Meta-analysis of efficacy and safety of bevacizumab combined with lomustine in treatment of recurrent glioblastoma
DING Xiurong1, LIU Jinlong2, HUANG Shengxuan3, LI Zhihong1
1. Emergency Medicine Department, Characteristics Medical Center of Chinese People's Armed Police Force, Tianjin 300162, China; 2. Department of Obstetrics and Gynecology, the 79th Group Army Hospital of PLA, Liaoyang 111000,China; 3. Neurosurgery Department, the First Hospital of Sanming Affiliated to Fujian Medical University, 365000 Sanming,China
Abstract:Objective To systematically evaluate the clinical efficacy and safety of bevacizumab combined with lomustine in the treatment of recurrent glioma.Methods A comprehensive computer search was conducted in both Chinese and English databases to search randomized controlled trials on the use of bevacizumab in combination with lomustine in patients with recurrent glioma. The search time was from the establishment of the database to April 2023. Two researchers independently searched the database, screened the literature, extracted and analyzed the data, analyzed the risk of bias in the included literature, and performed a meta-analysis using software (RevMan 5.4).Results Six randomized controlled trials were included, with a total of 1053 patients (523 in experimental group and 530 in control group). The results of Meta analysis showed that bevacizumab combined with lomustine significantly improved progression-free survival (PFS)(HR=0.52,95%CI:0.44-0.61,P<0.05)and Objective response rate (ORR)(OR=0.33,95%CI:0.14-0.78, P<0.05)in patients with recurrent glioblastoma, and had no significant on overall survival (OS)(HR=0.89,95%CI:0.75-1.07, P<0.05). In terms of adverse reactions: the incidence of proteinuria and grade Ⅲ or above adverse reactions in bevasizumab combined with lomustine was significantly higher than that in the control group, with statistical significance (P<0.05), while there was no statistical significance in other adverse reactions compared with the control group.Conclusions Bevacizumab combined with Lomustine can significantly improve PFS and ORR in patients with recurrent GBM, indicating that the combination therapy is recommended for the treatment of recurrent glioblastoma. At the same time, the combination of bevacizumab and lomustine is also associated with an increased rate of proteinuria and grade III or higher adverse reactions, so safety needs to be considered before adding bevacizumab to the lomustine regimen.
丁秀蓉, 刘金龙, 黄生炫, 李志宏. 贝伐单抗联合洛莫司汀治疗复发性胶质母细胞瘤疗效与安全性的Meta分析[J]. 武警医学, 2024, 35(2): 150-156.
DING Xiurong, LIU Jinlong, HUANG Shengxuan, LI Zhihong. Meta-analysis of efficacy and safety of bevacizumab combined with lomustine in treatment of recurrent glioblastoma. Med. J. Chin. Peop. Armed Poli. Forc., 2024, 35(2): 150-156.
Lan X Y,Li D,Li S,et al.Impact of angiogenic inhibition in the treatment of newly diagnosed and recurrent glioblastoma: a meta-analysis based on randomized controlled trials[J].Eur Rev Med Pharmacol Sci,2022,26(10): 3522-3533.
[1]
Schaff L R,Mellinghoff I K.Glioblastoma and other primary brain malignancies in adults: a review[J].JAMA, 2023, 329(7): 574-587.
[6]
Ellingson B M, Wen P Y, Chang S M,et al. Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival[J].Neuro Oncol,2023,25(6):1017-1028.
[2]
Luo C,Song K,Wu S,et al. The prognosis of glioblastoma: a large, multifactorial study[J]. Br J Neurosurg,2021, 35(5): 555-561.
[7]
Taal W,Oosterkamp H M,Walenkamp A M,et al.Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial[J].Lancet Oncol, 2014, 15(9): 943-953.
[3]
Lombardi G,De Salvo G L,Brandes A A,et al.Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial[J].Lancet Oncol,2019, 20(1):110-119.
[8]
Heiland D H,Masalha W,Franco P,et al.Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine[J].J Neurooncol,2016, 126(3): 567-575.
[4]
Reardon D A,Brandes A A,Omuro A,et al.Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the checkmate 143 phase 3 randomized clinical trial[J].JAMA Oncol, 2020, 6(7): 1003-1010.
[9]
Weathers S P,Han X,Liu D D,et al.A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma[J].J Neurooncol,2016,129(3): 487-494.
[5]
Lan X Y,Li D,Li S,et al.Impact of angiogenic inhibition in the treatment of newly diagnosed and recurrent glioblastoma: a meta-analysis based on randomized controlled trials[J].Eur Rev Med Pharmacol Sci,2022,26(10): 3522-3533.
[10]
Wick W,Gorlia T,Bendszus M,et al.Lomustine and bevacizumab in progressive glioblastoma[J].N Engl J Med,2017,377(20):1954-1963.
[6]
Ellingson B M, Wen P Y, Chang S M,et al. Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival[J].Neuro Oncol,2023,25(6):1017-1028.
[7]
Taal W,Oosterkamp H M,Walenkamp A M,et al.Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial[J].Lancet Oncol, 2014, 15(9): 943-953.
[11]
Jakobsen J N,Urup T,Grunnet K,et al.Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients[J].J Neurooncol,2018,137(2):439-446.
[8]
Heiland D H,Masalha W,Franco P,et al.Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine[J].J Neurooncol,2016, 126(3): 567-575.
[12]
Brandes A A,Gil-Gil M,Saran F,et al.A randomized phase ii trial (TAMIGA) evaluating the efficacy and safety of continuous bevacizumab through multiple lines of treatment for recurrent glioblastoma[J].Oncologist, 2019,24(4):521-528.
[9]
Weathers S P,Han X,Liu D D,et al.A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma[J].J Neurooncol,2016,129(3): 487-494.
[13]
Hundsberger T,Reardon D A,Wen P Y.Angiogenesis inhibitors in tackling recurrent glioblastoma[J].Expert Rev Anticancer Ther,2017,17(6):507-515.
[10]
Wick W,Gorlia T,Bendszus M,et al.Lomustine and bevacizumab in progressive glioblastoma[J].N Engl J Med,2017,377(20):1954-1963.
[14]
Beige A,Ghiringhelli F,Lecuelle J,et al.Efficacy of chemotherapy plus bevacizumab in recurrent glioblastoma multiform: a real-life study[J].Anticancer Res,2022,42(12): 5847-5858.
[11]
Jakobsen J N,Urup T,Grunnet K,et al.Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients[J].J Neurooncol,2018,137(2):439-446.
Brandes A A,Gil-Gil M,Saran F,et al.A randomized phase ii trial (TAMIGA) evaluating the efficacy and safety of continuous bevacizumab through multiple lines of treatment for recurrent glioblastoma[J].Oncologist, 2019,24(4):521-528.
[16]
Weller M,Rhun E.How did lomustine become standard of care in recurrent glioblastoma?[J].Cancer Treat Rev,2020,87(11):102029.
[13]
Hundsberger T,Reardon D A,Wen P Y.Angiogenesis inhibitors in tackling recurrent glioblastoma[J].Expert Rev Anticancer Ther,2017,17(6):507-515.
[17]
Yoon N,Kim H S,Lee J W,et al.Targeted genomic sequencing reveals different evolutionary patterns between locally and distally recurrent glioblastomas[J].Cancer Genom Proteom,2020,17(6): 803-812.
[14]
Beige A,Ghiringhelli F,Lecuelle J,et al.Efficacy of chemotherapy plus bevacizumab in recurrent glioblastoma multiform: a real-life study[J].Anticancer Res,2022,42(12): 5847-5858.
[18]
Erdem E L,Bent M J,Hoogstrate Y,et al.Identification of patients with recurrent glioblastoma who may benefit from combined bevacizumab and CCNU therapy:a report from the BELOB trial[J].Cancer Res,2016, 76(3):525-534.
Herrlinger U,Tzaridis T,Mack F,et al.Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised,open-label, phase 3 trial[J].Lancet,2019,393(10172): 678-688.
[16]
Weller M,Rhun E.How did lomustine become standard of care in recurrent glioblastoma?[J].Cancer Treat Rev,2020,87(11):102029.
[20]
Lin P,Jiang H,Zhao Y J,et al.Increased infiltration of CD8 T cells in recurrent glioblastoma patients is a useful biomarker for assessing the response to combined bevacizumab and lomustine therapy[J].Int Immunopharmacol, 2021,97(9):107826.
[17]
Yoon N,Kim H S,Lee J W,et al.Targeted genomic sequencing reveals different evolutionary patterns between locally and distally recurrent glioblastomas[J].Cancer Genom Proteom,2020,17(6): 803-812.
[21]
Jiguet J C,Boissonneau S,Denicolai E,et al.Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVA glio ancillary study[J].Acta Neuropathol Commun,2022,10(1): 1-10.
[18]
Erdem E L,Bent M J,Hoogstrate Y,et al.Identification of patients with recurrent glioblastoma who may benefit from combined bevacizumab and CCNU therapy:a report from the BELOB trial[J].Cancer Res,2016, 76(3):525-534.
[22]
Gittleman H,Lim D,Kattan M W,et al.An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma:NRG oncology RTOG 0525 and 0825[J].Neuro Oncol,2017,19(5): 669-677.
[19]
Herrlinger U,Tzaridis T,Mack F,et al.Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised,open-label, phase 3 trial[J].Lancet,2019,393(10172): 678-688.
[23]
Wang F,Cathcart S J,DiMaio D J,et al.Comparison of tumor immune environment between newly diagnosed and recurrent glioblastoma including matched patients[J].J Neurooncol,2022,159(1):163-175.
[20]
Lin P,Jiang H,Zhao Y J,et al.Increased infiltration of CD8 T cells in recurrent glioblastoma patients is a useful biomarker for assessing the response to combined bevacizumab and lomustine therapy[J].Int Immunopharmacol, 2021,97(9):107826.
[24]
Tsien C I,Pugh S L,Dicker A P,et al.NRG oncology/RTOG1205:a randomized phase ii trial of concurrent bevacizumab and reirradiation versus bevacizumab alone as treatment for recurrent glioblastoma[J].J Clin Oncol, 2023,41(6):1285-1295.
[21]
Jiguet J C,Boissonneau S,Denicolai E,et al.Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVA glio ancillary study[J].Acta Neuropathol Commun,2022,10(1): 1-10.
[25]
Kumar G,Dsouza H,Menon N,et al.Safety and efficacy of bevacizumab biosimilar in recurrent/ progressive glioblastoma[J].E Cancer Med Sci, 2021,15(5):1166.
[22]
Gittleman H,Lim D,Kattan M W,et al.An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma:NRG oncology RTOG 0525 and 0825[J].Neuro Oncol,2017,19(5): 669-677.
[26]
Patil V M,Menon N,Chatterjee A,et al.Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: a randomised open-label phase II trial[J].E Clin Med,2022, 49:101449.
[23]
Wang F,Cathcart S J,DiMaio D J,et al.Comparison of tumor immune environment between newly diagnosed and recurrent glioblastoma including matched patients[J].J Neurooncol,2022,159(1):163-175.
[24]
Tsien C I,Pugh S L,Dicker A P,et al.NRG oncology/RTOG1205:a randomized phase ii trial of concurrent bevacizumab and reirradiation versus bevacizumab alone as treatment for recurrent glioblastoma[J].J Clin Oncol, 2023,41(6):1285-1295.
[25]
Kumar G,Dsouza H,Menon N,et al.Safety and efficacy of bevacizumab biosimilar in recurrent/ progressive glioblastoma[J].E Cancer Med Sci, 2021,15(5):1166.
[26]
Patil V M,Menon N,Chatterjee A,et al.Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: a randomised open-label phase II trial[J].E Clin Med,2022, 49:101449.