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.

Optimizing combination dabrafenib and trametinib therapy in BRAF mutation‐positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists

“…27,28 However, there is a lack of definitive toxicity and efficacy data, and there is no standard approach to continuing or interrupting drug therapy while undergoing radiotherapy. The Eastern Cooperative Oncology Group consensus recommendations, 29 although not evidence based, include that BRAF inhibitors and MEK inhibitors should be stopped for a minimum of 3 days before and after fractionated radiotherapy, and for a minimum of 1 day before and after stereotactic radiotherapy (SRS). The same recommendations are provided for all BRAF inhibitor and MEK inhibitor therapy although most of the evidence assessed was from trials of the BRAF inhibitor vemurafenib.…”

Radiation Therapy for Melanoma

“…There were no fatal reactions documented with RT doses less than 4 Gy per fraction. More prospective trials are necessary to further clarify the optimal timing of BRAF inhibition with RT (143).…”

Targeted therapy for BRAF-mutation positive metastatic melanoma

“…Vemurafenib kezelés mellett gyakran észlelünk fotoszenzitivitást. Sugárkezelt bőrterület vagy belső szerv súlyos akut gyulladásos reakciója jelentkezhet a gyógyszerszedés alatt az irradiációval egyidejűleg vagy röviddel utána (radioszenzitizáció), de akár jóval később (átlag 1 hónappal) a sugárkezelés befejezése után ("radiation recall") (21,22). A BRAF inhibitorok specifikus mellékhatásaként benignus (pl.…”

“…sztereotaxiás sugársebészet [SRS]) együtt az agyi áttétekkel járó metasztatikus betegségben a túlélés esélye akár megkétszerezhető: egy prospektív vizsgálatban SRS utáni 1-éves OS 41% volt célzott kezelésben része-sülő BRAF-mutáns melanoma esetén, míg 19% volt BRAF vad típusú melanoma esetén (34). A radionecrosis elkerü-lése végett a szakmai ajánlás SRS előtt és után 1-1 nap, míg más radioterápiás metódusok esetén 3-3 nap gyógy-szerkihagyás (21).…”