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Nodal Resection in Ovarian Cancer: Does It Matter?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas, M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Synopsis: Complete lymphadenectomy appears to be important only in those patients without post-operative residual disease following surgical cytoreduction.
Source: Du Bois A, et al. Potential role of lymphadenectomy in advanced ovarian cancer: A combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol 2010;28:1733-1739.
The prognostic value of complete cytoreduction has been well described and supported by several meta-analyses. However, the impact of lymphadenectomy is more controversial. A previously reported randomized trial of lymphadenectomy in patients with advanced stage ovarian cancer demonstrated a benefit for the procedure only for progression-free survival (PFS), but not overall survival (OS), an endpoint it was underpowered to assess. Du Bois and colleagues combined the surgical data from three prospective phase III treatment trials performed by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) to address the impact of lymphadenectomy OS. The data were combined because eligibility criteria between the trials were nearly the same and the trials demonstrated no treatment effect between their randomized arms. They also analyzed only data from those in whom residual disease was less than 1 cm (so called "optimal" population), and divided this cohort into those with and without any residual disease. Previous reports from this group have documented a statistically different outcome in both PFS and OS between those with (1-10 mm) and those without (no macroscopic) residual disease. They looked at three categories of node evaluation: none, limited, and complete resection. Further, they addressed a subpopulation where complete information on pre-operative and intra-operative node status was documented. Overall, data were analyzed from 1924 patients (cohort 1), of whom 1496 patients had complete pre- and intra-operative data documented regarding nodal evaluation (cohort 2). Remarkably, in both cohorts, lymphadenectomy was significantly associated with improved OS in patients without post-operative residual disease (19 and 25 months, respectively). In the larger cohort, even a limited lymphadenectomy provided a benefit in this population. However, for patients left with tumor residuum after debulking, the performance of a lymphadenectomy barely impacted OS, unless the nodes were clinically abnormal. The authors conclude that performance of lymphadenectomy appears to benefit only patients without post-operative residual disease and can only support its use in this setting. However, this hypothesis can only formally be addressed in a prospective randomized trial, which has been developed and is currently enrolling patients.
There are several concepts surrounding the subject of this study which are important to recall with respect to ovarian cancer: 1) about 20% of patients with suspected early-stage or limited disease are upstaged by formal lymphadenectomy; 2) these (stage IIIC) patients fare better than those in whom nodal status is unknown and better than other stage IIIC patients with intraperitoneal tumor; 3) patients with metastatic disease at presentation have metastatic nodal disease in about 60% of cases; 4) intra-operative assessment of nodal disease in these patients is distinctly inaccurate with about 30% of normal appearing nodes harboring metastatic disease; 5) the new standard for "optimal" cytoreduction is no visible residuum. The current study tries to bring clarity to the impact of lymphadenectomy as an isolated procedure considering these "truisms" and largely confirms the bias of most gynecologic oncologists that the greatest impact of the procedure is in those in whom, whether by biology or surgical effort, are left with the least disease following debulking. Although the issue was seemingly resolved by a previous randomized phase III trial comparing complete pelvic and paraortic lymphadenectomy to removal of suspicious nodes alone, there are several issues to consider. These include the under-representation of truly optimally resected patients and low statistical power to address overall survival, which limited its interpretation to contemporary patient cohorts. The current report provides the necessary rationale to re-frame the question in patients most likely to benefit. Fortunately, the AGO has launched a randomized phase III clinical trial (the Lymphadenectomy in Ovarian Neoplasm [LION] Trial) to formally address this hypothesis.