Introduction

The incidence of cervical adenocarcinoma has increased markedly in recent decades, comprising approximately 20%–25% of women with cervical cancer [1, 2]. In general, patients with cervical adenocarcinoma receive the same primary treatment as those with cervical squamous cell carcinoma (SCC), which is the most common histopathological group [3]. However, several studies have found significantly worse survival of patients with cervical adenocarcinoma than those with cervical SCC after radiotherapy (RT)/concurrent chemoradiotherapy (CCRT) [4, 5].

In 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised the staging system for cervical carcinoma [6]. One of the major changes from the prior 2008 FIGO staging system was the incorporation of nodal status into stage III disease staging [6, 7]. In the 2018 FIGO staging system, patients with lymph node metastasis are specifically designated as stage IIIC disease, where stage IIIC1 denotes pelvic lymph node metastasis only and stage IIIC2 indicates para-aortic lymph node metastasis. This new staging system clearly reflects the importance of lymph node metastasis as a major prognostic factor in cervical cancer [8].

A randomized controlled trial (RCT) by the Southwest Oncology Group revealed that postoperative CCRT improves 4-year overall survival (OS) rate of patients in the high-risk group (81%), including pelvic nodes metastasis, compared with postoperative RT (71%) [9]. However, considering only adenocarcinoma, the survival benefit of additional CCRT was unclear.

In this study, we focused on patients with 2018 FIGO stage IIIC1 cervical adenocarcinoma who had undergone radical hysterectomy (RH). To elucidate the impact of additional CCRT in women with cervical adenocarcinoma, this retrospective study compared the clinical outcomes of patients with pelvic node-positive cervical adenocarcinoma treated by RH with or without adjuvant CCRT.

Materials and methods

This study was a retrospective cohort study of 80 patients diagnosed with clinical pelvic node-positive (2018 FIGO stage IIIC1) cervical adenocarcinoma who underwent RH at Hyogo Cancer Center between January 2000 and December 2016 (Fig. 1). Patients with pathologically negative pelvic nodes after RH were excluded in this study. Clinical stage and histological classification were based on the criteria established by the revised 2018 FIGO and 2014 World Health Organization classification [6, 10]. FIGO staging was determined via gynecologic examination, using pelvic magnetic resonance imaging. Lymph node metastasis were examined, using computed tomography or positron emission tomography-computed tomography scans.

Fig. 1
figure 1

Patient disposition. Abbreviations; RH group radical hysterectomy group, RH-CCRT group radical hysterectomy followed by concurrent chemoradiotherapy group, pN0 pathological pelvic nodes were negative, pN1 pathological pelvic nodes were positive, ypN0 pathological pelvic nodes were negative after neoadjuvant chemotherapy, ypN1 pathological pelvic nodes were positive after neoadjuvant chemotherapy

Full size image

RH comprised trans-abdominal Wertheim type III RH with systematic pelvic lymphadenectomy [11]. Pelvic lymphadenectomy included resection of the obturator, parametrial, sacral, internal, external, and common iliac nodes. A lymph node ratio was defined as the percent proportion of tumor‐positive lymph node among total harvested lymph nodes, dichotomized with the median value based on a previous study (high vs. low, ≥ 7.6% vs. < 7.6%) [12]. CCRT was performed at a dose of 45–50 Gy using whole pelvic external beams and in fractions of 1.8 Gy given daily five times per week for 5 weeks without intracavitary brachytherapy. Clinical target volume (CTV) comprised central vaginal CTV and regional nodal CTV; central vaginal CTV included proximal vagina and paravaginal tissues, whereas regional nodal CTV included common iliac, external and internal iliac, and presacral lymph nodes. Patients were followed-up every 3 months during the first 2 years, every 6 months until the fifth year, and yearly thereafter. Survival information was available from all patients.

Progression-free survival (PFS) was assessed from the date of initial treatment to the time of the first evidence of disease progression or last contact. OS was assessed from the date of initial treatment to the time of death or last contact. Adverse events were defined and graded according to the National Cancer Institute-Common Toxicity Criteria Version 5.0. Statistical analyses were performed using IBM SPSS statistics version 24.0 (IBM Corp.; Armonk, NY, USA) [13]. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test, and continuous variables were analyzed using the Mann–Whitney test. The log-rank test and Cox regression model were used for risk analysis of cancer recurrence and death, as measured using the Kaplan–Meier method. This study was approved by the institutional review board of Hyogo Cancer Center and was conducted according to the principles of the Declaration of Helsinki.

Results

In total, we identified 76 patients who met the eligibility for inclusion in this study (Fig. 1). Four patients who received primary RH and had pathologically negative pelvic node were excluded. On the other hand, 11 patients who received neoadjuvant chemotherapy (NACT) followed by RH were included even though pathological pelvic lymph nodes were negative. Adjuvant CCRT was not administered to 27 patients. Among them, 16 patients refused CCRT after receiving a full explanation of the advantages and disadvantages of CCRT from their radiologist and gynecologist, and 11 patients who received NACT had no pathological postoperative risk factors. The 76 patients were categorized into two groups according to the initial therapeutic strategy: RH alone (RH group, n = 27) and RH followed by adjuvant CCRT (RH-CCRT group, n = 49). Final pathology was used to determine the patient’s histological characteristics. The clinicopathologic characteristics of the two groups are shown in Table 1. The median age of the 76 patients with pelvic node-positive cervical adenocarcinoma at the time of diagnosis was 52 years. The median follow-up time was 53 months (range 9–145 months), and the recurrence rate for the whole population was 63.2%. Among the 76 patients, 35 (46.1%) were diagnosed with endocervical adenocarcinoma usual type, 24 (31.6%) were diagnosed with mucinous carcinoma, and 17 (19.3%) were diagnosed with other subtypes of adenocarcinoma. Among the patients diagnosed with mucinous adenocarcinomas, four were of the gastric type, whereas two patients each were in the RH and RH-CCRT groups. Thirty-eight patients received NACT via platinum-based regimens. The following NACT regimens were used: docetaxel and carboplatin, 15 patients; irinotecan and cisplatin, 10; paclitaxel and cisplatin, 5; paclitaxel and carboplatin, 5; and others, 3. The incidence of postoperative risk factors in the entire population, namely bulky tumor (> 4 cm), deep stromal invasion (> 1/3), lymph vascular space invasion, positive surgical margins, and parametrial invasion were 85.5%, 92.1%, 88.2%, 0%, and 68.4%, respectively. The following CCRT regimens were used: cisplatin weekly, 41 patients and nedaplatin weekly, 8 patients. No patient in the RH group received any adjuvant treatment within the initial therapeutic strategy.

Table 1 Patients characteristics
Full size table

The 5-year PFS rates of the RH and RH-CCRT groups were 35% [95% confidence interval (CI) 18%–53%] and 41% (95% CI 27%–54%), respectively [hazard ratio (HR) 1.034, 95% CI 0.56–1.91; p = 0.926, Fig. 2]. Furthermore, the 5-year OS rates of the RH and RH-CCRT groups were 51% (95% CI 30%–69%) and 53% (95% CI 38%–65%), respectively (HR 1.324, 95% CI 0.66–2.65; p = 0.455, Fig. 2). Similar trends were observed for 5-year OS and PFS in the two groups. The 5-year OS rates of the RH and RH-CCRT groups among patients who did not received NACT were 41.7% (95% CI 10.9%–70.8%) and 61.7% (95% CI 41.6%–76.7%), respectively (HR 0.92, 95% CI 2.52–0.87; p = 0.873, Fig. 3). The 5-year OS rates of pathological lymph node-negative (ypN0) and pathological lymph node-positive (ypN1) groups among patients who received NACT were 78.7% (95% CI 38.1%–94.3%) and 37.6% (95% CI 20.0%–55.2%), respectively (HR 3.38, 95% CI 0.78–14.66; p = 0.0826, Fig. 4). The 5-year cumulative local recurrence rate of the RH and RH-CCRT groups were 46.0% (95% CI 28.2%–68.2%) and 27.0% (95% CI 15.7%–44.0%) respectively (HR 0.68, 95% CI 0.32–1.54; p = 0.366, Fig. 5). Multivariate analysis was performed regarding the postoperative risk factors, and no significant factor was identified (Table 2).

Fig. 2
figure 2

Kaplan–Meier curves for progression-free survival and overall survival. The solid line represents the radical hysterectomy group (RH group), and the dotted line represents the radical hysterectomy followed by concurrent chemoradiotherapy group (RH-CCRT group)

Full size image
Fig. 3
figure 3

Kaplan–Meier curves for progression-free survival and overall survival in patients who did not received neoadjuvant chemotherapy. The solid line represents the radical hysterectomy group (RH group), and the dotted line represents the radical hysterectomy followed by concurrent chemoradiotherapy group (RH-CCRT group)

Full size image
Fig. 4
figure 4

Kaplan–Meier curves for progression-free survival and overall survival in patients who received neoadjuvant chemotherapy. Abbreviations; ypN0 pathological pelvic nodes were negative after neoadjuvant chemotherapy, ypN1 pathological pelvic nodes were positive after neoadjuvant chemotherapy

Full size image
Fig. 5
figure 5

Cumulative incidence curves for local recurrences. The solid line represents the radical hysterectomy group (RH group), and the dotted line represents the radical hysterectomy followed by concurrent chemoradiotherapy group (RH-CCRT group)

Full size image
Table 2 Multivariate analysis of overall survival
Full size table

Table 3 shows the number of grade 3 or 4 adverse events that could be associated with RH or CCRT. The incidence of acute adverse event was similar in both groups. One patient each in the RH-CCRT group exhibited grade 3 or 4 diarrhea, colonic obstruction, fracture, and lymphedema.

Table 3 Adverse events ≥ grade 3
Full size table

Discussion

We sought to elucidate the clinical outcomes of patients with pelvic node-positive cervical adenocarcinoma treated by RH with or without adjuvant CCRT. The addition of CCRT after RH did not significantly improve survival among patients with pelvic node-positive cervical adenocarcinoma. The 5-year OS rate of the current study population was similar to or better than that previously reported [14,15,16]. In the previous study, the 5-year OS rate was 41.7% for patients with 2008 FIGO stage IB-IVA adenosquamous and adenocarcinoma treated with primary CCRT, whereas the 5-year OS rate was 46.4% for patients with 2008 FIGO stage IB–IIB adenocarcinoma with pelvic node involvement who received hysterectomy and any adjuvant treatment [15, 16].

The optimal treatment strategy, both primary and additional treatment, for patients with cervical adenocarcinoma remains unclear given that adenocarcinoma is considered less sensitive to radiation than SCC. Regarding primary treatment, according to the National Comprehensive Cancer Network guidelines, CCRT is recommended in patients with 2008 FIGO stage IB–IIIB adenocarcinoma within the limits of lymph node metastasis, similar to SCC [3]. A Cochrane analysis in 2013 recommended primary CCRT as the first choice in patients with lymph nodes involvement [17]. However, in this Cochrane study, only one RCT was included in the analysis, and the number of adenocarcinoma cases included in the RCT was low (46 of 337 cases; 13.7%) [18]. An additional report of the RCT showed that the OS of patients with adenocarcinoma was better in the first surgery group than in the first RT group [19]. Given this background, we have chosen surgery as the initial treatment for adenocarcinoma whenever possible.

Now for additional treatment after RH, the effect of CCRT for patients with adenocarcinoma was unclear. The RCT found that the addition of chemotherapy to adjuvant RT significantly improves PFS and OS among patients with high-risk early-stage carcinoma of the cervix who underwent RH and pelvic lymphadenectomy [9]. However, fewer cases of adenocarcinoma with pelvic node involvement were registered in the RCT. Two retrospective studies showed that the added benefit of CCRT was insignificant in postoperative high-risk patients with cervical adenocarcinoma or adenosquamous carcinoma [15, 20]. For adenocarcinoma, a treatment strategy different from the one used for SCC should be considered.

On the other hand, NACT might be a treatment option for patients involving difficult initial surgery and not for improving prognosis. Two RCTs were conducted to compare NACT followed by surgery versus CCRT; however, the analysis of patients with only pelvic node-positive adenocarcinoma was insufficient [21, 22]. One of these RCTs included only SCC, and the other included 66 cases of adenocarcinoma. Two RCTs showed no difference in 5-year OS between NACT followed by surgery and primary CCRT among patients with 2008 FIGO stage IB2-IIB cervical cancer. In the present study, 11 patients in the NACT group exhibited pathologic nodal clearance (ypN0). All of patients with ypN0 were categorized into RH group, and might result in relatively favorable prognosis to patients in RH, because they had included patients with potential N0. Although patients with ypN0 were diagnosed with 2018 FIGO stage IIIC1 by imaging modalities, the correct classification might have been pN0 if surgery was performed at the start of the first treatment, leading to improved OS in the RH group and NACT group.

Our study had several limitations. First, the retrospective design prevented the elimination of potential confounding biases in the analysis, such as selection bias for the treatment method in each case. Furthermore, the NACT and CCRT regimens varied widely. Second, this was a single-institute study in Japan, and thus, our patients may not be representative of the general population. Third, the content of surgery is related with the prognosis of treatment and there was no standard objective measurement to assess the surgical completeness of RH. A previous study reported that surgery at high-volume centers for RH is associated with improved survival in women with a cervical cancer [23]. According to the previous study, our institution that has about 60 surgeries of RH every year is defined as a high-volume center. No additional treatment may be acceptable if the quantity and quality of RH are sufficiently guaranteed.

If the addition of CCRT is not sufficient as a postoperative treatment to improve prognosis, any further treatment might lead to an additional effect. Patients with 2018 FIGO stage IIIC1 cervical adenocarcinoma have a poor prognosis. The 5-year OS rate was 53.0% in the present study, whereas it was 46.4% in the previous study of 2018 FIGO stage IIIC1 cervical adenocarcinoma with hysterectomy and adjuvant treatment [15]. The retrospective previous studies revealed that adjuvant chemotherapy might be highly effective for patients with cervical adenocarcinoma with high-risk factors after surgery and decreased distant recurrence, but increased local recurrence when compared to CCRT [24, 25]. Therefore, a phase III study (AFTER trial) comparing postoperative CCRT to chemotherapy alone is ongoing. Another possible treatment is the addition of consolidation chemotherapy after adjuvant chemoradiotherapy. Regarding this treatment modality, GOG0724 trial (NCT00980954) evaluating the efficacy of consolidation chemoradiotherapy with paclitaxel and carboplatin in patients with high-risk factors after surgery is ongoing.

In conclusion, we found that the addition of CCRT after RH did not have a significant survival benefit for patients with pelvic node-positive cervical adenocarcinoma. More appropriate treatment strategies need to be evaluated and selected to improve the survival of patients with postoperative high-risk factors.