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Review article
peer-reviewed

Concurrent Radiosurgery and Systemic Therapies for Melanoma Brain Metastases: A Systematic Review



Abstract

Intracranial metastatic melanoma is a major challenge for neuro-oncological teams. Historically, treatment has focused on surgical or radiosurgical treatment of appropriate lesions, mostly for palliative purposes. Immunotherapies and other targeted therapies (BRAF/mitogen-activated protein kinase kinase inhibitors (BRAFi/MEKi)) are mainstays of advanced melanoma therapy, yet the optimal timing and synergistic properties of concurrent combinations of these systemic therapies and stereotactic radiosurgery (SRS) are poorly understood. We performed a systematic review of the MEDLINE and Scopus databases focused on outcomes after therapy using SRS and either immunotherapies or targeted therapies in an effort to define the optimal timing. We defined concurrent therapy as SRS within three months of treatment with any systemic therapy. End points included local control, distant control, overall survival, and toxicities. We identified five retrospective cohort studies from the literature. These studies found that concurrent SRS plus immunotherapy or BRAFi/MEKi is well tolerated by most patients and generally improved local control, distant control, and overall survival. Importantly, no significant increases in toxicities were noted with concurrent therapy. Combining concurrent SRS with immunotherapy or BRAFi/MEKi may offer important advances for patients with intracranial metastatic melanoma. To address interstudy heterogeneity, we propose reporting two major time intervals defining “concurrent treatment”: concurrent-SRS (≤4 weeks) and peri-SRS (≤3 months). Future large-scale, prospective trials considering truly concurrent SRS therapies with systemic therapies are desperately needed.

Introduction & Background

Intracranial metastatic melanoma is a devastating and common occurrence in patients with advanced melanoma. As of 2011, more than 40% of patients with metastatic melanoma experienced brain metastasis, and this number is increasing [1-2]. Stereotactic radiosurgery (SRS) is a safe and effective modality for treating many types of primary and metastatic brain tumors and is commonly used for the treatment of melanoma brain metastasis. BRAF-V600E is the most common activating mutation found in melanoma. After the molecular diagnosis is established, targeted therapies (TTs) such as BRAF/mitogen-activated protein (MAP) kinase kinase (MEK) inhibitors (BRAFi/MEKi), which block the activated MAP-kinase cascade are employed [3]. Immunotherapeutics (IMTs) such as ipilimumab (anti-CTLA4 [cytotoxic T-lymphocyte associated protein 4] therapy) have yielded improved overall survival from metastatic melanoma (two large, phase III trials), and along with nivolumab/pembrolizumab (anti-PD1 [programmed cell death protein 1] therapy), comprise the cornerstone of current melanoma immunotherapy [4-5]. Recently, phase II trials have begun investigating the effectiveness of IMTs with and without SRS [NCT02085070; NCT02374242; NCT02460068; NCT02320058]. Importantly, the optimal timing of combination systemic therapy and SRS is yet to be defined, particularly for IMTs, and preclinical studies suggest that concurrent therapy may be superior to staggered drug and SRS administration [6]. We undertook a systematic review of studies involving a window of concurrent systemic therapy within three months of SRS treatment, defined as administration of IMT or TT within three months of SRS, in an effort to better define the optimal timing.

Review

Database review

Two separate reviewers performed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-based systematic reviews of both Scopus and MEDLINE databases (October 2018) using “stereotactic radiosurgery” and “melanoma” as keywords. Articles were included if they examined the treatment of intracranial metastatic melanoma with SRS and BRAFi/MEKi inhibitors or immunotherapeutic checkpoint inhibitors (i.e., anti-PD1 and anti-CTLA4 monoclonal antibodies). Studies were included if they reported ≤30% of patients previously, or concurrently, treated with whole-brain radiotherapy. Critically, studies were included only if they described concurrent combinations of SRS and systemic therapies (i.e., systemic therapy within a three-month window before or after SRS treatment) (Table 1). Endpoints of interest included overall survival, local control, distant control, and treatment toxicities.

After a systematic review of the literature, five articles were included for qualitative analysis (Figure 1). Hazard ratios (HRs) reported were transformed from failure to control, if necessary, using 1/HR. If a study presented both univariate and multivariate analyses of an outcome measure, the multivariate analysis was included in our qualitative assessment.

Studies identified

The five retrospective cohort studies that met our inclusion criteria all provided only low-quality evidence with heterogeneous outcomes (Table 1; GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria); therefore, a meta-analysis of the data was not possible [7-11]. A major source of heterogeneity in all studies of SRS and systemic therapies is the definition of "concurrent" therapy. To address this issue, we propose assessment during two key intervals: a four-week interval (concurrent therapy) and a three-month window (peri-SRS therapy).

Article Number of patients Total no. of brain mets Type of radiosurgery Type(s) of targeted and immunotherapies Concurrent treatment definition Patients (% of total) who had WBRT Endpoints measured Statistics used GRADE quality and bias assessment
Acharya et al. (2017) 72 233 Single-fraction SRS Leksell Gamma Knife Anti-PD1/anti-CTLA4 = nivolumab/ pembrolizumab, ipilimumab; BRAFi/MEKi = dabrafenib/ trametinib, vemurafenib 3 months 9.7 Distant brain failure, local failure, overall survival, neurotoxicity Fisher's exact test and Wilcoxon rank-sum; Kaplan Meier and Cox proportional hazards regression model for hazard ratios LOW: small, retrospective cohort study. No downgrade required.
Ahmed et al. (2016) 96 314 Single-fraction BrainLab Novalis Classic LINAC Anti-PD1/anti-CTLA4 = nivolumab/ pembrolizumab, ipilimumab; BRAFi/MEKi = dabrafenib/ trametinib, vemurafenib 3 months; BRAF/ MEK inhibitors held for 2–3 days before/after SRS Not reported Distant brain control, local control, progression-free survival, overall survival, neurotoxicity Kruskal–Wallis, Pearson's Chi-squared, Fisher's exact tests. Kaplan Meier and log-rank tests. Cox prop hazards for hazard ratios. LOW: small, retrospective cohort study. No downgrade required.
Diao et al. (2018) 72 310 Single-fraction SRS Elekta Perfexion Gamma Knife(s) Anti-CTLA4 = ipilimumab 4 weeks 8.3 Local failure, treatment-related imaging changes, tumor, and edema volumes, neurotoxicity Kruskal–Wallis, Pearson’s Chi-squared, Fisher's exact tests. Kaplan Meier and Cox proportional hazards for hazard ratios. LOW: small, retrospective cohort study. No downgrade required.
Diao et al. (2018) 91 256 SRS Perfexion Gamma Knife Anti-CTLA4 = ipilimumab 4 weeks (peri = 4 wk–3 mo) 7.6 Distant brain failure, local failure, failure-free survival, overall survival, neurotoxicity Kruskal–Wallis, Pearson’s Chi-squared, Fisher's exact tests. Kaplan Meier and Cox proportional hazards for hazard ratios. LOW: small, retrospective cohort study. No downgrade required.
Yusuf et al. (2017) 51 167 CyberKnife/Varian Trilogy LINAC Anti-PD1/anti-CTLA4 = ipilimumab/ pembrolizumab 4 weeks (peri = 4 wk–3 mo) 5.8 Distant brain failure, local failure, percent lesion regression, overall survival, neurotoxicity Kruskal–Wallis, Pearson's Chi-squared, Fisher's exact tests. Kaplan Meier and Cox proportional hazards for hazard ratios. LOW: small, retrospective cohort study. No downgrade required.

Results of Concurrent Immunotherapy and SRS

Concurrent therapy was generally favored for all reported outcomes. Possibly, the largest effect was on distant brain control combining IMT+SRS (HRs ≥2 for distant control in all but one case; Figure 2). Local control favored concurrent therapy, but this trend was obscured by unexpected differences in HRs for similar patient populations (Figure 2) [9,11]. Overall survival with concurrent IMT+SRS was also improved. Only Acharya et al. found a statistically insignificant decrease in HR for overall survival in patients receiving concurrent IMT and SRS (Figure 2) [7]. There was no significant difference in toxicities between the SRS only and the SRS + IMT treatment groups (Table 2).

Study Overall Survival Local Control Distant Control Toxicities Comparator
Acharya et al. (2017) 0.53 (0.23–1.22) p = NS 2.70 (1.05–7.14) p=0.04* 2.08 (1.25–3.45) p=0.003* Toxicities were noted in all groups; no differences SRS alone; controlled for # MBM and steroid use
Ahmed et al. (2016) Anti-PD-1 3.4 (1.6–7.2) p = 0.0009; Anti-CTLA4 3.1 (1.5–6.4) p = 0.002 ** Anti-PD-1 3.35 (0.99–15.2) p=0.051; Anti-CTLA4 2.12 (0.82–5.6) p=0.12 ** Anti-PD1 3.1 (1.5–6.6) p=0.001; combined IMT 2.1 (1.1–3.6) p=0.02 ** Toxicities were noted in all groups; no differences SRS alone; chemotherapy controlled
Diao et al. (2018) NR Timing ≤4 weeks 2.78 (1.15–7.75);* timing ≥4 weeks 1.16 (0.63–2.09)* NR Any lesion hemorrhage HR = 2.13 (0.987–4.72)* Anti-CTLA4 vs SRS alone
Diao et al. (2018) Timing ≤4 weeks 1.67 (0.90–3.13)*; timing ≥4 weeks 1.96 (1.09–3.57)* p=0.02; NR NR Toxicities were noted in all groups; no differences Anti-CTLA4 vs SRS alone
Yusuf et al. (2017) Median peri-SRS = 7.4 mo; SRS alone = 7.1 mo; p=0.212 Concurrent 1.34 (0.33–5.41)*; peri 7.63 (1.64–35.7)* Concurrent 2.75 (1.21–6.21)*; peri 1.10 (0.74–1.64)* Toxicities were noted in all groups; no differences SRS alone

Regression or control of lesions outside of the initial radiation field, called the abscopal effect, may drive favorable outcomes for distant brain tumors in patients treated with concurrent IMT+SRS [12-14]. The abscopal effect is an immune system-mediated effect that requires T-cell effector function on tumor-associated neoantigens (TAAs) and immune-enhancing cytokine release in the tumor microenvironment. This may synergize with checkpoint inhibitors, releasing the brakes on antitumor immunity (Figure 3) [15-17]. The reactivation of innate immune-sensing and interferon responses in tumor cells, which is critical for antitumor immunity, is attributed to the expression of endogenous retroviral sequences and other genomic ‘dark matter’ after epigenetic therapies [18,19-21]. Combining epigenetic, stereotactic radiosurgical, and immune-checkpoint therapies may hold great promise for patients with melanoma brain metastasis.

Results of BRAFi/MEKi and Stereotactic Radiosurgery

Inhibitors of the MAP-kinase pathway have become a mainstay of melanoma treatment, particularly in the setting of activating BRAF mutations. Importantly, patients treated with targeted therapies after molecular diagnosis have significantly better progression-free and overall survival than patients treated with dacarbazine or placebo [22-25]. There is little information regarding the optimal timing of targeted therapy dosage relative to SRS, but many oncological teams withhold targeted therapies for 3-5 days surrounding SRS treatment. Studies that report the efficacy of SRS and targeted therapies are summarized in Table 4, including reason for exclusion from our systematic review [26-30]. Improved brain tumor control and overall survival evident in concurrent or post-SRS (Figure 4; Table 3) BRAFi/MEKi may reflect increased accessibility of these therapies to the brain tumor environment after SRS, yet concurrent vemurafenib or dabrafenib and SRS has been reported to increase risk for radiation necrosis and Grade ≥3 adverse events, especially skin toxicities [30-32]. Of interest, there were no significant differences in toxicities in patients receiving concurrent BRAFi/MEKi+SRS versus SRS alone, indicating that a small pause directly surrounding SRS may be sufficient to ensure patient safety (Table 3).

Study Overall Survival Local Control Distant Control Toxicities Comparator
Acharya et al. (2017) NR 1.96 (0.99–3.45)* p=0.054 0.85 (0.54–1.12)*; BRAFi/MEKi vs BRAFi alone p=0.011 Toxicities noted in all group; no differences SRS alone with multiple subgroup analyses
Ahmed et al. (2016) BRAFi/MEKi 2.4 (1.1–5.3) p = 0.02; BRAFi 1.79 (0.89–3.28) ** BRAFi/MiEKi 2.82 (0.85–12.8) p=0.09; BRAFi 2 (0.72–6.0) p = 0.18 ** BRAFi/MEKi 2.1 (1.1–4.4) p = 0.03; BRAFi alone 1.4 (0.75–2.9) p = 0.27 Toxicities noted in all group; no differences SRS alone; chemotherapy controlled
Diao et al. (2018) NR NR NR NR NR
Diao et al. (2018) NR NR NR NR NR
Yusuf et al. (2017) NR NR NR NR NR
Study Outcome Reason for Exclusion
Kotecha et al., (2017) Improved LC, OS in concurrent SRS High number (>30%) WBRT
Mastorakos et al., (2019) Improved OS initiating inhibitor after SRS No timing details, no HRs/statistics provided
Wolf et al., (2016) Improved OS in concurrent or after SRS strategies No timing details, no HRs/statistics provided
Xu et al., (2017) Improved LC with any BRAFi + SRS Small sample size, heterogeneous timing. No HRs/statistics provided
Hecht et al., (2018) Improved OS in an interrupted therapy group High number (>30%) WBRT

Conclusions

Five studies in the literature explore concurrent timing of stereotactic radiosurgery and immunotherapy or targeted therapies for the treatment of intracranial metastatic melanomas. Additional temporally specific studies are needed, but more vital is the need for well-designed prospective trials, several of which are under way [NCT02085070; NCT02374242; NCT02460068; NCT02320058]. Future studies should report outcomes based on a four-week window (concurrent SRS) or a three-month window (peri-SRS).


References

  1. Davies MA, Liu P, McIntyre S, et al.: Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011, 117:1687-1696. 10.1002/cncr.25634
  2. Peuvrel L, Saint-Jean M, Quéreux G, Brocard A, Khammari A, Knol A, Dréno B: Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib. J Neurooncol. 2014, 120:147-154. 10.1007/s11060-014-1533-z
  3. Flaherty KT, Infante JR, Daud A, et al.: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012, 367:1694-1703. 10.1056/NEJMoa1210093
  4. Hodi FS, O'day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010, 363:711-723. 10.1056/NEJMoa1003466
  5. Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011, 364:2517-2526. 10.1056/NEJMoa1104621
  6. Dovedi S, Illidge T: The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade. Oncoimmunology. 2015, 4:1016709. 10.1080/2162402X.2015.1016709
  7. Acharya S, Mahmood M, Mullen D, et al.: Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents. Adv Radiat Oncol. 2017, 2:572-580. 10.1016/j.adro.2017.07.003
  8. Ahmed KA, Abuodeh YA, Echevarria MI, et al.: Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol. 2016, 27:2288-2294. 10.1093/annonc/mdw417
  9. Diao K, Bian SX, Routman DM, et al.: Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J Neurosurg. 2018, 129:1397-1406. 10.3171/2017.7.JNS171286
  10. Diao K, Bian SX, Routman DM, et al.: Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. J Neurooncol. 2018, 139:421-429. 10.1007/s11060-018-2880-y
  11. Yusuf MB, Amsbaugh MJ, Burton E, Chesney J, Woo S: Peri-SRS administration of immune checkpoint therapy for melanoma metastatic to the brain: investigating efficacy and the effects of relative treatment timing on lesion response. World Neurosurg. 2017, 100:632-640. 10.1016/j.wneu.2017.01.101
  12. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC: Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Physics. 2004, 58:862-870. 10.1016/j.ijrobp.2003.09.012
  13. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S: Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009, 15:5379-5388. 10.1158/1078-0432.CCR-09-0265
  14. Mole R: Whole body irradiation—radiobiology or medicine?. Br J Radiol. 1953, 26:234-241. 10.1259/0007-1285-26-305-234
  15. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC: Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005, 11:728-734.
  16. Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J: The controversial abscopal effect. Cancer Treat Rev. 2005, 31:159-172. 10.1016/j.ctrv.2005.03.004
  17. Kiess AP, Wolchok JD, Barker CA, et al.: Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: Safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Physics. 2015, 92:368-375. 10.1016/j.ijrobp.2015.01.004
  18. Burnette BC, Liang H, Lee Y, et al.: The efficacy of radiotherapy relies upon induction of type I interferon-dependent innate and adaptive immunity. Cancer Res. 2011, 71:2488-2496. 10.1158/0008-5472.CAN-10-2820
  19. Brocks D, Schmidt CR, Daskalakis M, et al.: DNMT and HDAC inhibitors induce cryptic transcription start sites. Nat Genet. 2017, 49:1052. 10.1038/ng.3889
  20. Cañadas I, Thummalapalli R, Kim JW, et al.: Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med. 2018, 24:1143-1150. 10.1038/s41591-018-0116-5
  21. Chiappinelli KB, Strissel PL, Desrichard A, et al.: Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015, 162:974-986. 10.1016/j.cell.2015.07.011
  22. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011, 364:2507-2516. 10.1056/NEJMoa1103782
  23. Chapman PB, Solit DB, Rosen N: Combination of RAF and MEK inhibition for the treatment of BRAF-mutated melanoma: feedback is not encouraged. Cancer Cell. 2014, 26:603-604. 10.1016/j.ccell.2014.10.017
  24. Hauschild A, Grob J-J, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012, 380:358-365. 10.1016/S0140-6736(12)60868-X
  25. Long G, Flaherty K, Stroyakovskiy D, et al.: Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017, 28:1631-1639. 10.1093/annonc/mdx176
  26. Wolf A, Zia S, Verma R, et al.: Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol. 2016, 127:607-615. 10.1007/s11060-016-2072-6
  27. Kotecha R, Miller JA, Venur VA, et al.: Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome. J Neurosurg. 2017: 1-10. 10.3171/2017.1.JNS162797
  28. Mastorakos P, Xu Z, Yu J, et al.: BRAF V600 mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases: a multicenter retrospective study. Neurosurgery. 2019, 84:868-880. 10.1093/neuros/nyy203
  29. Xu Z, Lee C-C, Ramesh A, et al.: BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases. J Neurosurg. 2017, 126:726-734. 10.3171/2016.2.JNS1633
  30. Hecht M, Meier F, Zimmer L, et al.: Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients. Br J Cancer. 2018, 118:785-792. 10.1038/bjc.2017.489
  31. Hecht M, Zimmer L, Loquai C, et al.: Radiosensitization by BRAF inhibitor therapy—mechanism and frequency of toxicity in melanoma patients. Ann Oncol. 2015, 26:1238-1244. 10.1093/annonc/mdv139
  32. Kroeze SGC, Fritz C, Hoyer M, et al.: Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review. Cancer Treat Rev. 2017, 53:25-37. 10.1016/j.ctrv.2016.11.013
  33. Wolf A, Zia S, Verma R, et al.: Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol. 2016, 127:607-615. 10.1007/s11060-016-2072-6
Review article
peer-reviewed

Concurrent Radiosurgery and Systemic Therapies for Melanoma Brain Metastases: A Systematic Review


Author Information

Bradley D. Weaver

Oncology, University of Utah, Salt Lake City, USA

James R. Goodman

Anesthesiology, Oregon Health & Science University, Portland, USA

Randy Jensen Corresponding Author

Neurosurgery, University of Utah, Salt Lake City, USA


Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Acknowledgements

We thank Kristin Kraus, MSc, for editorial assistance.


Review article
peer-reviewed

Concurrent Radiosurgery and Systemic Therapies for Melanoma Brain Metastases: A Systematic Review


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