Clinical Option of Pemetrexed-Based Versus Paclitaxel-Based First-Line Chemotherapeutic Regimens in Combination With Bevacizumab for Advanced Non-Squamous Non-Small-Cell Lung Cancer and Optimal Maintenance Therapy: Evidence From a Meta-Analysis of Randomized Control Trials

Clinical Option of Pemetrexed-Based Versus Paclitaxel-Based First-Line Chemotherapeutic Regimens in Combination With Bevacizumab for Advanced Non-Squamous Non-Small-Cell Lung Cancer and Optimal Maintenance Therapy: Evidence From a Meta-Analysis of Randomized Control Trials | 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 Clinical Option of Pemetrexed-Based Versus Paclitaxel-Based First-Line Chemotherapeutic Regimens in Combination With Bevacizumab for Advanced Non-Squamous Non-Small-Cell Lung Cancer and Optimal Maintenance Therapy: Evidence From a Meta-Analysis of Randomized Control Trials Le-Tian Huang, Rui Cao, Yan-Ru Wang, Li Sun, Xiang-Yan Zhang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-43694/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Apr, 2021 Read the published version in BMC Cancer → Version 1 posted 11 You are reading this latest preprint version Abstract Background: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. Methods: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP±B) and paclitaxel-carboplatin with bevacizumab (PC+B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem+B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. Results: Data of 3,139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP±B and PC+B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP±B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC+B (all P<0.05). PP±B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC+B (all P<0.001). The other three RCTs were included in an analysis that compared Pem+B and B as a maintenance treatment. Compared with B, Pem+B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P<0.001). Conclusion: Although the first-line PP+B regimen had longer PFS and PFSR1y than the PC+B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity. Cancer Biology Oncology bevacizumab first-line treatment maintenance treatment meta-analysis non-small-cell lung cancer paclitaxel pemetrexed Figures Figure 1 Figure 2 Figure 3 Background Lung cancer remains the cancer with the highest incidence and fatality rates worldwide [ 1 ]. With the development and clinical application of molecular targeted drugs and immune checkpoint inhibitors, the survival of patients with advanced non-small cell lung cancer (NSCLC) has significantly improved [ 2 , 3 ]. Nevertheless, for patients with oncogenic driver negative non-squamous NSCLC (NS-NSCLC), especially patients with low or negative expression of programmed death-ligand 1 (PD-L1), platinum-based chemotherapy is still the cornerstone first-line treatment [ 4 ]. For patients with oncogenic driver (e.g., EGFR, ALK, and ROS1) positive NS-NSCLC whose disease progressed on prior targeted therapy, or patients with oncogenic driver negative NS-NSCLC who cannot tolerate immunotherapy, platinum-based chemotherapy with or without bevacizumab (a monoclonal antibody against vascular endothelial growth factor [VEGF]) remains the recommended first-line or subsequent therapy. Compared with chemotherapy alone, bevacizumab combined with chemotherapy can further prolong progression-free survival (PFS) and overall survival (OS) for patients with NS-NSCLC [ 5 – 8 ]. However, clinicians are still debating the better choice of first-line chemotherapy regimens (pemetrexed + platinum [PP] versus paclitaxel + carboplatin [PC]) in combination with bevacizumab. In addition, in classic studies of AVAPERL and PARAMOUNT, advanced NS-NSCLC patients with disease control after 4 to 6 cycles of first-line induction chemotherapy can benefit from continuation maintenance treatment with bevacizumab (B), pemetrexed (Pem) or bevacizumab in combination with pemetrexed (Pem + B). However, PFS benefits with doublet maintenance did not translate into an OS advantage [ 9 , 10 ]. Since two recent trials (COMPASS and EA5508) presented results on single-agent or doublet maintenance therapy at the 2019 American Society of Clinical Oncology meeting [ 11 , 12 ], we conducted a meta-analysis of randomized control trials (RCTs) to assess the optimal first-line and maintenance regimens for NS-NSCLC patients who are assumed to be intolerant to immunotherapy, by comparing the efficacy and toxicity of first-line treatment regimens between PP ± B and PC + B, and maintenance treatment regimens between Pem + B, Pem, and B. Methods Search strategy We identified eligible trials by an electronic search of the Cochrane library, PubMed, Embase, and Web of Science databases using the following terms: non-small cell lung cancer AND (pemetrexed OR bevacizumab OR paclitaxel). The search was performed on March 30, 2020. Two independent reviewers screened titles/abstracts and full text articles. The reference lists including related trials and review articles were manually retrieved. Selection criteria Eligible studies were RCTs of patients of untreated advanced NS-NSCLC who were randomized to receive treatment with cisplatin (or carboplatin) plus pemetrexed with or without bevacizumab (PP±B) or carboplatin plus paclitaxel with bevacizumab (PC+B), and to receive maintenance therapy (combined pemetrexed and bevacizumab or monotherapy with bevacizumab or pemetrexed). The main outcomes included at least one of the following: OS, PFS, objective response rate (ORR), or grade ≥3 treatment-related adverse events (TRAEs). Data collection and quality assessment Characteristics of trials extracted were: first author’s name, year of publication, patient characteristics, study name, study design and phase, sample size, treatment regimens of the study and control groups, maintenance regimens, and treatment cycles. Endpoints extracted were median PFS (mPFS), median OS (mOS), ORR, and grade ≥3 TRAEs. Engauge Digitizer 10.8 software (produced by Mark Mitchell 2014; https://github.com/markummitchell/engauge-digitizer) was used to extract hazard ratio (HR) and 95% confidence intervals (CI), as well as other details (such as numbers at risk) from survival curves if no detailed HR values or numbers at risk were given. Trial quality was assessed with the methods recommended by the Cochrane Collaboration for assessing risk of bias [13]. The criteria used for quality assessment were randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each item was categorized as having high, low, or unclear risk. Sensitivity analysis was performed for the primary outcome with the leave-one-out approach. Statistical analysis The meta-analysis was performed using STATA 12.0 (StataCorp, College Station). Analyses were stratified by trial. We compared the efficacy of each treatment regimen during the induction and maintenance phases. The evaluation included OS, PFS, ORR, and TRAEs. OS was evaluated from the beginning of randomized therapy until death due to any cause. PFS was defined as the beginning of randomized therapy until first event (progression or death from any cause). PFS and OS were expressed as HRs. The ORR, PFSR1y, and the rate of grade ≥3 TRAEs were expressed as risk ratios (RRs). All p-values were two-sided and were considered statistically significant at the 0.05 level. Heterogeneity was assessed with χ2 test (α=0.1) and I² statistics. When statistics heterogeneity did not exist among studies (P>0.10, I²<50%), we used a fixed-effect model; if heterogeneity did exist (P50%), we found the cause and changed to a random-effect model. Results Characteristics of included trials Based on the inclusion and exclusion criteria, six RCTs [9,11,12,14-16], including 3,144 NS-NSCLC patients were included in this meta-analysis. The baseline characteristics of the included studies are in Tables 1 and 2. Among them, three trials [14-16] were included in analysis comparing first-line treatment regimens between PP±B and PC+B. Three other trials [9,11,12] were included for analysis to compare maintenance regimens between Pem+B and B. The flow diagram of the literature retrieval and selection is in Figure 1. Comparisons of first-line therapy between PP ± B and PC+B Three RCTs including 1,418 patients were used to compare the efficacy and safety of PP±B and PC+B [14-16], in which PP+B and PP subgroups were compared with PC+B. Indirect comparisons between subgroups of PP+B and PP were also analyzed. Efficacy The results of efficacy comparison are in Figure 2. Compared with PC+B, PP±B showed a significant benefit in mPFS (HR 0.88; 95% CI, 0.78 to 0.99; P=0.04) and PFSR1y (RR 0.83; 95% CI, 0.74 to 0.93; P=0.001), no significant differences were seen in mOS (HR 1.01; 95% CI, 0.89 to 1.14; P=0.863), and ORR (RR 1.02; 95% CI, 0.92 to 1.15; P=0.675) between the two groups. We also calculated pooled mPFS and mOS using a weighted average of single study medians because of insufficient data on 95% CI values [17]. For subgroups of PP±B vs . PC+B, mPFS was 5.77 vs. 5.80 months and mOS was 12.16 vs. 13.04 months. In the subgroup analysis, compared with PC+B group, a PP+B group showed improved mPFS (HR 0.83; 95% CI, 0.71 to 0.97) and PFSR1y (RR 0.77; 95% CI, 0.68 to 0.89) (all P<0.05), but no significant difference in ORR and mOS was observed between the two groups. A PP subgroup showed no advantage compared with a PC+B group for any parameter. Indirect comparisons found no significant differences between PP+B and PP in mPFS (P=0.36), PFSR1y (P=0.11), mOS (P=0.83), or ORR (P=0.41). Safety The most common grade ≥3 TRAEs were hematologic toxicities, hypertension, and sensory neuropathy. Compared with PC+B, PP±B had a significantly higher risk of anemia (RR 1.75; 95% CI, 1.58 to 1.95; P<0.001) and thrombocytopenia (RR 1.70; 95% CI, 1.47 to 1.96; P<0.001), but a significantly lower risk of neutropenia (RR 0.67; 95% CI, 0.59 to 0.77; P=0.000), febrile neutropenia (RR 0.47; 95% CI, 0.25 to 0.90; P=0.023), and sensory neuropathy (RR 0.21; 95% CI, 0.06 to 0.76; P=0.017). No significant differences were seen in hypertension (P=0.117) or drug-related death (P=0.491) between the two groups (Table 3). Comparisons of maintenance treatment between Pem+B, Pem and B Three RCTs including 1,726 patients were used to compare the efficacy and safety of Pem+B and B maintenance [9,11,12]. Two RCTs used a continuation maintenance regimen in the study design [9,11], and one study used continuation and switch maintenance regimens [12]. Indirect comparisons between Pem+B versus Pem maintenance and between Pem versus B maintenance were also analyzed. Efficacy The results of efficacy comparison are in Figure 3. Compared with B alone maintenance, Pem+B maintenance showed significant benefit in mPFS (HR 0.64; 95% CI, 0.57 to 0.72; P<0.001), PFSR1y (RR 0.70; 95% CI, 0.63 to 0.77; P<0.001), and mOS (HR 0.88; 95% CI, 0.78 to 1.00; P=0.05). The mPFS and mOS (calculated using a weighted average of the single study medians) in subgroups Pem+B vs. B were 6.73 vs. 4.03 months and 19.39 vs. 16.36 months, respectively [17]. In subgroup analysis, compared with B maintenance, neither Pem+B continuation maintenance nor Pem+B switch maintenance showed obvious differences in mOS. Indirect comparisons showed that mPFS (P=0.024) and PFSR1y (odds ratio [OR] 0.57; 95% CI, 0.34 to 0.95; P=0.03) were significantly improved in a Pem+B maintenance group compared with a Pem maintenance group, but with no significant difference in mOS between the two groups (P=0.855). Pem maintenance showed no benefit compared with B maintenance through indirect comparison of PFSR1y (OR 1.22; 95% CI, 0.76 to 1.95; P=0.41). Safety The most common grade ≥3 TRAEs were hematologic toxicities and hypertension. The risk of anemia (RR 1.75; 95% CI, 1.46 to 2.09; P<0.001), neutropenia (RR 1.95; 95% CI, 1.80 to 2.12; P<0.001), or thrombocytopenia (RR 1.88; 95% CI, 1.55 to 2.28; P<0.001) were significantly higher in a Pem+B maintenance group than in a B alone maintenance group. No significant difference was observed in hypertension (P=0.864) between the two groups (Table 4). Quality of included studies and publication bias The risk of bias assessment of the included RCTs was low and is shown in Table 5; all studies were of high quality. To minimize publication bias, we executed strict inclusion criteria for selected papers and detected publication bias by several methods. No substantial asymmetry was found by visual inspection of the funnel plots. An Egger linear regression test and Begg rank correlation test also found no evidence of publication bias. Sensitivity analyses were conducted on PFS and OS to assess the heterogeneity in the first-line and maintenance phases. No significant heterogeneity in PFS or OS from any study was found. Discussion Chemotherapy combined with immunotherapy has become the current standard care for patients with negative oncogenic drivers regardless of squamous or non-squamous NSCLC or PD-L1 expression level [ 18 ]. However, some studies show that chemotherapy combined with the immunotherapy used in KEYNOTE-189 or IMpower150 trial is not cost effective [ 19 , 20 ]. Several meta-analyses demonstrated that immunotherapy combined with chemotherapy led to more toxicities as grade ≥ 3 TRAEs and more discontinuation of treatment than chemotherapy alone [ 18 , 21 ]. In fact, chemotherapy plus bevacizumab is still an important first-line treatment option for patients with oncogenic driver negative NS-NSCLC who cannot tolerate immunotherapy, and is also a subsequent treatment for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. Our study enhances understanding of the rational option of first-line chemotherapy regimens in combination with bevacizumab and the subsequent optimal maintenance therapy for these advanced NS-NSCLC cases. This study thus answers several controversial questions. One question is which first-line chemotherapy regimen (pemetrexed- versus paclitaxel-based) is a better choice when used in combination with bevacizumab. Bevacizumab combined with platinum-based doublet chemotherapy shows clinical benefits for advanced NS-NSCLC in multiple RCTs, with mPFS of 6.2–9.2 months and mOS of 12.3–24.3 months [ 5 – 8 ]. A meta-analysis showed comparable efficacy for taxane and non-taxane regimens in combination with bevacizumab for treatment of patients with NS-NSCLC. For taxane and non-taxane groups, respective weighted mOS was 14.4 and 13.7 months (P = 0.5), mPFS was 6.93 and 6.99 months (P = 0.61), and ORR was 41% and 39% (P = 0.65) [ 22 ]. Our meta-analysis found that PP ± B had a significant benefit for PFS and PFSR1y, but no difference in OS and ORR between PP ± B and PC + B. For subgroup comparisons with PC + B, PP + B had significant benefits for PFS and PFSR1y, but not OS. The negative OS outcome may be attributed to the subsequent maintenance treatment options. Among three studies included for comparison of first-line treatments, PRONOUNCE and ERACLE studies used Pem alone as maintenance therapy; only the PointBreak study used Pem + B maintenance [ 14 – 16 ]. In our meta-analysis, the two groups had different grade 3/4 toxicity profiles. In the PP ± B group, the risk of severe anemia was 1.75 times and the risk of thrombocytopenia was 1.7 times that in the PC + B group. In the PC + B group, the risk of severe sensory neuropathy was 4.76 times and the risk of febrile neutropenia was 2.13 times that in the PP ± B group (Table 3 ). Since we saw no significant difference in OS between the two groups, the tolerance of patients to different drug toxicities should be considered when choosing first-line chemotherapies. That is, the choice of first-line chemotherapy mainly depends on differences in toxicity profiles. The second question is which maintenance therapy (B versus Pem + B) is preferred. Maintenance therapy has emerged as a confirmed treatment strategy for advanced NSCLC. For NS-NSCLC patients, Pem + B in combination or as a single drug as a maintenance therapy is shown to be beneficial for survival [ 9 , 10 , 14 , 23 ]. Even though Pem + B showed significant benefits in PFS compared to monotherapy B maintenance, four previous studies did not recommend Pem + B as a standard maintenance regimen because of the lack of OS benefits and higher toxicity [ 9 , 11 , 12 , 14 ]. Combining two recent RCTs [ 11 , 12 ], our meta-analysis showed not only an improvement in PFS with Pem + B maintenance, but also a benefit in OS (P = 0.05). The PointBreak study showed a longer OS for Pem + B maintenance than B alone, but that trial could not be included in our meta-analysis, because the timepoint after random assignment was different from those in the other trials [ 14 ]. Although the addition of pemetrexed to bevacizumab as a maintenance therapy (Pem + B) can moderately improve survival, we still need to be cautious, as doublet maintenance leads to more toxicities, especially hematological toxicity. In our meta-analysis, the risk of grade 3/4 TRAEs including anemia, thrombocytopenia, and neutropenia were all significantly higher in the Pem + B groups. This may lead to a prolonged treatment interval, poor compliance with maintenance treatment, or even drug-related termination or death. Therefore, we recommend that only patients with NS-NSCLC with controlled disease after 4 to 6 cycles of PP + B induction therapy who have not experienced intolerable toxicity receive Pem + B continuation maintenance therapy whenever possible. The third question is whether bevacizumab should be added to a PP regimen. Pemetrexed combined with platinum is the preferred frontline chemotherapy for patients with NS-NSCLC in National Comprehensive Cancer Network (NCCN) guidelines [ 24 ]. Efficacy of PP + B has been observed in some trials [ 9 , 11 , 14 , 23 ], but no direct prospective comparison has been made between PP + B and PP. However, designing prospective trials comparing PP + B and PP seems increasingly infeasible. In both the PRONOUNCE and ERACLE study designs, bevacizumab was added to the PC regimen, but not to the PP regimen. Nevertheless, no significant difference in PFS or OS was observed between PP and PC + B [ 15 , 16 ]. Our meta-analysis indicated that PP + B significantly prolonged PFS, as compared to PC + B, but no significant differences were seen in any survival data between PP + B and PP by indirect comparisons. However, the strength of the evidence to clarify this issue remains limited. Currently, pembrolizumab in combination with chemotherapy is the preferred first-line regimen according to NCCN guidelines for patients with oncogenic driver negative NS-NSCLC and without contraindications to PD-1/PD-L1 inhibitors, regardless of PD-L1 expression level. Atezolizumab in combination with chemotherapy and bevacizumab is the other recommended regimen [ 25 ]. Interestingly, the chemotherapies in these two regimens differ (carboplatin/cisplatin + pemetrexed, and carboplatin + paclitaxel, respectively). In the future, we should focus on whether bevacizumab is a good partner to combine with chemotherapy and anti-PD-1 immunotherapy (e.g., pembrolizumab) for both first-line and maintenance treatment. In our meta-analysis, we strictly limited the inclusion criteria to RCTs. However, summary statistics rather than individual patient data were used for each trial, and the studies included were heterogeneous, with varying patient populations and different study designs. For example, EGFR-sensitizing mutation populations were excluded in the COMPASS trial, but not mentioned in the other five trials. This difference may lead to different subsequent line regimens and survival. Conclusions This study demonstrated that PP + B as first-line therapy is as effective as PC + B in patients with advanced NS-NSCLC, and the toxicity profile of the two therapies varies. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved survival, but led to more toxicity. Patients’ tolerance and toxicity profiles should be considered when choosing treatment regimens. On the basis of the answers to these three questions, we have made preliminary recommendations for first-line and maintenance treatment strategies for patients with advanced NS-NSCLC with negative drivers who cannot tolerate immunotherapy, and for patients with positive oncogenic drivers whose disease progressed on prior targeted therapy. Treatment with PP + B or PC + B followed by Pem + B rather than single-drug B or Pem maintenance might be the best choice under the premise of tolerable toxicity. List of Abbreviations NSCLC: non-small cell lung cancer; NS-NSCLC: non-squamous NSCLC; PD-L1: programmed death-ligand 1; RCTs: randomized controlled clinical trials; VEGF: vascular endothelial growth factor; PP±B: pemetrexed-platinum with or without bevacizumab; PC+B: paclitaxel-carboplatin with bevacizumab; Pem+B: pemetrexed and bevacizumab; TRAEs: treatment-related adverse events; CI: confidence intervals; ORR: objective response rate; OS: overall survival; PFS: progress free survival; PFSR1y: 1-year PFS rate; HR: hazard ratio; RR: risk ratio; NCCN: National Comprehensive Cancer Network. Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors declare no conflict of interest. Funding This study was supported by grants from the 345 Talent Project of Shengjing Hospital. Authors’ contributions All of the authors have read and approved the final manuscript. LH, JM and CH conceived and designed the study. LH, RC, YW, LS, and XZ took full responsibility for data collecting. LH, JZ, SZ, WJ and JS performed the meta-analysis, systematic review, and drafted the manuscript. CH and JM helped revise the manuscript. Acknowledgments The authors thank all the medical staff who contributed to the maintenance of the medical record database. References Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68:394-424. https://doi.org/10.3322/caac.21492 Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 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New England Journal of Medicine. 2018;378: 2288-2301. https://doi.org/ 10.1056/NEJMoa1716948 Behera M, Pillai RN, Owonikoko TK, Kim S , Steuer C , Chen Z , et al. Bevacizumab in combination with taxane versus non-taxane containing regimens for advanced/metastatic Nonsquamous Non–Small-Cell Lung Cancer: A systematic review. Journal of Thoracic Oncology. 2015;10:1142-1147. https://doi.org/ 10.1097/JTO.0000000000000572 Karayama M, Inui N, Fujisawa T, Enomoto N , Nakamura Y , Kuroishi S , et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. Eur J Cancer. 2016;58:30–37. https://doi.org/ 10.1016/j.ejca.2016.01.013 Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, et al. Systemic therapy for stage IV non-small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2015;33:3488-3515. https://doi.org/ 10.1200/JCO.2015.62.1342 Tables Table 1 Characteristics of the included studies Author/published year Induction arms (randomized) Induction sample size Induction regimen Induction Cycles Dose of Bevacizumab Maintenance arms (randomized) Maintenance sample size Primary endpoint Secondary endpoint Patel, 2013 (PointBreak) Pem + Cb + Bev (randomized) 442 Pem 500 mg/m2, Cb AUC 6, Bev 15 mg/kg, day 1 every 3 weeks 4 15 mg/kg Pem + Bev 292 OS PFS, ORR, DCR, TTPD, toxicity Pac + Cb + Bev (randomized) 443 Pac 200 mg/m2, Cb AUC 6, Bev 15 mg/kg, day 1 every 3 weeks Bev 298 - Zinner, 2015 (PRONOUNCE) Pem + Cb (randomized) 182 Pem 500 mg/m2, Cb AUC 6, day 1 every 3 weeks 4 15 mg/kg Pem 121 PFS without grade 4 toxicity PFS, OS, ORR, DCR, safety Pac + Cb + Bev (randomized) 179 Pac 200 mg/m2, Cb AUC 6, Bev 15 mg/kg, day 1 every 3 weeks Bev 113 Galetta, 2015 (ERACLE) Pem + Cis (randomized) 60 Pem 500 mg/m2, Cis 75 mg/m2, day 1 every 3 weeks 6 15 mg/kg Pem 44 QOL PFS, OS, ORR, safety Pac + Cb + Bev (randomized) 58 Pac 200 mg/m2, Cb AUC 6 Bev 15 mg/kg, day 1 every 3 weeks Bev 30 Barlesi, 2014 (AVAPERL) Pem + Cis + Bev 376 Pem 500 mg/m2, Cis 75 mg/m2, Bev 7.5 mg/kg, day 1 every 3 weeks 4 7.5 mg/kg Pem + Bev (randomized) 128 PFS OS, ORR, DOR Bev (randomized) 125 Ramalingam, 2019 (EA5508) Pac + Cb + Bev 1432 Pac 200 mg/m2, Cb AUC 6, Bev 15 mg/kg, day 1 every 3 weeks 4 15 mg/kg Bev (randomized) 287 OS PFS, ORR, safety Pem (randomized) 294 Pem + Bev (randomized) 293 Seto, 2019 (COMPASS) Pem + Cb + Bev 907 Pem 500 mg/m2, Cb AUC 6, Bev 15 mg/kg, day 1 every 3 weeks 4 15 mg/kg Bev (randomized) 295 OS (from Random Assignment) PFS and OS (from induction therapy), safety Pem + Bev (randomized) 299 Abbreviation: AUC, area under the curve; Bev, bevacizumab; Cb, carboplatin; Cis, cisplatin; DCR, disease control rate; DOR, duration of response; ORR, objective response rate; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progress free survival; QOL, quality of life; TTPD, time to progressive disease. Table 2 Clinicopathological characteristics of the included patients Study Randomized arms Age, Median (y) Stage IV (%) Male (%) ECOG PS 1 (%) Never Smoker (%) Adenocarcinoma (%) PointBreak PP + B 64.6 89.8% 53.2% 56.1% 10.6% 80.1% PC + B 64.9 90.1% 53.3% 55.6% 12.5% 78.3% PRONOUNCE PP 65.8 99.5% 57.7% 52.7% 19.9% 83.5% PC + B 65.4 100.0% 58.1% 53.1% 3.9% 76.5% ERACLE PP 60.0 95.0% 70.0% 22.0% 22.0% 97.0% PC + B 62.0 93.0% 78.0% 21.0% 28.0% 97.0% AVAPERL Pem + B 60.0 94.4% 57.6% 46.0% 24.8% 85.6% B 60.0 89.2% 56.7% 55.6% 26.1% 91.7% EA5508 B 65.0 93.0% 49.0% 57.0% 10.0% 91.0% Pem 63.0 93.0% 49.0% 54.0% 11.0% 88.0% Pem + B 64.0 93.0% 49.0% 55.0% 11.0% 91.0% COMPASS Pem + B 65.0 92.2% 73.9% 38.5% 24.7% 96.7% B 65.0 90.4% 70.8% 42.0% 20.0% 96.3% Abbreviation: PP ± B, pemetrexed-platinum with or without bevacizumab; PC + B, paclitaxel-carboplatin with bevacizumab; Pem + B, pemetrexed and bevacizumab; B, bevacizumab; ECOG PS, Eastern Cooperative Oncology Group Performance Status. Table 3 Summary of forest plot for TRAEs (PP ± B vs. PC + B) TRAEs PP ± B n/N (%) PC + B n/N (%) Heterogeneity I 2 Heterogeneity P value RR (95% CI) P value Drug–related deaths 9/684 (1.3%) 13/680 (1.9%) 0% 0.845 0.84 (0.52,1.37) 0.491 Grade 3/4 TRAEs Anemia 97/684 (14.2%) 23/680 (3.4%) 2.3% 0.359 1.75 (1.58,1.95) 0.000 Hypertension 15/684 (2.2%) 29/680 (4.3%) 0% 0.546 0.73 (0.49,1.08) 0.117 Neutropenia 161/684 (23.5%) 267/680 (39.3%) 1.0% 0.364 0.67 (0.59,0.77) 0.000 Thrombocytopenia 144/684 (21.1%) 42/680 (6.2%) 25.3% 0.262 1.70 (1.47,1.96) 0.000 Sensory neuropathy 1/684 (0.1%) 26/680 (3.8%) 0% 0.384 0.21 (0.06,0.76) 0.017 Febrile neutropenia 6/684 (0.9%) 22/680 (3.2%) 0% 0.875 0.47 (0.25,0.90) 0.023 Abbreviation: PP ± B, pemetrexed-platinum with or without bevacizumab; PC + B, paclitaxel-carboplatin with bevacizumab; RR, risk ratio; TRAEs, treatment-related adverse events. Table 4 Summary of forest plot for grade 3/4 TRAEs (Pem + B vs. B maintenance) Grade 3/4 TRAEs Pem + B n/N (%) B n/N (%) Heterogeneity I 2 Heterogeneity P value RR (95%CI) P value Anemia 35/620 (5.6%) 7/707 (1.0%) 41.8% 0.179 1.75 (1.46, 2.09) 0.000 Hypertension 97/620 (15.6%) 98/707 (13.9%) 60.8% 0.078 1.02 (0.78, 1.34) 0.864 Neutropenia 81/620 (13.1%) 6/707 (0.8%) 0% 0.872 1.95 (1.80, 2.12) 0.000 Thrombocytopenia 14/620 (2.3%) 1/707 (1.0%) 10.4% 0.291 1.88 (1.55, 2.28) 0.000 Abbreviation: Pem + B, pemetrexed and bevacizumab; B, bevacizumab; RR, risk ratio; TRAEs, treatment-related adverse events. Table 5 Evaluation of risk of bias in the included studies. Items PointBreak 2013 AVAPERL 2014 ERACLE 2015 PRONOUNCE 2015 COMPASS 2019 EA5508 2019 Randomization sequence generation low low low low low low Allocation concealment unclear unclear unclear unclear unclear unclear Blinding of participants and personnel high high unclear high unclear high Blinding of outcome assessment high high unclear high unclear unclear Incomplete outcome data high low high low unclear low Selective reporting unclear unclear low low low low Other biases low unclear low low unclear low Supplementary Files PRISMA2009ChecklistMSWord.doc Cite Share Download PDF Status: Published Journal Publication published 17 Apr, 2021 Read the published version in BMC Cancer → Version 1 posted Review # 3 received at journal 18 Oct, 2020 Review # 2 received at journal 17 Oct, 2020 Review # 1 received at journal 09 Oct, 2020 Reviewer # 4 agreed at journal 07 Oct, 2020 Reviewer # 3 agreed at journal 30 Sep, 2020 Reviewer # 2 agreed at journal 29 Sep, 2020 Reviewers invited by journal 07 Aug, 2020 Reviewer # 1 agreed at journal 07 Aug, 2020 Editor assigned by journal 27 Jul, 2020 Submission checks completed at journal 26 Jul, 2020 Editor invited by journal 26 Jul, 2020 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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12:02:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-43694/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-43694/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-021-08136-5","type":"published","date":"2021-04-17T19:02:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1810572,"identity":"ffd4e411-fa5d-435a-8ef9-a795c6170d82","added_by":"auto","created_at":"2020-08-05 23:43:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222360,"visible":true,"origin":"","legend":"Overview of study search and selection.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-43694/v1/Figure1.jpg"},{"id":1810573,"identity":"85863ab2-905d-4d72-9483-09fb5aa70d40","added_by":"auto","created_at":"2020-08-05 23:43:15","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2846109,"visible":true,"origin":"","legend":"Efficacy comparison of first-line therapy between PP±B and PC+B. A. mPFS; B. mOS; C. ORR; D. PFSR1y. Abbreviations: PP±B, pemetrexed-platinum with or without bevacizumab; PC+B, paclitaxel-carboplatin with bevacizumab; mPFS, median progression-free survival; mOS, median overall survival; ORR, objective response rates; PFSR1y, 1-year PFS rate.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-43694/v1/Figure2.jpg"},{"id":1810574,"identity":"eca118e1-9b50-41ab-a54c-bfe0448ee9c5","added_by":"auto","created_at":"2020-08-05 23:43:15","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1195458,"visible":true,"origin":"","legend":"Efficacy comparison of maintenance therapy between Pem+B and B. A. mPFS; B. mOS; C. ORR. Abbreviations: Pem+B, pemetrexed and bevacizumab; B, bevacizumab; mPFS, median progression-free survival; mOS, median overall survival; ORR, objective response rates.","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-43694/v1/Figure3.jpg"},{"id":13569912,"identity":"c8345f85-a888-44cf-881d-7db7a3d226e0","added_by":"auto","created_at":"2021-09-17 03:41:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":818357,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-43694/v1/a92c556e-5a81-4274-ba05-610388f6b957.pdf"},{"id":1810576,"identity":"88c27dda-f182-4476-b260-037cdd5ff46e","added_by":"auto","created_at":"2020-08-05 23:43:16","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":64512,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2009ChecklistMSWord.doc","url":"https://assets-eu.researchsquare.com/files/rs-43694/v1/PRISMA2009ChecklistMSWord.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eClinical Option of Pemetrexed-Based Versus Paclitaxel-Based First-Line Chemotherapeutic Regimens in Combination With Bevacizumab for Advanced Non-Squamous Non-Small-Cell Lung Cancer and Optimal Maintenance Therapy: Evidence From a Meta-Analysis of Randomized Control Trials\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eLung cancer remains the cancer with the highest incidence and fatality rates worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. With the development and clinical application of molecular targeted drugs and immune checkpoint inhibitors, the survival of patients with advanced non-small cell lung cancer (NSCLC) has significantly improved [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nevertheless, for patients with oncogenic driver negative non-squamous NSCLC (NS-NSCLC), especially patients with low or negative expression of programmed death-ligand 1 (PD-L1), platinum-based chemotherapy is still the cornerstone first-line treatment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. For patients with oncogenic driver (e.g., EGFR, ALK, and ROS1) positive NS-NSCLC whose disease progressed on prior targeted therapy, or patients with oncogenic driver negative NS-NSCLC who cannot tolerate immunotherapy, platinum-based chemotherapy with or without bevacizumab (a monoclonal antibody against vascular endothelial growth factor [VEGF]) remains the recommended first-line or subsequent therapy. Compared with chemotherapy alone, bevacizumab combined with chemotherapy can further prolong progression-free survival (PFS) and overall survival (OS) for patients with NS-NSCLC [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, clinicians are still debating the better choice of first-line chemotherapy regimens (pemetrexed\u0026thinsp;+\u0026thinsp;platinum [PP] versus paclitaxel\u0026thinsp;+\u0026thinsp;carboplatin [PC]) in combination with bevacizumab.\u003c/p\u003e \u003cp\u003eIn addition, in classic studies of AVAPERL and PARAMOUNT, advanced NS-NSCLC patients with disease control after 4 to 6 cycles of first-line induction chemotherapy can benefit from continuation maintenance treatment with bevacizumab (B), pemetrexed (Pem) or bevacizumab in combination with pemetrexed (Pem\u0026thinsp;+\u0026thinsp;B). However, PFS benefits with doublet maintenance did not translate into an OS advantage [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Since two recent trials (COMPASS and EA5508) presented results on single-agent or doublet maintenance therapy at the 2019 American Society of Clinical Oncology meeting [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], we conducted a meta-analysis of randomized control trials (RCTs) to assess the optimal first-line and maintenance regimens for NS-NSCLC patients who are assumed to be intolerant to immunotherapy, by comparing the efficacy and toxicity of first-line treatment regimens between PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B and PC\u0026thinsp;+\u0026thinsp;B, and maintenance treatment regimens between Pem\u0026thinsp;+\u0026thinsp;B, Pem, and B.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSearch strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified eligible trials by an electronic search of the Cochrane library, PubMed, Embase, and Web of Science databases using the following terms: non-small cell lung cancer AND (pemetrexed OR bevacizumab OR paclitaxel). The search was performed on March 30, 2020. Two independent reviewers screened titles/abstracts and full text articles. The reference lists including related trials and review articles were manually retrieved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection\u003c/strong\u003e\u003cstrong\u003e criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible studies were RCTs of patients of untreated advanced NS-NSCLC who were randomized to receive treatment with cisplatin (or carboplatin) plus pemetrexed with or without bevacizumab (PP\u0026plusmn;B) or carboplatin plus paclitaxel with bevacizumab (PC+B), and to receive maintenance therapy (combined pemetrexed and bevacizumab or monotherapy with bevacizumab or pemetrexed). The main outcomes included at least one of the following: OS, PFS, objective response rate (ORR), or grade \u0026ge;3 treatment-related adverse events (TRAEs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and quality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCharacteristics of trials extracted were: first author\u0026rsquo;s name, year of publication, patient characteristics, study name, study design and phase, sample size, treatment regimens of the study and control groups, maintenance regimens, and treatment cycles. Endpoints extracted were median PFS (mPFS), median OS (mOS), ORR, and grade \u0026ge;3 TRAEs. Engauge Digitizer 10.8 software (produced by Mark Mitchell 2014; https://github.com/markummitchell/engauge-digitizer) was used to extract hazard ratio (HR) and 95% confidence intervals (CI), as well as other details (such as numbers at risk) from survival curves if no detailed HR values or numbers at risk were given. Trial quality was assessed with the methods recommended by the Cochrane Collaboration for assessing risk of bias [13]. The criteria used for quality assessment were randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each item was categorized as having high, low, or unclear risk. Sensitivity analysis was performed for the primary outcome with the leave-one-out approach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe meta-analysis was performed using STATA 12.0 (StataCorp, College Station). Analyses were stratified by trial. We compared the efficacy of each treatment regimen during the induction and maintenance phases. The evaluation included OS, PFS, ORR, and TRAEs. OS was evaluated from the beginning of randomized therapy until death due to any cause. PFS was defined as the beginning of randomized therapy until first event (progression or death from any cause). PFS and OS were expressed as HRs. The ORR, PFSR1y, and the rate of grade \u0026ge;3 TRAEs were expressed as risk ratios (RRs). All p-values were two-sided and were considered statistically significant at the 0.05 level. Heterogeneity was assessed with \u0026chi;2 test (\u0026alpha;=0.1) and I\u0026sup2; statistics. When statistics heterogeneity did not exist among studies (P\u0026gt;0.10, I\u0026sup2;\u0026lt;50%), we used a fixed-effect model; if heterogeneity did exist (P\u0026lt;0.10, I\u0026sup2; \u0026gt;50%), we found the cause and changed to a random-effect model.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of included trials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the inclusion and exclusion criteria, six RCTs [9,11,12,14-16], including 3,144 NS-NSCLC patients were included in this meta-analysis. The baseline characteristics of the included studies are in Tables 1 and 2. Among them, three trials [14-16] were included in analysis comparing first-line treatment regimens between PP\u0026plusmn;B and PC+B. Three other trials [9,11,12] were included for analysis to compare maintenance regimens between Pem+B and B. The flow diagram of the literature retrieval and selection is in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of first-line therapy between PP\u003c/strong\u003e\u003cstrong\u003e\u0026plusmn;\u003c/strong\u003e\u003cstrong\u003eB and PC+B\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree RCTs including 1,418 patients were used to compare the efficacy and safety of PP\u0026plusmn;B and PC+B [14-16], in which PP+B and PP subgroups were compared with PC+B. Indirect comparisons between subgroups of PP+B and PP were also analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEfficacy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of efficacy comparison are in Figure 2. Compared with PC+B, PP\u0026plusmn;B showed a significant benefit in mPFS (HR 0.88; 95% CI, 0.78 to 0.99; P=0.04) and PFSR1y (RR 0.83; 95% CI, 0.74 to 0.93; P=0.001), no significant differences were seen in mOS (HR 1.01; 95% CI, 0.89 to 1.14; P=0.863), and ORR (RR 1.02; 95% CI, 0.92 to 1.15; P=0.675) between the two groups. We also calculated pooled mPFS and mOS using a weighted average of single study medians because of insufficient data on 95% CI values [17]. For subgroups of PP\u0026plusmn;B \u003cem\u003evs\u003c/em\u003e. PC+B, mPFS was 5.77 \u003cem\u003evs.\u003c/em\u003e 5.80 months and mOS was 12.16 \u003cem\u003evs.\u003c/em\u003e 13.04 months.\u003c/p\u003e\n\u003cp\u003eIn the subgroup analysis, compared with PC+B group, a PP+B group showed improved mPFS (HR 0.83; 95% CI, 0.71 to 0.97) and PFSR1y (RR 0.77; 95% CI, 0.68 to 0.89) (all P\u0026lt;0.05), but no significant difference in ORR and mOS was observed between the two groups.\u0026nbsp;A PP subgroup showed no advantage compared with a PC+B group for any parameter. Indirect comparisons found no significant differences between PP+B and PP in mPFS (P=0.36), PFSR1y (P=0.11), mOS (P=0.83), or ORR (P=0.41).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common grade \u0026ge;3 TRAEs were hematologic toxicities, hypertension, and sensory neuropathy. Compared with PC+B, PP\u0026plusmn;B had a significantly higher risk of anemia (RR 1.75; 95% CI, 1.58 to 1.95; P\u0026lt;0.001) and thrombocytopenia (RR 1.70; 95% CI, 1.47 to 1.96; P\u0026lt;0.001), but a significantly lower risk of neutropenia (RR 0.67; 95% CI, 0.59 to 0.77; P=0.000), febrile neutropenia (RR 0.47; 95% CI, 0.25 to 0.90; P=0.023), and sensory neuropathy (RR 0.21; 95% CI, 0.06 to 0.76; P=0.017). No significant differences were seen in hypertension (P=0.117) or drug-related death (P=0.491) between the two groups (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons of maintenance treatment between Pem+B, Pem and B\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree RCTs including 1,726 patients were used to compare the efficacy and safety of Pem+B and B maintenance [9,11,12]. Two RCTs used a continuation maintenance regimen in the study design [9,11], and one study used continuation and switch maintenance regimens [12]. Indirect comparisons between Pem+B versus Pem maintenance and between Pem versus B maintenance were also analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEfficacy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of efficacy comparison are in Figure 3. Compared with B alone maintenance, Pem+B maintenance showed significant benefit in mPFS (HR 0.64; 95% CI, 0.57 to 0.72; P\u0026lt;0.001), PFSR1y (RR 0.70; 95% CI, 0.63 to 0.77; P\u0026lt;0.001), and mOS (HR 0.88; 95% CI, 0.78 to 1.00; P=0.05). The mPFS and mOS (calculated using a weighted average of the single study medians) in subgroups Pem+B \u003cem\u003evs.\u003c/em\u003e B were 6.73 \u003cem\u003evs.\u003c/em\u003e 4.03 months and 19.39 \u003cem\u003evs.\u003c/em\u003e 16.36 months, respectively [17]. In subgroup analysis, compared with B maintenance, neither Pem+B continuation maintenance nor Pem+B switch maintenance showed obvious differences in mOS.\u003c/p\u003e\n\u003cp\u003eIndirect comparisons showed that mPFS (P=0.024) and PFSR1y (odds ratio [OR] 0.57; 95% CI, 0.34 to 0.95; P=0.03) were significantly improved in a Pem+B maintenance group compared with a Pem maintenance group, but with no significant difference in mOS between the two groups (P=0.855). Pem maintenance showed no benefit compared with B maintenance through indirect comparison of PFSR1y (OR 1.22; 95% CI, 0.76 to 1.95; P=0.41).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most common grade \u0026ge;3 TRAEs were hematologic toxicities and hypertension. The risk of anemia (RR 1.75; 95% CI, 1.46 to 2.09; P\u0026lt;0.001), neutropenia (RR 1.95; 95% CI, 1.80 to 2.12; P\u0026lt;0.001), or thrombocytopenia (RR 1.88; 95% CI, 1.55 to 2.28; P\u0026lt;0.001) were significantly higher in a Pem+B maintenance group than in a B alone maintenance group. No significant difference was observed in hypertension (P=0.864) between the two groups (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality of included studies and publication bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias assessment of the included RCTs was low and is shown in Table 5; all studies were of high quality. To minimize publication bias, we executed strict inclusion criteria for selected papers and detected publication bias by several methods. No substantial asymmetry was found by visual inspection of the funnel plots. An Egger linear regression test and Begg rank correlation test also found no evidence of publication bias. Sensitivity analyses were conducted on PFS and OS to assess the heterogeneity in the first-line and maintenance phases. No significant heterogeneity in PFS or OS from any study was found.\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eChemotherapy combined with immunotherapy has become the current standard care for patients with negative oncogenic drivers regardless of squamous or non-squamous NSCLC or PD-L1 expression level [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, some studies show that chemotherapy combined with the immunotherapy used in KEYNOTE-189 or IMpower150 trial is not cost effective [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Several meta-analyses demonstrated that immunotherapy combined with chemotherapy led to more toxicities as grade\u0026thinsp;\u0026ge;\u0026thinsp;3 TRAEs and more discontinuation of treatment than chemotherapy alone [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In fact, chemotherapy plus bevacizumab is still an important first-line treatment option for patients with oncogenic driver negative NS-NSCLC who cannot tolerate immunotherapy, and is also a subsequent treatment for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. Our study enhances understanding of the rational option of first-line chemotherapy regimens in combination with bevacizumab and the subsequent optimal maintenance therapy for these advanced NS-NSCLC cases. This study thus answers several controversial questions.\u003c/p\u003e \u003cp\u003eOne question is which first-line chemotherapy regimen (pemetrexed- versus paclitaxel-based) is a better choice when used in combination with bevacizumab. Bevacizumab combined with platinum-based doublet chemotherapy shows clinical benefits for advanced NS-NSCLC in multiple RCTs, with mPFS of 6.2\u0026ndash;9.2 months and mOS of 12.3\u0026ndash;24.3 months [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A meta-analysis showed comparable efficacy for taxane and non-taxane regimens in combination with bevacizumab for treatment of patients with NS-NSCLC. For taxane and non-taxane groups, respective weighted mOS was 14.4 and 13.7 months (P\u0026thinsp;=\u0026thinsp;0.5), mPFS was 6.93 and 6.99 months (P\u0026thinsp;=\u0026thinsp;0.61), and ORR was 41% and 39% (P\u0026thinsp;=\u0026thinsp;0.65) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our meta-analysis found that PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B had a significant benefit for PFS and PFSR1y, but no difference in OS and ORR between PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B and PC\u0026thinsp;+\u0026thinsp;B. For subgroup comparisons with PC\u0026thinsp;+\u0026thinsp;B, PP\u0026thinsp;+\u0026thinsp;B had significant benefits for PFS and PFSR1y, but not OS. The negative OS outcome may be attributed to the subsequent maintenance treatment options. Among three studies included for comparison of first-line treatments, PRONOUNCE and ERACLE studies used Pem alone as maintenance therapy; only the PointBreak study used Pem\u0026thinsp;+\u0026thinsp;B maintenance [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In our meta-analysis, the two groups had different grade 3/4 toxicity profiles. In the PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B group, the risk of severe anemia was 1.75 times and the risk of thrombocytopenia was 1.7 times that in the PC\u0026thinsp;+\u0026thinsp;B group. In the PC\u0026thinsp;+\u0026thinsp;B group, the risk of severe sensory neuropathy was 4.76 times and the risk of febrile neutropenia was 2.13 times that in the PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Since we saw no significant difference in OS between the two groups, the tolerance of patients to different drug toxicities should be considered when choosing first-line chemotherapies. That is, the choice of first-line chemotherapy mainly depends on differences in toxicity profiles.\u003c/p\u003e \u003cp\u003eThe second question is which maintenance therapy (B versus Pem\u0026thinsp;+\u0026thinsp;B) is preferred. Maintenance therapy has emerged as a confirmed treatment strategy for advanced NSCLC. For NS-NSCLC patients, Pem\u0026thinsp;+\u0026thinsp;B in combination or as a single drug as a maintenance therapy is shown to be beneficial for survival [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Even though Pem\u0026thinsp;+\u0026thinsp;B showed significant benefits in PFS compared to monotherapy B maintenance, four previous studies did not recommend Pem\u0026thinsp;+\u0026thinsp;B as a standard maintenance regimen because of the lack of OS benefits and higher toxicity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Combining two recent RCTs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], our meta-analysis showed not only an improvement in PFS with Pem\u0026thinsp;+\u0026thinsp;B maintenance, but also a benefit in OS (P\u0026thinsp;=\u0026thinsp;0.05). The PointBreak study showed a longer OS for Pem\u0026thinsp;+\u0026thinsp;B maintenance than B alone, but that trial could not be included in our meta-analysis, because the timepoint after random assignment was different from those in the other trials [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although the addition of pemetrexed to bevacizumab as a maintenance therapy (Pem\u0026thinsp;+\u0026thinsp;B) can moderately improve survival, we still need to be cautious, as doublet maintenance leads to more toxicities, especially hematological toxicity. In our meta-analysis, the risk of grade 3/4 TRAEs including anemia, thrombocytopenia, and neutropenia were all significantly higher in the Pem\u0026thinsp;+\u0026thinsp;B groups. This may lead to a prolonged treatment interval, poor compliance with maintenance treatment, or even drug-related termination or death. Therefore, we recommend that only patients with NS-NSCLC with controlled disease after 4 to 6 cycles of PP\u0026thinsp;+\u0026thinsp;B induction therapy who have not experienced intolerable toxicity receive Pem\u0026thinsp;+\u0026thinsp;B continuation maintenance therapy whenever possible.\u003c/p\u003e \u003cp\u003eThe third question is whether bevacizumab should be added to a PP regimen. Pemetrexed combined with platinum is the preferred frontline chemotherapy for patients with NS-NSCLC in National Comprehensive Cancer Network (NCCN) guidelines [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Efficacy of PP\u0026thinsp;+\u0026thinsp;B has been observed in some trials [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], but no direct prospective comparison has been made between PP\u0026thinsp;+\u0026thinsp;B and PP. However, designing prospective trials comparing PP\u0026thinsp;+\u0026thinsp;B and PP seems increasingly infeasible. In both the PRONOUNCE and ERACLE study designs, bevacizumab was added to the PC regimen, but not to the PP regimen. Nevertheless, no significant difference in PFS or OS was observed between PP and PC\u0026thinsp;+\u0026thinsp;B [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our meta-analysis indicated that PP\u0026thinsp;+\u0026thinsp;B significantly prolonged PFS, as compared to PC\u0026thinsp;+\u0026thinsp;B, but no significant differences were seen in any survival data between PP\u0026thinsp;+\u0026thinsp;B and PP by indirect comparisons. However, the strength of the evidence to clarify this issue remains limited.\u003c/p\u003e \u003cp\u003eCurrently, pembrolizumab in combination with chemotherapy is the preferred first-line regimen according to NCCN guidelines for patients with oncogenic driver negative NS-NSCLC and without contraindications to PD-1/PD-L1 inhibitors, regardless of PD-L1 expression level. Atezolizumab in combination with chemotherapy and bevacizumab is the other recommended regimen [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Interestingly, the chemotherapies in these two regimens differ (carboplatin/cisplatin\u0026thinsp;+\u0026thinsp;pemetrexed, and carboplatin\u0026thinsp;+\u0026thinsp;paclitaxel, respectively). In the future, we should focus on whether bevacizumab is a good partner to combine with chemotherapy and anti-PD-1 immunotherapy (e.g., pembrolizumab) for both first-line and maintenance treatment.\u003c/p\u003e \u003cp\u003eIn our meta-analysis, we strictly limited the inclusion criteria to RCTs. However, summary statistics rather than individual patient data were used for each trial, and the studies included were heterogeneous, with varying patient populations and different study designs. For example, EGFR-sensitizing mutation populations were excluded in the COMPASS trial, but not mentioned in the other five trials. This difference may lead to different subsequent line regimens and survival.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eThis study demonstrated that PP\u0026thinsp;+\u0026thinsp;B as first-line therapy is as effective as PC\u0026thinsp;+\u0026thinsp;B in patients with advanced NS-NSCLC, and the toxicity profile of the two therapies varies. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved survival, but led to more toxicity. Patients\u0026rsquo; tolerance and toxicity profiles should be considered when choosing treatment regimens. On the basis of the answers to these three questions, we have made preliminary recommendations for first-line and maintenance treatment strategies for patients with advanced NS-NSCLC with negative drivers who cannot tolerate immunotherapy, and for patients with positive oncogenic drivers whose disease progressed on prior targeted therapy. Treatment with PP\u0026thinsp;+\u0026thinsp;B or PC\u0026thinsp;+\u0026thinsp;B followed by Pem\u0026thinsp;+\u0026thinsp;B rather than single-drug B or Pem maintenance might be the best choice under the premise of tolerable toxicity.\u003c/p\u003e "},{"header":"List of Abbreviations","content":"\u003cp\u003eNSCLC: non-small cell lung cancer; NS-NSCLC: non-squamous NSCLC; PD-L1: programmed death-ligand 1; RCTs: randomized controlled clinical trials; VEGF: vascular endothelial growth factor; PP\u0026plusmn;B: pemetrexed-platinum with or without bevacizumab; PC+B: paclitaxel-carboplatin with bevacizumab; Pem+B: pemetrexed and bevacizumab; TRAEs: treatment-related adverse events; CI: confidence intervals; ORR: objective response rate; OS: overall survival; PFS: progress free survival; PFSR1y: 1-year PFS rate; HR: hazard ratio; RR: risk ratio; NCCN: National Comprehensive Cancer Network.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from the 345 Talent Project of Shengjing Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll of the authors have read and approved the final manuscript. LH, JM and CH conceived and designed the study. LH, RC, YW, LS, and XZ took full responsibility for data collecting. LH, JZ, SZ, WJ and JS performed the meta-analysis, systematic review, and drafted the manuscript. CH and JM helped revise the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the medical staff who contributed to the maintenance of the medical record database.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68:394-424. https://doi.org/10.3322/caac.21492\u003c/li\u003e\n\u003cli\u003eReck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 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J Thorac Oncol. 2015;10:134-142. https://doi.org/ 10.1097/JTO.0000000000000366\u003c/li\u003e\n\u003cli\u003eGaletta D, Cinieri S, Pisconti S, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Gebbia%20V%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=25582493\"\u003eGebbia V\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Morabito%20A%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=25582493\"\u003eMorabito A\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Borsellino%20N%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=25582493\"\u003eBorsellino N\u003c/a\u003e, et al. Cisplatin/pemetrexed followed by maintenance pemetrexed versus carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab in advanced nonsquamous lung cancer: the GOIM (Gruppo Oncologico Italia Meridionale) ERACLE phase III randomized trial. Clin Lung Cancer. 2015;16:262-273. https://doi.org/ 10.1016/j.cllc.2014.12.002\u003c/li\u003e\n\u003cli\u003eMa JT, Sun J, Sun L, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhang%20SL%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=30170427\"\u003eZhang SL\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Huang%20LT%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=30170427\"\u003eHuang LT\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Han%20CB%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=30170427\"\u003eHan CB\u003c/a\u003e. Efficacy and safety of apatinib in patients with advanced nonsmall cell lung cancer that failed prior chemotherapy or EGFR-TKIs: a pooled analysis. Medicine. 2018;97:e12083. https://doi.org/ 10.1097/MD.0000000000012083\u003c/li\u003e\n\u003cli\u003eCao R, Ma JT, Zhang SL, Sun L, Liu Y, Zhang XY, et al. 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New England Journal of Medicine. 2018;378: 2288-2301. https://doi.org/ 10.1056/NEJMoa1716948\u003c/li\u003e\n\u003cli\u003eBehera M, Pillai RN, Owonikoko TK, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Kim%20S%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26200267\"\u003eKim S\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Steuer%20C%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26200267\"\u003eSteuer C\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Chen%20Z%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26200267\"\u003eChen Z\u003c/a\u003e, et al. Bevacizumab in combination with taxane versus non-taxane containing regimens for advanced/metastatic Nonsquamous Non\u0026ndash;Small-Cell Lung Cancer: A systematic review. Journal of Thoracic Oncology. 2015;10:1142-1147. https://doi.org/ 10.1097/JTO.0000000000000572\u003c/li\u003e\n\u003cli\u003eKarayama M, Inui N, Fujisawa T, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Enomoto%20N%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26922170\"\u003eEnomoto N\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Nakamura%20Y%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26922170\"\u003eNakamura Y\u003c/a\u003e, \u003ca href=\"https://www.ncbi.nlm.nih.gov/pubmed/?term=Kuroishi%20S%5BAuthor%5D\u0026amp;cauthor=true\u0026amp;cauthor_uid=26922170\"\u003eKuroishi S\u003c/a\u003e, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer. Eur J Cancer. 2016;58:30\u0026ndash;37. https://doi.org/ 10.1016/j.ejca.2016.01.013\u003c/li\u003e\n\u003cli\u003eMasters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, et al. Systemic therapy for stage IV non-small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol. 2015;33:3488-3515. https://doi.org/ 10.1200/JCO.2015.62.1342\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor/published year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInduction arms (randomized)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInduction sample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInduction regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eInduction Cycles\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eDose of Bevacizumab\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eMaintenance arms (randomized)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eMaintenance sample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePrimary endpoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eSecondary endpoint\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatel, 2013 (PointBreak)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePem 500\u0026nbsp;mg/m2, Cb AUC 6, Bev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e15\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e292\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePFS, ORR, DCR, TTPD, toxicity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePac\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e443\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePac 200\u0026nbsp;mg/m2, Cb AUC 6, Bev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZinner, 2015 (PRONOUNCE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Cb\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePem 500\u0026nbsp;mg/m2, Cb AUC 6, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e15\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePFS without grade 4 toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePFS, OS, ORR, DCR, safety\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePac\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePac 200\u0026nbsp;mg/m2, Cb AUC 6, Bev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGaletta, 2015 (ERACLE)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Cis\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePem 500\u0026nbsp;mg/m2, Cis 75\u0026nbsp;mg/m2, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e15\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eQOL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePFS, OS, ORR, safety\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePac\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePac 200\u0026nbsp;mg/m2, Cb AUC 6\u003c/p\u003e \u003cp\u003eBev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarlesi, 2014 (AVAPERL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Cis\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e376\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePem 500\u0026nbsp;mg/m2, Cis 75\u0026nbsp;mg/m2, Bev 7.5\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e7.5\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eOS, ORR, DOR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRamalingam, 2019 (EA5508)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePac\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePac 200\u0026nbsp;mg/m2, Cb AUC 6, Bev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e15\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePFS, ORR, safety\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e294\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeto, 2019 (COMPASS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Cb\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePem 500\u0026nbsp;mg/m2, Cb AUC 6, Bev 15\u0026nbsp;mg/kg, day 1 every 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e15\u0026nbsp;mg/kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eBev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eOS (from Random Assignment)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePFS and OS (from induction therapy), safety\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;Bev\u003c/p\u003e \u003cp\u003e(randomized)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003eAbbreviation: AUC, area under the curve; Bev, bevacizumab; Cb, carboplatin; Cis, cisplatin; DCR, disease control rate; DOR, duration of response; ORR, objective response rate; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progress free survival; QOL, quality of life; TTPD, time to progressive disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinicopathological characteristics of the included patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized arms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge, Median (y)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStage IV (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eECOG PS 1 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNever Smoker (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePointBreak\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e80.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePC\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e78.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePRONOUNCE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e52.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e83.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePC\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e100.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e53.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e76.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eERACLE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e97.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePC\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e78.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e97.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAVAPERL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e94.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e85.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e91.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEA5508\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e91.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e88.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e91.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOMPASS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e96.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e96.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eAbbreviation: PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B, pemetrexed-platinum with or without bevacizumab; PC\u0026thinsp;+\u0026thinsp;B, paclitaxel-carboplatin with bevacizumab; Pem\u0026thinsp;+\u0026thinsp;B, pemetrexed and bevacizumab; B, bevacizumab; ECOG PS, Eastern Cooperative Oncology Group Performance Status.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of forest plot for TRAEs (PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B \u003cem\u003evs.\u003c/em\u003e PC\u0026thinsp;+\u0026thinsp;B)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTRAEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePP\u0026thinsp;\u0026plusmn;\u0026thinsp;B\u003c/p\u003e \u003cp\u003en/N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePC\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003cp\u003en/N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHeterogeneity P value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u0026ndash;related deaths\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/684 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13/680 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.845\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.84 (0.52,1.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eGrade 3/4 TRAEs\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97/684\u003c/p\u003e \u003cp\u003e(14.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23/680 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.75 (1.58,1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15/684\u003c/p\u003e \u003cp\u003e(2.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29/680 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.546\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.73 (0.49,1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161/684 (23.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e267/680 (39.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67 (0.59,0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e144/684 (21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42/680 (6.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.70 (1.47,1.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensory neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/684 (0.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26/680 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.21 (0.06,0.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFebrile neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/684 (0.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22/680 (3.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47 (0.25,0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviation: PP\u0026thinsp;\u0026plusmn;\u0026thinsp;B, pemetrexed-platinum with or without bevacizumab; PC\u0026thinsp;+\u0026thinsp;B, paclitaxel-carboplatin with bevacizumab; RR, risk ratio; TRAEs, treatment-related adverse events.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of forest plot for grade 3/4 TRAEs (Pem\u0026thinsp;+\u0026thinsp;B \u003cem\u003evs.\u003c/em\u003e B maintenance)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4\u003c/p\u003e \u003cp\u003eTRAEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePem\u0026thinsp;+\u0026thinsp;B\u003c/p\u003e \u003cp\u003en/N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eB\u003c/p\u003e \u003cp\u003en/N (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHeterogeneity I\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHeterogeneity P value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35/620 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/707 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.75 (1.46, 2.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97/620 (15.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98/707 (13.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.02 (0.78, 1.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81/620 (13.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/707 (0.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.95 (1.80, 2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14/620 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/707 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.88 (1.55, 2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviation: Pem\u0026thinsp;+\u0026thinsp;B, pemetrexed and bevacizumab; B, bevacizumab; RR, risk ratio; TRAEs, treatment-related adverse events.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \n\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEvaluation of risk of bias in the included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePointBreak 2013\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAVAPERL 2014\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eERACLE 2015\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRONOUNCE 2015\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCOMPASS 2019\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEA5508\u003c/p\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRandomization sequence generation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllocation concealment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlinding of participants and personnel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlinding of outcome assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncomplete outcome data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ehigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSelective reporting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther biases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eunclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003elow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"bevacizumab, first-line treatment, maintenance treatment, meta-analysis, non-small-cell lung cancer, paclitaxel, pemetrexed","lastPublishedDoi":"10.21203/rs.3.rs-43694/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-43694/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP±B) and paclitaxel-carboplatin with bevacizumab (PC+B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem+B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eData of 3,139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP±B and PC+B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP±B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC+B (all P\u0026lt;0.05). PP±B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC+B (all P\u0026lt;0.001). The other three RCTs were included in an analysis that compared Pem+B and B as a maintenance treatment. Compared with B, Pem+B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P\u0026lt;0.001).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Although the first-line PP+B regimen had longer PFS and PFSR1y than the PC+B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.\u003c/p\u003e","manuscriptTitle":"Clinical Option of Pemetrexed-Based Versus Paclitaxel-Based First-Line Chemotherapeutic Regimens in Combination With Bevacizumab for Advanced Non-Squamous Non-Small-Cell Lung Cancer and Optimal Maintenance Therapy: Evidence From a Meta-Analysis of Randomized Control Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-08-05 23:43:14","doi":"10.21203/rs.3.rs-43694/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-10-18T12:00:00+00:00","index":3,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-10-18T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-10-09T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-07T12:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-30T12:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-29T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-08-07T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-07T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-07-27T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-07-26T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-07-26T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7614174f-a9a7-4ac4-9a0b-fa7fe232ceaa","owner":[],"postedDate":"August 5th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":239817,"name":"Cancer Biology"},{"id":239818,"name":"Oncology"}],"tags":[],"updatedAt":"2021-08-18T19:44:15+00:00","versionOfRecord":{"articleIdentity":"rs-43694","link":"https://doi.org/10.1186/s12885-021-08136-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2021-04-17 19:02:57","publishedOnDateReadable":"April 17th, 2021"},"versionCreatedAt":"2020-08-05 23:43:14","video":"","vorDoi":"10.1186/s12885-021-08136-5","vorDoiUrl":"https://doi.org/10.1186/s12885-021-08136-5","workflowStages":[]},"version":"v1","identity":"rs-43694","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-43694","identity":"rs-43694","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}