title: Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial.
abstract: Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.
authors.affiliation: Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Nijkamp
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Christiaan H J
authors.initials: CH
authors.lastname: Terhaard
authors.forename: Patricia A H
authors.initials: PA
authors.lastname: Doornaert
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.forename: Piet L A
authors.initials: PL
authors.lastname: van den Ende
authors.forename: Martin
authors.initials: M
authors.lastname: de Jong
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D015687:Cell Hypoxia / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D007822:Laryngeal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D008875:Middle Aged; D011379:Prognosis; D000077195:Squamous Cell Carcinoma of Head and Neck; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D066246:ErbB Receptors
keywords: ARCON; EGFR; Hypoxia; Laryngeal carcinoma; Radiotherapy