Adjuvant chemotherapy for peritoneal cytology-positive stage IA endometrial cancer

Purpose This study aimed at evaluating the inuence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. Methods We retrospectively analyzed the data of patients with stage I A endometrial cancer admitted in our hospital between 2005 and 2015. Results


Introduction
Endometrial cancer is the most common gynecological cancer in advanced countries and its prevalence is expected to further rise with time. Most patients are diagnosed in the early stage because symptoms of atypical genital bleeding develop in more than 90% of patients. When reported early, approximately 75 to 80% of endometrial cancer (EEC) patients are diagnosed at Federation of Gynecology and Obstetrics (FIGO) Stage I, and stage IA patients are known to have a favorable prognosis with a 5-year survival rate ≥ 90% (1, 2).
Positive peritoneal cytology (PPC) has been reported to be a poor prognostic factor for endometrial cancers, but it is not included the International FIGO 2009 stage classi cation. Studies show that PPC does not in uence the prognosis of stage III cancers unlike other factors like lymph node metastasis, and uterine serosal or adnexal metastasis, but it is unclear whether PPC in uences the prognosis in patients with early stage endometrial cancer (3)(4)(5). A Although some studies have reported PPC to be a risk factor for recurrence in patients with EEC, other studies have not found PPC to be an independent risk factor for occurrence. So, no consensus has been established(6-18).
Several guidelines recommend postoperative adjuvant therapy for EEC patients having risk factors for recurrence (1,2). However, its e cacy, especially in stage IA EEC, is unclear.
The objective of this study was to evaluate the in uence of potential independent risk factors like PPC on the prognosis of patients with stage IA EEC, and to evaluate the usefulness of postoperative adjuvant chemotherapy in its treatment.

Patient population
This was a retrospective comparative study involving data on patients with endometrial cancer (FIGO stage IA) who received their rst treatment at The Cancer Institute Hospital between January 2005 and December 2015. The study was approved by The Cancer Institute Hospital of JFCR Review Board and was conducted in accordance with the relevant guidelines and regulations of the Institutional Review Board. We obtained signed informed consent from participants. We excluded the following patients: those who died from another disease, those who had undergone a hysteroscopic examination before surgery, patients who received preoperative hormone therapy or chemotherapy, and patients who had multiple cancers (thus affecting the EEC treatment protocol) (19,20).

Study de nition
Surgical staging was performed using the FIGO 2009 staging system (21). According to this classi cation, an invasion of < 50% of the uterine muscle is classi ed as stage IA. Concerning the tumor grading, the World Health Organization (WHO) 2014 classi cation was used (22). Ages and body mass index (BMI) were each grouped into two categories (ages < 60 and ages ≥ 60; BMI < 25 and BMI ≥ 25 kg / m 2 , respectively) on the basis of the grouping done in previous studies (23,24). A False PPC was classi ed as negative according to Japanese guidelines (2). The relapse-free survival time was de ned as the time lapse between the rst recurrence and the day of the surgery or (in patients without recurrence) the time lapse between the day of the surgery and last consultation (follow-up) day. The overall survival time was de ned as the time lapse between the day of the surgery and the date of death or the last consultation day (for patients who were still alive). The patterns of recurrence included locoregional recurrences (de ned as vaginal or intrapelvic recurrences) and distant recurrences (upper para-aortic lymph node metastasis, peritoneal dissemination, and metastasis to other organs).

Surgery and Adjuvant chemotherapy
The basic surgical procedures used to treat EEC in our hospital included: total hysterectomy, bilateral salpingo-oophorectomy, and regional lymph node biopsy/dissection. Two types of hysterectomy procedures could be performed: simple total hysterectomy and modi ed radical hysterectomy.
Omentectomy was performed in patients with non-endometrioid adenocarcinoma, or with PPC. Regional lymph node dissection was omitted (in some patients) when type I lymph node enlargement and uterine muscle invasion were absent on imaging diagnosis. Patients in whom a lymph node biopsy was performed without systematic dissection were grouped with patients without dissection. The choice between laparotomy and laparoscopy was made based on the size of the complicating uterine broids.
Specimens for peritoneal uid cytology were collected from the Douglas pouch by aspiration or washing at the initiation of surgery.
Patients who received three or more courses were included for analysis in this study (25).

Statistical analysis
Characteristics were compared using Fisher's exact test. For the analysis of the period of recurrence, Cox's regression analysis was used, and univariate and multivariate analyses were performed to identify the prognostic factors. The relapse-free survival curve and overall survival curve were prepared using the Kaplan-Meier method. P-values < 0.05 were considered statistically signi cant. The hazard ratio and 95% con dence interval were calculated. The software Easy R (EZR) Version 1.38 was used for statistical analyses (26).

Ethical approval and Consent for Participation and Consent for Publication
Before participating in the study, all subjects gave their informed consent to participate in it. We conducted this study in accordance with the Declaration of Helsinki, and the protocol was accepted by the Ethics Committee of the Cancer Institute Ariake Hospital, JFCR (approval number, N o 2018 − 1238).

Patients' characteristics
In total, 1041 patients with stage IA endometrial cancer were admitted into our institution during the study period and 989 were eligible for inclusion in this study ( Figure 1). The median age was 55 years (range: 26-87 years). The median duration of follow-up for all the patients was 70 months (range, 2-166 months). Out of the 989 patients who underwent peritoneal cytology, 135 patients (13.7 %) were positive ( Fig. 1) ( Table 1).
Univariate and multivariate analysis for recurrence Univariate analysis was performed to identify the risk factors for recurrence ( Table 2). In univariate analysis, the poor prognostic factors identi ed were age ≥ 60 years, BMI ≥ 25 Kg/m 2 , grade 2 cancer, type II cancer, PPC, muscle invasion, and lymphovascular space invasion. In multivariate analysis, BMI ≥ 25 kg/m 2 , grade 2 cancer, type II cancer, muscle invasion, and PPC were extracted as independent risk factors for recurrence ( Table 2).
There were 135 patients with PPC stage IA endometrial cancer (Table 3). In univariate analysis of stage IA EEC patients with PPC, the risk factors for recurrence were age ≥60 years and type II cancer. In multivariate analysis, type II cancer was identi ed as an independent risk factor ( Table 4).

The e cacy of postoperative adjuvant chemotherapy
In 135 patients with PPC, 13 (9.6%) developed a recurrence. Out of the 58 patients who received adjuvant chemotherapy, 6 (10.3%) developed recurrences (4 patients had distant metastases and 2 had local recurrences). Out of the 77 patients who did not receive adjuvant chemotherapy, 7 patients (9.1%) developed recurrences (1 had a local recurrence and 6 had distant metastases).
For the stage IA EEC patients with PPC, there was no signi cant difference in the 5-year relapse-free survival rate between those who did not receive adjuvant chemotherapy and those who did received (93.5% against 89.6%, p=0.78) (Fig. 2-1).
The relapse-free survival rates of patients with and without adjuvant chemotherapy were analyzed with the cancer type. In patients with type I cancer, there was no signi cant difference in the 5-year relapse-free survival rate between patients with and those without adjuvant chemotherapy (93.5 % against 97.1%, p=0.70) (Fig 2-2). Similarly, the difference between these two groups was not signi cant in patients with type II (85.2 % against 66.7%, p=0.11) (Fig. 2-3).
Also, in patients with type II cancer, there was no signi cantly difference in the 5-year overall survival rate between patients with and those without adjuvant chemotherapy (91.9% versus 77.8%, p=0.15) ( Supplementary Fig. 3).

Discussion
This study found that PPC, alongside a BMI ≥ 25, type II cancer, muscle invasion, and grade 2 cancer, was an independent poor prognostic factor in patients with stage IA EEC. In stage IA EEC with PPC, type II cancer was the only independent poor prognostic factor. The administration of adjuvant chemotherapy was not associated with a longer relapse-free survival in all the stage IA EEC patients with PPC.
Several studies have reported that PPC is a risk factor for cancer recurrence in patients with EEC (stage I and II) after revision of the FIGO 2009 staging (6-15). In our study which focused on stage IA EEC, PPC was an independent risk factor for recurrence (p = 0.036). Wang et al. however reported that PPC does not in uence the overall survival rate of patients with stage IA EEC (16). They excluded non-endometrioid cancers from their study and this could explain the difference in the ndings. The European Society for Medical Oncology guidelines recommend the collection of peritoneal cytology information, especially in patients with tumors of non-endometrioid histology. This is because a retrospective study showed that PPC has a prognostic value (1). In the present study, PPC was a risk factor for recurrence in stage IA endometrial cancer, and it is necessary to carefully manage it.
Atypical cells in peritoneal cytology were considered negative on the basis of the Japanese guidelines (2). Matsuo et al. suggested that the presence of malignant cells or atypical cells on peritoneal cytology should be de ned abnormal peritoneal cytology (14). Presently, we decided to create a cell block in case of atypical cells. The cell block method allows us to diagnose malignant cells by pathology. In the future, we need to examine the treatment of atypical cells, including their prognosis.

Matsuo et al. reported that adjuvant chemotherapy for PPC in EEC (stages I and II) may reduce the incidence of distant metastasis (14). Seagle et al. also reported that adjuvant chemotherapy increased
the survival rate of EEC with PPC (stage I and II) patients (15). However, Wang et al. reported that adjuvant chemotherapy did not improve the outcome of PPC stage IA EEC (with endometrioid carcinoma) (16). In our study, adjuvant chemotherapy for IA EEC with PPC did not improve the relapse-free survival. The 5-year relapse-free survival rate of stage IA EEC patients with PPC without chemotherapy was 93.8% in the overall population. These results suggest that adjuvant chemotherapy was not always necessary for the all stage IA patients with PPC because the baseline risk for recurrence in these patients was very good in our study. We should select patients with higher risk for recurrence among stage IA EEC patients with PPC.
In addition to advanced stage, high-grade endometrial carcinoma or non-endometrial carcinoma, de ned as type II subtype and the presence of vascular and/or muscle invasion, have been reported as poor prognostic factors (1,2,27). Melody, Tatebe, and Donovan et al. reported studies on stage IA serous adenocarcinoma and clear cell cancer among type II patients in which postoperative radiotherapy and chemotherapy prolonged the relapse-free survival (28-30) .
In our study, type II cancer was an independent risk factor for recurrence in stage IA EEC patients with PPC; therefore, we investigated the e cacy of adjuvant chemotherapy as a function to the cancer type. Adjuvant chemotherapy for type I patients (stage IA with PPC) did not improve the relapse-free survival with a good baseline risk (the 5-year relapse-free survival rate was 93.5%). In addition, adjuvant chemotherapy for type II patients did not signi cantly improve relapse-free survival. However, the baseline risk of 5-year relapse-free survival without chemotherapy was very low (66.7 %). Although there was no signi cant difference, the 5-year relapse-free survival rate of patients who received adjuvant chemotherapy with PPC stage IA type II EEC was 85.2%. On the other hand, the 5-year relapse-free survival rate of patients who did not receive adjuvant chemotherapy is 66.7%. Therefore, it may be better to treat them with adjuvant chemotherapy. Analyses involving a larger number of patients and prospective trials need to be carried out to ascertain the need for adjuvant chemotherapy in early stage patients with type II cancers. This lack of signi cant difference in our study could be due to the small sample size we used. More importantly, it is necessary to select treatment taking into consideration the risk for recurrence of individual factors because the baseline risk for recurrence was worse when multiple risk factors were present(31).

Conclusion
In patients with stage IA EEC, PPC is an independent risk factor for recurrence. Adjuvant chemotherapy was not recommended for all stage IA EEC patients with PPC. However, by analyzing the cancer type, the presence of a population with a higher risk for recurrence was con rmed. It is therefore necessary to investigate the e cacy of adjuvant chemotherapy in patients with early stage EEC having risk factors for recurrence, especially those with many factors.