RR outside target volumes was not affected, with similar results for patients with HPV-positive OPC. This could be an argument for a prospective randomized study on limited elective target volumes in OPC.
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå University, Umeå, Sweden. karin.soderstrom@onkologi.umu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Söderström
authors.affiliation: Department of Oncology and Radiation Physics, Skåne University Hospital, Lund University, Lund, Sweden. per.nilsson@skane.se.
authors.forename: Per
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden. tina.dalianis@ki.se.
authors.forename: Tina
authors.initials: T
authors.lastname: Dalianis
authors.affiliation: Department of Oncology and Radiation Physics, Skåne University Hospital, Lund University, Lund, Sweden. elisabeth.kjellen@med.lu.se.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kjellén
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University Hospital, Umeå University, Umeå, Sweden. bjorn.zackrisson@umu.se.
authors.forename: Björn
authors.initials: B
authors.lastname: Zackrisson
mesh_terms: D016022:Case-Control Studies; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D015182:Lymphatic Irradiation; D008207:Lymphatic Metastasis / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology*; D009959:Oropharyngeal Neoplasms / Q000532:radiotherapy*; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal; D061089:Radiotherapy, Image-Guided; D050397:Radiotherapy, Intensity-Modulated; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D040242:Risk Reduction Behavior; D014057:Tomography, X-Ray Computed