Abstract

Metastasis of solid tumors to the brain occurs in about 30% of cases. Surgery and whole-brain radiotherapy have been the standard treatments with very limited success rates. As a result of the unsatisfactory local control and long-term survival outcomes, stereotactic radiosurgery has been used as an alternative to surgery and whole-brain radiotherapy, or to improve the outcomes in conjunction with other treatments. However, stereotactic radiosurgery does not produce the desired survival results despite the striking increases in local control rates, primarily because of deaths attributed to extracranial systemic disease progression or unavoidably fatal distant brain recurrences. Lately, immunotherapy has become a part, or mainstay, of treatment algorithms for many cancer types. Several authors have proposed the integration of stereotactic radiosurgery and immunotherapy for the treatment of brain metastasis. This chapter evaluates the efficacy and safety of combining novel immunotherapeutics with traditional stereotactic radiosurgery for the treatment of brain metastasis.

INTRODUCTION

Brain metastasis occurs in 30–40% of adult patients with solid cancers (1, 2). Lung cancers (small and non-small cell), malignant melanoma (MM), renal cell carcinoma (RCC), and breast cancer are the most common causes of brain metastasis (3). Chemotherapy, surgery, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), targeted therapies, and immunotherapy are used to treat brain metastasis (4, 5). SRS is used more frequently in clinical practice because it produces better results with less toxicity than WBRT (6) (Figure 1). The main mechanisms by which the ionizing radiation used in WBRT functions are double-strand DNA damage, ‘oxygen fixation’ of the damage, and the production of cytotoxic free radicals in tumor cells. When ionizing radiation is used in the form of high-precision SRS, it affects the local and systemic immune responses against the tumor cells by inducing immunogenic cell death, improving neoantigen presentation, and activating cytotoxic T-cells (7). In comparison to conventional WBRT, SRS offers better local control rates with a lower risk of neurocognitive decline (8). Given this foundational understanding, several authors recently discussed their experiences using various combinations of immune checkpoint inhibitors (ICIs) and SRS in patients who presented with brain metastasis from various cancers. As a result, it has been proposed that immunoradiotherapy may facilitate a higher local control and an antitumor systemic response by activating the adaptive immune system through T-cells (7). The goal of the current chapter is to summarize our current knowledge on the role of combined SRS and ICIs for the treatment of brain metastasis.

Figure 1

A typical linear accelerator based stereotactic radiosurgery plan and related dose-volume histogram for a patient with single brain metastasis. A: Axial; B: Coronal; C: Sagittal view.

IMMUNE CHECKPOINT INHIBITORS

Immune cells, such as macrophages, natural killer cells (NKc), dendritic cells, T-lymphocytes, and B-lymphocytes, are frequently engaged in the antitumoral immune response. T-cells bear the greatest antitumor immune workload. The balance between stimulatory and inhibitory (immune-checkpoint) signals governs the final vehemence and efficiency of immune responses triggered by T-cell recognition of specific antigens. (9, 10). Tumors and peripheral tissues can also trigger an immune response, as can the lymph nodes. T-cells remain unresponsive unless they recognize matching antigens via their receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are the two immune checkpoints that have been most successfully targeted in the context of cancer immunotherapy, both being inhibitory receptors in controlling the immune response at various levels using different mechanisms. The antibodies, ipilimumab (IPI) for CTLA-4, and nivolumab (NIVO) and pembrolizumab (PEMBRO) for PD-1 receptor, block these inhibitory receptors on T-cells and are effective against tumors and are thus frequently used in the treatment of a range of cancers. This highly specialized activity blocks the transmission of the “off” signal, enabling the T cells to kill cancer cells.

INTERACTIONS BETWEEN THE IMMUNE SYSTEM AND RADIOTHERAPY

The biological effects of ionizing radiations are primarily caused by DNA damage. Double-strand DNA damage results in cell death if it is not properly repaired. Various studies investigating the impact of radiotherapy (RT) on the immune system over the last two decades indicated that local RT increased systemic immune response through antitumoral immune stimulant actions. Following RT, high levels of tumor-associated antigens are released from necrotic and apoptotic tumor cell debris. Dendritic cells then present these antigens to CD8+ cytotoxic T cells. The immune system is turned on to fight tumor cells all over the body when these antigens are recognized (11). Results from preclinical and clinical studies corroborated this crucial information by demonstrating that therapeutic radiation, especially when combined with ICIs, significantly increased systemic immune response, which led to immunogenic tumor cell death (12–15). Additional crucial information on the significance of RT doses and fractionation, as well as the ideal timing of RT that exerts maximum antitumor immune stimulation, were revealed by research examining the interactions between RT and the immune system. Schaue et al. examined the effects of the total dose, the dose per fraction, and the number of fractions of RT on the RT-induced immune response and the outcomes in a mouse melanoma model (16). According to the authors, tumor growth was effectively inhibited by single fraction doses of radiation, and successful local control rates were correlated with the radiation dose and the quantity of tumor-reactive T cells. ICIs can be administered prior to, during, or after the SRS. Concurrent use of both modalities was defined in most studies as the administration of ICIs 2 to 4 weeks before or after the SRS provided the best local control and overall survival outcomes. Based on this clinical evidence, it is currently recommended that the time between SRS and ICIs does not exceed four weeks (17, 18). It should be noted, however, that different ICIs may have sequence-dependent distinct efficacy in relation to their administration timing relative to the SRS.

CLINICAL EVIDENCE FOR COMBINATION THERAPY

Clinical trials examining various combinations of SRS and ICIs in patients with brain metastasis have been supported by hypothetical and preclinical evidence demonstrating a synergistic relationship between SRS and ICIs. However, there is still debate regarding the best sequence of administration of these two treatment modalities, SRS fractionation scheme and per-fraction/total dosages, the choice of appropriate ICIs, therapeutic impact, and side effects, among others. Furthermore, despite most studies indicating improved local control and overall survival with acceptable toxicity rates, such studies were retrospective cohort analyses with a small population where primary histology was mostly for MM, and IPI was the most used ICI. These constraints make it challenging to comprehend the published results and their true impact on brain metastasis originating from other tumor primaries (19). Tables 1, 2, and 3 provide an overview of the studies, which were primarily retrospective series of brain metastasis from MM (20–46), non-small cell lung cancer NSCLC (47–52), and RCC, among others (53–59).

Table 1

Clinical trials of combination stereotactic radiosurgery and immune checkpoint inhibitors in malignant melanoma patients with brain metastasis

Table 2

Clinical trials of combination stereotactic radiosurgery and immune checkpoint inhibitors in NSCLC patients with brain metastasis

Table 3

Clinical trials of combination stereotactic radiosurgery and immune checkpoint inhibitors in MM, NSCLC, RCC and other patients with brain metastasis

To assess the impact of IPI on survival outcomes, Knisely et al. retrospectively analyzed the data of 77 MM patients who underwent SRS (20). Patients who received IPI and SRS had a median overall survival of 21.3 months, compared to 4.9 months for patients who only received SRS. The 2-year survival rate was also higher for patients who received the combination therapy (19.7% vs. 47.2%). According to the authors, the addition of IPI to SRS was the unique factor that significantly lowered the risk of death (P = 0.03). The outcomes of 33 MM patients who underwent SRS with or without IPI were compared in a different comparative retrospective report by Silk et al. (21). The findings demonstrated that the addition of IPI to SRS was linked to significantly longer median overall survival durations (4.0 versus 19.9 months). Kiess et al. (26) examined the efficacy and safety of single-fraction SRS in 46 MM patients with brain metastasis who had previously received IPI. A total of 113 brain metastases were managed with a median dose of 21 Gy and 4 cycles of IPI. SRS was administered to patients before, during, or after IPI. The order of SRS and IPI was found to be significantly related to overall survival outcomes (P = 0.035). SRS administration during or before IPI resulted in significantly better 1-year overall survival (65% vs. 56% vs. 40%, P = 0.008) and regional recurrence rates than SRS administration after IPI (69% vs. 64% vs. 92%, P = 0.003). Notably, the authors reported that SRS administration during IPI produced numerically superior but not statistically significant 1-year local control rates (100% vs. 87% vs. 89%; P = 0.21) compared to SRS administration before or after IPI. Qian et al. conducted a study to determine the effect of the type and timing of ICIs on the response of MM brain metastasis to SRS treatment (29). The results of 75 MM patients with 566 brain metastases who received SRS and ICIs were examined. The authors considered SRS and ICIs to be concurrent if SRS was administered within 4 weeks of ICIs. Concurrent treatment with significantly reduced brain metastasis volumes at 1.5 (−63.1% vs. −43.2%, P < 0.0001), 3 (−83.0% vs. 52.8%, P < 0.0001), and 6 months (−94.9% vs. 66.2%, P < 0.0001) when compared to non-concurrent treatment. The authors also noted that anti-PD-1 agents resulted in a greater median volume reduction than their anti-CTLA-4 counterparts. The prospective non-randomized phase 2 study, ELEKTRA, is a considerable investigation into the effects of combination therapies such as pre-ICIs-RT or pre-RT-ICIs on antitumor and peripheral T cell responses in MM patients with brain metastasis (46). Patients with brain metastasis received RT (WBRT or SRS depending on the number of brain metastasis ) in two different sequences in combination with NIVOIPI (RT before or after ICIs). The comparison groups included patients who received either only chemotherapy (without brain metastasis) or combination chemotherapy (without IPI) and radiotherapy. The investigators of this study discovered that IPI-NIVO combination therapy resulted in a significant increase in activated CD4 and CD8 T cells in the RT-ICIs group. They also noted inhibition of the immunosuppressive effect and a decline in Treg activity in this group. Additionally, this group showed more evidence of the abscopal effect of radiotherapy. The final comment was that sequencing ICIs treatment after RT may improve immunological responses and clinical outcomes in patients with brain metastasis from MM, and RT before ICIs treatment also showed a better response rate and progression-free survival than the RT after ICIs regimens.

The SRS and ICIs combination protocols have also been tested at other tumor sites. Schapira et al. (48) conducted one such study, reviewing the medical records of NSCLC patients with brain metastasis who had previously been treated with PD-1 pathway inhibitors and SRS. A total of 37 patients received PD-1 pathway inhibitors (83.8% NIVO, 10.8% atezolizumab (ATEZO), and 5.4% PEMBRO) for 85 lesions, mostly with a single fraction dose of 18 Gy SRS. Concurrent SRS and PD-1 pathway inhibitors improved 1-year overall survival (87.3% vs. 70.0% vs. 0%; P = 0.008) and distant brain failure (DBF) rate (38.5% vs. 65.8% vs. 100%, P = 0.042) compared to SRS before or after PD-1 pathway inhibitor strategies. Similarly, the 1-year local control rate in SRS concurrent with or after PD-1 pathway inhibitor treatment was significantly higher than the 72.3% observed in SRS prior to PD-1 pathway inhibitor treatment. Chen et al. examined the outcomes of 260 patients who received SRS for 623 brain metastases of NSCLC, MM, and RCC (53). One hundred eighty-one patients were treated with SRS alone, while 79 received SRS and ICIs (35% received concurrent SRS and ICIs). The SRS with concurrent ICIs group outperformed the SRS with non-concurrent ICIs, and SRS alone groups in terms of median OS [24.7 vs. 14.5 (P = 0.006) vs. 12.9 (P = 0.002) months]. The survival benefit provided by SRS and concurrent ICIs was without an increase in neurologic toxicity rates.

Although IPI is the most used ICI in combination with SRS, especially in brain metastasis originating from MMs, results of studies comparing the efficacy of IPI to other ICIs are scarce. Robin et al. (40) compared the outcomes of anti-CTLA4 alone (N = 25) versus anti-PD-1 alone or anti-PD-1 plus CTLA-4 combination (N = 13) delivered within 8 weeks before or after SRS in 38 patients with brain metastasis of MM. The authors reported that the anti-PD-1 alone or anti-PD-1 plus CTLA-4 combination groups surpassed the anti-CTLA4 alone group in terms of out-of-field brain progression (P = 0.049), extracranial progression (P = 0.015), and progression-free survival (P = 0.043). As a result, these findings provided preliminary evidence that ICIs other than IPI may have higher viability with SRS for brain metastases, either alone or in combination, than IPI plus SRS, which will be addressed in future trials.

While the current evidence, for the most part, supports the improved local control and overall survival rates with the concurrent administration of ICIs and SRS, this sequence is associated with higher rates of perilesional brain edema and radionecrosis (RN). According to Cohen-Inbar et al. (33), overall, the post-SRS perilesional edema was 26.3%, 27.9%, 21.8%, and 24.1% of lesions at 3, 6, 9, and 12 months. The authors noticed that the incidence of perilesional edema was significantly higher in the concurrent than the sequential treatment group at 3 months (31.3% versus 15.3%; P = 0.011) and 12 months (30.2% versus 0%; P = 0.048). However, the overall intralesional hemorrhage and 12 months RN rates were not different between the two groups, though both were higher in the concurrent treatment arm.

Because the SRS and ICIs studies are small retrospective observational cohort series involving various SRS schemes and ICIs, meta-analyses may be more effective for statistically evaluating the true value of this approach more powerfully. In the first meta-analysis, Lu et al. (60) compared the survival outcomes of brain metastasis patients receiving concurrent ICIs with SRS against the non-concurrent ICIs administered before or after SRS. A total of 8 retrospective observational cohort studies incorporating 408 patients were included. Concurrent ICIs with SRS conferred a significant 1-year overall survival benefit (P = 0.011) over the non-concurrent protocols. A subsequent meta-analysis published by Lehrer et al. included a total of 534 patients with 1,570 brain metastases who participated in 17 studies (61). The one-year overall survival rate was 13% higher in the concurrent SRS and ICIs group than in the non-concurrent treatment group (51.6% versus 64.6%); Q < 0.001). The local control rates at 1-year also trended to favor the SRS and ICIs group over its non-concurrent treatment counterpart (89.2% versus 67.8%; P = 0.09). Further this meta-analysis provided the most reliable toxicity data on the RN incidence following various ICIs combined with SRS. The overall RN incidence was fortunately only 5.3%, suggesting a distinctive RN risk with different ICIs. The authors called attention to that the RN risk was more pronounced in patients treated with IPI than the PEMBRO or NIVO.

He et al. (62) evaluated more than 1,500 patients receiving ICIs and intracranial RT (SRS or WBRT) from 26 retrospective studies. Compared with intracranial RT alone, they found that combination therapy significantly improved overall survival in patients with brain metastases (P < 0.001). There was a significant difference in RN risk compared to RT alone (P = 0.55), whereas local brain failure (LBF) and DBF were not significantly improved with RT in combination with ICIs (12 months LBF: P = 0.48, DBF: P = 0.90). According to the authors, ICIs plus RT improved overall survival in patients with brain metastasis while having no discernible increase in treatment-related toxicity rates. Similarly, Gagliardi et al. found that there was a significant increase in overall survival and lesion response rates without an increase in RN frequency with the combination of SRS and immunotherapy (63). The researchers concluded that combining SRS and immunotherapy is safe and effective in achieving noticeable improvements in relevant clinical and radiological outcomes in patients with melanoma and NSCLC brain metastasis.

In another study, Badrigilan et al. examined 16 retrospective studies with a combined total of 1356 brain metastasis patients for their meta-analysis (64). They discovered that when compared to non-concurrent treatment, concomitant treatment resulted in a significantly longer overall survival (P = 0.008), 12 months of LBF (P = 0.04), and a similar DBF (P = 0.547). According to the authors, concurrent treatment had a significantly higher overall survival than ICIs before SRS (P = 0.0003). Finally, Chu et al. investigated the efficacy of immunotherapy by reviewing a total of 3160 NSCLC patients with brain metastasis from 46 studies (65). This meta-analysis is significant and noteworthy as it represents the first attempt to compare the effectiveness of immunotherapy, including ICIs, chemotherapy, RT, and ICIs combined with chemotherapy or RT. The authors found that patients treated with immunotherapy had a longer progression-free survival (Hazard ratio (HR):0.48,95% confidence interval (CI): 0.41–0.56) and overall survival (HR:0.64, 95%CI: 0.60–0.69) than patients who did not receive immunotherapy. Also in this study, it was shown that concurrent ICIs combined RT reduced the DBF rate (Odds ratio (OR) = 0.15, 95% CI: 0.03–0.73) compared to post-ICIs RT. Additionally, it was stated that single or dual ICIs in combination with RT were effective treatments for NSCLC patients with brain metastasis. Concurrent administration of SRS and ICIs led to better outcomes for patients in terms of response and survival than non-concurrent or non-SRS regimens.

Although the aforementioned studies offer crucial knowledge regarding the efficacy and side effects of combining SRS and ICIs, the outcomes of prospective studies will provide a much more trustworthy roadmap for clinicians in the field (Table 4).

Table 4

Completed or ongoing clinical trials whose results are awaited

CONCLUSION

The local and systemic immune responses induced by SRS can be strengthened when combined with ICIs. Such a plan might improve the effectiveness of both therapeutic modalities, which might benefit outcomes in patients with brain metastasis. Both preclinical and clinical studies substantiate this assertion. The mechanisms by which the SRS schedule and ICIs agents collaborate to provide antitumor effects, on the other hand, may overlap and increase the toxicity profiles of both modalities. Although the majority of the evidence comes from single-institutional retrospective cohort studies, the results show that the SRS and ICIs combination is more effective than either modality alone, at the cost of modest increases in severe toxicity rates. Finally, there is no doubt that ongoing research on the optimal dosage, fractionation, and timing of SRS with various ICIs and dosages will provide unique insights for maximizing benefits while minimizing toxicity risk.

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Cite this chapter as: Kucuk A, Topkan E, Durankus NK, Senyurek S, Akdemir EY, Duygu S, Bolukbasi Y, Selek U, Pehlivan B. Combined Stereotactic Radiosurgery and Immune Checkpoint Inhibitors for the Treatment of Brain Metastasis. In: Sergi CM, editor. Advancements in Cancer Research. Brisbane (AU): Exon Publications; Online first 03 Jan 2023. p. 57–74

Doi: https://doi​.org/10.36255​/treatment-brain-metastasis

Conflict of Interest: The author declares no potential of interest with respect to the research, authorship, and/or publication of this chapter.