Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects

Abstract

OBJECTIVE Tumor 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. METHODS This 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. RESULTS Of 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 cm and the mean volume by (length × width × height)/2 formula estimation was 7.79 cm with R = 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). CONCLUSIONS The 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.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

“…This result suggests that GKRS is a safe irradiation procedure for brain metastases from malignant melanomas, which is consistent with past reports of SRS for brain metastases [42]. However, the outcomes obtained in this series also showed that combining SRS with immune checkpoint inhibitors significantly increased the incidence of radiation injury, which supports results obtained in several prior studies [1,17,18,30,31,34,43,44]. We hypothesized that this observation might be attributable to the increased radiosensitivity of brain tumors, leading to subacute inflammatory changes and lymphocyte toxicity, as described in recent reports focusing on the novel systemic agents [1,17,18,31,32,35].…”

NPS - 2143 (hydrochloride) inhibits melanoma cancer cell proliferation and induces autophagy and apoptosis

“…Melanoma is a common skin cancer caused by hyperproliferation of abnormal melanocytes. It typically occurs in the skin, but, although rarely, also in the mouth, intestines, brain or eyes [1][2][3]. It is extremely aggressivet and accounts for a large proportion of death among skin tumors.…”

Integration of stereotactic radiosurgery or whole brain radiation therapy with immunotherapy for treatment of brain metastases

“…In fact, OS was significantly shorter in the non-concurrent treatment group at just 8 months compared to 19.1 months for the concurrent therapy cohort ( 84 ). Many trials, including those done by Diao et al ( 98 ), Anderson et al ( 82 ) and Yusuf et al ( 88 ), have also used “4 weeks or 1 month” as the threshold value to describe “concurrent therapy”. In these trials, patients treated with combined ICIs and SRS experienced better results than those diagnosed with non-concurrent therapy ( 79 , 82 , 90 , 98 ).…”

“…Many trials, including those done by Diao et al ( 98 ), Anderson et al ( 82 ) and Yusuf et al ( 88 ), have also used “4 weeks or 1 month” as the threshold value to describe “concurrent therapy”. In these trials, patients treated with combined ICIs and SRS experienced better results than those diagnosed with non-concurrent therapy ( 79 , 82 , 90 , 98 ). In the study carried out by An et al , they suggested that “5.5 months” could also be used to describe “concurrent therapy” as a threshold value ( 83 ).…”