Practical Radiation Oncology (2013) 3, e195–e198

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Teaching Case

Radiation-induced dermatitis with vemurafenib therapy Thomas M. Churilla BS a , Varun K. Chowdhry MD b,⁎, Dorothy Pan MD c , Gustavo de la Roza MD c , Timothy Damron MD d , Michael A. Lacombe MD b a

The Commonwealth Medical College, Scranton, Pennsylvania Department of Radiation Oncology, State University of New York Upstate Medical University, Syracuse, New York c Department of Pathology, State University of New York Upstate Medical University, Syracuse, New York d Department of Orthopedic Surgery, State University of New York Upstate Medical University, Syracuse, New York b

Received 30 October 2012; revised 28 November 2012; accepted 28 November 2012

Introduction

Case presentation

More than one-half of melanomas contain an activating mutation in the serine-threonine protein kinase B-RAF (BRAF) gene. 1,2 This mutation drives the constitutive activation of the Ras/Raf/MEK mitogen-activated protein kinase (MAP-K) pathway, which has been implicated in melanoma initiation, progression, and metastasis. 3 Vemurafenib (PLX-4032) is a potent kinase inhibitor with specificity for the BRAF V600E mutation and has been shown to have antitumor activity in vitro 4-6 and in phase 1 clinical study. 7 A phase 3 trial of vemurafenib versus dacarbazine demonstrated an increase in overall and progression-free survival. 8 The most frequent adverse effects of vemurafenib reported are arthralgias, skin reactions, and fatigue. The development of a rash of any severity has been reported to be in the range of 36%-52%, with 7%-8% of patients developing grade 3 toxicity. 8,9 We report the case of a 46-year-old male with metastatic melanoma who was being treated with vemurafenib and developed grade 3 radiation dermatitis shortly after radiation therapy for vertebral metastases.

A 46-year-old male presented with a 3-cm mass in the right antecubital fossa. He was originally diagnosed with a cutaneous melanoma of the right ankle 16 years prior that was treated via wide local excision. A core needle biopsy of the lesion confirmed the diagnosis of metastatic malignant melanoma involving the skeletal muscle, and was positive for S-100 protein and melanocytic markers HMB45 and MART-1 (Fig 1). Staging evaluation identified suspicious foci within the liver, bone, and lungs though disease was of small volume and pretreatment lactate dehydrogenase was 374 U/L. He was started on systemic therapy with ipilimumab. Imaging of the chest, abdomen, and pelvis performed at approximately the 16th week demonstrated progression of disease with new osseous metastases. Additional tissue was obtained, and the results demonstrated the presence of a BRAF V600E mutation. The patient began vemurafenib (960 mg orally twice daily). He developed a grade 1-2 diffuse erythematous rash predominantly in a truncal distribution as well as a follicular pattern rash on his distal extremities within 1 week of starting vemurafenib. Magnetic resonance imaging revealed metastatic disease in the T10, L4, and L5 vertebrae without spinal cord compression. The patient began palliative radiation therapy in a distribution from T10 to L5 (3000 cGy in 10 fractions) using posterioranterior–anterior-posterior (PA-AP) fields approximately 2 weeks after initiating vemurafenib. The patient continued on vemurafenib during radiation therapy. The patient

Conflicts of interest: None. ⁎ Corresponding author. State University of New York Upstate Medical University, Department of Radiation Oncology, 750 East Adams St, Syracuse, NY 13210. E-mail address: [email protected] (V.K. Chowdhry).

1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.11.012

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S-100

MART-1

Figure 1 Histologic sections of the right arm lesion show discohesive large malignant cells with eccentric nuclei and prominent nucleoli without melanin pigment. Reactivity with S-100 (top insert) and MART-1 antibodies (lower insert) confirmed the diagnosis of metastatic melanoma (magnification, × 40).

tolerated radiation well with clinical improvement of his back pain. He continued to receive monthly injections of denosumab with calcium and vitamin D supplementation. Within 1 week of completing radiation therapy, the patient developed a large patch of erythema and desquamation involving the thoracic and lumbar distributions of the

posterior trunk, in the region of the field (Fig 2). An area of erythema and hyperpigmentation was noted on the anterior abdominal wall, which was located at the same level as the rash on his back (Fig 3). The patient continued vemurafenib and was treated for radiation-induced dermatitis with emollients and silver sulfadiazine (2%) cream. Follow-up

Figure 2 Radiation-induced grade 3 dermatitis of the back while on vemurafenib.

Figure 3 Area of erythema and hyperpigmentation on the chest and abdomen at 1 week follow-up, corresponding to the field of radiation.

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Figure 5 Sagittal reconstruction of the treatment plan for palliative radiation therapy to the thoracic and lumbar spine (T10 to L5) for melanoma metastases. Figure 4 Follow-up at 1 week demonstrates improvement of the rash. The patient continued vemurafenib therapy without interruption and used an emollient for wound care.

examination demonstrated clinical improvement after 1 week (Fig 4). Approximately 1 month after starting vemurafenib, the patient had a demonstrated biochemical response to treatment with a lactate dehydrogenase that had declined to 249 U/L.

Discussion Here we report a case of a severe interaction with radiation therapy and vemurafenib. The area of erythema and desquamation on his back (Figs 2-4) correspond well to the field of external beam radiation (Figs 5 and 6). Figure 7 represents a dose-distance curve for this patient's treatment plan of the skin-sparing technique utilized to minimize radiation at the skin surfaces. Rash and photosensitivity reactions are well documented with vemurafenib therapy in metastatic melanoma. 8,9 Dummer and colleagues 10 demonstrated that vemurafenib photosensitivity likely arises from ultraviolet A (UVA) radiation and recommend sunscreen with UVA spectrum coverage for these patients. To the best of our knowledge, there are no prior reports of patients on vemurafenib who developed grade 3 dermatitis after a course of external beam radiation. A related case report by Wang et al 11 describes “diffuse follicular hyperkeratosis resembling keratosis pilaris” of a patient undergoing treatment with vemurafenib who underwent prior radiation therapy. In this case, the patient began vemurafenib 1 month after completing radiation therapy and developed a diffuse skin reaction after 8 days with increased erythema over the radiation field. 11

Our case differs in that our patient was already on vemurafenib before initiating radiation therapy, and the rash developed within days of completing radiation therapy. Our case raises awareness of a potential severe skin reaction with vemurafenib and radiation therapy. There are some limitations with regard to skin dose estimation in the Eclipse software, with variability of 20%. 12 It is believed that the computer software overestimates the skin-sparing effect. We estimate that the total dose delivered to skin on the back (grade 3 dermatitis) 2300-3100 cGy, while the dose delivered to skin on the chest and abdomen (mild erythema) was estimated at 1600-2000 cGy. Based on the cases reported by Wang et al 11 and us, it appears that there may be unique toxicity between ionizing radiation and skin sensitized to vemurafenib. To this end, an in vitro study reported that PLX-4032 effectively radiosensitized B-Raf+melanoma cells, including some radioresistant lines. 13 Although not previously studied, it is

Figure 6 Axial image at level L3 of the treatment plan for palliative radiation therapy to the thoracic and lumbar spine for melanoma metastases.

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Figure 7 Dose distance curve of treatment plan with skin-sparing technique. The entrance dose to the body corresponds to a distance of 1 cm. The graph shown shows the contribution of anterior and posterior fields to dose, as well as plan sum total at various points in the patient. Although the computer model estimates the dose at the skin to be 1000 cGy, our estimate is that the skin at the back is approximately 2300-3100 cGy. We estimate the dose to the chest and abdomen (mild erythema) to be 1600-2000 cGy.

possible that vemurafenib has radiosensitizing effects in normal keratinocytes as well. Further study is necessary to understand the therapeutic implications and toxicity of combined therapy with vemurafenib and external beam radiation. This case underscores the importance of exercising caution when combining novel agents with radiation therapy. Depending on the location and volume of irradiation, it is possible that concurrent radiation therapy with such agents may result in more serious toxicities.

References 1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954. 2. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135-2147. 3. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851-857. 4. Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A. 2010;107: 14903-14908.

5. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70:5518-5527. 6. Søndergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med. 2010;8:39. 7. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819. 8. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516. 9. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714. 10. Dummer R, Rinderknecht J, Goldinger SM. Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med. 2012;366:480-481. 11. Wang CM, Fleming KF, Hsu S. A case of vemurafenib-induced keratosis pilaris-like eruption. Dermatol Online J. 2012;18:7. 12. Court LE, Tishler R, Xiang H, Allen AM, Makrigiorgos M, Chin L. Experimental evaluation of the accuracy of skin dose calculation for a commercial treatment planning system. J Appl Clin Med Phys. 2008;9:2792. 13. Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol. 2011;98:394-399.

Radiation-induced dermatitis with vemurafenib therapy.

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