Role of systematic lymphadenectomy as part of primary debulking surgery for optimally cytoreduced advanced ovarian cancer: Reappraisal in the era of radical surgery

The prognostic significance of pelvic and para-aortic lymphadenectomy during primary debulking surgery for advanced-stage ovarian cancer remains unclear. This study aimed to evaluate the survival impact of lymph node dissection (LND) in patients treated with optimal cytoreduction for advanced ovarian cancer. Data from 158 consecutive patients with stage IIIC–IV disease who underwent optimal cytoreduction (<1 cm) were obtained via retrospective chart review. Patients were classified into two groups: (1) lymph node sampling (LNS), node count <20; and (2) LND, node count ≥20. Progression-free (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method. Among the included patients, 96 and 62 patients underwent LND and LNS as primary debulking surgery, respectively. There were no differences in the extent of debulking surgical procedures, including extensive upper abdominal surgery, between the groups. Patients who underwent LND had a marginally significantly improved PFS (P = 0.059) and significantly improved OS (P < 0.001) compared with those who underwent LNS. In a subgroup with negative lymphadenopathy on preoperative computed tomography scans, revealed LND correlated with a better PFS and OS (P = 0.042, 0.001, respectively). Follow-ups of subsequent recurrences observed a significantly lower nodal recurrence rate among patients who underwent LND. A multivariate analysis identified LND as an independent prognostic factor for PFS (hazard ratio [HR], 0.629; 95% confidence interval [CI], 0.400–0.989) and OS (HR, 0.250; 95% CI, 0.137–0.456). In conclusion, systematic LND might have therapeutic value and improve prognosis for patients with optimally cytoreduced advanced ovarian cancer.


INTRODUCTION
More than two-thirds of patients with epithelial ovarian cancer (EOC) have advanced disease at the time of diagnosis; hence, EOC remains a major cause of gynecologic cancerrelated mortality [1]. Currently, the primary standard treatment for advanced-stage EOC comprises debulking surgery and adjuvant taxane-and platinum-based chemotherapies [2].
Radical debulking surgery is a critical treatment strategy for advanced ovarian cancer, and several studies have supported the importance of maximal cytoreductive surgical efforts to minimize residual disease [3,4].
Notably, the role of systematic lymph node dissection (LND) in the treatment of stage IIIC-IV ovarian cancer remains controversial because this procedure does not is uncertain [5][6][7]. Consensus has not yet been reached Clinical Research Paper of retroperitoneal lymph node metastasis was reported as a major risk factor for poor prognosis [8][9][10]. Current National Comprehensive Cancer Network (NCCN) guidelines do not recommend systematic LND other than the removal of suspicious and/or enlarged nodes in patients with advanced disease. In addition, 2 previous randomized controlled trials LND for overall survival (OS) [5,11], whereas retrospective studies have demonstrated the potential favorable impact of this procedure on OS [9,10,12,13]].
Previous studies were, however, performed before radical surgery was generally accepted as a standard therapy for advanced ovarian cancer [14,15]. Therefore, the role of systematic LND merits further investigation in the era of radical surgery. The present study aimed to evaluate the survival impact of systematic LND as part of optimal primary debulking surgery for the treatment of advanced ovarian cancer.

RESULTS
Among 274 patients who were diagnosed with advanced epithelial ovarian cancer at our institution from 2006 to 2015, optimal cytoreduction was achieved in 175 (63.9%); of these, the lymphadenectomy status could characteristics of the patients included in this study are listed in Table 1. A total of 158 consecutive patients with optimally cytoreduced primary International Federation of Gynecology and Obstetrics (FIGO) stage IIIC and IV disease who had received adjuvant platinum-based chemotherapy during the study period were analyzed. Of these patients, 62 (39.2%) underwent lymph node sampling (LNS) and 96 (60.8%) underwent LND (including both pelvic and para-aortic lymphadenectomy) as part of primary debulking surgery. The groups were similar with respect to age, preoperative cancer antigen (CA) 125 level, suspected lymph node metastasis on preoperative computed tomography (CT) scan, histology, FIGO stage, and grade. In addition, the groups did not differ with regard to the radicality of surgical procedures, including bowel resection, diaphragm resection, peritonectomy, and video-assisted thoracoscopic surgery (VATS), but did differ nodes (P < 0.001; Table 2). Furthermore, the rates of no gross residual disease after debulking surgery did not differ A Kaplan-Meier survival analysis indicated an apparently favorable progression-free survival (PFS) in the LND group, compared to the LNS group, and this better PFS when compared with LNS among patients with negative lymphadenopathy on a preoperative CT scan those who underwent LNS (P < 0.001), and a subgroup longer OS, regardless of the suspected lymphadenopathy A comparison of the characteristics of patients who experienced subsequent recurrence is shown in Table 3

DISCUSSION
improvement in PFS in patients who underwent pelvic and para-aortic systematic LND during primary optimal debulking surgery for advanced-stage ovarian cancer. Moreover, in a subgroup analysis according to the gross lymphadenopathy status as assessed by preoperative LND on both PFS and OS were observed in patients with negative lymphadenopathy on a preoperative CT be attributed to the contribution of this procedure to the detection and removal of occult and chemoresistant lymph node metastases, as inferred from our data regarding the characteristics of subsequent nodal recurrence, the incidence of which might be decreased by LND.
Multidisciplinary treatment, which includes cytoreductive surgery and platinum-based chemotherapy, is the mainstay of management for women with advancedstage ovarian cancer [16]. Although medical treatment is nearly homogenous, surgical treatment is individualized according to the disease extent and patient characteristics and therefore remains heterogeneous. Moreover, the role of complete lymphadenectomy in a primary staging operation with the intent to gain information regarding prognostic relevance remains under debate by many authors [5,6,10,11,13,[17][18][19][20][21][22], and therefore a consensus regarding the therapeutic role of this procedure has not been established, particularly after radical surgery was accepted as standard EOC management.
Previous studies have demonstrated the potential importance of systematic LND for the detection of occult lymph node metastases [5,11,18]. In two previous RCTs, patients with EOC who were treated with systematic LND had a higher rate of histologically proven lymph node metastasis when compared with those who underwent macroscopic lymph node removal (22% vs. 9% for earlystage disease; 70% vs. 42% for advanced-stage disease) [5,11], suggesting a potential increase in the opportunity to detect occult lymph node metastasis via systematic LND in patients with advanced ovarian cancer. This the reported detection rates of lymph node metastasis in LNS, lymph node sampling; LND, lymph node dissection; SD, standard deviation; N/A, not available; LN, lymph node, NGR, no gross residual disease; R, residual disease patients with peritoneally advanced ovarian cancer ranged from 48% to 75% [18]. Of note, the data from our study of a preoperative CT scan for the detection of lymph node metastasis were 65.0% and 65.5%, respectively. Among 86 patients with suspected lymphadenopathy on preoperative CT scans, nodal metastasis was histologically proven in 67 patients (77.9%). In addition, the false negative rate, or detection rate of occult lymph node metastasis among patients with preoperative CT scans indicating negative lymphadenopathy, was 50% (36 of 72 patients). This observation suggests that a negative preoperative imaging result on lymph node metastasis could not justify the omission of systematic LND during debulking surgery for advanced ovarian cancer. Incompletely resected occult lymph node metastases may give rise to chemoresistance, a possibility that is supported by the "pharmacologic sanctuary hypothesis" of poor prognosis in patients with EOC with lymph that the diminished blood supply of lymph node metastases might promote resistance to chemotherapy [23], and further implies that systematic LND might be a favorable prognostic factor in patients with advanced ovarian cancer who have an increased risk of occult lymph node metastasis [24]. Because ovarian cancer is known to spread simultaneously both intraperitoneally and retroperitoneally, the lymphatic spread of a tumor might persist despite achieving optimal cytoreduction of intraperitoneal dissemination, thus contributing to a poor prognosis [25].
LND for patients with optimally cytoreduced advanced ovarian cancer, these data should be interpreted with caution. We attempted to minimize potential bias by accounting for all known prognostic variables associated with both the tumors and patients; however, selection bias regarding patient recruitment cannot be ruled out because of the retrospective nature of this study. Moreover, decisions regarding whether to perform systematic lymphadenectomy were made according to each surgeon's discretion, rather Notably, the prognostic relevance of lymphadenectomy is currently under investigation in the prospective phase III trial "Randomized, Multicentre Trial for Lymphadenectomy in Ovarian Neoplasms" (https://clinicaltrials.gov/ct2/show/ NCT00712218). This ongoing study compares the prognostic outcomes associated with systematic lymphadenectomy vs. no lymphadenectomy in patients without macroscopic systematic pelvic and para-aortic lymphadenectomy. This trial is expected to clarify the status of this important issue.
In conclusion, the present study has demonstrated the potential therapeutic value of systematic LND with respect to improved prognosis following the optimal removal of intra-abdominal peritoneal metastases, regardless of the preoperatively suspected lymphadenopathy status on CT lower nodal recurrence rate with systematic LND vs. LNS.     LNS, lymph node sampling; LND, lymph node dissection; Image(+), positive lymphadenopathy on preoperative CT scan; Image(-), negative lymphadenopathy on preoperative CT scan; LN, lymph node

Study design
is presented in Figure 3. Patients who were diagnosed with advanced-stage (FIGO IIIC and IV) EOC from January 2006 to December 2015 and underwent optimal cytoreduction, or had residual disease of <1 cm were included in this study. The retrospective study protocol of this study was approved by our Institutional Review Board.
A retrospective chart review was performed to identify all patients who underwent primary debulking surgery, including hysterectomy, bilateral oophorectomy, omentectomy, and retroperitoneal lymph node excision with or without various radical surgeries (e.g., bowel resection, diaphragm resection, peritonectomy) and received adjuvant standard platinum-based chemotherapy. A gynecologic oncology team comprising 5 surgeons at a single institute conducted all procedures, and 2 dedicated radiologists at the same institute reviewed preoperative computed tomography (CT) scan data.  To determine the therapeutic value of systematic [11,26,27]. Decisions regarding whether to perform LND or LNS were made according to each surgeon's discretion.
as systematic lymphadenectomy (total resected node count: node dissection. Systemic pelvic LND included the resection of all lymph nodes and fatty tissue between the external and internal iliac arteries from the bifurcation of the common nerve. Systemic para-aortic LND included the resection of all lymph nodes and fatty tissue overlying the common iliac artery, vena cava, and aorta anteriorly up to the renal vessels and laterally to the edge of the psoas major muscle. The surgical procedures and characteristics of recurrence and prognosis were compared between the groups. Additionally, a subgroup analysis was conducted to investigate the role of LND with respect to apparent nodal involvement on a preoperative CT scan. Both the suspected lymphadenopathy status on preoperative CT scans. Image(+) indicated positive preoperatively lymphadenopathy on a preoperative CT scan.

Statistical analysis
IBM SPSS version 20 for Windows (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. The Kolmogorov-Smirnov test was used to verify standard normal distributional assumptions. Pearson's chi square test, Fisher's exact test, and the Mann-Whitney U test were used in the univariate analysis. Survival outcomes were determined through a Kaplan-Meier survival analysis. Univariate and multivariate analyses of the effects of various prognostic factors on survival were performed using the Cox proportional hazards model. Multivariate analysis was performed with variables that