Efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy and concurrent chemoradiotherapy alone in locally advanced cervical cancer: a systematic review and meta-analysis
Original Article

Efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy and concurrent chemoradiotherapy alone in locally advanced cervical cancer: a systematic review and meta-analysis

Yaqiong Lu1#, Jing Zhao1#, Zhihong Jia2, Chunlin Zhang1

1Department of Radiotherapy, Gansu Provincial Cancer Hospital, Lanzhou, China; 2Department of Gynecological Oncology, Gansu Provincial Cancer Hospital, Lanzhou, China

Contributions: (I) Conception and design: Y Lu; (II) Administrative support: J Zhao; (III) Provision of study materials or patients: Y Lu, J Zhao; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: Y Lu, C Zhang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Chunlin Zhang, MD. Department of Radiotherapy, Gansu Provincial Cancer Hospital, No. 2 East Xiaoxihu Street, Qilihe District, Lanzhou 730050, China. Email: clzhang182@sohu.com.

Background: There is no conclusive evidence on whether neoadjuvant chemotherapy (NACT) is suitable for locally advanced cervical cancer (LACC). This study aimed to evaluate the efficacy and safety of NACT combined with concurrent chemoradiotherapy (CCRT) and CCRT alone in LACC. This evaluation aims to offer valuable insights for clinical diagnosis and treatment decisions.

Methods: A thorough investigation was performed across the CNKI, Medline, Cochrane Library, PubMed, and EMBASE records to search for studies that evaluated NACT in combination with CCRT, as well as CCRT alone, for individuals suffering from LACC. Subsequently, we computed the odds ratios (ORs) along with their respective 95% confidence intervals (CIs). Additionally, we considered the incidence of adverse events in our analysis.

Results: The review encompassed 12 eligible randomized controlled trials, comprising a total of 2,609 patients (Experiment: 1,313, Control: 1,296). NACT combined with chemoradiotherapy had higher complete response rate (CRR, OR =2.06, 95% CI: 1.27–3.34) and objective response rate (ORR, OR =2.41, 95% CI: 1.20–4.87), but there was no difference in disease control rate (DCR) and 3-year survival rate. However, leucopenia was more frequent (OR =2.37, 95% CI: 1.09–5.14), and there was no difference in other adverse reactions.

Conclusions: Compared with CCRT alone, combined NACT had a higher initial effect on individuals with LACC, rather than a sustained benefit. Taxol and platinum (TP) regimen may be a better option but more attention should be paid to leucopenia. Further prospective studies with larger sample sizes are needed for the development of therapy regimens for LACC.

Keywords: Cervical cancer; concurrent chemoradiotherapy (CCRT); neoadjuvant chemotherapy (NACT); meta-analysis

Submitted May 08, 2025. Accepted for publication Nov 05, 2025. Published online Jan 27, 2026.

doi: 10.21037/tcr-2025-966

Highlight box

Key findings

• The research revealed that compared to synchronous chemoradiotherapy alone, combination of neoadjuvant chemotherapy (NACT) has a higher initial effect on locally advanced cervical cancer (LACC), rather than sustained benefits, through systematic analysis methods.

What is known and what is new?

• NACT combined with radiotherapy and chemotherapy is gradually being applied to LACC, but the clear chemotherapy options and associated complications are still unclear.

• NACT has a clear initial effect rather than sustained benefits. Paclitaxel and platinum-based regimens may be better choices, but more attention should be paid to leukopenia. Further prospective studies with larger sample sizes are needed to develop treatment plans for LACC.

What is the implication, and what should change now?

• This finding challenges the current trend of relying solely on combined therapies for sustained disease control. Clinicians should reconsider the role of NACT in the long-term management of LACC and explore alternative or adjunctive therapies that may offer more sustained benefits. Additionally, the increased risk of leukopenia associated with certain chemotherapy regimens, such as paclitaxel and platinum-based combinations, necessitates closer monitoring and management of patients’ blood counts during treatment. Future research should focus on optimizing chemotherapy regimens to maximize efficacy while minimizing adverse effects, and on developing personalized treatment plans based on individual patient characteristics and disease stages.

Introduction

Cervical cancer represents a significant medical challenge for women, ranking as the top 4 prevalent cancers globally and among the top 4 causes of cancer-related mortality (1). The conventional approach for managing locally advanced cervical cancer (LACC) involves the utilization of neoadjuvant chemotherapy (NACT) combined with concurrent chemoradiotherapy (CCRT). Due to the lack of systematic screening strategies and the lack of promotion of human papillomavirus vaccination, about 90% of cervical cancer patients are found in middle-income countries. It is anticipated that more than 38% of LACC are diagnosed as stages IB2–IIB as per the International Federation of Gynecology and Obstetrics (FIGO) classification (2). Nonetheless, the approach to therapy for phase IB2–IIB, particularly phase IIB cervical cancer, continues to be a subject of debate. The overall survival (OS) rates for phase IIB and III–IV cancers are frustratingly low, at approximately 60–65% and 25–50%, respectively (3). Furthermore, CCRT would easily cause immediate and prolonged toxicities and related complications, such as pelvic adhesions, radiation enterocolitis, vaginal strictures, and radiation cystitis. Consequently, it is essential to formulate innovative therapeutic approaches for LACC to enhance survival outcomes.

NACT treatment is administered prior to local therapy with the objective of diminishing the extent of the illness, thereby enhancing the efficacy of next radiation or surgical interventions, all while managing micrometastatic disease (4). In addition, it can also shorten the waiting time of radiotherapy in some centers and reduce the need for tumor pre-treatment before close range radiotherapy, so as to avoid the use of interstitial technology. The integrated examination revealed that NACT resulted in improved medical and pathological responses and was linked to favorable OS and progression-free survival (PFS) (5). Despite the increased toxicity, adjuvant chemotherapy demonstrates greater efficacy than chemoradiotherapy alone, especially among individuals with cervical cancer with pre-albumin (PA) spread (6,7).

However, this therapeutic strategy is not without its drawbacks, including prolonged therapy period, heightened medical expenses, and the possibility of tumor advancement as a result of chemotherapy resistance (5). Currently, NACT plays an unproven role in cervical cancer treatment, the efficacy and safety between NACT in conjunction with CCRT and CCRT alone are not clearly specified (8-10). The results of an international, multi-center, randomized phase 3 trial showed that for patients with LACC, chemotherapy and radiotherapy after short-term induction chemotherapy significantly improved the survival rate of patients. However, that study is currently only reporting the mid-term results, and in fact, only half of the patients enrolled in the study are high-risk patients with advanced cervical cancer, so, more long-term follow-up results, more detailed subgroups analyses and more patients are required to verify the results (11). Subsequent investigations prompt an inquiry into the relative efficacy of treatments for individuals diagnosed with phase IB2–IIB cervical cancer. The current meta-analysis and comprehensive evaluation sought to evaluate the medical outcomes of individuals with advanced cervical cancer who received NACT in conjunction with CCRT, as opposed to those who underwent CCRT alone. We present this article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-966/rc).

Methods

Search methodology

Electronic repositories such as Cochrane Library, EMBASE, PubMed, CNKI, and Medline were employed to gather pertinent studies released from 2000 to 2024. The search phrases included “cervical cancer”, “neoadjuvant chemotherapy”, “chemoradiation”, and “radiotherapy”. Furthermore, the reference list of pertinent research was meticulously examined for including additional articles. This inquiry was collaboratively undertaken by two investigators.

Criteria for inclusion and exclusion

The inclusion criteria encompassed:

  • Randomized controlled trials;
  • Participants were categorized into two groups: one receiving NACT in conjunction with CCRT, and the other undergoing CCRT exclusively in the study;
  • The fundamental attributes of the patients were delineated, with the principal outcomes encompassing the ORR, DCR, OS, PFS, among others.

The criteria for exclusion encompassed:

  • Animal experiments, reviews, abstracts, reviews, reports;
  • Individuals diagnosed with early-stage cervical carcinoma or other cancers;
  • Patients receiving adjuvant treatment one month before grouping;
  • The article did not report survival results.

Extraction of data and evaluation of quality

Two researchers (Y.L. and J.Z.) autonomously obtained relevant information from each study: mean patient age, first author’s name, publication year, intervention strategy, sample size, disease stage, control strategy, follow-up, and main findings. The main endpoints of this study were complete control rate, objective control rate, disease control rate (DCR) and 3-year survival rate. The secondary endpoints were the incidence of skin reactions, blood and non-blood adverse events. Whenever there was uncertainty, a third reviewer (Z.J.) provided input. We procured the complete text to acquire sufficient information. In instances of uncertainty, we consulted the primary author for clarification. The approach advocated by the Cochrane Collaboration was employed to evaluate the methodological rigor of the investigations encompassed (12).

Statistical analysis

In accordance with the suggestions put forth by the Cochrane collaboration, a statistical evaluation of the markers incorporated into the investigation was conducted. The data were aggregated through the application of meta-analysis, contingent upon data availability, by utilizing Stata 16.0 software. We presented binary data as odds ratio (OR) with its 95% confidence interval (CI). The random-effects model was employed for the meta-analysis, taking into account of possible causes of clinical heterogeneity. In instances where I2 exceeds 50%, a subgroup analysis was undertaken, focusing on initial features, actions, and/or undertaking sensitivity analyses by systematically excluding investigations to investigate the origins of heterogeneity (13,14). Funnel plots revealed the presence of a small sample effect, while statistical experiments indicated the existence of publication bias.

Results

Fundamental attributes of the literature reviewed In line with the pre-screening methodology; this investigation incorporated 12 randomized controlled trials conducted by two academicians (15-26) (Figure 1). The screening process was summarized in Figure 1. These observational studies occurred in China, India, and Brazil. A total of 1,313 patients received NACT plus CCRT, and 1,296 patients received CCRT alone. The average age was about 45. The FIGO stage of cervical cancer was intermediate and advanced. NACT combined with CCRT main treatment were taxol and TP (taxol and platinum) and GP (gemcitabine and platinum) regimen. Follow-up periods also about ranged from 3 months to 5 years. Different findings were presented depending on the purpose of the study. A comprehensive evaluation of the scientific superiority of the incorporated investigations revealed that they were all low-risk of bias. More details were shown in Tables 1,2.

Figure 1 Article screening flowchart.

Table 1

The characteristic of included studies

Study Year Location NACT + CCRT CCRT alone Pathological type FIGO stage Follow-up (months)
Sample size Age (years) NACT scheme Sample size Age (years)
Tripathi et al. (15) 2019 India 40 46.85±8.448 TP 40 47.13±10.281 SSC IIB–IVB 6
da Costa et al. (16) 2019 Brazil 55 N/A GP 52 N/A SSC, AC IIB–IVA 31.7
Narayan et al. (17) 2016 India 309 N/A TP 313 N/A SSC, AC IIB2–IVA 36
Tang et al. (18) 2012 China 440 N/A TP 440 N/A SSC, AC IIB–IVA 60
Zhang et al. (19) 2019 China 56 53.69±13.20 TP 56 55.85±11.55 SSC, AC, ASC IIB–IVA 36
Tian et al. (20) 2017 China 48 N/A TP 46 N/A SSC, AC, ASC IIA–IVA 42
Wang et al. (21) 2020 China 43 61.23±0.52 TP 43 61.22±0.54 N/A IIB–IVA 28
Jiang et al. (22) 2014 China 28 42.6±3.3 TP 28 42.6±3.3 SSC, AC, ASC IIB–III 36
Li et al. (23) 2019 China 85 51.44±8.75 TP 46 55.48±11.65 N/A IIB–IVA 38
He et al. (24) 2019 China 58 52.61±6.33 TP 42 54.51±7.09 N/A IB–IIA 36
Li et al. (25) 2024 China 73 N/A TP 73 N/A N/A IIB–IVA 60
Yu et al. (26) 2021 China 78 N/A TP 117 N/A N/A II–III 60

Data are presented as mean ± standard deviation. AC, adenocarcinoma; ASC, adenosquamous carcinoma; CCRT, concurrent chemoradiotherapy; FIGO, International Federation of Gynecology and Obstetrics; GP, gemcitabine and platinum; N/A, not applicable; NACT, neoadjuvant chemotherapy; SSC, squamous cell carcinoma; TP, taxol and platinum.

Table 2

Methodological risk assessment of included studies

Study Selection of the study groups Comparability of the groups Outcome Total score
Tripathi et al. (15) ★★★ ★★ ★★ 7
da Costa et al. (16) ★★★ ★★ ★★ 7
Narayan et al. (17) ★★ ★★ ★★ 6
Tang et al. (18) ★★ ★★ ★★ 6
Zhang et al. (19) ★★★ ★★ ★★ 7
Tian et al. (20) ★★ ★★ ★★ 6
Wang et al. (21) ★★ ★★ ★★ 6
Jiang et al. (22) ★★ ★★ ★★ 6
Li et al. (23) ★★★ ★★ ★★ 7
He et al. (24) ★★ ★★ ★★ 6
Li et al. (25) ★★ ★★ ★★ 6
Yu et al. (26) ★★ ★★ ★★ 6

Main results

We found complete response rate (CRR) in patients receiving NACT in conjunction with CCRT and CCRT administered independently were examined across 11 investigations. The OR in this case was fitted using a random effects model. The test on heterogeneity turned up more variation (I2=79.9%, P<0.05, Figure 2). The study showed that NACT combined with CCRT have higher CRR than CCRT alone (OR =2.06, 95% CI: 1.27–3.34, P<0.05). The sensitivity analysis conducted by sequentially removing investigations failed to reveal any unstable results. The funnel plot and Egger’s test (P>0.05) revealed no evidence of bias in publishing. It is worth noting that only one study showed better superiority of CCRT alone (OR =0.31, 95% CI: 0.13–0.74, P<0.05). The majority of investigations indicated no variation in complete reaction rates across the two treatment regimens.

Figure 2 CRR of neoadjuvant chemotherapy combined with chemoradiation and concurrent chemoradiation alone. CI, confidence interval; CRR, complete response rate; DL, DerSimonian-Laird.

Likewise, we found the objective response rate (ORR) of NACT in conjunction with CCRT and CCRT by itself across 8 investigations. The heterogeneity test showed large heterogeneity among multiple investigations (I2=62.0%, P<0.05, Figure 3). The findings showed that NACT combined with CCRT have higher ORR than the CCRT alone (OR =2.41, 95% CI: 1.20–4.87, P<0.05). The sensitivity analysis conducted by sequentially removing investigations failed to reveal any unstable results. The funnel plot and Egger’s test (P>0.05) revealed no evidence of bias in publishing.

Figure 3 ORR of neoadjuvant chemotherapy combined with chemoradiation and concurrent chemoradiation alone. CI, confidence interval; DL, DerSimonian-Laird; ORR, objective response rate.

We found DCR of NACT in conjunction with CCRT and CCRT alone in 5 studies. The heterogeneity test showed low heterogeneity among multiple studies (I2=44.7%, P>0.10, Figure 4). The results showed that NACT combined with CCRT did not show a better prognosis than the CCRT alone (OR =1.25, 95% CI: 0.72–2.17, P>0.05). The sensitivity analysis conducted by sequentially removing investigations failed to reveal any unstable results. Funnel plot and Egger’s test (P>0.05) did not find publication bias. It should be noted that each study showed no difference in disease control between the two-chemotherapy regimen.

Figure 4 DCR of neoadjuvant chemotherapy combined with chemoradiation and concurrent chemoradiation alone. CI, confidence interval; DCR, disease control rate; MH, Mantel–Haenszel.

Four studies explained the difference in 3-year survival rate between NACT combined with concurrent chemoradiotherapy (CCRT) and CCRT alone. The heterogeneity test showed large heterogeneity among multiple studies (I2=74.1%, P<0.05, Figure 5). The results showed that NACT combined with CCRT did not show a better prognosis than the CCRT alone (OR =0.87, 95% CI: 0.38–2.03, P>0.05). The sensitivity analysis, with one investigation systematically removed at a time, failed to reveal any unstable results. The funnel plot and Egger’s test (P>0.05) revealed no evidence of bias in publishing. The results of two studies (17,20) showed that the 3-year survival rate of radiotherapy and chemotherapy alone was even higher.

Figure 5 Three-year survival rate of neoadjuvant chemotherapy combined with chemoradiation and concurrent chemoradiation alone. CI, confidence interval; DL, DerSimonian-Laird.

Other results

Eight studies compared the differences in acute skin reactions between NACT combined with radiochemotherapy and radiochemotherapy alone. The heterogeneity test showed large heterogeneity among multiple studies (I2=46.5%, P>0.05). The results showed that NACT combined with CCRT did not show diversity with the CCRT alone (OR =1.22, 95% CI: 0.94–1.60, P>0.05, Figure 6). The sensitivity analysis, which revoked the investigations one by one, failed to reveal any unstable results. The funnel plot and Egger’s test (P>0.05) revealed no evidence of bias in publishing.

Figure 6 Acute skin reaction of neoadjuvant chemotherapy combined with chemoradiation and concurrent chemoradiation alone. CI, confidence interval; MH, Mantel–Haenszel.

In addition, we carefully reviewed possible adverse events, including major hematologic or nonhematologic events. There were no variation in the occurrence of nausea (OR =1.07, 95% CI: 0.72–1.59), vomiting (OR =1.50, 95% CI: 0.83–2.70), diarrhea (OR =0.94, 95% CI: 0.67–1.33), anemia (OR =1.20, 95% CI: 0.73–1.97) and neutropenia (OR =1.49, 95% CI: 0.96–2.30) between the two groups of patients who experienced different treatment plans. However, the incidence rate of leucopenia (OR =2.37, 95% CI: 1.09–5.14) was higher in NACT combined with radiotherapy and chemotherapy. Please refer to Figures S1,S2 for details.

Discussion

The cervical cancer standards established by National Comprehensive Cancer Network (27) reveal that CCRT is a particularly suitable therapy for individuals with stage IB2-IIB cervical cancer. In conjunction with surgical intervention, it represents the most appropriate option for individuals diagnosed with stage IIA1. Nonetheless, the current general success rate for CCRT in individuals diagnosed with stage IB2–IIB cervical cancer remains unsatisfactory, and there is some controversy about whether there is an advantage of receiving NACT treatment (28). A retrospective study conducted by Lee et al. indicated a small variation in survival rates among individuals with stage IB–IIB cervical cancer who underwent NACT compared to those who received CCRT (29). Similarly, the findings from Singh et al. (stage IB2–IIIA) corroborated these results, as did the study by Ertas et al. (stage IB2–IIIA). IB2 and IIA2 stages) (30,31). Nonetheless, Ertas et al.’s findings indicate that NACT offers greater advantages for patients classified as stage IB2–IIIB. Consequently, it is imperative to address this enduring and significant clinical question regarding the medical care for individuals with advanced cervical cancer. We found a significant difference in CRR and ORR between the NACT combined with chemoradiation and concurrent chemoradiation alone in this study. Yet, this conclusion cannot be extended to analyzing DCRs and the 3-year survival rates. The fit of the random-effects model still showed significant heterogeneity. Compared with multiple studies showing no significant difference between the two intervention methods, da Costa et al.’s study showed a significant improvement in patients after NACT chemotherapy (OR =0.70, 95% CI: 0.53–0.91) (16). This significant difference is different from other studies and that is a source of heterogeneity. Considering the gemcitabine NAC chemotherapy regimen used by da Costa et al., this may be the likely reason for the clear advantage.

Thereafter, we summarized the survival benefits of NACT combined with chemoradiation and concurrent chemoradiation alone (HR=0.94, 95% CI: 0.27–1.61). Although there is obvious heterogeneity, the results of multiple studies are the same. We then found the same results after excluding Narayan et al.’s study and the results, respectively (17). The TP regimen demonstrated outstanding therapeutic capabilities, both in terms of degree of remission and favorable prognosis. What is more surprising is that the patients did not experience intolerable conditions after receiving the treatment, and there was no significant increase in hematological adverse events. The survival rate over a five-year period among individuals undergoing NACT was notably higher. Comparable findings were observed in an additional meta-analysis (32).

Gemcitabine functions as an antimetabolite, effectively inhibiting DNA synthesis and promoting programmed death of cells. Clinically, gemcitabine is recognized for its role as a radiosensitizer, exhibiting a profile of reduced adverse reactions. Although a retrospective study showed promising efficacy and acceptability for gemcitabine and cisplatin, our findings suggest that their use as part of a neoadjuvant chemotherapy (NACT) regimen prior to chemoradiation (CRT) in patients with LACC requires further validation (33). In addition, cervical cancer has a high level of telomerase expression, and in vitro studies have shown that paclitaxel has the capacity to suppress telomerase activity and promote apoptosis in cancer cells (34). The radiosensitizing effect of paclitaxel in NAC intervention could further elucidate its dose-response efficacy (35).

There are some shortcomings in this study, Firstly, the included studies come from different countries and regions, and there is a lack of unified standards for the cycle arrangement and medication regimen of NACT and CCRT. Therefore, it can be clearly seen from heterogeneity analysis that there is significant heterogeneity among studies, though we conducted corresponding grouping analysis to explain the existence of some heterogeneity. Secondly, the studies did not have a fully convincing sample size, which would limit the statistical power and generalization of the results. In addition, this study aims to explore the short-term killing effect on advanced cervical cancer cells, but it only represents the initial signal of chemotherapy. There is a lack of sufficient evidence on predicting survival, and the information of acquired drug resistance, distant metastasis, and minimal residual disease is unknown, which seriously affects how efficient initial responses can be transformed into lasting patient survival benefits. More large-scale multicenter randomized controlled trials are needed to further validate the findings.

Conclusions

Compared with CCRT alone, combined NACT had a higher initial effect on individuals with LACC, rather than a sustained benefit. TP regimen may be a better option but more attention should be paid to leucopenia. Further prospective studies with larger sample sizes are needed for the development of therapy regimens for LACC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-966/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-966/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-966/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Lu Y, Zhao J, Jia Z, Zhang C. Efficacy and safety of neoadjuvant chemotherapy combined with concurrent chemoradiotherapy and concurrent chemoradiotherapy alone in locally advanced cervical cancer: a systematic review and meta-analysis. Transl Cancer Res 2026;15(1):17. doi: 10.21037/tcr-2025-966

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