Open Access, Peer-reviewed
pISSN 2005-0380   eISSN 2005-0399
    J Gynecol Oncol. 2025;36:e2. Forthcoming. English.
    Published online May 01, 2024.
    https://doi.org/10.3802/jgo.2025.36.e2
    © 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
    Original Article

    Comparison of postoperative adjuvant platinum-based chemotherapy and no further therapy after radical surgery in intermediate-risk early-stage cervical cancer

    Hiroki Nishimura,1 Tsukuru Amano,1 Yutaka Yoneoka,1 Shunichiro Tsuji,1 Yukiko Taga,2 Megumi Aki,2 Masaya Uno,3 Suzuko Moritani,4 Ryusuke Murakami,2 Tomoyasu Kato,3 and Takashi Murakami1
      • 1Department of Obstetrics and Gynecology, Shiga University of Medical Science, Otsu, Japan.
      • 2Department of Obstetrics and Gynecology, Shiga General Hospital, Moriyama, Japan.
      • 3Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
      • 4Department of Pathological Diagnosis, Shiga University of Medical Science, Otsu, Japan.
    • Correspondence to Tsukuru Amano. Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta-Tsukinowa cho, Ootsu, Shiga 520-2192, Japan. Email: tsukuru@belle.shiga-med.ac.jp
    Received January 16, 2024; Revised February 22, 2024; Accepted April 15, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Objective

    To identify a relatively high-risk population in postoperative intermediate-risk cervical cancer and evaluate the effect of platinum-based adjuvant chemotherapy (CT).

    Methods

    We retrospectively reviewed the medical records of patients with stage IA2-IIA cervical cancer who had been treated with radical hysterectomy and pelvic lymphadenectomy and classified as the intermediate-risk group for recurrence by postoperative pathological examination from January 2007 to December 2018 at 3 medical centers in Japan. First, patients with intermediate-risk were stratified by histological type and the number of intermediate-risk factors (IRF; large tumor diameter, lymph vascular space invasion, and deep cervical stromal invasion) and then divided into 2 groups: high and low-risk population (estimated 5-year recurrence-free survival [RFS] rate with no further therapy [NFT] <90% and ≥90%, respectively). Second, the efficacy of CT for the high-risk population was evaluated by comparing RFS and overall survival (OS) between the patients receiving CT and those with NFT.

    Results

    In total, 133 patients were included in the analysis. Among patients with squamous cell carcinoma (SCC) with all IRF or those with non-SCC with 2 to 3 IRF, the 5-year estimated RFS was <90% when treated with NFT. In this population, adjuvant CT was significantly superior to NFT regarding RFS (log-rank, p=0.014), although there was no statistical difference in OS.

    Conclusion

    Patients with SCC with all 3 IRFs and those with non-SCC with 2 to 3 IRFs were at high risk for recurrence. Adjuvant CT is a valid treatment option for these populations.

    Synopsis

    Within the intermediate-risk group of cervical cancer, there are relatively high- and low-risk groups. Patients with squamous cell carcinoma (SCC) with 3 intermediate-risk factors (IRFs) and patients with non-SCC with 2 to 3 IRFs are high-risk within intermediate-risk (HRWI) group. Adjuvant chemotherapy benefits HRWI group.

    Graphical Abstract

    Keywords
    Cervical Cancer; Intermediate-Risk; Platinum-Based Chemotherapy; Radical Hysterectomy

    INTRODUCTION

    In Japan, radical hysterectomy (RH) and simultaneous pelvic lymphadenectomy are most frequently used for the treatment of early-stage (IA2-IIA in the revised International Federation of Gynecology and Obstetrics [FIGO] staging system for cervical cancer in 2018) cervical cancer, which accounts for more than half of all patients with cervical cancer [1, 2]. Histological parameters, most importantly lymph node metastasis and parametrial invasion, followed by large tumor diameter (LTD), lymph vascular space invasion (LVSI), and deep cervical stromal invasion (DSI), are risk factors for postoperative recurrence in early-stage cervical cancer [3, 4]. Patients positive for lymph node metastasis and/or parametrial invasion are classified as the high-risk group, and those without any of these parameters are classified as the low-risk group for recurrence. The intermediate-risk group for postoperative recurrence is defined as cases with no lymph node metastasis, invasion of the parametrium, and at least one of the following intermediate-risk factors (IRF): LTD, LVSI, or DSI [5].

    Concurrent chemoradiation therapy (CCRT) is suitable as adjuvant therapy for high-risk patients, and no further therapy (NFT) is recommended for patients at low risk of postoperative recurrence [6, 7]. Moreover, previous studies have reported that radiation therapy (RT) or CCRT reduces the risk of recurrence in patients with intermediate risk for recurrence [8, 9]. However, adjuvant RT and CCRT are associated with a risk of severe toxicity, such as lymphedema and intestinal obstruction. Therefore, adjuvant systemic chemotherapy (CT) is frequently used in Japan. Several studies have reported that postoperative CT may be effective for the treatment of early-stage cervical cancer [10, 11, 12, 13]. In a retrospective cohort study, there was no difference in recurrence rates among patients who received RT, CCRT, or systemic CT as adjuvant therapy for intermediate-risk stage IB cervical cancer [10]. However, no trials have compared adjuvant platinum-based CT with NFT after radical surgery for early-stage cervical cancer in the postoperative intermediate-risk group [9]. Moreover, despite the wide range of intermediate-risk groups, it is not known which populations within the intermediate-risk group would benefit more from adjuvant CT. Adenocarcinoma (AC) and adenosquamous carcinoma (ASC) histological types of cervical cancer are reported to be associated with a worse prognosis than squamous cell carcinoma (SCC) [14, 15, 16, 17, 18]; nevertheless, the choice of adjuvant therapy that considers the histological type has not been established. In this study, we first identified the high-risk population for recurrence within the postoperative intermediate-risk group when no adjuvant therapy had been done, considering the histologic type and the number of risk factors. Next, we investigated whether CT contributes to an improved prognosis in the high-risk population for recurrence within the postoperative intermediate-risk group.

    MATERIALS AND METHODS

    1. Patient characteristics

    We retrospectively reviewed the records of patients who underwent abdominal RH for stage IA2 to IIA2 cervical cancer and were diagnosed as the intermediate-risk group for postoperative recurrence with at least one of the IRF (LTD, LVSI, or DSI) by postoperative pathological examination between January 2007 and December 2018.

    The inclusion criteria were as follows: 1) age 20–75 years at the time of initial treatment; 2) follow-up period of more than 12 months; 3) SCC, endocervical AC usual type, or ASC histology; and 4) platinum-based CT or NFT after surgery. In this study, LTD positivity was defined as tumor size ≥4 cm as measured by resection specimen, and DSI positivity was defined as invasion of more than half of the cervical stroma observed in accordance with the report of Song et al. [8]. Patients were excluded if they had received an insufficient number of chemo cycles (<3) or received RT, CCRT, or any neoadjuvant therapy.

    RH consisted of the European Organisation for Research and Treatment of Cancer Gynecological Cancer Group (EORTC-GCG) class III hysterectomy and bilateral pelvic lymphadenectomy with or without paraaortic lymphadenectomy (PALN). For pelvic lymphadenectomy, the external iliac, internal iliac, common iliac, femoral, suprainguinal, and sacral lymph nodes were resected. At least one gynecologic oncologist participated in all surgeries as the primary surgeon or the supervisor.

    Based on each institution’s policy, NFT was conducted in the National Cancer Center Hospital, and adjuvant CT was given at Shiga General Hospital and Shiga University of Medical Science Hospital. The adjuvant CT consisted of 3 or more cycles of the platinum-based combination. A combination regimen was one of the following regimens: paclitaxel combined with cisplatin or carboplatin (area under the curve 5), irinotecan with nedaplatin, docetaxel with carboplatin, or ifosfamide and epirubicin with cisplatin. SCC was defined as the SCC group, whereas endocervical AC, usual type, and ASC were defined as the non-SCC group.

    2. Study design and setting

    First, patients subjected to NFT within the intermediate-risk group were categorized into the following six groups according to histological type (SCC or non-SCC) and number of IRFs (LTD, LVSI, or DSI), i.e., SCC with 1, 2, or 3 IRF (named categories 1, 2, and 3, respectively), and non-SCC with 1, 2, or 3 IRF (named categories 4, 5, and 6, respectively). Second, each category was divided into a high-risk group (population with a 5-year recurrence-free survival [RFS] rate of less than 90% when NFT was conducted) and a low-risk group (population with a 5-year RFS rate of 90% or better when NFT was conducted). In this study, a population that met the criteria of the high-risk group by histological type and risk factors was defined as the high-risk population for recurrence within the postoperative intermediate-risk group (HRWI). Similarly, the population meeting the low-risk group criteria was defined as the low-risk population for recurrence within the postoperative intermediate-risk group (LRWI). We investigated the impact of CT on RFS and overall survival (OS) for the HRWI. RFS was defined as the period from the date of surgery to the date of physical or radiological evidence of disease recurrence or the date of the patient’s last visit. OS was defined as the period from the date of surgery to death or the date of the patient’s last visit.

    3. Statistical analysis

    The χ2 test or Fisher’s exact test was used to compare discrete variables among groups. Survival curves were generated using the Kaplan–Meier method, and the comparisons between curves were performed using a log-rank test. In terms of the multivariate survival analysis conducted to identify independent predictors of OS and RFS, a Cox proportional hazards model was developed by backward, stepwise regression. All statistical analyses were performed using JMP 15 (SAS Institute Inc., Cary, NC, USA). All p-values in this study were obtained using 2-tailed tests, with values <0.05 considered significant. All termination points were updated in December 2021.

    4. Ethical approval and informed consent

    This study was approved by the ethics committee of each institution before the start of the study (approval number R2020-160). We replaced the acquisition of written informed consent by providing an opt-out form. Authors had access to information that could identify individual participants during and after data collection.

    RESULTS

    During the study period, 141 patients were diagnosed as intermediate-risk group cervical cancer through pathological examination after radical hysterectomy. Eight patients were excluded from the study: 5 because of a follow-up period of less than 12 months, 2 for insufficient courses of CT, and 1 for receiving adjuvant RT therapy. The remaining 133 eligible patients were included in the study. Of these, 90 patients were on the NFT regimen, and 43 patients were on the CT regimen. The median observation period was 60.5 (range, 12–157) months. Six patients underwent a PALN biopsy. As adjuvant CT, 19 patients were administered irinotecan and nedaplatin, 19 were administered paclitaxel and carboplatin, 2 were administered paclitaxel and cisplatin, 1 was administered docetaxel and carboplatin, 1 was administered ifosfamide, epirubicin, and cisplatin, and 2 were administered a combination of the above regimens.

    The characteristics of the patients of the six categories in the NFT group, described in the material and methods section, are shown in Table 1. The number of patients in categories 1 to 6 was 23, 25, 8, 17, 14, and 3, respectively. The mean follow-up period of categories 1 to 6 was 67 months (range: 25–157 months), 62 months (range: 12–143 months), 47 months (range: 15–116 months), 64 months (range: 34–125 months), 62 months (range: 20–95 months), and 72 months (range: 34–96 months), respectively.

    Table 1
    Patient characteristics in the NFT group according to pathological type and the number of risk factors

    In the NFT group, the estimated 5-year RFS rate was 90.3%, 100%, 58.3%, 94.1%, 79.6%, and 33.3% for categories 1, 2, 3, 4, 5, and 6, respectively (Fig. 1). Based on these results, patients matching the conditions of categories 3, 5, and 6 in both the NFT group and the CT group were HRWI. Conversely, patients who met the conditions of categories 1, 2, and 4 in the NFT and CT groups were LRWI. The characteristics of the patients in HRWI and LRWI are shown in Table 2. Of the 133 patients, 37 patients displayed HRWI, and 96 patients displayed LRWI. In the HRWI, 14 patients received CT, and the remaining 23 patients were treated with NFT. In the LRWI, 29 patients received CT, and the remaining 67 patients were subjected to NFT.

    Fig. 1
    RFS based on histological type and number of IRF. (A) RFS in patients with SCC histology with 1, 2, or 3 IRF (categories 1, 2, and 3, respectively). (B) RFS in patients with non-SCC histology with 1, 2, or 3 IRF (categories 4, 5, and 6, respectively).
    IRF, intermediate-risk factors; RFS, recurrence-free survival; SCC, squamous cell carcinoma.

    Table 2
    Patient characteristics in the HRWI and the LRWI

    In the HRWI, the estimated 5-year RFS of the CT and NFT groups were 92.3% and 56.1% (p=0.014) respectively. When the CT group was compared with the NFT group in the HRWI, CT was significantly superior in terms of RFS (Fig. 2A). Although the CT group displayed slightly longer OS than the NFT group, the difference was not significant (log-rank, p=0.241; Fig. 2B). By multivariate analysis, NFT was the only significant risk factor for RFS in the HRWI (hazard ratio=15.56; 95% confidence interval=1.68–144.01; p=0.016; Table 3).

    Fig. 2
    Survival curves based on presence or absence of adjuvant CT in patients with HRWI. (A) RFS in patients with HRWI. (B) OS in patients with HRWI.
    CT, chemotherapy; HRWI, high-risk group within the intermediate-risk group; NFT, no further therapy; OS, overall survival; RFS, recurrence-free survival.

    Table 3
    Multivariate analysis of RFS in the HRWI

    We also examined CT-related complications in the HRWI. The details are presented in Table 4. There were no treatment-related deaths in the 14 patients. Acute grades 3 and 4 hematologic toxicity was observed in 5 (35.7%), and all of them experienced neutropenia. No anemia or thrombocytopenia was observed. The rate of acute grade 3 or 4 hepatobiliary complications and allergic reactions was 14.2% and 7.1%, respectively. Grade 1 or 2 neutropenia, anemia, thrombocytopenia, hepatobiliary complications, allergic reactions, peripheral sensory neuropathy, and gastrointestinal complications was observed in 1 (7.1%), 6 (42.9%), 2 (14.2%), 3 (21.3%), 1 (7.1%), 3 (21.3%), and 2 (14.2%) patients, respectively.

    Table 4
    CT-related complications in the HRWI

    DISCUSSION

    This study revealed 2 important clinical issues. First, patients with SCC with all 3 IRFs and non-SCC exhibiting 2 to 3 IRFs were at high risk of recurrence when subjected to NFT. Second, platinum-based CT improved RFS in this group.

    When no adjuvant therapy was administered postoperatively, patients with SCC exhibiting all 3 IRFs and patients who were non-SCC exhibiting 2 to 3 IRFs were at high risk of recurrence. The estimated 5-year RFS of this population was poor at 56.2% when subjected to NFT. Therefore, these populations were defined as HRWI. In contrast, patients with SCC with one to 2 IRFs, as well as patients who were non-SCC with 1 IRF, had a better prognosis without adjuvant therapy. The estimated 5-year RFS of this population was elevated at 94.8% when NFT was conducted. Hence, these populations were defined as LRWI. Thus, patients with early-stage cervical cancer with IRFs should be divided into 2 subgroups: HRWI and LRWI, according to 4 specific histopathological parameters. When subjected to NFT, patients in the HRWI had a high risk of recurrence. Therefore, adjuvant therapy should be given for HRWI to prevent recurrence. Conversely, for LRWI, NFT is preferable to avoid unnecessary treatment. We believe that such a classification is necessary to provide more appropriate medical care due to the wide range of recurrence rates in early-stage cervical cancer with IRFs. Ryu et al. [19] advocated a “4-factor model” that defines the intermediate-risk group as including patients with at least 2 of the following risk factors: 1) AC or ASC, 2) tumor size ≥3 cm, 3) stromal invasion ≥ outer 1/3, and 4) LVSI. Furthermore, Zhang et al. [20] reported that the number of risk factors in the intermediate-risk group, histological type, differentiation grade, and adjuvant therapy were independent prognostic factors. These reports are consistent with the findings of the present study.

    Compared with NFT, platinum-based adjuvant CT significantly prolonged RFS in the HRWI. The 5-year RFS rates for CT and NFT were 92.3% and 56.1%, respectively. The 5-year RFS rate of 92.9% of CT for HRWI is comparable to previously reported results of RT or CCRT and is, therefore, an acceptable treatment method [3, 4, 21]. Our study suggests that postoperative adjuvant therapy is necessary for HRWI, and platinum-based CT is preferable because of its relapse prevention effect and minimal adverse events. In contrast, patients in the LRWI had a good prognosis with NFT; thus, postoperative adjuvant therapy may be unnecessary in this population.

    Recently, various pharmacological regimens or combinations, including CT, anti-angiogenic therapy, immune checkpoint inhibitors, DNA damage repair inhibitors, and antibody-drug conjugates have been investigated to improve the prognosis of advanced/recurrent cervical cancers, with some effects becoming apparent [22]. In the future, upon confirmation of these effects for advanced/recurrent cervical cancers, they may be introduced into adjuvant therapy for early-stage cervical cancers, further improving prognosis.

    The establishment of low-invasive and effective treatment for early-stage cervical cancer is eagerly desired. The Laparoscopic Approach to Cervical Cancer Trial suggested adverse effects associated with adopting minimally invasive surgery for the treatment of cervical cancer [23]. However, these detrimental effects of minimally invasive surgery were not observed in low-risk patients. Furthermore, a recent retrospective study showed that laparoscopic radical hysterectomy for low-risk patients yielded comparable 10-year outcomes to abdominal radical hysterectomy [24]. For the low-risk population, minimally invasive treatments such as NFT/adjuvant CT following laparoscopic surgery may be considered an option.

    The limitations of our study include the small sample size and the CT regimen not being uniform. However, as there have been no studies comparing NFT with CT for early-stage cervical cancer with IRFs on this scale, we believe that our results are valuable. Furthermore, since the regimen always included platinum, the key drug for cervical cancer, we believe that a certain degree of homogeneity is maintained.

    In conclusion, patients with early-stage cervical cancer with IRFs can be divided into 2 subgroups: the HRWI and the LRWI, according to four histopathological parameters. Platinum-based CT is deemed acceptable as adjuvant therapy for the HRWI. Larger studies comparing the prognostic values of CT and NFT are desirable to establish an optimal adjuvant therapy approach.

    Notes
    Presentation

    PresentationI certify that a part of this paper was presented orally at the 64th Annual Meeting of the Japan Society of Gynecologic Oncology (Fukuoka, July 15, 2022), but the entire paper has not been previously published.

    Conflict of Interest:No potential conflict of interest relevant to this article was reported.

    Author Contributions:

    • Conceptualization: N.H., A.T., Y.Y., T.S., M.T.

    • Data curation: N.H., A.T., Y.Y., T.S., M.T.

    • Formal analysis: N.H., A.T., Y.Y., T.S., T.Y., A.M., U.M., M.R., K.T., M.T.

    • Investigation: N.H., A.T., Y.Y., T.S., T.Y., A.M., U.M., M.R., K.T., M.T.

    • Methodology: N.H., A.T., Y.Y., T.S., M.T.

    • Validation: M.S.

    • Writing - original draft: N.H., A.T., Y.Y., T.S., M.T.

    • Writing - review & editing: N.H., A.T., Y.Y., T.S., M.T.

    ACKNOWLEDGEMENTS

    We would like to thank Editage (www.editage.com) for English language editing.

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