The Efficacy and Safety of PD-1/PD-L1 Checkpoint Blockade Immunotherapy in Recurrence Glioblastoma: A Meta-Analysis

The Efficacy and Safety of PD-1/PD-L1 Checkpoint Blockade Immunotherapy in Recurrence Glioblastoma: A Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Efficacy and Safety of PD-1/PD-L1 Checkpoint Blockade Immunotherapy in Recurrence Glioblastoma: A Meta-Analysis Nan Tang, Chen Chen, Lianxuan Gao, Shushu Hu, Yulei Chen, Yingying Zeng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1269120/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose : The efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence glioblastoma remains unclear. The aim of this meta-analysis is to access the survival outcomes of immunotherapy in these patients. Methods : A comprehensive electronic literature search of PubMed, Web of Science, Embase and Cochrane Library was conducted up to August 22, 2021. The main evaluation data were the overall survival (OS) rate at 12 months and the progression-free survival (PFS) rate at 6 months. The secondary evaluation data was the incidence of serious adverse events(grade 3 or greater AEs). The study was performed using R“meta” package. Results : Seven studies met the inclusion criteria, which totally contained 343 participants. The 12-month OS in recurrent GBM were 40% (95% CI: 89.2% -95.1%), while the 6-month PFS 16.0% (95%CI 9%–23%). The overall incidence of adverse reactions is approximately 25% [0.13; 0.40], the toxicity of immunotherapy was acceptable. Conclusions : Compared with survival data for BEV (bevacizumab) /BPC(best physician's choice chemotherapy) treatment, immunotherapy seemed to improve overall survival and progression-free survival, Meanwhile, the toxicity of immunotherapy was tolerable. Further randomised controlled clinical studies are needed to confirm these findings. And also suggests that the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1. Introduction Glioblastoma (WHO grade IV glioma, GBM) is the most common malignant brain tumor, that has aggressive biological behavior and resistance to treatment. Indeed, GBM (14.5% of all brain tumors and 48.6% of malignant brain tumors[1]) has an annual incidence from 0.6 to 3.7/100,000 individuals[2] and remarkably poor prognosis showing a 5-year survival rate of 4-5%[3]. Over the years, progress has been made in maximally possible surgical resection techniques, radiation therapy, and chemotherapeutic strategies, yet the current patients’ median overall survival is around 15 months[4]. Although current therapy regimens have improved over the past 20 years, overall patient survival has not risen to the levels obtained for other solid tumors. Researchers continue to explore new treatments for glioblastoma. Temozolomide(TMZ)is commonly used cytotoxic chemotherapies for newly diagnosed and recurrent GBM as well as lower-grade gliomas. They induce apoptosis and cell death by methylating guanine at the O6 position, initiating a double-strand break in the DNA, and cell cycle arrest[5, 6]. The O6-methylguanine-DNA methyltransferase (MGMT) protein removes the damaging alkyl groups from the O6 position of guanine and repairs the DNA. The alkylated protein is then degraded, requiring constant replenishment for DNA repair to be effective[6]. High expression of MGMT in cancer cells, account for the predominant mechanism of resistance to alkylating agents[7]. MGMT promoter methylation can silence MGMT that is associated with a favorable outcome after temozolomide chemotherapy in patients[8]. However, more than half of glioblastoma, the promoter is unmethylated, which means that these patients are resistant to TMZ. So, in the NCCN Guidelines (Central Nervous System Cancers) patients with unmethylated MGMT promoters are recommended to enter clinical trials to investigate whether there are better treatment options. For the past few years, Immunotherapy has transformed the management of many cancers, and consequently there has been considerable investigation and research into immune-based therapeutic approaches for glioblastoma. The CNS has a unique immune microenvironment and was long thought to simply be an immune-privileged site[9]. However immune surveillance in the CNS and the role of myeloid cells is now known to be much more complex[10].In the context of metastatic cancer to the brain, immunotherapy has demonstrated significant efficacy. Suggesting that immunotherapy is not impeded by the blood-brain tumor barrier[11]. Treatment of GBM patients with immune checkpoint inhibitors may benefit. Animal study have shown that fractionated RT synergizes with PD-1 blockade to produce tumor regression and long-term survival in mice with orthotopic brain tumors[12]. More and more clinical trials on immunotherapy for GBM have been performed[13], and immune checkpoint inhibitors (ICIs) have received considerable attention. However, the efficacy and safety of PD-1/PD-L1 checkpoint blockade for glioblastoma patients remains unclear. Therefore, we performed a meta-analysis to access efficacy and safety. Nowadays, the randomized control trial about PD-1/PD-L1 checkpoint blockade without age restrictions in newly diagnosed GBM is rare. Thus, the studies we included were immunotherapy of Recurrent Glioblastoma.Studies of PD-1/PD-L1 checkpoint blockade immunotherapy combination with targeted therapy or chemotherapy were excluded. Study did not provide specific survival data or survival curve (Kaplan–Meier curve) was excluded. 2. Methods 2.1. Study eligibility criteria and selection This study was prepared based on the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines for reporting systematic reviews[14]. The study should be designed to evaluate the efficacy of PD-1/PD-L1 checkpoint blockade in recurrence GBM. Eligible patients enrolled should have normal hematologic, renal, hepatic function and have no restriction on age. Patients enrolled less than 10 were excluded because of relatively high bias. 2.2. Data sources and search strategy The electronic database of PubMed, Web of Science，Embase and Cochrane Library were systematically searched from their inception to August 22, 2021. The search term comprised synonyms for “glioblastoma”, “Immunotherapy” and “PD-1/PD-L1 checkpoint blockade”. Reference lists of accepted studies and bibliographies of reviews were manually searched in order not to miss other relevant studies. Two investigators independently performed the literature search, screened titles and abstracts, and selected relevant full articles and assessed their eligibility. Different opinions between two investigators were resolved by consensus or by consultation of a third investigator 2.3. Literature quality evaluation It was inappropriate to evaluate literature quality using the Newcastle-Ottawa scale (NOS)[15] because most of the studies included were single arm trial. Referring to the NOS, we set some criteria to evaluate literature quality accommodating this study purpose and including: study population clearly defined; cohort representative for the population of recurrence GBM patients; therapeutic drug specifically defined; therapeutic dose specifically defined; clear and specific treatment process; follow-up long enough for outcomes to occur; adequacy of follow-up; assessment of outcome well performed; toxicities and comparison well recorded. 2.4. Data extraction Clinical endpoints including PFS-6 (PFS rate at 6 months), OS-12 (OS rate at 12 months) were the primary survival data to extract. The incidence of severe acute/late toxicity, which were defined by Common Terminology Criteria for Adverse Events, were also extracted for additional analysis. When survival data only provided in survival curve (Kaplan–Meier curve), figures were digitised to extract numeric data using Engauge Digitizer. 2.5. Statistical analysis Analyses were performed using R version 4.0 (https://cran.r-project.org/) with the “meta” package and Microsoft Excel 2019. The overall survival proportion was calculated with corresponding 95% confidence intervals (95%CI). Heterogeneity was assessed by calculating Cochran Q test and inconsistency index test (I2 test). Random effects model was used in case of the existence of heterogeneity, defined as a P-value of Cochran Q test 50% [15], whereas fixed effects model was used in the opposite case. A two-tailed P-value < 0.05 was considered statistically significant. 3. Results 3.1. Search results A total of 472 studies were identified after electronic and manual searches and after the removal of 15 duplicate articles, 472 articles remained. Then exclusion based on title and abstract, 73 full-text articles of potential interest were reviewed. After further evaluation, 7 prospective trials (contains 10 cohorts) were included in table. No additional articles were identified in reference lists of accepted studies and bibliographies of reviews. Fig. 1 shows a flowchart for procession of studies selection. 3.2. Study characteristics and quality evaluation Referring to the NOS, we performed a particular literature evaluation scale to evaluate each study (Supplement Table S1). In general, the included studies could completely record important information of trial. However, the existence of prospective single arm trials made overall research somewhat heterogeneous and limited the quality of reporting. 3.3. OS Overall survival was one of the primary clinical endpoints of interest in this study. A total of 343 patients in 7 trials (10 cohorts) provided survival data for recurrent glioblastomas treated with PD-1/PD-L1 checkpoint blockade immunotherapy. In these studies, the 1-year overall survival rates ranged from 19% to 69.0%. while the overall OS-12 rate was 40.0%(95% CI: 89.2% -95.1%) using fixed-effects model due to the heterogeneity (I 2=49.10%, p=0.004) (Figure 2). Among, eight cohorts with adjuvant PD-1/PD-L1 checkpoint blockade for recurrent glioblastoma had 1-year survival rates of 19% to 58%, with heterogeneity between studies (I2=29%, P=0.2), and the overall OS-12 rate was 38% (95% CI: 0.32 to 0.44) using a fixed-effects model, see Figure 3. The only two remaining cohorts were neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma, with 1-year overall survival rates of 60%-69% for neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy, with no heterogeneity between studies (I2=0%, P=0.63) and the overall OS-12 rate was 65% (95% CI: 0.46 to 0.81) using a fixed effects model (Figure 4) 3.4. PFS Another important clinical endpoint, progression-free survival, was analyzed subsequently. For the PFS-6 rate, a total of 343 patients reached this clinical endpoint. Meta-analysis indicated the overall PFS-6 rate was 16.0% (95%CI 9%–23%) using random effects model determined by a heterogeneity (I2=51%, P=0.03) (Fig. 5). Similarly, 8 cohorts of adjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma had PFS-6 rates ranging from 0% to 35%, with heterogeneity between studies (I2=35%, P=0.15), and overall PFS-6 rate was 13% (95% CI: 9%-17%) using a fixed-effects model, as shown in Figure6. Two cohorts of neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy had a 6-month progression-free survival range of 31%-40%, with no heterogeneity between studies (I2=0%, P=0.63) (Figure7). 3.5. Efficacy Adjuvant anti-PD-1/PDL-1 immunotherapy for recurrent glioblastoma (1-year overall survival rates was 38%) better than bevacizumab for recurrent glioblastoma published by Henry S. Friedman et al[16] , which had an 1-year overall survival rates was 24% (p=0.02). Adjuvant anti-PD-1/PD-L1 immunotherapy compared to physician's choice chemotherapy for relapsed glioblastoma[17] increased 1-year overall survival rates in patients by 18% (38% vs 20%, p<0.001). However, anti-PD-1/PDL-1 immunotherapy did not improve progression-free survival in patients with recurrent glioblastoma compared in comparison to bevacizumab or physician's choice chemotherapy(table2). 3.6. Safety and toxicity The incidence of serious adverse events（grade 3 or greater AEs） in recurrent glioblastoma treated with adjuvant anti-PD-1/PDL-1 immunotherapy is approximately 25% [0.13; 0.40](Figure8)，compared to Henry S. Friedman et al.[16] 2009, which published an incidence of grade 3-4 adverse events of 46.4% for bevacizumab in recurrent glioblastoma, that is a significant lower (p-value = 0.0002). Unfortunately, in the study of physician's choice chemotherapy for recurrent glioblastoma published by Roger Stupp et al[17]. in 2012, the incidence of grade 3-4 adverse events was not given. 4. Discussion Due to high invasiveness, the prognosis of glioblastoma is extremely poor even after receiving comprehensive treatments. Therefore, finding effective treatments to improve the prognosis of Glioma patients is an emerging issue. Researchers have constantly explored and tried new approaches for glioblastoma, but until now, only the new technique of Tumor-Treating Fields (TTF) has been shown to improve the prognosis of patients with high-grade glioma. However, TTF is currently not widely available in clinical practice in China due to its high expense. In recent years, with increasing research related to immune checkpoints, immunotherapy with PD-1/PD-L1 inhibitors has demonstrated durable and stable anti-tumors effects in a variety of tumors treatments. There are more and more clinical trials related to anti-PD-1/PDL-1 immunotherapy for GBM, but most of them are single-arm clinical studies, which cannot evaluate the efficacy Comparison against other anti-tumors treatments. Therefore, a single arm meta-analysis was done to assess how effective anti-PD-1/PDL-1 is in treating glioblastoma. In this single arm meta-analysis show that immunotherapy is more effective and safer than chemotherapy or bevacizumab in the treatment of recurrent glioblastoma. Neoadjuvant anti-PD-1 immunization versus adjuvant anti-PD-1 immunization for recurrent glioblastoma shows superior efficacy, but also a higher incidence of grade 3-4 adverse events and higher toxicity. This also suggests that the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be. However, this single-arm meta-analysis has a few limitations: firstly, the studies included in this meta are single-arm studies and the findings need to be further validated by randomized controlled clinical studies. Secondly, the inclusion of patients with recurrent glioblastoma in this meta is also somewhat biased, with some populations having a first recurrence and others having a second recurrence, and the prognosis in these two groups is inherently very different. Thirdly, the type and dose of anti-PD-1/PDL-1 drugs included in this meta also differed, which may also affect the prognostic assessment of patients with recurrent glioblastoma. In general, this single-arm meta-analysis also provides some evidence of the benefits of PD-1/PD-L1 immunotherapy for recurrent glioblastoma. However, a higher level of evidence, such as randomized controlled clinical study, is still needed to confirm. In addition, this meta-analysis appears that neoadjuvant immunotherapy for the recurrent glioblastoma has a superior 1-year OS rate for patients versus adjuvant immunotherapy. Suggesting that the earlier immunotherapy is applied to relapsed glioblastoma, the better the prognosis for the patients. Similar circumstances, does immunotherapy improves prognosis in newly diagnosed glioblastoma, especially in patients with unmethylated MGMT promoters? According to a clinical study published by Stupp Prof. et al[18], Median overall survival for patients with primary glioblastoma with unmethylated promoters was 11.8 months for radiotherapy alone and 12.6 months for radiotherapy combined with TMZ. Although the difference is statistically significant, it has little clinical benefit. This confirms that GBM with unmethylated MGMT promoter is inherently resistant to TMZ. How effective is the application of immunotherapy to newly diagnosed GBM with unmethylated MGMT promoters? 2019 ASCO Annual Meeting reported a study that MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastomas[19], Median OS was 15.1 (95% CI: 12.0, 18.4) months, clearly improved prognosis. Durvalumab + radiotherapy improved median OS by 3 months compared to radiotherapy alone for new unmeth GBM. Similarly, the efficacy is better than radiotherapy combined with TMZ for new unmeth GBM. Thus does RT+TMZ plus immunotherapy further improve the prognosis for patients with newly diagnosed glioblastoma? A clinical study was published on 2020 ASCO Annual Meeting that atezolizumab in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM)[20], median OS was 17.1 months (95% CI: 13.9, not reached). median PFS was 9.7 months (95% CI: 7.6-15). Median survival was 14.6 months with radiotherapy plus temozolomide[4]. Therefore, RT+TMZ plus immunotherapy may further improve the prognosis of patients with newly diagnosed glioblastoma. 5. Conclusions As far as we know, this study is the first systematic analysis to evaluate the efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence glioblastoma. In our meta-analysis uncovered that that immunotherapy offers new promising prognosis for newly diagnosed and relapsed glioblastoma patients, and the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be. The risk of toxicity was tolerance. Further research including phase II/III random control trials to evaluate the efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence/newly diagnosed glioblastoma, and explore optimal schedule for recurrence/newly diagnosed glioblastoma . Declarations Availability of data and materials No data, models, or code were generated or used during the study. Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Informed consent Informed consent was obtained from all individual participants included in the study. Research involving Human Participants and/or Animals This chapter does not contain any studies with human participants or animals performed by any of the authors. Acknowledgement This work was supported by the National Natural Science Foundation of China (Grant NO. 81972970 and NO. 82172671) and the Natural Science Foundation of Guangdong Province of China (Grant NO.2020A1515010186). References Ostrom, Q.T., et al., CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013-2017. Neuro Oncol, 2020. 22 (12 Suppl 2): p. iv1-iv96. Ostrom, Q.T., et al., The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol, 2014. 16 (7): p. 896-913. Carlsson, S.K., S.P. Brothers, and C. Wahlestedt, Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med, 2014. 6 (11): p. 1359-70. Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 2005. 352 (10): p. 987-96. Liu, L., S. Markowitz, and S.L. Gerson, Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. Cancer Res, 1996. 56 (23): p. 5375-9. Pegg, A.E., Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res, 2000. 462 (2-3): p. 83-100. Hotta, T., et al., O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. J Neurooncol, 1994. 21 (2): p. 135-40. Hegi, M.E., et al., MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med, 2005. 352 (10): p. 997-1003. Tan, A.C., et al., Management of glioblastoma: State of the art and future directions. CA Cancer J Clin, 2020. 70 (4): p. 299-312. Ransohoff, R.M. and B. Engelhardt, The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol, 2012. 12 (9): p. 623-35. Tawbi, H.A., et al., Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med, 2018. 379 (8): p. 722-730. Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys, 2013. 86 (2): p. 343-9. Romani, M., et al., Immune Checkpoints and Innovative Therapies in Glioblastoma. Front Oncol, 2018. 8 : p. 464. Moher, D., et al., Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Bmj, 2009. 339 : p. b2535. Wells, G.A., et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses . 2014. Friedman, H.S., et al., Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol, 2009. 27 (28): p. 4733-40. Stupp, R., et al., NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer, 2012. 48 (14): p. 2192-202. Stupp, R., et al., Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol, 2009. 10 (5): p. 459-66. Reardon, D.A., et al., Phase II study to evaluate safety and efficacy of MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma (new unmeth GBM). Journal of Clinical Oncology, 2019. 37 (15_suppl): p. 2032-2032. Weathers, S.-P.S., et al., Phase I/II study to evaluate the safety and clinical efficacy of atezolizumab (atezo; aPDL1) in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM). Journal of Clinical Oncology, 2020. 38 (15_suppl): p. 2511-2511. Omuro, A., et al., Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol, 2018. 20 (5): p. 674-686. Lukas, R.V., et al., Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma. J Neurooncol, 2018. 140 (2): p. 317-328. Cloughesy, T.F., et al., Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med, 2019. 25 (3): p. 477-486. Reardon, D.A., et al., Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol, 2020. 6 (7): p. 1003-1010. Nayak, L., et al., Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma. Clin Cancer Res, 2021. 27 (4): p. 1048-1057. Reardon, D.A., et al., Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. Cancer, 2021. 127 (10): p. 1620-1629. de Groot, J., et al., Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. Neuro Oncol, 2020. 22 (4): p. 539-549. Tables Table1：The basic characteristics of clinical trials included in this meta-analysis. Author Year Patin-ents Median age(range) KPS Drug and Dose Re-RT mOS (months) mPFS (months) OS-12 months PFS-6 months ORR Toxicity ≥G3 Antonio Omuro [21] 2018 10 58.5 (42–73) ≥70 adjuvant Nivolumab 3 mg/kg Q2W NOT 10.4 1.9 40%* 12%* 11% (1/9) 0 Antonio Omuro [21] 2018 10 57 (37–68) ≥70 adjuvant Nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W for 4 doses, followed by nivolumab 3 mg/kg Q2W NOT 9.2 1.5 30%* 0* 0 90% (9/10) Antonio Omuro [21] 2018 20 60 (27–73) ≥70 adjuvant Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses, followed by nivolumab 3 mg/kg Q2W NOT 7.3 2.1 33%* 15%* 10% (2/20) 30% (6/20) Rimas V. Lukas [22] 2018 16 52（31-75） ≥70 adjuvant atezolizumab 1200mg NOT 4.2 months (range 1.2 - 18.8+ months) 1.2 months (range 0.7–10.7 months) 21% (95% CI 0.3–42.6) 6.25%* 6% (1/16) 19%(3/16) Timothy F. Cloughesy [23] 2019 16 59.3 86 ± 6.2 adjuvant pembrolizumab 200 mg Q3W NOT 7.5 months 2.4 months 29%* 13%* ? 46.7%； 7/16 David A. Reardon [24] 2020 184 55.5 (22-77) 80 adjuvant Nivolumab 3 mg/kg Q2W NOT 9.8 months 1.5 months 41.8% 15.7% 7.8% (12/153) 18.1%; 33/182 Lakshmi Nayak [25] 2020 30 55 (42, 62) ≥70 adjuvant Pembrolizumab (200 mg) Q3W NOT 10.3 months 1.4 months 30% 6.7% 0 13.3%;4/30 David A. Reardon [26] 2021 26 55.5 [33-76] ECOG:0-1 adjuvant pembrolizumab 10 mg/kg Q2W NOT 13.1 months 2.8 months 58% 37.7% 8% (2/26) 19%; 5/26 Timothy F. Cloughesy [23] 2019 16 55.4 80 ±8.9 Neoadjuvant pembrolizumab 200 mg Q3W NOT 13.7 months 3.3 months 69%* 33%* ? 66.7%; 10/16 John de Groot [27] 2020 15 54 ≥70 Neoadjuvant pembrolizumab 200 mg Q3W YES 20.3 months 4.5 months 63% 40% 3/1 6/15 Table 2 :Comparison of various clinical endpoints between immunotherapy and BPC/BEV Treatment OS-12 PFS-6 n rate n rate BPC 117 20% 117 15% adiuvant PD-1 312 38% 312 13% P-value ＜0.001 0.7 BEV 85 24% 85 42.60% adiuvant PD-1 312 38% 312 13% P-value 0.02 ＜0.001 neoadiuvant 31 65% 31 35% adiuvant PD-1 312 38% 312 13% Value 0.0069 0.008 Supplementary Files SupplementTableS1.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1269120","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":78048874,"identity":"a90efbbf-8b8d-4daf-b22b-ee0854804671","order_by":0,"name":"Nan Tang","email":"","orcid":"https://orcid.org/0000-0002-5908-6377","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nan","middleName":"","lastName":"Tang","suffix":""},{"id":78048875,"identity":"6eadb214-ee91-4ab1-b6a3-fa3e4d32b069","order_by":1,"name":"Chen Chen","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Chen","suffix":""},{"id":78048876,"identity":"beae016f-ca39-45d7-9168-252a3918344d","order_by":2,"name":"Lianxuan Gao","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lianxuan","middleName":"","lastName":"Gao","suffix":""},{"id":78048877,"identity":"c1de5c89-2811-4560-bf3a-cd1430291dd5","order_by":3,"name":"Shushu Hu","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shushu","middleName":"","lastName":"Hu","suffix":""},{"id":78048878,"identity":"5cbb4b89-1c45-4031-a7c2-510655ce11ce","order_by":4,"name":"Yulei Chen","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yulei","middleName":"","lastName":"Chen","suffix":""},{"id":78048879,"identity":"be2ee01e-d9a1-46ff-b04e-e00408f3a038","order_by":5,"name":"Yingying Zeng","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yingying","middleName":"","lastName":"Zeng","suffix":""},{"id":78048880,"identity":"232372d0-8b45-46fc-b2d5-285cc41c9255","order_by":6,"name":"Shasha Du","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYDCCA0CcUCEhx8/MfPgB8Vo+nLExlmxnSzMgWgvjzLa0xA3neRQkiNLBdyP98WcetsOMmw/zMBgw1NhEE9QieSPHTJqH5zCz2WHeAw8YjqXlNhDSYnAjh42ZR+Iwm9lhvgQDxobDxGgBOczgMI9xM4+BBJFaEgwkZySkSRgwE6tF8swbM4kPB2wMgG5LM0ggxi98x9Mff0j8J1Hf33/48IMPNTaEtaCCBNKUj4JRMApGwSjABQD2y0Fm6VfcTAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-2650-7286","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shasha","middleName":"","lastName":"Du","suffix":""}],"badges":[],"createdAt":"2022-01-17 14:35:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1269120/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1269120/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":17679445,"identity":"24ff3580-c053-4d6f-aaab-8eec38ed8d0d","added_by":"auto","created_at":"2022-01-26 23:25:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":76741,"visible":true,"origin":"","legend":"\u003cp\u003eShows a flowchart for procession of studies selection.\u003c/p\u003e","description":"","filename":"Fig01.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/40af32c4b88da15cda4095e6.png"},{"id":17679294,"identity":"d6b94ac0-d7fd-4085-9dfb-17a83bda15b2","added_by":"auto","created_at":"2022-01-26 23:22:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":72961,"visible":true,"origin":"","legend":"\u003cp\u003eThe 1-year overall survival rates ranged from 19% to 69.0%. There was moderate between-study heterogeneity (I 2=49.10%, p=0.004) and a combined 1-year survival rate of 40% (95% CI: 89.2% -95.1%)\u003c/p\u003e","description":"","filename":"Fig02.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/372e84feef5ce5ce1e7da9f3.png"},{"id":17679290,"identity":"a90312f2-6be8-4325-9bbb-e7268d760a1d","added_by":"auto","created_at":"2022-01-26 23:22:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":64907,"visible":true,"origin":"","legend":"\u003cp\u003eAdjuvant PD-1/PD-L1 checkpoint blockade for recurrent glioblastoma had 1-year survival rates of 19% to 58%, with heterogeneity between studies (I2=29%, P=0.2), and a combined 1-year survival rate of 38% (95% CI: 0.32 to 0.44) using a fixed-effects model\u003c/p\u003e","description":"","filename":"Fig03.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/22598a27f66091a5d11e1692.png"},{"id":17679443,"identity":"cfa816c5-cab6-46ea-a6b0-2f3c419d77ff","added_by":"auto","created_at":"2022-01-26 23:25:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":34495,"visible":true,"origin":"","legend":"\u003cp\u003eNeoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma had 1-year overall survival rates of 60%-69% for neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy, with no heterogeneity between studies (I2=0%, P=0.63) and a combined 1-year survival rate of 65% (95% CI: 0.46 to 0.81) using a fixed effects model\u003c/p\u003e","description":"","filename":"Fig04.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/e04788ecabbc4cd523a6babc.png"},{"id":17679291,"identity":"b6cd2415-c0da-423c-97e5-8df3db9fb063","added_by":"auto","created_at":"2022-01-26 23:22:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":41039,"visible":true,"origin":"","legend":"\u003cp\u003eThe overall PFS-6 rate was 16.0% (95%CI 9%–23%) using random effects model determined by a heterogeneity (I2=51%, P=0.03).\u003c/p\u003e","description":"","filename":"Fig05.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/be902f2d2c44cb3ea0a06e39.png"},{"id":17679497,"identity":"08931f9f-6ac0-42c0-9361-3274ed8a0e1c","added_by":"auto","created_at":"2022-01-26 23:28:23","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":39855,"visible":true,"origin":"","legend":"\u003cp\u003eAdjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma had PFS-6 rates ranging from 0% to 35%, with heterogeneity between studies (I2=35%, P=0.15), and overall 6-month progression-free survival rate of 13% (95% CI: 9%-17%) using a fixed-effects model.\u003c/p\u003e","description":"","filename":"Fig06.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/aa326d605c38343a49db778b.png"},{"id":17679442,"identity":"b384fdf8-7690-41a6-9d94-ee9c3179efdc","added_by":"auto","created_at":"2022-01-26 23:25:23","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":20545,"visible":true,"origin":"","legend":"\u003cp\u003eNeoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy had a 6-month progression-free survival range of 31%-40%, with no heterogeneity between studies (I2=0%, P=0.63) .\u003c/p\u003e","description":"","filename":"Fig07.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/0cebe54ace3aafa1d862b72b.png"},{"id":17679292,"identity":"e595e114-3352-49be-a635-ae7589bc36e4","added_by":"auto","created_at":"2022-01-26 23:22:23","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":40160,"visible":true,"origin":"","legend":"\u003cp\u003eThe incidence of serious adverse events（grade 3 or greater AEs） in recurrent glioblastoma treated with adjuvant anti-PD-1/PDL-1 immunotherapy is approximately 25% [0.13; 0.40].\u003c/p\u003e\u003cp\u003e \u003c/p\u003e","description":"","filename":"Fig08.png","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/856f702ff155a567fa31c660.png"},{"id":17679498,"identity":"69414223-82a1-4a41-b002-b160f0f62a83","added_by":"auto","created_at":"2022-01-26 23:28:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":802075,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/f74eecf2-64ad-4173-8af8-323b519d03a7.pdf"},{"id":17679298,"identity":"ad79b121-bb31-4ca9-a135-74f40ab1270e","added_by":"auto","created_at":"2022-01-26 23:22:24","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":9404,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1269120/v1/3dbb57427bb034977d9835c2.xlsx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Efficacy and Safety of PD-1/PD-L1 Checkpoint Blockade Immunotherapy in Recurrence Glioblastoma: A Meta-Analysis\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eGlioblastoma (WHO grade IV glioma, GBM) is the most common malignant brain tumor, that has aggressive biological behavior and resistance to treatment. Indeed, GBM (14.5% of all brain tumors and 48.6% of malignant brain tumors[1]) has an annual incidence from 0.6 to 3.7/100,000 individuals[2] and remarkably poor prognosis showing a 5-year survival rate of 4-5%[3]. Over the years, progress has been made in maximally possible surgical resection techniques, radiation therapy, and chemotherapeutic strategies, yet the current patients\u0026rsquo; median overall survival is around 15 months[4]. Although current therapy regimens have improved over the past 20 years, overall patient survival has not risen to the levels obtained for other solid tumors. Researchers continue to explore new treatments for glioblastoma.\u003c/p\u003e \u003cp\u003eTemozolomide(TMZ)is commonly used cytotoxic chemotherapies for newly diagnosed and recurrent GBM as well as lower-grade gliomas. They induce apoptosis and cell death by methylating guanine at the O6 position, initiating a double-strand break in the DNA, and cell cycle arrest[5, 6]. The O6-methylguanine-DNA methyltransferase (MGMT) protein removes the damaging alkyl groups from the O6 position of guanine and repairs the DNA. The alkylated protein is then degraded, requiring constant replenishment for DNA repair to be effective[6]. High expression of MGMT in cancer cells, account for the predominant mechanism of resistance to alkylating agents[7]. MGMT promoter methylation can silence MGMT that is associated with a favorable outcome after temozolomide chemotherapy in patients[8]. However, more than half of glioblastoma, the promoter is unmethylated, which means that these patients are resistant to TMZ. So, in the NCCN Guidelines (Central Nervous System Cancers) patients with unmethylated MGMT promoters are recommended to enter clinical trials to investigate whether there are better treatment options.\u003c/p\u003e \u003cp\u003eFor the past few years, Immunotherapy has transformed the management of many cancers, and consequently there has been considerable investigation and research into immune-based therapeutic approaches for glioblastoma. The CNS has a unique immune microenvironment and was long thought to simply be an immune-privileged site[9]. However immune surveillance in the CNS and the role of myeloid cells is now known to be much more complex[10].In the context of metastatic cancer to the brain, immunotherapy has demonstrated significant efficacy. Suggesting that immunotherapy is not impeded by the blood-brain tumor barrier[11]. Treatment of GBM patients with immune checkpoint inhibitors may benefit. Animal study have shown that fractionated RT synergizes with PD-1 blockade to produce tumor regression and long-term survival in mice with orthotopic brain tumors[12].\u003c/p\u003e \u003cp\u003eMore and more clinical trials on immunotherapy for GBM have been performed[13], and immune checkpoint inhibitors (ICIs) have received considerable attention. However, the efficacy and safety of PD-1/PD-L1 checkpoint blockade for glioblastoma patients remains unclear. Therefore, we performed a meta-analysis to access efficacy and safety. Nowadays, the randomized control trial about PD-1/PD-L1 checkpoint blockade without age restrictions in newly diagnosed GBM is rare. Thus, the studies we included were immunotherapy of Recurrent Glioblastoma.Studies of PD-1/PD-L1 checkpoint blockade immunotherapy combination with targeted therapy or chemotherapy were excluded. Study did not provide specific survival data or survival curve (Kaplan\u0026ndash;Meier curve) was excluded.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch4\u003e2.1. Study eligibility criteria and selection\u003c/h4\u003e\n\u003cp\u003eThis study was prepared based on the preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines for reporting systematic reviews[14]. The study should be designed to evaluate the efficacy of PD-1/PD-L1 checkpoint blockade in recurrence GBM. Eligible patients enrolled should have normal hematologic, renal, hepatic function and have no restriction on age. Patients enrolled less than 10 were excluded because of relatively high bias.\u003c/p\u003e\n\u003ch4\u003e2.2. Data sources and search strategy\u003c/h4\u003e\n\u003cp\u003eThe electronic database of PubMed, Web of Science，Embase and Cochrane Library were systematically searched from their inception to August 22, 2021. The search term comprised synonyms for \u0026ldquo;glioblastoma\u0026rdquo;, \u0026ldquo;Immunotherapy\u0026rdquo; and \u0026ldquo;PD-1/PD-L1 checkpoint blockade\u0026rdquo;. Reference lists of accepted studies and bibliographies of reviews were manually searched in order not to miss other relevant studies. Two investigators independently performed the literature search, screened titles and abstracts, and selected relevant full articles and assessed their eligibility. Different opinions between two investigators were resolved by consensus or by consultation of a third investigator\u0026nbsp;\u003c/p\u003e\n\u003ch4\u003e2.3. Literature quality evaluation\u003c/h4\u003e\n\u003cp\u003eIt was inappropriate to evaluate literature quality using the Newcastle-Ottawa scale (NOS)[15]\u0026nbsp;because most of the studies included were single arm trial. Referring to the NOS, we set some criteria to evaluate literature quality accommodating this study purpose and including:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003estudy population clearly defined;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ecohort representative for the population of recurrence GBM patients;\u003c/li\u003e\n \u003cli\u003etherapeutic drug specifically defined;\u003c/li\u003e\n \u003cli\u003etherapeutic dose specifically defined;\u003c/li\u003e\n \u003cli\u003eclear and specific treatment process;\u003c/li\u003e\n \u003cli\u003efollow-up long enough for outcomes to occur;\u003c/li\u003e\n \u003cli\u003eadequacy of follow-up;\u003c/li\u003e\n \u003cli\u003eassessment of outcome well performed;\u003c/li\u003e\n \u003cli\u003etoxicities and comparison well recorded.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch4\u003e2.4. Data extraction\u003c/h4\u003e\n\u003cp\u003eClinical endpoints including PFS-6 (PFS rate at 6 months), \u0026nbsp;OS-12 (OS rate at 12 months) were the primary survival data to extract. The incidence of severe acute/late toxicity, which were defined by Common Terminology Criteria for Adverse Events, were also extracted for additional analysis. When survival data only provided in survival curve (Kaplan\u0026ndash;Meier curve), figures were digitised to extract numeric data using Engauge Digitizer.\u003c/p\u003e\n\u003ch4\u003e\u0026nbsp; 2.5. Statistical analysis\u003c/h4\u003e\n\u003cp\u003eAnalyses were performed using R version 4.0 (https://cran.r-project.org/) with the \u0026ldquo;meta\u0026rdquo; package and Microsoft Excel 2019. The overall survival proportion was calculated with corresponding 95% confidence intervals (95%CI). Heterogeneity was assessed by calculating Cochran Q test and inconsistency index test (I2 test). Random effects model was used in case of the existence of heterogeneity, defined as a P-value of Cochran Q test \u0026lt; 0.1 and I2 \u0026gt; 50% [15], whereas fixed effects model was used in the opposite case. A two-tailed P-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1. Search results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 472 studies were identified after electronic and manual searches and after the removal of 15 duplicate articles, 472 articles remained. Then exclusion based on title and abstract, 73 full-text articles of potential interest were reviewed. After further evaluation, 7 prospective trials (contains 10 cohorts) were included in table. No additional articles were identified in reference lists of accepted studies and bibliographies of reviews. Fig. 1 shows a flowchart for procession of studies selection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Study characteristics and quality evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReferring to the NOS, we performed a particular literature evaluation scale to evaluate each study (Supplement Table S1). In general, the included studies could completely record important information of trial. However, the existence of prospective single arm trials made overall research somewhat heterogeneous and limited the quality of reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. OS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall survival was one of the primary clinical endpoints of interest in this study. A total of 343 patients in 7 trials (10 cohorts) provided survival data for recurrent glioblastomas treated with PD-1/PD-L1 checkpoint blockade immunotherapy. In these studies, the 1-year overall survival rates ranged from 19% to 69.0%. while the overall OS-12 rate was 40.0%(95% CI: 89.2% -95.1%) \u0026nbsp;using fixed-effects model due to the heterogeneity \u0026nbsp;(I 2=49.10%, p=0.004) \u0026nbsp;(Figure 2). Among, eight cohorts with adjuvant PD-1/PD-L1 checkpoint blockade for recurrent glioblastoma had 1-year survival rates of 19% to 58%, with heterogeneity between studies (I2=29%, P=0.2), and the overall OS-12 rate was 38% (95% CI: 0.32 to 0.44) using a fixed-effects model, see Figure 3. The only two remaining cohorts were neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma, with 1-year overall survival rates of 60%-69% for neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy, with no heterogeneity between studies (I2=0%, P=0.63) and the overall OS-12 rate was 65% (95% CI: 0.46 to 0.81) using a fixed effects model (Figure 4)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4. PFS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnother important clinical endpoint, progression-free survival, was analyzed subsequently. For the PFS-6 rate, a total of 343 patients reached this clinical endpoint. Meta-analysis indicated the overall PFS-6 rate was 16.0% (95%CI 9%\u0026ndash;23%) using random effects model determined by a heterogeneity (I2=51%, P=0.03) (Fig. 5). Similarly, 8 cohorts of adjuvant PD-1/PD-L1 checkpoint blockade immunotherapy for recurrent glioblastoma had PFS-6 rates ranging from 0% to 35%, with heterogeneity between studies (I2=35%, P=0.15), and overall PFS-6 rate was 13% (95% CI: 9%-17%) using a fixed-effects model, as shown in Figure6. Two cohorts of neoadjuvant PD-1/PD-L1 checkpoint blockade immunotherapy had a 6-month progression-free survival range of 31%-40%, with no heterogeneity between studies (I2=0%, P=0.63) (Figure7).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;\u003cstrong\u003e3.5. Efficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdjuvant anti-PD-1/PDL-1 immunotherapy for recurrent glioblastoma (1-year overall survival rates was 38%) better than bevacizumab for recurrent glioblastoma published by Henry S. Friedman et al[16]\u0026nbsp;, which had an 1-year overall survival rates was 24% (p=0.02). Adjuvant anti-PD-1/PD-L1 immunotherapy compared to physician\u0026apos;s choice chemotherapy for relapsed glioblastoma[17]\u0026nbsp;increased 1-year overall survival rates in patients by 18% (38% vs 20%, p\u0026lt;0.001). However, anti-PD-1/PDL-1 immunotherapy did not improve progression-free survival in patients with recurrent glioblastoma compared in comparison to bevacizumab or physician\u0026apos;s choice chemotherapy(table2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6. Safety and toxicity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of serious adverse events（grade 3 or greater AEs） in recurrent glioblastoma treated with adjuvant anti-PD-1/PDL-1 immunotherapy is approximately 25% [0.13; 0.40](Figure8)，compared to Henry S. Friedman et al.[16] 2009, which published an incidence of grade 3-4 adverse events of 46.4% for bevacizumab in recurrent glioblastoma, that is a significant lower (p-value = 0.0002). Unfortunately, in the study of physician\u0026apos;s choice chemotherapy for recurrent glioblastoma published by Roger Stupp et al[17]. in 2012, the incidence of grade 3-4 adverse events was not given.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eDue to high invasiveness, the prognosis of glioblastoma is extremely poor even after receiving comprehensive treatments. Therefore, finding effective treatments to improve the prognosis of Glioma patients is an emerging issue. Researchers have constantly explored and tried new approaches for glioblastoma, but until now, only the new technique of Tumor-Treating Fields (TTF) has been shown to improve the prognosis of patients with high-grade glioma. However, TTF is currently not widely available in clinical practice in China due to its high expense. In recent years, with increasing research related to immune checkpoints, immunotherapy with PD-1/PD-L1 inhibitors has demonstrated durable and stable anti-tumors effects in a variety of tumors treatments. There are more and more clinical trials related to anti-PD-1/PDL-1 immunotherapy for GBM, but most of them are single-arm clinical studies, which cannot evaluate the efficacy Comparison against other anti-tumors treatments. Therefore, a single arm meta-analysis was done to assess how effective anti-PD-1/PDL-1 is in treating glioblastoma.\u003c/p\u003e \u003cp\u003eIn this single arm meta-analysis show that immunotherapy is more effective and safer than chemotherapy or bevacizumab in the treatment of recurrent glioblastoma. Neoadjuvant anti-PD-1 immunization versus adjuvant anti-PD-1 immunization for recurrent glioblastoma shows superior efficacy, but also a higher incidence of grade 3-4 adverse events and higher toxicity. This also suggests that the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be.\u003c/p\u003e \u003cp\u003eHowever, this single-arm meta-analysis has a few limitations: firstly, the studies included in this meta are single-arm studies and the findings need to be further validated by randomized controlled clinical studies. Secondly, the inclusion of patients with recurrent glioblastoma in this meta is also somewhat biased, with some populations having a first recurrence and others having a second recurrence, and the prognosis in these two groups is inherently very different. Thirdly, the type and dose of anti-PD-1/PDL-1 drugs included in this meta also differed, which may also affect the prognostic assessment of patients with recurrent glioblastoma.\u003c/p\u003e \u003cp\u003eIn general, this single-arm meta-analysis also provides some evidence of the benefits of PD-1/PD-L1 immunotherapy for recurrent glioblastoma. However, a higher level of evidence, such as randomized controlled clinical study, is still needed to confirm.\u003c/p\u003e \u003cp\u003eIn addition, this meta-analysis appears that neoadjuvant immunotherapy for the recurrent glioblastoma has a superior 1-year OS rate for patients versus adjuvant immunotherapy. Suggesting that the earlier immunotherapy is applied to relapsed glioblastoma, the better the prognosis for the patients. Similar circumstances, does immunotherapy improves prognosis in newly diagnosed glioblastoma, especially in patients with unmethylated MGMT promoters? According to a clinical study published by Stupp Prof. et al[18], Median overall survival for patients with primary glioblastoma with unmethylated promoters was 11.8 months for radiotherapy alone and 12.6 months for radiotherapy combined with TMZ. Although the difference is statistically significant, it has little clinical benefit. This confirms that GBM with unmethylated MGMT promoter is inherently resistant to TMZ. How effective is the application of immunotherapy to newly diagnosed GBM with unmethylated MGMT promoters? 2019 ASCO Annual Meeting reported a study that MEDI4736 (durvalumab) + radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastomas[19], Median OS was 15.1 (95% CI: 12.0, 18.4) months, clearly improved prognosis. Durvalumab + radiotherapy improved median OS by 3 months compared to radiotherapy alone for new unmeth GBM. Similarly, the efficacy is better than radiotherapy combined with TMZ for new unmeth GBM. Thus does RT+TMZ plus immunotherapy further improve the prognosis for patients with newly diagnosed glioblastoma? A clinical study was published on 2020 ASCO Annual Meeting that atezolizumab in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM)[20], median OS was 17.1 months (95% CI: 13.9, not reached). median PFS was 9.7 months (95% CI: 7.6-15). Median survival was 14.6 months with radiotherapy plus temozolomide[4]. Therefore, RT+TMZ plus immunotherapy may further improve the prognosis of patients with newly diagnosed glioblastoma.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eAs far as we know, this study is the first systematic analysis to evaluate the efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence glioblastoma. In our meta-analysis uncovered that that immunotherapy offers new promising prognosis for newly diagnosed and relapsed glioblastoma patients,\u0026nbsp;and the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be. The risk of toxicity was tolerance. Further research including phase II/III random control trials to evaluate the efficacy of \u0026nbsp;PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence/newly diagnosed glioblastoma, and explore optimal schedule for recurrence/newly diagnosed glioblastoma .\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data, models, or code were generated or used during the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch involving Human Participants and/or Animals\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis chapter does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant NO. 81972970 and NO. 82172671) and the Natural Science Foundation of Guangdong Province of China (Grant NO.2020A1515010186).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOstrom, Q.T., et al., \u003cem\u003eCBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013-2017.\u003c/em\u003e Neuro Oncol, 2020. \u003cstrong\u003e22\u003c/strong\u003e(12 Suppl 2): p. iv1-iv96.\u003c/li\u003e\n\u003cli\u003eOstrom, Q.T., et al., \u003cem\u003eThe epidemiology of glioma in adults: a \"state of the science\" review.\u003c/em\u003e Neuro Oncol, 2014. \u003cstrong\u003e16\u003c/strong\u003e(7): p. 896-913.\u003c/li\u003e\n\u003cli\u003eCarlsson, S.K., S.P. 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539-549.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Table1：The basic characteristics of clinical trials included in this meta-analysis.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"98%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.291666666666667%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.208333333333333%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatin-ents\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.291666666666667%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age(range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.208333333333333%\"\u003e\n \u003cp\u003e\u003cstrong\u003eKPS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"10.416666666666666%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.583333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDrug and\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRe-RT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003emOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003emPFS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS-12\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emonths\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePFS-6\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emonths\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eORR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003eToxicity\u003c/strong\u003e\u003cstrong\u003e\u0026ge;G3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntonio Omuro\u003c/strong\u003e[21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e58.5 (42\u0026ndash;73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.736842105263158%\"\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003cp\u003e3 mg/kg Q2W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e40%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e12%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e11% (1/9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntonio Omuro\u003c/strong\u003e[21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e57\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(37\u0026ndash;68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.736842105263158%\"\u003e\n \u003cp\u003eNivolumab 1 mg/kg + ipilimumab 3 mg/kg\u003c/p\u003e\n \u003cp\u003eQ3W for 4 doses, followed by\u003c/p\u003e\n \u003cp\u003enivolumab 3 mg/kg Q2W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e30%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003cp\u003e(9/10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntonio Omuro\u003c/strong\u003e[21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e60\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(27\u0026ndash;73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.368421052631579%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.736842105263158%\"\u003e\n \u003cp\u003eNivolumab 3 mg/kg + ipilimumab 1 mg/kg\u003c/p\u003e\n \u003cp\u003eQ3W for 4 doses, followed by\u003c/p\u003e\n \u003cp\u003enivolumab 3 mg/kg Q2W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e33%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e15%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e10% (2/20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.315789473684211%\"\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003cp\u003e(6/20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRimas\u0026nbsp;V.\u0026nbsp;Lukas\u003c/strong\u003e[22]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e52（31-75）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003eatezolizumab\u003c/p\u003e\n \u003cp\u003e1200mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e4.2 months (range 1.2\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- 18.8+ months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e1.2 months (range 0.7\u0026ndash;10.7\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emonths)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e21% (95% CI 0.3\u0026ndash;42.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e6.25%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e6%\u003c/p\u003e\n \u003cp\u003e(1/16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e19%(3/16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTimothy F. Cloughesy\u003c/strong\u003e[23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e59.3\u0026thinsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e86\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003epembrolizumab 200\u0026thinsp;mg Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e29%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e13%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e46.7%；\u003c/p\u003e\n \u003cp\u003e7/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDavid A. Reardon\u003c/strong\u003e[24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e55.5 (22-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003eNivolumab\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 mg/kg Q2W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e9.8\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e1.5 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e41.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e15.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e7.8%\u003c/p\u003e\n \u003cp\u003e(12/153)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e18.1%;\u003c/p\u003e\n \u003cp\u003e33/182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLakshmi Nayak\u003c/strong\u003e[25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e55 (42, 62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003ePembrolizumab (200 mg) Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e10.3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e1.4 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e6.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e13.3%;4/30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDavid A. Reardon\u003c/strong\u003e[26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e55.5 [33-76]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eECOG:0-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003epembrolizumab\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 mg/kg Q2W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e13.1 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2.8 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e58%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e37.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e8%\u003c/p\u003e\n \u003cp\u003e(2/26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e19%;\u003c/p\u003e\n \u003cp\u003e5/26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTimothy F. Cloughesy\u003c/strong\u003e[23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e55.4\u0026thinsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e80\u0026thinsp;\u0026plusmn;8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eNeoadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003epembrolizumab 200\u0026thinsp;mg Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eNOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e69%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e33%*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e66.7%;\u003c/p\u003e\n \u003cp\u003e10/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u003cstrong\u003eJohn\u0026nbsp;de\u0026nbsp;Groot\u003c/strong\u003e[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.319148936170213%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003e\u0026ge;70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.446808510638298%\"\u003e\n \u003cp\u003eNeoadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.893617021276595%\"\u003e\n \u003cp\u003epembrolizumab 200\u0026thinsp;mg Q3W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003eYES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e20.3\u0026nbsp;\u003c/p\u003e\n \u003cp\u003emonths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e4.5\u0026nbsp;months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e63%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e3/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.382978723404255%\"\u003e\n \u003cp\u003e6/15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 :Comparison of various clinical endpoints between immunotherapy and BPC/BEV\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.716486902927581%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"36.517719568567024%\"\u003e\n \u003cp\u003eOS-12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"47.76579352850539%\"\u003e\n \u003cp\u003ePFS-6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003erate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003erate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eBPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e15%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eadiuvant PD-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.716486902927581%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"36.517719568567024%\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"47.76579352850539%\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eBEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e24%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e42.60%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eadiuvant PD-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.716486902927581%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"36.517719568567024%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"47.76579352850539%\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eneoadiuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e65%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e35%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.74074074074074%\"\u003e\n \u003cp\u003eadiuvant PD-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.277777777777779%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.141975308641975%\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.15432098765432%\"\u003e\n \u003cp\u003e312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.685185185185187%\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.716486902927581%\"\u003e\n \u003col\u003e\n \u003cli\u003eValue\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"36.517719568567024%\"\u003e\n \u003cp\u003e0.0069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"47.76579352850539%\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1269120/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1269120/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: The efficacy of PD-1/PD-L1 checkpoint blockade immunotherapy in recurrence glioblastoma remains unclear. The aim of this meta-analysis is to access the survival outcomes of immunotherapy\u0026nbsp;in these patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A comprehensive electronic literature search of PubMed, Web of Science, Embase and Cochrane Library was conducted up to August 22, 2021. The main evaluation data were the overall survival (OS) rate at 12 months and the progression-free survival (PFS) rate at 6\u0026nbsp;months. The secondary evaluation data was the incidence of serious adverse events(grade 3 or greater AEs). The study was performed using R“meta” package.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Seven studies met the inclusion criteria, which totally contained 343 participants. The 12-month OS\u0026nbsp;in recurrent GBM were 40% (95% CI: 89.2% -95.1%), while the 6-month PFS 16.0% (95%CI 9%–23%).\u0026nbsp;\u0026nbsp;The overall incidence of adverse reactions is approximately 25% [0.13; 0.40], the toxicity of immunotherapy was acceptable.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Compared with survival data for BEV (bevacizumab) /BPC(best physician's choice chemotherapy) treatment, immunotherapy seemed to improve overall survival and progression-free survival, Meanwhile, the toxicity of immunotherapy was tolerable. Further randomised controlled clinical studies are needed to confirm these findings. And also suggests that the earlier we apply anti-PD-1/PDL-1 immunotherapy to patients with relapsed glioblastoma, the greater the benefit may be.\u003c/p\u003e","manuscriptTitle":"The Efficacy and Safety of PD-1/PD-L1 Checkpoint Blockade Immunotherapy in Recurrence Glioblastoma: A Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-01-26 23:22:21","doi":"10.21203/rs.3.rs-1269120/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"656a3d31-c296-402a-9c15-e4eb252a5211","owner":[],"postedDate":"January 26th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-01-26T23:22:23+00:00","versionOfRecord":[],"versionCreatedAt":"2022-01-26 23:22:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1269120","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1269120","identity":"rs-1269120","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}