The occurrence of brain metastases and leptomeningeal melanomatosis has a dismal impact on life expectancy in patients with malignant melanoma: median overall survival rates range between only 3 and 5 months [22]. Various factors influence survival times, including age, performance score, existence of extracranial metastases and interval from the diagnosis of cerebral lesions to radiotherapy (RT). Moreover, coexisting intracranial leptomeningeal carcinomatosis reduces survival rates dramatically [10, 13].

Recently, the introduction of novel therapeutic agents like the BRAF inhibitors dabrafenib and vemurafenib has resulted in substantial tumor regression in patients with metastatic melanoma who carry the activating V600E mutation in the BRAF gene. This mutation accounts for the majority of BRAF mutations and is found in approximately 50 % of all patients with metastatic melanoma. The BRAF-V600 gene mutation leads to uncontrolled downstream activation of the MAPK/ERK pathway, resulting in excessive cell proliferation [3, 6, 8]. Vemurafenib has been shown to be a highly effective anticancer drug in previously untreated melanoma patients with the BRAF-V600 mutation, eliciting superior response rates compared to dacarbacine alone (48 % vs. 5 %) [7]. Therefore, simultaneous or sequential application of vemurafenib and palliative RT for brain metastases or leptomeningeal meningeosis is increasingly observed in daily clinical practice.

Preliminary evidence for unexpected acute skin toxicity resulting from a combination of BRAF inhibitors and RT has recently been reported and experiences with increased late skin toxicity have come into focus [2, 4, 19]. We here report two cases of skin toxicity which arose in the context of RT with concomitant vemurafenib application. In one case, excessive acute skin toxicity was observed during RT; in the second case, delayed skin toxicity was observed 4 weeks after whole-brain RT.

Case 1

A 54-year-old female patient with visceral and bone metastases from a malignant melanoma, with newly diagnosed leptomenigeal melanomatosis and multiple intracerebral metastases was referred to our department for palliative whole-brain RT.

The initial diagnosis of an amelanotic malignant melanoma of the right heel with involvement of two inguinal lymph nodes was histologically confirmed in 2003 by wide excision of the primary tumor and inguinal lymph node dissection. The patient subsequently underwent adjuvant therapy with interferon-α for 18 months. In 2012, multiple visceral metastases and bone metastasis of the scalp were diagnosed. In April 2013, progressive disease with multiple diminutive cerebral metastases and leptomeningeal melanomatosis was diagnosed. The V600E mutation was confirmed by gene sequencing of an occipital skull metastasis biopsy sample. Systemic therapy with vemurafenib (960 mg twice daily) was commenced and palliative whole-brain RT began 1 week thereafter. RT was performed using a conventional 6-MeV photon source with two opposing beams (90 and 270°; cumulative dose 30.0 Gy with 3.0 Gy per fraction administered 5 days per week). After only 3 fractions and a total dose of 9.0 Gy, the patient began to develop exceptionally distinct radiodermatitis, with painful general erythema, dry desquamation within the irradiated area of the scalp and moist desquamation in the region of the earlobes. These lesions were delimited strictly to the irradiated areas (Fig. 1). According to the recommendations of the attending dermatologist, vemurafenib treatment was stopped during RT, to be recontinued shortly after completion of whole-brain RT.

Fig. 1
figure 1

Radiodermatitis after a cumulative dose of 9.0 Gy: left panel painful, desquamating erythema localized strictly to the irradiated areas of the scalp and erosions in the area of the earlobe. Right panel corresponding digitally reconstructed radiograph (DRR) of the 90-degree radiotherapy (RT) field. Red outline whole-brain irradiation (target) volume. Reproduction with kind permission of the patient

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The skin lesions were treated with topical corticosteroids and a urea-containing skin cream. Lesions began to resolve shortly after the start of topical treatment and omission of vemurafenib. No interruption of RT was necessary. At the end of RT, the scalp showed only mild erythema and general hyperpigmentation contained strictly within the borders of the RT fields. Further examinations showed no vemurafenib-related late effects.

Case 2

A 47-year-old male patient with a superficial spreading melanoma of the chest that was diagnosed and excised in 2001 was referred to our department in April 2013. It was intended that the patient receive whole-brain RT for multiple intracerebral metastases and leptomenigeal melanomatosis. One month before the start of RT, chest and abdominal CT scans revealed disseminated visceral and cutaneous progression and systemic therapy with vemurafenib (960 mg twice daily) was thus initiated. The presence of the BRAF-V600E mutation was confirmed using a cutaneous metastasis biopsy sample. Whole-brain RT was performed in the same manner as described above. During RT, no relevant or unusual acute skin toxicity was noted; mild scalp erythema only was observed at the end of RT. Approximately 4 weeks after RT, the scalp showed general edema and multiple small cystic lesions, distributed in a milia-like fashion and resembling in part Favre–Racouchot disease (Fig. 2). Again, these alterations were strictly delimited to the formerly irradiated areas and showed a maximum at the borders of the RT fields. A biopsy of one of these lesions showed cystic epithelium with a proliferative activation, which was considered to be a reactive response associated with vemurafenib and RT (Fig. 3). This clinical finding remained unaltered during the following weeks and was still present at the last follow-up visit, 16 weeks after completion of RT. It was not necessary to discontinue vemurafenib at any time.

Fig. 2
figure 2

Left and center panels edema and multiple small cystic lesions of the scalp, distributed in a milia-like fashion and strictly delimited to the irradiated areas, 16 weeks after completion of radiotherapy (RT). Lesions showed a maximum at the borders of the RT fields. Right panel the corresponding digitally reconstructed radiograph (DRR) demonstrates the borders of the 90-degree RT field. Red outline whole-brain irradiation (target) volume, blue outline optic nerves, yellow outline orbit, pink outline brainstem, purple outline spinal cord. Reproduction with kind permission of the patient

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Fig. 3
figure 3

Enlarged view of the hyperprolifertive skin area with corresponding histological findings (Alcian/PAS staining). Microscopy shows multiple activated proliferating epidermal cysts with extension into the deep layers of the dermis and without any evidence for atypical spindle-shaped cell-formations

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Discussion

Brain metastases are detected in 10–40 % of all patients with malignant melanomas and autopsy studies have shown occult intracerebral metastases in more than two thirds of all melanoma patients [1, 17, 18, 21]. In instances of a limited number of brain metastases, surgery or radiosurgery may achieve sustained local tumor control and improved survival rates [11, 16]. In the case of multiple brain metastases or leptomenigeal melanomatosis, whole-brain RT is the therapy of choice (provided the patient is in a fair general condition).

In recent years, several novel agents have been introduced for therapy of brain metastases. A comprehensive review was provided by Fokas et al. [12]. Vemurafenib in combination with whole-brain RT seems to be a promising option for the treatment of brain metastases from malignant melanomas [14].

Nonetheless, little is known about the combination of BRAF inhibitors and RT. Vemurafenib is reported to cause severe cutaneous side effects and even among nonirradiated patient populations, up to 52 % of all patients showed phototoxic skin reactions [5, 9]. RT in combination with vemurafenib apparently has the potential to severely enhance this effect, resulting in early and/or unusual acute radiodermatitis. In most of the cases reported so far, including the first of the two cases reported here, this acute skin reaction resolved without sequelae shortly after the end of RT and cessation of vemurafenib treatment.

Another cutaneous side effect of BRAF inhibitors is the promotion of squamoproliferative eruptions, particularly keratoakanthoma and squamous cell cancer, which are supposed to be driven by preexisting (RAS) mutations within these lesions [5, 15, 20, 23]. Whether RT has the potential to enhance the oncogenic effects of BRAF inhibitors remains to be elucidated. Given that the proliferative lesions in our second case report occurred only in the irradiated areas, it is tempting to speculate that a combination of RT and vemurafenib may indeed accelerate epithelioproliferative processes from dormant (RAS) mutations compared to vemurafenib alone and that a higher incidence of malignant skin tumors may be expected to result from this combination. Further basic research and clinical trials are necessary to address this issue.

As our cases illustrate, multidisciplinary collaboration is urgently required to facilitate development of optimal treatment algorithms for patients with brain metastases from malignant melanomas. A combination of vemurafenib and RT seems to be feasible and effective in these patients, but is associated with relevant cutaneous side effects and may even be associated with accelerated tumorigenesis. We recommend paying particular attention to early and delayed skin reactions when combining both therapeutic modalities and to perform this multimodal therapy under strict dermatological supervision.