Treatment for Locally Resectable Stage IIIC1 Cervical Cancer: A Retrospective, Single-Institution Study

According to the revision of the FIGO 2018 staging system, cervical cancer with pelvic lymph node metastases was changed to stage IIIC1. We retrospectively analyzed the prognosis and complications of locally resectable (classified as T1/T2 by TNM classification of the Union for International Cancer Control) stage IIIC1 cervical cancer. A total of 43 patients were divided into three groups: surgery with chemotherapy (CT) (ope+CT group) (T1; n = 7, T2; n = 16), surgery followed by concurrent chemoradiotherapy (CCRT), or radiotherapy (RT) (ope+RT group) (T1; n = 5, T2; n = 9), and CCRT or RT alone (RT group) (T1; n = 0, T2; n = 6). In T1 patients, recurrence was observed in three patients, but there was no difference among the treatment groups, and no patients died. In contrast, in T2 patients, recurrence and death were observed in nine patients (8 in ope+CT; 1 in ope+RT), and recurrence-free survival and overall survival were lower in the ope+CT group (p = 0.02 and 0.04, respectively). Lymphedema and dysuria were more common in the ope+RT group. A randomized controlled trial comparing CT and CCRT as an adjuvant therapy after surgery in T1/T2 patients, including those with pelvic lymph node metastases, is currently underway. However, our data suggest that performing CT alone after surgery in T2N1 patients is likely to worsen the prognosis.


Introduction
Cervical cancer is the fourth most common cancer among women, with 604,000 reported patients and 342,000 deaths worldwide in 2020 [1]. In Japan, the number of patients with cervical cancer is increasing among young women in their 50s or younger [2]. Although cervical cancer cases are expected to decrease worldwide with the increased human papillomavirus (HPV) vaccination [3,4], HPV vaccination rates are low in Japan [5].
In cervical cancer, lymph node (LN) metastasis is an important prognostic factor [6][7][8][9]. According to the latest International Federation of Gynecological Organizations classification (FIGO 2018), if the tumor reaches the lower third of the vagina, extends to the pelvic wall, or if there is lymph node metastasis and no distant metastasis, it is classified as stage III. In addition, if there is metastasis in the pelvic lymph nodes by imaging or pathology, it is subclassified as stage IIIC1. Patients with para-aortic LN metastasis (N2) are now classified as stage IIIC2 [10]. Concurrent chemoradiotherapy (CCRT) has substantially improved both the recurrence-free survival (RFS) and overall survival (OS) of locally advanced cervical cancer with LN metastases and has become the international standard of care. For example, the National Comprehensive Cancer Network 2022 guideline recommends external pelvic beam radiation therapy and brachytherapy with platinum regimens as CCRT for patients who are positive for pelvic LN metastases on a surgical biopsy [11]. Furthermore, if the results of imaging studies are positive for pelvic LN metastases and are negative for para-aortic LN metastases, a surgical biopsy of the para-aortic LN is recommended, Healthcare 2023, 11, 632 2 of 9 followed by an extended irradiation if para-aortic LN metastases are pathologically confirmed [11]. Radiotherapy (RT)-based treatment is less invasive than surgery and can be safely performed in elderly patients and those with multiple comorbidities. RT can avoid the urinary dysfunction that is associated with extensive surgical resection.
In the Japanese guidelines in 2011 and 2017, a radical hysterectomy was recommended for patients corresponding to stage IB-II of the FIGO 2008 classification (FIGO 2008), regardless of the presence or absence of LN metastases [12,13]. Additionally, neoadjuvant chemotherapy (NAC) was listed as an option [12,13]. Therefore, in Japan, surgery has been the main treatment for patients whose tumor is locally resectable (classified as T1/T2 by TNM classification of the Union for International Cancer Control), even for the FIGO 2018 stage IIIC. In addition, chemotherapy (pre-operative and post-operative), RT, or CCRT have been used as adjuvant therapies. In Japan, the staging was revised in 2020 following the FIGO 2018, and the new treatment guidelines were issued in 2022. However, no clear recommendation has been made as to whether surgery or CCRT should be selected as the main treatment for patients with stage IIIC [14]. Surgery has the following advantages: the accurate detection of disease extent based on pathological diagnosis, the treatment of tumors refractory to chemotherapy and radiotherapy, and the preservation of ovarian function in young patients.
Until early 2018, in our institution, an NAC plus radical hysterectomy was generally performed for patients with tumor diameters greater than 4 cm. However, there are reports that the NAC plus radical hysterectomy has a significantly lower disease-free survival rate than CCRT [15,16], and NAC has not been performed since then. As for adjuvant therapy, CCRT has generally been performed in patients who are at a very high risk of recurrence with chemotherapy alone, such as those with a positive or questionable surgical margin, while chemotherapy alone has been used in other cases. Although radical surgery is not recommended internationally for stage IIIC patients [11], there is currently no clear evidence for the treatment of patients with locally resectable T1/T2 tumors with pelvic LN metastases. In this study, we retrospectively examined the prognosis and complications of each treatment for stage IIIC1 cervical cancer, especially in patients with T1 or T2. To the best of our knowledge, this is the first report comparing surgery without RT and RT-based treatment for FIGO 2018 stage IIIC1 cervical cancer.

Materials and Methods
Among cervical cancers initially treated at Kindai University Hospital between January 2013 and March 2021, we included those with FIGO 2008 stage IA2 to stage IIB. Neuroendocrine carcinomas were excluded. Among eligible patients with FIGO 2018 stage IIIC1. Those with Union for International Cancer Control (UICC) T1/T2 were selected [17]. Age, histopathology, first-line treatment, RFS, OS, and treatment-related complications were retrospectively evaluated.
Patients were divided into three groups according to treatment: the ope+CT group (surgery and chemotherapy (neoadjuvant and/or adjuvant)), the ope+RT group (surgery followed by CCRT or RT), and the RT group (CCRT or RT without surgery). In addition, patients were divided into four groups according to whether they had squamous cell carcinoma (SCC) or non-squamous cell carcinoma (non-SCC) and treatment with or without RT (CCRT or RT). Complications caused by treatment, leg lymphedema, and dysuria at least one month after completion of the initial treatment were investigated. Leg lymphedema was defined based on their medical records. Dysuria was defined as the administration of medication or self-catheterization.
Statistical analyses were performed using GraphPad Prism version 9.4.1 (GraphPad Software, San Diego, CA, USA), the Kruskal-Wallis test for the age distribution. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. Fisher's exact test was performed using R version 4.2.2 for complication frequency. p values less than 0.05 were considered statistically significant. This study was approved by the Institutional Review Board of Kindai University Faculty of Medicine (R04-186). Patients in this study were allowed to refuse to participate in the survey by opting out on the website of the Kindai University Faculty of Medicine (https://www.kindai.ac.jp/medicine/ (accessed on 18 February 2023)).

19
47 SCC  ope+RT  -NED  20  52  SCC  ope+RT  -NED  21  48  Ad-G  ope+RT  -NED  22  47  Ad-E  ope+RT  -NED  +  23  52  SCC  ope+RT  -NED  24  35  SCC  ope+RT  -NED  +  +  25  48  SCC  ope+RT  -NED  +  26  62  SCC  ope+RT  -NED  27  37  SCC  ope+RT  +  12  BSC  DOD  28  65  SCC  ope+CT  -NED  29  37  SCC  ope+CT  +  28  ope  DOD  30  46  Ad  ope+CT  -NED  31 52   Among the stage IIIC1 patients, all those with T1N1 underwent surgery as the main treatment: five in the ope+RT group (surgery followed by CCRT in four patients and surgery followed by CCRT and systemic chemotherapy in one patient) and seven in the ope+CT group (surgery followed by adjuvant chemotherapy in six patients and NAC followed by surgery and adjuvant chemotherapy in one patient (case12)) ( Table 1). Recurrence occurred in three patients, with metastases to the vagina, lung, and mediastinal LN, all of which responded to treatment of the recurrent tumor. There was no significant difference in RFS and OS between the ope+CT group and the ope+RT group (Figure 2).
Healthcare 2023, 11, x FOR PEER REVIEW 5 of 9 Among the stage IIIC1 patients, all those with T1N1 underwent surgery as the main treatment: five in the ope+RT group (surgery followed by CCRT in four patients and surgery followed by CCRT and systemic chemotherapy in one patient) and seven in the ope+CT group (surgery followed by adjuvant chemotherapy in six patients and NAC followed by surgery and adjuvant chemotherapy in one patient (case12)) ( Table 1). Recurrence occurred in three patients, with metastases to the vagina, lung, and mediastinal LN, all of which responded to treatment of the recurrent tumor. There was no significant difference in RFS and OS between the ope+CT group and the ope+RT group (Figure 2).

Figure 2. Prognosis of patients with (tumor and node) T1N1. (A) Recurrence-free survival (RFS). (B)
Overall survival (OS). ope+CT, patients who underwent surgery and chemotherapy (neoadjuvant or adjuvant); ope+RT, patients who underwent surgery followed by radiotherapy (including concurrent chemoradiotherapy). N.S.: not significant. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test.
Among stage IIIC1 patients with T2N1, nine were in the ope+RT group (surgery followed by CCRT in three patients, surgery followed by RT alone in one patient, NAC followed by surgery and RT alone in one patient (case 23), and NAC followed by surgery and CCRT in four patients (case 24-27)) ( Table 2). A total of six patients were in the ope+CT group (surgery followed by adjuvant chemotherapy in five patients and NAC followed by surgery and adjuvant chemotherapy in eleven patients [case 33-43]), and six patients were in the RT group (all received CCRT) ( Table 2). Recurrence was observed in eight patients in the ope+CT group and one patient in the ope+RT group; all nine of these patients had a relapse site in the pelvis and died of the disease. There were significant differences in the RFS and OS among the three groups (p = 0.02; p = 0.04, respectively; Figure 3A,B). Similarly, patients who did not receive CCRT or RT alone had a worse prognosis in terms of both RFS and OS among SCC and non-SCC groups (p = 0.009, 0.02; Figure  3C,D). Among stage IIIC1 patients with T2N1, nine were in the ope+RT group (surgery followed by CCRT in three patients, surgery followed by RT alone in one patient, NAC followed by surgery and RT alone in one patient (case 23), and NAC followed by surgery and CCRT in four patients (case 24-27)) ( Table 2). A total of six patients were in the ope+CT group (surgery followed by adjuvant chemotherapy in five patients and NAC followed by surgery and adjuvant chemotherapy in eleven patients (case 33-43)), and six patients were in the RT group (all received CCRT) ( Table 2). Recurrence was observed in eight patients in the ope+CT group and one patient in the ope+RT group; all nine of these patients had a relapse site in the pelvis and died of the disease. There were significant differences in the RFS and OS among the three groups (p = 0.02; p = 0.04, respectively; Figure 3A,B). Similarly, patients who did not receive CCRT or RT alone had a worse prognosis in terms of both RFS and OS among SCC and non-SCC groups (p = 0.009, 0.02; Figure 3C,D).
Healthcare 2023, 11, x FOR PEER REVIEW 5 of 9 Among the stage IIIC1 patients, all those with T1N1 underwent surgery as the main treatment: five in the ope+RT group (surgery followed by CCRT in four patients and surgery followed by CCRT and systemic chemotherapy in one patient) and seven in the ope+CT group (surgery followed by adjuvant chemotherapy in six patients and NAC followed by surgery and adjuvant chemotherapy in one patient (case12)) ( Table 1). Recurrence occurred in three patients, with metastases to the vagina, lung, and mediastinal LN, all of which responded to treatment of the recurrent tumor. There was no significant difference in RFS and OS between the ope+CT group and the ope+RT group (Figure 2). Overall survival (OS). ope+CT, patients who underwent surgery and chemotherapy (neoadjuvant or adjuvant); ope+RT, patients who underwent surgery followed by radiotherapy (including concurrent chemoradiotherapy). N.S.: not significant. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test.
Among stage IIIC1 patients with T2N1, nine were in the ope+RT group (surgery followed by CCRT in three patients, surgery followed by RT alone in one patient, NAC followed by surgery and RT alone in one patient (case 23), and NAC followed by surgery and CCRT in four patients (case 24-27)) ( Table 2). A total of six patients were in the ope+CT group (surgery followed by adjuvant chemotherapy in five patients and NAC followed by surgery and adjuvant chemotherapy in eleven patients [case 33-43]), and six patients were in the RT group (all received CCRT) ( Table 2). Recurrence was observed in eight patients in the ope+CT group and one patient in the ope+RT group; all nine of these patients had a relapse site in the pelvis and died of the disease. There were significant differences in the RFS and OS among the three groups (p = 0.02; p = 0.04, respectively; Figure 3A,B). Similarly, patients who did not receive CCRT or RT alone had a worse prognosis in terms of both RFS and OS among SCC and non-SCC groups (p = 0.009, 0.02; Figure  3C,D). As for complications, in patients with stage IIIC1 T1/T2, lymphedema occurred in 17% (4/23) of the patients in the ope+CT group, 43% (6/14) in the ope+RT group, and 17% (1/6) in the RT group; dysuria occurred in 13% (3/23) of patients in the ope+CT group, 14% (2/14) in the ope+RT group, and 17% (1/6) in the RT group. Lymphedema was more common in the ope+RT group, although there were no significant differences between the groups for both lymphedema and dysuria ( Figure 4).  . ope+CT, patients who underwent surgery and chemotherapy (neoadjuvant or adjuvant); ope+RT, patients who underwent surgery followed by radiotherapy (including concurrent chemoradiotherapy); and RT, patients who underwent radiotherapy (including concurrent chemoradiotherapy). (C) RFS by histological subtype. (D) OS by histological subtype. Patients were divided according to whether they had squamous cell carcinoma (SCC) or non-squamous cell carcinoma (non-SCC), and whether radiotherapy (including concurrent chemoradiotherapy) was performed or not. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test.
As for complications, in patients with stage IIIC1 T1/T2, lymphedema occurred in 17% (4/23) of the patients in the ope+CT group, 43% (6/14) in the ope+RT group, and 17% (1/6) in the RT group; dysuria occurred in 13% (3/23) of patients in the ope+CT group, 14% (2/14) in the ope+RT group, and 17% (1/6) in the RT group. Lymphedema was more common in the ope+RT group, although there were no significant differences between the groups for both lymphedema and dysuria ( Figure 4).
Healthcare 2023, 11, x FOR PEER REVIEW 6 of 9 Overall survival (OS). ope+CT, patients who underwent surgery and chemotherapy (neoadjuvant or adjuvant); ope+RT, patients who underwent surgery followed by radiotherapy (including concurrent chemoradiotherapy); and RT, patients who underwent radiotherapy (including concurrent chemoradiotherapy). (C) RFS by histological subtype. (D) OS by histological subtype. Patients were divided according to whether they had squamous cell carcinoma (SCC) or non−squamous cell carcinoma (non−SCC), and whether radiotherapy (including concurrent chemoradiotherapy) was performed or not. Survival curves were estimated by the Kaplan-Meier method and compared by the log−rank test.
As for complications, in patients with stage IIIC1 T1/T2, lymphedema occurred in 17% (4/23) of the patients in the ope+CT group, 43% (6/14) in the ope+RT group, and 17% (1/6) in the RT group; dysuria occurred in 13% (3/23) of patients in the ope+CT group, 14% (2/14) in the ope+RT group, and 17% (1/6) in the RT group. Lymphedema was more common in the ope+RT group, although there were no significant differences between the groups for both lymphedema and dysuria ( Figure 4).   ); ope+RT, patients who underwent surgery followed by radiotherapy (including concurrent chemoradiotherapy); and RT, patients who underwent radiotherapy (including concurrent chemoradiotherapy). Complication frequency was performed the Fisher's exact test.