title: Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons.
abstract: OBJECTIVE
  To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer.
  
  
  METHODS
  A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy.
  
  
  RESULTS
  In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site.
  
  
  CONCLUSIONS
  For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.
authors.affiliation: Department of Radiation Oncology (MAASTRO), GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. bram.ramaekers@maastro.nl
authors.forename: Bram L T
authors.initials: BL
authors.lastname: Ramaekers
authors.forename: Madelon
authors.initials: M
authors.lastname: Pijls-Johannesma
authors.forename: Manuela A
authors.initials: MA
authors.lastname: Joore
authors.forename: Piet
authors.initials: P
authors.lastname: van den Ende
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Langendijk
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.forename: Alfons G H
authors.initials: AG
authors.lastname: Kessels
authors.forename: Janneke P C
authors.initials: JP
authors.lastname: Grutters
mesh_terms: D002244:Carbon / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000532:radiotherapy*; D006801:Humans; D007477:Ions / Q000627:therapeutic use; D017785:Photons / Q000627:therapeutic use*; D061766:Proton Therapy; D011878:Radiotherapy / Q000379:methods*
chemical_list: D007477:Ions; D002244:Carbon