Abstract
Objective
This study aimed to evaluate and compare recurrence-free survival (RFS) between radical hysterectomy followed by adjuvant chemotherapy and initial chemoradiotherapy for cervical cancer at our institution.
Methods
In this retrospective study, we enrolled patients diagnosed with stage IB2–IIB cervical cancer according to the International Federation of Gynecology and Obstetrics 2018 staging system, who underwent either radical hysterectomy with pelvic lymphadenectomy followed by adjuvant chemotherapy or initial concurrent chemoradiation at our institution between 2009 and 2022.
Results
Among these patients, 74 and 110 underwent radical hysterectomy and chemoradiation, respectively. The radical hysterectomy group exhibited significantly improved RFS compared with the chemoradiation group; however, no significant difference was observed in overall survival between the groups. Cox hazard analysis for RFS showed that, among the clinical risk factors identified before the initial treatment, only parametrial invasion was statistically significant. No significant difference in RFS was observed between the radical hysterectomy group and chemoradiation group. Regarding recurrence patterns, para-aortic lymph node recurrence occurred significantly more frequently in the chemoradiation group than in the radical hysterectomy group. Postoperative ureteral injury was reported in once case and postoperative ureteral stenosis in 2 cases in the radical hysterectomy group. In contrast, vesicovaginal fistula and rectovaginal fistula were reported in one case each in the chemoradiation group.
Conclusion
Radical hysterectomy followed by adjuvant chemotherapy provided RFS outcomes comparable to those achieved with initial chemoradiotherapy for stage IB2-IIB and IIIC1-2 cervical cancer. These findings suggest that both approaches are viable, although further prospective studies are needed.
Keywords: Hysterectomy, Cervical Cancer, Chemoradiotherapy, Adjuvant Chemotherapy
Synopsis
Radical hysterectomy followed by adjuvant chemotherapy yields oncologic outcomes comparable to those of chemoradiation for stage IB2-IIB and IIIC1-2 cervical cancer. Although both treatment approaches showed similar overall survival, distinct recurrence patterns and manageable complications were noted, highlighting the viability of both approaches.
INTRODUCTION
Globally, cervical cancer remains one of the most prevalent malignant tumors in women and ranks fourth in both incidence and mortality, with approximately 600,000 new cases and 340,000 deaths reported annually [1]. In Japan, most cervical cancer cases are detected at an early stage, leading to the widespread adoption of surgical intervention as the primary treatment modality for patients diagnosed at stages I–II and IIIC1–2 [2]. Even in stage IIB cervical cancer, which accounts for approximately 25% of all cervical cancer cases, surgical intervention remains the preferred approach, with 30%–50% of patients undergoing primary surgery in Japan [3].
In Japan, surgical intervention for cervical cancer prioritizes the preservation of postoperative function while ensuring radical cure [4,5,6], particularly for type III radical hysterectomy [7]. Recent advancements have focused on preserving both motor and sensory functions, rather than solely addressing urinary function [4,5,6]. Surgery offers several advantages, such as the ability to assess recurrence risk based on histopathological findings and provide tailored treatment based on factors such as lymphovascular invasion, pathological lymph node status, and pathological cervical stromal invasion. Additionally, advanced surgical techniques, such as ovarian preservation through transposition, can be applied [8,9,10]. Studies from Western countries have suggested that surgery and radiotherapy yield similar prognoses for stage IB2–II cervical cancer [11,12]. Studies from Eastern countries have indicated that surgery followed by adjuvant chemotherapy yields similar outcomes [13,14,15]. Although chemoradiation is widely considered the standard adjuvant treatment, its long-term adverse effects are concerning [11]. At our institution, nerve-sparing radical hysterectomy followed by adjuvant chemotherapy has traditionally been performed for cervical cancer up to stages IIB and IIIC1–2. We hypothesized that if the oncologic survival outcomes (recurrence-free survival [RFS] and overall survival [OS]) of this treatment approach are comparable to those of chemoradiotherapy, it would be more advantageous.
Therefore, this study aimed to evaluate and compare RFS between radical hysterectomy followed by adjuvant chemotherapy and initial chemoradiotherapy for cervical cancer at our institution.
MATERIALS AND METHODS
This study adhered to the principles outlined in the Declaration of Helsinki and was approved by the appropriate Institutional Review Board (approval number S19-130). The requirement for informed consent was waived owing to the retrospective nature of the study. This study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines for reporting observational studies. Data were sourced from our institution’s cancer database and are available upon request for further analysis or comparison to ensure reproducibility of the study at other institutions.
The inclusion criteria were as follows: 1) individuals aged >20 years diagnosed with stage IB2–IIB cervical cancer according to the International Federation of Gynecology and Obstetrics 2018 staging system, and 2) patients who underwent either radical hysterectomy with pelvic lymphadenectomy followed by adjuvant chemotherapy or initial concurrent chemoradiation therapy (CCRT) between 2009 and 2022 at our institution. In Japan, surgical intervention or chemoradiation is the recommended treatment for patients with stage IIB cervical cancer [16]. All histological subtypes of cervical carcinoma were eligible for inclusion. The exclusion criteria included patients with a history of other malignancies or specific treatments. The patients were followed up for 60 months before being referred to their primary care provider.
This retrospective cohort study was conducted at a single institution. On average, 2 attending surgeons and one fellow performed 10 radical hysterectomies annually. All radical hysterectomies in this study were supervised by a board-certified gynecologic oncologist with extensive experience in Okabayashi radical hysterectomies and had performed over 50 such procedures.
Patient demographics and clinicopathological data, including age, lymph node status at initial treatment, pretreatment parametrial invasion, and final histological type, were extracted from medical records, anesthesia and surgical records, and pathology reports.
All the included patients underwent preoperative magnetic resonance imaging (MRI) and computed tomography (CT), and the primary outcome was RFS.
1. Follow-up protocol
A post-treatment follow-up protocol was established for patients with cervical cancer to monitor for potential recurrence and complications. The protocol included the following components: 1) vaginal vault cytology and ultrasonographic evaluations performed every 3 months during the first 2 years postoperatively and every 6 months for the subsequent 3 years, and 2) CT performed every 6 months to detect signs of recurrence or complications [16].
This protocol ensures comprehensive postoperative monitoring while minimizing the risk of overlooking potential issues, such as local recurrence at the vaginal vault, distant metastases to organs (e.g., liver or lungs), lymph node enlargement indicative of disease spread, or complications related to the surgical/radiation site (e.g., fistula formation or infection).
2. Surgical procedure and adjuvant chemotherapy
The surgical procedures included the classic Okabayashi nerve-sparing radical hysterectomy, which involves complete resection of the dorsal leaf of the vesicouterine ligament following Fujii’s technique [4,17]. This approach differs fundamentally from Piver Type III radical hysterectomy, as it specifically involves resection of the dorsal leaf of the vesicouterine ligament while employing nerve-sparing techniques [4,7,17]. In Japan, Okabayashi radical hysterectomy is traditionally regarded as effective in achieving favorable local cancer control rates, largely due to extensive resection of the parametrium [16,18]. While specific numerical data are not available in the literature or Japanese guidelines [16,18], evidence from laparoscopic radical hysterectomy (LRH) studies suggests that incomplete parametrial resection increases the risk of recurrence. In addition, precise handling of the cardinal ligament during surgery has been associated with a lower recurrence risk [19]. Although these findings are specific to LRH, the emphasis on extensive parametrial resection in Okabayashi radical hysterectomy may contribute to favorable oncological outcomes.
Alternatively, a simplified nerve-sparing radical hysterectomy, which involves preserving part of the dorsal leaf of the vesicouterine ligament and resecting the deep uterine vein, was performed as described by Yabuki et al. [6,20,21]. Additionally, vesical veins draining into the deep uterine vein were meticulously resected, and fatty tissues within the dorsal layer of the vesicouterine ligament and bladder nerves were preserved [5]. Notably, the connective tissue in the dorsal layer of the vesicouterine ligament remained intact. The paravaginal tissue was sectioned at the vaginal cutting line, effectively separating the surrounding connective tissue and dorsal layer of the vesicouterine ligament from the paravaginal tissue. This approach allowed for reduced resection of the dorsal layer of the vesicouterine ligament while providing adequate resection of the paravaginal tissue. Comprehensive details of these surgical techniques have been previously described [22].
Adjuvant therapy was administered according to the guidelines of the Japan Society of Gynecologic Oncology guidelines [16]. Patients categorized as intermediate-risk (i.e., with lymphovascular involvement status, large tumor size, such as tumors >4 cm in diameter, and/or deep cervical stromal invasion) received chemotherapy. In addition, those classified as high-risk (i.e., with positive surgical margins, metastatic lymph nodes, and/or parametrial invasion) received adjuvant chemotherapy [23,24].
3. Chemoradiotherapy
All patients received concurrent weekly cisplatin or paclitaxel/carboplatin with radiotherapy as the primary treatment modality. External beam radiotherapy (total dose, 45–50 Gy) was administered to the pelvis, followed by brachytherapy. A minimal total dose of 75 Gy equivalent dose Gy 2 to point A (or 80 Gy to the high-risk planning target volume) was mandatory. A central split was performed at 20–30 Gy. For patients receiving high-dose-rate brachytherapy, 2–4 fractions of intracavitary high-dose-rate brachytherapy were administered weekly, with each fraction delivering 5–6 Gy to point A based on the external os of the uterus, overlapping with the external beam, and considering the tumor volume. The total brachytherapy dose ranged from 12 to 24 Gy. Cisplatin was administered weekly at a dose of 40 mg/m2, whereas 60–70 mg/m2 paclitaxel was administered weekly. Carboplatin dosing was determined based on the area under the curve 2 [25]. We offer cisplatin as the standard treatment to our patients; however, hydration cannot be administered on an outpatient basis at our hospital, thus necessitating inpatient admission for each treatment cycle. If outpatient treatment is strongly preferred by the patient, we alternatively offer paclitaxel/carboplatin as a feasible option. This approach allows for flexibility while maintaining efficacy in disease management.
4. Statistical analysis
All statistical analyses were performed using IBM SPSS for Windows, version 26 (IBM Corp., Armonk, NY, USA). Continuous variables with normal distribution were compared using Student’s t test, whereas non-normally distributed variables were assessed using Wilcoxon’s signed-rank test. Fisher’s exact test was used to examine associations among demographic parameters. RFS was evaluated using the Kaplan–Meier method and log-rank tests because of the limited study duration. Additionally, a Cox proportional hazards model was employed to adjust for prognostic factors, including lymph node swelling on CT/MRI, parametrial invasion on CT/MRI, and initial treatment. As this study compared the outcomes of radical hysterectomy and CCRT, we deemed it appropriate to compare these treatment approaches based on clinical status, which is known prior to surgery and radiation therapy. Odds ratio and hazard ratio (HR) were calculated with 95% confidence intervals. Statistical significance was determined using a 2-sided p-value <0.05.
RESULTS
In this study, we identified 206 patients diagnosed with cervical cancer who had undergone surgery. After applying the exclusion criteria, 11 patients who did not undergo radical hysterectomy, 7 who had been pretreated with neoadjuvant chemotherapy followed by radical hysterectomy, and 4 who had a history of other malignancies were excluded. Finally, 184 patients underwent curative-intent radical hysterectomy followed by adjuvant chemotherapy or chemoradiotherapy were included. The median follow-up period was 60 months. Among the included patients, 74 and 110 underwent radical hysterectomy and chemoradiation, respectively. Significant differences were observed in patient demographics between the 2 groups, particularly regarding age, disease stage, and pathology (Table 1). In the radical hysterectomy group, 11 of 74 (14.9%) patients underwent ovarian preservation, with the oldest patient aged 46 years. In the same group, of the 58 patients without swelling lymph nodes on CT/MRI, 9 had positive lymph nodes on excisional pathology specimens.
Table 1. Patients’ characteristics.
| Characteristics | RH group (n=74) | CCRT group (n=110) | p-value | |
|---|---|---|---|---|
| Age (yr) | 49.0±12.6 | 55.7±12.4 | 0.001 | |
| Stage | <0.001 | |||
| IB2 | 32 (43.2) | 3 (2.7) | ||
| IB3 | 9 (12.2) | 19 (17.3) | ||
| IIA1 | 5 (6.8) | 3 (2.7) | ||
| IIA2 | 1 (1.4) | 8 (7.3) | ||
| IIB | 11 (14.9) | 35 (31.8) | ||
| IIIC1 | 15 (20.3) | 38 (34.5) | ||
| IIIC2 | 1 (1.4) | 4 (3.6) | ||
| Pathology | <0.001 | |||
| Squamous cell carcinoma | 39 (52.7) | 94 (85.5) | ||
| Adenocarcinoma | 20 (27.0) | 12 (10.9) | ||
| Gastric carcinoma | 2 (2.7) | 0 | ||
| Adenosquamous carcinoma | 3 (4.1) | 2 (1.8) | ||
| Others | 7 (9.5) | 2 (1.8) | ||
| Neuroendocrine tumor | 3 (4.1) | 0 | ||
Values are presented as mean ± standard deviation or number (%).
CCRT, cervical chemoradiation therapy; RH, radical hysterectomy.
Pathological findings were presented in Table S1. Three patients in the radical hysterectomy group had positive surgical margins, and all had a negative vaginal margin and a positive parametrial margin. The radical hysterectomy group exhibited significantly improved RFS compared to the chemoradiation group; however, the OS did not differ significantly between these groups (Fig. 1 and Fig. S1).
Fig. 1. Kaplan–Meier analysis of RFS in patients undergoing radical hysterectomy followed by chemotherapy or chemoradiation. Radical hysterectomy followed by chemotherapy resulted in significantly better RFS than chemoradiation (p=0.044).
CCRT, cervical chemoradiation therapy; RFS, recurrence-free survival; RH, radical hysterectomy.
Table 2 presents Cox HRs for RFS. Among the clinical risk factors identified before the initial treatment, only parametrial invasion was statistically significant. Table 3 lists the recurrence sites. Notably, para-aortic lymph node recurrence was significantly higher in the chemoradiation group than in the radical hysterectomy group. Four of the 19 patients in the chemoradiation group with para-aortic lymph node recurrence survived. Three of the four surviving patients were treated with radiation to the para-aortic lymph node, and one patient was treated with chemotherapy only. Of the 15 patients who died, 14 were treated for recurrence with chemotherapy alone, and one received radiation therapy and chemotherapy.
Table 2. Cox HRs for recurrence-free survival.
| Variables | Cox HR (95% CI) | p-value |
|---|---|---|
| CCRT ref RH | 1.81 (0.90–3.65) | 0.95 |
| Non-SCC ref SCC | 1.79 (0.91–3.52) | 0.9 |
| LN swelling in CT/MRI | 1.68 (0.94–3.00) | 0.081 |
| Parametrial invasion in CT/MRI | 1.83 (1.01–3.33) | 0.046* |
CCRT, cervical chemoradiation therapy; CI, confidence interval; CT, computed tomography; HR, hazard ratio; MRI, magnetic resonance imaging; RH, radical hysterectomy; SCC, squamous cell carcinomas.
*p<0.05.
Table 3. Recurrent sites.
| Recurrent sites | RH group (n=74) | CCRT group (n=110) | p-value |
|---|---|---|---|
| Apex | 2 (2.7) | 8 (7.3) | 0.32 |
| Pelvic | 5 (6.8) | 12 (10.9) | 0.44 |
| Para-aortic lymph node | 1 (1.4) | 19 (17.3) | <0.001* |
| Supraclavicular lymph nodes | 0 | 3 (2.7) | 0.28 |
| Distant metastasis | 6 (8.1) | 14 (12.7) | 0.47 |
Values are presented as number (%).
CCRT, cervical chemoradiation therapy; RH, radical hysterectomy.
*p<0.001.
Adverse events are presented in Table S2. The incidence of genitourinary adverse events and lymphedema was significantly higher in the radical hysterectomy group than in the chemoradiation group. The incidence of neutropenia and gastrointestinal adverse events was significantly higher in the chemoradiation group. In the radical hysterectomy group, 29/45 (64.4%) received pegfilgrastim from the first chemotherapy regimen at the patient's request. Postoperative ureteral injury was reported in one case and postoperative ureteral stenosis was reported in 2 cases in the radical hysterectomy group. In contrast, vesicovaginal fistula and rectovaginal fistula were reported in one case each in the chemoradiation group. Patients with grade 3 or higher adverse events had a significantly worse RFS (Fig. S2).
DISCUSSION
In this study, we compared outcomes (such as RFS) between radical hysterectomy followed by adjuvant chemotherapy and initial chemoradiotherapy for cervical cancer. Our study findings demonstrated that radical hysterectomy followed by adjuvant chemotherapy yields RFS and OS rates comparable to those of chemoradiation for stage IB2–IIB and IIIC1–2 cervical cancer. Furthermore, radical hysterectomy and chemoradiation were comparable in the multivariate analysis of risk factors that could be assessed preoperatively.
Several prospective studies conducted in Japan have suggested that surgical treatment with adjuvant chemotherapy produces outcomes similar to those achieved with chemoradiotherapy [14,15]. In Japan, radical hysterectomy for cervical cancer is commonly performed using Okabayashi’s method [16], which is believed to reduce the risk of vaginal apex recurrence owing to its more extensive parametrium resection than that with the usual type III technique [26]. Additionally, lymph nodes are resected using the en bloc technique at our institution [27]. Research has indicated that the quality of surgery is associated with pelvic recurrence of cervical cancer [28]. These studies demonstrated that if local tumor control is achieved through lymph node dissection and adequate parametrial resection, additional treatment with chemotherapy targeting distant metastases may be sufficient, eliminating the need for further ‘local dual therapy’ with radiation.
The strength of our study lies in the finding that, even after multivariate analyses based on preoperative measurable risk factors, the treatment effects of radical hysterectomy followed by chemotherapy and chemoradiation were comparable. While several retrospective studies have investigated adjuvant chemotherapy after radical hysterectomy, most of these studies focused on multivariate analyses using prognostic factors, such as the number of lymph nodes removed, lymphovascular invasion, pathological tumor size, and parametrial involvement identified postoperatively [13,29,30,31]. Although prospective studies have been performed [14,15], they are non-comparative and involve small cohorts. Furthermore, these studies primarily compared adjuvant chemotherapy with adjuvant radiation or chemoradiation, rather than comparing radical hysterectomy with definitive chemoradiation as an initial treatment. Thus, the significance of our study lies in the direct comparison of definitive surgical treatment with definitive chemoradiation, highlighting the possibility of avoiding “local dual therapy.” This unique perspective adds considerable insights to the existing literature and underscores the clinical relevance of our findings.
Radical hysterectomy followed by adjuvant chemotherapy offers advantages for the treatment of cervical cancer, including the potential for ovarian preservation through fertility-sparing surgery [8,9,10]. Furthermore, it helps mitigate the risk of late toxicities associated with radiotherapy [11,12]. This approach is particularly beneficial in young individuals diagnosed with cervical cancer [1]. Moreover, surgery is considered more cost-effective than radiotherapy, making it a valuable option in developing countries [32].
Regarding adverse events, patients who experienced grade 3 or higher adverse events had a significantly worse RFS. Serious complications during primary cancer treatment, such as gastrointestinal anastomotic leakage, bowel obstruction, massive hemorrhage, respiratory or cardiovascular-related events, and intra-abdominal abscesses associated with inflammation, have been widely reported to negatively impact disease-free survival and OS across various carcinomas. These complications may delay or interrupt the timely administration of adjuvant therapy, reduce treatment intensity, and exacerbate systemic inflammation, ultimately contributing to poorer outcomes [33,34,35,36]. In cases of advanced-stage malignancies, prompt and effective management of such complications is imperative to optimize survival outcomes. Although pegfilgrastim is not routinely recommended for the primary prevention of febrile neutropenia, our institution, as a regional core hospital, has administered pegfilgrastim from the first cycle of chemotherapy to patients who request it, particularly to those who must travel long distances for treatment. This practice aims to significantly reduce both the total number of hospital visits during chemotherapy and of unscheduled hospital visits [37]. This approach may have influenced the difference in the incidence of neutropenia during concurrent chemoradiation, where chemotherapy is administered on a weekly basis.
Despite its strengths, this study has some limitations. As this was a single-center retrospective study, it may have been prone to bias. Additionally, differences were observed in patient backgrounds, with advanced cancer occurring more commonly in the chemoradiation group. This group also had more cases of squamous cell carcinomas, which are more responsive to radiation, whereas the surgery group had more cases of non-squamous cell carcinomas, which tend to have poorer prognosis. This discrepancy may have introduced bias. In the radical hysterectomy group, 15.5% of patients were unexpectedly diagnosed with stage IIIC due to the absence of lymph node swelling on preoperative CT or MRI. These patients would belong to a high-risk group; however, the chemoradiotherapy group in this study included a higher proportion of stage IIIC1 and IIIC2 cases, suggesting a potentially high-risk population in that group. To address this potential imbalance, we conducted multivariate analyses to minimize biases and provide a more accurate evaluation of outcomes. While radical hysterectomy followed by adjuvant chemotherapy showed oncological outcomes similar to those of chemoradiotherapy, this study does not provide a definitive conclusion regarding whether chemotherapy or radiation/chemoradiotherapy is the preferred adjuvant therapy for radical hysterectomy.
Nonetheless, it is noteworthy that RFS did not differ significantly between the surgery and chemoradiation groups in multivariate analysis, with variables reflecting these results. Furthermore, this study included a substantial number of cases despite the declining prevalence of cervical cancer [38,39]. Another strength of this study is that a board-certified gynecologic oncologist with extensive experience in Okabayashi radical hysterectomy (>50 cases) supervised the standardized surgical procedures.
In conclusion, radical hysterectomy followed by adjuvant chemotherapy for cervical cancer stages IB2–IIB and IIIC1–2 yielded oncological outcomes comparable to those of chemoradiation. Currently, a randomized controlled phase III trial investigating concurrent chemotherapy and radiotherapy in high-risk relapse patients is ongoing in Japan, and its findings are anticipated [40].
Footnotes
Funding: K. Chikazawa received lecture honoraria from Ethicon (Tokyo, Japan), Terumo (Tokyo, Japan), and Chugai Pharmaceutical Co. (Tokyo, Japan). K. Imai received lecture honoraria from AstraZeneca (Tokyo, Japan). R. Konno received research funds from Yakult Pharmaceutical Industry Co., Ltd. (Tokyo, Japan) and Chugai Pharmaceutical Co. (Tokyo, Japan), and lecture honoraria from Japan Vaccine Co. (Tokyo, Japan), MSD Japan (Tokyo, Japan), and Chugai Pharmaceutical Co. (Tokyo, Japan). The fourth author declares no conflicts of interest. The funding organizations did not contribute to any aspect of conducting or reporting this study.
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
- Conceptualization: C.K.
- Data curation: K.H.
- Investigation: K.T.
- Methodology: C.K.
- Supervision: K.R.
- Visualization: I.K.
- Writing - original draft: K.H.
- Writing - review & editing: K.R.
SUPPLEMENTARY MATERIALS
Pathological findings in the radical hysterectomy group
Adverse events of treatments
Kaplan–Meier analysis of OS in patients undergoing radical hysterectomy followed by adjuvant chemotherapy or chemoradiation. No significant difference was observed in the OS between the groups (p=0.12).
Kaplan–Meier analysis of overall survival for patients with grade 3 and 4 adverse events and grade 1 and 2 adverse events. Patients with grade 3 or higher adverse events had a significantly worse RFS (p=0.02).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Pathological findings in the radical hysterectomy group
Adverse events of treatments
Kaplan–Meier analysis of OS in patients undergoing radical hysterectomy followed by adjuvant chemotherapy or chemoradiation. No significant difference was observed in the OS between the groups (p=0.12).
Kaplan–Meier analysis of overall survival for patients with grade 3 and 4 adverse events and grade 1 and 2 adverse events. Patients with grade 3 or higher adverse events had a significantly worse RFS (p=0.02).