Lymph node metastasis is one of the main metastasis pathways of ovarian cancer, with a total probability of 20% to 41%, while retroperitoneal lymph node metastasis rate of advanced ovarian cancer is as high as 50% to 75% [12-13], so retroperitoneal lymphadenectomy plays an important role in the surgical treatment of ovarian cancer patients. There are three main ways to remove lymph nodes: lymph node sampling, removal of palpable nodes and systematic/radical lymphadenectomy. Systemic retroperitoneal lymphadenectomy refers to the complete removal of lymphatic and adipose tissue around the abdominal aorta and inferior vena cava, as well as the pelvic cavity on both sides, generally last to the level of the left renal vein, the lower boundary to the inguinal ligament level. Including three regions: Upper aortic region: left renal vein level to the root of the inferior mesenteric artery; Lower aortic region: root of the inferior mesenteric artery to the middle point of the common iliac artery; The pelvic area region: common iliac, external iliac, internal iliac, obturator and presacral. In a retrospective analysis of systematic retroperitoneal lymphadenectomy in 208 patients with untreated ovarian, endometrial and cervical cancer between January 1986 and June 1990, Panici et al [14] divided the para-aortic nodes into eight groups:paracaval (right side of inferior vena cava), precaval, retrocaval, para-aortic (left side of abdominal aorta), pre-aortic, retro-aortic and intercavo-aortic. Para-aortic lymphadenectomy is difficult, and the current criteria for determining whether para-aortic lymphadenectomy is complete are as follows: bilateral psoas, anterior longitudinal ligament of the spine and sacral periosteum should be exposed and visible after surgery.
Systemic retroperitoneal lymphadenectomy should be included in the first operation for early-stage ovarian cancer, which can not only fully stage and guide postoperative adjuvant therapy, but also eliminate the microscopic metastasis in lymph nodes, improve the sensitivity to chemotherapy and the prognosis of patients. Chan JK et al [15] conducted a retrospective study on 6686 patients with stage I ovarian cancer in 2007, which showed that lymphadenectomy improved the 5-year survival rate of epithelial ovarian cancer patients with non-clear cell carcinoma. However, it is still controversial about whether systemic retroperitoneal lymphadenectomy can improve the prognosis of advanced ovarian cancer patients.
Most early retrospective studies have suggested a favorable prognosis of systematic retroperitoneal lymphadenectomy in patients with macroscopically completely resected advanced ovarian cancer. du Bois A et al [6] reviewed 1942 epithelial ovarian cancer patients, the results showed that among the 996 patients without residual tumor, the 5-year survival rate was significantly higher in the group receiving lymph node resection of different degrees than that in the group without lymph node resection (67.4% vs 59.2%, P=0 .0166); lymphadenectomy also showed a significant survival impact in these patients without clinically suspect nodes (the median OS was 108 vs 83 months, P=0.0081); meanwhile, patients with small residual tumor also showed a positive impact of lymphadenectomy regardless of clinical lymph node status. A retrospective study of 488 patients with untreated advanced ovarian cancer also indicated that among patients with optimal or suboptimal cytoreduction, 5-year survival in patients who underwent lymphadenectomy was higher than the patients who did not (P = 0.05, P < 0.005) [7]. Aletti GD et al [8] also found a favorable prognosis in the stage IIIC/IV epithelial ovarian cancer patients who underwent lymphadenectomy, 5-year OS was 50% (lymphadenectomy) vs 33% (lymph node sampling) vs 29% (no lymph node assessment); P = 0.01. Chan JK et al [9] reported that among the ovarian cancer patients of stage III-IV, expand the scope of lymph node resection can improve the survival rate. A comparative study in patients with no residual disease of advanced ovarian cancer (stage IIIC-IV) showed that systematic pelvic and para-aortic lymphadenectomy significantly improved the survival (P = 0.02) [10]. Burghardt et al [16] analyzed stage III ovarian cancer patients, also found a superior prognosis of lymphadenectomy. Kikkawa et al [17] indicated that the danger of death in the lymphadenectomy group was lower than the control group (Hazard Ratio: 0. 677; P = 0. 0497).
However, some studies have reported that systematic pelvic and para-aortic lymphadenectomy is of no benefit to patients' prognosis.
Spirtos NM et al [18] reviewed the role of retroperitoneal lymphadenectomy in patients with advanced ovarian cancer (Stage IIIA-IVA) undergoing suboptimal cytoreductive surgery (residual tumor was less than 1 centimeter), the result showed that patients undergoing removal of macroscopically positive lymph nodes didn’t have survival benefit than those with microscopically positive and/or negative lymph nodes. Sakai K et al [3] also reported among the advanced ovarian cancer patients with optimal cytoreduction (residual tumor <1 cm), there was no significant difference in 5-year OS (59 vs 62.9%, P=0.853) or PFS (41.9 vs 46.7%, P=0.658) in patients who underwent systematic retroperitoneal lymphadenectomy or not. In addition, there was no therapeutic benefit for advanced ovarian cancer patients who underwent systematic retroperitoneal lymphadenectomy during interval debulking surgery after neoadjuvant chemotherapy [19].
Based on the results shown in our study, advanced ovarian cancer patients with optimal or suboptimal cytoreduction who underwent systematic retroperitoneal lymphadenectomy did not show a significant improvement in survival (either 2-year PFS or 5-year OS).
A randomized clinical trial was carried out in 2005, Panici PB et al [12] randomly divided 427 patients with optimally debulked advanced ovarian cancer (stage IIIB-IV) to systematic pelvic and para-aortic lymphadenectomy group (n = 216) and resection of bulky nodes only group (n = 211). After a median follow-up of 68.4 months, the risk for recurrence was significantly lower in the systematic lymphadenectomy group (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.59 - 0.94; P = 0.01) than in the no-lymphadenectomy group, but the risk of death was similar in both groups (HR = 0.97, 95% CI = 0.74 - 1.29; P = 0.85). The majority of ovarian cancer patients treated in our hospitals had macroscopic peritoneal metastasis beyond pelvic. So we also performed a subgroup analysis of patients with stage IIIB-IV, and the result indicated that lymphadenectomy had no significant effect on patients’ survival, 5-year OS rates was 77 and 78% in the lymphadenectomy group and no-lymphadenectomy group, P = 0.440; 2-year PFS was 26 and 24% in the two arms, P = 0.331.
Patients with serous ovarian cancer has a higher rate of lymph node metastasis than other epithelial ovarian tumors types [20]. Takeshima N et al [21] performed an analysis of 208 ovarian cancer patients with systematic lymphadenectomy: 60 cases of serous tumor, 22 had positive lymph nodes (36.7%); 148 cases of Non-serous tumor, 25 had positive lymph nodes (16.9%). In this study, patients with serous tumor and non-serous tumor were analyzed separately. As the data showed, whether it was serous type or not, systematic retroperitoneal lymphadenectomy was not a prognostic factor for PFS or OS.
Lymphadenectomy in patients without clinically suspect lymph nodes and small residual disease intraperitoneally might not change the residual disease status but may reduce tumor burden that is possibly resistant to chemotherapy. The Lymphadenectomy in Ovarian Neoplasms (LION) trial, a prospectively randomized trial of systematic pelvic and paraaortic lymphadenectomy in 647 stage IIB-IV primary ovarian cancer patients with macroscopically completely resected indicated systematic retroperitoneal lymphadenectomy in patients with no gross residual tumor of advanced ovarian cancer and clinically negative lymph nodes was not associated with better outcomes than no lymphadenectomy and was associated with a higher incidence of postoperative complications, such as incidence of lymph cysts, infection treated with antibiotics, repeat laparotomy and mortality within 60 days after surgery [11]. Similarly, a subgroup analysis about the patients with clinically negative lymph nodes was performed in this study, there was also no survival benefit in patients who underwent systematic lymphadenectomy.