Enhanced Radiation Dermatitis Associated With Concurrent Palliative Radiation and Vemurafenib Therapy

The exact mechanism of increased radiosensitivity caused by targeted chemotherapies such as cetuximab and vemurafenib is unclear. One possible explanation is that the drug interferes with the mitogen-activated protein kinase (MAPK) pathway, which plays a crucial role in controlling cell survival and regeneration following radiation exposure.⁸ Disruption of this signaling pathway through targeted therapies leads to impaired keratinocyte cell survival and recovery, and thus may enhance susceptibility to radiation-induced skin injury (Figure 2). In vivo studies have demonstrated that the epidermal growth factor receptor is activated following UV irradiation in human keratinocytes, leading to activation of the downstream MAPK signal transduction pathway required for cellular proliferation mediated via the RAF family of proteins.^9,10 Further supporting the importance of this pathway in keratinocyte survival and recovery are findings that somatic deletion of BRAF in fibroblasts results in decreased growth factor–induced MAPK activation and enhanced apoptosis,⁸ whereas activated BRAF has been shown to exert protective effects against oxidative stress as well as tumorigenesis.¹¹ The observation that mutant BRAF melanoma cells demonstrated increased radiosensitivity following BRAF inhibition with vemurafenib¹² is consistent with our hypothesis that increased radiosensitivity occurs when signal transduction mediated by MAPK pathway is blocked, thereby inhibiting cell survival. As a result, radiation dermatitis is likely to occur more frequently and at a lower dose when signaling pathways upstream in the MAPK pathway required for keratinocyte regeneration, such as epidermal growth factor receptor and BRAF, are inhibited by targeted therapies. This hypothesis supports the observation that patients on medications that inhibit these signaling pathways, such as cetuximab and vemurafenib, develop enhanced sensitivity to both UV radiation and radiation therapy.

We report a case of enhanced radiation dermatitis occurring at a total dose of 0.75 Gy of radiotherapy, well below the threshold commonly recognized to cause radiation-induced skin toxicities. Our observation suggests that vemurafenib likely acts as a radiosensitizing agent that notably decreases the threshold for radiotherapy-related skin toxicities. Furthermore, the radiosensitizing effect of vemurafenib appears to be transient, as our patient showed no evidence of any skin reaction to subsequent radiation treatment soon after vemurafenib was discontinued. As more patients with metastatic melanoma are treated with vemurafenib, the combination of palliative or adjuvant radiation therapy with vemurafenib will likely be used more frequently. Caution should be exercised in patients on vemurafenib who receive concurrent radiotherapy, even at low radiation doses.

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