Tumor Primary Site and Histology Subtypes Role in Radiotherapeutic Management of Brain Metastases

Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mutation status (EGFR/ALK) in lung cancer and receptor status (ER/PR/HER2) in breast cancer also exhibit diversity in their response to radiotherapy. Radioresistant tumors like renal cell carcinoma and melanoma brain metastases have achieved better results when treated with SRS alone. Secondly, single brain metastasis may benefit from local and distant brain control achieved with combined treatment. These diverse outcomes suggest a primary histology-based analysis of the radiotherapy regimens (WBRT, SRS, or their combination) would more ideally establish the role of radiotherapy in the management of brain metastases. Molecularly targeted therapeutic and immunotherapeutic agents have revealed synergism with radiation therapy particularly SRS in treating cancer patients with brain metastases. Clinical updates in this regard have also been reviewed.

Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mutation status (EGFR/ALK) in lung cancer and receptor status (ER/PR/HER2) in breast cancer also exhibit diversity in their response to radiotherapy. Radioresistant tumors like renal cell carcinoma and melanoma brain metastases have achieved better results when treated with SRS alone. Secondly, single brain metastasis may benefit from local and distant brain control achieved with combined treatment. These diverse outcomes suggest a primary histology-based analysis of the radiotherapy regimens (WBRT, SRS, or their combination) would more ideally establish the role of radiotherapy in the management of brain metastases. Molecularly targeted therapeutic and immunotherapeutic agents have revealed synergism with radiation therapy particularly SRS in treating cancer patients with brain metastases. Clinical updates in this regard have also been reviewed.
Keywords: whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), brain metastases (BM), tumor control (TC), overall survival (OS), primary histology RATIONALE Brain metastasis is associated with worst prognosis and considered a major cause of cancer morbidity and mortality (1). Radiation therapy has long been the mainstay of treatment for brain metastases and is still contributing to this group of patients (2). A number of randomized controlled trials were conducted comparing different types of radiation therapies. Whole brain radiotherapy alone or in combination with stereotactic radiosurgery or stereotactic radiosurgery alone were the main components of investigation in these trials. These modes of treatments were compared for their safety and efficacy in terms of control and overall survival ( Table 1) (3)(4)(5)(6)(7)(8). Combined approach has revealed better brain control but no survival advantage (56). However, a survival advantage was demonstrated for combined approach when secondary analyses were restricted to patients with favorable prognosis (13,14). Interesting point to note here is, these analyses were restricted to NSCLC primary histology (13,14). Another aspect is if this benefit in control achieved with combined treatment could also lead to survival advantage in patients with solitary brain metastases. In fact, surge in survival with combined approach was reported when single brain metastases were considered only (4). These observations may make one think that the better local and distant control associated with combined approach might lead to survival advantage if a more dynamic selection of patient is exercised. Here, we report some of the related evidence highlighting these two points: a possible miscalculation in designing randomized controlled trial for this group of patients. The scope of this paper is restricted to the three radiotherapeutic treatment regimens (WBRT alone, SRS alone and WBRT plus SRS) in the treatment of brain metastases. In addition, relevant advancements in the field of targeted therapy and immunotherapy alone or in combination with radiotherapy have also been reviewed.

PRIMARY CANCER HISTOLOGY
Brain metastases originate from various primary cancers with different frequency and propensity. Lung cancer (40-50%) being the most frequent followed by breast (15-25%), or melanoma (5-20%), and to a smaller extent from renal cell carcinoma, colorectal cancer and sarcoma (Figure 1) (57). It has been suggested that primary cancer histology may play an important role in determining the survival due to its response to different treatments (radiation or chemotherapeutic), propensity to metastasize and aggressiveness (11).
Apart from these primary trials, there are a number of retrospective studies in which combined treatment have resulted in better survival for patients with lung cancer brain metastases in comparison to WBRT alone (16-19, 22, 24). Li et al. showed significant improvement in survival for combined treatment in comparison to WBRT alone but not SRS alone for patients with single NSCLC brain metastasis (16). In a large retrospective study of patients with newly diagnosed brain metastases (n = 4,259) from various primary tumors reported significant survival benefit for SRS alone (HR: 0.62; 0.51-0.75, p < 0.0001) and WBRT plus SRS (HR: 0.53; 0.45-0.63, p < 0.0001) against WBRT alone for patients with brain metastases from NSCLC (n = 1,888) (17). Lin et al. concluded that GK radiosurgery combined with WBRT increased the survival of NSCLC patients with brain metastases (18). Minniti et al. also reported WBRT plus SRS to be a safe, minimally invasive and well-tolerated treatment for patients with up to three brain metastases from NSCLC resulting in longer survival and better disease control in comparison with WBRT alone (19). Marko (20). In multivariate analysis of a study of 100 patients and 184 brain metastases from NSCLC evaluating GKRS and prognostic factors for overall survival, adenocarcinoma histology revealed to be prognostic for survival. Addition of WBRT had no impact on survival in this study (21). Overall, SRS boost to Frontiers in Oncology | www.frontiersin.org FIGURE 1 | Primary cancer sites with corresponding frequencies of causing brain metastases. Lung cancer is the most frequent to cause brain metastases followed by breast, melanoma and renal cell carcinoma. Histology subtypes and mutation status (EGFR/ALK) in lung cancer, and receptor status (+/-) in breast cancer have also shown relevance when it comes to their response in terms of brain control and survival to radiation therapy in the form of WBRT (whole brain radiotherapy), SRS (stereotactic radiosurgery) and combination of both (WBRT plus SRS).
WBRT reveals general superiority over WBRT alone but not SRS alone. In fact, omission of WBRT had no impact on survival (HR: 1.06; 0.90-1.26, p = 0.8084) for NSCLC patients with brain metastases in a comparative trial of WBRT plus optimum standard care (dexamethasone) compared to optimum standard care alone (60). Small cell lung carcinoma constitutes a rather small group of lung cancer patients (15-20%) (58). Andrews et al. demonstrated survival benefit for patients with WBRT plus SRS in comparison to WBRT alone when analyses were restricted to 24 SCLC patients (n = 24) with 1 to 3 brain metastases (p = 0.039) (4). Sun et al. also revealed that WBRT plus a radiation boost (Cyberknife) was significantly associated with improved OS in patients with 1-3 SCLC brain metastases when compared to WBRT-alone (13.4 vs. 9.6 months, p = 0.022) (22). The 6-, 12-, and 24 month survival rates were also comparatively higher for combined treatment (84.5%, 62.7%, and 21.5 vs. 59.8%, 29.9%, 9.6%, p = 0.004). Similar survival rates (84.5, 62.7, and 21.5%) were repeated in study of 36 patients with SCLC brain metastases who had received WBRT boost (23). In comparison to SRS alone, WBRT with SRS boost had also shown survival efficacy as revealed in a study of 44 SCLC patients (WBRT + SRS vs. SRS; 14 vs. 6 m, p = 0.04). However, number of patients in combined group were comparatively smaller (n = 6) while patients in the SRS alone group had also received prior WBRT, PCI (prophylactic irradiation), or both (24). Sperduto et al. (17) retrospective analysis also contained a total of 299 patients with brain metastases from SCLC. A significant surge in survival (HR: 0.29; 0.13-0.66, p = 0.003) was derived with SRS boost to WBRT (n = 21) in contrast to WBRT alone (n = 247) (17). Elaimy et al. retrospective study disclosed patients with different primary histology responded differently to treatment. In univariate analysis, NSCLC was favored statistically in terms of survival than SCLC, and classified in the other primary histology group. Moreover, NSCLC patients derived significant survival benefit when compared to the combined melanoma and renalcell carcinoma group on multivariate analysis (12). Overall, Lung cancer brain metastases seems to respond better to combined treatment and maybe recommended in patients with better prognostic standings.
There is considerable amount of progress in targeted therapy aimed at the mutation carrying by NSCLC patients such as EGFR (epidermal growth factor receptor) and ALK. Gefitinib and erlotinib (first generation EGFR targeting agents) have shown greater efficacy in the brain (61,62). Studies that included randomized controlled trials, prospective trials and retrospective studies have reported conflicting results in terms of OS outcome for addition of radiation therapy to EGFR-TKIs in these patients (18,(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77). However, Meta-analyses comprising most of these studies have suggested a significantly better survival associated with receiving additional radiation therapy (78)(79)(80). WBRT addition to EGFR-TKIs (gefitinib, erlotinib, and icotinib) have significantly increased survival for brain metastatic NSCLC patients with unknown EGFR status or without molecular selection (61,64,65,(71)(72)(73). Evidence included a randomized controlled trial revealing a median survival of 13.3 vs. 12.7 months (P < 0.05) (64). This advantage in OS has also been demonstrated in EGFR-mutated NSCLC patients (74)(75)(76)(77). SRS plus EGFR-TKIs were reported to be equally effective in treating EGFR-mutated NSCLC patients against EGFR-TKIs alone in a retrospective study (70). However, Magnuson et al. study identified significant improvement for such patients either receiving upfront WBRT or SRS as compared to upfront EGFR-TKIs alone (76). Despite the fact that low prognostic patients were allocated to WBRT group, upfront WBRT followed by EGFR-TKIs produced better survival outcome (HR: 0.70; 0.50-0.98, p = 0.039) in comparison to upfront EGFR-TKIs. In the same study, SRS followed by EGFR-TKIs also derived better survival benefit as opposed to upfront EGFR-TKIs (HR: 0.39; 0.26-0.58, p = 0.001) (76). An RCT by Sperduto et al. revealed WBRT plus SRS in combination showed slight superior median survival, however not significant, for molecularly unselected NSCLC patients as opposed to addition of EGFR-TKIs to WBRT and SRS (13.4 vs. 6.1, p = NS) (81). Nonetheless, a retrospective study demonstrated efficacy of adding gefitinib to WBRT or WBRT plus SRS (18). In fact, efficacy was greater when WBRT plus SRS were applied. Addition of WBRT or WBRT + SRS to gefitinib reported significant improvement in survival for brain metastatic NSCLC patients opposite to WBRT alone (p < 0.0001). Furthermore, results of WBRT + SRS + gefitinib were superior to WBRT + SRS as well as WBRT + gefitinib (p < 0.001) (18). ALK inhibitors, particularly the second-generation agents alectinib and brigatinib, have also shown promising responses in the treatment of brain metastases (82). However, there is no study done for comparison of the combination with radiation therapy to ALK inhibitors alone. A prior RT delivery was shown to have a positive impact on brain efficacy of these agents. Immunotherapy agents like nivolumab and pembrolizumab are also being used rigorously making the treatment paradigm diverse (83). Furthermore, combination of these agents with WBRT plus SRS or WBRT alone or SRS alone would clearly establish the role of each radiation therapy for this group of patients.

Breast Cancer
Like NSCLC histology, breast cancer as primary site for brain metastases has also demonstrated a distinct behavior in response to radiation therapy. A control rate between 90 and 94%, and median survival between 10 and 16 months, prognosis for breast cancer brain metastases appears to be superior in comparison to other histologic groups (84). Multivariate analysis of Elaimy et al. retrospective study showed breast cancer group was statistically better in term of survival to patients with NSCLC brain metastases (12). Frazier et al. identified primary breast cancer site to be prognostic of survival, which also included several other primary histologic sites including NSCLC, melanoma and renal cell carcinoma (11). Sperduto et al. retrospective analysis revealed superior survival for WBRT plus SRS vs. WBRT alone (HR: 0.72; 0.53-0.98, p = 0.035) in breast cancer patients (n = 642) (17). Radiosurgery as salvage therapy for tumor recurrence after fractionated WBRT has been helpful in prolonging the median survival from 3-5 to 10.3-14 months suggesting a better result for combined treatment compare to WBRT alone (84). Moreover, a longer interval from WBRT to SRS was identified on multivariate analyses as prognostic for breast cancer patients in a study of salvage SRS for BM after prior WBRT (25). Studies have shown breast cancer patients responding well to SRS alone and contribution of adding WBRT in this group of patients has not been determined (11,12,17,(26)(27)(28). Addition of WBRT together with SRS as well as prior intervention of WBRT followed by SRS as salvage therapy have not been superior to SRS alone (17,(25)(26)(27)(28)(29)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84). Perez et al. has registered survival boost for SRS alone in comparison to combined approach (30). Univariate analysis showed negative correlation for prior WBRT (HR: 1.58; 1.12-2.22, p = 0.0087) while WBRT after SRS was shown to impact survival negatively on multivariate analysis (HR: 1.78; 1.06-2.99, p = 0.030) (30). It has been suggested that the better response might have been due to advancement of surgery and chemotherapeutic care of breast cancer patients (26,85). Breast cancer, not only as the primary site has behaved distinctly, in fact, breast cancer histologic subtypes as primary histology for brain metastases have also been revealed to be distinct entities when it comes to their response to radiation therapy. The prognosis for basal subtype (triple negative), luminal A (ER/PR positive/HER2 negative), HER2 positive/ER/PR negative and luminal B (triple positive) subtype were different in terms of median survival as 7.3, 10, 17.9, and 22.9 months (p < 0.01), respectively (31). In a retrospective study of 131 patients who received SRS for breast cancer brain metastases between 2001 and 2013 revealed a median overall survival of 16, 26, 23, and 7 months for ER positive/HER2 negative, ER positive/HER2 positive, ER negative/HER2 positive, and TNBC (triple negative breast cancer), respectively (p < 0.001) (32). HER2 positive breast cancer brain metastases responded to SRS better as compared to HER2 negative breast cancer patients (median survival of 31.3 vs. 14.1 months (p < 0.01) (33). Patients with TNBC had the shortest time to retreatment with WBRT or SRS or death with hazard ratio of 3.12 (p < 0.001) compared to ER positive/HER2 negative (32). Triple negative subtype is associated with worst prognosis after SRS treatment (median survival of TN vs. Non-TN: 6 vs. 16 months) (34). Breast cancer brain metastases, as a whole have good response to SRS alone except for some histology subtypes and the role of WBRT plus SRS could be contested for survival outcome. Control of the primary disease with advancements in surgical and chemotherapeutic interventions might have something to do with the better outcome.
In context of molecular targeted therapy for BM with breast cancer histology, a number of agents have been approved and others are being under investigations. However, agents like transtuzumab (a monoclonal humanized antibody approved for the treatment of HER2-positive breast cancer) has limited intracranial efficacy due to its lack of BBB crossing ability (86). Lapatinib (a dual HER2 and EGFR inhibitor) has also revealed a mere CNS ORR of 6% in a phase II trial of 242 patients that had previously received transtuzumab and radiation therapy (WBRT or SRS) (87). However, in a separate study, patients with concurrent lapatinib had higher rates of complete response (35 vs. 11%, P = 0.008) in comparison to SRS alone (88). In patients with HER2-amlified lesions who also had undergone prior radiation therapies (WBRT, SRS and surgery), both HER2 antibodies (17.9 vs. 15.1 m; p < 0.04) as well as lapatinib (21.1 vs. 15.4 months; P < 5.03) were associated with improved median survival (89). WBRT was associated with better local [LC (SRS+/-WBRT); 6.9 vs. 11.0%, p < 0.02] and distant control [DF (WBRT+/-); 17.4 vs. 28.4%, p < 0.01] in combination with SRS or other targeted agents (transtuzumab, lapatinib), respectively (90). Concurrent lapatinib and transtuzumab with SRS compared to SRS alone had also significantly improved local control among HER2-amplified lesions [LF (lapatinib); 15.1 vs. 5.7%, p < 0.001, and (transtuzumab); 18.4 vs. 10.2%, p < 0.003] (90, 91). Yomo et al. also revealed significant 1year local control in lapatinib group as per lesion analysis but not patient analysis (LC; 86 vs. 69%, p < 0.001) (92). Though concurrent use of lapatinib with SRS vs. SRS alone has not yield survival advantage, patients ever using lapatinib were associated with improved median survival (88)(89)(90)(91). In retrospective study of 126 BM patients with HER2+ breast cancer undergoing SRS had also received lapatinib (n = 47) during the treatment. Use of lapatinib with SRS resulted in significant survival improvement (27.3 vs. 19.5 months, p = 0.03) for these patients as opposed to SRS alone (89). A similar result was reciprocated in a separate study with patients ever (n = 43) or never (n = 41) using lapatinib increased median survival from 23.6 months to 33.3 months (p = 0.009) (88). Currently, lapatinib in combination with WBRT or SRS is being investigated (NCT01622868, NCT00470847) which will more clearly establish the role of either radiation therapy in the treatment of HER2 positive breast cancer patients. Lapatinib in combination with capecitabine has also reported a 66% CNS ORR in a study that included 45 RT naïve patients (92). Trastuzumab emtansine (T-DM1) had also reported an intracranial clinical efficacy in 5 out of 10 (50%) patients, suggesting a similar response rate observed with lapatinib plus capecitabine (93). This result is also supported by the retrospective analysis of EMILIA trial that revealed similar PFS (HR = 1.00; P = 1.000; median PFS, 5.9 vs. 5.7 months) for patients with baseline brain metastases comparing the two treatments (94). Other agents like afatinib and neratinib had also been tried with mere CNS responses (95,96). Furthermore, immunotherapy has also entered clinical trial (NCT03449238) in this group of patients in combination with SRS in optimism for synergistic responses.

Radioresistant Tumors
Melanoma and renal cell carcinoma brain metastases are considered radioresistant, however, their response to SRS have been encouraging (35). Adjuvant WBRT in addition to SRS, in a study of 31 patients with brain metastases from renal cell carcinoma, melanoma, or sarcoma, resulted in 6 month actuarial local control and distant brain failure rate (DBF) of 100 and 17% as compared with 85 and 64% in patients with no WBRT addition (P = 0.018 and P = 0.0027), respectively. This suggests a role of WBRT in controlling distant failure for these radioresistant histology (36). A Phase II trial of radiosurgery for one to three newly diagnosed brain metastases (n = 36) from renal cell carcinoma, melanoma, and sarcoma reported high degree of failures within the brain (∼50% of patients by 6 months) with the omission of WBRT (37). Outcome variation among "radioresistant" brain metastases treated with stereotactic radiosurgery was also reported in retrospective study of 189 patients. Survival after SRS was significantly (P = 0.0354) worse for patients with melanoma (n = 103) and sarcoma (n = 9) brain metastases compared to patients with renal cell carcinoma (n = 77). The actuarial freedom from progression after 1 year was 64% for renal cell carcinoma patients, 47% for melanoma patients, and 0% for sarcoma patients (P < 0.001) (38). Of the radioresistant tumors brain metastases, renal cell carcinoma has resulted in better survival. Overall, a role of WBRT is observed in control of the disease and hence a trial is warranted to identify which primary histology would derive better survival out of the better control.

Renal Cell Carcinoma
WBRT has achieved survival of only 3.0-4.4 months in RCC brain metastases (39) while a better survival from 9.5 months to as high as 17.8 months have been reported with SRS (36,40,41). Primary renal cell carcinoma was identified as predictor of longer survival in a study which also had contained melanoma and sarcoma (36). Addition of WBRT (upfront or as salvage therapy) to SRS was not associated with local control or survival in patients with RCC brain metastases (42). There was no significant difference in distant control either with upfront WBRT [n = 2/8 (25%) vs. n = 3/9 (33%)] as well (42). A similar scenario of additive WBRT failure in prolonging survival and distant control (46 vs. 50%) was reported in another study (43 (46). Renal cell carcinoma, though, has derived better survival compared to melanoma, the role of WBRT is not clear. RCC related medical evidence is distinct because of no brain control with WBRT addition.
Though several targeted agents for RCC have been approved so far, their efficacy data in regard to the RCC brain metastases is limited. Sorafenib in combination with radiation therapy used after surgery in a case report of a patient with brain metastasis from RCC revealed a 4-year recurrence free survival (97). Sunitinib has shown safety and efficacy in metastatic RCC in a number of case reports and trials (98)(99)(100)(101)(102)(103). Pazopanib and cabozatinib have also demonstrated intracranial activity in this group of patients (104)(105)(106)(107). Concurrent multi-kinase inhibitors (mKIs) with SRS have revealed superior median survival (108)(109)(110). Significant local control (LF: 93 vs. 60%, p = 0.01) and improved median survival (16.6 vs. 7.2 m, p = 0.04) was reported in patients with receiving targeted agents in addition to SRS (108). A similar result was achieved in a separate study as well (16.8 (46). Sunitinib or other targeted agents mentioned above or immunotherapeutic agents combined with radiotherapy could be evaluated in clinical trials particularly the SRS as suggested by some authors in order to achieve a more potent response as observed in the case of metastatic melanoma (111).

Melanoma
Use of WBRT alone in treating melanoma brain metastases has merely achieved a median survival of 3.5 months (47). Melanoma brain metastases responds better to SRS, however, median survival reported in the range of 5.3 to 10.6 months is comparatively lower to that of renal cell carcinoma (36,(48)(49)(50)(51)(52)(97)(98)(99)(100)(101). Up-front WBRT omission was associated with worse overall survival (multivariate HR 2.56, p = 0.08), and distant intracranial progression (multivariate HR 2.24, p = 0.005) (53). On the other hand, in a study of 185 patients, the addition of WBRT was shown to lack a LC, OS or PFS advantage in these patients (54). Initial WBRT was associated with no survival advantage (p = 0.88) but a delay in distant progression was observed; however, not significant (P = 0.13; n = 6) (55). Role of WBRT cannot be assessed clearly from these studies due to their retrospective nature and the fact that WBRT is usually administered in aggressive disease or in patients with multiple brain metastases (38,52).
Immunotherapy in the treatment of brain metastases has mainly been assessed in melanoma patients. Recent studies have suggested role of immunotherapy (anti-CTLA-4/anti-PD-1 agents) and targeted therapy (BRAFi/MEKi) in combination with SRS leading to improved survival in comparison to SRS alone (112,113). SRS followed by immunotherapy or targeted therapy have shown better local control (1-year LC; 100 vs. 83.3%, p = 0.023) as well as improvement in survival (MST; 10.95 vs. 2.29 m, p < 0.001) (114,115). A met-analysis of ipilimumab plus SRS revealed significantly better survival over SRS alone in melanoma BMs (112). As well, this benefit from SRS plus Ipilimumab seems to be comparatively superior to ipilimumab combination with WBRT (116). Furthermore, there is theoretical and clinical evidence of this combination leading to brain control other than the therapeutic target area that is also termed as abscopal effect (117,118). Targeted therapies in melanoma patients aimed at mutation such as BRAF inhibitors (50% of malignant melanomas) and MEK inhibitors have also been studied extensively. Vemurafenib and dabrafenib (BRAF inhibitors) alone or dabrafenib plus trametinib have shown excellent intracranial responses (119)(120)(121)(122)(123)(124)(125). Comparative studies have suggested combination of SRS and BRAF inhibitors resulting in better outcome for BRAF-mutant melanoma patients (126)(127)(128)(129)(130). Improved local control as well as superior median survival with BRAFi with SRS particularly when used concurrently or initiated after SRS (126)(127)(128)(129)(130). Side effects remains a concern as intracranial hemorrhage and radionecrosis has been associated with the SRS in conjunction with BRAF inhibitors (126,131). These results suggest that this group of patients respond better with SRS in comparison to WBRT even in combination with immunotherapy and targeted molecular agents such as BRAF inhibitors.
It can be suggested that primary histology and subtypes may have a role in defining the outcome in these patients. Hence, pooling them together might have compromised the outcome of the aforementioned primary trials (3)(4)(5)(6)(7)(8). In fact, the diverse prognostic factors associated with each histology had led to the creation of diagnosis specific graded prognostic assessment (DS-GPA), which associates different sets of prognostic factors to each histology (13).

SINGLE BRAIN METASTASES
Previously, Kondziolka et al., suggested omission of WBRT for single brain metastases while denying the existence of micrometastases (not apparent on high-resolution imaging) or diffuse brain disease based on the result of one study (132). However, there is Class I evidence showing a clear role of addition of WBRT reducing the local and distant failure significantly with subsequent improvement in survival. Andrew et al. reported a significant survival for single brain metastatic patients for treatment comparison (WBRT plus SRS vs. WBRT alone) (4). In the overall analysis, SRS boost was not received in some patients (single BM = 15% and 2-3 BM = 24%; 19% overall), which might have also influenced overall survival analysis (4,13). Post-stratification by DS-GPA of Andrew et al. trial revealed significant survival advantage for favorable recipients (DS-GPA 3.5-4.0) which included single brain metastasis at large (13). Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial revealed significantly improved survival from combined treatment for prognostically better placed recipients (DS-GPA 2.5-4.0) in comparison to SRS alone. Participants were single brain metastases at majority, however, 2-3 and even 4 brain metastases were also present (14). Li et al. reported SRS alone and SRS+WBRT to be better in prolonging life and improving quality of life than WBRT alone for patients with single brain metastasis from lung cancer (16). It is unfortunate that an overall assessment of the single to multiple (2, 3) brain metastases was reported in primary trials but no assessment of treatment comparison for single brain metastasis was carried out except for Andrew et al. The addition of WBRT to SRS seems to essential to treat single brain metastases where a clear advantage in survival is achieved with this approach particularly in comparison to WBRT alone. The significant intracranial control in the majority of the studies and reported better survival for single brain metastasis suggest a diffuse disease state which leads to distant failure when SRS alone is used. SRS alone has been associated with significant local and particularly distant cranial failure and requires high salvage therapy as compared to combined treatment, thereby increasing the number of hospital visits which can increase psychological burden for patients.

Future Perspective
Treatment paradigms for brain metastases are shifting with the entries of molecular targeted agents and immune checkpoint inhibitors. However, radiation therapy continues to play a role in this group of patients. SRS is taking a more robust role in combination with new agents. However, the local and distant control achieved with combined approach in selected patients might reveal a superior alternative. Or, would the abscopal effect of immunotherapy provide distant brain control associated with additive WBRT? As absence of immunotherapy after radiosurgery (HR: 0.380, p = 0.002) increased the odds of developing new brain metastases (50). Moreover, radiation therapy and immunotherapy are still the only options for cancer patients with no harboring mutations. Our study reports a slight clinical benefit for each primary histology with either WBRT or SRS, for example, WBRT plus SRS for NSCLC, SRS for breast cancer and radioresistant tumors like RCC and melanoma. It's encouraging to see that EGFR inhibitors were combined with WBRT for comparison in NSCLC patients with brain metastases and SRS combined with targeted or immunotherapeutic agents is mainly investigated in melanoma and RCC patients. Therefore, to clearly validate the role of each radiotherapeutic approach (WBRT, SRS, or WBRT + SRS) for patients with brain metastases would be essential through a clinical trial with a much more precise selection design based on primary histology along with other influencing factors.