Abstract
Background
Cervical cancer is one of the most common gynecologic malignancies worldwide, and the optimal adjuvant treatment strategy remains controversial for patients with early-stage cervical cancer with intermediate-risk factors who undergo radical surgery. This study aimed to identify the risk factors affecting prognosis and to evaluate the clinical efficacy of sequential chemoradiotherapy (SCRT) as adjuvant therapy.
Methods
The data of 152 patients with stage IA2–IIA1 cervical cancer who underwent radical hysterectomy with postoperative adjuvant therapy at Changzhou Maternal and Child Health Care Hospital between January 2014 and December 2019 were retrospectively analyzed. The patients were divided into three groups according to the mode of postoperative adjuvant therapy: the concurrent chemoradiotherapy (CCRT) group (n=56), the SCRT group (n=50), and the radiotherapy (RT) alone group (n=46). Disease-free survival (DFS), overall survival (OS), and adverse reactions were compared among the three groups. Follow-up was performed every 3–6 months until December 2023 or death. Univariate and multivariate Cox regression analyses were performed to identify prognostic factors.
Results
The 3-year DFS rates were 67.4%, 85.7%, and 92.0% in the RT, CCRT, and SCRT groups, respectively, and the 5-year DFS rates were 43.4%, 60.7%, and 76.0%, respectively. The 3-year OS rates were 87.0%, 91.1%, and 94.0%, respectively, and the 5-year OS rates were 49.7%, 66.1%, and 84.0%, respectively. The patients receiving SCRT demonstrated significantly improved DFS (P=0.002) and OS (P=0.001) compared with those receiving RT alone, whereas no significant differences were observed between the SCRT and CCRT groups (P=0.18 and P=0.11, respectively). Tumor size was imbalanced at baseline: tumors >4 cm were present in 35/46 (76.09%), 39/56 (69.64%), and 26/50 (52.00%) patients in the RT, CCRT, and SCRT groups, respectively. Severe myelosuppression occurred in 2/46 (4.35%), 20/56 (35.71%), and 15/50 (30.00%) patients in the RT, CCRT, and SCRT groups, respectively (P<0.05 for SCRT and CCRT vs. RT), with no significant difference between the SCRT and CCRT groups (P>0.05). The multivariate analysis identified pathological type and lymph node metastasis as independent prognostic factors for DFS and OS (P<0.05).
Conclusions
In this retrospective cohort, SCRT after radical hysterectomy was associated with longer DFS and OS than RT alone in patients with stage IA2–IIA1 cervical cancer, whereas no statistically significant difference was detected between SCRT and CCRT, which should not be interpreted as evidence of equivalence. SCRT was associated with a higher incidence of severe myelosuppression than RT alone; however, its toxicity profile was comparable to that of CCRT and remained clinically manageable. These findings suggest that SCRT may serve as a viable postoperative adjuvant treatment option for selected patients with early-stage cervical cancer and risk factors for recurrence, subject to confirmation in adequately powered randomized trials.
Keywords: Cervical cancer, postoperative, adjuvant therapy, sequential chemoradiotherapy (SCRT), prognosis
Highlight box.
Key findings
• Sequential chemoradiotherapy (SCRT) after radical hysterectomy significantly improved disease-free survival (DFS) and overall survival (OS) compared with radiotherapy (RT) alone in patients with stage IA2–IIA1 cervical cancer, with no statistically detectable difference in efficacy or toxicity compared with concurrent chemoradiotherapy (CCRT).
What is known, and what is new?
• The National Comprehensive Cancer Network guidelines recommend adjuvant RT or CCRT for patients with early-stage cervical cancer and postoperative risk factors; however, controversy continues regarding the optimal adjuvant treatment strategy for patients with intermediate-risk factors, as research comparing RT alone, CCRT, and SCRT is limited.
• This study demonstrated that SCRT significantly improved 5-year DFS (76.0% vs. 43.4%, P=0.002) and 5-year OS (84.0% vs. 49.7%, P=0.001) compared with RT alone, with no statistically significant difference in survival outcomes compared with CCRT. The incidence of severe myelosuppression was significantly higher in the SCRT (30.00%) and CCRT (35.71%) groups than in the RT alone group (4.35%); however, no significant difference was observed between SCRT and CCRT. The multivariate analysis identified pathological type and lymph node metastasis as independent prognostic factors for DFS and OS.
What is the implication, and what should change now?
• SCRT may represent a viable postoperative adjuvant treatment option for selected patients with early-stage cervical cancer and postoperative risk factors, offering survival benefits over RT alone with manageable toxicity comparable to that of CCRT; treatment choice should be individualized according to pathological risk factors. Larger multicenter prospective randomized controlled trials are warranted to validate these findings and establish personalized treatment strategies.
Introduction
Cervical cancer is one of the most common malignant tumors in gynecology worldwide. According to the latest global cancer statistics from GLOBOCAN 2022, there were approximately 661,000 new cases of cervical cancer and 342,000 cervical cancer-related deaths globally in 2022, making it the fourth most common cancer among women in terms of both incidence and mortality (1). The burden of cervical cancer is particularly high in low- and middle-income countries, where access to screening and vaccination programs remains limited (2). In China, cervical cancer continues to pose a notable public health challenge, with an estimated 110,000 new cases of cervical cancer and 59,000 cervical cancer-related deaths annually, representing ~17% of the global cervical cancer burden (3).
For patients with early-stage cervical cancer [International Federation of Gynecology and Obstetrics (FIGO) stage IA2–IIA1], radical hysterectomy with pelvic lymph node dissection remains the standard treatment approach. However, patients with postoperative risk factors for recurrence, including pelvic lymph node metastasis, parametrial tissue infiltration, and vascular invasion, have notably higher rates of recurrence and metastasis than those without such risk factors (4). Further, a recent nationwide propensity score-matched analysis of 1,687 patients with T1b cervical cancer demonstrated that postoperative adjuvant chemotherapy alone was associated with significantly superior overall survival (OS) compared with concurrent chemoradiotherapy (CCRT), particularly among subgroups with squamous histology, large tumor size (>4 cm), and negative lymph node metastasis (5). Thus, the identification and management of these risk factors are crucial for optimizing postoperative adjuvant therapy and improving patient outcomes.
Currently, the National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemoradiotherapy after surgery for patients with high-risk factors, such as positive lymph nodes, positive margins, and parametrial tissue infiltration (6). For patients with two or more intermediate-risk factors (e.g., a preoperative tumor diameter ≥4 cm, deep stromal invasion, and vascular invasion), adjuvant radiotherapy (RT) is recommended postoperatively; however, to date, there is no consensus on the need for additional chemotherapy (6,7). In routine practice, patients with high-risk pathological factors are generally offered postoperative CCRT, whereas those with intermediate-risk factors are typically treated with RT alone; whether the addition of systemic chemotherapy as sequential chemoradiotherapy (SCRT) benefits the latter group remains unresolved, and the choice among adjuvant therapy modalities remains an area of ongoing research and debate.
While postoperative adjuvant chemoradiotherapy reduces recurrence rates and improves survival outcomes, it also increases the risk of treatment-related adverse effects (8). Therefore, selecting a reasonable and effective postoperative adjuvant treatment strategy is crucial for patients who have undergone radical surgery for cervical cancer. SCRT, which involves administering systemic chemotherapy before and after RT, has emerged as a potential alternative approach that may offer improved survival outcomes while maintaining manageable toxicity profiles.
Relevant randomized evidence is now available: in the STARS phase 3 randomized trial (n=1,048), adjuvant SCRT, CCRT, and RT alone after hysterectomy were compared in patients with cervical cancer with pathological risk factors, and SCRT improved the 3-year disease-free survival (DFS) rate compared with CCRT (90.0% vs. 85.0%, P=0.04) and reduced the distant metastasis rate (6.5% vs. 11%, P=0.04) (9). However, the generalizability of randomized findings to routine practice, where patients may have different comorbidity profiles, risk-factor distributions, and treatment delivery than trial participants, remains uncertain. The present single-center study therefore evaluated the real-world efficacy and toxicity of the three postoperative strategies in a clinic-based cohort treated outside a randomized trial setting, with follow-up extending to December 2023, complementing the available randomized evidence.
The present study retrospectively analyzed the clinical efficacy and severity of treatment-related toxicities of postoperative RT, SCRT, and CCRT in 152 patients with stage IA2–IIA1 cervical cancer. The study findings may inform shared decision-making regarding postoperative adjuvant treatment in this population and provide real-world evidence to complement the available randomized data. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-2410/rc).
Methods
Patients
Patients with cervical cancer admitted to Changzhou Maternal and Child Health Care Hospital (Changzhou, China) from January 2014 to December 2019 were included in the study. The inclusion criteria were as follows: (I) cervical cancer staged as ⅠA2–ⅡA1 according to the revised 2018 FIGO staging system; (II) abdominal or laparoscopic radical hysterectomy with or without bilateral salpingo-oophorectomy, together with pelvic lymph node dissection, with or without para-aortic lymph node sampling, as well as pathological confirmation of at least one pathological risk factor (including positive lymph nodes, positive margins, parametrial tissue infiltration, preoperative tumor diameter ≥4 cm, deep stromal invasion, and vascular invasion); (III) receipt of standard adjuvant RT or chemoradiotherapy according to cervical cancer treatment guidelines with signed informed consent for chemoradiotherapy; and (IV) availability of complete clinical data and follow-up information. The exclusion criteria were as follows: (I) other malignancies or a history of malignancy; (II) previous surgery or antitumor treatment before inclusion; (III) failure to complete chemotherapy or RT as prescribed; and (IV) incomplete clinical data or loss to follow-up after discharge.
A total of 215 patients with cervical cancer were initially screened during the study period. After applying the exclusion criteria, 18 patients were excluded due to other malignancies or a history of malignancy, 12 patients were excluded due to previous surgery or antitumor treatment, 15 patients did not complete the prescribed chemotherapy or RT, and 18 patients had incomplete clinical data or were lost to follow-up. Consequently, 152 patients with cervical cancer were included in the final analysis, with an average age of 56.33±11.20 years (range, 34–78 years). According to the different postoperative treatment methods, the patients were divided into the following groups: (I) the RT alone group (n=46); (II) the CCRT group (n=56); and (III) the SCRT group (n=50). The baseline clinical characteristics of the three groups are shown in Table 1. Treatment allocation was not randomized: the adjuvant strategy was determined by the treating physician in consultation with the patient, mainly according to the pathological risk factors present (patients with high-risk factors were generally considered for CCRT, whereas those with intermediate-risk factors received RT alone or chemoradiotherapy after individualized assessment), together with patient age, comorbidities, and preference. Because treatment was not assigned randomly, confounding by indication cannot be excluded; this is addressed through multivariate adjustment and acknowledged in the “Limitations” section. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University (Changzhou, China; approval No. 202284). Written informed consent was obtained from all participants.
Table 1. Comparison of clinicopathological characteristics among patients with cervical cancer in the RT, CCRT, and SCRT groups.
| Variables | RT (n=46) | SCRT (n=50) | CCRT (n=56) | χ2 | P value |
|---|---|---|---|---|---|
| Age (years) | 0.514 | 0.77 | |||
| ≤50 | 18 (39.13) | 23 (46.00) | 25 (44.64) | ||
| >50 | 28 (60.87) | 27 (54.00) | 31 (55.36) | ||
| FIGO stage | 7.018 | 0.14 | |||
| IA2 | 13 (28.26) | 8 (16.00) | 10 (17.86) | ||
| IB1 | 3 (6.52) | 7 (14.00) | 10 (17.86) | ||
| IB2 | 6 (13.04) | 9 (18.00) | 11 (19.64) | ||
| IB3 | 4 (8.70) | 2 (4.00) | 7 (12.50) | ||
| IIA1 | 20 (43.48) | 24 (48.00) | 18 (32.14) | ||
| LVSI | 2.939 | 0.23 | |||
| Positive | 26 (56.52) | 35 (70.00) | 40 (71.43) | ||
| Negative | 20 (43.48) | 15 (30.00) | 16 (28.57) | ||
| DSI | 1.167 | 0.56 | |||
| >1/2 | 31 (67.39) | 37 (74.00) | 43 (76.79) | ||
| ≤1/2 | 15 (32.61) | 13 (26.00) | 13 (23.21) | ||
| Tumor size (cm) | 6.761 | 0.03* | |||
| ≤4 | 11 (23.91) | 24 (48.00) | 17 (30.36) | ||
| >4 | 35 (76.09) | 26 (52.00) | 39 (69.64) | ||
| Pathological type | 1.123 | 0.89 | |||
| Squamous cell carcinoma | 30 (65.22) | 37 (74.00) | 41 (73.21) | ||
| Adenocarcinoma | 11 (23.91) | 9 (18.00) | 10 (17.86) | ||
| Other types | 5 (10.87) | 4 (8.00) | 5 (8.93) | ||
| Histological grade | 0.776 | 0.94 | |||
| Well-differentiated | 6 (13.04) | 5 (10.00) | 5 (8.93) | ||
| Moderately differentiated | 25 (54.35) | 27 (54.00) | 29 (51.79) | ||
| Poorly differentiated | 15 (32.61) | 18 (36.00) | 22 (39.28) | ||
| Parametrial tissue infiltration | 0.475 | 0.79 | |||
| Negative | 41 (89.13) | 45 (90.00) | 52 (92.86) | ||
| Positive | 5 (10.87) | 5 (10.00) | 4 (7.14) | ||
| Positive margins | 0.261 | 0.88 | |||
| Negative | 42 (91.30) | 47 (94.00) | 52 (92.86) | ||
| Positive | 4 (8.70) | 3 (6.00) | 4 (7.14) | ||
| Number of positive lymph nodes | 2.192 | 0.70 | |||
| 0–1 | 19 (41.30) | 15 (30.00) | 19 (33.93) | ||
| 2 | 17 (36.96) | 18 (36.00) | 21 (37.50) | ||
| ≥3 | 10 (21.74) | 17 (34.00) | 16 (28.57) |
Data are presented as n (%), and P values were calculated using the Chi-squared test. *, P<0.05 indicates statistical significance. CCRT, concurrent chemoradiotherapy; DSI, depth of stromal invasion; FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion; RT, radiotherapy; SCRT, sequential chemoradiotherapy.
Treatment
Postoperative RT included pelvic external beam RT and intracavitary brachytherapy. After simulator-based positioning, the clinical target area, including the vaginal stump, cervix, and pelvic lymphatic drainage areas (the obturator, internal iliac, external iliac, presacral, and common iliac regions), was treated once daily, five times per week (6-MV X-rays; 2 Gy/session), to a total dose of 40–50 Gy. For patients with positive pelvic lymph nodes, the total dose was increased by an additional 10–15 Gy. Intracavitary brachytherapy was administered at 5–7 Gy/session, once per week, to a total dose of 30–40 Gy.
Patients in the CCRT group received concurrent chemotherapy with cisplatin (30–40 mg/m2) once per week for 4–6 weeks during RT.
Patients in the SCRT group received 1–2 cycles of systemic chemotherapy before and after RT. The chemotherapy regimens included: (I) the paclitaxel plus cisplatin (TP) regimen (paclitaxel 175 mg/m2 on day 1; cisplatin 60–75 mg/m2 on days 1–2; every 21 days as one cycle); and (II) the paclitaxel plus carboplatin (TC) regimen (paclitaxel 175 mg/m2 on day 1; carboplatin at an area under the curve of 5–6 on day 2; every 21 days as one cycle). The RT regimen was the same as described above. Chemotherapy was generally started after postoperative recovery, and post-RT chemotherapy was resumed once hematologic parameters had recovered; the timing was individualized according to surgical recovery and blood counts. Patients who did not complete the prescribed chemoradiotherapy were excluded during screening (see the “Patients” section). The same institutional RT and chemotherapy protocols were applied throughout the study period.
Efficacy and adverse reaction evaluation
DFS, OS, and chemoradiotherapy-related adverse reactions were evaluated in the three patient groups. DFS was defined as the time from treatment initiation to recurrence, metastasis, death from any cause, or the last follow-up. OS was defined as the time from treatment initiation to death from any cause or the last follow-up. Chemotherapy-related adverse reactions were evaluated according to the World Health Organization grading criteria for anticancer drug adverse reactions. The primary indicators included hematologic parameters, such as platelet count, hemoglobin level, and white blood cell count, with grade III or higher bone marrow suppression defined as severe. RT-related adverse reactions, including bone marrow suppression, acute gastrointestinal adverse reactions (e.g., nausea, vomiting, and radiation enteritis), and urinary system adverse reactions, were graded according to the acute radiation injury criteria of the Radiation Therapy Oncology Group.
Follow-up
All patients were followed up regularly until December 2023 or death, through telephone consultations and medical record inquiries. A total of 13 patients were lost to follow-up, resulting in a loss to follow-up rate of 8.55% (13/152). Follow-up was conducted every 3 months during the first 1–2 years and every 6 months during years 3–5.
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA). Normally distributed measurement data are presented as the mean ± standard deviation, and intergroup comparisons were performed using analysis of variance. Categorical data are presented as numbers (percentages) and were compared using the Chi-squared test or Fisher’s exact test, as appropriate. Survival analysis was performed using the Kaplan-Meier method, and survival curves were compared using the log-rank test. Univariate and multivariate analyses of prognostic factors were conducted using the Cox proportional hazards regression model; variables with P<0.05 in the univariate analysis were entered into the multivariate model, and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. The proportional hazards assumption was assessed using Schoenfeld residuals. All statistical tests were two-sided. Because this was a retrospective cohort assembled from available medical records, no a priori sample size calculation was performed; statistical precision is therefore reported using 95% CIs, and non-significant results must be interpreted in light of the number of events available. Patients with incomplete clinical or follow-up data were excluded during screening, and no imputation of missing data was performed. A P value <0.05 was considered statistically significant.
Results
Comparison of clinical case data for patients with cervical cancer under different treatment regimens
There were no statistically significant differences in age, clinical pathological stage, pathological type, differentiation degree, presence of vascular invasion, stromal invasion depth (>1/2), parametrium involvement, margin positivity, and number of positive lymph nodes among the RT, CCRT, and SCRT groups (P>0.05; Table 1); however, given the modest group sizes, these non-significant results should not be taken as evidence of baseline balance. Conversely, tumor size differed significantly among the three groups (P=0.03; Table 1): tumors >4 cm were present in 35/46 (76.09%) patients in the RT group, 26/50 (52.00%) in the SCRT group, and 39/56 (69.64%) in the CCRT group, an imbalance in a variable closely related to recurrence risk. When analyzed further as a covariate in the multivariate analysis, tumor size was not found to be an independent prognostic factor.
Comparison of prognosis in patients with cervical cancer
During follow-up, 71/152 (46.7%) patients experienced the composite endpoint of death or lost to follow-up [RT group 28/46 (60.9%), CCRT group 26/56 (46.4%), SCRT group 17/50 (34.0%)]; the remaining 81 patients were censored (alive and under follow-up). In pairwise Cox regression models adjusted for tumor size, pathological type, FIGO stage, LVSI, depth of stromal invasion, and lymph node status, the HRs (95% CIs) for DFS were: SCRT vs. RT 0.67 (0.35–1.29); CCRT vs. RT 0.95 (0.54–1.68); SCRT vs. CCRT 0.70 (0.37–1.33); the corresponding HRs (95% CIs) for OS were: SCRT vs. RT 0.63 (0.33–1.22); CCRT vs. RT 1.13 (0.63–2.02); SCRT vs. CCRT 0.56 (0.30–1.07).
The DFS times in the RT, CCRT, and SCRT groups were 57.13±3.99, 72.75±3.52, and 80.99±3.62 months, respectively. The SCRT group had a significantly longer DFS time than the RT group (P=0.002), but no significant difference was observed between the SCRT and CCRT groups (P=0.18). The OS times in the RT, CCRT, and SCRT groups were 63.30±3.42, 75.18±3.21, and 84.49±2.95 months, respectively. The SCRT group had a significantly longer OS time than the RT group (P=0.001), but no significant difference was observed between the SCRT and CCRT groups (P=0.11).
In terms of survival rates, the 3-year DFS rates for the RT, CCRT, and SCRT groups were 67.4%, 85.7%, and 92.0%, respectively, and the 5-year DFS rates were 43.4%, 60.7%, and 76.0%, respectively. The SCRT group had significantly higher DFS rates than the RT group (P=0.002). No significant difference was observed in the 3- and 5-year DFS rates between the SCRT and CCRT groups (P=0.18). The 3-year OS rates for the RT, CCRT, and SCRT groups were 87.0%, 91.1%, and 94.0%, respectively, and the 5-year OS rates were 49.7%, 66.1%, and 84.0%, respectively. The SCRT group had significantly higher OS rates than the RT group (P=0.001), but no significant difference was observed between the SCRT and CCRT groups (P=0.11; Figures 1,2).
Figure 1.
Kaplan-Meier survival curves comparing DFS among patients with cervical cancer treated with RT, CCRT, and SCRT after radical hysterectomy. CCRT, concurrent chemoradiotherapy; DFS, disease-free survival; RT, radiotherapy; SCRT, sequential chemoradiotherapy.
Figure 2.
Kaplan-Meier survival curves comparing OS among patients with cervical cancer treated with RT, CCRT, and SCRT after radical hysterectomy. CCRT, concurrent chemoradiotherapy; OS, overall survival; RT, radiotherapy; SCRT, sequential chemoradiotherapy.
Comparison of chemoradiotherapy-related adverse reaction rates in patients with cervical cancer
No statistically significant differences were observed in the incidence of RT-related adverse reactions or gastrointestinal adverse reactions among the RT, CCRT, and SCRT groups (P>0.05). Severe bone marrow suppression (grade III/IV) occurred in 2/46 (4.35%) patients in the RT group, 15/50 (30.00%) in the SCRT group, and 20/56 (35.71%) in the CCRT group; the incidence was significantly higher in the SCRT and CCRT groups than in the RT alone group (P<0.05; Table 2). No statistically significant difference was observed in the incidence of severe myelosuppression between the SCRT and CCRT groups (15/50, 30.00% vs. 20/56, 35.71%; P>0.05). All adverse reactions reported were acute events graded during treatment according to the World Health Organization criteria for chemotherapy-related toxicity and the Radiation Therapy Oncology Group criteria for radiation-related toxicity. Whether hematologic toxicity resulted in treatment delays, dose reductions, or hospitalization was not systematically recorded (see the “Limitations” section).
Table 2. Incidence of severe (grade III/IV) adverse reactions among the RT, CCRT, and SCRT groups.
| Adverse reaction | RT (n=46) | SCRT (n=50) | CCRT (n=56) | χ2 | P value |
|---|---|---|---|---|---|
| Bone marrow suppression | 7.851 | 0.02* | |||
| None | 23 (50.00) | 5 (10.00) | 8 (14.29) | ||
| Grade I/II | 21 (45.65) | 30 (60.00) | 28 (50.00) | ||
| Grade III/IV | 2 (4.35) | 15 (30.00) | 20 (35.71) | ||
| Gastrointestinal reactions | 3.263 | 0.20 | |||
| None | 14 (30.43) | 2 (4.00) | 6 (10.71) | ||
| Grade I/II | 32 (69.57) | 44 (88.00) | 45 (80.36) | ||
| Grade III/IV | 0 (0.00) | 4 (8.00) | 5 (8.93) | ||
| Radiation proctitis | 2.127 | 0.35 | |||
| Grade I/II | 4 (8.70) | 8 (16.00) | 10 (17.86) | ||
| Grade III/IV | 1 (2.17) | 0 (0.00) | 3 (5.36) | ||
| Radiation cystitis | – | – | |||
| Grade I/II | 5 (10.87) | 6 (12.00) | 8 (14.29) | ||
| Grade III/IV | 0 (0.00) | 0 (0.00) | 0 (0.00) | ||
| Radiation dermatitis | 14 (30.43) | 18 (36.00) | 20 (35.71) | 0.419 | 0.81 |
Data are presented as n (%). *, P<0.05 indicates statistical significance. Adverse events were evaluated according to the World Health Organization criteria (for hematologic toxicity) and the Radiation Therapy Oncology Group criteria (for gastrointestinal and urinary toxicity); all reported events were acute toxicities graded during treatment. Grade III/IV indicates severe toxicity. CCRT, concurrent chemoradiotherapy; RT, radiotherapy; SCRT, sequential chemoradiotherapy.
Analysis of factors affecting DFS and OS in patients with cervical cancer
The univariate analysis results showed that pathological type, clinical stage, lymphovascular space invasion (LVSI), depth of stromal invasion (DSI, >1/2), tumor size (≥4 cm), and lymph node metastasis were associated with DFS and OS in patients with cervical cancer (P<0.05; Table 3). Multivariate analysis using the Cox regression model, including factors with statistical significance from the univariate analysis, revealed that pathological type and lymph node metastasis were independent prognostic factors affecting DFS and OS (Table 4 and Figure 3). Notably, the wide CIs observed for several HRs, particularly for positive lymph nodes, were likely due to the limited number of events in certain subgroups rather than multicollinearity, as all variance inflation factors were <2.0.
Table 3. Univariate analysis of factors associated with DFS in patients with cervical cancer.
| Variables | DFS | OS | ||
|---|---|---|---|---|
| χ2 | P value | χ2 | P value | |
| Age | 2.91 | 0.88 | 2.509 | 0.11 |
| Pathological type | 20.7 | <0.001* | 19.3 | <0.001* |
| FIGO stage | 11.3 | 0.003* | 10.801 | 0.005* |
| Histological grade | 0.16 | 0.69 | 0.481 | 0.49 |
| LVSI | 5.67 | 0.02* | 6.165 | 0.01* |
| Parametrial tissue infiltration | 2.75 | 0.10 | 2.306 | 0.13 |
| DSI | 5.2 | 0.02* | 5.588 | 0.02* |
| Positive margins | 2.09 | 0.15 | 1.427 | 0.23 |
| Tumor size | 6.29 | 0.01* | 6.057 | 0.01* |
| Positive lymph nodes | 53.4 | <0.001* | 50.418 | <0.001* |
The analysis was performed using the log-rank test. *, P<0.05 indicates statistical significance. DFS, disease-free survival; DSI, depth of stromal invasion; FIGO, International Federation of Gynecology and Obstetrics; LVSI, lymphovascular space invasion; OS, overall survival.
Table 4. Multivariate analysis of factors associated with DFS in patients with cervical cancer.
| Variables | DFS | OS | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Pathological type (ref: squamous) | ||||
| Adenocarcinoma | 1.880 (1.448–3.731) | 0.01* | 1.898 (1.460–3.754) | 0.043* |
| Other types | 2.733 (1.388–5.384) | 0.004* | 2.499 (1.266–4.930) | 0.008* |
| FIGO stage (ref: IA2) | ||||
| IB1–IB3 | 0.434 (0.172–1.097) | 0.08 | 0.528 (0.214–1.304) | 0.17 |
| IIA1 | 0.682 (0.301–1.544) | 0.36 | 0.915 (0.418–2.005) | 0.83 |
| LVSI (ref: negative) | 1.456 (0.762–2.783) | 0.26 | 1.499 (0.780–2.880) | 0.22 |
| DSI (ref: ≤1/2) | 1.225 (0.495–3.035) | 0.66 | 1.323 (0.542–3.229) | 0.54 |
| Tumor size (ref: ≤4 cm) | 1.890 (0.876–4.076) | 0.10 | 1.739 (0.821–3.683) | 0.15 |
| Positive lymph nodes (ref: 0–1) | ||||
| 2 | 6.479 (2.479–16.931) | <0.001* | 5.908 (2.336–14.942) | <0.001* |
| ≥3 | 11.953 (4.699–30.408) | <0.001* | 9.376 (3.885–22.631) | <0.001* |
Variables with P<0.05 in the univariate analysis were included in the multivariate Cox proportional hazards regression model. *, P<0.05 indicates statistical significance. The wide CIs for positive lymph nodes may reflect limited events in subgroups. CI, confidence interval; DFS, disease-free survival; DSI, depth of stromal invasion; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; LVSI, lymphovascular space invasion; OS, overall survival.
Figure 3.
Kaplan-Meier survival curves for DFS and OS stratified by pathological type (A,C) and number of positive lymph nodes (B,D) in patients with cervical cancer. (A) DFS stratified by pathological type: squamous cell carcinoma, adenocarcinoma, and other types (P<0.001). (B) DFS stratified by the number of positive lymph nodes: 0–1, 2, and ≥3 (P<0.001). (C) OS stratified by pathological type (P<0.001). (D) OS stratified by the number of positive lymph nodes (P<0.001). DFS, disease-free survival; OS, overall survival.
Discussion
According to the NCCN guidelines, patients with high-risk recurrence factors require adjuvant therapy after surgery for cervical cancer, whereas opinions vary as to the need for adjuvant therapy in patients with intermediate-risk factors (6). The main postoperative adjuvant treatment modalities include RT alone, chemotherapy alone, CCRT, and SCRT. Postoperative RT is a traditional treatment method that can reduce local recurrence rates but has limitations in controlling distant metastases. Conversely, postoperative chemotherapy provides systemic treatment and can reduce the risk of distant metastases. Studies have shown that the combination of RT with chemotherapy significantly improves the prognosis of patients with cervical cancer compared with RT alone (10-12).
A meta-analysis of 11 retrospective cohort studies and two randomized clinical trials compared the survival rates of patients with early-stage cervical cancer and intermediate-risk factors who underwent adjuvant chemoradiotherapy and those who received RT alone. The results showed that the combination of RT and chemotherapy significantly improved DFS (P=0.001) and OS (P=0.001) in patients with cervical cancer (13). This is mainly because the effects of chemoradiotherapy are not merely additive, but involve a synergistic effect that enhances the efficacy of both RT and chemotherapy. The underlying primary mechanisms include the ability of chemotherapy drugs to directly enhance tumor cell killing, inhibit the repair of radiation-induced damage in tumor cells, promote the entry of non-proliferating cells into the cell cycle, and improve the hypoxic state within tumor cells, thereby increasing treatment efficacy (14).
Consistent with previous research results (15), the 5-year DFS and OS rates in the CCRT and SCRT groups were improved compared with those in the RT group in the present study. Regarding safety, while chemoradiotherapy kills tumor cells, it also damages normal tissues and organs. Most previous studies have shown that the incidence of adverse reactions associated with combined chemoradiotherapy is high; however, these reactions are generally tolerable after treatment (16). In the present study, compared with the RT alone group, the incidence of severe bone marrow suppression was significantly higher in the SCRT (30.00%) and CCRT (35.71%) groups (both P<0.05). Notably, there was no statistically significant difference in the incidence of severe bone marrow suppression between the SCRT and CCRT groups (P>0.05), suggesting that SCRT does not result in additional toxicity compared with CCRT. Further, no statistically significant differences were observed in the incidence of RT-related adverse reactions or gastrointestinal adverse reactions among the groups (P>0.05).
Notably, tumor size differed significantly among the groups (P=0.03), with a higher proportion of tumors >4 cm (76.09%) observed in the RT group compared with the SCRT (52.00%) and CCRT (69.64%) groups. This difference may have contributed to the worse outcomes observed in the RT group. However, the multivariate analysis showed that tumor size was not an independent prognostic factor for DFS or OS. Thus, while differences in tumor size were observed among the groups, tumor size alone is unlikely to fully explain the observed survival differences. Nevertheless, tumor size should be acknowledged as a potential confounding factor given the non-randomized study design.
At present, no consensus has been reached regarding the choice between CCRT and SCRT. A large multicenter phase III clinical trial conducted in China (n=1,048) in 2021 reported that the 3-year DFS rate was higher in the SCRT group than in the CCRT group (9). Compared with CCRT, SCRT improved the 3-year DFS rate (90.0% vs. 85.0%, P=0.04) and reduced the distant metastasis rate (6.5% vs. 11%, P=0.04) in patients with early-stage cervical cancer, with tolerable chemoradiotherapy toxicities, indicating the superiority of SCRT treatment (17).
In the present study, no statistically significant differences were observed in the 5-year DFS rate (76.0% vs. 60.7%, P=0.18) or the 5-year OS rate (84.0% vs. 66.1%, P=0.11) between the SCRT and CCRT groups. This absence of a statistically detectable difference should not be interpreted as evidence of equivalence: with approximately 50 patients per group and a limited number of events, a type II error is a realistic possibility, and the point estimates, which numerically favored SCRT, carry wide uncertainty. Compared with the STARS trial, in which SCRT improved the 3-year DFS rate by 5.0 percentage points over CCRT (90.0% vs. 85.0%) (9), the 5-year DFS difference observed here (15.3 percentage points) was larger in magnitude but much less precise, and our estimates are compatible both with a clinically meaningful benefit and with no true difference. Several factors may explain these findings. First, the sample size was small, and the study may have been underpowered to detect differences between the SCRT and CCRT groups; the retrospective design also precluded a sample size calculation for this comparison. Second, the chemotherapy regimens differed: the SCRT group received full-dose TP or TC regimens, while the CCRT group received weekly low-dose cisplatin. Third, similar radiotherapy protocols in the SCRT and CCRT groups may partly explain the comparable local control rates. Fourth, the non-randomized design may have introduced selection bias, and patient compliance with the more intensive sequential approach may have affected outcomes.
No current guidelines recommend the SCRT model, and our observational data cannot establish an optimal postoperative strategy for all patients with stage IA2–IIA1 cervical cancer. Rather, the choice of adjuvant therapy should weigh expected benefit against toxicity for specific pathological risk groups: for patients with a higher burden of risk factors, the greater hematologic toxicity of SCRT or CCRT may be an acceptable trade-off if recurrence risk is meaningfully reduced, whereas for patients with a single intermediate-risk factor, RT alone may remain appropriate, and the addition of systemic chemotherapy requires individual justification. This hypothesis is supported by a recent randomized non-inferiority trial, which demonstrated that adjuvant chemotherapy alone was non-inferior to CCRT in terms of 3-year progression-free survival (91.9% vs. 91.9%) for early-stage patients with risk factors, while providing additional benefits in ovarian function preservation and quality of life (18). These findings suggest that intensified systemic therapy, whether through SCRT or chemotherapy-sparing strategies, warrants further investigation.
The multivariate analysis in the present study identified pathological type as an independent prognostic factor affecting DFS and OS in patients. A study by Seki et al. (19) showed that compared with cervical squamous cell carcinoma, patients with adenocarcinoma and adenosquamous carcinoma had significantly shorter progression-free survival (P=0.002) and that pathological type was an independent prognostic factor for shorter progression-free survival in patients undergoing adjuvant RT or CCRT. For tumors with an adenocarcinoma component, postoperative radiotherapy may be considered according to a pathological risk-factor model (the “four-factor model”), which includes one-third outer cervical stromal invasion, LVSI, tumor diameter >3 cm, and adenocarcinoma or adenosquamous carcinoma histology. If any two of these factors are present, postoperative adjuvant RT is considered beneficial (6). Hu et al. reported that due to the low radiosensitivity of adenocarcinoma, achieving a complete response after RT may require a longer duration, resulting in lower OS rates (20). Therefore, for patients with special pathological types of cervical cancer, treatment strategies should consider adjuvant chemoradiotherapy to improve survival rates.
Positive lymph nodes are currently recognized as a risk factor affecting the prognosis of patients with cervical cancer after surgery, and patients with early-stage cervical cancer and lymph node metastasis generally have a relatively worse prognosis. Retrospective cohort studies by van Kol et al. and Radojević et al. (21,22) showed that, compared with patients without lymph node metastasis, those with pelvic and/or para-aortic lymph node metastasis in stages IB–IIB had decreased survival rates. Additionally, as the number of lymph node metastases increases, DFS and OS significantly decrease (21). Further, Kim et al. (4) reported that, for patients with 0, 1–2, and ≥3 lymph node metastases, the median PFS after surgery for cervical cancer was 100.8, 87.6, and 57.7 months, respectively, with statistically significant differences among groups.
The results of the present study indicate that positive lymph nodes are an independent prognostic factor affecting DFS and OS in patients. Consistent with previous research findings (23), the 5-year DFS rates among patients with 0–1, 2, and ≥ 3 positive lymph nodes were 86.8%, 62.5%, and 25.6%, respectively, while the 5-year OS rates were 86.8%, 69.6%, and 39.5%, respectively; these differences were statistically significant. Therefore, patients with positive lymph nodes should receive active adjuvant therapy after surgery.
Limitations
The present study had several limitations. First, it was a retrospective, non-randomized study, which inherently carries a risk of selection bias. The treatment allocation was based on clinical decisions made by treating physicians in consultation with patients, which may have introduced confounding factors that influenced the outcomes. Although multivariate analyses were performed to adjust for established confounders, undetermined or unmeasured confounders may still exist. Additionally, the surgical approaches (open surgery vs. laparoscopic surgery) were not randomly stratified among the treatment groups, which represents another potential source of bias. Second, the sample size was relatively small, which may have limited the statistical power to detect differences between the SCRT and CCRT groups, as evidenced by the wide CIs for some HRs. Third, the significant difference in tumor size among groups represents a potential confounding factor. Fourth, toxicities were assessed as acute treatment-related adverse reactions; late toxicities and the clinical consequences of severe myelosuppression (treatment delays, dose reductions, and hospitalizations) were not systematically recorded. Fifth, given the limited number of outcome events, propensity-score or inverse-probability-weighting sensitivity analyses were not performed; such analyses could partly address the measured baseline imbalance but cannot eliminate unmeasured confounding. Finally, the follow-up period may not have been sufficient to capture all late recurrences and long-term complications. Future prospective randomized controlled trials with larger sample sizes are warranted to validate the findings of the present study.
Conclusions
In conclusion, the preliminary results of the present single-center retrospective study indicated that, compared with RT alone, SCRT was associated with longer DFS and OS in patients with stage IA2–IIA1 cervical cancer after surgery, whereas the difference between SCRT and CCRT was not statistically detectable and should not be interpreted as evidence of equivalence. SCRT was associated with a higher incidence of severe myelosuppression than RT alone; however, this toxicity profile was comparable to that of CCRT and remained clinically manageable. Within these limitations, SCRT remains a viable option for postoperative adjuvant therapy in selected patients with cervical cancer, and the choice among RT, CCRT, and SCRT should be individualized according to pathological risk factors and expected toxicity. As the present study was a single-center retrospective analysis with a relatively small sample size and inherent selection bias, these findings should be interpreted with caution. Future multicenter prospective randomized controlled trials with larger sample sizes are needed to establish personalized treatment strategies for patients with cervical cancer after surgery.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Changzhou Maternal and Child Health Care Hospital, Changzhou Medical Center, Nanjing Medical University (Changzhou, China; approval No. 202284). Written informed consent was obtained from all participants.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-2410/rc
Funding: This study was funded by the Application Foundation Project of Changzhou Science and Technology Bureau (No. CJ20220251), the Top Talent of Changzhou “The 14th Five-Year Plan” High-Level Health Talents Training Project (No. 2022CZBJ085), and the Science and Technology Development Foundation of Nanjing Medical University (No. 20230054).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-2410/coif). The authors have no conflicts of interest to declare.
(English Language Editor: L. Huleatt)
Data Sharing Statement
Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-2410/dss
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