There is little doubt that maximal removal of intraperitoneal disease has a survival benefit for patients with metastatic epithelial ovarian cancer (EOC). This is particularly true when there is no visible disease at the completion of the operation.1–3 There is also agreement that detection of nodal metastasis is useful in patients with disease limited to the pelvis to determine surgical stage and the need for appropriate adjuvant therapy.4,5 Controversy, however, remains in the role of detection and removal of positive nodes in patients with advanced intraperitoneal metastatic disease because this does not affect surgical stage and the therapeutic benefit is unclear.6
The aim of this study was to evaluate the therapeutic role of pelvic and aortic lymphadenectomy in patients with advanced intraperitoneal disease (stages III and IV). The impact of lymphadenectomy on overall survival (OS) was evaluated by the overall number of nodes removed and the number of positive nodes.
MATERIALS AND METHODS
Data were collected retrospectively from 116 consecutive cases with primary EOC and stage IIIC or IV disease having nodal metastasis and treated at Mayo Clinic in Arizona, Florida, and Rochester, Minnesota between 1996 and 2000. Of the entire cohort, 98 patients had a systematic pelvic and aortic lymphadenectomy performed, whereas the remaining patients had a selective lymphadenectomy. Approval was granted by the Mayo Clinic Institutional Review Board. Abstracted data included patients’ age, tumor type and grade, International Federation of Gynecology and Obstetrics stage, clinical stage (extent of peritoneal metastases before surgery), size of residual tumor after cytoreductive surgery, overall number of nodes removed, number and location of positive nodes, location gross versus microscopic nodal disease, and type of chemotherapy.
Follow-up was measured in months from the time of primary surgery until death or censoring. Censoring for survivors was performed at a minimum of 5 years of follow-up. Actuarial 5 years OS was calculated for all patients who died from any cause. The anatomic borders for pelvic lymphadenectomy were from the deep circumflex iliac vein to the aortic bifurcation. For the aortic lymphadenectomy, borders were from the aortic bifurcation to the left renal vein. To evaluate the impact of the lymphadenectomy in patients with advanced intraperitoneal disease (stages IIIC and IV), patients with residual disease (RD) were compared to those with no residual disease (residual disease, zero): C1: 1 to 20 nodes versus more than 20 nodes removed; C2: 1 to 30 nodes versus more than 30 nodes removed; and C3: 1 to 40 nodes versus more than 40 nodes removed. To evaluate the impact of nodal metastases, the patients were compared according to the number of positive nodes as follows: P1: 1 to 5 positive nodes versus more than 5 positive nodes, and P2: 1 to 10 positive nodes versus more than 10 positive nodes. Nodal counts were made by identifying the nodes after removal of the fat tissue. Each node was submitted to 7 sections.
Analysis of variance test for parametric variables and the Mann-Whitney U test for nonparametric variables were used to compare simultaneously the means and medians of nodal involvement. Lymph nodes’ median value (P50) was expressed by percentiles, and P25 to P75 was the range. P < 0.05 was considered significant. Univariate Cox regression analysis was used between factors and risk of death when the groups compared were more than 15 patients.7 In subgroups with a smaller sample size, only descriptive analysis and the correlation with OS was performed. Any P < 0.25 in univariate analysis was subjected to multivariable analysis.8 Survival analysis and predictors of outcome were calculated using the Kaplan-Meier and Cox proportional hazard methods. On multivariate analysis, P < 0.05 was considered significant. The homogeneity of the groups compared in survival analysis was confirmed by analysis of variance and subsequent Bonferroni correction test. Statistical analysis was performed using an SPSS statistical package.
A total of 116 patients were entered into the study: stage IIIC, 81 patients, and stage IV, 35 patients. The median age was 65 years (range, 24–87 years). The median number of nodes removed was 31 (P25 = 17 to P75 = 51) (median pelvic, 21.5, and aortic, 10), and the median number of positive nodes was 5 (P25 = 2 to P75 = 11). The 5-year OS was 44.8% (range, 30.1–57.9 months), and the median length of survival was 44 months (range, 0.13–60 months; 95% confidence interval, 30.1–57.9). All patients received adjuvant postoperative paclitaxel and platinum-based chemotherapy.
All survivors were censored at a minimum follow-up of 5 years (range, 61.4–123.8 months). At study censure, 52 patients were alive and 64 were dead. Among the 52 patients alive, the median numbers of pelvic and aortic nodes were 26 (P25 = 10.5 to P75 = 29) and 10.5 (P25 = 7 to P75 = 18,75), respectively, and the median numbers of positive pelvic and aortic nodes were 2 (P25 = 0.25 to P75 = 6) and 2 (P25 = 1 to P75 = 6), respectively. Among the 64 nonsurvivors, the median numbers of pelvic and aortic nodes were 20 (P25 = 13 to P75 = 28) and 10 (P25 = 6 to P75 = 14), respectively, and the median numbers of positive pelvic and aortic nodes for those patients were 2 (P25 = 1 to P75 = 5) and 2.5 (P25 = 0.75 to P75 = 7). There were no statistically significant differences between alive and dead patients relative to the number of nodes (P = 0.474) or the number of positive nodes (P = 0.938).
Univariate and multivariate Cox regression analyses of OS for all patients are shown in Table 1. On univariate analysis, significant factors for survival were tumor type, clinical stage, size of residual disease, and removal of more than 40 lymph nodes. There was no survival difference relative to the extent of the lymphadenectomy when comparing patients with a median of 31 or more removed nodes versus less than 31 nodes (P = 0.612). The number of positive nodes was not significant for OS (Table 2). On multivariate analysis, the extent of peritoneal disease before debulking (clinical stage) was a significant factor (P = 0.001 for stages IIIC and P = 0.004 for stage IV; Table 1).
To determine the impact of peritoneal disease before debulking, univariate and multivariate Cox regression analyses were performed on 83 patients with advanced peritoneal disease of more than 2 cm (stages IIIC and IV). Results are shown on Table 2. Gross nodal disease was identified in 65 (78%) of these patients. On univariate and multivariate analyses, removal of more than 40 lymph nodes was a significant prognostic factor for OS (24.5% vs 54.3%; P = 0.032; hazard ratio, 0.52; 95% CI, 0.29–0.35). The Kaplan-Meier survival curves are shown in Figure 1. There was a subset of 29 patients with advanced peritoneal disease of more than 2 cm (stages IIIC and IV) and with no residual disease after debulking who were further analyzed to determine the impact of lymphadenectomy in patients with no residual disease. Results are shown in Table 3. Removal of more than 10 positive nodes seemed to have a positive impact on OS, although the number of patients is too low to establish a valid conclusion.
The National Institute of Health Consensus Development Conference on Ovarian Cancer held in Bethesda in April 1994 concluded that “aggressive attempts at cytoreductive surgery as the primary management of ovarian cancer will improve the patient’s opportunity for long-time survival.” There was no reference to nodal removal as part of cytoreductive surgery. Wimberger et al9 in 2009 concluded that “radicality in primary surgical management in gynaecological cancers, especially in ovarian cancer, is the most important factor influencing patient survival.” Radical pelvic and para-aortic lymphadenectomy is recommended in cases of complete resection because of the high incidence of lymph node metastases, especially in the high para-aortic region.9
The role of complete or systematic lymphadenectomy, pelvic and aortic, for patients with advanced EOC is not well defined. Some studies have observed a benefit relative to OS10 and cause-specific survival (CSS)11,12 compared to no lymphadenectomy. In a review of 3 prospective randomized trials, a significant therapeutic role for systematic pelvic and aortic lymphadenectomy was noted compared to patients with no lymphadenectomy.13 The impact was greater for patients cytoreduced to microscopic disease status.12 In another study, Rouzier et al11 observed a significant improvement in 5-year CSS regardless of the stage and extent of surgery. Five-year CSS was decreased when no lymphadenectomy was performed, and CSS increased as the number of nodes increased. Others have noted a significant increase in 5-year CSS in patients with stage IIIC as the number of nodes removed increased.12 The performance of lymphadenectomy had a positive impact on 5-yr CSS compared to patients with no lymphadenectomy.11 In a meta-analysis by Kim et al,14 a possible survival benefit of systematic lymphadenectomy was noted in patients with advanced disease, most noticeable when a complete debulking was accomplished. In a prospective randomized trial comparing systematic lymphadenectomy versus selective removal of enlarged nodes, Benedetti et al6 noted a significant improvement of the progression-free survival, but not OS. It is important to note that many patients with nodal metastases did not have enlarged nodes, as the difference of positive nodes between both patient groups was quite different: 70% for patients with systematic lymphadenectomy versus 42% for resection of enlarged nodes only. Unfortunately, the authors did not address the impact of systematic lymphadenectomy in completely debulked patients. Others have found a benefit of lymphadenectomy for patients with platinum-resistant disease.15 There is agreement that lymphadenectomy is beneficial for patients with isolated recurrent nodal disease.16
The extent of lymphadenectomy was limited (aortic or pelvic lymphadenectomy) in 15% of the patients. This was secondary to surgeon’ decision, no enlarged nodes detected, residual intraperitoneal disease, amount of blood loss, length of surgery, and other factors.
In this study, neither the extent of the lymphadenectomy (evaluated by the number of removed nodes) nor the extent of nodal metastases (based on the number of positive nodes) was a prognostic factor (Table 1). Patients with International Federation of Gynecology and Obstetrics stage IIIC due only to positive nodes or with no peritoneal disease before surgery (clinical stages I, II, IIIA, and IIIB) were excluded from a survival reanalyses, observing a survival benefit of lymphadenectomy in the patients with EOC with advanced peritoneal disease of more than 2 cm when more than 40 lymph nodes were removed. Because the extent of peritoneal disease before surgery is an important prognostic factor for survival in patients with positive nodes,17,18 we analyzed the role of lymphadenectomy in patients with advanced peritoneal disease of more than 2 cm before debulking. In a subset of 29 patients with no residual disease after debulking, we observed that removal of more than 10 positive nodes had a positive impact on OS compared to patients with less than 10 positive nodes. However, the number of patients is too low to draw any valid conclusions. Microscopic or macroscopic nodal disease was not an independent prognostic factor on survival. The patients with EOC with advanced peritoneal disease of more than 2 cm had a high rate (78%) of enlarged nodes.
In conclusion, we observed a survival benefit of lymphadenectomy in the patients with EOC with advanced peritoneal disease of more than 2 cm when more than 40 lymph nodes were removed. There was a survival benefit in a small subset of patients with advanced peritoneal disease of more than 2 cm and no residual disease after debulking when more than 10 positive nodes were removed, although the number of patients is too low to establish a valid conclusion. We hope the prospectively randomized international cooperative multicenter trial lymphadenectomy in ovarian neoplasms (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom OP.3) will provide answers to multiple remaining questions.
1. Winter WE 3rd, Maxwell GL, Tian C, et al.. Gynecologic Oncology Group Study. Prognostic factors
for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007; 25: 3621–3627.
2. du Bois A, Reuss A, Pujade-Lauraine E, et al.. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer
: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009; 115: 1234–1244.
3. Eisenkop SM, Spirtos NM, Friedman RL, et al.. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival
for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003; 90: 390–396.
4. Benedet JL, Pecorelli S. Why cancer staging? Int J Gynecol Obstet. 2006; 95 (suppl 1): S3.
5. Heintz AP, Odicino F, Maisonneuve P, et al.. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006; 95 (suppl 1): S161–S192.
6. Benedetti Panici P, Maggioni A, Hacker N, et al.. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005; 97: 560–566.
7. Harrell FE Jr. (2001b) Re: (S) model fitting with logistic regression. Semail@example.com. April 6, 2011.
8. Hosmer DW, Lemeshow S. Applied Logistic Regression. Wiley-Interscience. 2000.
9. Wimberger P, Kimmig R. The role of radical lymphadenectomy. Experiences from the AGO Ovarian Cancer Study Group. Urologe A. 2009; 48: 26–31.
10. Morice P, Pautier P, Lhommé C, et al.. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes in optimally debulked advanced ovarian cancer: a randomized clinical trial. JNCI J Natl Cancer Inst. 2005; 97: 1620–1621.
11. Rouzier R, Bergzoll C, Brun JL, et al.. The role of lymph node resection in ovarian cancer: analysis of the Surveillance, Epidemiology, and End Results (SEER) database. BJOG. 2010; 117: 1441–1443.
12. Chan JK, Urban R, Hu JM, et al.. The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients. Br J Cancer. 2007; 96: 1817–1822.
13. du Bois A, Reuss A, Harter P, et al.. Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). J Clin Oncol. 2010; 28: 1733–1739.
14. Kim HS, Ju W, Jee BC, et al.. Systematic lymphadenectomy for survival
in epithelial ovarian cancer: a meta-analysis. Int J Gynecol Cancer. 2010; 20: 520–528.
15. Isonishi S, Niimi S, Sasaki H, et al.. Drug sensitivity–related benefit of systematic lymphadenectomy during cytoreductive surgery in optimally debulked stages IIIc and IV ovarian cancer. Gynecol Oncol. 2004; 93: 647–652.
16. Benedetti Panici P, Perniola G, Angioli R, et al.. Bulky lymph node resection in patients with recurrent epithelial ovarian cancer: impact of surgery. Int J Gynecol Cancer. 2007; 17: 1245–1251.
17. Cliby WA, Aletti GD, Wilson TO, et al.. Is it justified to classify patients to stage IIIC epithelial ovarian cancer based on nodal involvement only? Gynecol Oncol. 2006; 103: 781–782.
18. Pereira A, Magrina JF, Magtibay PM, et al.. The impact of peritoneal metastases in epithelial ovarian cancer with positive nodes. Int J Gynecol Cancer. 2011; 21: 1375–1379.
Keywords:Copyright © 2012 by IGCS and ESGO
Advanced epithelial ovarian cancer; Prognostic factors; Survival; Therapeutic role pelvic and aortic lymphadenectomy