The efficacy and safety of neoadjuvant chemotherapy plus immune check point inhibitors for locally advanced cervical cancer: A systematic review and meta-analysis

The efficacy and safety of neoadjuvant chemotherapy plus immune check point inhibitors for locally advanced cervical cancer: A systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The efficacy and safety of neoadjuvant chemotherapy plus immune check point inhibitors for locally advanced cervical cancer: A systematic review and meta-analysis Jianqing Xu, Jing Chen, Lin Zhu, Ming Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9393686/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Objective Immune checkpoint inhibitors (ICIs) enable organ preservation strategies and surgical de-escalation in multiple cancers.In locally advanced cervical cancer (LACC), neoadjuvant chemotherapy plus immune checkpoint inhibitors (NACI) may improve tumor response and enable fertility-sparing strategies.This study conducted a systematic review and meta-analysis to evaluate the response rates and safety of NACI in LACC. Methods We systematically searched PubMed, Web of Science, Cochrane Library, and Embase from inception to March 2025, including major congress abstracts. Phase II/III trials or retrospective analyses reporting pathological complete response (pCR), objective response rate (ORR), and adverse events (AEs) for NACI in LACC were included. Two investigators independently extracted data. Pooled rates were calculated using STATA 18.0 with random-effects models (I² statistic assessed heterogeneity). Results Three clinical studies involving 162 patients with locally advanced cervical cancer were included in the meta-analysis. The pooled ORR was 95.5% (95% confidence interval [CI],90.8–98.6%), while the pooled pCR rate was 45.5% (95% CI, 27.7–63.2%). Grade 3 or higher AEs occurred at a pooled rate of 35.5% (95% CI, 28.2–42.9%). Sensitivity analysis confirmed the reliability of the meta-analytic findings. Conclusion The combination of chemotherapy and PD-1/PD-L1 inhibitors achieved 45.5% pCR and tolerable toxicity which supports its potential role in fertility preservation strategies. Cervical Cancer Neoadjuvant Chemotherapy PD-1/PD-L1 inhibitors Pathological Complete Response Adverse Events Figures Figure 1 Figure 2 What is already known on this topic The standard care for locally advanced cervical cancer is concurrent chemoradiotherapy, which is associated with significant toxicity and suboptimal outcomes. While neoadjuvant chemotherapy offers a fertility-sparing alternative, many patients respond poorly. Although immunotherapy is standard for advanced disease, its role in the neoadjuvant setting for this population lacks systematic evaluation, highlighting the need for this study. What this study adds This first meta-analysis of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer demonstrates exceptional efficacy. Pooled data show a 95.5% overall response rate and a 45.5% pathological complete response rate—significantly higher than with chemotherapy alone—along with a manageable safety profile. This provides strong preliminary evidence for neoadjuvant chemo-immunotherapy as a highly effective, fertility-preserving strategy. How this study might affect research, practice or policy These findings justify larger trials comparing neoadjuvant chemo-immunotherapy to standard therapies and support its consideration in clinical discussions for fertility preservation . The compelling data may also inform future guideline updates, potentially establishing neoadjuvant chemo-immunotherapy as a recommended option for specific patient subgroups. Introduction Cervical cancer persists as a major contributor to global female morbidity and mortality, where locally advanced cervical cancer (LACC), accounting for approximately 37% of cases, presents particularly grave threats to survival outcomes and quality of life [ 1 ]. Characterized by tumors ≥ 4 cm (FIGO stages IB3-IVA) without distant metastasis, LACC is currently treated with concurrent chemoradiotherapy (CCRT) as per international guidelines, though this approach yields suboptimal therapeutic outcomes [ 2 ]. Approximately 30% of patients develop recurrence or metastasis following CCRT, highlighting its limitations in achieving sustained disease control [ 3 ]. The treatment paradigm further raises concerns regarding substantial late-term toxicities, including ovarian failure (premature menopause in 70–100% of premenopausal women), sexual dysfunction, and radiation-induced vaginal fibrosis-sequelae particularly detrimental to young patients pursuing fertility preservation [ 4 – 7 ]. Neoadjuvant chemotherapy followed by radical surgery(NACT-S) represents a potential alternative for resectable LACC (FIGO IB3-IIA2), theoretically enabling tumor downstaging and fertility preservation [ 8 ]. However, current evidence remains inconclusive, with meta-analyses showing comparable 3-year overall survival (HR = 0.97, 95% CI: 0.69–1.24, p = 0.841) and 5-year progression-free survival (HR = 0.89, 95% CI: 0.71–1.08, p = 0.268) between NACT-S and CCRT cohorts [ 9 ]. Clinical implementation faces additional hurdles, as 12.0%-29.1% of patients exhibit suboptimal pathological responses (< 50% tumor regression), resulting in deferred definitive treatment and frequent requirement for adjuvant therapies that escalate healthcare costs and complication risks [ 9 – 11 ]. Such limitations emphasize the necessity to augment NACT efficacy through strategic therapeutic combinations. In mismatch repair-deficient or microsatellite instability-high locally advanced rectal cancer, anti-PD-1 therapy enables clinical complete response in most patients, avoiding chemoradiation and surgical morbidity. A phase II trial evaluated sintilimab (anti-PD-1) as neoadjuvant therapy for dMMR locally advanced rectal cancer [ 12 ]. Patients received four cycles of sintilimab followed by: surgery with adjuvant therapy, four additional immunotherapy cycles before surgery, or surveillance for clinical complete responders. Of 17 patients enrolled, 16 were evaluable: 15 demonstrated tumor regression. Six underwent surgery with three achieving pathological complete response (pCR); nine attained clinical complete response and entered surveillance; one discontinued due to adverse events. The overall complete response rate reached 75%. Median time to complete CR was 5.2 months, suggesting the promising alternative conservative treatment with immunotherapy [ 12 ].Beyond colorectal cancer, an ongoing trial (NCT06278857) is assessing dostarlimab (anti-PD-1) efficacy in early-stage dMMR endometrioid endometrial adenocarcinoma [ 13 ]. The oncology landscape has been transformed by immunotherapy advances, particularly immune checkpoint inhibitors (ICIs) demonstrating robust efficacy in multiple advanced cancers. Cervical cancer exhibits molecular features that provide a strong rationale for immunotherapy, such as high tumor mutational burden, microsatellite instability, elevated programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression, and inflammatory tumor microenvironments [ 14 ]. HPV-infected tumor cells evade immune responses partly through upregulated PD-L1 expression, which inhibits T-lymphocyte activation via PD-1/PD-L1 interactions. High PD-L1 expression (reported in 35–96% of cervical cancers) suggests ICIs can reverse immune evasion mechanisms [ 15 ]. Pivotal trials have established immunochemotherapy as a new standard: KEYNOTE-826 demonstrated pembrolizumab combined with chemotherapy (± bevacizumab) significantly improved median overall survival (29.6 vs. 26.4 months; HR 0.67) and objective response rates (66.2% vs. 51.5%) over chemotherapy alone in recurrent/metastatic disease [ 16 ]. The COMPASSION-16 trial further validated this synergy, where cadonilimab (a PD-1/CTLA-4 bispecific antibody) plus chemotherapy achieved superior median progression-free survival (12.7 vs. 8.1 months; HR 0.43) and 24-month overall survival rates (62.6% vs. 48.4%) [ 17 ]. Mechanistically, preclinical models reveal chemotherapy enhances tumor immunogenicity through immunogenic cell death and PD-L1 upregulation (PD-L1 + cells increase from 43.75% to 87.5% in the tumor microenvironment), thereby potentiating ICI efficacy [ 18 ]. This biological synergy provides compelling rationale for incorporating ICIs into neoadjuvant protocols. However, the utility of combining ICIs with NACT specifically remains underexplored, with only preliminary data from small-scale trials [ 19 , 20 ]. As ongoing studies investigate this approach, a synthesis of current evidence is critical to evaluate its safety and efficacy, inform clinical practice, and guide future research. This systematic review and meta-analysis therefore seeks to consolidate current knowledge on neoadjuvant chemo-immunotherapy for LACC, addressing a crucial evidence gap in developing precision-based, patient-tailored treatment frameworks. Methods Search strategy and study selection A systematic search was conducted across four electronic databases (PubMed, Web of Science, Cochrane Library, and Embase) from inception through March 2025. Search terms encompassed "cervical cancer", "neoadjuvant OR preoperative OR perioperative", and "programmed cell death 1 (PD-1) OR programmed cell death ligand 1 (PD-L1) OR cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)", supplemented by specific immune checkpoint inhibitor agents including "pembrolizumab, durvalumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, and tislelizumab". Relevant abstracts from major international congresses were screened, with only English-language publications considered eligible. Eligibility criteria Studies were included if they satisfied all the following criteria: enrollment of patients with locally advanced cervical cancer; administration of neoadjuvant chemotherapy combined with PD-1/PD-L1 inhibitors as the primary intervention; phase II/III clinical trial or retrospective study design; and reported outcomes including pathological complete response rate (pCR), objective response rate (ORR), and adverse events (AEs). Tumor response assessment required application of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, while AEs were graded per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All studies failing to meet these criteria were excluded. Data extraction and outcomes measures Extracted data comprised study characteristics (first author, publication year, country, recruitment period, sample size, median age, median follow-up duration, FIGO stage distribution, treatment regimen specifics, and reported endpoints). Efficacy assessments included pCR defined as absence of residual viable tumor cells in surgical specimens following neoadjuvant therapy and resection; ORR defined as proportion of patients achieving complete or partial response according to RECIST 1.1; and disease control rate (DCR) calculated as the proportion with complete response, partial response, or stable disease. Safety evaluation focused on incidence of all-grade AEs and specifically grade ≥ 3 immune-related adverse events (irAEs), with severity graded according to National Cancer Institute CTCAE version 4 or 5 criteria. Quality assessment and risk of bias Two independent investigators (MW and JQX) performed data extraction, with discrepancies resolved by a third reviewer. Methodological quality of non-randomized studies was evaluated using the Methodological Index for Non-Randomized Studies instrument, which contains eight items scored 0–2 (maximum 16 points). Studies scoring > 9 points were designated high quality. Statistical analysis Funnel plots generated in Review Manager 5.3 assessed publication bias. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated via Mantel-Haenszel methods. Heterogeneity was quantified using chi-square tests and I² statistics, with random-effects models applied when I² >50% and P < 0.1; otherwise, fixed-effects models were used. Proportions approaching 0 or 1 underwent Freeman-Tukey double arcsine transformation prior to meta-analysis. Sensitivity analyses evaluated result robustness. Results Study selection and characteristics Systematic screening identified 85 records from four databases and international congress abstracts (Fig. 1 ). Following duplicate removal and title/abstract assessment, eight studies underwent full-text review. Five were excluded due to inaccessible full texts, duplicate reports, or non-conforming study designs. Three studies ultimately met inclusion criteria and were included in the meta-analysis: two clinical trials (NCT04516616, NCT04799639) and one prospective investigation (ChiCTR2200065392) [ 19 , 21 – 22 ]. These single-arm studies collectively enrolled 162 patients with locally advanced cervical cancer in China (Table 1), with median follow-up durations ranging from 11 to 17 months. All participants received neoadjuvant chemotherapy combined with PD-1/PD-L1 inhibitors administered every 3 weeks for 3 cycles. Tumor response and surgical outcomes are comprehensively detailed in Table 2 . Methodological quality assessment using the MINORS instrument confirmed high study quality (scores > 9; Supplemental Table S1 ). Table 1. Baseline characteristics of the included studies. Study Country Clinical Trial Registry Identifier Recruitment period Sample size Median Age(years) FIGO stage Median follow-up months Treatment (PD−1 inhibitors+chemotherapy) Endpoints Li et al.2024 China NCT04516616 December 2020 to February 2023 85 51 IB3/IIA2 IIB/IIIC1r 11 (IQR 6−14.5) Camrelizumab 200 mg+ Nab-paclitaxel, 260 mg/m²+ Cisplatin 75–80 mg/m²every 3 weeks for 3 cycles ORR, AEs pCR, EFS OS Wan et al.2024 China NCT04799639 March 2021 to February 2024 47 NR IB3/IIA2 17 (range1−35) Sindilimab 200mg+ Paclitaxel 150mg/m 2 +Cisplantin 70mg/m²every 3 weeks for 3 cycles pCR, ORR AEs, PFS Sheng et al. China ChiCTR2200065392 November 2022 to March 2024 30 51.5 IB3/IIA2 14.7(IQR 11.6–21.4) Tislelizumab 200 mg + Paclitaxel 175 mg/m² + Cisplatin 60 mg/m² or Carboplatin AUC 5 every 3 weeks for 3 cycles pCR, ORR AEs Note: ORR, overall response rate; pCR, pathological complete response;OS, overall survival; EFS, event-free survival; PFS, progression-free survival; AEs, adverse events; NR, not reported. Table 2 The surgery information of patients after NACI. Study Complete evaluated ORR surgery pCR optimal remission rate* Histology adjuvant treatment Li et al.2024 83/85 83 ( CR 16 + PR 67) 81/83 32/81 NR SSC/AC/ASCC 20/32 Wan et al.2024 43/47 42 43/43 14/43 22/43 SSC/AC/ASCC NR Sheng et al.2024 30/30 27( CR 17 + PR 10) 30/30 20/30 24/30 SSC/AC 7/30 Tumor response​ ​ All included studies reported efficacy outcomes. The pooled ORR was 95.5% (95% CI: 90.8–98.6%; fixed-effects model; I² = 29.0%, P = 0.245; Fig. 2 A). pCR rates varied from 32.6% to 66.7%, with the highest pCR observed in the tislelizumab cohort (66.7%). Meta-analysis yielded a pooled pCR of 45.5% (95% CI: 27.7–63.2%; random-effects model; I² = 80.2%, P = 0.006; Fig. 2 B). Sensitivity analysis confirmed result robustness (Supplemental Figure S2). Safety of NACI AEs are detailed in Table 3 . Hematologic toxicities predominated, primarily comprising grade 1–2 events(Table 4 ). Camrelizumab was associated with elevated leukopenia rates, while lymphopenia was frequent in both camrelizumab and tislelizumab groups. Among sintilizumab-treated patients, 32% (15/47) experienced grade 3–4 neutropenia. The pooled rate of grade ≥ 3 AEs was 35.5% (95% CI: 28.2–42.9%), with grade 1–2 skin rash occurring in 21.0% of patients (95% CI: 4.7–37.4%; Supplemental Figure S1 ). Table 3 Adverse events of the included studies(CTCAE 5.0). Study Li et al.2024 Wan et al.2024 Sheng et al.2024 AEs Grade I-II Grade III-IV Grade I-II Grade III-IV Grade I-II Grade III-IV Leukopenia 43(51%) 7(8%) - - 16(53%) - Lymphopenia 23(27%) 21(25%) - - 23(77%) 4(13%) Anaemia 27(32%) 4(5%) - - 21(70%) 0 Neutropenia 17(20%) 10(12%) - 15(32%) 12(40%) 1(3%) Thrombocytopenia 14(16%) 0(0%) - - 6(40%) 1(3%) Hypoalbuminaemia 14(16%) 0(0%) - - 21(70%) - Aspartate aminotransferase increased 12(14%) 2(2%) - - 9(30%) 1(3%) Alanine aminotransferase increased 8(9%) 2(2%) 8(17%) - 6(20%) 2(7%) Hypocalcaemia 9(11%) 0(0%) - - - - Hypokalaemia 4(5%) 2(2%) - - - - Hyperglycemia - - - - 3(10%) - γ-glutamyl transferase increased 4(5%) 2(2%) - - - - Creatinine increased - - 5(11%) - - - Hyperlipidemia - - 1(2%) - - - Decreased appetite 17(20%) 0(0%) - - 5(17%) - Alopecia 15(18%) 0(0%) - - - - Nausea 38(45%) 0(0%) - - 5(17%) - Vomiting 33(39%) 0(0%) - - 4(13%) - Fever 10(12%) 0(0%) - - - - Skin rash 8(9%) 0(0%) 17(36%) - 6(40%) 0 Itching - - - - 4(13%) - Headache/Pain 0(0%) 1(1%) - - 5(17%) - Abnormal feeling - - - - 4(13%) - Hypothyroidism - - 6(13%) - 5(17%) - Guillain-Barré syndrome - - - - - 1(3%) Lower extremity venous thrombosis - - - - 1(3%) - Table 4 Hematologic toxicities of the included studies (CTCAE 5.0). AEs Grade I-II Grade III-IV ES % ,(95 CI) I2 ,% ES % ,(95 CI) I2 ,% Neutropenia 0.29(0.09–0.48) 75.3 0.14 (0.03–0.31) 84.1 Anaemia 0.50 (0.13–0.88) 93.5 0.03 (0.00−0.07) 0 Lymphopenia 0.52(0.03−1.00) 96.6 0.20 (0.09–0.31) 53.3 Skin rash 0.21(0.05–0.37) 84.2 - - Total - - 0.36 (0.28–0.43) 0 Discussion Summary of Main Results: The advent of immune checkpoint inhibitors has revolutionized the treatment landscape for cervical cancer. This meta-analysis synthesizes evidence on neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy in LACC, suggesting favorable tolerability and enhanced tumor response. Results in the Context of Published Literature: PD-1/PD-L1 inhibitors alleviate immune checkpoint suppression on T cells, activating cancer-specific immunity. Anti-PD-1 antibodies (e.g., camrelizumab, tislelizumab) restore cytotoxic T lymphocyte activity and promote memory T-cell differentiation for potential long-term protection [ 23 – 24 ].PD-L1 expression, prevalent in cervical cancer, correlates with stromal tumor-infiltrating lymphocytes (TILs) [ 25 – 27 ]. Neoadjuvant chemotherapy modulates the tumor immune microenvironment by increasing dendritic cells, CD3+/CD4+/CD8 + T cells, and reducing regulatory T cells [ 23 ]. It enhances neoantigen presentation, induces immunogenic cell death, alters cytokine profiles, downregulates myeloid-derived suppressor cells and Tregs, and influences PD-1/PD-L1 expression [ 24 ]. Pooled analysis revealed an ORR of 95.5% (95% CI: 90.8–98.6%) and pCR of 45.5% (95% CI: 27.7–63.2%), significantly surpassing chemotherapy-alone outcomes. These results align with emerging evidence: Wan et al. reported 98% ORR and 33% pCR with camrelizumab [ 26 ], while ChiCTR2200065392 documented 90% ORR and 67% pCR with tislelizumab. Li et al. corroborated these findings (98% ORR, 39% pCR; 95% surgery completion) [ 19 ]. Strengths and Weaknesses: The safety profile of PD-1/PD-L1 inhibitors plus chemotherapy appears manageable. irAEs occur in 15–90% of patients, predominantly skin toxicity, hypothyroidism, hepatotoxicity, and pneumonitis [ 30 ]. Prior studies reported grade 3–4 adverse events in 12.2–33% [ 31 – 32 ]. Our pooled grade ≥ 3 AE rate was 35.5% (95% CI: 28.2–42.9%), with most events being grade 1–2. Notably, camrelizumab showed higher rates of grade 3–4 AEs, and with increased leukopenia/lymphopenia. There is also some limitations of this study. First, the sample sizes were relatively small. These factors may limit the clinical using of the findings to other populations. Second, long term survival outcomes of the three studies is still unclear. Future research should focus on large-scale randomized controlled trials to validate the pathological complete responses of neoadjuvant immunotherapy in diverse populations and across different PD-1/PD-L1 inhibitors. Implications for Practice and Future Research: Three additional ongoing clinical trials are evaluating novel neoadjuvant approaches: NCT04238988 (pembrolizumab plus chemotherapy), NCT05013268 (tislelizumab combined with chemotherapy), and CTR20220443 (cadonilimab [a PD-1/CTLA-4 bispecific antibody] monotherapy). Except for NACI comnbined with surgery, ICIs also showed promising results when combined with radiaiton. The KEYNOTE-A18 trial demonstrated superior 24-month progression-free survival with pembrolizumab-CCRT versus CCRT alone (73% vs. 57%) in high-risk LACC [ 33 ], supporting earlier immunotherapy integration. Another multicenter phase II/III trial (NCT06288373) is evaluating neoadjuvant cisplatin/nab-paclitaxel plus camrelizumab versus CCRT in FIGO 2018 IB3-IIB (> 4 cm) LACC, potentially establishing a new neoadjuvant paradigm. However, whether ICIs treatment provide chances to allow lower radiation dosage is still unclear. Liquid biopsy advances also promote the detection of minimal residual disease (MRD). HPV cell-free DNA represents a specific biomarker given HPV's causal role in cervical cancer, particularly valuable where vaccination/screening access is limited [ 34 ]. A prospective multicenter study (n = 70) validated HPV circulating tumor DNA (ctDNA) for relapse prediction: detectable ctDNA post-chemoradiation significantly associated with inferior 2-year progression-free survival (82% vs. 24% undetectable at 3 months; P < 0.001; median lead time 5.9 months). Multivariable analyses confirmed ctDNA as an independent prognostic factor, enabling early high-risk identification [ 35 ].Based on the above results, post-NACI monitoring with combined cervical biopsies, MRD testing, and imaging may allow surgery de-escalation or omission for patients with imaging resolution and negative MRD. Conclusions In conclusion,the combination of chemotherapy and PD-1/PD-L1 inhibitors achieved a promising pathological complete response with a tolerable toxicity which supports its further use in the special population, such as younger patients. Also, further studies are needed to explore its most suitable population. Abbreviations ICIs Immune checkpoint inhibitors LACC locally advanced cervical cancer NACI neoadjuvant chemotherapy plus immune checkpoint inhibitors pCR pathological complete response ORR objective response rate AE adverse events CCRT concurrent chemo-radiotherapy PD-1 programmed cell death 1 PD-L1 programmed cell death ligand-1 RECIST response Evaluation Criteria in Solid Tumors CTCAE Common Terminology Criteria for Adverse Events DCR disease control rate irAEs immune-related adverse events ctDNA circulating tumor DNA. Declarations Ethics approval and consent for publication: Not available. Availability of data and materials All data generated or analysed during this study are included in this published article[and its supplementary information files. Conflict Interests: The authors declare no conflict of interest. Funding: There is no funding support of this study. Author contributions Conception and design: Ming Wang and Jianqing Xu Data collection and analysis : Ming Wang, Jianqing Xu, Lin Zhu and Jing Chen Manuscript writing: Jianqing Xu Writing review and editing: Ming Wang, Lin Zhu Final approval of manuscript: All authors Accountable for all aspects of the work: All authors Acknowledgements: Not available. References Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. 10.3322/caac.21834 . Monk BJ, Tan DSP, Hernández Chagüi JD, et al. Proportions and incidence of locally advanced cervical cancer: a global systematic literature review. Int J Gynecol Cancer. 2022;32(12):1531–9. 10.1136/ijgc-2022-003801 . National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2024. 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Br J Cancer. 2018;118(3):312–24. 10.1038/bjc.2017.376 . Duranti S, Pietragalla A, Daniele G, et al. Role of immune checkpoint inhibitors in cervical cancer: from preclinical to clinical data. Cancers (Basel). 2021;13(9):2089. 10.3390/cancers13092089 . Frenel JS, Le Tourneau C, O’ Neil B, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;35(36):4035–41. 10.1200/JCO.2017.74.5471 . Naumann RW, Hollebecque A, Meyer T, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. J Clin Oncol. 2019;37(31):2825–34. 10.1200/JCO.19.00739 . Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024;403(10434):1341–50. 10.1016/S0140-6736(24)00317-9 . Parida P, Baburaj G, Rao M, et al. Circulating cell-free DNA as a diagnostic and prognostic marker for cervical cancer. Int J Gynecol Cancer. 2024;34(2):307–16. 10.1136/ijgc-2023-004873 . Han K, Zou J, Zhao Z, et al. Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer. J Clin Oncol. 2024;42(4):431–40. 10.1200/JCO.23.00954 . Additional Declarations No competing interests reported. Supplementary Files supplmaterialsfile.rar Figure S1. Quality assessment of the included studies. Figure S2.Adverse events of NACI (A) All Grades 3-4 AEs;(B) Grades 1-2skin related AEs. Figure S3 Sensitivity analysis of NACI. (A) Sensitivity analysis for ORR; (B) Sensitivity analysis for pCR; (C) Sensitivity analysis for grade 3-4 AEs ; (D) Sensitivity analysis for grade 3-4 skin rash. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 13 May, 2026 Reviewers agreed at journal 30 Apr, 2026 Reviewers invited by journal 28 Apr, 2026 Editor assigned by journal 28 Apr, 2026 Editor invited by journal 27 Apr, 2026 Submission checks completed at journal 27 Apr, 2026 First submitted to journal 27 Apr, 2026 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9393686","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":633616301,"identity":"c7b22183-7dc2-4aca-bf16-3a6b370be0c4","order_by":0,"name":"Jianqing Xu","email":"","orcid":"","institution":"Haidian District Maternal and Child Health Care Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jianqing","middleName":"","lastName":"Xu","suffix":""},{"id":633616302,"identity":"369efdd6-3830-4f1b-9b5d-fc30df01f512","order_by":1,"name":"Jing Chen","email":"","orcid":"","institution":"Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Chen","suffix":""},{"id":633616303,"identity":"70e03d3d-5157-4ddb-aa07-8419faebefd7","order_by":2,"name":"Lin Zhu","email":"","orcid":"","institution":"Haidian District Maternal and Child Health Care Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Zhu","suffix":""},{"id":633616304,"identity":"a62df0d1-21db-4e30-b97b-99d66826fb0a","order_by":3,"name":"Ming Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYBADGTZmxsYHUI4BUVp4+NiZm2FKidQix8/eJkGUFvmI3IOPC2pseIAOa6v4UbMtsYG9eZsEQ80dnFoMb+QlG884lgbWcrPn2O3EBp5jZRIMx57h1jIjx0yat+EwWMttxgagFokcMwnGhsPEaSkGa5F/g1+LvASSFmaILTz4tRjwvDE25oH4pVkS6BfjNp60YouEY3hsac8xfMxTYyMn33/84YcfNbdl+9kPb7zxoQaPLRcS0ETYQAS6IIot/QfwyI6CUTAKRsEoAAEA2QRMRLGxQpoAAAAASUVORK5CYII=","orcid":"","institution":"Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital","correspondingAuthor":true,"prefix":"","firstName":"Ming","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-04-12 11:09:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9393686/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9393686/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108941684,"identity":"84ade699-b5bf-4bdf-aa1d-90576a35dd85","added_by":"auto","created_at":"2026-05-11 05:37:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":267485,"visible":true,"origin":"","legend":"\u003cp\u003ePreferred reporting items for systematic reviews and meta-analysis (PRISMA) flowchart for study selection.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9393686/v1/268a1cff49fc0fab01a56522.png"},{"id":108978298,"identity":"92076949-a8ec-468e-ac94-b202055b5876","added_by":"auto","created_at":"2026-05-11 11:36:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":144187,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the tumor response of locally advanced cervical cancer patients after neoadjuvant immune checkpoint inhibitors and chemotherapy.\u003c/p\u003e\n\u003cp\u003e(A) HR for objective response rates between neoadjuvant chemoimmune treatment and neoadjuvant chemotherapy in locally advanced cervical cancer. (B) HR for pathological complete response between neoadjuvant chemoimmune treatment and neoadjuvant chemotherapy in locally advanced cervical cancer.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9393686/v1/ccbdd74b1a029f996e0bdff6.png"},{"id":108980075,"identity":"65216328-3b4c-448e-9a50-02e6057c0f45","added_by":"auto","created_at":"2026-05-11 12:03:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":715160,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9393686/v1/b9dba2d5-5125-46b2-810c-219478ffd98c.pdf"},{"id":108941682,"identity":"776e552a-0455-499c-9846-903edd0d65db","added_by":"auto","created_at":"2026-05-11 05:37:38","extension":"rar","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":207979,"visible":true,"origin":"","legend":"\u003cp\u003eFigure S1. Quality assessment of the included studies.\u003c/p\u003e\n\u003cp\u003eFigure S2.Adverse events of NACI\u003c/p\u003e\n\u003cp\u003e(A) All Grades 3-4 AEs;(B) Grades 1-2skin related AEs.\u003c/p\u003e\n\u003cp\u003eFigure S3 Sensitivity analysis of NACI.\u003c/p\u003e\n\u003cp\u003e(A) Sensitivity analysis for ORR; (B) Sensitivity analysis for pCR; (C) Sensitivity analysis for grade 3-4 AEs ; (D) Sensitivity analysis for grade 3-4 skin rash.\u003c/p\u003e","description":"","filename":"supplmaterialsfile.rar","url":"https://assets-eu.researchsquare.com/files/rs-9393686/v1/8830cd1263df47a30191bb11.rar"}],"financialInterests":"No competing interests reported.","formattedTitle":"The efficacy and safety of neoadjuvant chemotherapy plus immune check point inhibitors for locally advanced cervical cancer: A systematic review and meta-analysis","fulltext":[{"header":"What is already known on this topic","content":"\u003cp\u003eThe standard care for locally advanced cervical cancer is concurrent chemoradiotherapy, which is associated with significant toxicity and suboptimal outcomes. While neoadjuvant chemotherapy offers a fertility-sparing alternative, many patients respond poorly. Although immunotherapy is standard for advanced disease, its role in the neoadjuvant setting for this population lacks systematic evaluation, highlighting the need for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat this study adds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis first meta-analysis of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer demonstrates exceptional efficacy. Pooled data show a 95.5% overall response rate and a 45.5% pathological complete response rate—significantly higher than with chemotherapy alone—along with a manageable safety profile. This provides strong preliminary evidence for neoadjuvant chemo-immunotherapy as a highly effective, fertility-preserving strategy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHow this study might affect research, practice or policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese findings justify larger trials comparing neoadjuvant chemo-immunotherapy to standard therapies and support its consideration in clinical discussions for fertility preservation . The compelling data may also inform future guideline updates, potentially establishing neoadjuvant chemo-immunotherapy as a recommended option for specific patient subgroups.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCervical cancer persists as a major contributor to global female morbidity and mortality, where locally advanced cervical cancer (LACC), accounting for approximately 37% of cases, presents particularly grave threats to survival outcomes and quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Characterized by tumors\u0026thinsp;\u0026ge;\u0026thinsp;4 cm (FIGO stages IB3-IVA) without distant metastasis, LACC is currently treated with concurrent chemoradiotherapy (CCRT) as per international guidelines, though this approach yields suboptimal therapeutic outcomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 30% of patients develop recurrence or metastasis following CCRT, highlighting its limitations in achieving sustained disease control [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The treatment paradigm further raises concerns regarding substantial late-term toxicities, including ovarian failure (premature menopause in 70\u0026ndash;100% of premenopausal women), sexual dysfunction, and radiation-induced vaginal fibrosis-sequelae particularly detrimental to young patients pursuing fertility preservation [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeoadjuvant chemotherapy followed by radical surgery(NACT-S) represents a potential alternative for resectable LACC (FIGO IB3-IIA2), theoretically enabling tumor downstaging and fertility preservation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, current evidence remains inconclusive, with meta-analyses showing comparable 3-year overall survival (HR\u0026thinsp;=\u0026thinsp;0.97, 95% CI: 0.69\u0026ndash;1.24, p\u0026thinsp;=\u0026thinsp;0.841) and 5-year progression-free survival (HR\u0026thinsp;=\u0026thinsp;0.89, 95% CI: 0.71\u0026ndash;1.08, p\u0026thinsp;=\u0026thinsp;0.268) between NACT-S and CCRT cohorts [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Clinical implementation faces additional hurdles, as 12.0%-29.1% of patients exhibit suboptimal pathological responses (\u0026lt;\u0026thinsp;50% tumor regression), resulting in deferred definitive treatment and frequent requirement for adjuvant therapies that escalate healthcare costs and complication risks [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Such limitations emphasize the necessity to augment NACT efficacy through strategic therapeutic combinations.\u003c/p\u003e \u003cp\u003eIn mismatch repair-deficient or microsatellite instability-high locally advanced rectal cancer, anti-PD-1 therapy enables clinical complete response in most patients, avoiding chemoradiation and surgical morbidity. A phase II trial evaluated sintilimab (anti-PD-1) as neoadjuvant therapy for dMMR locally advanced rectal cancer [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patients received four cycles of sintilimab followed by: surgery with adjuvant therapy, four additional immunotherapy cycles before surgery, or surveillance for clinical complete responders. Of 17 patients enrolled, 16 were evaluable: 15 demonstrated tumor regression. Six underwent surgery with three achieving pathological complete response (pCR); nine attained clinical complete response and entered surveillance; one discontinued due to adverse events. The overall complete response rate reached 75%. Median time to complete CR was 5.2 months, suggesting the promising alternative conservative treatment with immunotherapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].Beyond colorectal cancer, an ongoing trial (NCT06278857) is assessing dostarlimab (anti-PD-1) efficacy in early-stage dMMR endometrioid endometrial adenocarcinoma [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe oncology landscape has been transformed by immunotherapy advances, particularly immune checkpoint inhibitors (ICIs) demonstrating robust efficacy in multiple advanced cancers. Cervical cancer exhibits molecular features that provide a strong rationale for immunotherapy, such as high tumor mutational burden, microsatellite instability, elevated programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression, and inflammatory tumor microenvironments [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. HPV-infected tumor cells evade immune responses partly through upregulated PD-L1 expression, which inhibits T-lymphocyte activation via PD-1/PD-L1 interactions. High PD-L1 expression (reported in 35\u0026ndash;96% of cervical cancers) suggests ICIs can reverse immune evasion mechanisms [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Pivotal trials have established immunochemotherapy as a new standard: KEYNOTE-826 demonstrated pembrolizumab combined with chemotherapy (\u0026plusmn;\u0026thinsp;bevacizumab) significantly improved median overall survival (29.6 vs. 26.4 months; HR 0.67) and objective response rates (66.2% vs. 51.5%) over chemotherapy alone in recurrent/metastatic disease [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The COMPASSION-16 trial further validated this synergy, where cadonilimab (a PD-1/CTLA-4 bispecific antibody) plus chemotherapy achieved superior median progression-free survival (12.7 vs. 8.1 months; HR 0.43) and 24-month overall survival rates (62.6% vs. 48.4%) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Mechanistically, preclinical models reveal chemotherapy enhances tumor immunogenicity through immunogenic cell death and PD-L1 upregulation (PD-L1\u0026thinsp;+\u0026thinsp;cells increase from 43.75% to 87.5% in the tumor microenvironment), thereby potentiating ICI efficacy [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This biological synergy provides compelling rationale for incorporating ICIs into neoadjuvant protocols. However, the utility of combining ICIs with NACT specifically remains underexplored, with only preliminary data from small-scale trials [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. As ongoing studies investigate this approach, a synthesis of current evidence is critical to evaluate its safety and efficacy, inform clinical practice, and guide future research. This systematic review and meta-analysis therefore seeks to consolidate current knowledge on neoadjuvant chemo-immunotherapy for LACC, addressing a crucial evidence gap in developing precision-based, patient-tailored treatment frameworks.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy and study selection\u003c/h2\u003e \u003cp\u003eA systematic search was conducted across four electronic databases (PubMed, Web of Science, Cochrane Library, and Embase) from inception through March 2025. Search terms encompassed \"cervical cancer\", \"neoadjuvant OR preoperative OR perioperative\", and \"programmed cell death 1 (PD-1) OR programmed cell death ligand 1 (PD-L1) OR cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)\", supplemented by specific immune checkpoint inhibitor agents including \"pembrolizumab, durvalumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, and tislelizumab\". Relevant abstracts from major international congresses were screened, with only English-language publications considered eligible.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eStudies were included if they satisfied all the following criteria: enrollment of patients with locally advanced cervical cancer; administration of neoadjuvant chemotherapy combined with PD-1/PD-L1 inhibitors as the primary intervention; phase II/III clinical trial or retrospective study design; and reported outcomes including pathological complete response rate (pCR), objective response rate (ORR), and adverse events (AEs). Tumor response assessment required application of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, while AEs were graded per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All studies failing to meet these criteria were excluded.\u003c/p\u003e\n\u003ch3\u003eData extraction and outcomes measures\u003c/h3\u003e\n\u003cp\u003eExtracted data comprised study characteristics (first author, publication year, country, recruitment period, sample size, median age, median follow-up duration, FIGO stage distribution, treatment regimen specifics, and reported endpoints). Efficacy assessments included pCR defined as absence of residual viable tumor cells in surgical specimens following neoadjuvant therapy and resection; ORR defined as proportion of patients achieving complete or partial response according to RECIST 1.1; and disease control rate (DCR) calculated as the proportion with complete response, partial response, or stable disease. Safety evaluation focused on incidence of all-grade AEs and specifically grade\u0026thinsp;\u0026ge;\u0026thinsp;3 immune-related adverse events (irAEs), with severity graded according to National Cancer Institute CTCAE version 4 or 5 criteria.\u003c/p\u003e\n\u003ch3\u003eQuality assessment and risk of bias\u003c/h3\u003e\n\u003cp\u003eTwo independent investigators (MW and JQX) performed data extraction, with discrepancies resolved by a third reviewer. Methodological quality of non-randomized studies was evaluated using the Methodological Index for Non-Randomized Studies instrument, which contains eight items scored 0\u0026ndash;2 (maximum 16 points). Studies scoring\u0026thinsp;\u0026gt;\u0026thinsp;9 points were designated high quality.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFunnel plots generated in Review Manager 5.3 assessed publication bias. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated via Mantel-Haenszel methods. Heterogeneity was quantified using chi-square tests and I\u0026sup2; statistics, with random-effects models applied when I\u0026sup2; \u0026gt;50% and P\u0026thinsp;\u0026lt;\u0026thinsp;0.1; otherwise, fixed-effects models were used. Proportions approaching 0 or 1 underwent Freeman-Tukey double arcsine transformation prior to meta-analysis. Sensitivity analyses evaluated result robustness.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and characteristics\u003c/h2\u003e \u003cp\u003eSystematic screening identified 85 records from four databases and international congress abstracts (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Following duplicate removal and title/abstract assessment, eight studies underwent full-text review. Five were excluded due to inaccessible full texts, duplicate reports, or non-conforming study designs. Three studies ultimately met inclusion criteria and were included in the meta-analysis: two clinical trials (NCT04516616, NCT04799639) and one prospective investigation (ChiCTR2200065392) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These single-arm studies collectively enrolled 162 patients with locally advanced cervical cancer in China (Table\u0026nbsp;1), with median follow-up durations ranging from 11 to 17 months. All participants received neoadjuvant chemotherapy combined with PD-1/PD-L1 inhibitors administered every 3 weeks for 3 cycles. Tumor response and surgical outcomes are comprehensively detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Methodological quality assessment using the MINORS instrument confirmed high study quality (scores\u0026thinsp;\u0026gt;\u0026thinsp;9; Supplemental Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 1. \u003c/strong\u003e\u003cstrong\u003eBaseline characteristics of the included studies.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eStudy\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eCountry\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eClinical Trial\u003c/div\u003e\n \u003cdiv\u003eRegistry Identifier\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eRecruitment period\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eSample\u003c/div\u003e\n \u003cdiv\u003esize\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eMedian Age(years)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eFIGO stage\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eMedian\u003c/div\u003e\n \u003cdiv\u003efollow-up\u003c/div\u003e\n \u003cdiv\u003emonths\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eTreatment\u003c/div\u003e\n \u003cdiv\u003e(PD−1 inhibitors+chemotherapy)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv\u003eEndpoints\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eLi et al.2024\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eChina\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eNCT04516616\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eDecember 2020 to February 2023\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cdiv\u003e85\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003e51\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eIB3/IIA2 IIB/IIIC1r\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003e11 (IQR 6−14.5)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eCamrelizumab 200 mg+\u003c/div\u003e\n \u003cdiv\u003eNab-paclitaxel, 260 mg/m²+ Cisplatin 75–80 mg/m²every 3 weeks for 3 cycles\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eORR, AEs\u003c/div\u003e\n \u003cdiv\u003epCR, EFS\u003c/div\u003e\n \u003cdiv\u003eOS\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eWan et al.2024\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eChina\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eNCT04799639\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eMarch 2021 to February 2024\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cdiv\u003e47\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eNR\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eIB3/IIA2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003e17 (range1−35)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eSindilimab 200mg+\u003c/div\u003e\n \u003cdiv\u003ePaclitaxel 150mg/m\u003csup\u003e2\u003c/sup\u003e+Cisplantin 70mg/m²every 3 weeks for 3 cycles\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003epCR, ORR\u003c/div\u003e\n \u003cdiv\u003eAEs, PFS\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eSheng et al.\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eChina\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eChiCTR2200065392\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eNovember 2022\u003c/div\u003e\n \u003cdiv\u003eto March 2024\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cdiv\u003e30\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003e51.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eIB3/IIA2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003e14.7(IQR 11.6–21.4)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003eTislelizumab 200 mg + Paclitaxel 175 mg/m² + Cisplatin 60 mg/m² or Carboplatin AUC 5 every\u003c/div\u003e\n \u003cdiv\u003e3 weeks for 3 cycles\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv\u003epCR, ORR\u003c/div\u003e\n \u003cdiv\u003eAEs\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eNote: \u003c/strong\u003eORR, overall response rate; pCR, pathological complete response;OS, overall survival; EFS, event-free survival; PFS, progression-free survival; AEs, adverse events; NR, not reported.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe surgery information of patients after NACI.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\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\u003eComplete\u003c/p\u003e \u003cp\u003eevaluated\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003esurgery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003epCR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eoptimal remission rate*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eadjuvant treatment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi et al.2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83/85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 ( CR 16\u0026thinsp;+\u0026thinsp;PR 67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81/83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32/81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSSC/AC/ASCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20/32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWan et al.2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43/47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSSC/AC/ASCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSheng et al.2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30/30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27( CR 17\u0026thinsp;+\u0026thinsp;PR 10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30/30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20/30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24/30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSSC/AC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7/30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eTumor response​\u003c/b\u003e​\u003c/p\u003e \u003cp\u003eAll included studies reported efficacy outcomes. The pooled ORR was 95.5% (95% CI: 90.8\u0026ndash;98.6%; fixed-effects model; I\u0026sup2; = 29.0%, P\u0026thinsp;=\u0026thinsp;0.245; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). pCR rates varied from 32.6% to 66.7%, with the highest pCR observed in the tislelizumab cohort (66.7%). Meta-analysis yielded a pooled pCR of 45.5% (95% CI: 27.7\u0026ndash;63.2%; random-effects model; I\u0026sup2; = 80.2%, P\u0026thinsp;=\u0026thinsp;0.006; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Sensitivity analysis confirmed result robustness (Supplemental Figure S2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSafety of NACI\u003c/h3\u003e\n\u003cp\u003eAEs are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Hematologic toxicities predominated, primarily comprising grade 1\u0026ndash;2 events(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Camrelizumab was associated with elevated leukopenia rates, while lymphopenia was frequent in both camrelizumab and tislelizumab groups. Among sintilizumab-treated patients, 32% (15/47) experienced grade 3\u0026ndash;4 neutropenia. The pooled rate of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs was 35.5% (95% CI: 28.2\u0026ndash;42.9%), with grade 1\u0026ndash;2 skin rash occurring in 21.0% of patients (95% CI: 4.7\u0026ndash;37.4%; Supplemental Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\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 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events of the included studies(CTCAE 5.0).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eLi et al.2024\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eWan et al.2024\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eSheng et al.2024\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade I-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade III-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade I-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGrade III-IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGrade I-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGrade III-IV\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43(51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16(53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21(25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23(77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4(13%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21(70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\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\u003e17(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15(32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(3%)\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(16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoalbuminaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21(70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9(30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8(17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2(7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypocalcaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypokalaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperglycemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3(10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-glutamyl transferase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased appetite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlopecia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38(45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33(39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin rash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17(36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItching\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache/Pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal feeling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4(13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGuillain-Barr\u0026eacute; syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower extremity venous thrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHematologic toxicities of the included studies (CTCAE 5.0).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGrade I-II\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGrade III-IV\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eES % ,(95 CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eI2 ,%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eES % ,(95 CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI2 ,%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.29(0.09\u0026ndash;0.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14 (0.03\u0026ndash;0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.50 (0.13\u0026ndash;0.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.03 (0.00\u0026minus;0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.52(0.03\u0026minus;1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20 (0.09\u0026ndash;0.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin rash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.21(0.05\u0026ndash;0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.36 (0.28\u0026ndash;0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSummary of Main Results:\u003c/h2\u003e \u003cp\u003eThe advent of immune checkpoint inhibitors has revolutionized the treatment landscape for cervical cancer. This meta-analysis synthesizes evidence on neoadjuvant PD-1/PD-L1 inhibitors combined with chemotherapy in LACC, suggesting favorable tolerability and enhanced tumor response.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eResults in the Context of Published Literature:\u003c/h2\u003e \u003cp\u003ePD-1/PD-L1 inhibitors alleviate immune checkpoint suppression on T cells, activating cancer-specific immunity. Anti-PD-1 antibodies (e.g., camrelizumab, tislelizumab) restore cytotoxic T lymphocyte activity and promote memory T-cell differentiation for potential long-term protection [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].PD-L1 expression, prevalent in cervical cancer, correlates with stromal tumor-infiltrating lymphocytes (TILs) [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Neoadjuvant chemotherapy modulates the tumor immune microenvironment by increasing dendritic cells, CD3+/CD4+/CD8\u0026thinsp;+\u0026thinsp;T cells, and reducing regulatory T cells [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It enhances neoantigen presentation, induces immunogenic cell death, alters cytokine profiles, downregulates myeloid-derived suppressor cells and Tregs, and influences PD-1/PD-L1 expression [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Pooled analysis revealed an ORR of 95.5% (95% CI: 90.8\u0026ndash;98.6%) and pCR of 45.5% (95% CI: 27.7\u0026ndash;63.2%), significantly surpassing chemotherapy-alone outcomes. These results align with emerging evidence: Wan et al. reported 98% ORR and 33% pCR with camrelizumab [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], while ChiCTR2200065392 documented 90% ORR and 67% pCR with tislelizumab. Li et al. corroborated these findings (98% ORR, 39% pCR; 95% surgery completion) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and Weaknesses:\u003c/h2\u003e \u003cp\u003eThe safety profile of PD-1/PD-L1 inhibitors plus chemotherapy appears manageable. irAEs occur in 15\u0026ndash;90% of patients, predominantly skin toxicity, hypothyroidism, hepatotoxicity, and pneumonitis [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Prior studies reported grade 3\u0026ndash;4 adverse events in 12.2\u0026ndash;33% [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Our pooled grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AE rate was 35.5% (95% CI: 28.2\u0026ndash;42.9%), with most events being grade 1\u0026ndash;2. Notably, camrelizumab showed higher rates of grade 3\u0026ndash;4 AEs, and with increased leukopenia/lymphopenia.\u003c/p\u003e \u003cp\u003eThere is also some limitations of this study. First, the sample sizes were relatively small. These factors may limit the clinical using of the findings to other populations. Second, long term survival outcomes of the three studies is still unclear. Future research should focus on large-scale randomized controlled trials to validate the pathological complete responses of neoadjuvant immunotherapy in diverse populations and across different PD-1/PD-L1 inhibitors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImplications for Practice and Future Research:\u003c/h2\u003e \u003cp\u003eThree additional ongoing clinical trials are evaluating novel neoadjuvant approaches: NCT04238988 (pembrolizumab plus chemotherapy), NCT05013268 (tislelizumab combined with chemotherapy), and CTR20220443 (cadonilimab [a PD-1/CTLA-4 bispecific antibody] monotherapy). Except for NACI comnbined with surgery, ICIs also showed promising results when combined with radiaiton. The KEYNOTE-A18 trial demonstrated superior 24-month progression-free survival with pembrolizumab-CCRT versus CCRT alone (73% vs. 57%) in high-risk LACC [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], supporting earlier immunotherapy integration. Another multicenter phase II/III trial (NCT06288373) is evaluating neoadjuvant cisplatin/nab-paclitaxel plus camrelizumab versus CCRT in FIGO 2018 IB3-IIB (\u0026gt;\u0026thinsp;4 cm) LACC, potentially establishing a new neoadjuvant paradigm. However, whether ICIs treatment provide chances to allow lower radiation dosage is still unclear.\u003c/p\u003e \u003cp\u003eLiquid biopsy advances also promote the detection of minimal residual disease (MRD). HPV cell-free DNA represents a specific biomarker given HPV's causal role in cervical cancer, particularly valuable where vaccination/screening access is limited [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. A prospective multicenter study (n\u0026thinsp;=\u0026thinsp;70) validated HPV circulating tumor DNA (ctDNA) for relapse prediction: detectable ctDNA post-chemoradiation significantly associated with inferior 2-year progression-free survival (82% vs. 24% undetectable at 3 months; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; median lead time 5.9 months). Multivariable analyses confirmed ctDNA as an independent prognostic factor, enabling early high-risk identification [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].Based on the above results, post-NACI monitoring with combined cervical biopsies, MRD testing, and imaging may allow surgery de-escalation or omission for patients with imaging resolution and negative MRD.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion,the combination of chemotherapy and PD-1/PD-L1 inhibitors achieved a promising pathological complete response with a tolerable toxicity which supports its further use in the special population, such as younger patients. Also, further studies are needed to explore its most suitable population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eICIs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune checkpoint inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eLACC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elocally advanced cervical cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNACI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneoadjuvant chemotherapy plus immune checkpoint inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003epCR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epathological complete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eORR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eobjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eAE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCCRT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econcurrent chemo-radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePD-1\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed cell death 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePD-L1\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed cell death ligand-1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRECIST\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eresponse Evaluation Criteria in Solid Tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDCR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease control rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eirAEs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune-related adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ectDNA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecirculating tumor DNA.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All data generated or analysed during this study are included in this published article[and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict Interests:\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThere is no funding support of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Ming Wang and Jianqing Xu\u003c/p\u003e\n\u003cp\u003eData collection and analysis : Ming Wang, Jianqing Xu, Lin Zhu and Jing Chen\u003c/p\u003e\n\u003cp\u003eManuscript writing: Jianqing Xu\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWriting review and editing: Ming Wang, Lin Zhu\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript: All authors\u003c/p\u003e\n\u003cp\u003eAccountable for all aspects of the work: All authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H, et al. 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Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer. J Clin Oncol. 2024;42(4):431\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.23.00954\u003c/span\u003e\u003cspan address=\"10.1200/JCO.23.00954\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"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":"Cervical Cancer, Neoadjuvant Chemotherapy, PD-1/PD-L1 inhibitors, Pathological Complete Response, Adverse Events","lastPublishedDoi":"10.21203/rs.3.rs-9393686/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9393686/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitors (ICIs) enable organ preservation strategies and surgical de-escalation in multiple cancers.In locally advanced cervical cancer (LACC), neoadjuvant chemotherapy plus immune checkpoint inhibitors (NACI) may improve tumor response and enable fertility-sparing strategies.This study conducted a systematic review and meta-analysis to evaluate the response rates and safety of NACI in LACC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe systematically searched PubMed, Web of Science, Cochrane Library, and Embase from inception to March 2025, including major congress abstracts. Phase II/III trials or retrospective analyses reporting pathological complete response (pCR), objective response rate (ORR), and adverse events (AEs) for NACI in LACC were included. Two investigators independently extracted data. Pooled rates were calculated using STATA 18.0 with random-effects models (I\u0026sup2; statistic assessed heterogeneity).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThree clinical studies involving 162 patients with locally advanced cervical cancer were included in the meta-analysis. The pooled ORR was 95.5% (95% confidence interval [CI],90.8\u0026ndash;98.6%), while the pooled pCR rate was 45.5% (95% CI, 27.7\u0026ndash;63.2%). Grade 3 or higher AEs occurred at a pooled rate of 35.5% (95% CI, 28.2\u0026ndash;42.9%). Sensitivity analysis confirmed the reliability of the meta-analytic findings.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe combination of chemotherapy and PD-1/PD-L1 inhibitors achieved 45.5% pCR and tolerable toxicity which supports its potential role in fertility preservation strategies.\u003c/p\u003e","manuscriptTitle":"The efficacy and safety of neoadjuvant chemotherapy plus immune check point inhibitors for locally advanced cervical cancer: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 05:37:34","doi":"10.21203/rs.3.rs-9393686/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-13T21:23:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"240590727193224846155673250772993619214","date":"2026-04-30T18:29:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-28T09:06:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-28T09:05:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-28T01:15:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-27T15:46:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-04-27T14:58:30+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":"c081d3c8-9b1d-4763-9a49-6867477e0965","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-13T21:23:25+00:00","index":87,"fulltext":""},{"type":"reviewerAgreed","content":"240590727193224846155673250772993619214","date":"2026-04-30T18:29:53+00:00","index":37,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T05:37:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 05:37:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9393686","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9393686","identity":"rs-9393686","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}