Radiol Oncol 2024; 58(1): 145-152. doi: 10.2478/raon-2024-0002 145 research article Multi-institutional study of ‘Sandwich treatment’ for motor area large brain metastases (LBM) with diameter over 3 cm Zheng Wang1, Haining Chen2, Qun Chen3, Yucun Zhu4, Min Li1, Jia Zhou1 1 Cancer Center, Gamma Knife Treatment Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China 2 Gamma Knife Treatment Center, Anhui Provincial Hospital, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China 3 Gamma Knife Treatment Center. Jiangsu Province People’s Hospital, the First Affiliated Hospital of Nanjing Medical University Nanjing, China 4 Gamma Knife Treatment Center, Ming ji Hospital, Affiliated to Nanjing Medical University, Nanjing, China Radiol Oncol 2024; 58(1): 145-152. Received 3 July 2023 Accepted 23 September 2023 Correspondence to: Jia Zhou, Cancer Center, Gamma Knife Treatment Center, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China. E-mail: cneagles@sina.com Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The objective of the present study was to explore the effectiveness and safety of ‘Sandwich treatment’ strategy for large brain metastases (LBM) with diameter over 3 cm (minimum volume >= 15 cm3) located in motor area. Patients and methods. Patients from four gamma knife center that received ‘Sandwich treatment’ were retro- spectively studied from January 2016 to March 2023. The strategy was one-week treatment course including 2 stages of stereotactic radiosurgery (SRS) and using bevacizumab once during SRS gap. The tumor volume and peri-tumor edema changes were analyzed before and after ‘Sandwich treatment’. Manual muscle testing (MMT) score and Barthel Index (BI) score were used to evaluate the changes of patients’ movement and physical strength rehabilita- tion. The patients’ overall survival (OS) and tumor local control (TLC) rate was calculated. Cox regression model was used to analyze the risk factors that related to TLC. Results. 61 patients with 72 lesions received the ‘Sandwich treatment’. The median prescription dose was 13.0 Gy and 12.5 Gy at the first- and second-stage SRS. The mean tumor volume at the time of ‘Sandwich treatment’ and 3 months later was 20.1 cm³ and 12.3, respectively (P < 0.01). The mean peri-tumor edema volume at the first- and second-stage SRS was 12.6 cm³ and 5.2 cm³, respectively (P < 0.01). Patients’ median MMT score improved from 6 at the beginning to 8 at the end of ‘Sandwich treatment’ (P < 0.01), BI score was also greatly improved from 45 at the time of ‘Sandwich treatment’ to 95 after 3 months (P < 0.01). Patients’ median OS was 14.0 months, and the 3, 6, 12 months OS rate was 92.0%, 86.0% and 66.0%, respectively. The TLC rate at 3, 6, 12 months was 98.4%, 93.4%, and 85.3%, respectively. Patients with lung cancer had lower risk of tumor relapse. The cumulative incidence of patient’s hemor- rhage and radiation necrosis was 4.92% (3/61) and 13.11% (8/61) after ‘Sandwich treatment’. Conclusions. ‘sandwich treatment’ strategy is safe and effective for LBM located in motor area. The strategy could rapidly improve the patients’ movement and enhance their physical strength rehabilitation. Key words: Sandwich treatment; bevacizumab; two-staged SRS; motor area; large brain metastases Introduction Brain metastases (BM) is the most common intrac- ranial malignant tumor in adults, and is also the main cause of mortality of cancer patients.1 The current guidelines suggest that patient with lim- ited number of BM with good performance can be treated with stereotactic radiosurgery (SRS) Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases146 alone.2-5 For patients with BM number less than 10, or the total volume smaller than 4 cm3, fractioned radiosurgery or two-staged stereotactic radiosur- gery (2-SSRS) could control the tumor growth with low neurotoxicity and not delay the consequent systemic treatment.6-11 However, for large BM (LBM) with diameter over 3 cm (minimum volume >= 15 cm3) and lo- cated in motor area, even 2-SSRS is still challeng- ing.12 The risk mainly comes from the compression of LBM and consequent peri-tumor edema to the brain, results in devastating intracranial hyperten- sion. Further, the SRS-induced edema would add to the risk of intracranial hypertension, limb hemi- plegia and refractory epilepsy.13,14 Meanwhile, SRS would cause the brain radiation necrosis (RN).15-17 These potential risks make it difficult for patients with LBM to receive 2-SSRS in outpatient depart- ment. Patient after SRS needs long-term inpatient steroids therapy to control peri-tumor and SRS- induced edema to improve their symptoms, and lower the potential risk of RN. Bevacizumab, an anti-VEGF monoclonal molecular drug, has been utilized by practitioners in anti-tumor therapy for cancer patients.18,19 Also, its anti-angiogenesis effect could be used for SRS-edema and RN con- trol.20,21 To help patient with motor area LBM and shorten their treatment course, the practition- ers from four gamma knife center developed the ‘Sandwich treatment’ strategy. The strategy was one-week treatment course that includes 2-SSRS and using bevacizumab once during SRS gap. In the present study, the authors retrospectively re- viewed the patients that received ‘Sandwich treat- ment’. The purpose of this study was to evaluate the efficacy of and safety of this strategy. Patients and methods Patients From January 2016 to March 2023, patients with LBM that received the ‘Sandwich treatment’ were retrospectively studied. The inclusion criteria are as follows: patients had (1) at least one newly di- agnosed BM in the motor area; (2) tumor diameter larger than 3 cm and no previous whole brain ra- diation therapy; (3) received steroid therapy for tumor or peri-tumor edema controlling; (4) not ongoing systemic therapy. Because the retrospec- tive observation study was focused mainly on the effectiveness and safety of ‘Sandwich treatment’ for LBM in motor area, patients fitted the inclusion criteria were all included despite they received treatment for previous primary tumor or not. The present study was approved by the Institutional Ethics Committee of Zhejiang Provincial People’s Hospital (ZHRYRS 2022 No. 005). FIGURE 1. The mean tumor and peri-tumor edema volume changes. (A) The mean tumor volume decreased dramatically from 20.1 cm³ (range: 17.2–29.7 cm³) at the time of ‘Sandwich treatment’ to 12.3 cm³ (range: 7.7–22.4 cm³) 3 months later (P < 0.001); (B) The mean peri-tumor edema volume at first-stage SRS and second-stage SRS of ‘Sandwich treatment’ was 12.6 cm³ (range: 4.9–19.6 cm³) and 5.2 cm³ (range: 1.2–13.2 cm³) (P < 0.001). 2-SSRS = two-staged stereotactic radiosurgery A B Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases 147 ‘Sandwich treatment’ strategy The ‘Sandwich treatment’ was a one-week treat- ment course. Two-SSRS were delivered to patients with mean dose of 13 Gy and 12.5 Gy at first and second SRS respectively. At each stage of SRS, the 45% – 60% isodose line covered the whole lesion. The bevacizumab was used once 3 days later af- ter the first-stage SRS, for the purpose of tumor growth and peri-tumor edema control. The dose of bevacizumab was 5 mg/kg according to previous studies had suggested of 5–10 mg/kg.22,23 Target volumes were obtained from Gadolinium en- hanced T1-weighted magnetic resonance images (MRI). The edema volume was accessed from MRI T2-FLAIR. Evaluation of efficacy and adverse events Tumor local control (TLC) failure was defined as 20% increase in product of perpendicular diam- eter on T1-enhanced MR after ‘Sandwich treat- ment’ according to the revised RANO guidelines.24 Radiation necrosis (RN) was determined MRI per- fusion and PET results and clinical symptoms.25,26 The manual muscle testing (MMT) score was used for the evaluation of patients’ muscle strength change.27 The scale proposed by the Medical Research Council (MRC) uses the numeral grades 0–5, 0: No contraction; 1) Flicker or trace contrac- tion; 2) Active movement, with gravity eliminat- ed; 3) Active movement against gravity; 4) Active movement against gravity and resistance; 5) Normal power. The total score of upper limb and lower limb was summed up as the baseline stand- ard for the evaluation of patients’ muscle strength. The Barthel Index (BI) is used to assess patients’ early rehabilitation after radiosurgery.28 Overall survival (OS) was defined as the time interval from patients finished the ‘Sandwich treatment’ to their death. Statistical analysis Follow-up time were defined as the time from completion of ‘Sandwich strategy’ to the time of most recent follow-up. End-point events were il- lustrated using Kaplan-Meier method. Categorical data were presented as percentages and compared by Mann-Wittney U test. Continuous data using t- test. Cox regression model was used to analyze the risk factors that related to TLC. All statistical anal- yses were performed using SPSS version 19.0 (IBM Corp., Armonk, New York) or GraphPad Prism 8.0 (La Jolla, California, United States). Values with P < 0.05 were considered statistically significant. Results Patient characteristics A total of 61 patients with 72 LBM located in the motor area received the ‘Sandwich treatment’ from January 2016 to March 2023. 36 patients were female and 35 were male. Patients’ median age was 62 years (range: 34–81 years). The median FIGURE 2. A typical case with LBM located in motor area that received ‘Sandwich treatment’. (A) The lesion had severe peri-tumor edema and invading towards the frontal lobe; (B) 3 months after ‘Sandwich treatment’, peri-tumor edema and tumor volume significantly reduced. TABLE 1. Patient characteristics Characteristic Value Range Age(median, years) 62 34–81 Sex Female 36 Male 25 Primary tumor Lung 39 Breast 13 Gastric-intestinal tract 9 KPS (median) 60 50–80 Dose at first-stage SRS (median, Gy) 13.0 11–15 Dose at second-stage SRS (median, Gy) 12.5 11–14 Total tumor volume (mean, cm³) 20.1 17.2–29.7 Peri-tumor edema volume (mean, cm³) 12.6 4.9–19.6 Follow-up time (median, months) 18.3 6.3–47.9 KPS = Karnofsky performance status A B Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases148 Karnofsky performance status (KPS) score before treatment was 60 (range: 50–80). The median dose at the first and second SSRS was 13 Gy (range: 11– 15 Gy) and 12.5 Gy (range: 11–14 Gy), respectively. The median follow-up time of 61 patients was 18.3 months (range: 6.3–47.9 months). None of the treated patients had accidental intracranial hem- orrhage after bevacizumab treatment. Detailed general patient characteristics are presented in Table 1. The volume changes of tumor and peri- tumor edema There was no statistical tumor volume change at first-stage SRS and second-stage SRS during the ‘Sandwich treatment’. However, the mean tumor volume decreased dramatically from 20.1 cm³ (range: 17.2–29.7 cm³) at the time of ‘Sandwich treat- ment’ to 12.3 cm³ (range: 7.7–22.4 cm³) 3 months later (P < 0.001, Figure 1 A). The mean peri-tumor edema volume at the 1-SSRS and the 2-SSRS of ‘Sandwich treatment’ was 12.6 cm³ (range: 4.9–19.6 cm³) and 5.2 cm³ (range: 1.2–13.2 cm³), with significant statistical difference (P < 0.001, Figure 1 B). Figure 2 shows a patient that received ‘Sandwich treatment’ for LBM located in motor area, the peri-tumor edema and tumor volume significantly reduced 3 months later. Patients’ MMT score and BI score changes Patients’ median MMT score improved from 6 (range: 5–8) at the beginning to 8 (range: 7–10) at the end of ‘Sandwich treatment’ (P < 0.001, Figure 3 A). Patients’ median BI score was also greatly improved from 45 (range: 15–85) at the time of ‘Sandwich treatment’ to 95 (range: 40–100) after 3 months (P < 0.001, Figure 3 B). Patients’ OS, TLC and prognostic factors for TLC As Kaplan - Meyer curve showed in Figure 4A, the patient’s median survival time was 14.0 months, and the overall survival rates at 3, 6, 12 months was 92.0%, 86.0% and 66.0%, respectively. The TLC rate at 3, 6, 12 months was 98.4%, 93.4%, and 85.3%, respectively (Figure 4B). Primary tumor types (Lung/Breast/GI tract cancer) were prognostic fac- tors for TLC in Univariate analysis. Multivariate analysis revealed that patients with lung cancer had lower risk of tumor relapse [Lung/Breast: HR = 0.539, 95% CI:(0.339–0.812); Lung/GI tract: HR = 0.784, 95%CI:(0.498–0.987)] (Table 2). Side effects of ‘Sandwich treatment’ The side effects of ‘Sandwich treatment’ mainly consist of hemorrhage hazard by bevacizumab and radiation necrosis (RN) by SRS. However, no patients had accidental intracranial hemorrhage after ‘Sandwich treatment’, and the cumulative incidence of hemorrhage was 4.92% (3/61), mainly oral and nasal bleeding. The cumulative radiation necrosis was 13.11% (8/61) in all patients, only 3.3% (2/61) presented with symptoms. FIGURE 3. Patients’ median MMT and BI score. (A) MMT score at the beginning and the end of ‘Sandwich treatment’ (P < 0.001); (B) BI score before ‘Sandwich treatment’ and at 3 months later (P < 0.001). BI score = Barthel Index score; MMT score = manual muscle testing score; 2-SSRS = two-staged stereotactic radiosurgery A B Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases 149 FIGURE 4. Kaplan - Meier curve of the patient’s (A) Overall survival (OS) and (B) tumor local control (TLC) rate. TABLE 2. Risk factors of TLC for LBM in motor area after ‘Sandwich treatment’ Univariate analysis Multivariate analysis HR ratio 95%CI P-value HR ratio 95%CI P-value Age 0.978 (0.598–1.686) 0.697 >=62 <62 Sex 1.678 (0.913–2.174) 0.781 Male Female Primary tumor Lung/Breast 0.459 (0.359–0.898) < 0.01 0.539 (0.339–0.812) 0.007 Lung/GL tract 0.913 (0.478–1.316) < 0.01 0.784 (0.498–0.987) 0.006 Breast/Gl tract 1.987 (0.878–1.974) 0.411 KPS score 2.113 (1.159–6.733) 0.139 >= 60 <60 Total tumor volume 0.719 (0.419–1.598) 0.211 >=20.1cm3 <20.1cm3 Peri-tumor edema volume 1.589 (0.973–2.894) 0.566 >=12.6cm3 <12.6cm3 Dose at first-stage SRS 1.325 (0.53–1.734) 0.989 >= 13.0 Gy < 13.0 Gy Dose at second-stage SRS 0.845 (0.356–1.250) 0.593 >= 12.5 Gy < 12.5 Gy KPS = Karnofsky performance status; LBM = large brain metastases; 2-SSRS = two-staged stereotactic radiosurgery; TLC = tumor local control A B Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases150 Study limitations This study has several limitations. Firstly, the number of patients is not large and would inter- fere the results of statistical analysis. Secondly, pa- tients received ‘Sandwich treatment’ may receive different consequent systemic therapy, so the in- fluence weight of these different therapies on the local control of BM cannot be precisely accessed. However, it cannot be avoided in other similar researches and commonly exists in the treatment cause of patients. Finally, there are still disputes about the personalized dose of bevacizumab for edema control after SRS. A larger cohort and pro- spective studies are needed to provide more thrill- ing results. Discussion In recent years, SRS has been recognized as effec- tive alternative treatment for BM.2-4 For BM with diameter at 2-3 cm, fractionated or staged SRS is preferable.9,11,29 One of the representative study on 2-SSRS method for BM is reported by Angelov et al. in 2018.10 In their case series, the volume of 63 BMs in 54 patients reduced significantly, and the TLC rate in 3, 6 months after treatment reaches 95% and 88%, respectively; the incidence of overall radia- tion side effects was 11%. Another representative study was conducted by Serizawa T et al.11 They compared the treatment results between 3- and 2-stage Gamma Knife radiosurgery for large BM and found no differences between in terms of pa- tients’ overall survival, tumor progression, neuro- logical death, and radiation-related adverse events. Dohm Amoren et al. reported 2-SRSS for BM that are difficult to be removed by surgery8, the cumu- lative incidence of local treatment failure at 6 and 12 months was 3.2% and 13.3% respectively. The study of Damron et al. in 2022 also supports the ef- fectiveness and safety of 2-SSRS for BM patients.30 According to the results of these studies, 2-SSRS for the BM treatment is satisfactory and local con- trol failure rate is low. Table 3 listed 8 studies that adopted 2-SSRS strategy for BM. The listed studies mainly focused on the op- timal prescription doses of the 2-SSRS. The re- searchers suggested dose reduction strategy was suitable for lessening of SRS-induced edema and RN. However, the 2-SSRS strategy might not be enough for the LBM located in motor ar- ea. Meanwhile, these conventional 2-SSRS strat- egy have treatment course longer than 1 month. Patients may have to receive even longer time of inpatient dehydration and steroid treatment dur- ing the 2-SSRS when the diameter of BM was over 3 cm and located in the motor area. The long-term usage of mannitol and steroid hormones would bring a series of side effects to the patient, delay their consequent systemic treatment, increase their treatment cost. On the other hand, patient’s intracranial hypertension, neuro-dysfunction symptoms and the risk of suffering from refrac- tory epilepsy would make them hardly to receive SRS at outpatient department. The side effect of 2-SSRS should not be ne- glected as well. The SRS-induced edema would aggravate the edema caused by LBM compression in the motor area, patients would experience de- TABLE 3. Comparison between ‘Sandwich treatment’ and other reports of 2-SSRS strategy for BM Author Year Case number Median diameter/ volume of BM Total dose 2-SSRS interval 6 Months OS/ median OS 6 Months TLC/ median TLC Radiation necrosis Yomo et al.9 2012 27 17.8 cm3 27 Gy 3-4 weeks 8.8 months 89.8% 11.1% Yomo and Hayashi29 2014 58 16.4 cm 3 28 Gy 3-4 weeks 63% 85.0% 8.6% Angelov et al.10 2018 54 Diameter>=2cm 30 Gy 34 days 65% 88.0% 11.0% Dohm et al.8 2018 33 LBM 29 Gy 30 days 65% 96.8% 6.06% Hori et al.31 2020 181 4 cm3 N/A N/A 14.6 months 91.0% N/A Ito et al.32 2020 178 10 cm3 26 Gy 7-38 days 6.6 months 93.2% 6.20% Damron et al.30 2022 24 8.1 cm3 30 Gy 32 days 9.1months 80% N/A Cho et al.33 2022 142 Median 7.4 cm3 27-28 Gy 32 days 14 months 88-90% 17% Present study 2023 51 20.1 cm3 25.5 Gy 7 days 91.8%, 14 months 93.4% 13.11% N/A = not available; BM = brain metastases; 2-SSRS = two-staged stereotactic radiosurgery Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases 151 terioration of limb movement and their life qual- ity. Cho et al. pointed out even 2-SSRS strategy for BM could cause RN as high as 17% and affects the life quality of patients.33 Considering these tough issues, we introduce bevacizumab. Juan et al. had applied bevacizumab for the treatment of SRS re- lated edema, and found the edema volume reduc- tion at 49.0%–66.0% on MRI-T2FLAIR.34 As bevaci- zumab could reduce the angiogenesis around the lesion, it could also lower the brain RN risk.35 Its anti-angiogenesis effect could be used to control tumor growth had synergies with SRS. Therefore, the ‘Sandwich treatment’ strategy would have ob- vious advantage in the treatment of LBM in motor area, especially for those with primary lung ad- enocarcinoma.36 The results of this retrospective study con- firmed the effectiveness and safety of ‘Sandwich treatment’. The results indicated that using beva- cizumab during SRS gap could reduce the me- dian volume of peri-tumor edema by 38.8% (from 12.6 cm³ to 5.2 cm³). Meanwhile, patient’s muscle strength score that reflecting the patients’ physical activities also significantly improved. The strategy would shorten the whole treatment course while preserve patients’ neuro-function or improve their life quality. Patients with primary lung adenocar- cinoma had significant lower risk of tumor relapse. Compared to previous 2-SSRS reports as showed in Table 3, the present study had the largest medi- an tumor volume, shortest treatment course, while the TLC were similar compared to other studies. The 6-month OS rate and median survival in our present study exceeded 6 of the 8 studies. The incidence of RN in this study was higher than other eight 2-SSRS cohorts listed in Table 3. The main reason may be that in these cohort the patient’s median OS was short and they failed to report the potential RN symptoms. On contrary, the LBM in the present study were all located in the motor area, and patients’ SRS-induced symp- toms could be much more obvious. Conclusions As far as we know, this is the first report of ‘Sandwich treatment’ strategy for the LBM with diameter over 3 cm at motor area. The statistical results verified the effectiveness and safety of this strategy. This strategy could significantly improve patients’ life quality and greatly shortened treat- ment interval. However, a larger cohort is still needed for prospective study. Funding statement Zhejiang Provincial Department of Education Research Support Project (Y202249332); Zhejiang Provincial Medical and Health Research Project (2022KY570; 2023KY475). References 1. Cagney DN, Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: A population-based study. Neuro Oncol 20217; 19: 1511-21. doi: 10.1093/neuonc/nox077 2. Graber JJ, Cobbs CS, Olson JJ. Congress of neurological surgeons systematic review and evidence-based guidelines on the use of stereotactic radiosur- gery in the treatment of adults with metastatic brain tumors. Neurosurgery 2019; 84: E168-E170. doi: 10.1093/neuros/nyy543 3. Han JH, Kim DG, Chung HT, Paek SH, Park CK, Jung HW. Radiosurgery for large brain metastases. Int J Radiat Oncol Biol Phys 2012; 83: 113-20. doi: 10.1016/j.ijrobp.2011.06.1965 4. Arvold ND, Lee EQ, Mehta MP, Margolin K, Alexander BM, Lin NU, et al. Updates in the management of brain metastases 2016; Neuro Oncol 2016; 18: 1043-65. doi: 10.1093/neuonc/now127 5. Devoid HM, McTyre ER, Page BR, Metheny-Barlow L, Ruiz J, Chan MD. Recent advances in radiosurgical management of brain metastases. Front Biosci 2016; 8: 203-14. doi: 10.2741/s458 6. Milano MT, Chiang VLS, Soltys SG, Wang TJC, Lo SS, Brackett, et al. Executive summary from American Radium Society’s appropriate use criteria on neu- rocognition after stereotactic radiosurgery for multiple brain metastases. Neuro Oncol 2020; 22: 1728-41. doi: 10.1093/neuonc/noaa192 7. Hasegawa T, Kato T, Yamamoto T, Iizuka H, Nishikawa T, Ito H, et al. Multisession gamma knife surgery for large brain metastases. J Neurooncol 2017; 131: 517-24. doi: 10.1007/s11060-016-2317-4 8. Dohm AE, Hughes R, Wheless W, Lecompte M, Lanier C, Ruiz J. Surgical re- section and postoperative radiosurgery versus staged radiosurgery for large brain metastases. J Neurooncol 2018; 140: 749-56. doi: 10.1007/s11060- 018-03008-8 9. Yomo S, Hayashi M, Nicholson C. A prospective pilot study of two-session Gamma Knife surgery for large metastatic brain tumors. J Neurooncol 2012; 109: 159-65. doi: 10.1007/s11060-012-0882-8 10. Angelov L, Mohammadi AM, Bennett EE, Abbassy M, Elson P, Chao ST, et al. Impact of 2-staged stereotactic radiosurgery for treatment of brain metasta- ses ≥ 2 cm. J Neurosurg 2018; 129: 366-82. doi: 10.3171/2017.3.JNS162532 11. Serizawa T, Higuchi Y, Yamamoto M, Matsunaga S, Nagano O, Sato Y, et al. Comparison of treatment results between 3- And 2-stage Gamma Knife radiosurgery for large brain metastases: A retrospective multi-institutional study. J Neurosurg 2018; 131: 227-37. doi: 10.3171/2018.4.JNS172596 12. Vogelbaum MA, Brown PD, Messersmith H, Brastianos PK, Burri S, Cahill D, et al. Treatment for brain metastases: ASCO-SNO-ASTRO guideline. J Clin Oncol 2022; 40: 492-516. doi: 10.1200/JCO.21.02314 13. Lehrer EJ, Peterson JL, Zaorsky NG, Brown PD, Sahgal A, Chiang VL, et al. Single versus multifraction stereotactic radiosurgery for large brain metas- tases: An international meta-analysis of 24 trials. Int J Radiat Oncol Biol Phys 2019; 103: 618-30. doi: 10.1016/j.ijrobp.2018.10.038 14. Pintea B, Baumert B, Kinfe TM, Gousias K, Parpaley Y, Boström JP. Early mo- tor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resec- tion: A retrospective study of two consecutive cohorts. Radiat Oncol 2017; 12: 177. doi: 10.1186/s13014-017-0917-6 15. Loganadane G, Dhermain F, Louvel G, Kauv P, Deutsch E, Le Péchoux C, et al. Brain radiation necrosis: Current management with a focus on non- small cell lung cancer patients. Front Oncol 2018; 8: 336. doi: 10.3389/ fonc.2018.00336 Radiol Oncol 2024; 58(1): 145-152. Wang Z et al. / Sandwich treatment strategy for large brain metastases152 16. Miller JA, Bennett EE, Xiao R, Kotecha R, Chao ST, Vogelbaum MA, et al. Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys 2016; 96: 1060-9. doi: 10.1016/j.ijrobp.2016.08.039 17. Linskey ME, Andrews DW, Asher AL, Burri SH, Kondziolka D, Robinson PD, et al. The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: A systematic review and evidence- based clinical practice guideline. J Neurooncol 2010; 96: 45-68. doi: 10.1007/s11060-009-0073-4 18. Desai B, Rassam D, Ezeh P, et al. Phase III trial of PF-06439535 or bevacizum- ab-eu plus paclitaxel/ carboplatin in NSCLC. J Thorac Oncol 2015; 10: S665. 19. Tamura R, Tanaka T, Miyake K, Yoshida K, Sasaki H. Bevacizumab for ma- lignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 2017; 34: 62-77. doi: 10.1007/ s10014-017-0284-x 20. Lubelski D, Abdullah KG, Weil RJ, Marko NF. Bevacizumab for radiation ne- crosis following treatment of high grade glioma: A systematic review of the literature. J Neurooncol 2013; 115: 317-22. doi: 10.1007/s11060-013-1233- 0 21. Delishaj D, Ursino S, Pasqualetti F, Cristaudo A, Cosottini M, Fabrini MG, et al. Bevacizumab for the treatment of radiation-induced cerebral necrosis: A systematic review of the literature. J Clin Med Res 2017; 9: 273-80. doi: 10.14740/jocmr2936e 22. Alanin MC, Klausen C, Caye-Thomasen P, Thomsen C, Fugleholm K, Poulsgaard L, et al. Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 – a retrospective case series. Int J Neurosci 2016; 126: 1002-6. doi: 10.3109/00207454.2015.1092443 23. Hawasli AH, Rubin JB, Tran DD, Adkins DR, Waheed S, Hullar TE, et al. Antiangiogenic agents for nonmalignant brain tumors. J Neurol Surg B Skull Base 2013; 74: 136-41. doi: 10.1055/s-0033-1338262 24. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol 2015; 16: e270-e8. doi: 10.1016/S1470- 2045(15)70057-4 25. Kano H, Kondziolka D, Lobato-Polo J, Zorro O, Flickinger JC, Lunsford LD. T1/T2 matching to differentiate tumor growth from radiation effects after stereotactic radiosurgery. Neurosurgery 2010, 66: 486-91. doi: 10.1227/01. NEU.0000360391.35749.A5 26. Minamimoto R, Saginoya T, Kondo C, Tomura N, Ito K, Matsuo Y, et al. Differentiation of brain tumor recurrence from post-radiotherapy necrosis with 11C-methionine PET: Visual assessment versus quantitative assess- ment. PLoS One 2015; 10: e0132515. doi: 10.1371/journal.pone.0132515 27. Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu G, Mittermaier C, et al. Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med 2008; 40: 665-71. doi: 10.2340/16501977-0235 28. Hankemeier A, Rollnik JD. The Early Functional Abilities (EFA) scale to assess neurological and neurosurgical early rehabilitation patients. BMC Neurol 2015; 15: 207. doi: 10.1186/s12883-015-0469-z 29. Yomo S, Hayashi M. A minimally invasive treatment option for large metastatic brain tumors: Long-term results of two-session Gamma Knife stereotactic radiosurgery. Radiat Oncol 2014; 9: 132. doi: 10.1186/1748- 717X-9-132 30. Damron EP, Dono A, Chafi H, Martir M, Yu TK, Khwaja S, et al. Metastatic neoplasm volume kinetics following 2-stage stereotactic radiosurgery. World Neurosurg 2022; 161: e210-e9. doi: 10.1016/j.wneu.2022.01.109 31. Hori Y, Muhsen B, Joshi K, Wei W, Borghei-Razavi H, Chao S et al. The efficacy and safety of two-staged stereotactic radiosurgery for large posterior fossa metastases: post-treatment volumetric changes in tumor size, peri-tumoral edema, and fourth ventricle. Neuro Oncol 2020; 22 Suppl2: ii181. doi: 10.1093/neuonc/noaa215.756 32. Ito D, Aoyagi K, Nagano O, Serizawa T, Iwadate Y, Higuchi Y. Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers. J Neurooncol 2020; 147: 237-46. doi: 10.1007/ s11060-020-03421-y 33. Cho A, Medvedeva K, Kranawetter B, Untersteiner H, Hirschmann D, Lepilina O, et al. How to dose-stage large or high-risk brain metastases: an alterna- tive two-fraction radiosurgical treatment approach. J Neurosurg 2022; 137: 1666-75. doi: 10.3171/2022.2.JNS212440 34. Li J, He J, Cai L, Lai M, Hu Q, Ren C, et al. Bevacizumab as a treatment for radiation necrosis following stereotactic radiosurgery for brain metastases: clinical and radiation dosimetric impacts. Ann Palliat Med 2021; 10: 2018- 26. doi: 10.21037/apm-20-2417 35. Erpolat OP, Demircan NV, Sarıbas GS, Kuzucu P, Senturk E, Elmas C, et al. A comparison of Ramipril and Bevacizumab to mitigate radiation-induced brain necrosis: An experimental study. World Neurosurg 2020; 144: e210- e20. doi: 10.1016/j.wneu.2020.08.081 36. Ai B, Zhang L, Huang D, Chen J, Liu Z, Hu X, et al. Efficacy and safety of bevaci- zumab in advanced lung adenocarcinoma patients with stable disease after two cycles of first-line chemotherapy: A multicenter prospective cohort study. Thorac Cancer 2020; 11: 3641-4. doi: 10.1111/1759-7714.13687