Table 4. Stereotactic radiotherapy combined with targeted therapy or immunotherapy for the treatment of brain metastases of malignant melanoma.

Reference	Study type	Study population	Treatment	Toxicity	Intracranial response	Median overall survival
Tétu 2019 (28)	retrospective	n = 262	anti-PD1, anti- CTLA4, BRAFi, BRAFi + MEKi +/− RT*	no increased neurotoxicity in the RT group	not reported	median OS: combined RT: 16.8 m, non combined: 6.9 m (HR: 0.6; 95% CI [0.4; 0.8] after propensity score matching)
Mathew 2013 (33)	retrospective	n = 58	RS +/− ipilimumab	no increased bleeding rate with the addition of ipilimumab	LC at 6 months: RS: 65% RS + ipilimumab: 63% (NS)	6-month OS RS: 45% RS + ipilimumab: 56% (NS)
Kiess 2016 (34)	retrospective	n = 46	RS + ipilimumab	grade III/IV toxicity = 20% (pruritus, hepatitis, CNS hemorrhage, seizures)	not reported	median OS: 12.4 months
Diao 2018 (35)	retrospective	n = 91	RS +/− ipilimumab	radionecrosis = 5%	1 year without local recurrence: RS: 45% RS + conc. ipilimumab: 58% RS + non-conc. ipilimumab: 70% (NS)	median OS: RS: 7.8 m RS + ipilimumab: 15.1 m (p = 0.02)
Ahmed 2016 (36)	retrospective	n = 26	SRT/RS + nivolumab	no grade III/IV toxicity	LC at 12 months: 85%	median OS: 11.8 m
Ahmed 2015 (37)	retrospective	n = 24	RS + vemurafenib	1 case of early recurrence with hemorrhage and necrotic components	LC at 12 months: 75%	median OS: 11.9 m

* Radiotherapy was considered “combined” when it was given within the period from 30 days before to 30 days after the first dose of systemic treatment.

BRAFi, BRAF inhibitor; CNS, central nervous system; conc., concomitant; CTLA4, cytotoxic T-lymphocyte-associated protein 4; HR, hazard ratio; LC, local control; m, months; MEKi, MEK inhibitor; NS, not significant; OS, overall survival; PD1, programmed cell death protein 1; RS, radiosurgery; RT, radiotherapy; SRT, stereotactic radiotherapy; 95% CI, 95% confidence interval