Although series on BMs are heterogeneous in terms of primary tumors, prognosis, treatments and patients clinical characteristics, outcome in our cohort are similar to the one reported in other studies [22, 23].
We found that addition of concurrent IT to SRT was able to increase survival and provide long term control in patients with BMs from solid tumors. In our study, the estimated 1-year LC rates were 96% and 78% in BM irradiated with versus without concurrent IT (p = 0.022). This finding is in line with the recent metaanalyse of Petrelli et al showing that the addition of IT to RT is associated with improved OS (HR = 0.54, 95%CI 0.44–0.67; p < 0.001) compared to RT alone in patients treated with BM . The interesting point is that RT given before or concurrently to IT seemed to provide better results than the reverse sequence. Due to the small number of patients (19 received IT before RT, 17 after RT and 9 before and after), we were not able to confirm this hypothesis. One of the explanations for the synergism of that sequence specifically is the RT induced enhancement of cross presentation of antigens by dentritic cells during cancer cell death, triggering the innate immune system to activate tumor-specific T cells . Moreover, RT administered before systemic treatment may improve the blood-brain barrier permeability, allowing drugs to better penetrate metastases .
Moreover, we observed that patients irradiated with a heterogeneous dose developed less distant brain metastases than those irradiated with a homogenous dose (47% and 71% at one year (p < 0.001). This is in line with our previous report, highlighting the importance of SRT planning . An interesting finding here is the trend to a lower intracerebral relapse rate observed in patients receiving concurrent IT compared to those who did not (24% versus 47% at 1 year, p = 0.08 ). This result should however be interpreted with caution given the small number of patients. This observation may reflect the immune-mediated “abscopal effect”, defined as tumor regression at sites distant to the irradiated field . Few cases of abscopal effects have been reported in the literature so far, and optimal biological and physical conditions to trigger this immune modulation are unknown. But, case reports on abscopal effects occurring with the combination of anti-CTLA4 and SRT in patients with melanoma are increasing and suggest a clinical benefit in terms of survival [27, 28].
The release of antigen for cross presentation depends on the fraction size and total dose of radiation. But, for now, no consensus exists regarding the optimal dose to trigger antigen presentation. Low-dose radiation may better stimulate immune cells and modulate the stromal microenvironment than higher dose . On the opposite, Lee et al showed that a dose of 20 Gy administered in one fraction only induces T cell proliferation in lymph nodes whereas this was not observed with the delivery of the same total dose but given in 4 fractions .
Radiation-induced brain necrosis is a relatively uncommon but potentially severe adverse event of SRT. Its incidence varies between 2% and 30% depending on dose prescription and isodose line, dosimetric parameters [26, 31], disease characteristics  as well as RN diagnosis criteria [33, 34]. Minniti et al reported RN rates that were significantly different between single- and multiple-fraction SRT (20% and 8% respectively) . Other authors have reported similar results, with a lower incidence of RN (3–11%) with dose delivery in 3–5 fractions [35, 36]. Although the risk of RN is known to increase with time, little data are available regarding the risk in longer-term survivors, as survival has generally been poor in the era prior to effective systemic therapy. In a series on 271 BM treated with single-fraction SRT, RN occurred in 25.8% of treated lesions and, in patients still alive at 2 years, an increase to 34% was observed .
RN could thus be more prevalent in long survivor’s patients treated with IT. Furthermore, as RT stimulates the immune response through T-cell activation, it might exacerbate RN . Few studies with limited number of patients have already suggested an increases incidence of RN with the addition of IT to SRT compared to SRT alone in patients with melanoma [38–40]. But most patients in these reports were treated with the anti-CTLA-4 monoclonal antibody Ipilimumab, and OS rarely exceeded one year. In a recent study of Kaidar-Person et al on longer‐term surviving patients with metastatic melanoma treated with anti‐PD‐1 therapy, the incidence of RN was estimated as 18% at 2 years . We observed a RN rate of 10% in the present study, and this rate was higher in patients receiving concomitant IT. This finding has also been reported by Martin et al, who found that receipt of IT was associated with symptomatic RN (HR, 2.56; p = .004) in a cohort of patients with melanoma, non–small-cell lung cancer, or renal cell carcinoma, this association being especially strong in patients with melanoma. The association with PD-1 inhibition was however not statistically significant .
Our study has inherent bias due to its retrospective nature. First it is heterogeneous, with various tumor types and systemic drugs represented. Many variables were tested including the RPA score, although it can be considered as a confounding factor. Indeed, RPA score combines age, KPS, presence or absence of extracranial metastasis, and control of the primary tumor, which were also tested separately. The number of patients who received IT is also limited. Additionally, patients who received concomitant systemic treatment may have been selected based on their performance status or favorable disease presentation or prognosis. Moreover, oncologists are usually reluctant to interrupt IT in very good responders, this representing a potential selection bias. Systemic treatments could also impact outcome, even without RT. The delay chosen (one month) to consider systemic treatments as concomitant is also controversial, although largely used in the literature [19, 20, 43]. In a recent meta-analysis published by Lu et al, it seems that ICI administration within 4 weeks of SRS for BMs provides a statistically significant better 12-month OS compared to administration outside that time period. Regarding toxicities, only RN was reported as it usually relies on MRI and is therefore relatively easy to collect. But, in the context of systemic treatments, others toxicities are awaited like headaches, cognitive changes, bleeding, or ataxia. These are more difficult to evaluate in the retrospective setting.
This report provides valuable insight into tolerance and efficacy of combination of IT and SRT. Future clinical trials examining the efficacy and safety of this combination and the optimal schedule of RT in terms of irradiation field, fractionation and dose will hopefully answer these questions. For now, clinicians can rely on the guidelines of the American Society for Radiation Oncology (ASTRO) on combining precision RT with molecular targeting and immunomodulatory agents . Beyond clinical factor and PDL1 expression, other parameters like measure of inflammatory cytokines or tumour-specific T-cells in serum following administration of SRT could act as surrogates for the efficacy of the treatment related immune response, and provide further insight into the appropriate selection of patients.