Concurrent versus non-concurrent immune checkpoint inhibition with stereotactic radiosurgery for metastatic brain disease: a systematic review and meta-analysis
Immune checkpoint inhibition (ICI) is an emerging immunotherapy for metastatic brain disease (MBD). Current management options include stereotactic radiosurgery (SRS), which has been shown to confer prognostic benefit in combination with ICI. However, the effect, if any, of ICI timing on this benefit is currently unclear. The aim of this study was to evaluate the effect of concurrent ICI with SRS on survival outcomes in MBD compared to non-concurrent ICI administered before or after SRS.
Searches of 7 electronic databases from inception to April 2018 were conducted following the appropriate guidelines. 1210 articles were identified for screening. Kaplan Meier estimation of 12-month overall survival (OS), local progression free survival (LPFS) and distant progression free survival (DPFS) were pooled as odd ratios (ORs) and analyzed using the random effects model.
A total of 8 retrospective observational cohort studies satisfied selection criteria. Compared to non-concurrent ICI, concurrent ICI with SRS conferred a significant 12-month OS benefit (OR = 1.74; p = 0.011), and comparable 12-month LPFS (OR = 2.09; p = 0.154) and DPFS (OR = 0.88; p = 0.839). These significances were reflected in the subgroup of melanoma metastases.
Based on the trends of our findings, there appears to exist an optimal time window around SRS of which ICI may confer the most survival benefit. However, current literature is limited by a number of clinical parameters requiring further delineation which limits the certainty of these findings. Larger, prospective, and randomized studies will assist in identifying the time period for which ICI can provide the best outcome in MBD managed with SRS.
KeywordsBrain metastases Immunotherapy Checkpoint inhibition Melanoma, radiation Radiosurgery
Compliance with ethical standards
Conflict of interest
The authors report no funding sources or conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
- 1.Cagney DN, Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, Wen PY, Dunn IF, Bi WL, Weiss SE, Haas-Kogan DA, Alexander BM, Aizer AA (2017) Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. Neuro Oncol 19(11):1511–1521. https://doi.org/10.1093/neuonc/nox077 CrossRefGoogle Scholar
- 2.Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 22(14):2865–2872. https://doi.org/10.1200/jco.2004.12.149 CrossRefGoogle Scholar
- 6.Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A (2015) Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532. https://doi.org/10.1056/NEJMoa1503093 CrossRefGoogle Scholar
- 7.Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, Shepherd FA, Antonia S, Goldman JW, Juergens RA, Laurie SA, Nathan FE, Shen Y, Harbison CT, Hellmann MD (2016) Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34(25):2980–2987. https://doi.org/10.1200/jco.2016.66.9929 CrossRefGoogle Scholar
- 8.McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, Brahmer JR, Carvajal RD, Hammers HJ, Puzanov I, Hodi FS, Kluger HM, Topalian SL, Pardoll DM, Wigginton JM, Kollia GD, Gupta A, McDonald D, Sankar V, Sosman JA, Atkins MB (2015) Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving Nivolumab. J Clin Oncol 33(18):2013–2020. https://doi.org/10.1200/jco.2014.58.1041 CrossRefGoogle Scholar
- 9.Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, Naghavi AO, Kim S, Kim Y, Patel BG, Sarangkasiri S, Johnstone PAS, Sahebjam S, Khushalani NI, Forsyth PA, Harrison LB, Yu M, Etame AB, Caudell JJ (2016) 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 27(12):2288–2294. https://doi.org/10.1093/annonc/mdw417 CrossRefGoogle Scholar
- 10.Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466 CrossRefGoogle Scholar
- 11.Long GV, Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, Wilmott JS, Edwards J, Gonzalez M, Scolyer RA, Menzies AM, McArthur GA (2018) Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol 19(5):672–681. https://doi.org/10.1016/s1470-2045(18)30139-6 CrossRefGoogle Scholar
- 12.Gauvain C, Vauleon E, Chouaid C, Lerhun E, Jabot L, Scherpereel A, Vinas F, Cortot AB, Monnet I (2018) Intracerebral efficacy and tolerance of nivolumab in non-small-cell lung cancer patients with brain metastases. Lung Cancer 116:62–66. https://doi.org/10.1016/j.lungcan.2017.12.008 CrossRefGoogle Scholar
- 13.Gaudy-Marqueste C, Dussouil AS, Carron R, Troin L, Malissen N, Loundou A, Monestier S, Mallet S, Richard MA, Regis JM, Grob JJ (2017) Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery. Eur J Cancer 84:44–54. https://doi.org/10.1016/j.ejca.2017.07.017 CrossRefGoogle Scholar
- 16.Chen L, Douglass J, Kleinberg L, Ye X, Marciscano AE, Forde PM, Brahmer J, Lipson E, Sharfman W, Hammers H, Naidoo J, Bettegowda C, Lim M, Redmond KJ (2018) Concurrent immune checkpoint inhibitors and stereotactic radiosurgery for brain metastases in non-small cell lung cancer, melanoma, and renal cell carcinoma. Int J Radiat Oncol Biol Phys 100(4):916–925. https://doi.org/10.1016/j.ijrobp.2017.11.041 CrossRefGoogle Scholar
- 21.Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, Zaza S (2004) Grading quality of evidence and strength of recommendations. BMJ 328(7454):1490. https://doi.org/10.1136/bmj.328.7454.1490 CrossRefGoogle Scholar
- 22.Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2016) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute, OttawaGoogle Scholar
- 28.Kiess AP, Wolchok JD, Barker CA, Postow MA, Tabar V, Huse JT, Chan TA, Yamada Y, Beal K (2015) Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment. Int J Radiat Oncol Biol Phys 92(2):368–375. https://doi.org/10.1016/j.ijrobp.2015.01.004 CrossRefGoogle Scholar
- 29.Patel KR, Shoukat S, Oliver DE, Chowdhary M, Rizzo M, Lawson DH, Khosa F, Liu Y, Khan MK (2017) Ipilimumab and STEREOTACTIC RADIOSURGERY VERSUS STEREOTACTIC RADIOSURGERY ALONE FOR NEWLY DIAGNOSED MELANOMA BRAIN METASTASES. Am J Clin Oncol Cancer Clin Trials 40(5):444–450. https://doi.org/10.1097/COC.0000000000000199 CrossRefGoogle Scholar
- 31.Rahman R, Cortes A, Niemierko A, Oh KS, Flaherty KT, Lawrence DP, Sullivan RJ, Shih HA (2018) The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity. J Neuro-Oncol. https://doi.org/10.1007/s11060-018-2795-7 Google Scholar
- 32.Schapira E, Hubbeling H, Yeap BY, Mehan WA Jr, Shaw AT, Oh K, Gainor JF, Shih HA (2018) Improved Overall Survival and Locoregional Disease Control With Concurrent PD-1 Pathway Inhibitors and Stereotactic Radiosurgery for Lung Cancer Patients With Brain Metastases. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2018.02.175 Google Scholar
- 33.Ahmed KA, Kim S, Arrington J, Naghavi AO, Dilling TJ, Creelan BC, Antonia SJ, Caudell JJ, Harrison LB, Sahebjam S, Gray JE, Etame AB, Johnstone PA, Yu M, Perez BA (2017) Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases. J Neuro Oncol 133(2):331–338. https://doi.org/10.1007/s11060-017-2437-5 CrossRefGoogle Scholar
- 34.An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, Logan J, D’Souza NM, Haydu LE, Wang XA, Hess KR, Kluger H, Glitza IC, Mahajan A, Welsh JW, Lin SH, Yu JB, Davies MA, Hwu P, Sulman EP, Brown PD, Chiang VLS, Li J (2017) Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol 125(1):80–88. https://doi.org/10.1016/j.radonc.2017.08.009 CrossRefGoogle Scholar
- 39.Caballero JA, Sneed PK, Lamborn KR, Ma L, Denduluri S, Nakamura JL, Barani IJ, McDermott MW (2012) Prognostic factors for survival in patients treated with stereotactic radiosurgery for recurrent brain metastases after prior whole brain radiotherapy. Int J Radiat Oncol Biol Phys 83(1):303–309. https://doi.org/10.1016/j.ijrobp.2011.06.1987 CrossRefGoogle Scholar
- 40.Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M (2012) Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30(4):419–425. https://doi.org/10.1200/jco.2011.38.0527 CrossRefGoogle Scholar
- 44.Kim S, Ramakrishnan R, Lavilla-Alonso S, Chinnaiyan P, Rao N, Fowler E, Heine J, Gabrilovich DI (2014) Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice. Cancer Immunol Immunother 63(10):1009–1021. https://doi.org/10.1007/s00262-014-1573-4 CrossRefGoogle Scholar