Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects
Authors: Diao Kevin , Bian Shelly X. , Routman David M. , Yu Cheng , Kim Paul E. , Wagle Naveed A. , Wong Michael K. , Zada Gabriel , Chang Eric L. 
Published: January 2018

OBJECTIVETumor and edema volume changes of brain metastases after stereotactic radiosurgery (SRS) and ipilimumab are not well described, and there is concern regarding the safety of combination treatment. The authors evaluated tumor, edema, and adverse radiation-induced changes after SRS with and without ipilimumab and identified associated risk factors.METHODSThis single-institution retrospective study included 72 patients with melanoma brain metastases treated consecutively with upfront SRS from 2006 to 2015. Concurrent ipilimumab was defined as ipilimumab treatment within 4 weeks of SRS. At baseline and during each follow-up, tumor and edema were measured in 3 orthogonal planes. The (length × width × height/2) formula was used to estimate tumor and edema volumes and was validated in the present study for estimation of edema volume. Tumor and edema volume changes from baseline were compared using the Kruskal-Wallis test. Local failure, lesion hemorrhage, and treatment-related imaging changes (TRICs) were analyzed with the Cox proportional hazards model.RESULTSOf 310 analyzed lesions, 91 were not treated with ipilimumab, 59 were treated with concurrent ipilimumab, and 160 were treated with nonconcurrent ipilimumab. Of 106 randomly selected lesions with measurable peritumoral edema, the mean edema volume by manual contouring was 7.45 cm3 and the mean volume by (length × width × height)/2 formula estimation was 7.79 cm3 with R2 = 0.99 and slope of 1.08 on line of best fit. At 6 months after SRS, the ipilimumab groups had greater tumor (p = 0.001) and edema (p = 0.005) volume reduction than the control group. The concurrent ipilimumab group had the highest rate of lesion response and lowest rate of lesion progression (p = 0.002). Within the concurrent ipilimumab group, SRS dose ≥ 20 Gy was associated with significantly greater median tumor volume reduction at 3 months (p = 0.01) and 6 months (p = 0.02). The concurrent ipilimumab group also had the highest rate of lesion hemorrhage (p = 0.01). Any ipilimumab was associated with higher incidence of symptomatic TRICs (p = 0.005). The overall incidence of pathologically confirmed radiation necrosis (RN) was 2%. In multivariate analysis, tumor and edema response at 3 months were the strongest predictors of local failure (HR 0.131 and HR 0.125) and lesion hemorrhage (HR 0.225 and HR 0.262). Tumor and edema response at 1.5 months were the strongest predictors of TRICs (HR 0.144 and HR 0.297).CONCLUSIONSThe addition of ipilimumab improved tumor and edema volume reduction but was associated with a higher incidence of lesion hemorrhage and symptomatic TRICs. There may be a radiation dose-response relationship between SRS and ipilimumab when administered concurrently. Early tumor and edema response were excellent predictors of subsequent local failure, lesion hemorrhage, and TRICs. The incidence of pathologically proven RN was low, supporting the relative safety of ipilimumab in radiosurgery treatment.