Effectiveness of Lymph Node Dissection in Women over Age 70 with Stage I Ovarian Cancer

Background : Considering the possibility of surgical intervention affecting the survival benefit of elderly patients, the relationship be-tween lymph node dissection and the survival of elderly patients with stage I ovarian cancer (OC) was retrospectively analyzed. Methods : This was a retrospective cohort study using the database in Surveillance, Epidemiology and End Results (SEER) which was queried to identify 8191 women with stage I OC treated with surgery from 1975 to 2016. Frequencies and percentages were presented to describe the categorical data. Pearson χ 2 test was used to compare the correlation between the patient characteristics and lymph node dissection. Kaplan–Meier test was used to analyze the relationship between overall survival (OS) and patients at all age levels. The log-rank test was used for pairwise comparisons of OS. Cox proportional hazard regression analyses were performed to determine the association between lymph node dissection status and the OS in women with stage I OC. Results : There were 8191 stage I OC patients in this study. Among all patients undergoing lymph node dissection, 11.23% patients were older than 70 years. However, 17.44% of the patients over 70 years of age did not undergo lymph node dissection. Lymph node conservation was associated with a higher mortality risk compared to lymph node dissection. Kaplan–Meier analysis revealed that patients had a worse prognosis with lymph node conservation in people older than 70 years. Univariate and multivariate analysis showed that age and lymph node dissection both remained independent prognostic factors for improved OS with stage I OC. Conclusions : Lymph node dissection was an independent predictor of improved long-term OS in stage I OC patients and had a significant benefit in women over age 70.


Introduction
Ovarian Cancer (OC) is the most lethal gynecological malignancy [1], and has the highest mortality rate among female reproductive tract malignancies [2].Early diagnosis and staging determine the prognosis of the disease.The proportion of patients with early-stage ovarian cancer is increasing as diagnostic and treatment technologies continue to improve.As life expectancy continues to increase, this results in an increase in the proportion of elderly patients with OC.Advances in the treatment of ovarian cancer, such as advanced surgical procedures, intravenous chemotherapy with carboplatin and paclitaxel, and abdominal chemotherapy, have led to an increase in 5-year survival rates from 34.8% in 1975 to 44.6% in 2011 [3].However, the treatment progress of ovarian cancer is still significantly worse than that of other types of solid tumors [4].Greater than 10 years ago, an analysis of the European research on adjuvant chemotherapy for ovarian malignant tumors demonstrated that the surgical staging of patients with early ovarian malignant tumors improved tumor-free survival and overall survival [5].This finding has led to national and international guidelines for the treatment of early ovarian malignancies recommending surgical staging [6,7], including hysterectomy, bilateral salpingo-oophorectomy, omentectomy, cytological examination, peritoneal biopsy, and pelvic and paraaortic lymphadenectomy.The purpose of definitive surgery is to completely remove the tumor, determine the pathological diagnosis and staging of ovarian cancer, determine the histological subtype and grade of the disease, and determine the risk factors, in order to select the appropriate follow-up treatment (including chemotherapy and treatment duration, etc.).Based on the Surveillance, Epidemiology and End Results (SEER) database, this study evaluated the clinicopathological features and prognostic factors of early ovarian cancer and to provide new ideas for the therapeutic benefits of lymph node dissection in the clinical diagnosis and treatment of early ovarian cancer in women over age 70.

Study Population
Ovarian cancer cases were identified through the SEER program of the National Cancer Institute, which included data of 27.8% of the US population from 11 states and 7 areas.The information was accessed from the SEER database, and the requirement for informed consent was exempted by the University of Southern California Institutional Review Board.Data were extracted from the SEER18 Regs Research Data as well as Hurricane Katrina Impacted Louisiana Cases (1975-2016) using SEER*STat

Clinicopathological Data and Observational Indicators
Demographic characteristics included age at diagnosis, specific year, race, place of SEER registration, and marital status.The pathological features of the tumor, including the location of the primary tumor, histological grade, lymph node metastasis and lymph node resection are shown in Ta-ble 1.The tumor stage was determined by the 7th edition AJCC ovarian cancer TNM stage.Histological classification was based on the World Health Organization (WHO) standards for ovarian cancer, and histological classification included Grade Ⅰ, Grade Ⅱ, Grade III, and Grade IV.According to the extent of surgical intervention, the patients were divided into lymph node resection group and lymph node preservation group.The follow-up period was extended to 31 December 2019.The main outcome measures included overall survival (OS) and cancer-specific survival (CSS).OS time is defined as the time interval from the time of pathological diagnosis of the patient to the time of death.CSS time was defined as the time interval from when a patient was pathologically diagnosed with ovarian cancer to the time the patient died of ovarian cancer.

Statistical Analysis
SPSS for Windows version 25.0 (IBM SPSS Inc, Chicago, IL, USA) was used for statistical analysis and chisquare test was used to compare the characteristic distribution of baseline data.The influencing factors of lymph node metastasis were analyzed by logistic regression.Survival information and survival curves were obtained by Kaplan-Meier survival analysis.Univariate and multivariate Cox regression models were used to analyze the independent prognostic factors.All statistical analyses were the twoside test, and p < 0.05 was considered to be statistically significant.

Baseline Characteristics of Patients with Stage I Ovarian Cancer
Baseline data of all patients are shown in Table 2.A total of 7916 patients were included according to the inclusion criteria, among whom intraoperative lymph node dissection was performed at the same time: 1135 patients (71.9%) aged 61-69, 456 patients (62.7%) aged 70-79, and 144 patients (44.7%) aged 80 years or older.Among the patients who underwent surgery, there was a difference in overall survival when lymph node dissection was performed in patients older than 70 years.

Survival Analysis
Kaplan-Meier survival curve analysis: Fig. 2A showed that there was no significant correlation between intraoperative lymph node dissection and specific survival (CSS) in stage I ovarian cancer patients over age 70 (p = 0.190).Fig. 2B showed that there was a significant correlation between intraoperative lymph node dissection and OS in stage I ovarian cancer patients over age 70 (p = 0.002).
Univariate and multivariate analyses were performed using Cox proportional hazard method.Univariate analysis showed that age ≥70 years, histological grade, and lymph node dissection were influencing factors for OS and CSS in stage I ovarian cancer (p < 0.05).In univariate analysis,  3).

Discussion
In the treatment of early ovarian cancer, the initial staging operation is very important [8].In clinical practice, whether the surgical scope of early ovarian cancer requires systematic lymph node dissection has been a controversial issue [9].According to statistics, the lymph node positive rate of early ovarian cancer is approximately 13%-20% [10].In the current guidelines for ovarian cancer, the mainstream view is to recommend intraoperative lymph node dissection for early stage patients.In a retrospective analysis of over 6000 patients, Chan et al. [11] concluded that lymph node dissection improved the 5-year survival rate of Federation International of Gynecology and Obstetrics (FIGO) Stage I patients from 87.0% to 92.6% (p < 0.001).On the contrary, other investigators found that there was no significant difference in progression-free survival between patients with early ovarian cancer undergoing lymph node dissection and those who did not receive lymph node dissection [12].Some researchers believe that systematic lymph node dissection could not only not prolong the progression-free survival of patients with early ovarian cancer, but also increase the incidence of complications.Other investigators have proposed that lymph node dissection prolongs the operative time and hospital stay, and increases the incidence of surgical complications [13].The scope of comprehensive staging surgery mainly includes pelvic and para-aortic lymph node dissection, large mesh membrane resection, random peritoneal biopsy and ascites cytology.For patients over age 70, systematic lymph node dissection is not necessary when performing comprehensive staging surgery, avoiding the possibility of extensive surgery and prolonged surgical time may affect the survival benefit of patients.Moreover, the proportion of complications in patients with lymph node dissection is significantly increased, including intraoperative bleeding, postoperative hematoma formation, infection, adjacent organ and nerve injury, and tumor dissemination, especially in patients over age 70.Therefore, in order to determine whether patients over age 70 with early ovarian cancer could benefit from lymph node dissection, survival period analysis was performed on patients with early ovarian cancer age ≥70 years.The results demonstrated that the prognosis was poor without lymph node dissection, and lymph node dissection was an independent prognostic factor affecting the overall survival of patients over age 70 (p < 0.001).
There are some limitations to this study.First, this study was a retrospective clinical study over a large time span.The improvement in surgical instruments and better trained surgeons have affect the survival benefits to patients.This study was based on the prognosis of ovarian cancer in the United States, which may be different from the real situation of ovarian cancer in China.Therefore, it is necessary to conduct a multi-center with a large-sample size on the Chinese population in order to obtain results applicable to Chinese women.

5.Conclusions
In our study, lymph node dissection was found to be an independent predictor of improved long-term OS in patients with stage I ovarian cancer, with a significant benefit in older women.Therefore, we need to carefully consider the choice of surgical methods in order to obtain a more beneficial prognosis.

Fig. 2 .
Fig. 2. Kaplan-Meier survival curves showing the CSS (A) and OS (B) analysis of patients over 70 years of age with intraoperative lymph node dissection.CSS, cancer-specific survival; OS, overall survival.