Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

Abstract

BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS. No fatal reactions have been described with a dose <4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.

Fig. 1

Cystic proliferation and underlying brisk dermatitis noted over right flank and axilla 1 month after palliative radiation therapy given concurrently with vemurafenib.

Fig. 2

Images of cutis verticis gyrata appearance obtained 2 weeks after starting vemurafenib; the BRAFi was started 4 days after whole brain radiation therapy. (A) Lateral view with biopsy site circled, showing follicular hyperkeratosis and syringosquamous metaplasia (B) Posterior view.

Fig. 3

(A) Axial, (B) sagittal, and (C) coronal views of radiation plan for patient with bowel perforation 1 month after dabrafenib and trametinib were started. These systemic agents were started 10 days after 20 Gy in 5 fractions using a 4 field technique with 10 MV photons to pelvic bone metastases (shaded red). The V_{18 Gy} and V_{20 Gy} of the large bowel loops (green), small bowel loops (orange), and bowel bag volume (not shown) were 180 and 90 cc, 460 and 230 cc, and 1450 and 750 cc, respectively. (A color version of this figure is available at www.redjournal.org.)