Abdominal Radical Hysterectomy as an Alternative Treatment Option for Patients with Cervical Cancer without Access to Radiotherapy Facilities

Background : To compare the oncological outcomes of Chinese patients with International


Introduction
Cervical cancer (CC) represents a significant global health issue, with an estimated 570,000 cases and 311,000 deaths worldwide in 2018, ranking as the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths in women [1].Several studies have indicated lymph node metastasis (LNM) as a poor prognostic factor for CC [2][3][4][5][6][7][8][9].Tumor staging is high-ranking for overall management and guidance of treatment [10].The International Federation of Gynecology and Obstetrics (FIGO) staging system [11] is relatively well-recognized for CC and includes a prominent revision to classify patients with LNM as stage IIIC.Patients with pelvic LNM are classified as stage IIIC1, whereas those with para-aortic LNM are classified as stage IIIC2.This classification emphasizes the significance of LNM and its location for prognosis and treatment.
Abdominal radical hysterectomy (ARH) and radical chemoradiotherapy (R-CT) are the primary initial treatments for CC.R-CT improves mortality in CC by approximately 30-50% [12][13][14][15][16] and can be used in all stages of CC; however, it is associated with a range of concomitant complications [17][18][19].In contrast, ARH allows for the resection of tumor tissues and metastatic lymph nodes (LNs) to reduce tumor burden and determine LN status, which can guide postoperative adjuvant therapy.In recent years, neoadjuvant chemotherapy and radical surgery (NACT) have also been used to treat CC because of their positive effect in reducing tumor volume and lowering tumor stage.In the FIGO 2018 staging system [11], stage IIIC CC includes cases of FIGO 2009 stages IA to III CC with LNM.Prior to 2018, the standard initial treatments for FIGO 2009 stages IA to IIA and stages IIB to III CC were ARH and R-CT, respectively.Nevertheless, both the FIGO 2018 [11] and 2023 National Comprehensive Cancer Network (NCCN) [20] guidelines recommend R-CT for stage IIIC CC only, leading to the loss of opportunity for surgery in some patients with FIGO 2009 early-stage CC, which represents a significant departure from past treatment strategies.As a result, the treatment of stage IIIC CC remains controversial.
Overall, less developed regions account for 85% of the incidence and 90% of the mortality of CC [21].In light of the World Health Organization (WHO) country profile for CC [22], Canada has 11 radiotherapy units per 10,000 cancer patients, whereas China has 4 and Uganda 1, highlighting the lack of radiotherapy resources in such less developed regions.Therefore, options to initial treatment for FIGO 2018 stage IIIC CC is particularly critical in less developed regions with both a high CC prevalence and a lack of radiotherapy resources.Nevertheless, most studies on stage IIIC CC have largely focused on the prognostic and influencing factors, validating their plausibility and causes, whereas fewer studies have focused on treatment strategies, and studies from less developed regions are also lacking.Consequently, this study addresses the treatment strategy for FIGO 2018 Stage IIIC CC in developing countries to provide evidence for the selection of alternative initial treatment options for less developed regions.

Data Collection
For this retrospective study, the data used were obtained from the Project 1538 developed through a clinical trial (Project 1538; Ethics Clearance NFEC-2017-135; Clinical trial registration number: CHiCTR1800017778, http://apps.who.int/trialsearch/), which was authorized by the Ethics Committee of Southern Hospital.The database includes 63,926 cases of CC, collected across 47 hospitals in China.Included are patients' clinical information, pretreatment biopsy results, laboratory and imaging information, treatment plans, treatment complications, and postoperative pathology reports.Data were collected by two gynecologists, who received specific training for the clinical trial, using EpiData 3.1 (EpiData Association, Odense, Denmark) for dual data entry and standard interviews for follow-up data by telephone calls or outpatient visits.Details of the data collection and follow-up methods have been previously described [23,24].

Inclusion and Exclusion Criteria
For our study, the selection criteria for eligible cases were as follows: age ≥18 years; CC detected through cervical biopsy; histological diagnosis of squamous cell carcinoma (SCC), adenocarcinoma (AC), or adenosquamous cell carcinoma (ASC); FIGO 2018 stage IIIC classifica-tion; and availability of follow-up data.With regards to initial treatment, the inclusion criteria were as follows: R-CT, external radiation therapy (RT) at a dose of ≥45 Gy/brachytherapy at a dose of ≥40 Gy, on or off concurrent platinum-based chemotherapy (an example of the dose of R-CT: the doses of the external radiation therapy is 1.8-2 Gy per fraction, the doses of the brachytherapy (high dose rate) is 6-7 Gy per fraction, and the total dose of external radiation therapy and brachytherapy is usually ≥85 Gy); ARH, Q-M type-B or type-C radical hysterectomy pelvic lymphadenectomy, with or without para-aortic lym-phadenectomy; and NACT, consisting of platinum-based neoadjuvant therapy (2-3 cycles) and radical surgery; and patients with available follow-up data.The patients of stage IIIC2 received extended-field external irradiation radiotherapy, concurrent platinum-based chemotherapy, and brachytherapy.Exclusion criteria consisted of violation of selection criteria, cancer of the uterine cervix stump, and CC combined with other malignancies or pregnancy.

Outcome Measurement
The outcomes for this study were overall survival (OS) and disease-free survival (DFS), with a cutoff point of 5 years post-treatment.OS is the last point in time from diagnosis to valid follow-up or death for any reason.DFS is the last point in time from diagnosis to follow-up, relapse, or death.

Statistical Analysis
Continuous variables were described as the mean ± standard deviation, while the independent samples t-test was used for between-group comparisons.Categorical values were described as their percentages, and the chi-squared test or Fisher's exact probability test was used, as appropriate, for between-group comparisons.The Kaplan-Meier method was applied for survival analysis.Independent risk factors were established with Cox proportional hazards models along with hazard ration (HR) and 95% confidence interval (CI).Propensity score matching (PSM) was used to minimize the influence of baseline differences between groups.All analyses were performed using SPSS (version 29; IBM Corp., Armonk, NY, USA), with significance set at a p-value < 0.05.

Case Screening Results
Based on the inclusion and exclusion criteria, 4086 CC cases were selected from the Project 1538 database, with no missing values.Fig. 1 exemplifies the patient screening process.The findings from baseline profiling for stages IIIC1 and IIIC2 are presented in Supplementary Table 1.The findings from baseline profiling for the R-CT and ARH groups, R-CT and NACT groups, and ARH and NACT groups for stage IIIC1 are described in Supplementary Tables 2,3,4, respectively.The findings from baseline profiling for the ARH and NACT groups for stage IIIC2 are depicted in Supplementary Table 5.
Cox regression analyses (post-PSM) showed that stage IIIC2 was correlated with worse DFS (HR = 2.295, 95% CI 1.470-3.581,p < 0.001) compared with stage IIIC1 but not with worse OS (p = 0.716).Additionally, the ARH group was not correlated with 5-year OS (p = 0.076) or DFS (p = 0.371) as opposed to the R-CT group; moreover, the NACT group was not correlated with 5-year OS (p = 0.630) or DFS (p = 0.817).Finally, age was not correlated with 5year OS or DFS (p > 0.05); compared with SCC, AC was correlated with worse 5-year OS and DFS (p < 0.05); however, ASC was not correlated with 5-year OS or DFS (p > 0.05; Table 1).

Comparison of the Oncological Outcomes of the ARH and NACT Groups for Stage IIIC2
PSM could not be performed because of the small number of cases in both groups.Kaplan-Meier analysis revealed a marked distinction in 5-year DFS (45.4% vs. 30.1%,p = 0.025) but not in 5-year OS (69.7% vs. 73.9%,p = 0.750) between the ARH and NACT groups (Fig. 6).

Discussion
The FIGO 2018 IIIC staging system highlights the relevance of LNM in oncology treatment and prognosis.For patients at this stage, the 2018 FIGO [11] and the 2023 NCCN [20] guidelines recommend only R-CT with no alternative treatment options described.However, performing R-CT is often a challenge for underdeveloped areas where radiotherapy facilities are lacking.Consequently, this study focused on FIGO 2018 stage IIIC CC patients to investigate the oncological outcomes of R-CT, ARH, and NACT and to provide a real-world basis for selecting an appropriate alternative initial treatment in less developed areas.We found that different stages and treatments affected the prognosis of stage IIIC CC patients, with higher mortality and risk of recurrence for stage IIIC2 than for stage IIIC1.In addition, for patients with stage IIIC1, ARH showed better oncological outcomes than R-CT and NACT.In contrast, for patients with stage IIIC2, ARH was superior to NACT, but R-CT data were insufficient to conclude whether it was appropriate in the current study.As such, ARH may thus represent a viable alternative treatment option.

Comparison of the Oncological Outcomes of Stages IIIC1 and IIIC2
Substantial evidence supports para-aortic LNM as a clear adverse prognostic factor [5,18,19,[25][26][27][28][29]. Cho et al. [25] analyzed stage IIIC CC patients and observed that patients with para-aortic LNM exhibited noticeably worse 5- year OS and DFS than those without para-aortic LNM (p < 0.001), which was similar to the results of the studies of Guo et al. [26] and Yan et al. [5].In the present study, the 5-year DFS was found to be superior in stage IIIC1 compared with that in stage IIIC2, and stage IIIC2 was related to worse 5-year DFS.As such, this research further classified stage IIIC CC patients into stages IIIC1 and IIIC2 subgroups for individualized treatment studies.

Comparison of the Oncological Outcomes among the Three Treatments for Patients with Stages IIIC1 and IIIC2
Although R-CT is used in patients with all stages of CC to improve the oncological outcomes, it may also damage nearby organs and cause adverse effects [17][18][19].Contrastingly, ARH offers several advantages, including avoidance of the adverse effects of R-CT; removal of the primary tumor, infiltrating tissues, and LN; and the possibility of personalized postoperative treatment based on pathological findings.As such, ARH is the preferred treatment option for early CC [10].However, it was demonstrated by Wu et al. [30] and Landoni et al. [31] that the therapeutic efficacies of ARH and R-CT are similar.Furthermore, investigations by Yan et al. [32] and Jang et al. [33] indicated that the prognosis after ARH was significantly better than that after R-CT, which is in keeping with the outcomes of the present research.In the present study, compared with the R-CT group, the ARH group had superior 5-year OS (post-PSM: 71.0% vs. 80.0%, p < 0.001) and DFS (post-PSM: 67.2% vs. 71.0%,p < 0.001) and was related to better 5-year OS and DFS (post-PSM: p < 0.05) for stage IIIC1.The patients treated with R-CT may develop serious immediate or long-term complications, including impaired ovarian function, damaged vaginal structure and function, and inflammation of the bladder and rectum [17][18][19], which may affect their physical condition.For tumor treatment, whether it is initial treatment or treatment after the occurrence of recurrence and metastasis, the patient's physical condition is a key component influencing the outcome [34,35].This may account for the poor treatment outcome in the R-CT group.Considering the undesirable effects of R-CT and the paucity of radiotherapy equipment in developing countries, ARH may be a suitable alternative option, especially for patients who desire to preserve their fertility.
Interestingly, NACT positively lowers tumor stage, reduces tumor burden, and enhances the chance of surgical tumor removal; however, conclusive evidence on whether NACT has a positive effect on the prognosis of CC is still lacking [36][37][38][39].A meta-analysis by Ye et al. [40] revealed that oncological outcomes were significantly superior in the NACT group compared with those in the direct surgery group (p < 0.05).Similar findings were confirmed by Hu et al. [41] and Rydzewska et al. [42].However, a phase III randomized controlled study by Katsumata et al. [43] in Japan that included 134 FIGO 2009 patients with stage IB2, IIA2, and IIB (including LNM) CC displayed a distinctively inferior OS in the NACT group compared with that in the radical surgery group (58% vs. 80%, p = 0.015), leading to the early termination of the study.In the present study, compared with the ARH group, the NACT group experienced the worse 5-year OS and DFS and was correlated with worse 5-year OS and DFS for stage IIIC1 (post-PSM: p < 0.001); simultaneously for stage IIIC2, NACT had a worse 5-year DFS and was correlated with a worse DFS (post-PSM: p < 0.05).For both stages, NACT showed no oncological advantages over ARH.
Duenas-Gonzalez et al. [44] also observed that, compared with R-CT, NACT did not have an improved prognosis for CC.Similar findings were showed in this research, where for stage IIIC1, R-CT had a better 5-year DFS than NACT, and NACT was also correlated with a worse 5-year DFS (post-PSM: p < 0.05).Owing to the lack of R-CT cases, in-depth study is required to investigate the effect of R-CT on stage IIIC2.Nwankwo et al. [45] suggested that NACT may introduce confounding pathological factors in surgical specimens, influence postoperative pathological findings, complicate the assessment of the need for postoperative adjuvant therapy, and lead to missed or overtreatment.This may provide an explanation for the inferior effectiveness of NACT compared with ARH and R-CT in this research.As such, NACT should be used with caution for stage IIIC CC.This current study is notable, as it is one of the largest studies based on the 2018 FIGO staging system for stage IIIC1 and IIIC2 CC from less developed regions.This study is innovative, as it stratified patients based on different LNM locations and compared the oncological prognosis of three commonly used CC treatments.In spite of the wideranging application of minimally invasive approaches, abdominal hysterectomy remains a general surgical procedure of intervention [46].Furthermore, the Laparoscopic Approach to Cervical Cancer (LACC) confirmed that the prognosis of minimally invasive surgery was worse than that of ARH [47].Therefore, only patients treated with ARH were included in this study.Nevertheless, this study has a few limitations.First, being retrospective, this study may have involved data imbalance between groups.Second, the lack of information on the specific treatment regimen, dose and duration of postoperative adjuvant therapy, R-CT, and NACT was also a shortcoming of the current study.Third, only 57 stage IIIC2 cases and no R-CT cases were available, which may have affected the reliability of the results.Fourth, stratification was performed based on only two LNM locations and did not include LN size and number and other LNM locations.

Conclusions
In the present study, the oncological prognosis of patients with stage IIIC1 CC was generally better than that of patients with stage IIIC2, indicating that the rationale behind the classification of stage IIIC is justified.The oncological outcome of ARH was superior to those of R-CT and NACT for stage IIIC1 and superior to that of NACT for stage IIIC2.As such, ARH is an acceptable initial treatment option for patients with stage IIIC in less developed areas; however, consideration should be given to the use of NACT.Given the small number of stage IIIC2 cases analyzed, confirmation of the results of this research is warranted in future prospective studies.

Fig. 3 .
Fig. 3. OS and DFS of the R-CT and ARH groups (stage IIIC1).Direct comparison of 5-year OS (A) and 5-year DFS (B) for R-CT and ARH in stage IIIC1.Comparison of 5-year OS (C) and 5-year DFS (D) for R-CT and ARH in stage IIIC1 after PSM.PSM, propensity score matching; OS, overall survival; DFS, disease-free survival; R-CT, radical chemoradiotherapy; ARH, abdominal radical hysterectomy.

Fig. 4 .
Fig. 4. OS and DFS of the R-CT and NACT groups (stage IIIC1).Direct comparison of 5-year OS (A) and 5-year DFS (B) for R-CT and NACT in stage IIIC1.Comparison of 5-year OS (C) and 5-year DFS (D) for R-CT and NACT in stage IIIC1 after PSM.PSM, propensity score matching; OS, overall survival; DFS, disease-free survival; R-CT, radical chemoradiotherapy; NACT, neoadjuvant chemotherapy and radical surgery.

Fig. 5 .
Fig. 5. OS and DFS of the ARH and NACT groups (stage IIIC1).Direct comparison of 5-year OS (A) and 5-year DFS (B) for ARH and NACT in stage IIIC1.Comparison of 5-year OS (C) and 5-year DFS (D) for ARH and NACT in stage IIIC1 after PSM.PSM, propensity score matching; OS, overall survival; DFS, disease-free survival; ARH, abdominal radical hysterectomy; NACT, neoadjuvant chemotherapy and radical surgery.