The standard therapy for advanced epithelial ovarian carcinoma includes total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, washings, blind biopsies of diaphragm and peritoneum, and optimal surgical cytoreduction, followed by platinum-based chemotherapy. The prognostic value of complete tumour debulking on the overall survival has been demonstrated in many retrospective analyses (Piver et al, 1988
; Covens, 2000
; Bristow et al, 2002
). On the basis of a recent meta-analysis of 81 cohorts of patients with stage III–IV disease, it was found that for each 10% increase in maximal cytoreduction, there was an associated 5.5% increase in median survival (Bristow et al, 2002
). However, the role of retroperitoneal nodal resection remains unclear, particularly for advanced-stage disease.
In a retrospective review of 127 patients, Carnino et al (1997)
reported that the probability of finding a lymph node metastasis was significantly higher when more lymph nodes were removed. These authors suggested that systematic lymphadenectomy should be performed, rather than lymph node sampling, to determine the therapeutic impact of lymph node resection in epithelial ovarian cancers. Determining nodal metastases by palpation at the time of surgery has been found to have significant limitations (Petru et al, 1994
; Arango et al, 2000
; Eisenkop and Spirtos, 2001
; Tangjitgamol et al, 2003
The potential benefit of performing of a systematic lymphadenectomy in the primary surgical evaluation of presumed early-stage ovarian cancer patients has been previously investigated. The value of systematic retroperitoneal node dissection may be associated with the upstaging of patients with clinical stage I cancers, which directs them to further treatment with chemotherapy. Furthermore, when initial surgical staging is adequate, patients with low-risk disease may be spared cytotoxic chemotherapy (Trimbos et al, 2003
; Chan et al, 2007
The role of systematic lymphadenectomy in advanced stages of ovarian cancer is somewhat unclear. Some prior studies have found an association between systematic node dissection and improved survival. In a retrospective study of 82 patients with stage III disease, Burghardt et al (1986)
showed that pelvic lymphadenectomy was associated with an improved survival compared with those patients who did not have a lymphadenectomy. In a retrospective review of 150 epithelial cancer patients based on the Tokai Ovarian Tumor Study Group, Kikkawa et al (1995)
found that the performance of a lymphadenectomy was associated with improved survival in a multivariate analysis after controlling for the effects of stage, residual disease, and histological subtype (Hazard Ratio: 0.677; P
In a randomised, controlled multi-institutional study of 427 advanced-staged optimally debulked patients, Benedetti Panici et al (2005)
showed a 7-month improvement in disease-free survival in those who underwent a systematic lymphadenectomy compared with patients who had removal of only pathologically enlarged lymph nodes. In another randomised trial of 268 patients with epithelial ovarian cancer macroscopically confined to the pelvis after cytoreductive surgery, Maggioni et al (2006)
compared the effects of a systematic lymphadenectomy to random sampling of retroperitoneal lymph nodes. These authors revealed that systematic lymphadenectomy was associated with an improvement in both progression-free and overall survival; however, neither was statistically significant. The investigators stated that this trial lacked the power to detect a significant difference between the two groups. These two studies may also have been limited by the short follow-up duration for assessing long-term survival outcomes (Benedetti Panici et al, 2005
). As such, we performed a large population-based study to evaluate the potential role of an extensive lymphadenectomy in women diagnosed with advanced-stage epithelial ovarian cancer.
In this report of 13
918 women with stages III–IV ovarian cancer, 4260 patients had a dissection of at least one lymph node performed as part of their initial surgical evaluation. Our data suggested that a more extensive lymph node dissection was associated with an improved 5-year disease-specific survival. These findings were consistent in patients within substages of stage III disease and those with nodal metastases. Although an increase in the number of positive nodes was associated with a worsened survival, the removal of 1, 2–5, 6–10, and 11–20 nodes improved the outcomes of these patients from 32.8, 36.8, 38.7, 42.0, and 41.7%, respectively. More importantly, multivariate analysis demonstrated that a more extensive node resection, both as a categorical and continuous variable, was associated with an improved survival after adjusting for age, stage, grade, number of positive nodes, and year of diagnosis ().
This study is one of the largest series to evaluate the role of lymphadenectomy in surgically staged advanced ovarian cancer patients. A large proportion of these patients had an extensive lymph node resection; in fact, 707 patients had >20 lymph nodes removed. Given the large size of this cohort, with 13
918 patients, we were able to perform subset analyses on node-positive stage IIIC and/or IV patients showing consistent results. Similar to the results of a randomised trial, our data also showed that metastatic lymph node involvement is associated with poorer survival. However, in our current separate analysis of over 2563 patients with stage IIIC disease and nodal metastases, we were able to perform a detailed subset analysis showing that increasing numbers of metastatic lymph nodes (1, 2–5, and >5) is associated with a worsened survival (40.1, 37.0, and 35.6%, respectively).
Our analysis was limited by the lack of information on surgeon's subspecialty, volume of residual disease, medical comorbidities, location of nodal resection (pelvic vs
paraaortic), adjuvant chemotherapy, and treatment of recurrence. In particular, the extent of extranodal residual disease in stage IIIC and IV patients and its potential impact on the extent of lymphadenectomy were not available in the SEER database. Nevertheless, even among those with stage IIIA disease, defined as microscopic disease in the upper abdomen, the extent of nodal dissection (6–10, 11–20, and >20 nodes) was associated with an improved survival from 61.5, 71.4, and 74.7%, respectively. Moreover, there was no central pathology review. Patients who had a less extensive lymphadenectomy may have had significant medical and/or surgical comorbidities, thus, representing patients with poor prognostic cancers. Furthermore, owing to the retrospective nature of this analysis, there may exist a selection bias where those patients who underwent a more extensive lymphadenectomy may have had less comorbidity, as well as having tumours with more favourable prognostic features. In addition, the extent of a lymphadenectomy may not be truly reflected by the reported number of recovered nodes in our study. Clearly, the extent of the nodal resection by the surgeon as well as comprehensive processing of the specimens by the pathologists influences nodal recovery. In addition, a more thorough lymphadenectomy may be a marker for quality comprehensive medical and surgical care rather than the procedure itself resulting in the improved survival of these patients. Lastly, there are certain patients in whom lymph node sampling or lymphadenectomy may not be feasible owing to comorbidity factors, blood loss, or body habitus. In a prospective randomised trial reported by Benedetti Panici et al (2005)
women who underwent a systematic lymphadenectomy were found to have more postoperative complications, mostly consisting of lymphocytes or lymphoedema. Furthermore, the median operating time was 90
min longer and blood loss was 350
ml higher, with 12% more blood transfusions given when a systematic lymphadenectomy was performed.
There are several possible mechanisms that may explain the improvement in survival that was found to be associated with a more extensive lymphadenectomy in advanced cancers. A more complete lymphadenectomy is likely to remove occult microscopic disease, resulting in a more complete cytoreduction. In the randomised trial reported by Benedetti Panici et al (2005)
, patients with stage IIIB–C and IV epithelial ovarian cancer randomised to undergo systematic pelvic and paraaortic lymphadenectomy were found to have a statistically significant increase in positive lymph nodes compared to those randomised to resection of bulky nodes only (70 vs
<0.001). Thus, compared to those who had a limited lymphadenectomy, 28% more patients in the extensive lymphadenectomy arm benefited from cytoreduction of occult nodal metastases. A meta-analysis of the survival effect of maximum cytoreductive surgery in advanced ovarian carcinoma reported that each 10% increase in maximum cytoreduction was associated with a 5.5% increase in median survival time (Bristow et al, 2002
). The magnitude of improved survival reported in our current study is consistent with these estimates, suggesting that the improvement in disease-specific survival may be associated with the removal of additional occult disease.
Furthermore, an extensive lymph node resection may lead to an improvement in survival by removing micrometastatic disease within the lymph nodes that may be resistant to chemotherapy. Prior studies on patients who underwent chemotherapy followed by second-look surgery showed that 33.3–65.3% of patients with advanced-stage disease had residual disease in the retroperitoneal lymph nodes (Burghardt and Winter, 1989
; Baiocchi et al, 1998
). These studies suggested that chemotherapy appears to have minimal effect on tumour deposit in the nodes; thus, retroperitoneal lymphadenectomy should be an integral component of ovarian cancer cytoreductive surgery.
In summary, our retrospective analysis suggests that the extent of lymphadenectomy is associated with an improvement in disease-specific survival in patients with advanced ovarian carcinoma. Furthermore, the extent of nodal disease provides additional prognostic information. Further trials are warranted to investigate the treatment of these high-risk patients with nodal metastases.