title: Severe radiotherapy-induced extracutaneous toxicity under vemurafenib.
abstract: BACKGROUND
  Vemurafenib is a BRAF inhibitor indicated for the treatment of metastatic melanoma. We report the two first cases of severe and prolonged radiotherapy-induced visceral toxicity in patients treated concomitantly with vemurafenib: a brain radionecrosis and an anorectitis. It raises the question of both the risks of this association and its benefit in melanoma.
  
  
  METHODS
  The first patient, a female aged 32, treated with vemurafenib for three months, presented a steroid-dependent radionecrosis after brain stereotactic radiosurgery. Symptoms persisted until her death six months later. The second patient, a male aged 64 and treated with vemurafenib for nineteen days, presented a radiation-induced anorectitis complicated by diarrhoea, anorexia and weight loss following the concomitant radiation of a primary rectal tumour. A colostomy was needed after ten months in order to improve local status and general health.
  
  
  CONCLUSIONS
  In our patients, the radiotherapy-induced toxicity under vemurafenib was unusual in its intensity and duration, suggesting a radiosensitization phenomenon. This hypothesis is reinforced by the publication of six cases of severe radiodermatitis under vemurafenib and by in vitro data. The combination of vemurafenib and radiotherapy should thus lead to discussion of a transient cessation of vemurafenib, given the severity of the adverse events experienced. Meanwhile, further studies are needed to determine the potential benefit of this combined treatment in metastatic melanoma.
authors.affiliation: Department of Dermato-Cancerology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, 1 place Ricordeau, 44000 Nantes, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Peuvrel
authors.affiliation: Pharmacovigilance, Department of Clinical Pharmacology, Nantes University Hospital, Nantes, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Ruellan
authors.affiliation: Service de radiothérapie, ICO René Gauducheau, 44800 Saint-Herblain, France.
authors.forename: François
authors.initials: F
authors.lastname: Thillays
authors.affiliation: Department of Dermato-Cancerology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, 1 place Ricordeau, 44000 Nantes, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Quereux
authors.affiliation: Department of Dermato-Cancerology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, 1 place Ricordeau, 44000 Nantes, France.
authors.forename: Anabelle
authors.initials: A
authors.lastname: Brocard
authors.affiliation: Department of Dermato-Cancerology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, 1 place Ricordeau, 44000 Nantes, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Saint-Jean
authors.affiliation: Service de radiothérapie, ICO René Gauducheau, 44800 Saint-Herblain, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Aumont
authors.affiliation: Service de radiothérapie, ICO René Gauducheau, 44800 Saint-Herblain, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Drouet
authors.affiliation: Department of Dermato-Cancerology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, 1 place Ricordeau, 44000 Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
mesh_terms: D000328:Adult; D001003:Anal Canal / Q000528:radiation effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001921:Brain / Q000473:pathology* / Q000528:radiation effects; D001932:Brain Neoplasms / Q000556:secondary / Q000601:surgery*; D059248:Chemoradiotherapy / Q000009:adverse effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D008297:Male; D008545:Melanoma / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D009336:Necrosis / Q000209:etiology; D016609:Neoplasms, Second Primary / Q000532:radiotherapy*; D011349:Proctitis / Q000209:etiology; D011832:Radiation Injuries / Q000209:etiology / Q000473:pathology*; D016634:Radiosurgery / Q000009:adverse effects*; D012004:Rectal Neoplasms / Q000532:radiotherapy*; D012007:Rectum / Q000528:radiation effects; D013449:Sulfonamides / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: BRAF inhibitor; anorectitis; brain radionecrosis; melanoma; radiotherapy; vemurafenib