Case and Review Received: June 4, 2014 Accepted after revision: July 12, 2014 Published online: November 29, 2014
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
Vemurafenib-Induced Radiation Recall Dermatitis: Case Report and Review of the Literature Katrin Conen a Katarzyna Mosna-Firlejczyk b Christoph Rochlitz a Andreas Wicki a Peter Itin c Andreas W. Arnold c Markus Gross b Frank Zimmermann b Alfred Zippelius a Departments of a Medical Oncology, b Radiooncology and c Dermatology, University Hospital Basel, Basel, Switzerland
Abstract The cutaneous effects of BRAF (serine/threonine protein kinase B-raf) inhibitors such as vemurafenib remain poorly defined. Rash, squamous cell carcinoma, keratoacanthoma and photosensitivity are the most common grade 2 or 3 adverse events observed in clinical trials. We here report the case of a patient with a BRAF V600E mutated metastatic melanoma who developed severe radiation recall dermatitis 6 weeks after completing radiotherapy. Vemurafenib treatment had been initiated 1 week before the development of dermatitis because of rapidly progressing disease. Upon topical treatment of the affected skin areas, clinical symptoms regressed over a period of 2 months, although vemurafenib was continuously administered. As our case goes in line with other reports, we believe that physicians should be aware of this additional cutaneous side effect of vemurafenib and that continuation of the treatment is safe when close clinical control and interdisciplinary management can © 2014 S. Karger AG, Basel be provided.
Introduction
Metastatic melanoma reflects the most aggressive type of skin cancer [1]. A number of chemotherapeutic agents show clinical activity in patients with metastatic melanoma but do not impact on overall survival: dacarbazine, nitrosoureas, platinum analogs, vinca alkaloids and taxanes. Of these, dacarbazine only has gained Food and Drug Administration approval based on response rates of 7–15%. However, a Cochrane review did not find evidence for a relevant survival benefit of dacarbazine [2–4]. In 2010, the anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab demonstrated for the first time an improved overall survival in metastatic melanoma patients as compared to the gp100 vaccine [5]. In 2011, the serine/threonine protein kinase B-raf (BRAF) inhibitor vemurafenib was introduced. Vemurafenib inhibits kinase activity of V600E and most likely V600K mutated BRAF, thus suppressing aberrant mitogen-activated protein kinase signaling [6]. In a randomized phase III trial, vemurafenib was superior to dacarbazine in the first-line treatment of advanced melanoma with a 67% risk reduction of death in the treat-
© 2014 S. Karger AG, Basel 1018–8665/14/2301–0001$39.50/0 E-Mail [email protected] www.karger.com/drm
ment group [3]. Vemurafenib is generally well tolerated. The most common vemurafenib-related grade 2 or 3 adverse events are related to the skin, including rash, photosensitivity and skin malignancies [3]. Radiation recall dermatitis reflects the reappearance of radiotherapy-induced skin reactions in the previously irradiated skin regions after the introduction of drugs [7]. It was first described by D’Angio et al. in 1959 with actinomycin D treatment [8]. Since then many other drugs have been associated with this phenomenon: anthracyclines, taxanes, 5-fluorouracil, hydroxyurea, methotrexate and cisplatin. The pathophysiology of this phenomenon remains poorly understood [9–11]. Meanwhile, increasing numbers of reports describe radiation recall effects also for targeted therapies [12]. Of high importance is the clear discrimination of a direct sensitizing effect of any systemic therapy on the acute radiation-induced dermatitis versus a real recall phenomenon, when the risk of acute radiation dermatitis has been endured. The latter is most likely more than 4 weeks after irradiation. F. Zimmermann and A. Zippelius contributed equally to this work.
Katrin Conen, MD Department of Medical Oncology, University Hospital Basel Petersgraben 4 CH–4031 Basel (Switzerland) E-Mail katrin.conen @ usb.ch
Downloaded by: University of Pittsburgh 198.143.32.65 - 8/10/2015 8:25:50 PM
Key Words Melanoma · Radiotherapy · Vemurafenib · Radiation recall dermatitis
Color version available online
Fig. 1. Vemurafenib radiation recall der-
a
b
b
c
Color version available online
matitis. a Seven days after start of vemurafenib, 6 weeks after the end of irradiation. Arrow: area of desquamation with crusts. b After 21 days of vemurafenib treatment.
a
Fig. 2. Vemurafenib treatment effect and recall dermatitis. a Melanotic lesions 7 days after treatment start. b Eight weeks after treatment start. c Twelve weeks after treatment start.
A 78-year-old man with a melanoma history of the left flank in 2009 treated with wide local excision presented to our department in March 2012. He showed multiple skin metastases on the left to right thoracic wall, back and flank. A biopsy of one lesion confirmed metastatic melanoma (stage IV); further pathological assessments revealed a BRAF V600E mutation detected by Sanger sequencing. The metastases presented as black, dense lesions, most of them less than 1 cm in diameter. Additional staging using PET/CT revealed enlarged, fluorodeoxyglucose-positive lymph nodes in the left axillary region. The patient suffered from coronary heart disease that was currently stable under medication. Due to comorbidities and the localized and skin-only metastatic spread, we primarily discussed local irradiation that was performed in the affected skin region up to 30 Gy (6 fractions of 5.0 Gy). Additionally, radiotherapy of the axillary lymph nodes up to 35 Gy (5 × 3.5 Gy/week)
2
was performed from March 2012 to April 2012. Shortly after radiation, new and rapidly growing lesions developed outside of the irradiated field. Therefore, we decided to start systemic therapy with vemurafenib 2 × 960 mg in June 2012. Seven days later, the patient developed a maculopapular rash, edema and severe erythema with an area of desquamation in the previously irradiated skin (fig. 1a). Pruritus and moderate pain as well as an increased tactile sensitivity were described. There were no systemic signs of inflammation. A dermatological evaluation was performed and the diagnosis of a radiation recall dermatitis was made based on clinical symptoms. Systemic pain medication and local treatment with corticosteroids class III (mometasone 1 mg/mg) and a fat-liquoring skin lotion was started. We decided to continue the treatment under close observation, due to the underlying rapid growth of the metastases. Though vemurafenib at a dose of 2 × 960 mg was continuously administered, the dermatitis improved over the following weeks with a decrease in skin rash and ede-
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
ma (fig. 1b). After 2 months the skin changes had completely disappeared. In addition, the metastases showed a partial response to vemurafenib and decreased in fullness and quantity (fig. 2). Disease control with vemurafenib lasted for a total of 6 months. Discussion
Radiation recall dermatitis is a known side effect with a reported incidence of less than 5–10% [13]. Diagnosis is usually established by clinical judgment alone and is obvious by the sharp edges which indicate the radiation field. There are only isolated case reports of skin biopsies of affected areas, and nonspecific changes on hematoxylin and eosin staining have been reported. Features include vacuolization in basal cells, psoriasiform epidermal hyperplasia, apoptotic keratinocytes and follicular hyperkeratosis. The histological appearance is nonspecific, e.g. may be associated with acute radiation dermatitis [11, 14]. In the
Conen et al.
Downloaded by: University of Pittsburgh 198.143.32.65 - 8/10/2015 8:25:50 PM
Case Report
Table 1. Overview of the literature on vemurafenib and radiation recall dermatitis Case
Onset time after vemurafenib
after irradiation
Action taken
Radiation dose
Anker [19], Tender rash and mild 2013 erythema
Vemurafenib and in between radiotherapy
12 days after vemurafenib
14 days
None
20 Gy, 5 fractions
Boussemart Pruriginous erythematous [20], 2013 vesicles
Irradiation and immediate sequential vemurafenib
10 days after vemurafenib
11 days
Topical corticosteroids
18 Gy, 3 fractions
Pruriginous eczematous plaque
Irradiation and sequential vemurafenib
7 days after vemurafenib
30 days
Betamethasone valerate cream
20 Gy, 5 fractions
Braunstein [21], 2014
Ulceration, erythema, scar dehiscence
Irradiation and sequential vemurafenib
2 weeks after 8 weeks vemurafenib and 8 weeks after radiotherapy
Vemurafenib stopped
71 Gy, 38 fractions
Ducassou [22], 2013
Intensive erythema
Vemurafenib and late simultaneous radiotherapy
6 months after vemurafenib
4 days
None
30 Gy, 10 fractions
Harding [23], 2014
Erythematous hyperkeratotic plaques Cutis verticis gyrata
Whole brain irradiation and simultaneous vemurafenib
10 days after vemurafenib
During radiotherapy
Topical aclometasone
30 Gy, 10 fractions
Erythema and hyperkeratosis
Whole brain irradiation and vemurafenib 3 weeks thereafter
3 weeks after vemurafenib
6 weeks
Dose reduction, topical salicylic acid
35 Gy, 14 fractions
Levy [18], 2013
Erythematous skin reaction
Not stated
Not stated
Not stated
None
18 Gy, 3 fractions
Schulze [24], 2014
Painful general erythema
Vemurafenib and whole brain irradiation after 1 week
10 days after vemurafenib
During radiotherapy
Topical corticosteroids and ureacontaining cream
30 Gy, 10 fractions
General edema, multiple small cystic lesions
Vemurafenib and 4 weeks later simultaneous whole brain irradiation
8 weeks after vemurafenib
4 weeks
None
Not stated
Diffuse pilaris-like keratosis, folliculocentric papules within erythematous patch
Irradiation and sequential vemurafenib
1 week after vemurafenib
5 weeks
Ammonium lactate cream
Not stated
Wang [25], 2012
clinical routine, we therefore recommend not to perform a biopsy in the absence of further diagnostic or therapeutic consequences. The exact mechanism that triggers skin changes is poorly understood. In particular, there is large heterogeneity with regard to the drugs that induce radiation recall dermatitis and the time between radiotherapy, the start of systemic treatment and the onset of the skin rash. No specific risk factors like additional toxic agents (e.g. UV light) have been reported so far. In general, there are mainly 3 etiological hypotheses to explain the key characteristics of radiation recall dermatitis. First, vascular damage induced by radiotherapy has been proposed leading to a higher concentration of the cytotoxic agent in the irradiated tissue areas. As there are case reports of ra-
Vemurafenib and Radiation Recall Dermatitis
diation recall dermatitis 7–15 years after stopping radiotherapy [11, 15], this hypothesis is considered controversial. Second, the theory of epithelial stem cell inadequacy has been proposed [9, 16]. Hellman and Botnick [16] observed that radiationdepleted and/or -damaged epithelial stem cells lead to dysregulated proliferation after completion of radiotherapy. The subsequent administration of a cytotoxic agent which causes epithelial cell damage may inhibit adequate regeneration of epithelial cells in the previously irradiated skin. Finally, epithelial stem cell sensitivity hypothesizes that radiation leads to damage of the stem cell program [10]. Thus, the stem cells still maintain an adequate functional role, but only by cycling at a faster rate. If cytotoxic agents are given, they may be more
active in rapidly proliferating cells. Camidge and Price [17] proposed a novel hypothesis in a review in 2001, suggesting a drug hypersensitivity reaction of the skin on an immune or nonimmunologic, inflammatory reaction. New targeted therapies do affect the skin in very specific ways. Interestingly, cases of erlotinib-induced radiation recall dermatitis were described in the literature [12, 18]. This observation suggests that targeted therapies, particularly tyrosine kinase inhibitors, should be added to the list of radiation recall dermatitis-inducing substances. Also, for vemurafenib, the reports on a radiation-sensitizing and recall phenomenon are gradually increasing (table 1) [19–25]. The clinical presentations, however, are heterogeneous, applying sequential or combined approaches of
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
3
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First author Skin reaction
vemurafenib and radiation. Generally, the radiation recall phenomenon occurs 7–14 days after initiation of either treatment and is independent of the radiation dose. One report using 71 Gy describes radiation recall with edema and ulcerations [21]. Skin reactions were mainly mild to ulcerative erythema. The main symptoms were pruritus and mild to moderate pain. In the majority of cases, only topical corticosteroid treatment was performed without dose reduction or drug discontinuation. Though our understanding is still poor, mechanistically, this phenomenon may be associated with an increased sensitivity to radiation, as vemurafenib increases the risk of UVA-
dependent phototoxicity [26]. Yet, according to the reported cases, the key question for clinical practice remains whether drug discontinuation is needed or not. As melanomas are highly aggressive and growing fast, treatment should not be discontinued over a long time. Moreover, reinduction of a treatment that once caused radiation recall dermatitis will likely reinduce the skin changes after re-exposure. From our experience, a continuity of vemurafenib application despite significant recall skin dermatitis is possible provided that a close monitoring of the skin and local treatment in an interdisciplinary network are performed. Although only limited clinical data
is available, it seems not necessary to interrupt the application of vemurafenib, as long as the radiotherapy has been of limited or intermediate aggressiveness, with only moderate, spontaneously regressing skin reactions being a consequence. Topical corticosteroid creams or salicylic acids may be used to speed up the healing process [24].
10 Abadir R, Liebmann J: Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol) 1995;7: 325–326. 11 Bostrom A, et al: Radiation recall – another call with tamoxifen. Acta Oncol 1999;38:955– 959. 12 Dauendorffer JN, Dupuy A: Radiation recall dermatitis induced by erlotinib. J Am Acad Dermatol 2009;61:1086. 13 Kodym E, et al: Frequency of radiation recall dermatitis in adult cancer patients. Onkologie 2005;28:18–21. 14 Solberg LA Jr, Wick MR, Bruckman JE: Doxorubicin-enhanced skin reaction after wholebody electron-beam irradiation for leukemia cutis. Mayo Clin Proc 1980;55:711–715. 15 Mayer EG, Poulter CA, Aristizabal SA: Complications of irradiation related to apparent drug potentiation by Adriamycin. Int J Radiat Oncol Biol Phys 1976;1:1179–1188. 16 Hellman S, Botnick LE: Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977;2:181–184. 17 Camidge R, Price A: Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001;59:237–245.
18 Levy A, et al: Targeted therapy-induced radiation recall. Eur J Cancer 2013;49:1662–1668. 19 Anker CJ, et al: Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol 2013;31:e283–e287. 20 Boussemart L, et al: Vemurafenib and radiosensitization. JAMA Dermatol 2013;149:855– 857. 21 Braunstein I, et al: Vemurafenib-induced interface dermatitis manifesting as radiationrecall and a keratosis pilaris-like eruption. J Cutan Pathol 2014;41:539–543. 22 Ducassou A, et al: Radiosensitization induced by vemurafenib. Cancer Radiother 2013; 17: 304–307. 23 Harding JJ, et al: Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. J Clin Oncol 2014;32:e54–e56. 24 Schulze B, et al: Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 2014;190:229–232. 25 Wang CM, Fleming KF, Hsu S: A case of vemurafenib-induced keratosis pilaris-like eruption. Dermatol Online J 2012;18:7. 26 Dummer R, Rinderknecht J, Goldinger SM: Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med 2012; 366: 480–481.
Disclosure Statement
No funding was obtained for this case report. The authors indicate no financial relationships.
1 Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 2004;351: 998–1012. 2 Middleton MR, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18:158–166. 3 Chapman PB, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507–2516. 4 Crosby T, et al: Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000;2:CD001215. 5 Hodi FS, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723. 6 Curtin JA, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353: 2135–2147. 7 Saif MW, Ramos J, Knisely J: Radiation recall phenomenon secondary to bevacizumab in a patient with pancreatic cancer. JOP 2008; 9: 744–747. 8 D’Angio GJ, Farber S, Maddock CL: Potentiation of x-ray effects by actinomycin D. Radiology 1959;73:175–177. 9 Seymour CB, Mothersill C, Alper T: High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med 1986; 50:167–179.
4
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
Conen et al.
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References
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
Vemurafenib-Induced Radiation Recall Dermatitis: Case Report and Review of the Literature Katrin Conen a Katarzyna Mosna-Firlejczyk b Christoph Rochlitz a Andreas Wicki a Peter Itin c Andreas W. Arnold c Markus Gross b Frank Zimmermann b Alfred Zippelius a Departments of a Medical Oncology, b Radiooncology and c Dermatology, University Hospital Basel, Basel, Switzerland
Abstract The cutaneous effects of BRAF (serine/threonine protein kinase B-raf) inhibitors such as vemurafenib remain poorly defined. Rash, squamous cell carcinoma, keratoacanthoma and photosensitivity are the most common grade 2 or 3 adverse events observed in clinical trials. We here report the case of a patient with a BRAF V600E mutated metastatic melanoma who developed severe radiation recall dermatitis 6 weeks after completing radiotherapy. Vemurafenib treatment had been initiated 1 week before the development of dermatitis because of rapidly progressing disease. Upon topical treatment of the affected skin areas, clinical symptoms regressed over a period of 2 months, although vemurafenib was continuously administered. As our case goes in line with other reports, we believe that physicians should be aware of this additional cutaneous side effect of vemurafenib and that continuation of the treatment is safe when close clinical control and interdisciplinary management can © 2014 S. Karger AG, Basel be provided.
Introduction
Metastatic melanoma reflects the most aggressive type of skin cancer [1]. A number of chemotherapeutic agents show clinical activity in patients with metastatic melanoma but do not impact on overall survival: dacarbazine, nitrosoureas, platinum analogs, vinca alkaloids and taxanes. Of these, dacarbazine only has gained Food and Drug Administration approval based on response rates of 7–15%. However, a Cochrane review did not find evidence for a relevant survival benefit of dacarbazine [2–4]. In 2010, the anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab demonstrated for the first time an improved overall survival in metastatic melanoma patients as compared to the gp100 vaccine [5]. In 2011, the serine/threonine protein kinase B-raf (BRAF) inhibitor vemurafenib was introduced. Vemurafenib inhibits kinase activity of V600E and most likely V600K mutated BRAF, thus suppressing aberrant mitogen-activated protein kinase signaling [6]. In a randomized phase III trial, vemurafenib was superior to dacarbazine in the first-line treatment of advanced melanoma with a 67% risk reduction of death in the treat-
© 2014 S. Karger AG, Basel 1018–8665/14/2301–0001$39.50/0 E-Mail [email protected] www.karger.com/drm
ment group [3]. Vemurafenib is generally well tolerated. The most common vemurafenib-related grade 2 or 3 adverse events are related to the skin, including rash, photosensitivity and skin malignancies [3]. Radiation recall dermatitis reflects the reappearance of radiotherapy-induced skin reactions in the previously irradiated skin regions after the introduction of drugs [7]. It was first described by D’Angio et al. in 1959 with actinomycin D treatment [8]. Since then many other drugs have been associated with this phenomenon: anthracyclines, taxanes, 5-fluorouracil, hydroxyurea, methotrexate and cisplatin. The pathophysiology of this phenomenon remains poorly understood [9–11]. Meanwhile, increasing numbers of reports describe radiation recall effects also for targeted therapies [12]. Of high importance is the clear discrimination of a direct sensitizing effect of any systemic therapy on the acute radiation-induced dermatitis versus a real recall phenomenon, when the risk of acute radiation dermatitis has been endured. The latter is most likely more than 4 weeks after irradiation. F. Zimmermann and A. Zippelius contributed equally to this work.
Katrin Conen, MD Department of Medical Oncology, University Hospital Basel Petersgraben 4 CH–4031 Basel (Switzerland) E-Mail katrin.conen @ usb.ch
Downloaded by: University of Pittsburgh 198.143.32.65 - 8/10/2015 8:25:50 PM
Key Words Melanoma · Radiotherapy · Vemurafenib · Radiation recall dermatitis
Color version available online
Fig. 1. Vemurafenib radiation recall der-
a
b
b
c
Color version available online
matitis. a Seven days after start of vemurafenib, 6 weeks after the end of irradiation. Arrow: area of desquamation with crusts. b After 21 days of vemurafenib treatment.
a
Fig. 2. Vemurafenib treatment effect and recall dermatitis. a Melanotic lesions 7 days after treatment start. b Eight weeks after treatment start. c Twelve weeks after treatment start.
A 78-year-old man with a melanoma history of the left flank in 2009 treated with wide local excision presented to our department in March 2012. He showed multiple skin metastases on the left to right thoracic wall, back and flank. A biopsy of one lesion confirmed metastatic melanoma (stage IV); further pathological assessments revealed a BRAF V600E mutation detected by Sanger sequencing. The metastases presented as black, dense lesions, most of them less than 1 cm in diameter. Additional staging using PET/CT revealed enlarged, fluorodeoxyglucose-positive lymph nodes in the left axillary region. The patient suffered from coronary heart disease that was currently stable under medication. Due to comorbidities and the localized and skin-only metastatic spread, we primarily discussed local irradiation that was performed in the affected skin region up to 30 Gy (6 fractions of 5.0 Gy). Additionally, radiotherapy of the axillary lymph nodes up to 35 Gy (5 × 3.5 Gy/week)
2
was performed from March 2012 to April 2012. Shortly after radiation, new and rapidly growing lesions developed outside of the irradiated field. Therefore, we decided to start systemic therapy with vemurafenib 2 × 960 mg in June 2012. Seven days later, the patient developed a maculopapular rash, edema and severe erythema with an area of desquamation in the previously irradiated skin (fig. 1a). Pruritus and moderate pain as well as an increased tactile sensitivity were described. There were no systemic signs of inflammation. A dermatological evaluation was performed and the diagnosis of a radiation recall dermatitis was made based on clinical symptoms. Systemic pain medication and local treatment with corticosteroids class III (mometasone 1 mg/mg) and a fat-liquoring skin lotion was started. We decided to continue the treatment under close observation, due to the underlying rapid growth of the metastases. Though vemurafenib at a dose of 2 × 960 mg was continuously administered, the dermatitis improved over the following weeks with a decrease in skin rash and ede-
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
ma (fig. 1b). After 2 months the skin changes had completely disappeared. In addition, the metastases showed a partial response to vemurafenib and decreased in fullness and quantity (fig. 2). Disease control with vemurafenib lasted for a total of 6 months. Discussion
Radiation recall dermatitis is a known side effect with a reported incidence of less than 5–10% [13]. Diagnosis is usually established by clinical judgment alone and is obvious by the sharp edges which indicate the radiation field. There are only isolated case reports of skin biopsies of affected areas, and nonspecific changes on hematoxylin and eosin staining have been reported. Features include vacuolization in basal cells, psoriasiform epidermal hyperplasia, apoptotic keratinocytes and follicular hyperkeratosis. The histological appearance is nonspecific, e.g. may be associated with acute radiation dermatitis [11, 14]. In the
Conen et al.
Downloaded by: University of Pittsburgh 198.143.32.65 - 8/10/2015 8:25:50 PM
Case Report
Table 1. Overview of the literature on vemurafenib and radiation recall dermatitis Case
Onset time after vemurafenib
after irradiation
Action taken
Radiation dose
Anker [19], Tender rash and mild 2013 erythema
Vemurafenib and in between radiotherapy
12 days after vemurafenib
14 days
None
20 Gy, 5 fractions
Boussemart Pruriginous erythematous [20], 2013 vesicles
Irradiation and immediate sequential vemurafenib
10 days after vemurafenib
11 days
Topical corticosteroids
18 Gy, 3 fractions
Pruriginous eczematous plaque
Irradiation and sequential vemurafenib
7 days after vemurafenib
30 days
Betamethasone valerate cream
20 Gy, 5 fractions
Braunstein [21], 2014
Ulceration, erythema, scar dehiscence
Irradiation and sequential vemurafenib
2 weeks after 8 weeks vemurafenib and 8 weeks after radiotherapy
Vemurafenib stopped
71 Gy, 38 fractions
Ducassou [22], 2013
Intensive erythema
Vemurafenib and late simultaneous radiotherapy
6 months after vemurafenib
4 days
None
30 Gy, 10 fractions
Harding [23], 2014
Erythematous hyperkeratotic plaques Cutis verticis gyrata
Whole brain irradiation and simultaneous vemurafenib
10 days after vemurafenib
During radiotherapy
Topical aclometasone
30 Gy, 10 fractions
Erythema and hyperkeratosis
Whole brain irradiation and vemurafenib 3 weeks thereafter
3 weeks after vemurafenib
6 weeks
Dose reduction, topical salicylic acid
35 Gy, 14 fractions
Levy [18], 2013
Erythematous skin reaction
Not stated
Not stated
Not stated
None
18 Gy, 3 fractions
Schulze [24], 2014
Painful general erythema
Vemurafenib and whole brain irradiation after 1 week
10 days after vemurafenib
During radiotherapy
Topical corticosteroids and ureacontaining cream
30 Gy, 10 fractions
General edema, multiple small cystic lesions
Vemurafenib and 4 weeks later simultaneous whole brain irradiation
8 weeks after vemurafenib
4 weeks
None
Not stated
Diffuse pilaris-like keratosis, folliculocentric papules within erythematous patch
Irradiation and sequential vemurafenib
1 week after vemurafenib
5 weeks
Ammonium lactate cream
Not stated
Wang [25], 2012
clinical routine, we therefore recommend not to perform a biopsy in the absence of further diagnostic or therapeutic consequences. The exact mechanism that triggers skin changes is poorly understood. In particular, there is large heterogeneity with regard to the drugs that induce radiation recall dermatitis and the time between radiotherapy, the start of systemic treatment and the onset of the skin rash. No specific risk factors like additional toxic agents (e.g. UV light) have been reported so far. In general, there are mainly 3 etiological hypotheses to explain the key characteristics of radiation recall dermatitis. First, vascular damage induced by radiotherapy has been proposed leading to a higher concentration of the cytotoxic agent in the irradiated tissue areas. As there are case reports of ra-
Vemurafenib and Radiation Recall Dermatitis
diation recall dermatitis 7–15 years after stopping radiotherapy [11, 15], this hypothesis is considered controversial. Second, the theory of epithelial stem cell inadequacy has been proposed [9, 16]. Hellman and Botnick [16] observed that radiationdepleted and/or -damaged epithelial stem cells lead to dysregulated proliferation after completion of radiotherapy. The subsequent administration of a cytotoxic agent which causes epithelial cell damage may inhibit adequate regeneration of epithelial cells in the previously irradiated skin. Finally, epithelial stem cell sensitivity hypothesizes that radiation leads to damage of the stem cell program [10]. Thus, the stem cells still maintain an adequate functional role, but only by cycling at a faster rate. If cytotoxic agents are given, they may be more
active in rapidly proliferating cells. Camidge and Price [17] proposed a novel hypothesis in a review in 2001, suggesting a drug hypersensitivity reaction of the skin on an immune or nonimmunologic, inflammatory reaction. New targeted therapies do affect the skin in very specific ways. Interestingly, cases of erlotinib-induced radiation recall dermatitis were described in the literature [12, 18]. This observation suggests that targeted therapies, particularly tyrosine kinase inhibitors, should be added to the list of radiation recall dermatitis-inducing substances. Also, for vemurafenib, the reports on a radiation-sensitizing and recall phenomenon are gradually increasing (table 1) [19–25]. The clinical presentations, however, are heterogeneous, applying sequential or combined approaches of
Dermatology 2015;230:1–4 DOI: 10.1159/000365918
3
Downloaded by: University of Pittsburgh 198.143.32.65 - 8/10/2015 8:25:50 PM
First author Skin reaction
vemurafenib and radiation. Generally, the radiation recall phenomenon occurs 7–14 days after initiation of either treatment and is independent of the radiation dose. One report using 71 Gy describes radiation recall with edema and ulcerations [21]. Skin reactions were mainly mild to ulcerative erythema. The main symptoms were pruritus and mild to moderate pain. In the majority of cases, only topical corticosteroid treatment was performed without dose reduction or drug discontinuation. Though our understanding is still poor, mechanistically, this phenomenon may be associated with an increased sensitivity to radiation, as vemurafenib increases the risk of UVA-
dependent phototoxicity [26]. Yet, according to the reported cases, the key question for clinical practice remains whether drug discontinuation is needed or not. As melanomas are highly aggressive and growing fast, treatment should not be discontinued over a long time. Moreover, reinduction of a treatment that once caused radiation recall dermatitis will likely reinduce the skin changes after re-exposure. From our experience, a continuity of vemurafenib application despite significant recall skin dermatitis is possible provided that a close monitoring of the skin and local treatment in an interdisciplinary network are performed. Although only limited clinical data
is available, it seems not necessary to interrupt the application of vemurafenib, as long as the radiotherapy has been of limited or intermediate aggressiveness, with only moderate, spontaneously regressing skin reactions being a consequence. Topical corticosteroid creams or salicylic acids may be used to speed up the healing process [24].
10 Abadir R, Liebmann J: Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol) 1995;7: 325–326. 11 Bostrom A, et al: Radiation recall – another call with tamoxifen. Acta Oncol 1999;38:955– 959. 12 Dauendorffer JN, Dupuy A: Radiation recall dermatitis induced by erlotinib. J Am Acad Dermatol 2009;61:1086. 13 Kodym E, et al: Frequency of radiation recall dermatitis in adult cancer patients. Onkologie 2005;28:18–21. 14 Solberg LA Jr, Wick MR, Bruckman JE: Doxorubicin-enhanced skin reaction after wholebody electron-beam irradiation for leukemia cutis. Mayo Clin Proc 1980;55:711–715. 15 Mayer EG, Poulter CA, Aristizabal SA: Complications of irradiation related to apparent drug potentiation by Adriamycin. Int J Radiat Oncol Biol Phys 1976;1:1179–1188. 16 Hellman S, Botnick LE: Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977;2:181–184. 17 Camidge R, Price A: Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001;59:237–245.
18 Levy A, et al: Targeted therapy-induced radiation recall. Eur J Cancer 2013;49:1662–1668. 19 Anker CJ, et al: Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol 2013;31:e283–e287. 20 Boussemart L, et al: Vemurafenib and radiosensitization. JAMA Dermatol 2013;149:855– 857. 21 Braunstein I, et al: Vemurafenib-induced interface dermatitis manifesting as radiationrecall and a keratosis pilaris-like eruption. J Cutan Pathol 2014;41:539–543. 22 Ducassou A, et al: Radiosensitization induced by vemurafenib. Cancer Radiother 2013; 17: 304–307. 23 Harding JJ, et al: Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. J Clin Oncol 2014;32:e54–e56. 24 Schulze B, et al: Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 2014;190:229–232. 25 Wang CM, Fleming KF, Hsu S: A case of vemurafenib-induced keratosis pilaris-like eruption. Dermatol Online J 2012;18:7. 26 Dummer R, Rinderknecht J, Goldinger SM: Ultraviolet A and photosensitivity during vemurafenib therapy. N Engl J Med 2012; 366: 480–481.
Disclosure Statement
No funding was obtained for this case report. The authors indicate no financial relationships.
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Dermatology 2015;230:1–4 DOI: 10.1159/000365918
Conen et al.
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