When what should work doesn’t: Routine lymphadenectomy does not improve overall survival in advanced ovarian cancer

EBM Focus - Volume 14, Issue 6

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Reference: N Engl J Med 2019 Feb 28;380(9):822 (level 1 [likely reliable] evidence)

Much of what is taught in medical school comes from the pathophysiologic principles of what should work based on what is already known. Modern medicine, however, has allowed us to connect some of these dots with trials that test these hypotheses. When the evidence doesn’t align with what we expect to work based on pathophysiology, it is sometimes easier to find flaws in the data than to try to rearrange our thinking. Based on the work of John Meigs, the pathophysiology-based approach to the management of advanced epithelial ovarian cancer includes primary debulking surgery with resection of all macroscopically visible tumor. Ovarian cancer can spread lymphatically, with as many as 50% of patients having lymph node metastasis regardless of the presence of macroscopically bulky lymph nodes on intraoperative evaluation. As such, a pathology-based approach to care would lead the logical clinician to perform standard lymphadenectomy regardless of the presence of bulky lymph nodes, as maximal debulking has been found to improve progression-free and overall survival.

A recent multicenter randomized open-label trial with allocation concealment compared lymphadenectomy versus no lymphadenectomy among women with stage IIb - stage IV epithelial ovarian cancer. Over 600 women were included in the trial, with an average age of 60 years and over 75% with stage IIIB or higher disease. All women had debulking surgery; women with clinically bulky lymph nodes or residual macroscopic disease were excluded from the trial. In an intention to treat analysis, there was no difference in overall survival (69.2 months in no lymphadenectomy group versus 65.5 months in lymphadenectomy group) or progression-free survival. Patients undergoing lymphadenectomy had longer operative times by 1 hour and higher rates of repeat laparotomy, need for blood transfusion, intensive care admission, and mortality within 60 days of surgery. There was no difference in quality of life measures between the two groups.

For clinicians trained under the Flexner model of medical education driven by pathology-based medical practices, the findings in this trial make little sense. Minimal residual disease improves survival. Since the work of Meigs and initial Gynecology Oncology Group trials, lymph nodes have been found to house a significant amount of disease. Removal of such disease should, by the biological theory, improve outcomes. However, two prospective trials have now demonstrated no improvement in overall survival with routine lymphadenectomy compared to no lymphadenectomy (Panici et al 2005).

These findings are another reminder that medical education needs to evolve, much along the lines articulated by Shaughnessy and Slawson. Pathology-based models provide context, but probability-based teaching focused on what has been shown to be effective translates into improved patient outcomes. Additionally, this trial highlights the importance of focusing on patient-oriented outcomes, such as overall survival, as compared to progression-free survival, an outcome fraught with measurement error and bias. The practice of medicine requires clinicians to learn to adapt based upon the best available evidence demonstrating improvement in patient-oriented outcomes.

For more information, see the topic Ovarian cancer in DynaMed Plus. DynaMed users click here.

DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.