Primary chemoradiation versus radical hysterectomy with lymphadenectomy for stage IIICr cervical cancer without parametrial involvement: gynecologic oncology research investigators collaboration study (GORILLA-1002)

Abstract

Objective

To compare the effectiveness and adverse events of primary chemoradiation versus radical hysterectomy with pelvic or para-aortic lymphadenectomy in patients with 2018 International Federation of Gynecology and Obstetrics stage IIICr cervical cancer without clinical parametrial involvement.

Methods

This retrospective study included patients diagnosed with stage IIICr cervical cancer who had pelvic or para-aortic lymph nodes measuring at least 1 cm in short diameter on preoperative imaging between 2000 and 2020. Primary chemoradiation consisted of external beam radiation therapy and brachytherapy, while adjuvant chemoradiation following radical surgery was administered based on pathological results.

Results

A total of 204 patients underwent primary chemoradiation (n=66) or radical hysterectomy with systematic lymphadenectomy (n=138). There were no significant differences in disease stage or histological type between the groups. In patients with tumors ≥4 cm, primary chemoradiation improved progression-free survival (PFS) compared to radical surgery (5-year survival: 91.1% vs. 61.7%; p<0.005). Favorable factors for PFS included stage IIIC1 disease, primary chemoradiation, and tumor size <4 cm. Stage IIIC1 was associated with better PFS and overall survival than stage IIIC2 (p=0.048 and p=0.020, respectively). Central recurrence was more common after primary chemoradiation, while pelvic sidewall or distant recurrence was more frequent after radical hysterectomy with lymphadenectomy (p=0.009). Anemia was more frequent in the primary chemoradiation group, while lymphedema was less common than in the radical surgery group.

Conclusion

Primary chemoradiation may be more effective than radical hysterectomy with systematic lymphadenectomy in patients with stage IIICr cervical cancer without parametrial invasion.

Synopsis

Primary chemoradiation improved progression-free survival in stage IIICr cervical cancer with tumors ≥4 cm and no parametrial involvement. Central recurrence was more frequent after chemoradiation, while pelvic sidewall or distant metastasis was more common after radical surgery. Grade 2 or higher anemia was more frequent after chemoradiation.

Graphical Abstract

INTRODUCTION

Cervical cancer incidence has declined in developed countries since the introduction of the human papillomavirus vaccine and routine screening, while prevalence remains high in developing countries [1]. Historically, management options for early-stage and locally advanced cervical cancer included radical hysterectomy with lymphadenectomy or primary chemoradiation. In 2018, the International Federation of Gynaecology and Obstetrics (FIGO) staging system reclassified lymph node metastasis (LNM) as stage IIIC disease: stage IIIC1 for pelvic lymph node involvement only and IIIC2 for para-aortic lymph node involvement. Additionally, stage IIICr can be assigned based only on imaging findings, regardless of pathological confirmation [2].

Before this revision, radical hysterectomy with lymphadenectomy was an option for patients without parametrial involvement, even with suspected LNM, particularly in low- and middle-income countries where access to preoperative imaging such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/CT was limited. Furthermore, 5-year survival rates of 70%–85% have been reported in patients undergoing radical hysterectomy with lymphadenectomy followed by adjuvant radiotherapy [3]. In other words, advancements in radiation techniques have improved survival outcomes and reduced treatment-related toxicity in primary chemoradiation therapy [4]. Although the superiority between radical hysterectomy and primary chemoradiation therapy for cervical cancer with suspicious LNM but no parametrial involvement has not yet been clearly established, approximately 80% of patients undergoing radical surgery for locally advanced cervical cancer require adjuvant radiation or chemoradiation, which is associated with increased morbidity [5]. In contrast, primary radiotherapy has been shown to improve survival and reduce the risk of local recurrence avoiding surgical complications [6].

However, direct comparative evidence regarding survival outcomes and treatment-related complications remains limited. Therefore, we conducted a multicenter retrospective study to compare the outcomes and adverse events of radical hysterectomy with systematic lymphadenectomy (RHSL) versus primary chemoradiation (PRT) in this patient population to determine the most appropriate treatment approach.

MATERIALS AND METHODS

1. Study design

We conducted this multicenter study at 4 tertiary centers: Ajou University Hospital, Konkuk University Medical Center, Seoul National University Hospital, and Seoul National University Bundang Hospital. The study was approved by the Institutional Review Boards of each institution (AJOUIRB-DB 2023-530, 2021-11-068, 2110-034-1260, and B-2112-725-401).

Patients diagnosed between January 2000 and December 2020 were included based on the following criteria: histological diagnosis of squamous cell carcinoma, endocervical adenocarcinoma, or adenosquamous carcinoma; 2018 FIGO stage IIICr disease with pelvic or para-aortic lymph nodes measuring ≥1 cm in short diameter on CT or MRI; and 2009 FIGO stage IB1 to IIA2 disease without parametrial invasion on CT or MRI.

2. Procedures and outcomes

Patients were categorized into the RHSL or PRT group based on the treatment received. In the RHSL group, type B or C hysterectomy with pelvic or para-aortic lymphadenectomy was performed. Adjuvant external beam radiation therapy (EBRT, 45–50 Gy) with weekly cisplatin (40 mg/m²) was administered in cases with positive pelvic or para-aortic LNM, positive surgical margins, or positive parametrial involvement pathologically. In addition, EBRT was selectively administered according to the Sedlis criteria including lymphovascular space invasion (LVSI), depth of stromal invasion, and tumor size [7]. EBRT was administered in the following cases according to the National Comprehensive Cancer Network guidelines [8]: positive LVSI with deep one-third stromal invasion regardless of tumor size; positive LVSI with middle one-third stromal invasion and tumor size ≥2 cm; positive LVSI with superficial one-third stromal invasion and tumor size ≥5 cm; and negative LVSI with middle or deep one-third stromal invasion and tumor size ≥4 cm. Brachytherapy (5.5 Gy × 2 fractions or 6 Gy × 3 fractions) was added if the vaginal resection margin was positive. In the PRT group, EBRT (45–50 Gy) with brachytherapy (5.5 Gy × 2 fractions or 6 Gy × 3 fractions) was administered alongside weekly cisplatin (40 mg/m²). Surgical nodal staging was permitted before initiating PRT.

The following data were collected: age, body mass index (BMI, kg/m²), radiologic tumor size, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, 2009 and 2018 FIGO stage, number and extent of pelvic or para-aortic lymphadenectomy (including surgical nodal staging), surgical approach, chemoradiation modalities, pathologic tumor size, depth of cervical stromal invasion, LVSI, resection margin, and parametrial involvement. The recurrence pattern was classified into 3 categories: central, pelvic sidewall, and distant recurrence. Lymph node recurrence was further categorized as pelvic sidewall or distant recurrence based on the anatomical location of the metastatic lymph nodes.

Survival outcomes included progression-free survival (PFS), defined as the time from diagnosis to disease recurrence or last follow-up, and overall survival (OS), defined as the time from diagnosis to cancer-related death or last follow-up. Adverse events and their grades were assessed according to the Common Terminology Criteria for Adverse Events version 5.0.

3. Statistical analysis

We compared categorical variables by using the χ² or Fisher’s exact test, and continuous variables by using the Mann-Whitney U test. We compared PFS and OS between primary chemoradiation and radical hysterectomy by using the Kaplan-Meier analysis with the log-rank test by expression with p-value, and prognostic factors affecting PFS and OS were investigated by multivariate analysis with the Cox regression hazard model with hazard ratio (HR) and 95% confidence interval (CI). We used SPSS ver. 22.0 (IBM Corp., Armonk, NY, USA), and all p-values were considered significant if less than 0.05.

RESULTS

1. Patients’ characteristics

Table 1 shows the baseline characteristics of 204 patients treated with RHSL (n=138) and PRT (n=66). The median follow-up time was 55.3 months (range, 3.2–178.5). There were no significant differences between the two groups in terms of BMI, ECOG performance status, 2009 FIGO stage, 2018 FIGO stage, or histological type. Most of the study population had a squamous cell histology: 110 (79.9%) in RHSL group and 60 (90.9%) in the PRT group (p=0.119). The proportion of patients older than 49 years was significantly higher in the PRT group than in the RHSL group (p<0.001). The median radiologic tumor size at diagnosis was 38 mm in the RHSL group and 45 mm in the PRT group (range: 0–72 mm vs. 15–76 mm; p=0.005). All patients in the RHSL group underwent pelvic or para-aortic lymphadenectomy. In contrast, 9 patients (13.6%) underwent surgical nodal staging in the PRT group.

Table 1. Baseline characteristics.

Characteristics			RHSL (n=138)	PRT (n=66)	p-value
Age (yr)					<0.001
	<49		79 (57.2)	20 (30.3)
	≥49		59 (42.8)	46 (69.7)
BMI (kg/m2)					0.416
	<25		99 (71.7)	43 (65.2)
	≥25		39 (28.3)	23 (34.8)
ECOG performance status					0.591
	0		135 (97.8)	64 (97.0)
	1		2 (1.4)	2 (3.0)
	2		1 (0.7)	0 (0.0)
2009 FIGO stage					0.259
	IB1		71 (51.4)	25 (37.9)
	IB2		37 (26.8)	25 (37.9)
	IIA1		12 (8.7)	5 (7.6)
	IIA2		18 (13.1)	11 (16.6)
2018 FIGO stage					0.340
	IIIC1r		127 (92)	58 (87.9)
	IIIC2r		11 (8)	8 (12.1)
Histological types					0.119
	Squamous cell carcinoma		110 (79.7)	60 (90.9)
	Non-squamous cell carcinoma
		Endocervical adenocarcinoma	22 (15.9)	5 (7.6)
		Adenosquamous carcinoma	6 (4.3)	1 (1.5)
Radiologic tumor size (cm)					0.005
	<2		20 (14.5)	3 (4.5)
	≥2, <4		54 (39.1)	17 (25.8)
	≥4		64 (46.4)	46 (69.7)
Lymphadenectomy					<0.001
	No		0 (0)	57 (86.4)
	Pelvic		76 (55.1)	6 (9.1)
	Para-aortic		2 (1.4)	1 (1.5)
	Pelvic and para-aortic		60 (43.5)	2 (3.0)

Values are presented as number (%).

BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; PRT, primary chemoradiation; RHSL, radical hysterectomy with systematic lymphadenectomy.

Minimally invasive surgery (MIS; conventional laparoscopic or robotic-assisted) was performed in 64 (46.4%) patients in the RHSL group and 9 (13.6%) in the PRT group (Table 2). All patients in the PRT group received both EBRT and brachytherapy. In contrast, in the RHSL group, 110 patients (79.7%) received adjuvant concurrent chemoradiation following surgery, including 110 (79.7%) who received EBRT and 10 (7.2%) who received brachytherapy. Pathologic examination after radical hysterectomy showed tumor size ≥4 cm in 85 patients (61.6%) and deep stromal invasion (≥2/3) was found in 92 patients (68.7%). LVSI was present in 97 patients (70.3%), while positive resection margins were found in 10 patients (7.2%). Pathologic parametrial involvement occurred in 35 patients (25.4%), and LNM was detected in 76 patients (55.1%).

Table 2. Operative outcomes.

Characteristics		RHSL (n=138)	PRT (n=66)
Surgical approach
	Laparotomy	74 (53.6)	0 (0.0)
	Laparoscopic, conventional	56 (40.6)	9 (13.6)
	Robotic-assisted	8 (5.8)	0 (0.0)
Chemoradiation
	EBRT	110 (79.7)	66 (100.0)
	Brachytherapy	10 (7.2)	66 (100.0)
Number of lymph nodes resected
	Pelvic	24 (3–81)	19.5 (3–38)
	Para-aortic	0 (0–53)	12 (9–16)
Number of metastatic lymph nodes (median, range)
	Pelvic	1 (0–42)	1 (0–3)
	Para-aortic	0 (0–29)	0 (0–0)
Pathologic lymph node metastasis
	No lymph node metastasis	62 (44.9)	3 (50.0)
	Positive pelvic lymph node	60 (43.5)	3 (50.0)
	Positive para-aortic lymph node	16 (11.6)	0 (0.0)
Pathologic tumor size (cm)			–
	<2	14 (10.1)
	≥2, <4	39 (28.3)
	≥4	85 (61.6)
Depth of cervical stromal invasion			–
	<1/3	14 (10.4)
	≥1/3, <2/3	28 (20.9)
	≥2/3	92 (68.7)
Positive LVSI		97 (70.3)	–
Positive resection margin		10 (7.2)	–
Positive pathologic parametrial involvement		35 (25.4)	–

Values are presented as number (%) or median (range).

EBRT, external beam radiation therapy; LVSI, lymphovascular space invasion; PRT, primary chemoradiation; RHSL, radical hysterectomy with systematic lymphadenectomy.

In the RHSL group, patients with radiologically larger tumors (≥4 cm) were more likely to undergo open surgery compared to MIS (p=0.010; Table S1). In contrast, there were no significant differences in FIGO stages or tumor histology between the open surgery and MIS groups. Tumor histology was significantly associated with radiologic tumor size: 99 patients (58.2%) with squamous cell carcinoma had tumors ≥4 cm, whereas 11 patients (32.4%) with non-squamous cell carcinoma had tumors ≥4 cm (p=0.008). However, patients’ age, stage, and recurrence rates did not differ significantly between histological subtypes (Table S2).

2. Survival

PRT demonstrated superior PFS compared to RHSL in all patients (5-year survival rate: 83.7% vs. 71.1%; p=0.027). When stratified by tumor size (<4 cm vs. ≥4 cm), there was no significant difference in PFS between treatments for tumors <4 cm. However, for tumors ≥4 cm, PRT showed significantly better PFS than RHSL (5-year survival rate: 91.1% vs. 61.7%; p=0.005). OS did not differ between the 2 treatments, regardless of tumor size (Fig. 1). When stratified by tumor size (<2 cm vs. ≥2 cm), surgical approach (open surgery vs. MIS) was not associated with PFS. OS was not assessed, as all cases were censored (Fig. S1). After excluding patients who underwent surgical nodal staging, the PRT group showed superior PFS compared to the RHSL group in patients with tumors ≥4 cm (p=0.016; Fig. S2). In the PRT group, only 9 patients (13.6%) underwent laparoscopic nodal staging. We observed an HR of 0.458 (95% CI=0.005–133,090.580) for PFS, though the wide confidence interval reflects substantial uncertainty due to the limited sample size (Fig. S3).

Fig. 1. Comparison of survival outcomes between the PRT group and the RHSL group using Kaplan-Meier analysis. (A) PFS and (B) OS. Stratification analysis was performed based on tumor size 4 cm. PFS and OS were assessed in patients with tumors <4 and ≥4 cm.

OS, overall survival; PFS, progression-free survival; PRT, primary chemoradiation; RHSL, radical hysterectomy with systematic lymphadenectomy.

In the multivariate analysis, FIGO 2018 IIIC disease (adjusted HR=0.448; 95% CI=0.202–0.991), PRT (adjusted HR=0.421; 95% CI=0.189–0.938), and tumor size (adjusted HR=0.545; 95% CI=0.298–0.997) were significantly associated with PFS (Table 3). Deep stromal invasion was not associated with PFS (HR=0.869; 95% CI=0.354–2.131; p=0.759) or OS (HR=0.917; 95% CI=0.151–5.554; p=0.925). Additionally, FIGO 2018 IIIC1r disease was significantly associated with better OS compared to IIIC2r disease (adjusted HR=0.205; 95% CI=0.063–0.782; Table 3). In the RHSL group, positive parametrial involvement identified after surgery was significantly associated with worse PFS (adjusted HR=2.713; 95% CI=1.300–5.662; p=0.008), while FIGO stage IIIC1r disease was significantly correlated with OS (adjusted HR=0.256; 95% CI=0.054–0.691; p=0.015; Table 3). Among patients in the RHSL group with radiologic tumor size based on 4 cm, pathologic parametrial involvement remained an independent predictor of reduced PFS (p=0.016), and FIGO stage IIIC1r disease continued to be significantly associated with OS (adjusted HR=0.024; 95% CI=<0.001–0.676; p=0.028; Table 3).

Table 3. Factors affecting PFS and OS in IIICr cervical cancer.

Prognostic factors		PFS			OS
		Adjusted HR	95% CI	p-value	Adjusted HR	95% CI	p-value
Survival in all study population (n=204)
	FIGO 2018 IIIC1r disease (reference: IIIC2r)	0.448	0.202–0.991	0.048	0.205	0.063–0.782	0.020
	Squamous cell carcinoma (reference: non-squamous cell carcinoma)	0.644	0.318–1.304	0.222	0.729	0.181–2.939	0.657
	Primary radiation therapy (reference: radical hysterectomy)	0.421	0.189–0.938	0.034	0.255	0.030–2.138	0.208
	Radiologic tumor size <4 cm (reference: tumor size ≥4 cm)	0.545	0.298–0.997	0.049	0.711	0.208–2.433	0.587
Survival in RHSL group (n=138)
	FIGO 2018 IIIC1r disease (reference: IIIC2r)	0.596	0.239–1.484	0.266	0.256	0.054–0.691	0.015
	Squamous cell carcinoma (reference: non-squamous cell carcinoma)	0.624	0.290–1.342	0.227	0.510	0.120–2.170	0.362
	Minimally invasive surgery (reference: open surgery)	0.751	0.364–1.545	0.436	1.144	0.288–4.544	0.848
	Pathological tumor size <4 cm (reference: tumor size ≥4 cm)	0.989	0.463–2.114	0.977	0.891	0.198–4.020	0.881
	Positive resection margin (reference: negative margin)	1.846	0.682–4.999	0.228	0.454	0.079–2.608	0.376
	Positive parametrial involvement (reference: no involvement)	2.713	1.300–5.662	0.008	2.678	0.654–10.971	0.171
Survival in the PRT group (n=66)
	FIGO IIIC1r disease (reference: IIIC2r)	0.399	0.168–0.949	0.038	0.196	0.047–0.812	0.025
	Squamous cell carcinoma (reference: non-squamous cell carcinoma)	0.673	0.318–1.425	0.301	0.678	0.162–2.841	0.595
	Minimally invasive surgery (reference: open surgery)	1.097	0.560–2.151	0.787	0.670	0.183–2.450	0.545
	Radiological tumor size <4 cm (reference: tumor size ≥4 cm)	1.708	0.876–3.331	0.116	0.992	0.262–3.763	0.991
Survival in RHSL group with tumor size ≥4 cm group (n=85)
	FIGO IIIC1r disease (reference: IIIC2r)	0.444	0.117–1.681	0.232	0.024	<0.001–0.676	0.028
	Squamous cell carcinoma (reference: non-squamous cell carcinoma)	0.756	0.247–2.314	0.624	0.163	0.007–3.912	0.264
	Minimally invasive surgery (reference: open surgery)	1.873	0.720–4.868	0.198	0.572	0.050–6.581	0.654
	Positive resection margin (reference: negative margin)	3.307	0.980–11.155	0.054	11.858	0.561–250.477	0.112
	Positive parametrial involvement (reference: no involvement)	3.465	1.256–9.555	0.016	3.620	0.286–45.826	0.321

All factors were adjusted together, including age.

CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PRT, primary chemoradiation; RHSL, radical hysterectomy with systematic lymphadenectomy.

In the subgroup analysis, adjuvant chemoradiation in the RHSL group was not significantly associated with improved PFS and OS (Fig. S4). Based on stratified analysis using the Cox proportional hazards model, squamous cell histology was associated with prolonged PFS compared with non-squamous cell histology in FIGO stage IIIC1r disease (HR=2.415; 95% CI=1.155–5.048; p=0.019), but not in stage IIIC2r disease (HR=0.259; 95% CI=0.022–3.023; p=0.281). Kaplan–Meier survival analysis with log-rank tests for PFS according to tumor histology are shown in Fig. S5. Similarly, PFS differed significantly by tumor histology in stage IIIC1p disease (p=0.013), but not in stage IIIC2p disease (p=0.755). Survival analyses were presented as forest plots with HRs and 95% CIs from multivariate analysis in Fig. S6.

3. Pattern of recurrence and adverse events

We found that disease recurrence occurred in 39 patients (28.3%) in the RHSL group and 8 patients (12.1%) in the PRT group (p=0.018; Table 4). Notably, central recurrence was more frequent in the PRT group compared to the RHSL group (87.5% vs. 33.3%), whereas pelvic sidewall or distant recurrence was more common in the RHSL group (36.9% vs. 12.5%, p=0.004). However, FIGO 2018 stage IIICr, radiologic tumor size (2- or 4-cm cutoffs), tumor histology, cervical stromal invasion, and surgical approach were not associated with recurrence patterns (Table S3). Furthermore, in the Cox proportional hazards model, distant metastasis was associated with worse OS compared with pelvic sidewall or central recurrence (HR=8.563; 95% CI=1.140–64.288; p=0.037).

Table 4. Recurrence patterns and adverse events in the RHSL and PRT groups.

Characteristics		RHSL (n=138)	PRT (n=66)	p-value
No. of recurrence		39 (28.3)	8 (12.1)	0.018
Recurrence pattern				0.009
	Central	13 (33.3)	7 (87.5)
	Pelvic sidewall		0 (0.0)
	Distant	20 (51.3)	1 (12.5)
No. of adverse events (all grade)
	Ileus	1 (0.7)	0 (0.0)	0.676
	Rectovaginal fistula	0 (0.0)	1 (1.5)	0.324
	Vesicovaginal fistula	1 (0.7)	1 (1.5)	0.543
	Radiation colitis	4 (2.8)	6 (9.0)	0.062
	Anemia	1 (0.7)	12 (18.2)	<0.001
	Thrombocytopenia	1 (0.7)	0 (0.0)	0.676
	Pulmonary thromboembolism	3 (2.2)	1 (1.5)	0.610
	Wound complication	1 (0.7)	0 (0.0)	0.676
	Lymphedema	16 (11.6)	2 (3.0)	0.033
	Lymphocele	3 (2.2)	0 (0.0)	0.307
No. of adverse events (grade 2 or more)
	Ileus	1 (0.7)	0 (0.0)	0.676
	Rectovaginal fistula	0 (0.0)	1 (1.5)	0.324
	Vesicovaginal fistula	1 (0.7)	1 (1.5)	0.543
	Radiation colitis	3 (2.1)	4 (6.0)	0.155
	Anemia	1 (0.7)	1 (1.5)	0.543
	Thrombocytopenia	1 (0.7)	0 (0.0)	0.676
	Pulmonary thromboembolism	3 (2.1)	1 (1.5)	0.312
	Wound complication	1 (0.7)	0 (0.0)	0.676
	Lymphedema	5 (3.6)	2 (3.0)	0.594
	Lymphocele	3 (2.1)	0 (0.0)	0.307

PRT, primary chemoradiation; RHSL, radical hysterectomy with systematic lymphadenectomy.

In the RHSL group, intraoperative complications occurred in 7 patients (5.07%), including bladder injury (n=2), vessel injury (n=2), nerve injury (n=1), and ureter injury (n=2). Anemia was more frequently observed in the PRT group (p<0.001; Table 4); however, the incidence of grade ≥2 anemia was not significantly different between the RHSL and PRT groups. Although lymphedema was more commonly observed in the PRT group than in the RHSL group (p=0.033), there was no significant difference in the incidence of grade ≥2 lymphedema between the 2 groups. Regardless of adverse event grade, there were no significant differences between the 2 groups in the incidence of ileus, rectovaginal or vesicovaginal fistula, radiation colitis, thrombocytopenia, pulmonary thromboembolism, wound complications, or lymphocele. According to the subgroup analysis, lymphedema and lymphocele were more frequently observed in patients who underwent pelvic or para-aortic systemic lymphadenectomy (Table S4). All figures and tables are presented in accordance with the analytical process shown in the flowchart (Fig. S7).

DISCUSSION

In this study, we compared oncologic outcomes and treatment-related adverse events between RHSL and PRT in patients with 2018 FIGO stage IIICr cervical cancer without parametrial involvement. Our findings suggest that PRT improved PFS compared to RHSL, particularly in patients with tumors ≥4 cm. Additionally, central recurrence was more frequent in the PRT group, whereas pelvic sidewall recurrence and distant metastasis were more common in the RHSL group. Anemia was also more frequently observed in the PRT group compared to the RHSL group.

Our study provides strong support for the shift in the treatment paradigm from RHSL to PRT, even in patients initially considered suitable for radical surgery due to the absence of parametrial involvement. Previous studies, which included subsets of early-stage disease patients with suspicious LNM, have reported conflicting results regarding the effectiveness of radical surgery versus PRT [9]. However, our study found that RHSL was associated with worse PFS than PRT, despite no significant difference in OS between the two treatments.

Although the 2018 FIGO staging system reclassified cervical cancer with imaging-detected LNM as FIGO IIICr, recommending PRT as the preferred treatment [2], there is no universally established management strategy for these patients. Furthermore, PRT and advanced imaging modalities may not be readily available in developing countries with a high cervical cancer burden [10]. Currently, prospective studies are being conducted worldwide to compare survival outcomes between PRT and radical surgery in patients with 2018 FIGO stage IIICr cervical cancer [11,12,13]. Our data may provide valuable evidence to guide treatment decisions and support ongoing clinical trials.

For deciding the management option for early-stage cervical cancer, tumor size and LNM are the main factors [14]. The ABRAX study reported no significant differences in survival between PRT and radical hysterectomy in patients with early-stage cervical cancer and surgically detected LNM, regardless of tumor size [15]. However, in our study, the improving effect of PRT on PFS was not observed in patients with tumors <4 cm, whereas it was clear in those with tumors ≥4 cm. The LACC trial evaluated survival outcomes of minimally invasive radical hysterectomy in patients with FIGO 2009 stage IA1 to IB1 cervical cancer and found that it was associated with worse outcomes compared to open radical hysterectomy. In the subgroup analysis of the LACC trial, disease-free survival for tumors ≥2 cm was more favorable in the open surgery arm than in the MIS arm [16]. In our study, 46.4% of patients in the RHSL group underwent conventional laparoscopic or robotic-assisted radical hysterectomy. In the subgroup analysis of the RHSL group, we did not detect a statistically significant difference in survival between surgical approaches (HR=0.978; 95% CI=0.513–1.864; 64 for MIS vs. 74 for open surgery); however, the study was not powered for this comparison. Owing to the retrospective design of our study, the choice of surgical approach was determined by individual clinicians; consequently, open surgery was more frequently selected for tumors larger than 4 cm compared to MIS.

Tumor histology is known to influence survival outcomes in cervical cancer. Patients with adenocarcinoma histology generally have poorer outcomes compared with those with squamous cell carcinoma [17]. Furthermore, survival differences have been reported between adenosquamous carcinoma and adenocarcinoma [18]. In our cohort of patients with stage IIICr cervical cancer, squamous cell histology was a prognostic factor only in stage IIIC1r, but not in stage IIIC2r. Similarly, after pathological confirmation, squamous cell histology was a prognostic factor only in stage IIIC1p, not in stage IIIC2p. These findings are consistent with previous studies on tumor histology and lymph node metastasis. Non-squamous cell carcinoma is more frequently associated with nodal metastasis in early-stage cervical cancer under the 2018 FIGO staging system, and non-squamous histology is a well-established poor prognostic factor in patients with cervical cancer and pelvic lymph node metastasis [19]. However, the prognostic significance of tumor histology in cervical cancer with para-aortic lymph node metastasis remains unclear. Future well-designed prospective studies are warranted to clarify the association between tumor histology and pelvic as well as para-aortic lymph node metastasis [20].

LNM is associated with a higher risk of disease recurrence and poor prognosis [21]. Pelvic lymphadenectomy plays a role in local control of LNM. However, some studies have suggested that lymphadenectomy or the number of harvested lymph nodes is not associated with survival [22]. A recent meta-analysis did not show superior outcomes for radical hysterectomy compared to abandoning surgery in cervical cancer patients with LNM detected during surgery [23]. In this high-risk situation, tumor cells leaking from disrupted lymph nodes during lymphadenectomy may increase the risk of pelvic sidewall or distant recurrence [24]. According to this study, PRT achieved local control, and the remaining disease may result in central recurrence. On the other hand, RHSL removed primary tumor sites, but microscopic metastases from lymph nodes or distant sites may induce the pelvic sidewall or distant metastasis.

Local recurrence after radiotherapy for cervical cancer has been reported in 10%–50% of cases, and the 5-year survival rate following salvage surgery with pelvic exenteration ranges from 20% to 60%. In a previous retrospective study, postoperative complications occurred in 76.9% of patients, with the majority involving the urinary tract [25]. When cervical cancer recurs, salvage radiation therapy has been shown to be more effective for central recurrences [26]. In cases of oligorecurrent cervical cancer previously treated with radiation, salvage re-irradiation has demonstrated clinical benefit. One study reported a median PFS of 16 months and an OS of 28 months, with grade ≥3 toxicity observed in 19% of patients undergoing re-irradiation [25]. Additionally, salvage radiation using intensity-modulated radiotherapy has been reported as a safe and effective option [27]. In our study, follow-up data regarding management and prognosis after tumor recurrence were not available. Therefore, OS was used as the only indicator to estimate prognosis according to recurrence patterns. Because the number of recurrence cases was small, no significant differences were observed between pelvic sidewall and central recurrence.

Discrepancies were observed between radiologic and pathologic assessments of LNM in our study. However, considering that the positive predictive value of pathological LNM in FIGO 2018 stage IIIC1r has been reported as 43.3%, and in stage IIIC2 as 24.4%–29.7%, our findings were consistent with previous reports [28]. To improve imaging accuracy, PET/MRI and machine-learning based techniques have recently been developed [29]. Although this study population was enrolled based on the presence of pelvic or para-aortic lymph nodes measuring ≥1 cm in short diameter on CT or MRI, the specific size or number of suspicious lymph nodes were not collected. In locally advanced cervical cancer with bulky lymph nodes (≥1.5 cm), a recent study reported that debulking surgery followed by adjuvant radiation therapy was associated with worse survival outcomes [30]. In an aspect of parametrium, we enrolled patients without parametrial involvement clinically. However, 25.4% of RHSL group had pathological parametrial involvement. In addition, parametrial involvement was a prognostic factor for PFS in RHSL group irrespective of tumor size 4cm. Parametrial involvement is a known prognostic factor in stage IIIC1 cervical cancer [31].

Although patient-reported outcomes regarding quality of life and adverse events could not be obtained due to the retrospective design of this study, we monitored and followed up on frequent and predictable adverse events. Both the number and grade of adverse events were analyzed. In early-stage cervical cancer, complications after radical hysterectomy with pelvic lymph node dissection have been reported in 31%–45% of patients during the acute phase and in 2.96% during long-term follow-up [32]. The results of future prospective studies on para-aortic lymphadenectomy in locally advanced cervical cancer are highly anticipated [33].

Anemia was more frequently observed in the PRT group compared to the RHSL group. Chemoradiation for cervical cancer is known to be associated with hematologic toxicity and radiation-associated cytopenia is a common finding in patients with cervical cancer [34]. In a previous retrospective cohort study, the incidence of anemia increased to 44.3% following cervical cancer treatment, and 93.6% of these patients had received radiation therapy [34]. Radiation therapy induces bone marrow suppression, and concurrent chemoradiation exacerbates anemia [35]. Although the prognostic effect of anemia remains controversial, it has been identified as a prognostic factor for PFS in patients with locally advanced cervical cancer [36]. Even though anemia can be effectively managed with iron supplementation or transfusion, this highlights the need for careful monitoring and supportive care for hematologic toxicity during chemoradiation.

Our study has several limitations. First, its retrospective nature may introduce selection bias. MIS has been identified as a prognostic factor in locally advanced cervical cancer, as reported in the LACC trial. In our study with retrospective design, surgical approach was determined based on the preference of the treating clinicians. In addition, relatively young patients (<49 years) and those with relatively small tumors were more likely to be assigned to the RHSL group. However, survival outcomes were better in the PRT group compared to the RHSL group among relatively old patients with tumor size ≥4 cm. Second, variations in surgical techniques and radiation protocols across institutions may have influenced treatment outcomes. However, our study is a large, multicenter cohort study investigating oncologic outcomes and treatment-related adverse effects between RHSL and PRT in real-world clinical practice. While previous studies have shown controversial results in selecting the optimal management strategy for these patients, our study demonstrated that PRT achieved better PFS than RHSL in 2018 FIGO IIICr cervical cancer without parametrial involvement, particularly in tumors ≥4 cm. These favorable outcomes for PRT provide a key foundation for selecting primary treatment options. Third, the overall number of patients included in our study was relatively small for analyzing the histological effect on survival, despite being a multicenter study. In our study, adenocarcinoma accounted for only 16.7% of the study population, lower than its typical prevalence of approximately 20% among cervical cancer patients, which limited our ability to perform meaningful comparative analyses between histological subtypes. Although previous studies have suggested that patients with cervical adenocarcinoma tend to experience worse survival outcomes compared to those with squamous cell carcinoma, these associations were found only in IIIC1r disease [37]. These findings should be interpreted as hypothesis-generating and warrant validation in adequately powered prospective studies. An ongoing prospective study with a larger sample size will be valuable in confirming these results.

Conclusively, this study suggests that PRT may be more effective than RHSL for 2018 FIGO IIICr cervical cancer without parametrial involvement. Therefore, radical hysterectomy should be reconsidered in favor of PRT for patients with suspected LNM on pretreatment imaging, even if they were initially considered candidates for surgery. Although central recurrence rates were higher after PRT, local control can still be achieved with salvage therapy [38]. A previous study reported that patients with central recurrence had a better prognosis compared to those with distant metastasis [39]. From an effective standpoint, PRT appears to be the preferred primary treatment option for these patients.

SUPPLEMENTARY MATERIALS

Table S1

Comparison of surgical approaches in the RHSL group

Table S2

Clinicopathological characteristics of patients according to tumor histology

Table S3

Recurrence patterns

Table S4

Association between lymphadenectomy and the development of lymphedema or lymphocele in the radical hysterectomy with systematic lymphadenectomy group

Fig. S1

Subgroup analysis for survival in the radical hysterectomy with systematic lymphadenectomy group stratified by surgical approach and tumor size (<2 cm vs. ≥2 cm).

Fig. S2

Kaplan-Meier curves for survival outcomes between the RHSL and the PRT groups excluding patients who undertook surgical nodal staging. (A) PFS and (B) OS. Survival curves were divided into tumor size <4 and ≥4 cm.

Fig. S3

Subgroup analysis based on laparoscopic nodal staging prior to chemoradiation in the PRT group.

Fig. S4

Kaplan-Meier graph for PFS and OS according to the adjuvant chemoradiation in the RHSL group.

Fig. S5

Kaplan-Meier graphs for PFS between squamous cell carcinoma and non-squamous cell carcinoma.

Fig. S6

Forest plots of survival analyses showing HRs and 95% CIs from multivariate analysis.

Fig. S7

Flowchart of the analytical process.