Should All Cervical Cancer Patients with Positive Lymph Node Receive Definitive Radiotherapy: A Population-Based Comparative Study

doi:10.21203/rs.3.rs-4740838/v1

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Should All Cervical Cancer Patients with Positive Lymph Node Receive Definitive Radiotherapy: A Population-Based Comparative Study

https://doi.org/10.21203/rs.3.rs-4740838/v1

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Objective: The optimal initial treatment for lymph node metastases (LNM) cervical cancer remains a subject of controversy. This study aimed to investigate the association between surgery plus postoperative radiotherapy (PORT) and definitive radiotherapy (RT), and the prognosis of patients with LNM cervical cancer. Methods: Patients with positive lymph nodes (PLNs) in 2009 FIGO stage I-III cervical cancer were selected from SEER database. Kaplan-Meier and log-rank analysis were utilized to assess survival outcomes. Cox regression and Interaction analyses were used to compare the survival benefits. Results: 2936 patients were included in this study. Multivariate analysis revealed that the choice of primary treatment significantly influenced both cancer-specific survival (CSS) and overall survival (OS), serving as an independent prognostic factor for patients with LNM. After adjusting for imbalanced variables, surgery plus PORT significantly improved CSS and OS in the stage I-II and PLNs ≤ 5 subgroups. However, no significant difference was observed between the two treatment modalities in patients with stage III and PLNs > 5 subgroups. Through interaction analysis, it was observed that patients with stage I-II and PLNs ≤ 5 exhibited a significant survival benefit from surgery plus PORT. Conclusion: For cervical cancer patients at FIGO stage I-II or those with PLNs ≤ 5, combining surgery with PORT could lead to improved outcomes. However, this approach did not apply to those at stage III or individuals with PLNs > 5. Therefore, a comprehensive assessment of LNM and local tumor spread should guide rationalized treatment options when managing patients presenting LNM.

cervical cancer

lymph node metastasis

treatment

prognosis

Cervical cancer ranks as the third most prevalent malignant tumor globally, posing a significant threat to women's health. It also stands out as one of the primary causes of female cancer-related mortality in developing countries^[1]. Despite cervical cancer becoming preventable through prophylactic HPV vaccination based on its etiology, the persistent trends of younger incidence and high mortality rates continue to present serious health challenges worldwide^[2]. While standardized treatment has led to a 90% survival rate among patients with early-stage disease, recurrence remains alarmingly high at approximately 30% for those with locally advanced patients, often manifesting within 2 to 3 years following initial treatment^{[3, 4]}.

Lymph node metastasis (LNM) serves as a crucial pathway for the spread of cervical cancer. The incidence of LNM in cervical cancer patients can escalate from 7.4–60% with advancing stages, exhibiting a positive correlation with disease severity^[5]. Although the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system does not incorporate LNM into its criteria, it is widely acknowledged that lymph node metastasis, along with positive surgical margins and parametrial involvement, represents a high-risk factor for cervical cancer recurrence and significantly influences postoperative adjuvant treatment strategies^[6]. Notably, research has demonstrated that patients with stage IB - IIA who are negative for LNM exhibited an overall survival rate ranging from approximately 82–90%, whereas those who are positive for LNM experience a substantially lower overall survival (OS) rate ranging from only 38–61%. Furthermore, pelvic lymph node metastasis emerges as an independent risk factor impacting both disease-free survival (DFS) and OS in cervical cancer^[7]. It is noteworthy that the number of positive lymph nodes (PLNs) constitutes a primary prognostic factor for cervical cancer patients with LNM. Increasing the extent of lymph node excision can potentially impact DFS in patients with LNM. Moreover, complete removal of intraoperatively identified metastatic lymph nodes may contribute to reducing tumor burden^[8]. The 2018 edition of FIGO staging has incorporated pelvic and/or para-aortic LNM into cervical cancer staging, designating it as the new IIIC stage. This further underscores the crucial role of LNM in both prognosis and treatment outcomes for cervical cancer^[9]. Prior to this update, radical hysterectomy combined with pelvic lymph node dissection was considered the preferred treatment approach for patients classified as group IA2-IB2 and some IB3-IIA1. Satisfactory resection of involved lymph nodes not only allows assessment of surgical completeness but also facilitates accurate determination of nodal involvement based on postoperative pathological findings, thereby guiding decisions regarding adjuvant therapy ^[10]. For locally advanced patients, guidelines recommend primary treatment with radical radiotherapy combined with chemotherapy as first-line therapy. However, in the 2018 version of the staging system, patients with positive pelvic and/or para-aortic lymph nodes were classified as stage IIIC without considering tumor size and local infiltration range. There is still some controversy regarding the extent of tumor invasion and survival prognosis. A retrospective study conducted in 2019 analyzed both versions of the staging system and found that cervical cancer patients with stage IIIC1 according to FIGO 2018 had a higher survival rate compared to stages IIIA and IIIB. However, including all cases with LNM in the same stage resulted in high heterogeneity of survival outcomes within the population^[11]. Additionally, Grigsby et al revealed that higher overall survival rates of patients with stage IIICr may be attributed to a significant number of early-stage cervical primary site T tumors among these patients. Among them, the 5-year progression-free survival (PFS) for T1 was 72%, T2 was 63%, while PFS for T3 decreased to 41%. This indicated variations in survival rates among patients with PLNs based on tumor size^[12]. Therefore, the decision regarding chemoradiotherapy treatment for all patients with LNM regardless of local cervical tumor size, spread, or number/status of lymph node metastasis remains widely debated in clinical practice.

This study aimed to assess the impact of different treatments on the survival outcomes of high-risk cervical cancer patients with 2009 FIGO stage I-III and lymph node metastasis using SEER database analysis. Furthermore, it evaluated how the condition of the primary cervical site and the number of LNM influence treatment outcomes, providing a theoretical basis for individualized clinical management due to the high heterogeneity observed in cervical cancer patients with LNM.

Data Source

The data analyzed in this study, including incidence and population, were downloaded from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program 1975–2016 SEER is the largest and most authoritative cancer registry system in the United States^[13]. To date, the SEER dataset contains data from more than 1,450,709 cases, including 9,428,053 malignancies and more than 95,218 cervical cancer cases. The original patient-related data was extracted using the SEER∗Stat software version 8.3.8 (IMS Inc. USA). Since data from SEER are publicly available, this study has been approved to be exempted research for no human subject involved by the Faculty of Science Ethics Committee at Liaoning Cancer Hospital & Institute.

Patient

The study involved patients with 2009 FIGO stage I-III cervical cancer during 1988–2016. Patients were selected based on the following criteria: (1) Patients only diagnosed with primary cervical cancer. (2) International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) codes 53.0-53.1, 53.8, and 53.9; The histology showing squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma. (3) Pathological diagnosis of lymph node metastasis^[14]; (4) Underwent hysterectomy postoperative radiotherapy (PORT) or radiotherapy (RT) as primary treatment. Patients who conformed to the following criteria were excluded: (1) Records with missing data; (2) In situ tumors; (3) Death occurs within 30 days after diagnosis; (4) Lymph node sampling only and the number of lymph nodes removed or positive lymph nodes were unknown. (5) Cases involving an unspecified or unknown radiotherapy plan, those who received RT only before surgery, or those which received radioisotope/radioactive implants. A flow chart showing the experimental design is shown in Fig. 1.

Study Variables

The following variables were included: age, race, marital status, histological type, grade, FIGO stage, tumor size, number of PLNs, and chemotherapy. Patients in this study who received an unknown chemotherapy regimen were classified as “None/Unknown”. The primary study endpoints were cancer-specific survival (CSS) and overall survival (OS).

Statistical Analysis

The χ²-test was adopted for statistical analysis of categorical variables. We performed Kaplan–Meier survival analysis and log-rank tests to compare CSS and OS among groups. Subgroup stratified analyses were used to determine the differences in survival outcomes of treatment. We established Cox proportional hazards models to explore the prognostic factors of survival. IBM SPSS Statistics version 25 (IBM Corporation, Armonk, NY, USA), STATA MP version 14 (StataCorp LP, College Station, TX, USA), and R version 3.5.3 (https://www.r-project.org/) were used for statistical analyses. A P value = 0.050 was set as the threshold of statistical significance in this study.

1. Overall Cohort Characteristics

A total of 2936 eligible patients diagnosed with the 2009 FIGO stage I-III cervical cancer and presenting LNM were included in this study. Among them, 73.91% of the patients underwent surgery plus PORT, while definitive RT was administered to 26.09% of the patients. The clinical and pathological data of enrolled patients stratified by the different treatment groups are summarised in Table 1. The results revealed significant disparities in age, marital status, histological type, grade, FIGO stage, tumor size, number of PLNs, and chemotherapy between the two treatment groups (P < 0.05). The squamous cell carcinoma accounted for 81.59% in the definitive RT group, whereas it was 63.32% in the surgery plus PORT group. For the selection of different treatment modalities, patients with stage III were more inclined to undergo definitive RT (19.19% vs. 4.56%). Moreover, in the definitive RT group, tumors larger than 4cm constituted a significantly higher proportion (72.98%) compared to the surgery plus PORT group (45.16%). Additionally, the incidence of number of PLNs ≤ 5 was lower in the definitive RT group than in the surgery plus PORT group (82.11% vs. 90.97%).

Table 1

Characteristics of the patients in this study
		Definitive RT	Surgery plus PORT	P*
Age (years)				0.019
	< 45 years	382 (49.87%)	1191 (54.88%)
	45–60 years	284 (37.08%)	685 (31.57%)
	> 60 years	100 (13.05%)	294 (13.55%)
Race				0.235
	White	612 (79.89%)	1720 (79.26%)
	Black	71 (9.27%)	173 (7.97%)
	Others§	83 (10.84%)	277 (12.77%)
Marital status				< 0.001
	Never married	253 (33.03%)	591 (27.24%)
	Used married	156 (20.37%)	416 (19.17%)
	Married	328 (42.82%)	1112 (51.24%)
	Unknown	29 (3.78%)	51 (2.35%)
Histology type				< 0.001
	SCC	625 (81.59%)	1374 (63.32%)
	ADC	84 (10.97%)	543 (25.02%)
	ASC	37 (4.83%)	199 (9.17%)
	Others	20 (2.61%)	54 (2.49%)
Grade†				< 0.001
	Grade I	23 (3.01%)	92 (4.24%)
	Grade II	223 (29.11%)	817 (37.65%)
	Grade III	300 (39.16%)	1050 (48.39%)
	Grade IV	20 (2.61%)	87 (4.01%)
	Unknown	200 (26.11%)	124 (5.71%)
Number of PLNs				< 0.001
	≤ 5	629 (82.11%)	1974 (90.97%)
	> 5	137 (17.89%)	196 (9.03%)
FIGO stage				< 0.001
	I	13 (1.69%)	46 (2.12%)
	II	606 (79.12%)	2025 (93.32%)
	III	147 (19.19%)	99 (4.56%)
Tumor size				< 0.001
	< 2 cm	49 (6.39%)	286 (13.18%)
	2–4 cm	158 (20.63%)	904 (41.66%)
	> 4 cm	559 (72.98%)	980 (45.16%)
Chemotherapy				< 0.001
	Received	667 (87.08%)	1657 (76.36%)
	No/Unknown	99 (12.92%)	513 (23.64%)
Abbreviations: SCC = squamous cell carcinoma, AC = adenocarcinoma. * P was made by χ²-test.
§ Other = American Indian/AK Native, and Asian/Pacific Islander and Unknown. † Grade I = well differentiated; grade II = moderately differentiated; grade III = poorly differentiated; grade IV = undifferentiated; anaplastic.

2. Survival Difference Analysis of Primary Treatment

Kaplan-Meier survival analysis revealed that patients who underwent definitive RT exhibited a significantly inferior CSS rate compared to those who received surgery plus PORT (5-year cancer-specific survival rate [5-YCSR]: 70.90% vs. 53.70%, P < 0.001, Fig. 2A). Furthermore, the definitive RT group demonstrated a markedly lower OS rate as well (5-year overall survival rate [5-YSR] 69.20% vs. 50.40%, P < 0.001, Fig. 2B).

To further investigate the impact of different treatment methods and clinicopathological characteristics on survival, we conducted Cox proportional hazard model analysis on overall patients. The results for CSS and OS are presented in Table 2and Supplementary Table 1, respectively. Our findings demonstrated that definitive RT group exhibited a risk of adverse CSS compared to surgery plus PORT group (HR = 0.614, 95% CI: 0.525–0.719, P < 0.001, Table 2). Similarly, receiving definitive RT was associated with an increased risk of poor OS (HR = 0.592, 95%CI: 0.510–0.687, P < 0.001, Supplementary Table 1). Additionally, the COX analysis results indicated that in patients with LNM, the 2009 FIGO stage served as an independent prognostic factor. This suggests that the stage not only reflects patient survival but also influences treatment modality options. Therefore, after stratifying patients according to the 2009 FIGO stage, Kaplan-Meier survival analysis revealed that for FIGO I-II patients, surgery plus PORT group resulted in better CSS (P < 0.001, Fig. 3A-B) and OS (P < 0.001, Fig. 3D-E) compared to definitive RT group. However, for FIGO stage III patients, there was no statistical difference observed between both groups in terms of CSS (42.60% vs. 41.10%; P = 0.465; Fig. 3C) and OS (41.40% vs.34 .80%; P = 0 .083; Fig. 3F).

Table 2

Cox proportional hazard model for prognostic factors in CSS
		Univariate Analysis		Multivariate Analysis
		HR (95%CI)	P	HR (95%CI)	P*
Treatment			< 0.001		< 0.001
	Definitive RT	1		1
	Surgery plus PORT	0.531(0.464–0.608)		0.614(0.525–0.719)
Age			< 0.001		0.338
	< 45 years	1		1
	45–60 years	1.270(1.104–1.462)		1.086(0.938–1.257)
	> 60 years	1.434(1.187–1.733)		1.142(0.936–1.393)
Race			0.026		0.029
	White	1		1
	Black	1.040(0.849–1.273)		1.330(1.075–1.647)
	Others§	1.373(1.045–1.803)		0.984(0.801–1.207)
Marital status			0.028		0.288
	Never married	1		1
	Used married	1.135(0.948–1.358)		1.068(0.886–1.287)
	Married	0.891(0.765–1.037)		0.913(0.781–1.067)
	Unknown	0.845(0.547–1.305)		0.903(0.583–1.399)
Histology type			< 0.001		< 0.001
	SCC	1		1
	ADC	1.395(1.198–1.624)		1.723(1.464–2.027)
	ASC	1.282(1.019–1.611)		1.388(1.100-1.752)
	Others	2.620(1.908–3.597)		2.335(1.672–3.259)
Grade†			< 0.001		0.008
	Grade I	1		1
	Grade II	1.092(0.740–1.611)		1.270(0.854–1.891)
	Grade III	1.437(0.981–2.105)		1.572(1.060–2.331)
	Grade IV	2.392(1.511–3.788)		1.875(1.168–3.008)
	Unknown	1.751(1.162–2.638)		1.430(0.938–2.182)
Number of PLNs			< 0.001		< 0.001
	≤ 5	1		1
	> 5	1.952(1.645–2.317)		1.611(1.352–1.921)
FIGO stage			< 0.001		< 0.001
	I	1		1
	II	1.885(1.640–2.165)		1.529(1.322–1.770)
	III	2.961(2.435–3.602)		1.993(1.611–2.466)
Tumor size					< 0.001
	< 2 cm	1		1
	2–4 cm	1.632(1.219–2.184)		1.400(1.044–1.878)
	> 4 cm	2.839(2.149–3.750)		1.942(1.458–2.587)
Chemotherapy			0.183		0.003
	No/Unknown	1		1
	Received	0.904(0.778–1.049)		.0793(0.680–0.925)
Abbreviations: SCC = squamous cell carcinoma, AC = adenocarcinoma, HR = Hazard ratio, 95%CI = 95% Confidence interval.
* Multivariate analysis adjusted for Age, Race, Marital status, Histological type, Grade, FIGO stage, Tumour size, Number of PLNs, and Chemotherapy.
§ Other = American Indian/AK Native, and Asian/Pacific Islander and Unknown.
† Grade I = well differentiated; grade II = moderately differentiated; grade III = poorly differentiated; grade IV = undifferentiated; anaplastic.

Moreover, utilizing prognostic risk factors identified through multivariate COX analysis, we stratified the data based on age, number of PLNs, and tumor size to assess the impact of different treatment regimens on survival outcomes. The results found that among patients with number of PLNs ≤ 5, those who underwent surgery plus PORT exhibited significantly improved CSS in contrast to those with definitive RT (5-YCSR: 72.80% vs. 55.80%; P < 0.001; Fig. 4A), as well as OS (5-YSR: 71.20% vs. 52.70%; P < 0.001; Fig. 4C). However, in the subgroup of patients number of PLNs > 5, there was no significant difference between CSS and OS for the two treatment modalities (CSS: P = 0.149, Fig. 4B; OS: P = 0.080, Fig. 4E). Furthermore, when analyzing different age groups and tumor sizes, it was evident that surgery plus PORT yielded significantly better CSS and OS across all subgroups compared to definitive RT (Fig. 5, Supplementary Fig. 1). Therefore, these results suggested that FIGO stage and number of PLNs were the main factors influencing divergent clinical outcomes between the two treatment modalities.

3. Effect of Primary Treatment on Survival outcomes

FIGO stage and number of PLNs are the key factors affecting the prognosis. To accurately assess the impact of treatment modalities on prognosis, multivariate COX analysis was conducted on CSS and OS data, stratified by FIGO stage and number of PLNs. In patients with FIGO stage I-II, those who received surgery plus PORT were equipped with significantly higher CSS (HR 0.544, P < 0.001; HR 0.532, P < 0.001; univariate and multivariate analysis, respectively; Table 3) and OS (HR 0.557, P < 0.001; HR 0.536, P < 0.001; univariate and multivariate analysis, respectively; Supplementary Table 2) compared to those with definitive RT. However, in patients with FIGO stage III, there were no statistically significant differences observed in CSS (HR 0.879, P = 0.470; HR 1.090, P = 0.698; univariate and multivariate analysis, respectively; Table 3) and OS (HR 0.747, P = 0.087; HR 0.747, P = 0.087; univariate and multivariate analysis, respectively; Supplementary Table 2) between the two treatment modalities. Considering the impact of FIGO staging and number of PLNs involvement on treatment decisions, an interaction analysis was conducted to evaluate the treatment effect on survival outcomes in different subgroups. Given the similar survival benefits observed in FIGO stage I and II subgroups, we combined their data for analysis. Our findings revealed a distinctly different interaction effect on CSS of these two treatment modalities between FIGO stage I-II and stage III (univariate P interaction = 0.020, multivariate P interaction = 0.007; Fig. 6). Specifically, surgery plus PORT was identified as a protective factor for CSS in patients with stage I-II. Conversely, no significant interaction effects were observed between different treatment modalities for overall survival (OS) (univariate P interaction = 0.125, multivariate P interaction = 0.051; Supplementary Fig. 2). Furthermore, there were significant differences in the CSS and OS interactions between the two treatment modalities based on number of PLNs > 5 and ≤ 5 within subgroups (CSS: univariate P interaction = 0.020, multivariate P interaction = 0.026; Fig. 6; OS: univariate P interaction = 0.025, multivariate P interaction = 0 .028; Supplementary Fig. 2). In the subgroup with number of PLNs ≤ 5, patients who underwent surgery plus PORT showed superior CSS compared to those with definitive RT (univariate HR 0.517, P < 0.001; multivariate HR 0.587, P < 0.001; Table 3) as well as OS (univariate HR 0.507, P < 0.001; Multivariate HR 0.569, P < 0.001; Supplementary Table 2). However, in patients with number of PLNs > 5, both groups showed no significant difference in survival benefit in respect of CSS (univariate HR 0.792, P = 0.152; Multivariate HR 0.769, P = 0.190; Table 3) and OS (univariate HR 0.765, P = 0.083; Multivariate HR 0.713, P = 0.077; Supplementary Table 2).

Table 3

Stratified analysis of 5-year cancer specific survival in this study
	Subgroup	5-year cancer specific survival rate (95% CI)		HR (95% CI); P value
		Surgery plus PORT	Definitive RT	Univariate	Multivariate*
FIGO stage
	I	0.770(0.746–0.793)	0.637(0.576–0.691)	0.544(0.439–0.672) ;<0.001	0.532(0.420–0.673) ;<0.001
	II	0.608(0.564–0.649)	0.481(0.412–0.547)	0.664(0.535–0.824) ;<0.001	0.584(0.459–0.744) ;<0.001
	III	0.426(0.318–0.529)	0.411(0.321–0.498)	0.879(0.619–1.248);0.470	1.090(0.705–1.687);0.698
Number of PLNs
	≤ 5	0.728(0.706–0.748)	0.558(0.513–0.601)	0.517(0.445–0.601) ;<0.001	0.587(0.493–0.699) ;<0.001
	> 5	0.517(0.438–0.591)	0.436(0.339–0.530)	0.792(0.576–1.090) ;0.152	0.769(0.519–1.139) ;0.190
* Multivariate analysis adjusted for Age, Race, Marital status, Histological type, Grade, FIGO stage, Tumour size, Number of PLNs, and Chemotherapy.

Initial treatment of cervical cancer with positive lymph nodes remains disputed, particularly regarding whether positive lymph nodes found intraoperatively should be abandoned or if a completely radical surgery is warranted due to limited and inconsistent data. In this retrospective study, we compared the survival outcomes of patients with node-positive cervical cancer who underwent surgery combined with PORT versus those who received definitive radiotherapy alone. To enhance comparability between different subgroups, interactions were used to analyze the impact of FIGO stage and number of PLNs on the prognosis of different treatment modalities. Our analysis indicated that primary treatment modality was an independent prognostic factor for patients with LNM. Specifically, for patients with FIGO stage I-II or a number of PLNs less than 5, choosing primary radical surgery may confer a survival benefit. These findings provide crucial insights for guiding the management of cervical cancer with lymph node metastasis.

Several studies have confirmed that lymph node metastasis is an independent risk factor for the recurrence and survival of cervical cancer, significantly impacting DFS and OS [19]. Accurate assessment of LNM plays a crucial role in determining the clinical treatment approach for cervical cancer. Surgical resection and biopsy remain the gold standard for diagnosing lymph node status. In recent years, various imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT) have also been utilized to evaluate lymph node status before treatment, providing targeted guidance for selective lymph node biopsy ^{[15, 16]}. The PET-CT, which is the most sensitive imaging modality for detection, can identify LNM as small as 5 mm in size ^[17]. The 2018 FIGO staging system has recognized the significance of imaging techniques in diagnosing and staging lymph node status, thereby directly influencing cervical cancer treatment decisions. However, findings from current studies have confirmed significant heterogeneity in survival outcomes among patients with LNM detected through either advanced imaging techniques or surgical pathology. Factors such as local tumor invasion depth, tumor size, and number of PLNs remain critical determinants of poor prognosis. Consequently, there is still no clear consensus on the preferred approach for treating patients with PLNs based on imaging diagnosis or surgical pathology.

According to the 2009 FIGO staging system, radical surgery is recommended for early-stage cervical cancer by NCCN guidelines, with or without individualized postoperative adjuvant therapy based on prognostic risk factors. Large clinical trials have shown that pelvic radiotherapy after radical surgery significantly reduced recurrence rates and improved progression-free survival in early-stage cervical cancer patients compared to chemoradiotherapy^{[18, 19]}. Furthermore, primary surgery for early-stage cervical cancer patients is advantageous in protecting ovarian function and identifying risk factors^[20]. For locally advanced cervical cancer, definitive radiotherapy combined with chemotherapy is recommended as the preferred treatment option^[21]. However, after adjusted by the 2018 FIGO staging, the ABRAX international retrospective cohort study revealed that dual treatment of radical hysterectomy combined with adjuvant chemoradiotherapy does not demonstrate significant benefits to patients regardless of tumor size or histological type and instead increases treatment-related complications and medical resource burden after adjustment of FIGO staging version 2018^[22]. Currently, the NCCN guidelines recommend that all patients with LNM should consider chemoradiotherapy. Nevertheless, some studies have indicated that surgical treatment provides better survival outcomes than radiotherapy in cases of localized early-stage cervical cancer with LNM ^[23]. This suggests that the involvement of lymph nodes may not be the sole criterion for treatment options and the degree of primary tumor invasion should also be comprehensively considered. In this study, after adjusting for several variables such as histological type, grade, FIGO stage, tumor size, number of PLNs, and chemotherapy, it was found that the treatment regimen combining surgery plus PORT conferred greater benefits in terms of OS and CSS among stage I-II patients with LNM. Numerous studies in recent years have provided several ideas and results that can elucidate the significant disparity in survival rates. Firstly, from a macroscopic perspective, primary radical surgery enables the removal of lesions and facilitates accurate pathological characterization, thereby reducing tumor burden and boosting improved postoperative adjuvant therapy for individualized treatment^[24]. Secondly, systematic pelvic and abdominal lymph node dissection has been shown to substantially decrease the recurrence rate among local early-stage patients^[25]. Although patients with LNM should receive radiotherapy regardless of whether they undergo lymph node resection, surgical resection of lymph nodes can guide subsequent precise radiotherapy field setting and mitigate low response to radiotherapy as well as treatment failure caused by organ-at-risk dose limitations^[26]. Therefore, primary surgery may be the preferred treatment option for accurate staging and determining postoperative adjuvant therapy in localized early-stage cervical cancer patients with LNM. Furthermore, this study revealed that surgical treatment did not demonstrate a significant survival advantage compared to definitive radiotherapy in stage III cervical cancer patients with LNM, which is consistent with previous findings^[27]. This observation could be attributed to incomplete resection of pelvic lesions during the primary surgical intervention in these patients, resulting in a high residual tumor occurrence of approximately 50% after surgery and subsequent rapid recurrence within a short time^[28]. Moreover, the local residual tumor following surgery hampers the attainment of a clinically effective radiotherapy dose, thereby constituting a pivotal factor contributing to suboptimal treatment outcomes and tumor recurrence^[29]. Simultaneously, owing to the intricate nature and extensive scope of the surgery, the amalgamation of comprehensive treatments significantly heightens the risks of surgery-related complications such as urinary system, digestive system, and sexual dysfunction. Consequently, this may impede timely postoperative adjuvant therapy initiation and trigger uncontrolled tumor growth along with rapid recurrence.

The number of LNM is a crucial prognostic factor that has garnered significant attention in clinical decision-making for cervical cancer^[30]. Additionally, the varying numbers of PLNs contribute to heterogeneity in prognosis and clinical outcomes^[31]. Hosaka et al. conducted a study involving 108 cases of FIGO IB-IIB cervical cancer and found that patients with more than two PLNs had poorer survival rates^[32]. Mika's study revealed that patients with more than three PLNs experienced significantly shorter DFS and an increased risk of distant metastasis^[33]. Furthermore, Hyun and Young et al. analyzed the classification variables based on the number of PLNs and observed a sharp increase in the risk of death as the quantity exceeded five^{[34, 35]}. Therefore, treatment strategies should be tailored differently for multiple LNM. Our study revealed that after adjusting for bias factors, the number of PLNs is ≤ 5, and the adverse prognosis seems to be eliminated by systematic surgery, indicating that primary surgery plus PORT can achieve better treatment outcomes. However, among patients with more than 5 PLNs, there was no significant difference in prognosis between the two treatment options. These findings may also be influenced by changes in surgical techniques and radiotherapy methods over the years, and further analysis is still warranted.

We realize that our study is limited by utilizing SEER data. Firstly, being a retrospective study, it unavoidably carries inherent bias. Secondly, given the extensive time span covered by this study, there have been notable changes in the management of cervical cancer over recent decades. Specifically, the standardized use of chemotherapy may have influenced survival outcomes. The SEER program lacks comprehensive information regarding chemotherapy protocols, dosages, and operation sequencing of chemotherapy, radiotherapy, and surgery. Consequently, we could not thoroughly evaluate variables related to chemotherapy data. Instead, our analysis considered these factors as calibration variables. Thirdly, the SEER database lacks information on the pattern of treatment complications and recurrence-specific treatment options, thereby limiting the assessment of different approaches to treating complications and preventing recurrences. Despite conducting interaction analysis, we observed a significant interaction effect between FIGO staging and CSS but not on OS, possibly due to the smaller sample size in stage III.

In conclusion, our investigation suggested that cervical cancer patients with 2009 FIGO stage I-II or number of PLNs ≤ 5 who initially choose surgery may achieve longer survival compared to definitive radiotherapy. However, for patients with FIGO stage III or number of PLNs > 5, considering that combination therapy not only failed to provide significant benefits but also increased adverse prognostic factors such as treatment-related complications and treatment delays, definitive radiotherapy remains the optimal primary treatment choice for these patients. Since there is evident heterogeneity in LNM among cervical cancer patients regarding primary treatment options for prognosis, it is necessary to consider the local tumor invasion condition and number of PLNs for stratified management. Moreover, large-scale prospective studies are warranted to investigate the impact of diverse treatment regimens on recurrence, prognosis, perioperative and long-term complications, as well as quality of life.

Authors’ Contribution

Statement

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Should All Cervical Cancer Patients with Positive Lymph Node Receive Definitive Radiotherapy: A Population-Based Comparative Study

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