Abstract
Objective
This study evaluated efficacy and safety of concurrent chemoradiotherapy (CCRT) versus CCRT plus adjuvant chemotherapy (CCRT+ACT) in 2018 Federation International of Gynecology and Obstetrics (FIGO) Stage III locally advanced cervical cancer (LACC) patients. This study provides clinical evidence to optimize treatment strategies for stage III LACC.
Methods
A total of 72 patients diagnosed with stage III LACC were retrospectively enrolled from the Cancer Hospital of Guangdong Medical University between May 2018 and May 2024. They were divided into the CCRT group (n = 33) and the CCRT+ACT group (n = 39). Survival endpoints were analyzed using the Kaplan–Meier method with log-rank tests, and Cox proportional hazards regression models were applied to identify prognostic factors.
Results
The 3-year OS (79.5% vs. 63.6%,P = 0.238) and PFS (56.4% vs. 45.5%,P = 0.706) rates showed no significant differences between the CCRT+ACT and CCRT groups. Kaplan–Meier survival analysis suggested that a positive lymph node size ≥ 10 mm (relative to a < 10 mm reference) may be associated with an increased hazard for mortality (HR = 8.235; P = 0.020) and disease progression (HR = 2.986; P = 0.020). Furthermore, abnormal post-brachytherapy SCC-Ag levels (> 1.5 ng/mL vs. ≤ 1.5 ng/mL reference) appeared to be strongly linked to adverse OS (HR = 13.641; P < 0.001) and PFS (HR = 4.722; P = 0.007). Regarding safety, CCRT+ACT did not increase grade 3–4 toxicities, suggesting a manageable safety profile.
Conclusion
While CCRT+ACT did not significantly improve survival in the un-selected stage III LACC population, a positive lymph node size of ≥ 10 mm and elevated post-brachytherapy SCC-Ag levels may serve as important prognostic indicators for adverse outcomes. These findings are hypothesis-generating, suggesting that integrating these factors into clinical risk assessment might aid in refining the identification of high-risk subsets who could potentially benefit from more personalized, intensified adjuvant strategies in future prospective trials.
Introduction
Cervical cancer remains a significant global health burden among women. 2022 global statistics reveal 660,000 newly diagnosed cases and 350,000 fatalities, accounting for a significant portion of female cancer mortality and ranking as the fourth most common female cancer [1]. As defined by the National Comprehensive Cancer Network (NCCN) guidelines [2], locally advanced cervical cancer (LACC) includes tumors staged IB3–IVA under the 2018 Federation International of Gynecology and Obstetrics (FIGO) criteria. Clinically, a narrower LACC subset (≥4 cm, cervix or upper vagina-confined, no metastasis) aligns with 2018 FIGO IB3 and IIA2 stages.
1999 landmark multicenter trials [3–7] established concurrent platinum-based chemoradiotherapy (CCRT) as the cornerstone of LACC management, showing a 30%−50% relative mortality reduction via synergistic effects. These findings led the NCCN to adopt CCRT as LACC’s standardized treatment [8], still in use today. Despite this, 30%−40% of LACC patients face post-treatment recurrence or metastasis risk [7], linked to poor tumor biology (e.g., low differentiation, lymph node metastasis, chemotherapy or radiotherapy resistance) [9]. To improve survival, researchers have explored intensified strategies, including neoadjuvant chemotherapy [10, 11] and adjuvant chemotherapy (ACT) [12, 13].
ACT efficacy in LACC remains debated. The OUTBACK trial [12] initially found no survival benefit, but post-hoc staging adjustments [14] revealed subgroup gains, suggesting earlier stage II-enriched studies may have masked ACT benefits [15–17]. Subsequent studies [14,18] reported survival improvements with ACT in lymph node-positive patients. A meta-analysis [19] demonstrated significant survival advantages with CCRT+ACT, while A 2018 FIGO staging-based model [20] suggested stage IVA LACC patients might derive greater benefit from CCRT+ACT.
To address this controversy, unlike prior studies, this research focuses on high-risk stage III LACC patients. We included 72 such patients treated at our center from May 2018 to May 2024, comparing CCRT vs CCRT+ACT outcomes and toxicities to assess intensified treatment value in this subgroup.
Methods
Study participants
This was a single-center, retrospective observational cohort study. Between May 2018 and May 2024, a total of 222 patients initially diagnosed with 2018 FIGO stage III LACC were identified at the Cancer Hospital of Guangdong Medical University. After applying our inclusion and exclusion criteria, 150 patients were excluded from the study. The primary reasons for exclusion were: 70 patients underwent surgery, 36 patients were diagnosed with non-stage III LACC, 26 patients had distant metastasis, and 18 patients were lost to follow-up..The final analyzed cohort consisted of 72 patients. Treatment assignment to either the CCRT group (n = 33) or the CCRT+ACT group (n = 39) was not randomized; it was determined based on physician discretion, grouping per inclusion and exclusion criteria, and institutional clinical guidelines at the time.Inclusion criteria were as follows: (1) Cervical cancer with histopathological confirmation of squamous cell or adenocarcinoma subtype, as determined by accredited pathology laboratories;(2) Aged between 38 and 77 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2;(3) Staged IIIA-IIIC 2018 FIGO criteria via gynecological exam and imaging (e.g., MRI/CT) by two gynecologists;(4) Completed CCRT (with/without subsequent ACT) and signed pre-treatment consent. Exclusion criteria: (1) CCRT intolerance;(2) Pre-existing distant metastasis;(3) Incomplete data/loss to follow-up before treatment completion;(4) Prior surgery. The technical roadmap flowchart of the research is shown in Fig 1. Following the journal’s guidelines, we commit to making our data accessible to a team designated by the Editorial Board for supplementary analysis or reproducibility verification at other institutions, if requested.
Fig 1. Study flow diagram.
LACC: Locally Advanced Cervical Cancer.
Treatment
CCRT Group: All patients received a standardized radiotherapy regimen comprising external beam radiotherapy (EBRT) and 3D high-dose-rate (HDR) brachytherapy. EBRT was delivered via volumetric modulated arc therapy (VMAT) using 6 MV photons, to a total dose of 45–50 Gy administered in 1.8–2.0 Gy fractions (five fractions per week). Target volumes and dose constraints were delineated according to RTOG guidelines [21]. The clinical target volume (CTV) encompassed the gross tumor, cervix, uterus, parametria, vagina, and regional lymph nodes. For patients with involved pelvic and/or para-aortic lymph nodes, an additional 10–15 Gy conformal boost was delivered to the positive nodes.
During EBRT, patients received concurrent systemic therapy. The standard regimen consisted of weekly intravenous cisplatin (30–40 mg/m2 for 1–5 cycles). For patients intolerant to cisplatin, alternative platinum agents (carboplatin or nedaplatin) were substituted. Systemic regimens broadly included: (1) single-agent cisplatin, or (2) a combination of liposomal/albumin-bound paclitaxel plus a platinum agent (cisplatin, carboplatin, or nedaplatin). Dose reductions or cycle delays were mandated in the event of grade 3–4 hematologic or gastrointestinal toxicities.
Following the completion of EBRT, 3D HDR intracavitary brachytherapy was performed using an Iridium-192 source via a Vienna applicator. Although historical Point A prescriptions (6–7 Gy/fraction for 4–5 fractions) were used as a reference, treatment planning was primarily optimized based on volumetric parameters. The median equivalent dose in 2 Gy fractions (EQD2) to the high-risk clinical target volume (HR-CTV D90) was 85 Gy. Radiation doses to organs at risk (OARs) were rigorously constrained, with the median D2cc limited to 80–90Gy for the bladder and 65–75 Gy for the rectum.
Clinical efficacy and toxicity assessment
Post-treatment follow-ups were conducted on a quarterly to semi-annual basis via outpatient visits or telephone consultations. Routine monitoring for disease recurrence and metastasis included clinical examinations, hematological tests, pelvic magnetic resonance imaging (MRI), and chest/abdominal/pelvic computed tomography (CT). The efficacy evaluation period concluded in September 2025. Tumor response was formally assessed at 1-month post-treatment using the RECIST 1.1 criteria [22], categorizing outcomes as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). We deliberately selected this early 1-month assessment window—rather than the traditional 3-month timeline—to facilitate the prompt identification of non-responders for timely salvage interventions. However, we acknowledge that this accelerated timeline may capture ongoing radiation-induced acute inflammation and tumor necrosis, which could potentially underestimate the ultimate CR rate compared with later evaluations.
Treatment-related toxicities were rigorously monitored and documented. Systemic adverse events, including myelosuppression, gastrointestinal reactions, proteinuria, and transaminase elevation, were graded from I to IV according to the CTCAE 5.0 criteria [23]. Additionally, acute radiation-induced toxicities were evaluated using the RTOG/EORTC criteria [21].
Statistical analysis
Statistical analysis employed SPSS 26.0. Categorical variables underwent chi-square or Fisher’s exact tests. Survival endpoints were analyzed via Kaplan-Meier curves with log-rank tests. Univariate and multivariate Cox regression identified prognostic factors, with P < 0.05 denoting significance.
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University (Date May 6th, 2025/No. PJKT2025−101).
Results
This study enrolled 222 treatment-naive patients with 2018 FIGO stage III LACC from Cancer Hospital of Guangdong Medical University from May 2018 to May 2024, all completing CCRT or CCRT plus ACT. After screening, 72 patients were analyzed, divided into CCRT (n = 33) and CCRT+ACT (n = 39) groups. We observed no significant differences in age, FIGO stage, pathological type, lymph node metastasis, positive lymph node size, tumor size, post-brachytherapy response, or admission levels of SCC-Ag and CEA between the two groups.Among the 55 patients with lymph node metastasis, 45 patients had pelvic lymph node involvement only, while 10 patients had both pelvic and para-aortic lymph node involvement. Notably, 11 patients presented with clinically early-stage primary tumors (≤4 cm) but were upstaged to FIGO IIIC strictly due to positive lymph node disease. These findings confirm that the cohorts were well-balanced at baseline (see Table 1).
Table 1. Baseline characteristic comparison of the two patient groups.
| Characteristics | All group | CCRT(n = 33) | CCRT+ACT(n = 39) | χ² | P value |
|---|---|---|---|---|---|
| Age(years) | 0.914 | 0.339 | |||
| ≤ 65 | 54 (75%) | 23 (69.7%) | 31 (79.5%) | ||
| > 65 | 18 (25%) | 10 (30.3%) | 8 (20.5%) | ||
| FIGO Stage | 1.331 | 0.722 | |||
| IIIA | 5 (6.9%) | 2 (6.1%) | 3 (7.7%) | ||
| IIIB | 12 (16.7%) | 6 (18.2%) | 6 (15.4%) | ||
| IIIC1r | 45 (62.5%) | 22 (66.7%) | 23 (59%) | ||
| IIIC2r | 10 (13.9%) | 3 (9.1%) | 7 (17.9%) | ||
| Pathological type | 0.906 | 0.341 | |||
| Squamous cell carcinoma | 60 (83.3%) | 29（87.9%） | 31 (79.5%) | ||
| Adenocarcinoma | 12 (16.7%) | 4（12.1%） | 8 (20.5%) | ||
| Lymph node metastasis | 1.510 | 0.219 | |||
| No | 17 (23.6%) | 10 (30.3%) | 7 (17.9%) | ||
| Yes | 55 (76.4%) | 23 (69.7%) | 32 (82.1%) | ||
| Positive lymph node size(mm) | 0.640 | 0.425 | |||
| < 10 | 30（54.5%） | 14（60.9%） | 16（50%） | ||
| ≥ 10 | 25（45.5%） | 9（39.1%） | 16（50%） | ||
| Tumor size（cm） | 0.260 | 0.610 | |||
| ≤ 4 | 15 (20.8%) | 6 (18.2%) | 9 (25%) | ||
| > 4 | 57 (79.2%) | 27 (81.8%) | 30 (75%) | ||
| post-brachytherapy response | 0.380 | 0.538 | |||
| CR | 20 (27.8%) | 8 (24.2%) | 12 (30.8%) | ||
| PR | 52 (72.2%) | 25 (75.8%) | 27 (69.2%) | ||
| initial admission SCC-Ag(ng/mL) | 0.690 | 0.405 | |||
| ≤ 1.5 | 9 (15%) | 6 (20.7%) | 3 (9.7%) | ||
| > 1.5 | 51 (85%) | 23 (79.3%) | 28 (90.3%) | ||
| post-brachytherapy SCC-Ag（ng/mL） | 2.630 | 0.105 | |||
| ≤ 1.5 | 56 (93.3%) | 25 (86.2%) | 31 (100%) | ||
| > 1.5 | 4 (6.7%) | 4 (13.8%) | 0 (0) | ||
| initial admission CEA(ng/mL) | 1.016 | 0.313 | |||
| ≤ 5 | 40 (69%) | 19 (76%) | 21 (63.6%) | ||
| > 5 | 18 (31%) | 6 (24%) | 12 (36.4%) |
CCRT: Concurrent chemoradiotherapy; ACT: Adjuvant chemotherapy; CEA: Carcinoembryonic antigen; SCC-Ag: Squamous cell carcinoma antigen; FIGO: Federation International of Gynecology and Obstetrics; CR: Complete response; PR: Partial response.The data of SCC – Ag were exclusively obtained from patients with squamous cell carcinoma.
After a median follow-up duration of 41 months (range, 9–89 months), survival outcomes were compared between groups using Kaplan-Meier methods. For overall survival, the CCRT+ACT group demonstrated 1, 2, and 3 year rates of 100.0%, 94.9%, and 79.5%, respectively, compared with 100.0%, 81.8%, and 63.6% in the CCRT group (P = 0.238; Fig 2A). Regarding progression-free survival, the corresponding 1, 2, and 3 year rates were 82.1%, 66.7%, and 56.4% in the CCRT+ACT group versus 69.7%, 54.5%, and 45.5% in the CCRT group (P = 0.706; Fig 2B). For local recurrence-free survival, the 1 and 2 year rates were 82.1% and 66.7% in the CCRT+ACT group compared with 69.7% and 54.5% in the CCRT group (P = 0.242; Fig 2C). Similarly, the 1 and 2 year distant metastasis-free survival rates were 82.1% and 66.7% in the CCRT+ACT group versus 69.7% and 54.5% in the CCRT group (P = 0.923; Fig 2D). No statistically significant differences were observed across all survival endpoints.
Fig 2. Comparison of survival curves between CCRT and CCRT+ACT groups.
CCRT: Concurrent chemoradiotherapy; ACT: Adjuvant chemotherapy.
Univariate analysis was conducted to identify prognostic factors associated with survival outcomes in patients with stage III LACC following CCRT. Variables assessed included: treatment modality, age, pathological type, lymph node metastasis status, primary tumor size, positive lymph node size, concurrent chemotherapy cycles, post-brachytherapy treatment response, baseline SCC-Ag level, post-brachytherapy SCC-Ag level, and baseline CEA level. Results revealed that post-brachytherapy SCC-Ag level was significantly associated with overall survival (P = 0.004, Fig 3A). Additionally, positive lymph node size, post-brachytherapy treatment response, and post-brachytherapy SCC-Ag level were significantly correlated with progression-free survival (P = 0.029, P = 0.041, and P < 0.001, respectively, Fig 3B).
Fig 3. Forest plot of univariate analysis.
A:Univariate analysis for overall survival;(B) Univariate analysis for progression-free survival; SCC-Ag: Squamous cell carcinoma antigen；CEA: Carcinoembryonic antigen.
To identify independent prognostic factors for survival outcomes in patients with LACC, a Cox proportional hazards regression model was constructed, incorporating clinically relevant baseline variables: treatment method, positive lymph node size, post-brachytherapy response, and post-brachytherapy SCC-Ag levels.In this model, positive lymph node size was identified as an independent risk factor for both overall survival and progression-free survival (P = 0.042;P = 0.008). Additionally, post-brachytherapy SCC-Ag levels independently predicted adverse overall survival and progression-free survival outcomes, with statistical significance (P = 0.009;P < 0.001).These findings indicate that positive lymph node size and post-brachytherapy SCC-Ag serve as robust independent predictors of survival in LACC patients, highlighting their potential clinical utility for risk stratification and treatment optimization.For details, refer to Table 2.
Table 2. Multivariate analysis affecting survival outcomes.
| Factors | OS | PFS | ||
|---|---|---|---|---|
| HR (95%CI) | P | HR (95%CI) | P | |
| Treatment method | 2.207(0.239-20.347) | 0.485 | 1.394(0.489-3.968） | 0.534 |
| Positive Lymph node size | 14.453(1.102-189.637） | 0.042* | 4.272(1.468-12.434） | 0.008* |
| post-brachytherapy SCC-Ag | 19.151(2.122-172.835） | 0.009* | 11.096(3.151-39.072) | <0.001* |
| post-brachytherapy response | – | – | 3.608(0.793-16.426） | 0.097 |
OS: Overall Survival; PFS: Progression-Free Survival; SCC-Ag: Squamous cell carcinoma antigen.
Kaplan–Meier survival analyses suggest that positive lymph node size and post-brachytherapy SCC-Ag levels are potential prognostic indicators in patients with stage III LACC. In these models, patients with a positive lymph node diameter < 10 mm were defined as the reference category. Compared to this reference, the group with nodes ≥ 10 mm appeared to have a higher risk of adverse outcomes, with estimated hazard ratios of 8.235 for overall survival (95% CI: 0.991–68.440, P = 0.020) (Fig 4A) and 2.986 for progression-free survival (95% CI: 1.119–7.967, P = 0.020) (Fig 4B). Similarly, using patients with post-brachytherapy SCC-Ag levels ≤ 1.5 ng/mL as the reference group, levels > 1.5 ng/mL were suggestive of significantly increased hazards for mortality (HR = 13.641, 95% CI: 3.317–56.104, P < 0.001) (Fig 4C)and disease progression (HR = 4.722, 95% CI: 1.350–16.522, P = 0.007) (Fig 4D). While these preliminary findings indicate that integrating nodal burden and dynamic biomarker monitoring might aid in risk stratification, they should be interpreted as hypothesis-generating given the retrospective nature of the study.
Fig 4. Prognostic Impact of Positive Lymph Node Size and Post-brachytherapy SCC-Ag Levels on Survival Outcomes.
A Overall survival and B progression-free survival stratified by positive lymph node size (< 10 mm vs. ≥ 10 mm).C Overall survival and D progression-free survival stratified by post-brachytherapy SCC-Ag levels (≤ 1.5 ng/mL vs. > 1.5 ng/mL).
To evaluate the impact of treatment modalities (CCRT vs. CCRT+ACT) on survival outcomes in lymph node-positive patients stratified by lymph node size (≥10 mm vs. < 10 mm), subgroup analyses were performed. In the < 10 mm subgroup (Fig 5A, B), survival curves of the two treatment groups overlapped, with log-rank P values of 0.480 and 0.175, indicating no significant survival difference. Similarly, in the ≥ 10 mm subgroup (Fig 5C, D), no significant separation of survival curves was observed, with log-rank P values of 0.423 and 0.631; HR with 95% CI all included 1, confirming no statistically significant difference in survival benefits between regimens. Limitations include small subgroup sample sizes (e.g., 9 patients in the ≥ 10 mm CCRT group) leading to insufficient statistical power, and rapid late-stage patient attrition (e.g., 1 patient remaining in Panel A’s CCRT group at 72 months) affecting long-term analysis stability, highlighting the need for larger studies with extended follow-up for validation.
Fig 5. Survival Analysis of Treatment Modality in Lymph Node-Positive Patients with Different Lymph Node Sizes.
A: Comparison of overall survival between CCRT and CCRT+ACT groups in <10 mm groups; B: Comparison of progression-free survival between CCRT and CCRT+ACT groups in <10 mm groups; C: Comparison of overall survival between CCRT and CCRT+ACT groups in ≥10 mm groups; D: Comparison of progression-free survival between CCRT and CCRT+ACT groups in ≥10 mm groups.
We compared late treatment-related toxicities between CCRT and CCRT+ACT, focusing on hematologic and non-hematologic adverse events (see Table 3). Toxicity rates did not differ significantly between groups (P > 0.05), indicating comparable safety profiles. Neutropenia was most common (CCRT vs. CCRT+ACT: 60.6% vs. 61.5% [grades 1–2]; 18.2% vs. 25.6% [grades 3–4], χ² = 1.544, P = 0.819), with leukopenia rates comparable (CCRT: 63.6%/33.3% [grades 1–2/3–4]; CCRT+ACT: 59%/35.9%, χ² = 1.616, P = 0.806). CCRT+ACT had slightly more grade 3–4 anemia (43.6% vs. 36.4%, P = 0.830) and CCRT more grade 3–4 thrombocytopenia (9.1% vs. 2.6%, P = 0.281); grade 1–2 AST elevation was marginally higher in CCRT+ACT (20.5% vs. 6.1%, χ² = 2.030, P = 0.154). Non-hematologic toxicities included proteinuria (CCRT: 42.5% vs. CCRT+ACT: 38.9%, χ² = 1.816, P = 0.611), more frequent grade 1–2 nausea/vomiting in CCRT+ACT (41.0% vs. 27.3%, χ² = 1.897, P = 0.387), and low comparable diarrhea rates (P = 0.802). Overall, CCRT+ACT did not increase grade 3–4 toxicities, suggesting manageable safety, though trends toward higher neutropenia and AST elevation in CCRT+ACT warrant attention.
Table 3. Toxic side effects of the two treatment groups.
| CCRT group n = 33 N(%) |
CCRT+ACT group n = 39 N(%) |
χ² | P | |||
|---|---|---|---|---|---|---|
| 1-2 | 3-4 | 1-2 | 3-4 | |||
| Hematologic toxicity | ||||||
| Neutropenia | 21 (60.6) | 6 (18.2) | 24 (61.5) | 10 (25.6) | 1.544 | 0.819 |
| Hemoglobin reduction | 17 (51.6) | 12 (36.4) | 15 (38.5) | 17 (43.6) | 1.483 | 0.830 |
| Thrombocytopenia | 12 (36.4) | 3 (9.1) | 10 (25.6) | 1 (2.6) | 5.061 | 0.281 |
| AST | 2 (6.1) | 0 (0.0) | 8 (20.5) | 0 (0.0) | 2.030 | 0.154 |
| ALT | 6 (18.2) | 0 (0.0) | 9 (23.1) | 0 (0.0) | 0.260 | 0.210 |
| eGFR | 15 (45.5) | 0 (0.0) | 20 (51.3) | 0 (0.0) | 0.243 | 0.886 |
| Creatinine | 6 (18.2) | 0 (0.0) | 7 (17.9) | 1 (2.6) | 2.124 | 0.547 |
| Non-hematologic toxicity | ||||||
| Proteinuria | 14 (42.5) | 1 (3.0) | 28 (38.9) | 0 (0.0) | 1.816 | 0.611 |
| Nausea and vomiting | 9 (27.3) | 1 (3.0) | 16 (41.0) | 2 (5.1) | 1.897 | 0.387 |
| Diarrhea | 4 (12.1) | 0 (0.0) | 4 (10.3) | 0 (0.0) | 0.063 | 0.802 |
CCRT: Concurrent chemoradiotherapy; ACT: Adjuvant chemotherapy; AST: Aspartate Aminotransferase; eGFR: estimated Glomerular Filtration Rate; ALT: Alanine Aminotransferase.
Discussion
Results in the context of published literature
Our findings reflect the ongoing controversy regarding ACT in LACC. While Yavas et al. [24] and a meta-analysis of 1,659 patients [25] reported significant OS and PFS benefits with CCRT+ACT, the OUTBACK trial [12] found comparable 5-year OS between groups. However, post-hoc adjustments in OUTBACK suggested benefits in high-risk subsets, implying that including lower-risk stage II patients in earlier studies may have masked ACT efficacy [15–17]. Although our focus on stage III disease aligns with Fabri et al. [26] —who noted survival gains in lymph node-positive patients—we observed no significant benefit, likely due to our modest sample size (n = 72) and short follow-up (41 months).
The 27.8% complete response rate, lower than the literature-reported 54%–91% [27,28], is attributable to three factors.First, our 1-month efficacy assessment window is earlier than the traditional 3-month timeline; this may underestimate complete response as radiation-induced inflammation and necrosis often take longer to resolve.Second, 79.2% of our cohort presented with tumors >4 cm, which typically exhibit greater hypoxia and resistance, limiting drug penetration [29].Third, suboptimal delivery of the 5-cycle concurrent chemotherapy regimen may have weakened the synergistic radiosensitizing effect.
Unexpectedly, traditional factors like tumor size and lymph node metastasis did not reach statistical significance in this study. This may stem from a homogeneous cohort distribution reducing statistical power, or because nodal status was already incorporated into treatment stratification, thereby attenuating its independent prognostic impact.Furthermore, the anatomical focus of current FIGO staging may not fully capture the biological heterogeneity of these tumors, highlighting the need for more nuanced indicators like nodal size and dynamic biomarkers.
Positive Lymph Node Size and Post-Brachytherapy SCC-Ag: Prognostic Factors and Clinical Significance in Stage III LACC
In our cohort, a positive lymph node size of ≥ 10 mm and post-brachytherapy SCC-Ag levels > 1.5 ng/mL were identified as potential prognostic factors for adverse outcomes. Using the < 10 mm group as the reference category, our findings suggest that a lymph node size of ≥ 10 mm may be associated with an increased hazard for mortality and disease progression, as indicated by corrected hazard ratios of 8.235 for overall survival and 2.986 for progression-free survival. This observation aligns with the premise that lymph node burden—represented here by the maximum short-axis diameter—may serve as an informative prognostic metric, consistent with prior studies linking larger nodal size to adverse survival [14]. Similarly, relative to the reference group (≤ 1.5 ng/mL), persistently elevated post-brachytherapy SCC-Ag (> 1.5 ng/mL) appeared to be associated with significantly higher risks of death and progression. This supports its potential role as a dynamic surrogate marker for incomplete tumor eradication or micrometastatic disease [17,30,31]. Regarding clinical application, these findings should be interpreted as hypothesis-generating. While CCRT+ACT did not significantly improve survival in the overall un-selected stage III population, the subset of patients presenting with multiple high-risk features (e.g., lymph nodes ≥ 10 mm and abnormal post-treatment SCC-Ag) might represent a group with an elevated risk of systemic failure. However, the interpretation of potential survival benefits from adjuvant therapies in this specific subgroup remains limited by our study’s small sample size (n = 72) and inherent treatment heterogeneity. Therefore, rather than directly guiding routine clinical practice, these parameters could serve as reference variables for risk stratification in future large-scale, prospective trials to further evaluate the efficacy of intensified systemic treatments in this population.
Strengths and weaknesses
The study’s strengths stem from its targeted focus on stage III LACC, filling a key gap in the literature where prior investigations often included broader, more heterogeneous LACC stages [18,32,33]. By rigorously analyzing lymph node size and SCC-Ag as critical prognostic factors, our study offers actionable insights for personalized risk stratification. Additionally, comprehensive toxicity assessments validated the manageable safety profile of CCRT+ACT, confirming that there was no significant escalation in the prevalence of grade 3–4 treatment-emergent toxicities.
Despite these strengths, several limitations must be explicitly acknowledged. First, the retrospective, single-center design and the significant attrition rate during patient selection (from 222 initially identified to 72 analyzed) may introduce considerable selection bias. Second, the CCRT+ACT cohort exhibited notable treatment heterogeneity, including variable adjuvant chemotherapy regimens (single-agent vs. paclitaxel-based combinations), differing numbers of cycles, and concurrent platinum substitutions. This variability inherently weakens the causal interpretation of the survival outcomes and the null findings. Third, as a retrospective observational study, no a priori power and sample-size calculations were performed. The small sample size of 72 patients severely limits the statistical power of the study; consequently, our non-significant survival differences and subgroup analyses (e.g., lymph node burden stratification) are under-powered and must be interpreted with great caution. Fourth, the relatively short follow-up (median 36 months) may have underestimated long-term survival trends. Finally, relying on MRI for lymph node evaluation—which has a reported 40% micrometastasis miss rate [34] —instead of the more sensitive FDG PET-CT [35] risks overlooking high-risk patients, potentially biasing our risk stratification results.Furthermore, because our cohort underwent definitive chemoradiotherapy without surgical lymphadenectomy, we could not determine the exact absolute count of positive lymph nodes (due to the limitation of MRI in distinguishing conglomerated nodes), prompting our reliance on the maximum lymph node diameter (≥10 mm) and anatomical location as primary surrogate markers for nodal tumor burden.
Implications for Practice and Future Research
Clinically, these studies reveal CCRT+ACT does not significantly improve survival in stage III LACC but shows a potential benefit trend, supporting lymph node size≥10 mm in lymph node-positive patients and post-brachytherapy SCC-Ag > 1.5 ng/mL as high-risk markers to guide intensified treatment. Future research should prioritize several key directions: First, multicenter, large-scale RCTs to validate ACT efficacy in high-risk subsets (e.g., ≥ 2 lymph nodes or size≥10 mm); second, FDG PET-CT for accurate lymph node assessment; third, molecular profiling (e.g., PD-L1, HPV) and immunotherapy (e.g., pembrolizumab [36], durvalumab [37]) to optimize personalized regimens; and finally quality-of-life evaluations to balance ACT benefits and toxicities.
Conclusion
In conclusion, our study suggests that the addition of adjuvant chemotherapy following CCRT does not significantly improve OS or PFS in the un-selected population of stage III LACC patients. Nevertheless, a positive lymph node size of ≥ 10 mm and elevated post-brachytherapy SCC-Ag levels were identified as potent indicators of adverse outcomes compared to their respective reference categories (< 10 mm and ≤ 1.5 ng/mL). Specifically, these features appeared to be associated with significantly increased hazards for both mortality and disease progression. While these findings may aid in identifying high-risk subsets who could potentially benefit from intensified adjuvant strategies, they should be interpreted as hypothesis-generating due to the retrospective nature and limited sample size of this investigation. Further large-scale randomized controlled trials are warranted to refine treatment strategies and validate the efficacy of intensified care for these high-risk subgroups.
Data Availability
Data cannot be shared publicly because of patient privacy and confidentiality requirements established by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University. Data are available from the Ethics Committee (contact via fyllwyh@126.com) for researchers who meet the criteria for access to confidential data.
Funding Statement
This work was supported by Scientific Research Initiation Funding for High-Level Personnel (No. 1027Z20230062)、the Big Data Platform of Affiliated Hospital of Guangdong Medical University and Guangdong Medical University Special Program for Clinical and Basic Scientific and Technological Innovation (No.GDMULCJC2024025). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Associated Data
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Data Availability Statement
Data cannot be shared publicly because of patient privacy and confidentiality requirements established by the Ethics Committee of the Affiliated Hospital of Guangdong Medical University. Data are available from the Ethics Committee (contact via fyllwyh@126.com) for researchers who meet the criteria for access to confidential data.