Severe radiation dermatitis associated with concomitant vemurafenib therapy in a patient with metastatic melanoma
Authors: Michael Saco, Christina Mitchell
Journal: Journal of the American Academy of Dermatology (2014)

To the Editor: A 31-year-old woman was diagnosed with a nonulcerated 2.01-mm deep melanoma on her left arm. She underwent wide excision with negative surgical margins and a negative sentinel lymph node biopsy. Seven months later, she started having left hip pain that became progressively worse. A noncontrast magnetic resonance image revealed a large lesion in her left proximal femur that was subsequently biopsied, confirming the diagnosis of metastatic melanoma. Subcutaneous lesions on her trunk and thighs also developed. Biopsies revealed melanoma with positive BRAF V600E mutation. She was started on vemurafenib, a selective BRAF V600E inhibitor,1Dummer R. Rinderknecht J. Goldinger S.M. Ultraviolet A and photosensitivity during vemurafenib therapy.N Engl J Med. 2012; 366: 480-481Crossref PubMed Scopus (125) Google Scholar dosed at 960 mg twice daily. After 3 weeks of vemurafenib, she began receiving localized radiotherapy to treat her femoral lesion. After 1 week of daily radiotherapy, a brisk, raised, erythematous skin reaction restricted to her left anterior and posterior thigh developed. The erythematous regions were confined to the areas where she was receiving radiotherapy. With continuation of radiotherapy for 3 more days, an acute, rapidly worsening, and extremely painful burning sensation developed in her left anterior and posterior thigh. Physical examination revealed blistered and erythematous skin with dry and moist desquamation in the radiotherapy fields on her left anterior and posterior thigh, indicative of a worsening skin reaction consistent with radiation burns. She had received a total radiation dose of 30 Gy in 10 uninterrupted daily 3-Gy fractions as originally planned. With discontinuation of radiotherapy, her radiation dermatitis healed after 1 month.Two cases of localized radiation dermatitis that resolved with topical corticosteroids and did not require cessation of vemurafenib have been reported in patients who started vemurafenib after completion of radiotherapy.2Boussemart L. Boivin C. Claveau J. Tao Y.G. Tomasic G. Routier E. et al.Vemurafenib and radiosensitization.JAMA Dermatol. 2013; 149: 855-857Crossref PubMed Scopus (84) Google Scholar Another case of radiodermatitis was reported in a patient receiving concomitant vemurafenib and radiotherapy who had been earlier administered 60 Gy of local radiotherapy to the same area that 4.5 years later developed radiodermatitis upon administration of 20 Gy of radiotherapy.3Satzger I. Degen A. Asper H. Kapp A. Hauschild A. Gutzmer R. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy.J Clin Oncol. 2013; 31: e220-e222Crossref PubMed Scopus (62) Google Scholar To our knowledge, our case represents the first reported instance in the English literature of localized radiation dermatitis developing in a patient receiving concomitant vemurafenib and radiotherapy who was previously naive to both treatment modalities. Sustained erythema seen in radiation dermatitis typically manifests 10 to 14 days after dosing, whereas sustained erythema developed in our patient after 7 days of radiotherapy. Moreover, the severity of the radiation dermatitis seen in our patient after 10 days of radiotherapy is not usually seen until after 4 to 5 weeks of radiotherapy at doses of 40 Gy or greater. The radiosensitizing effect of vemurafenib leads to increased cellular damage and impaired DNA repair.4Hymes S.R. Strom E.A. Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006.J Am Acad Dermatol. 2006; 54: 28-46Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar One proposed mechanism for radiosensitization secondary to vemurafenib suggests that vemurafenib activates wild-type BRAF in keratinocytes and leads to radiosensitization as a result.3Satzger I. Degen A. Asper H. Kapp A. Hauschild A. Gutzmer R. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy.J Clin Oncol. 2013; 31: e220-e222Crossref PubMed Scopus (62) Google Scholar However, the exact mechanism remains unclear. Dermatologists should be aware that radiosensitization may be associated with vemurafenib administration and carefully monitor patients receiving concomitant radiotherapy, as well as patients who start vemurafenib after radiotherapy. Neither radiotherapy nor vemurafenib need be stopped if radiation dermatitis develops, in that reported cases resolved without further adverse events after topical corticosteroid administration, cessation of radiotherapy, or both. To the Editor: A 31-year-old woman was diagnosed with a nonulcerated 2.01-mm deep melanoma on her left arm. She underwent wide excision with negative surgical margins and a negative sentinel lymph node biopsy. Seven months later, she started having left hip pain that became progressively worse. A noncontrast magnetic resonance image revealed a large lesion in her left proximal femur that was subsequently biopsied, confirming the diagnosis of metastatic melanoma. Subcutaneous lesions on her trunk and thighs also developed. Biopsies revealed melanoma with positive BRAF V600E mutation. She was started on vemurafenib, a selective BRAF V600E inhibitor,1Dummer R. Rinderknecht J. Goldinger S.M. Ultraviolet A and photosensitivity during vemurafenib therapy.N Engl J Med. 2012; 366: 480-481Crossref PubMed Scopus (125) Google Scholar dosed at 960 mg twice daily. After 3 weeks of vemurafenib, she began receiving localized radiotherapy to treat her femoral lesion. After 1 week of daily radiotherapy, a brisk, raised, erythematous skin reaction restricted to her left anterior and posterior thigh developed. The erythematous regions were confined to the areas where she was receiving radiotherapy. With continuation of radiotherapy for 3 more days, an acute, rapidly worsening, and extremely painful burning sensation developed in her left anterior and posterior thigh. Physical examination revealed blistered and erythematous skin with dry and moist desquamation in the radiotherapy fields on her left anterior and posterior thigh, indicative of a worsening skin reaction consistent with radiation burns. She had received a total radiation dose of 30 Gy in 10 uninterrupted daily 3-Gy fractions as originally planned. With discontinuation of radiotherapy, her radiation dermatitis healed after 1 month. Two cases of localized radiation dermatitis that resolved with topical corticosteroids and did not require cessation of vemurafenib have been reported in patients who started vemurafenib after completion of radiotherapy.2Boussemart L. Boivin C. Claveau J. Tao Y.G. Tomasic G. Routier E. et al.Vemurafenib and radiosensitization.JAMA Dermatol. 2013; 149: 855-857Crossref PubMed Scopus (84) Google Scholar Another case of radiodermatitis was reported in a patient receiving concomitant vemurafenib and radiotherapy who had been earlier administered 60 Gy of local radiotherapy to the same area that 4.5 years later developed radiodermatitis upon administration of 20 Gy of radiotherapy.3Satzger I. Degen A. Asper H. Kapp A. Hauschild A. Gutzmer R. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy.J Clin Oncol. 2013; 31: e220-e222Crossref PubMed Scopus (62) Google Scholar To our knowledge, our case represents the first reported instance in the English literature of localized radiation dermatitis developing in a patient receiving concomitant vemurafenib and radiotherapy who was previously naive to both treatment modalities. Sustained erythema seen in radiation dermatitis typically manifests 10 to 14 days after dosing, whereas sustained erythema developed in our patient after 7 days of radiotherapy. Moreover, the severity of the radiation dermatitis seen in our patient after 10 days of radiotherapy is not usually seen until after 4 to 5 weeks of radiotherapy at doses of 40 Gy or greater. The radiosensitizing effect of vemurafenib leads to increased cellular damage and impaired DNA repair.4Hymes S.R. Strom E.A. Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006.J Am Acad Dermatol. 2006; 54: 28-46Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar One proposed mechanism for radiosensitization secondary to vemurafenib suggests that vemurafenib activates wild-type BRAF in keratinocytes and leads to radiosensitization as a result.3Satzger I. Degen A. Asper H. Kapp A. Hauschild A. Gutzmer R. Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy.J Clin Oncol. 2013; 31: e220-e222Crossref PubMed Scopus (62) Google Scholar However, the exact mechanism remains unclear. Dermatologists should be aware that radiosensitization may be associated with vemurafenib administration and carefully monitor patients receiving concomitant radiotherapy, as well as patients who start vemurafenib after radiotherapy. Neither radiotherapy nor vemurafenib need be stopped if radiation dermatitis develops, in that reported cases resolved without further adverse events after topical corticosteroid administration, cessation of radiotherapy, or both.