title: Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients.
abstract: BACKGROUND
  Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism.
  
  
  METHODS
  A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation.
  
  
  RESULTS
  With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment.
  
  
  CONCLUSIONS
  Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen.
authors.forename: M
authors.initials: M
authors.lastname: Hecht
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen.
authors.forename: L
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Department of Dermatology, University Hospital Mainz, Mainz.
authors.forename: C
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Department of Dermatology, University Hospital Münster, Münster.
authors.forename: C
authors.initials: C
authors.lastname: Weishaupt
authors.affiliation: Department of Dermatology, Hannover Medical School, Hannover.
authors.forename: R
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen.
authors.forename: B
authors.initials: B
authors.lastname: Schuster
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen.
authors.forename: S
authors.initials: S
authors.lastname: Gleisner
authors.affiliation: Department of Radiation Oncology, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schulze
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: S M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: Department of Dermatology, University Hospital München (LMU), München.
authors.forename: C
authors.initials: C
authors.lastname: Berking
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Forschner
authors.affiliation: Department of Radiation Oncology, Hospital Feldkirch, Feldkirch, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Clemens
authors.affiliation: Department of Radiation Oncology, Hospital Coburg, Coburg.
authors.forename: G
authors.initials: G
authors.lastname: Grabenbauer
authors.affiliation: Department of Radiation Oncology, University Hospital Mainz, Mainz.
authors.forename: T
authors.initials: T
authors.lastname: Müller-Brenne
authors.affiliation: Department of Radiation Oncology, University Hospital Münster, Münster.
authors.forename: J
authors.initials: J
authors.lastname: Bauch
authors.affiliation: Department of Radiation Oncology, University Hospital Münster, Münster.
authors.forename: H T
authors.initials: HT
authors.lastname: Eich
authors.affiliation: Department of Dermatology, University Hospital Mainz, Mainz.
authors.forename: S
authors.initials: S
authors.lastname: Grabbe
authors.affiliation: Department of Dermatology, University Hospital Essen, Essen.
authors.forename: D
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Keikavoussi
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen.
authors.forename: S
authors.initials: S
authors.lastname: Semrau
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen.
authors.forename: R
authors.initials: R
authors.lastname: Fietkau
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Erlangen. Electronic address: luitpold.distel@uk-erlangen.de.
authors.forename: L V
authors.initials: LV
authors.lastname: Distel
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Heinzerling
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy / Q000379:methods*; D005060:Europe; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011855:Radiodermatitis / Q000209:etiology / Q000517:prevention & control; D016634:Radiosurgery / Q000009:adverse effects; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000077484:Vemurafenib; D014916:Whole-Body Irradiation / Q000009:adverse effects; D055815:Young Adult
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF; dabrafenib; radiation; radiosensitization; radiotherapy; vemurafenib