Efficacy of concurrent intensity modulated chemoradiotherapy combined with induction chemotherapy or adjuvant chemotherapy in the treatment of locally advanced cervical cancer with 2018FIGO stage correction：a multicenter Retrospective Cohort Study

Efficacy of concurrent intensity modulated chemoradiotherapy combined with induction chemotherapy or adjuvant chemotherapy in the treatment of locally advanced cervical cancer with 2018FIGO stage correction：a multicenter Retrospective Cohort Study | 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 Efficacy of concurrent intensity modulated chemoradiotherapy combined with induction chemotherapy or adjuvant chemotherapy in the treatment of locally advanced cervical cancer with 2018FIGO stage correction：a multicenter Retrospective Cohort Study Shaojun Chen, Li Hua, Lulu Chen, Manyun Liao, Yurong Chen, Guilan Yang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7409240/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and purpose Concurrent chemoradiotherapy (CCRT) is currently the standard treatment for locally advanced cervical cancer (LACC), but there is a lot of room for treatment strategies improvement and the 5-year survival rate of patients is low, Comprehensive treatment is the treatment direction for LACC, The current comprehensive treatment models for LACC mainly include induction chemotherapy (IC) plus CCRT and CCRT plus adjuvant chemotherapy (AC),but it remains unclear which is optimal sequence of combined chemotherapy. The purpose of this study is to retrospectively report the outcome of long-term survival and related toxicity that IC plus CCRT versus CCRT plus AC in LACC. Materials/Methods: From December 2016 to December 2022, 525 patients of LACC with 2009FIGO(IB2, IIA2, and IIB-IVA)/2018FIGO staging༈IB3, IIA2, and IIB-IVA༉who initially underwent IC plus CCRT or CCRT plus AC from the Forth Affiliated Hospital of Guangxi Medical University, Yulin First People's Hospital and Liuzhou Hospital of Guangzhou Women and Children's Medical Center. All patients with 2009FIGO༈IB2, IIA2, and IIB-IVA༉were re-staged after 2018FIGO staging༈IB3, IIA2, and IIB-IVA༉correction. All patients were treated with IMRT to 50.4 Gy with concurrent weekly cisplatin 40 mg/m2 followed by intra-cavitary brachytherapy. The IC plus CCRT group received platinum-based combined chemotherapy with two or three cycles before CCRT. CCRT plus AC group received platinum-based combined chemotherapy with two cycles after CCRT. Propensity score matching (PSM) method was used to match the proportion of 1:1 between the neoadjuvant treatment group and the adjuvant treatment group,5-year overall survival (OS), 5-year progression free Survival survival(PFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and treatment-related adverse reactions were evaluated and compared between the two groups.Cox proportional hazard regression model was used to analyze the effect of neoadjuvant or adjuvant therapy on the survival of patients with locally advanced cervical cancer. Results A total of 525 patients with complete follow-up data are available were included our study. Among these patients, 250 patients were treated with IC plus CCRT and 275 patients were treated with CCRT plus AC. IC/AC regimens included TP/DP(cisplatin + Paclitaxel/Docetaxel) and TC/DC(carboplatin་Paclitaxel/Docetaxel). The median follow-up of 56 months (range 20–80 ). Before propensity score matching(PSM), there were no significant differences in survival rates between the neoadjuvant treatment group and the adjuvant treatment group ( P > 0.05). After propensity score matching(191 matched pairs), there were also no significant differences between the two group on the 5-year OS rates (83.9% vs. 84.7%), PFS rates (76.0% vs. 71.4%) or LRFS rates (79.3% vs 76.5%)and DMFS rates (88.7% vs 89.1%)) (all P > 0.05).But Subgroup analysis revealed that CCRT plus AC showed a trend of improving OS (HR = 0.455, 95% CI (0.206–1.006), P = 0.052) in 2018FIGO III-IVA stage and was associated with significantly improved OS(HR = 0.191,95%CI (0.057–0.641), P = 0.007), PFS(HR = 0.288,95%CI(0.118–0.702), P = 0.006) ,DMFS(HR = 0.211, 95% CI (0.068–0.654), P = 0.007) in patients with positive pelvic lymph nodes. IC plus CCRT was associated with significantly improved PFS (HR = 2.276, 95% CI (1.187–4.363), P = 0.013) in 2018FIGO IIB stage. There was no significant difference in adverse events between the two groups ( P > 0.05). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for OS, PFS, LRFS and Pathology and LNMS were an independent risk factor for DMFS Conclusion There is no statistical difference between IC plus CCRT and CCRT plus AC in the outcome of long-term survival of LACC. However, for patients with stage III-IVA advanced cervical cancer, the CCRT plus AC shows a trend of improving survival benefits, especially for those with pelvic lymph node metastasis, where the benefit is more significant. For stage IIB patients, IC plus CCRT can reduce the risk of local progression. Lymph node status is a key decision factor: patients with positive pelvic lymph nodes should prioritize CCRT plus AC for enhanced treatment. Locally advanced cervical cancer Induction chemotherapy Adjuvant chemotherapy Chemoradiotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Cervical cancer remains the second most prevalent gynecological malignancy worldwide, with over 80% of cases occurring in developing countries. Recent epidemiological data reveal both increasing incidence rates and a concerning trend toward younger patient demographics [1] . The insidious nature of early-stage disease frequently leads to delayed diagnosis, with most patients presenting at advanced clinical stages (IIB-IVA) [2–3] . Current clinical staging classifications underwent significant revision in 2018, with the FIGO system updating the broad definition of LACC from IB2-IVA (FIGO 2009) to IB3-IVA(FIGO 2018). Therapeutic strategies for locally cervical cancer primarily involve two modalities: radical surgery (applicable to select cases) and definitive radiotherapy, with the latter constituting the mainstay of treatment [4] . The standard treatment for newly diagnosed IB2 (FIGO2009) or IB3 (FIGO 2018)、IIA2 and IIB-IVA cervical cancer involves cisplatin-based CCRT. While the National Comprehensive Cancer Network (NCCN) guidelines classify this approach as a Category 1 recommendation, The 5-year progression free survival rate is still low, which means that many patients have not meant cured. Therefore, there is always for further optimization and improvement of the prevailing treatment mode of LACC radical radiotherapy combined with concurrent chemotherapy to improve the outcome and survival prognosis of disease progression in these patients. Current research focuses on integrating CCRT with either IC/AC. the clinical utility of various chemotherapy sequencing protocols with CCRT requires further elucidation. Methods Eligibility criteria We conducted a retrospective cohort study of patients with newly diagnosed LACC, pathologically confirmed under FIGO 2009 criteria and subsequently restaged according to FIGO 2018. The study population comprised patients treated at three regional cancer centers in Guangxi:The Fourth Affiliated Hospital of Guangxi Medical University, Yulin Municipal People's Hospital, and Liuzhou Hospital of Guangzhou Women and Children's Medical Center from December 2016 to December 2022. All participants received either IC + CCRT or CCRT followed by CCRT + AC. Treatment protocols featured intensity-modulated radiation therapy (IMRT) delivering 50.4 Gy with concurrent weekly cisplatin (40 mg/m²), followed by intracavitary brachytherapy. The IC + CCRT cohort received 2–3 cycles of platinum-based combination chemotherapy prior to CCRT, while the CCRT + AC cohort underwent 2 cycles post-CCRT. Concurrent chemotherapy duration was individualized (5–6 cycles) based on treatment tolerance. Comprehensive data collection included clinical assessments, diagnostic imaging (abdominopelvic MRI, chest CT, whole-body bone scintigraphy), inguinal lymph node ultrasonography, hematological profiles, and serum biochemistry. Tumor characteristics (stage, lymph node status), biochemical parameters, and Eastern Cooperative Oncology Group (ECOG) performance status were systematically documented and analyzed. Radiotherapy Patients underwent radiotherapy employing intensity-modulated radiation therapy (IMRT) techniques. The gross tumor volume (GTV), which included the primary tumor (GTV-P) and lymph node tumor volume (GTV-LN), was demarcated based on the visible extent of the tumor as identified by CT/MRI scans and clinical examinations, adhering to the guidelines of the International Commission on Radiation Units and Measurements Report 89 (ICRU89). The radiation treatment was delivered in 5 fractions weekly over a 6-week period, with dose limits to organs-at-risk conforming to the guidelines set by the Radiation Therapy Oncology Group (RTOG). Gross Tumor Volume (GTV) includes imaging diagnosis of pelvic and paraaortic lymph node metastases. Clinical Target Volume (CTV) includes the uterus, cervix, partial vagina, pelvic lymph node drainage area (including the iliac common, inner and outer areas, obturator area, and sacral anterior area), and paraaortic lymph node drainage area.The delineation of the lymphatic drainage area is based on the expert consensus of RTOG in 2008 on the delineation of the target area for cervical cancer radiotherapy. The prescription dosage is PCTV 50.4Gy/28f and PGTVnd 61.60Gy/28f.The plan design requires the prescription dosage to be wrapped around 100% CTV and 95% PTV.During the treatment period, CBCT (Cone Beam Computed Tomography) was performed 1–2 times a week, and IMRT was performed 5 times a week for a total of 5–6 weeks. Limit of dose to organs at risk: Rectal V50Gy ≤ 50%; Bladder V50Gy ≤ 50%; Femoral head V50Gy ≤ 5%; Spinal cord Dmax ≤ 45Gy; Small intestine V50Gy ≤ 10–15%; Renal V20Gy ≤ 25%; Liver V30Gy ≤ 30%.All patients received three-dimensional brachytherapy design ,DT36 Gy, 6 Gy x 6 times. Depending on the reduction of cervical local tumors, the number and dose of intracavitary radiotherapy were increased if necessary. No external radiotherapy was given on the day of intracavitary radiotherapy.. Chemotherapy regimen IC started 6 ~ 8 weeks follow up CCRT, and AC after CCRT respectively. The IC and AC groups all received platinum-based combined chemotherapy. IC/AC regimens included TP/DP (cisplatin་Paclitaxel/Docetaxel) and TC/DC(carboplatin་Paclitaxel/Docetaxel). IC regimens included TP /DP (Paclitaxel135-150mg/m2 /docetaxel 75 mg/m2 D1,cisplatin 75 mg/m2 D1, every 3 weeks) or TC/DC (Paclitaxel135-150mg/m2 /docetaxel 75 mg/m 2 D1,carboplatin AUC 4–5 D1, every 3 weeks). AC regimens included TP/DP and TC/DC. Data was gathered on all patients undergoing concurrent chemoradiation, which was scheduled of radiotherapy.The regimen comprised weekly intravenous infusions of cisplatin (40mg/m2) throughout the radiotherapy period, limited to a maximum of 5–6 cycles. Full-dose chemotherapy was administered as per the protocol, with the option to adjust the cisplatin dosage in response to toxicity. The chemotherapy dosage was adaptable, allowing for a reduction of up to 20% or even complete discontinuation, contingent upon the severity of side effects. In instances of grade 3–4 or more severe toxicity, chemotherapy administration could be delayed. Follow-up and patient assessment All patients underwent thorough evaluations at regular intervals. These evaluations included clinical examinations and toxicity monitoring every 3 months for the first 2 years post-concurrent chemoradiation, and semi-annually from years 3 to 5. Beyond 5 years, annual reviews were conducted. Detailed data were meticulously collected. Local recurrences were confirmed through MRI imaging of the abdomen and pelvic cavity, CT scans of the chest, whole-body bone scans, inguinal ultrasound, Regional recurrences were diagnosed by physical examination, fine-needle aspiration, or additional MRI/CT scans. Distant metastases were identified based on clinical symptoms, physical examination, and the previously mentioned imaging methods. The response to IC and CCRT was assessed using the Response Evaluation Criteria in Solid Tumors, according to the Revised RECIST guidelines (version 1.1). Adverse events during treatment were graded using the Common Terminology Criteria for Adverse Events (CTCAE version 3.0), with the assessment of toxic side effects based on the classification of acute radiation injury. Endpoints The main goal of our research was to evaluate and contrast the 5-year OS rates and PFS between two group after 2018FIGO staging correction, one receiving IC prior to CCRT, and the other undergoing CCRT followed by AC. This comparison was made by measuring the time from the commencement of treatment to the date of death due to any cause, or to the last follow-up date. The secondary endpoints included LRFS, DMFS and treatment-related toxicity. PFS was determined by the period from the beginning of treatment until the first recurrence or the last follow-up date. LRFS was determined by the period from the beginning of treatment until the first locoregional recurrence or the last follow-up date. Likewise, DMFS was assessed from the start of treatment to the identification of the first distant metastasis or the last follow-up date. Statistical Analysis Descriptive statistics, T tests, and Chi-square tests were employed to summarize patient characteristics. Propensity score matching (1:1 ratio) balanced pretreatment variables (age, ps scores, pathology, FIGO Stage, tumor et al.). OS, PFS, LRFS, and DMFS were computed using the Kaplan-Meier method, with group differences assessed via the Log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using the Cox proportional hazards model. Main toxicity outcomes were compared using the Chi-square test or Fisher’s exact test when required. Kaplan-Meier survival curves, forest plots for Cox regression results, and bar charts depicting adverse event profiles—were generated using R statistical software(version 4.4) Results Patient characteristics Data of 525 ligible patients with diagnosed LACC with 2009FIGO(IB2, IIA2, and IIB-IVA)who initially underwent IC plus CCRT or CCRT plus AC from the Forth Affiliated Hospital of Guangxi Medical University,Yulin First People's Hospital and Liuzhou Hospital of Guangzhou Women and Children's Medical Center.All patients were re-staged after 2018FIGO staging༈IB3, IIA2, and IIB-IVA༉correction were analyzed, including 250 patients in the IC + CCRT group and 275 patients in the CCRT + AC group. The median follow-up of 50 months (range10-80). Table 1 outlines the comprehensive characteristics and staging details of the study participants before PSM. There was a statistically significant difference between the two groups in terms of age, PS scores and Tumor diameter ( P = 0.026, P = 0.006, P <0.001), and there was no significant difference between the two groups in terms of Pathology, FIGO. Stage, HPV, LNMS, Chemotherapy regimen, CCRT cycles. Baseline characteristics of both groups after PSM are presented in Table 2 , revealing no statistically significant differences in distribution. Survival Figure 1 Presented the OS of all patients. Figure 2 Displayed the Kaplan-Meier curves for 5-year OS, PFS, LRFS, and DMFS between the two groups before PSM. No significant differences were detected between the two groups on the 5 -year OS rates (82.2% vs. 82.4%), PFS rates(73.1% vs 70.2%), or LRFS rates (77.8% vs 75.9%) and DMFS rates (86.5% vs 89.1%)(all P > 0.05).After PSM (191 matched pairs), but also no significant differences were detected between the two groups on the 5-year OS rates (83.9% vs. 84.7%), PFS rates (76.0% vs. 71.4%) or LRFS rates (79.3% vs 76.5%)and DMFS rates (88.7% vs 89.1%)) (all P > 0.05). We carried out a subgroup analysis to assess efficacy based on independent evaluations, with subgroups established according to baseline stratification factors such as treatment modalities, 2018FIGO stage .As illustrated in Fig. 4, the subgroup analysis revealed that CCRT plus AC showed a trend of improving OS (HR = 0.455, 95% CI (0.206–1.006), P = 0.052) in 2018FIGO III-IVA stage, and AC was associated with significantly improved OS(HR = 0.191,95%CI(0.057–0.641),P = 0.007), PFS (HR = 0.288,95%CI(0.118–0.702), P = 0.006) ,DMFS(HR = 0.211, 95% CI (0.068–0.654), P = 0.007) in patients with positive pelvic lymph nodes. Figure 5–7, IC plus CCRT was associated with significantly improved PFS (HR = 2.276, 95% CI (1.187–4.363), P = 0.013) in 2018FIGO IIB. Figure 5 Unifactorial analysis of OS showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors ( P < 0.001, P < 0.001, P < 0.001, P = 0.001, respectively). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for OS ( P < 0.001, 0.037, < 0.001, 0.005). Table 3 . For PFS, Age, Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors ( P = 0.035, P < 0.001, P < 0.001, P < 0.001, P < 0.001, respectively). Multifactorial analysis showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were an independent risk factor for PFS ( P < 0.001, 0.004, < 0.001, 0.002). (Table 4 ). Unifactorial analysis of LRFS showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors ( P < 0.001, P < 0.001, P < 0.001, P < 0.001, respectively). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for LRFS ( P < 0.001, 0.016, < 0.001, 0.002). Table 5 . For DMFS, Age, Pathology, FIGO Stage and LNMS were the most significant factors ( P = 0.030, P < 0.001, P < 0.001, P < 0.001, respectively). Multifactorial analysis showed that relatively Pathology and LNMS were an independent risk factor for DMFS ( P < 0.001, < 0.001). (Table 6 ). Adverse Reactions No grade 5 toxicity, which refers to death due to adverse events, was observed throughout the course of treatment. The common acute adverse events the two groups were mainly hematotoxicity. Nausea, Vomiting, Anorexia, Fatigue, Neurotoxicity, Radiation Colitis, Radiation Cystitis, Radiation Vaginitis and Radiation Dermatitis among which the incidence of adverse events in the induction treatment group was slightly higher than that in the adjuvant treatment group, but the difference was not statistically significant (all P values were > 0.05, Table.7、Fig. 8). Discussion Current Therapeutic Landscape and Unmet Needs in LACC Management The current standard for LACC, as established by NCCN guidelines and supported by landmark trials (SWOG-8797, GOG-120, RTOG 90 − 01)[5–9], remains cisplatin-based CCRT. While alternative agents such as taxanes have demonstrated comparable efficacy with potentially reduced toxicity profiles [10–12], none have proven superior to cisplatin in terms of survival outcomes. This therapeutic plateau, evidenced by persistently suboptimal 5-year survival rates (< 66%) [13], underscores the critical need for optimized treatment strategies and has fueled ongoing investigation into the potential benefits of adjuvant or consolidation chemotherapy approaches [14–17]. Controversies in Adjuvant Chemotherapy: Evidence and Limitations The role of AC in LACC management remains controversial, with current evidence presenting a complex and often contradictory picture. While retrospective analyses and some clinical data suggest potential improvements in both progression-free survival (PFS) and OS [18], the phase III evidence base remains limited and inconsistent. Negative trials such as Lorvidhaya 2003 (n = 210), which found no benefit with 5-FU monotherapy [19], and OUTBACK (2021) [20], which showed no improvement in predominantly low-risk stage IB/II patients, contrast with more promising signals from studies like Dueñas-González 2015 (improved 3-year OS: 72% vs. 64%) [21] and ACTLACC (reduced distant metastases: 5.4% vs. 10.1%, P = 0.029) [22]. These discrepancies likely reflect significant heterogeneity in trial design, patient selection criteria, and evolving radiotherapy techniques. Importantly, the advent of modern intensity-modulated radiotherapy (IMRT) and the revised FIGO 2018 staging system (introducing stage IIIC) necessitate a critical reevaluation of historical data and treatment paradigms. Induction Chemotherapy: Reassessing the Evidence Base Early investigations of IC in LACC (pre-2016) were hampered by methodological limitations including small sample sizes and inconsistent outcome measures [23–25]. More recent phase III data present a mixed but potentially promising picture. The INTERLACE trial (2024) demonstrated significant improvements in both 5-year PFS (73% vs. 64%) and OS (80% vs. 72%) with paclitaxel/carboplatin IC [26], though its applicability to high-risk patients may be limited by the predominance (70%) of stage IIB cases. Conversely, the ASCO 2019 trial reported concerning results, with IC associated with worse 3-year PFS (40.9% vs. 60.4%) and OS (60.7% vs. 86.8%) [27], highlighting the potential risks of unselected application of this approach. Stage- and Risk-Adapted Therapeutic Strategies Our comprehensive analysis supports a paradigm shift toward more nuanced, risk-adapted treatment strategies for LACC: For stage IIB disease with parametrial invasion, IC followed by CCRT demonstrates particular promise, showing significant PFS benefits (HR = 2.276, 95%CI 1.187–4.363, P = 0.013) in our study. The mechanistic rationale for this approach lies in IC's ability to achieve meaningful tumor volume reduction, thereby optimizing subsequent IMRT delivery. This volumetric reduction enhances radiation precision while minimizing exposure to adjacent organs at risk, potentially explaining the observed improvements in local control. These findings are supported by multiple lines of evidence, including the EMBRACE-I trial's demonstration of increased local recurrence risk with larger tumor volumes [28], and RTOG 0417's validation of IMRT's dosimetric advantages [29]. For patients with more advanced disease (stage III-IVA) or lymph node involvement, our data strongly support the use of ACT following CCRT. This approach demonstrated a significant 14.2% reduction in distant metastasis risk ( P = 0.013) and improved OS in node-positive subgroups (HR = 0.211, 95% CI 0.068–0.654, P = 0.007). The biological basis for this benefit aligns with the conceptual framework proposed by Monk et al. [30], wherein lymph node metastases serve as conduits for systemic dissemination. Our findings are further corroborated by OUTBACK's subgroup analysis showing a 7% OS improvement in stage III-IVA patients [20] and a 2020 meta-analysis demonstrating 24% mortality risk reduction in stage III patients [31]. Critical Considerations and Future Directions Several key factors must inform the clinical implementation of these strategies: Patient Selection: The identification of pelvic lymph node metastasis emerges as a critical determinant of therapeutic approach, with node-positive patients deriving particular benefit from ACT (45.5% mortality risk reduction, HR = 0.455, 95% CI 0.206–1.006, P = 0.052). This underscores the importance of comprehensive nodal staging, potentially incorporating advanced imaging modalities like PET-CT. Technological Integration: The evolution of radiotherapy techniques, particularly the widespread adoption of IMRT, has fundamentally altered the therapeutic landscape. Future studies must account for these technological advances when evaluating chemotherapy sequencing strategies. Global Health Equity: With 85% of cervical cancer cases occurring in low- and middle-income countries (WHO, 2024), practical considerations of resource availability and treatment accessibility must guide protocol development. Strategies such as carboplatin substitution may help address financial toxicity while maintaining therapeutic efficacy. Conclusion and Clinical Implications While current guidelines appropriately maintain caution regarding routine incorporation of neoadjuvant or adjuvant chemotherapy, our findings support a more tailored approach guided by disease stage and nodal status. For stage IIB tumors with parametrial involvement, IC offers clear benefits in optimizing local control. Conversely, for advanced-stage or node-positive disease, ACT provides meaningful systemic protection against distant metastases. These risk-adapted strategies should be considered within the context of modern radiotherapy techniques and comprehensive staging. Future research must address several critical gaps: validation in larger, prospectively designed trials; development of predictive biomarkers to guide patient selection; and adaptation of protocols for resource-limited settings. By addressing these challenges, we may finally overcome the current therapeutic plateau in LACC management and achieve meaningful improvements in patient outcomes. Declarations Acknowledgement This study was supported by the important Scientific Research & Technology Development Plan with LACC from Science & Technology of Guangxi（AB21196104) Disclosure No competing financial interests relevant to this article exist. Authors' contributions S.Chen, L.Hua, L.Chen, M.Liao, Y.Chen,G.Yang,C,Feng, X.Wang ,Zhan Lin, D.Zeng ,Q.Shi S.Chen contributed to the study design, literature research, interpretation of findings and writing of themanuscript. L.Hua and L.Chen provided suggestion of statistics. L.Chen,M.Liao,Y.Chen,G.Yang contributed to the follow-up, data collection and analyses. ,and X.Wang ,Zhan Lin ,C.Feng contributed to review of data analyses, D.Zeng ,Q.Shi contributed to critical edit of the manuscript. All authors reviewed and approved the final manuscript. Availability of data and materials The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approval by the Ethics Committee of Yulin Municipal People's Hospital ,Liuzhou Hospital of Guangzhou Women and Children's Medical Center, The Forth Affiliated Hospital of Guangxi Medical University, written informed consent was obtained from each patient. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Yang H, Sun LX. Research progress of type Ⅱ endometrial cancer [J]. Cancer Research and Clinic, 2016, 28(4): 276–279. 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Neoadjuvant Chemotherapy With Cisplatin and Gemcitabine Followed by Chemoradiation Versus Chemoradiation for Locally Advanced Cervical Cancer:A Randomized Phase II Trial[J].J Clin Oncol, 2019,37(33):3124–3131. Tanderup, K, Nesvacil, N, Kirchheiner, K, et al. Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer. Semin Radiat Oncol. 2020; 30 (4): 311–327. doi: 10.1016/j.semradonc.2020.05.008 Schefter, T, Winter, K, Kwon, J, et al. RTOG 0417: Efficacy of Bevacizumab in Combination With Definitive Radiation Therapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma INT J RADIAT ONCOL. 2012; 84 (3): S17. doi: 10.1016/j.ijrobp.2012.07.048 Monk, BJ, Sill, MW, McMeekin, DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J CLIN ONCOL. 2009; 27 (28): 4649–55. doi: 10.1200/JCO.2009.21.8909 Liu, H, Ma, X, Sun, C, et al. Concurrent chemoradiotherapy followed by adjuvant chemotherapy versus concurrent chemoradiotherapy alone in locally advanced cervical cancer: A systematic review and meta-analysis. Front Oncol. 2022; 12 997030. doi: 10.3389/fonc.2022.997030 Tables Tables 1 to 7 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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16:36:38","extension":"html","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":115888,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/353998f6f477e86786191a05.html"},{"id":92736536,"identity":"910f825b-ddde-42f4-9ddf-7c209638c3b2","added_by":"auto","created_at":"2025-10-03 16:36:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129683,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of OS, PFS, LRFS and DMFS of all patients\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/4fe7db9e7786da242a7bc923.jpg"},{"id":92735263,"identity":"bbd9aa6d-3cd2-4bd7-8aae-6b2c21b1c609","added_by":"auto","created_at":"2025-10-03 16:28:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61799,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of OS, PFS, LRFS and DMFS before propensity score matching\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/e764e4291e1f117c16cbd871.jpg"},{"id":92735268,"identity":"837b6a5b-3de8-4f1c-bc0a-d8b12b6becca","added_by":"auto","created_at":"2025-10-03 16:28:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107669,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier estimates of OS, PFS, LRFS and DMFS after propensity score matching\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/d75d8fe65c7a6a0fa78cf043.jpg"},{"id":92736538,"identity":"8beff8e0-b201-4854-b914-f17df07b9817","added_by":"auto","created_at":"2025-10-03 16:36:37","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":136895,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of overall survival(OS) after propensity score matching(PSM)\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/59dceb3c4cbe6fd7f13a941b.jpg"},{"id":92735265,"identity":"518eb698-b203-4a21-b0fc-fde87cb965d4","added_by":"auto","created_at":"2025-10-03 16:28:37","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":133185,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of progression-free survival （PFS）after propensity score matching (PSM)\u003c/p\u003e","description":"","filename":"Fig.5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/b185cccaf002938b883aa172.jpg"},{"id":92735273,"identity":"e863333c-6007-4f92-8272-f4efdf0f248b","added_by":"auto","created_at":"2025-10-03 16:28:37","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":132872,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of local recurrence-free survival (LRFS) after propensity score matching(PSM)\u003c/p\u003e","description":"","filename":"Fig.6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/8e2e2772a613a6ca7126c07f.jpg"},{"id":92737350,"identity":"2aa724e3-633c-4097-96ea-19c9fb3f6581","added_by":"auto","created_at":"2025-10-03 16:44:37","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":129020,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses of distant metastasis-free survival (DMFS)after propensity score matching (PSM)\u003c/p\u003e","description":"","filename":"Fig.7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/c677901eb2fd1f670560d732.jpg"},{"id":92736544,"identity":"cd842493-871a-49d8-af0f-aa3b29d6895a","added_by":"auto","created_at":"2025-10-03 16:36:37","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":91400,"visible":true,"origin":"","legend":"\u003cp\u003eBar charts depicting adverse event grade I-II(A) and grade III-IV(B) profiles\u003c/p\u003e","description":"","filename":"Fig.8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/73e211013028f136f3cafbea.jpg"},{"id":100741742,"identity":"efabb558-ce4f-48b4-b67f-1df82add5b71","added_by":"auto","created_at":"2026-01-21 01:58:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1744866,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/acbdbd2d-1df7-460b-8b6f-5d6baeb9d6aa.pdf"},{"id":92736539,"identity":"02f6f7e8-0ebd-423f-8e8a-81022b57409b","added_by":"auto","created_at":"2025-10-03 16:36:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":269537,"visible":true,"origin":"","legend":"","description":"","filename":"table.docx","url":"https://assets-eu.researchsquare.com/files/rs-7409240/v1/6948df1035916bb23c9bdaa1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of concurrent intensity modulated chemoradiotherapy combined with induction chemotherapy or adjuvant chemotherapy in the treatment of locally advanced cervical cancer with 2018FIGO stage correction：a multicenter Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCervical cancer remains the second most prevalent gynecological malignancy worldwide, with over 80% of cases occurring in developing countries. Recent epidemiological data reveal both increasing incidence rates and a concerning trend toward younger patient demographics\u003csup\u003e[1]\u003c/sup\u003e. The insidious nature of early-stage disease frequently leads to delayed diagnosis, with most patients presenting at advanced clinical stages (IIB-IVA)\u003csup\u003e[2\u0026ndash;3]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eCurrent clinical staging classifications underwent significant revision in 2018, with the FIGO system updating the broad definition of LACC from IB2-IVA (FIGO 2009) to IB3-IVA(FIGO 2018). Therapeutic strategies for locally cervical cancer primarily involve two modalities: radical surgery (applicable to select cases) and definitive radiotherapy, with the latter constituting the mainstay of treatment\u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe standard treatment for newly diagnosed IB2 (FIGO2009) or IB3 (FIGO 2018)、IIA2 and IIB-IVA cervical cancer involves cisplatin-based CCRT. While the National Comprehensive Cancer Network (NCCN) guidelines classify this approach as a Category 1 recommendation, The 5-year progression free survival rate is still low, which means that many patients have not meant cured. Therefore, there is always for further optimization and improvement of the prevailing treatment mode of LACC radical radiotherapy combined with concurrent chemotherapy to improve the outcome and survival prognosis of disease progression in these patients. Current research focuses on integrating CCRT with either IC/AC. the clinical utility of various chemotherapy sequencing protocols with CCRT requires further elucidation.\u003c/p\u003e"},{"header":"Methods","content":"\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eWe conducted a retrospective cohort study of patients with newly diagnosed LACC, pathologically confirmed under FIGO 2009 criteria and subsequently restaged according to FIGO 2018. The study population comprised patients treated at three regional cancer centers in Guangxi:The Fourth Affiliated Hospital of Guangxi Medical University, Yulin Municipal People's Hospital, and Liuzhou Hospital of Guangzhou Women and Children's Medical Center from December 2016 to December 2022.\u003c/p\u003e\u003cp\u003eAll participants received either IC\u0026thinsp;+\u0026thinsp;CCRT or CCRT followed by CCRT\u0026thinsp;+\u0026thinsp;AC. Treatment protocols featured intensity-modulated radiation therapy (IMRT) delivering 50.4 Gy with concurrent weekly cisplatin (40 mg/m\u0026sup2;), followed by intracavitary brachytherapy. The IC\u0026thinsp;+\u0026thinsp;CCRT cohort received 2\u0026ndash;3 cycles of platinum-based combination chemotherapy prior to CCRT, while the CCRT\u0026thinsp;+\u0026thinsp;AC cohort underwent 2 cycles post-CCRT. Concurrent chemotherapy duration was individualized (5\u0026ndash;6 cycles) based on treatment tolerance.\u003c/p\u003e\u003cp\u003eComprehensive data collection included clinical assessments, diagnostic imaging (abdominopelvic MRI, chest CT, whole-body bone scintigraphy), inguinal lymph node ultrasonography, hematological profiles, and serum biochemistry. Tumor characteristics (stage, lymph node status), biochemical parameters, and Eastern Cooperative Oncology Group (ECOG) performance status were systematically documented and analyzed.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eRadiotherapy\u003c/h2\u003e\u003cp\u003ePatients underwent radiotherapy employing intensity-modulated radiation therapy (IMRT) techniques. The gross tumor volume (GTV), which included the primary tumor (GTV-P) and lymph node tumor volume (GTV-LN), was demarcated based on the visible extent of the tumor as identified by CT/MRI scans and clinical examinations, adhering to the guidelines of the International Commission on Radiation Units and Measurements Report 89 (ICRU89). The radiation treatment was delivered in 5 fractions weekly over a 6-week period, with dose limits to organs-at-risk conforming to the guidelines set by the Radiation Therapy Oncology Group (RTOG). Gross Tumor Volume (GTV) includes imaging diagnosis of pelvic and paraaortic lymph node metastases. Clinical Target Volume (CTV) includes the uterus, cervix, partial vagina, pelvic lymph node drainage area (including the iliac common, inner and outer areas, obturator area, and sacral anterior area), and paraaortic lymph node drainage area.The delineation of the lymphatic drainage area is based on the expert consensus of RTOG in 2008 on the delineation of the target area for cervical cancer radiotherapy. The prescription dosage is PCTV 50.4Gy/28f and PGTVnd 61.60Gy/28f.The plan design requires the prescription dosage to be wrapped around 100% CTV and 95% PTV.During the treatment period, CBCT (Cone Beam Computed Tomography) was performed 1\u0026ndash;2 times a week, and IMRT was performed 5 times a week for a total of 5\u0026ndash;6 weeks. Limit of dose to organs at risk: Rectal V50Gy\u0026thinsp;\u0026le;\u0026thinsp;50%; Bladder V50Gy\u0026thinsp;\u0026le;\u0026thinsp;50%; Femoral head V50Gy\u0026thinsp;\u0026le;\u0026thinsp;5%; Spinal cord Dmax\u0026thinsp;\u0026le;\u0026thinsp;45Gy; Small intestine V50Gy\u0026thinsp;\u0026le;\u0026thinsp;10\u0026ndash;15%; Renal V20Gy\u0026thinsp;\u0026le;\u0026thinsp;25%; Liver V30Gy\u0026thinsp;\u0026le;\u0026thinsp;30%.All patients received three-dimensional brachytherapy design ,DT36 Gy, 6 Gy x 6 times. Depending on the reduction of cervical local tumors, the number and dose of intracavitary radiotherapy were increased if necessary. No external radiotherapy was given on the day of intracavitary radiotherapy..\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eChemotherapy regimen\u003c/h3\u003e\n\u003cp\u003eIC started 6\u0026thinsp;~\u0026thinsp;8 weeks follow up CCRT, and AC after CCRT respectively. The IC and AC groups all received platinum-based combined chemotherapy. IC/AC regimens included TP/DP (cisplatin་Paclitaxel/Docetaxel) and TC/DC(carboplatin་Paclitaxel/Docetaxel). IC regimens included TP /DP (Paclitaxel135-150mg/m2 /docetaxel 75 mg/m2 D1,cisplatin 75 mg/m2 D1, every 3 weeks) or TC/DC (Paclitaxel135-150mg/m2 /docetaxel 75 mg/m 2 D1,carboplatin AUC 4\u0026ndash;5 D1, every 3 weeks). AC regimens included TP/DP and TC/DC. Data was gathered on all patients undergoing concurrent chemoradiation, which was scheduled of radiotherapy.The regimen comprised weekly intravenous infusions of cisplatin (40mg/m2) throughout the radiotherapy period, limited to a maximum of 5\u0026ndash;6 cycles. Full-dose chemotherapy was administered as per the protocol, with the option to adjust the cisplatin dosage in response to toxicity. The chemotherapy dosage was adaptable, allowing for a reduction of up to 20% or even complete discontinuation, contingent upon the severity of side effects. In instances of grade 3\u0026ndash;4 or more severe toxicity, chemotherapy administration could be delayed.\u003c/p\u003e\n\u003ch3\u003eFollow-up and patient assessment\u003c/h3\u003e\n\u003cp\u003eAll patients underwent thorough evaluations at regular intervals. These evaluations included clinical examinations and toxicity monitoring every 3 months for the first 2 years post-concurrent chemoradiation, and semi-annually from years 3 to 5. Beyond 5 years, annual reviews were conducted. Detailed data were meticulously collected. Local recurrences were confirmed through MRI imaging of the abdomen and pelvic cavity, CT scans of the chest, whole-body bone scans, inguinal ultrasound, Regional recurrences were diagnosed by physical examination, fine-needle aspiration, or additional MRI/CT scans. Distant metastases were identified based on clinical symptoms, physical examination, and the previously mentioned imaging methods. The response to IC and CCRT was assessed using the Response Evaluation Criteria in Solid Tumors, according to the Revised RECIST guidelines (version 1.1). Adverse events during treatment were graded using the Common Terminology Criteria for Adverse Events (CTCAE version 3.0), with the assessment of toxic side effects based on the classification of acute radiation injury.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe main goal of our research was to evaluate and contrast the 5-year OS rates and PFS between two group after 2018FIGO staging correction, one receiving IC prior to CCRT, and the other undergoing CCRT followed by AC. This comparison was made by measuring the time from the commencement of treatment to the date of death due to any cause, or to the last follow-up date.\u003c/p\u003e\u003cp\u003eThe secondary endpoints included LRFS, DMFS and treatment-related toxicity. PFS was determined by the period from the beginning of treatment until the first recurrence or the last follow-up date. LRFS was determined by the period from the beginning of treatment until the first locoregional recurrence or the last follow-up date. Likewise, DMFS was assessed from the start of treatment to the identification of the first distant metastasis or the last follow-up date.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics, T tests, and Chi-square tests were employed to summarize patient characteristics. Propensity score matching (1:1 ratio) balanced pretreatment variables (age, ps scores, pathology, FIGO Stage, tumor et al.). OS, PFS, LRFS, and DMFS were computed using the Kaplan-Meier method, with group differences assessed via the Log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined using the Cox proportional hazards model. Main toxicity outcomes were compared using the Chi-square test or Fisher\u0026rsquo;s exact test when required. Kaplan-Meier survival curves, forest plots for Cox regression results, and bar charts depicting adverse event profiles\u0026mdash;were generated using R statistical software(version 4.4)\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient characteristics\u003c/h2\u003e\n\u003cp\u003eData of 525 ligible patients with diagnosed LACC with 2009FIGO(IB2, IIA2, and IIB-IVA)who initially underwent IC plus CCRT or CCRT plus AC from the Forth Affiliated Hospital of Guangxi Medical University,Yulin First People's Hospital and Liuzhou Hospital of Guangzhou Women and Children's Medical Center.All patients were re-staged after 2018FIGO staging༈IB3, IIA2, and IIB-IVA༉correction were analyzed, including 250 patients in the IC\u0026thinsp;+\u0026thinsp;CCRT group and 275 patients in the CCRT\u0026thinsp;+\u0026thinsp;AC group. The median follow-up of 50 months (range10-80). Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e outlines the comprehensive characteristics and staging details of the study participants before PSM. There was a statistically significant difference between the two groups in terms of age, PS scores and Tumor diameter (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001), and there was no significant difference between the two groups in terms of Pathology, FIGO. Stage, HPV, LNMS, Chemotherapy regimen, CCRT cycles. Baseline characteristics of both groups after PSM are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, revealing no statistically significant differences in distribution.\u003c/p\u003e\n\u003ch2\u003eSurvival\u003c/h2\u003e\n\u003c/div\u003e\n\u003cp\u003eFigure 1 Presented the OS of all patients. Figure 2 Displayed the Kaplan-Meier curves for 5-year OS, PFS, LRFS, and DMFS between the two groups before PSM. No significant differences were detected between the two groups on the 5 -year OS rates (82.2% vs. 82.4%), PFS rates(73.1% vs 70.2%), or LRFS rates (77.8% vs 75.9%) and DMFS rates (86.5% vs 89.1%)(all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).After PSM (191 matched pairs), but also no significant differences were detected between the two groups on the 5-year OS rates (83.9% vs. 84.7%), PFS rates (76.0% vs. 71.4%) or LRFS rates (79.3% vs 76.5%)and DMFS rates (88.7% vs 89.1%)) (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eWe carried out a subgroup analysis to assess efficacy based on independent evaluations, with subgroups established according to baseline stratification factors such as treatment modalities, 2018FIGO stage .As illustrated in Fig.\u0026nbsp;4, the subgroup analysis revealed that CCRT plus AC showed a trend of improving OS (HR\u0026thinsp;=\u0026thinsp;0.455, 95% CI (0.206\u0026ndash;1.006), P\u0026thinsp;=\u0026thinsp;0.052) in 2018FIGO III-IVA stage, and AC was associated with significantly improved OS(HR\u0026thinsp;=\u0026thinsp;0.191,95%CI(0.057\u0026ndash;0.641),P\u0026thinsp;=\u0026thinsp;0.007), PFS\u003c/p\u003e\n\u003cp\u003e(HR\u0026thinsp;=\u0026thinsp;0.288,95%CI(0.118\u0026ndash;0.702), P\u0026thinsp;=\u0026thinsp;0.006) ,DMFS(HR\u0026thinsp;=\u0026thinsp;0.211, 95% CI (0.068\u0026ndash;0.654), P\u0026thinsp;=\u0026thinsp;0.007) in patients with positive pelvic lymph nodes. Figure 5\u0026ndash;7, IC plus CCRT was associated with significantly improved PFS (HR\u0026thinsp;=\u0026thinsp;2.276, 95% CI (1.187\u0026ndash;4.363), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) in 2018FIGO IIB. Figure\u0026nbsp;5\u003c/p\u003e\n\u003cp\u003eUnifactorial analysis of OS showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, respectively). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 0.037, \u0026lt; 0.001, 0.005). Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eFor PFS, Age, Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Multifactorial analysis showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were an independent risk factor for PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 0.004, \u0026lt; 0.001, 0.002). (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eUnifactorial analysis of LRFS showed that relatively Pathology, FIGO Stage, LNMS and Tumor diameter were the most significant factors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for LRFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, 0.016, \u0026lt; 0.001, 0.002). Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eFor DMFS, Age, Pathology, FIGO Stage and LNMS were the most significant factors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). Multifactorial analysis showed that relatively Pathology and LNMS were an independent risk factor for DMFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026lt; 0.001). (Table \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eAdverse Reactions\u003c/h2\u003e\n\u003cp\u003eNo grade 5 toxicity, which refers to death due to adverse events, was observed throughout the course of treatment. The common acute adverse events the two groups were mainly hematotoxicity. Nausea, Vomiting, Anorexia, Fatigue, Neurotoxicity, Radiation Colitis, Radiation Cystitis, Radiation Vaginitis and Radiation Dermatitis among which the incidence of adverse events in the induction treatment group was slightly higher than that in the adjuvant treatment group, but the difference was not statistically significant (all \u003cem\u003eP\u003c/em\u003e values were \u0026gt;\u0026thinsp;0.05, Table.7、Fig. 8).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eCurrent Therapeutic Landscape and Unmet Needs in LACC Management\u003c/h2\u003e\u003cp\u003e The current standard for LACC, as established by NCCN guidelines and supported by landmark trials (SWOG-8797, GOG-120, RTOG 90 − 01)[5–9], remains cisplatin-based CCRT. While alternative agents such as taxanes have demonstrated comparable efficacy with potentially reduced toxicity profiles [10–12], none have proven superior to cisplatin in terms of survival outcomes. This therapeutic plateau, evidenced by persistently suboptimal 5-year survival rates (\u0026lt; 66%) [13], underscores the critical need for optimized treatment strategies and has fueled ongoing investigation into the potential benefits of adjuvant or consolidation chemotherapy approaches [14–17].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eControversies in Adjuvant Chemotherapy: Evidence and Limitations\u003c/h2\u003e\u003cp\u003eThe role of AC in LACC management remains controversial, with current evidence presenting a complex and often contradictory picture. While retrospective analyses and some clinical data suggest potential improvements in both progression-free survival (PFS) and OS [18], the phase III evidence base remains limited and inconsistent. Negative trials such as Lorvidhaya 2003 (n = 210), which found no benefit with 5-FU monotherapy [19], and OUTBACK (2021) [20], which showed no improvement in predominantly low-risk stage IB/II patients, contrast with more promising signals from studies like Dueñas-González 2015 (improved 3-year OS: 72% vs. 64%) [21] and ACTLACC (reduced distant metastases: 5.4% vs. 10.1%, \u003cem\u003eP\u003c/em\u003e = 0.029) [22]. These discrepancies likely reflect significant heterogeneity in trial design, patient selection criteria, and evolving radiotherapy techniques. Importantly, the advent of modern intensity-modulated radiotherapy (IMRT) and the revised FIGO 2018 staging system (introducing stage IIIC) necessitate a critical reevaluation of historical data and treatment paradigms.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eInduction Chemotherapy: Reassessing the Evidence Base\u003c/h2\u003e\u003cp\u003eEarly investigations of IC in LACC (pre-2016) were hampered by methodological limitations including small sample sizes and inconsistent outcome measures [23–25]. More recent phase III data present a mixed but potentially promising picture. The INTERLACE trial (2024) demonstrated significant improvements in both 5-year PFS (73% vs. 64%) and OS (80% vs. 72%) with paclitaxel/carboplatin IC [26], though its applicability to high-risk patients may be limited by the predominance (70%) of stage IIB cases. Conversely, the ASCO 2019 trial reported concerning results, with IC associated with worse 3-year PFS (40.9% vs. 60.4%) and OS (60.7% vs. 86.8%) [27], highlighting the potential risks of unselected application of this approach.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStage- and Risk-Adapted Therapeutic Strategies\u003c/h2\u003e\u003cp\u003eOur comprehensive analysis supports a paradigm shift toward more nuanced, risk-adapted treatment strategies for LACC: For stage IIB disease with parametrial invasion, IC followed by CCRT demonstrates particular promise, showing significant PFS benefits (HR = 2.276, 95%CI 1.187–4.363, \u003cem\u003eP\u003c/em\u003e = 0.013) in our study. The mechanistic rationale for this approach lies in IC's ability to achieve meaningful tumor volume reduction, thereby optimizing subsequent IMRT delivery. This volumetric reduction enhances radiation precision while minimizing exposure to adjacent organs at risk, potentially explaining the observed improvements in local control. These findings are supported by multiple lines of evidence, including the EMBRACE-I trial's demonstration of increased local recurrence risk with larger tumor volumes [28], and RTOG 0417's validation of IMRT's dosimetric advantages [29]. For patients with more advanced disease (stage III-IVA) or lymph node involvement, our data strongly support the use of ACT following CCRT. This approach demonstrated a significant 14.2% reduction in distant metastasis risk (\u003cem\u003eP\u003c/em\u003e = 0.013) and improved OS in node-positive subgroups (HR = 0.211, 95% CI 0.068–0.654, \u003cem\u003eP\u003c/em\u003e = 0.007). The biological basis for this benefit aligns with the conceptual framework proposed by Monk et al. [30], wherein lymph node metastases serve as conduits for systemic dissemination. Our findings are further corroborated by OUTBACK's subgroup analysis showing a 7% OS improvement in stage III-IVA patients [20] and a 2020 meta-analysis demonstrating 24% mortality risk reduction in stage III patients [31].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eCritical Considerations and Future Directions\u003c/h2\u003e\u003cp\u003eSeveral key factors must inform the clinical implementation of these strategies: Patient Selection: The identification of pelvic lymph node metastasis emerges as a critical determinant of therapeutic approach, with node-positive patients deriving particular benefit from ACT (45.5% mortality risk reduction, HR = 0.455, 95% CI 0.206–1.006, \u003cem\u003eP\u003c/em\u003e = 0.052). This underscores the importance of comprehensive nodal staging, potentially incorporating advanced imaging modalities like PET-CT. Technological Integration: The evolution of radiotherapy techniques, particularly the widespread adoption of IMRT, has fundamentally altered the therapeutic landscape. Future studies must account for these technological advances when evaluating chemotherapy sequencing strategies. Global Health Equity: With 85% of cervical cancer cases occurring in low- and middle-income countries (WHO, 2024), practical considerations of resource availability and treatment accessibility must guide protocol development. Strategies such as carboplatin substitution may help address financial toxicity while maintaining therapeutic efficacy.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion and Clinical Implications","content":"\u003cp\u003e While current guidelines appropriately maintain caution regarding routine incorporation of neoadjuvant or adjuvant chemotherapy, our findings support a more tailored approach guided by disease stage and nodal status. For stage IIB tumors with parametrial involvement, IC offers clear benefits in optimizing local control. Conversely, for advanced-stage or node-positive disease, ACT provides meaningful systemic protection against distant metastases. These risk-adapted strategies should be considered within the context of modern radiotherapy techniques and comprehensive staging.\u003c/p\u003e\u003cp\u003eFuture research must address several critical gaps: validation in larger, prospectively designed trials; development of predictive biomarkers to guide patient selection; and adaptation of protocols for resource-limited settings. By addressing these challenges, we may finally overcome the current therapeutic plateau in LACC management and achieve meaningful improvements in patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the important Scientific Research \u0026amp; Technology Development Plan with LACC from Science \u0026amp; Technology of Guangxi（AB21196104)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing financial interests relevant to this article exist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.Chen, L.Hua, L.Chen, M.Liao, Y.Chen,G.Yang,C,Feng, X.Wang ,Zhan Lin,\u003c/p\u003e\n\u003cp\u003eD.Zeng ,Q.Shi\u003c/p\u003e\n\u003cp\u003eS.Chen contributed to the study design, literature research, interpretation of findings and writing of themanuscript. L.Hua and L.Chen provided suggestion of statistics. L.Chen,M.Liao,Y.Chen,G.Yang contributed to the follow-up, data collection and analyses. ,and X.Wang ,Zhan Lin ,C.Feng contributed to review of data analyses, D.Zeng ,Q.Shi contributed to critical edit of the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approval by the Ethics Committee of Yulin Municipal People's Hospital ,Liuzhou Hospital of Guangzhou Women and Children's Medical Center, The Forth Affiliated Hospital of Guangxi Medical University, written informed consent was obtained from each patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYang H, Sun LX. 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Int J Gynecol Cancer, 2017, 27(2):344\u0026ndash;349.\u003c/li\u003e\n\u003cli\u003eUmayahara K, Takekuma M, Hirashima Y, et al. Phase II study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel in patients with locally advanced uterine cervical cancer: the JACCRO GY\u0026ndash;01 trial[J].Gynecol Oncol, 2016, 140(2): 253\u0026ndash;258.\u003c/li\u003e\n\u003cli\u003eRose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin\u0026ndash;based radiotherapy and chemotherapy for locally advanced cervical cancer[J]. N Engl J Med, 1999, 340(15):1144\u0026ndash;1153. DOI: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJM199904153401502\u003c/span\u003e\u003c/span\u003e.\u003c/li\u003e\n\u003cli\u003eKong TW, Chang SJ, Paek J, et al. Comparison of concurrent chemoradiation therapy with weekly cisplatin versus monthly fluorouracil plus cisplatin in FIGO stage IB-IVA cervical cancer[J].J Gynecol Oncol, 2012, 23(4):235\u0026ndash;241.\u003c/li\u003e\n\u003cli\u003eMarth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Annals of Oncology. 2017,28(suppl_4):iv72-83.\u003c/li\u003e\n\u003cli\u003eCohen PA, Jhingran A, Oaknin A, et al. Cervical cancer[J].Lancet, 2019, 393(10167): 169\u0026ndash;182\u003c/li\u003e\n\u003cli\u003eYavas G, Yavas C, Sen E, et al. Adjuvant carboplatin and paclitaxel after concurrent cisplatin and radiotherapy in patients with locally advanced cervical cancer [J]. Int J Gynecol Cancer, 2019, 29(1): 42\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eAtci MM, Akagunduz B, Demir M, et al. Effect of Adjuvant Chemotherapy in Stage III Cervical Cancer Patients Treated with Concurrent Chemoradiation: A Multicenter Study [J]. Oncol Res Treat, 2022, 45(5): 254\u0026ndash;61.\u003c/li\u003e\n\u003cli\u003eYavas G, Yavas C, Sen E, et al. Adjuvant carboplatin and paclitaxel after concurrent cisplatin and radiotherapy in patients with locally advanced cervical cancer[J]. Int J Gynecol Cancer, 2019, 29:42\u0026ndash;47.\u003c/li\u003e\n\u003cli\u003eYuan YD, You J, Li XF,et al. Adjuvant chemotherapy after radiotherapy or concurrent chemoradiotherapy for pelvic lymph node-positive patients with localy advanced cervical cancer; a propensity score matching analysis[J]. Int J Gynecol Cancer, 2020,0:1\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eWu N, Su X, Song HL, et al. A multi-Institutional retrospective analysis of oncologic outcomes for patients with locally advanced cervical cancer undergoing platinum-based adjuvant chemotherapy after concurrent chemoradiotherapy[J]. Cancer Control, 2021,28:1\u0026ndash;12\u003c/li\u003e\n\u003cli\u003eAo MH, Li LY. A meta-analysis of the effect of consolidation and chemotherapy on the prognosis of cervical cancer after concurrent radiotherapy and chemotherapy [J]. Progress in Obstetrics and Gynecology, 2015: 24 (07): 528\u0026ndash;530.\u003c/li\u003e\n\u003cli\u003eLORVIDHAYA V,CHIT APANARUX I,SANGRUCHI d S ,et al. Concurrent mitomycin C,5-fluorouracil ,and radiotherapy in the treatment of c locally ] advanced carcinoma of the cervix :a J random- ized 5 trial [J ] .Int J RadiatOncol Biol Phys ,2003,55(5): 1226\u0026ndash;1232 .\u003c/li\u003e\n\u003cli\u003eLinda R. Mileshkin, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). ASCO Annual Meeting 2021. Abstract LBA3.\u003c/li\u003e\n\u003cli\u003eDuenas-Gonzalez A, Zarba J J, Patel F, et al. Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix[J]. Journal of Clinical Oncology, 2011, 29(13):1678\u0026ndash;1685.\u003c/li\u003e\n\u003cli\u003eTANGJITGAMOL STHARAVICHITKULE,TOVANA BUTRA XC,et al .A randomized controlled trial comparing concurrent chemora- diation versus concurrent chemoradiation followed by adjuvant chemo- therapy in locally advanced cervical cancer patients :ACTLACC trial [J] .J Gynecol Oncol ,2019 ,30(4):e82\u003c/li\u003e\n\u003cli\u003eNarky S, Sharma N, Kapoor A, et al. Pros and Cons of Adding of Neoadjuvant Chemotherapy to Standard Concurrent Chemoradiotherapy in Cervical Cancer: A Regional Cancer Center Experience[J].J Obstet Gynaecol India,2016,66(5):385\u0026ndash;390.\u003c/li\u003e\n\u003cli\u003eHarsh KK, Kapoor A, Paramanandhan M, et al. Induction Chemotherapy Followed by Concurrent Chemoradiation in the Management of Different Stages of Cervical Carcinoma: 5-year Retrospective Study[J].J Obstet Gynaecol India,2016,66(5):372\u0026ndash;378.\u003c/li\u003e\n\u003cli\u003ede Azevedo CR, Thuler LC, de Mello MJ, et al. Neoadjuvantchemotherapy followed by chemoradiation in cervical carcinoma: a review[J]. Int J Gynecol Cancer, 2016, 26(4):729\u0026ndash;736.\u003c/li\u003e\n\u003cli\u003eMcCormack M, Rinc\u0026oacute;n D G, Eminowicz G, et al. LBA8 A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial[J]. Annals of Oncology, 2023, 34: S1276.\u003c/li\u003e\n\u003cli\u003eda Costa SCS, Bonadio RC, Gabrielli FCG, et al. Neoadjuvant Chemotherapy With Cisplatin and Gemcitabine Followed by Chemoradiation Versus Chemoradiation for Locally Advanced Cervical Cancer:A Randomized Phase II Trial[J].J Clin Oncol, 2019,37(33):3124\u0026ndash;3131.\u003c/li\u003e\n\u003cli\u003eTanderup, K, Nesvacil, N, Kirchheiner, K, et al. Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer. Semin Radiat Oncol. 2020; 30 (4): 311\u0026ndash;327. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.semradonc.2020.05.008\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eSchefter, T, Winter, K, Kwon, J, et al. RTOG 0417: Efficacy of Bevacizumab in Combination With Definitive Radiation Therapy and Cisplatin Chemotherapy in Untreated Patients With Locally Advanced Cervical Carcinoma INT J RADIAT ONCOL. 2012; 84 (3): S17. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2012.07.048\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eMonk, BJ, Sill, MW, McMeekin, DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J CLIN ONCOL. 2009; 27 (28): 4649\u0026ndash;55. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2009.21.8909\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eLiu, H, Ma, X, Sun, C, et al. Concurrent chemoradiotherapy followed by adjuvant chemotherapy versus concurrent chemoradiotherapy alone in locally advanced cervical cancer: A systematic review and meta-analysis. Front Oncol. 2022; 12 997030. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2022.997030\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\n\u003cp\u003eTables 1 to 7 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Locally advanced cervical cancer, Induction chemotherapy, Adjuvant chemotherapy, Chemoradiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7409240/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7409240/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and purpose\u003c/h2\u003e\u003cp\u003eConcurrent chemoradiotherapy (CCRT) is currently the standard treatment for locally advanced cervical cancer (LACC), but there is a lot of room for treatment strategies improvement and the 5-year survival rate of patients is low, Comprehensive treatment is the treatment direction for LACC, The current comprehensive treatment models for LACC mainly include induction chemotherapy (IC) plus CCRT and CCRT plus adjuvant chemotherapy (AC),but it remains unclear which is optimal sequence of combined chemotherapy. The purpose of this study is to retrospectively report the outcome of long-term survival and related toxicity that IC plus CCRT versus CCRT plus AC in LACC.\u003c/p\u003e\u003ch2\u003eMaterials/Methods:\u003c/h2\u003e\u003cp\u003eFrom December 2016 to December 2022, 525 patients of LACC with 2009FIGO(IB2, IIA2, and IIB-IVA)/2018FIGO staging༈IB3, IIA2, and IIB-IVA༉who initially underwent IC plus CCRT or CCRT plus AC from the Forth Affiliated Hospital of Guangxi Medical University, Yulin First People's Hospital and Liuzhou Hospital of Guangzhou Women and Children's Medical Center. All patients with 2009FIGO༈IB2, IIA2, and IIB-IVA༉were re-staged after 2018FIGO staging༈IB3, IIA2, and IIB-IVA༉correction. All patients were treated with IMRT to 50.4 Gy with concurrent weekly cisplatin 40 mg/m2 followed by intra-cavitary brachytherapy. The IC plus CCRT group received platinum-based combined chemotherapy with two or three cycles before CCRT. CCRT plus AC group received platinum-based combined chemotherapy with two cycles after CCRT. Propensity score matching (PSM) method was used to match the proportion of 1:1 between the neoadjuvant treatment group and the adjuvant treatment group,5-year overall survival (OS), 5-year progression free Survival survival(PFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and treatment-related adverse reactions were evaluated and compared between the two groups.Cox proportional hazard regression model was used to analyze the effect of neoadjuvant or adjuvant therapy on the survival of patients with locally advanced cervical cancer.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 525 patients with complete follow-up data are available were included our study. Among these patients, 250 patients were treated with IC plus CCRT and 275 patients were treated with CCRT plus AC. IC/AC regimens included TP/DP(cisplatin\u0026thinsp;+\u0026thinsp;Paclitaxel/Docetaxel) and TC/DC(carboplatin་Paclitaxel/Docetaxel). The median follow-up of 56 months (range 20\u0026ndash;80 ). Before propensity score matching(PSM), there were no significant differences in survival rates between the neoadjuvant treatment group and the adjuvant treatment group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After propensity score matching(191 matched pairs), there were also no significant differences between the two group on the 5-year OS rates (83.9% vs. 84.7%), PFS rates (76.0% vs. 71.4%) or LRFS rates (79.3% vs 76.5%)and DMFS rates (88.7% vs 89.1%)) (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).But Subgroup analysis revealed that CCRT plus AC showed a trend of improving OS (HR\u0026thinsp;=\u0026thinsp;0.455, 95% CI (0.206\u0026ndash;1.006), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.052) in 2018FIGO III-IVA stage and was associated with significantly improved OS(HR\u0026thinsp;=\u0026thinsp;0.191,95%CI (0.057\u0026ndash;0.641),\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), PFS(HR\u0026thinsp;=\u0026thinsp;0.288,95%CI(0.118\u0026ndash;0.702), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006) ,DMFS(HR\u0026thinsp;=\u0026thinsp;0.211, 95% CI (0.068\u0026ndash;0.654), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007) in patients with positive pelvic lymph nodes. IC plus CCRT was associated with significantly improved PFS (HR\u0026thinsp;=\u0026thinsp;2.276, 95% CI (1.187\u0026ndash;4.363), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013) in 2018FIGO IIB stage. There was no significant difference in adverse events between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Multivariate Cox analysis identified Pathology, FIGO Stage, LNMS and Tumor diameter as independent prognostic factors for OS, PFS, LRFS and Pathology and LNMS were an independent risk factor for DMFS\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThere is no statistical difference between IC plus CCRT and CCRT plus AC in the outcome of long-term survival of LACC. However, for patients with stage III-IVA advanced cervical cancer, the CCRT plus AC shows a trend of improving survival benefits, especially for those with pelvic lymph node metastasis, where the benefit is more significant. For stage IIB patients, IC plus CCRT can reduce the risk of local progression. Lymph node status is a key decision factor: patients with positive pelvic lymph nodes should prioritize CCRT plus AC for enhanced treatment.\u003c/p\u003e","manuscriptTitle":"Efficacy of concurrent intensity modulated chemoradiotherapy combined with induction chemotherapy or adjuvant chemotherapy in the treatment of locally advanced cervical cancer with 2018FIGO stage correction：a multicenter Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 16:28:32","doi":"10.21203/rs.3.rs-7409240/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"29793637-385a-4960-bf5b-ec095f481423","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T01:57:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 16:28:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7409240","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7409240","identity":"rs-7409240","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}