The Potential Role of Lymphadenectomy in Advanced Ovarian Cancer: A Combined Exploratory Analysis of Three Prospective Randomized Phase III Multicenter Trials
objective
Platinum-based/taxane-based chemotherapy after initial surgery is the standard treatment for advanced ovarian cancer. The prognostic role of complete debulking is well described. However, the effects of systemic pelvic and para-aortic lymphadenectomy and their interaction with biological factors have not been fully determined.
way
This is an exploratory analysis of three prospective randomized trials conducted between 1995 and 2002 (Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom Trials 3, 5 and 7) investigating platinum/taxane chemotherapy regimens in advanced ovarian cancer.
outcome
One thousand nine hundred and twenty-four patients were analyzed. Lymphadenectomy is associated with higher survival in patients with no significant residual disease. Median survival was 103 months and 84 months, and 5-year survival was 67.% and 59.2%, respectively, in patients who underwent and did not undergo lymphadenectomy (P = .0166), and multivariate analysis confirmed a significant effect of lymphadenectomy on overall survival (OS; hazard ratio [HR] = 0.74; 95% CI, 0.59 to 0.94; P = 0.0123). For small patients with residual tumour less than 1 cm, the effect of lymphadenectomy on OS was barely significant (HR = 0.85; 95% CI, 0.72 to 1.00; P = .0497). For patients with small residual tumour and clinically suspicious lymph nodes, lymphadenectomy was associated with a 16% improvement in 5-year OS (log-rank test, P = .0038).
conclusion
Lymphadenectomy for advanced ovarian cancer may primarily confer benefit for patients with complete intraperitoneal debulking. However, this hypothesis should be confirmed in the context of prospective randomized trials.
introduce
Epithelial ovarian cancer is the fifth most common cause of cancer death in women and remains the leading cause of gynecologic cancer-related deaths in the United States and Europe. The mainstay of treatment for advanced ovarian cancer is primary surgery, which aims to completely remove all visible tumor material, followed by combination chemotherapy including platinum-based and paclitaxel. While medical treatment is homogeneous, surgical treatment is heterogeneous. Tumor spread and patient characteristics determine individualized surgical treatment. Therefore, the manner and outcome of surgery depends on the resectability of the tumor and the patient's ability to tolerate extensive surgery. Further sources of heterogeneity are surgical skills, infrastructure, and capacity. The surgical outcome of ovarian cancer is usually classified based on the amount of tumor that remains after surgery. If no macroscopic tumor is left, resection is considered complete. If any visible tumor remains after surgery, it is classified according to its maximum diameter. The previous definition classified surgery resulting in residual tumors up to 1 cm in maximum diameter as optimal debulking, whereas surgery resulting in any larger residual tumors was defined as suboptimal debulking. The prognostic value of complete and/or optimal debulking has been reported several times and confirmed in meta-analyses. Lymphatic spread has been reported to be a common feature of both early and advanced ovarian cancer. The unselected series, including all stages of the International Federation of Obstetrics and Gynecology, reported a rate of 44% to 53% of lymph node metastases detected by systematic lymphadenectomy. A prospective study of ovarian cancer confined to the pelvis showed a 22% rate of lymph node metastases diagnosed by systemic pelvic and para-aortic lymphadenectomy. After systemic lymphadenectomy in advanced disease, this increases to 70%. The prognostic role of comprehensive lymph node staging in early ovarian cancer has been determined through exploratory analysis of prospective trials and large epidemiological series. The latter not only suggests the stage migration effect after lymph node dissection, but also shows the effect of lymph node dissection on the prognosis of node-positive patients, thus indicating the treatment effect. This observation could not be confirmed in a prospective randomized trial, however, the trial was underpowered for survival analysis.
Several clinical situations of lymphadenectomy associated with achieving intraperitoneal reduction can be discussed separately. First, patients with a residual tumor larger than 1 cm in the result of intraperitoneal reductive surgery will not benefit from lymphadenectomy at all in terms of the maximum diameter of the residual tumor material. Second, patients with large lymph nodes who have complete or near-complete intraperitoneal debulking can benefit from removing enlarged metastatic lymph nodes by reducing the size of the residual tumor. Third, lymphadenectomy in patients without clinically suspicious lymph nodes and small intra-abdominal residual disease may not alter the status of residual disease, but may reduce tumor burden that may be resistant to chemotherapy. The latter hypothesis was tested by the International Multicenter Lymphadenectomy Trial, which showed a beneficial effect of systemic lymphadenectomy on progression-free survival (PFS). However, the trial did not report a survival benefit, and some authors concluded that systemic lymphadenectomy should no longer be considered the standard of care for advanced ovarian cancer. This conclusion may not be correct for patients with complete macroscopic intraperitoneal resection, as this subgroup did not contribute substantially to the results of the international multicenter lymphadenectomy trial. Only 37% of patients in this trial (159 of 427 patients) underwent macrototal resection, and due to a better prognosis, the proportion of events observed in this subgroup may be lower, so the effect on outcomes is small. The international multicenter lymphadenectomy trial showed metastatic disease in 28% of lymph nodes that were not clinically suspicious. Others have also confirmed the poor reliability of intraoperative palpation in diagnosing lymph node metastases, possibly due to similar node sizes between metastatic and non-metastatic lymph nodes.
Finally, for patients undergoing macroscopic complete intraperitoneal reduction, systemic lymphadenectomy may theoretically increase complete resection of retroperitoneal disease, thereby achieving true macroscopic complete resection status in those patients with undiagnosed residual retroperitoneal disease in the absence of lymphadenectomy. A retrospective series and exploratory analysis of a prospective chemotherapy trial supported this hypothesis by demonstrating the prognostic effect of lymphadenectomy. The latter is supported by surveillance, epidemiology, and database analysis of final results. Data from prospective randomized trials evaluating the potential role of systemic lymphadenectomy in advanced ovarian cancer and complete intraperitoneal resection remain unavailable. Therefore, the Arbeitsgemeinschaft Gynaekologische Onkologie research group decided to conduct an analysis of a large group of patients included in three consecutive prospective randomized trials of advanced ovarian cancer to evaluate the potential impact of lymphadenectomy on PFS and overall survival (OS) and to determine the basis for a follow-up prospective trial on this issue (lymphadenectomy regimen for ovarian tumors).
discuss
Lymphatic spread is a common feature of advanced epithelial ovarian cancer. Histopathology report showed lymphadenopathy positivity in 52.2% of patients in Cohort 1. This rate is very consistent with other reports of lymph node metastases in more than 50% of patients with advanced disease. Positive lymph nodes cannot be reliably diagnosed by imaging or intraoperative palpation, and therefore, the observed rate of positive lymph nodes depends primarily on the completeness of lymphadenectomy. In our series, 24.8% of patients who underwent pelvic and para-aortic lymphadenoadenectomy without intraoperative suspicious lymph nodes developed histologically positive lymph nodes, compared with 17.1% of patients who underwent less well-defined incomplete retroperitoneal surgery. Similar observations have been reported by others when limited lymphadenectomy is compared to systemic lymphadenectomy, possibly because almost one-third of positive lymph nodes are clinically unsuspicious and may be missed during incomplete lymphadenectomy. Thus, the role of complete lymphadenectomy as a staged surgery is well established and provides prognostic information. However, despite the recommendations of many authors and retrospective single-agency series, the role of lymphadenectomy as a treatment is not well accepted. A prospective international lymphadenectomy study comparing systemic pelvic and para-aortic lymphadenectomy to a predominantly incomplete but purported optimal debulking group of patients with only enlarged lymph nodes was removed and found a significant benefit for PFS, but not for OS. Our data suggest a survival benefit for specific subgroups defined based on clinical lymph node status and residual intraperitoneal tumors. A significant effect of combined lymphadenectomy on survival was observed in patients without residual disease, but not in patients with small residual disease.
Further detailed analysis limited to patients with known clinical lymph node status revealed a significant survival benefit only in patients with suspicious lymph nodes preoperatively or intraoperatively, suggesting the role of this procedure as part of debulking by resection of macroscopic visible tumour. Our observations support the latter effect, i.e., more than 90% of patients with clinically suspicious lymph nodes have histologically positive lymph nodes.
The combination of residual disease and clinical lymph node status showed that lymphadenectomy had a significant effect on patients with small residual disease and clinically suspicious lymph nodes, but not on patients with small residual tumors and clinically unaffected lymph nodes. This is in stark contrast to other data that suggest that lymphadenectomy has a positive effect even in patients with macroscopic residual disease. Our data do not support any recommendation for lymphadenectomy in patients with residual intraperitoneal disease, unless lymph node dissection would alter the residual disease status from substantial to minimal. Lymphadenectomy in patients with macroscopic residual disease and no suspicious lymph nodes must balance the small benefits of progression-free survival (PFS) of approximately 6 months12 with increased surgical morbidity, including increased blood loss, increased blood transfusion rates, and lymphoceles or lymphedema in 7% to 22% of patients.
A subgroup of patients with complete intraperitoneal resection and suspicious lymph nodes could not be analyzed, as almost all patients with this condition underwent lymphadenectomy. Finally, patients with complete intraperitoneal resection and clinically unaffected lymph nodes will have a significant survival benefit of 43 months if they undergo lymphadenectomy. This observation may suggest that lymphadenectomy complements complete macroscopic intraperitoneal reduction by removing macroscopic tumor remnants from unenlarged lymph nodes. As mentioned earlier, this condition is observed in about one-third of patients.
Although our data on advanced ovarian cancer are impressive, their interpretation should be approached with caution. Our retrospective studies could not rule out bias in the distribution of patients. We sought to reduce potential bias by performing multivariate analyses, taking into account all known prognostic tumor and patient variables. However, the decision to undergo lymphadenectomy is not made by random assignment but by each surgeon. We cannot rule out the possibility that prognostic factors that were not included in the adjustment panel and were only aware based on the surgeon's intuition (but not included in the case report form) skewed our cohort. Therefore, we used these results only to generate hypotheses for prospective randomized trials in patients with advanced ovarian cancer who had undergone complete intraperitoneal tumor resection without clinically suspicious lymph nodes (the ovarian tumor lymphadenectomy protocol was funded by the German Research Foundation). This study has begun recruiting and the comparison of systemic lymphadenectomy versus no lymphadenectomy in patients without macroscopic residual intra-abdominal tumors may shed light on this important question. Until then, our data suggest that lymphadenectomy should be limited to patients with resection of clinically suspicious lymph node metastases to improve residual disease status.
Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials - PubMed