Recent advances in research on epigenetic alterations and clinical significance of para-aortic lymphadenectomy in endometrial cancer: an introduction

Abstract

Endometrial cancer is the most frequent cancer of the female reproductive organs in industrialized countries. In 2012, the numbers of new cases and deaths from endometrial cancer in the US were estimated to be 47,130 and 8,010, respectively [1]. The incidence of endometrial cancer is also increasing steadily in Japan, where the estimated number of new cases in 2007 was 9,104 [2] and the number of deaths in 2011 was 2,034 [3]. Endometrial cancer is a surgically staged disease and post-operative therapy is offered to patients with a high risk of recurrence according to the extent and aggressiveness of the tumor. Current topics in endometrial cancer include: the therapeutic significance of lymphadenectomy, the role of epigenetic alterations, and revision of the International Federation of Gynecology and Obstetrics staging criteria (FIGO 2008) for this disease. There was a paradigm shift in the treatment strategy for endometrial cancer after the introduction of a surgical staging system (FIGO 1988) that replaced the older clinical staging system. The newer paradigms of extended-surgical staging containing lymphadenectomy with more restricted use of adjuvant therapy and the older paradigm of simple hysterectomy bilateral salpingo-oophorectomy with more frequent use of adjuvant radiotherapy need to be compared prospectively in terms of survival benefits, quality of life, and cost of treatment [4]. Several issues regarding surgical staging need to be clarified. They include: how should suitable patients for complete lymphadenectomy be selected and what is the optimal extent of lymphadenenctomy? The therapeutic significance of lymphadenectomy has long been a matter of great debate. In 1964, Lewis suggested a therapeutic effect of pelvic lymphadenectomy in nodepositive patients [5]. He employed pelvic lymphadenectomy because endometrial cancer often recurred at the pelvic side wall after conventional hysterectomy and bilateral salpingo-oophorectomy, which suggested inadequate primary surgery. Retrospective studies suggest a therapeutic significance for lymphadenectomy, which is a function of removed lymph node count (thoroughness) and area of dissection (pelvic only versus pelvic and para-aortic lymphadenectomy) [6–8]. However, two prospective randomized controlled trials (RCTs) that intended to prove the therapeutic role of pelvic lymphadenectomy failed to show any survival advantage of pelvic lymphadenectomy versus no lymphadenectomy [9, 10]. However, there has been some criticism about the design of these trials because para-aortic lymphadenectomy was not included in the study arm. A retrospective cohort study which compared pelvic lymphadenectomy with combined pelvic and paraaortic lymphadenectomy revealed survival improvement in the pelvic and para-aortic lymphadenectomy group if this treatment was offered to intermediate-/high-risk endometrial cancer patients [11]. Based on these findings, discussions have begun about the design of future clinical trials to validate the therapeutic significance of lymphadenectomy. Topics for discussion include the eligibility of patients (all patients or selected patients at some risk of nodal metastasis), extent of lymphadenectomy (area: pelvic alone versus pelvic plus para-aortic, thoroughness: number of nodes removed), and type of experimental design (RCT versus cohort study). The difficulties and pitfalls of RCTs for validating surgical procedures have often been addressed [12–16]. These include the participating surgeons’ expertise in experimental N. Sakuragi (&) Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, North 15, West 7, Kitaku, Sapporo 060-8638, Japan e-mail: sakuragi@med.hokudai.ac.jp