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POINT: Is Lymphadenectomy Required in Endometrial Cancer for Adequate Surgical Staging?

POINT: Is Lymphadenectomy Required in Endometrial Cancer for Adequate Surgical Staging?

Oncology (Williston Park). 31(5):390-391, 401.
Francesco Multinu, MD
Jvan Casarin, MD
Andrea Mariani, MD

Sentinel Lymph Node Mapping: A Novel and Promising Approach for Surgical Staging

Endometrial cancer is the most common gynecologic cancer. It is estimated that 61,380 new cases and 10,920 deaths from endometrial cancer will occur in the United States in 2017.[1] More than two-thirds of patients with endometrial cancer are diagnosed at stage I (tumor confined to the corpus uteri) and have a good prognosis (with a 5-year survival rate of 89.6%)[2]; however, approximately 10% of patients who are believed to be at an early stage of disease based on the preoperative evaluation will be found to have lymph node metastases.[3]

Because there are no accurate, cost-effective means of identifying lymph node metastasis preoperatively, current guidelines recommend surgical staging including lymphadenectomy as the standard-of-care treatment in patients at risk for lymphatic dissemination.[4] Although more than 25 years have passed since the International Federation of Gynecology and Obstetrics incorporated surgical staging into the management of endometrial cancer,[5] the role of lymphadenectomy is still debated. This controversy stems mainly from the results of two randomized controlled trials that failed to demonstrate a survival benefit from pelvic lymphadenectomy in patients with early-stage endometrial cancer.[6,7] Although one can argue whether or not lymphadenectomy has any therapeutic benefit, its diagnostic and prognostic role are unquestioned. Indeed, the primary purpose of lymphadenectomy is to determine the extent of tumor spread, thereby identifying patients at risk of recurrence, who might benefit from adjuvant treatment. However, comprehensive lymphadenectomy, which includes both pelvic and para-aortic areas, is associated with increased morbidity and costs.[8]

In the search for a balance between the benefits and drawbacks of performing a comprehensive lymphadenectomy, sentinel lymph node (SLN) mapping has recently gained credibility among gynecologic oncologists and has been included in the National Comprehensive Cancer Network guidelines as an option for the management of endometrial cancer.[9] Although different sites have been proposed for injection of the contrast agent,[10] the SLN mapping protocol developed at Memorial Sloan Kettering Cancer Center (MSKCC) is performed with cervical injection using methylene blue or indocyanine green dye.[11] Also, in this MSKCC algorithm, SLN mapping is followed by lymph node ultrastaging by immunohistochemistry using cytokeratin AE1/AE3.[12] The reliability of this approach has been demonstrated by several studies, including the recently published FIRES trial,[13] showing high sensitivity and a high detection, with a negligible rate of false-negative SLNs.[14-16] As a consequence of its high sensitivity, the MSKCC algorithm does not recommend additional lymphadenectomy in patients for whom SLN mapping is successful.[15] In support of the MSKCC algorithm, a recent study comparing comprehensive lymphadenectomy (performed in a Mayo Clinic historical cohort from 2004 to 2008) vs SLN mapping (in an MSKCC cohort from 2006 to 2013) in low-risk endometrial cancer (myometrial invasion, < 50%) demonstrated that SLN mapping without completing lymphadenectomy does not affect oncologic outcomes.[17] Moreover, preliminary analyses on patients with positive lymph nodes did not show significant difference in survival between comprehensive lymphadenectomy vs SLN mapping.[18] Nevertheless, as with many other innovations in medicine, there are still many uncertainties regarding how to use this new approach, and data are still lacking in many areas. Specific areas for improvement include the following:

• Although ultrastaging allows for detection of a higher number of patients with low-volume disease (isolated tumor cells, < 0.2 mm; micrometastasis, 0.2 to 2 mm),[14] more studies assessing the clinical significance of these metastases and the role of adjuvant treatment in these patients are warranted.

• Additional studies are required to determine the role of frozen section in SLN evaluation during surgery, and in the identification of a subgroup of patients at negligible risk (those with grade 1 to 2 disease; minimal invasion; and small tumors, ie, ≤ 2 cm[19]) who do not need to undergo SLN mapping.

• Because of the limited data available evaluating the optimal treatment for patients with both low-volume metastasis (< 2 mm) and macrometastasis (> 2 mm) detected with SLN mapping, future investigations should address the following questions in patients with lymphatic dissemination: Do we need to complete pelvic and/or para-aortic lymphadenectomy? Do we need to modify the radiation field based on SLN data? Do we need systemic treatment?

• Although SLN mapping is likely to be associated with less morbidity than comprehensive lymphadenectomy, data on this topic are still lacking, so further investigation of this question is needed.

In summary, the diagnostic benefits of SLN evaluation include an ability to identify the extent of tumor dissemination and the utility of SLN mapping in guiding targeted adjuvant treatment in high-risk patients. Therefore, we anticipate rapidly expanding use of SLN mapping by practitioners, especially if future studies confirm the reduced morbidity that is likely associated with this approach.

Financial Disclosure: The authors have no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7-30.

2. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri: FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95(suppl 1):S105-S143.

3. AlHilli MM, Mariani A. The role of para-aortic lymphadenectomy in endometrial cancer. Int J Clin Oncol. 2013;18:193-9.

4. Practice Bulletin No. 149: endometrial cancer. Obstet Gynecol. 2015;125:1006-26.

5. Creasman WT. Announcement, FIGO stages: 1988 revisions. Gynecol Oncol. 1989;35:125-7.

6. Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008;100:1707-16.

7. ASTEC Study Group, Kitchener H, Swart AM, et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373:125-36.

8. Dowdy SC, Borah BJ, Bakkum-Gamez JN, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol. 2012;127:5-10.

9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Uterine neoplasms. Version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

10. Niikura H, Kaiho-Sakuma M, Tokunaga H, et al. Tracer injection sites and combinations for sentinel lymph node detection in patients with endometrial cancer. Gynecol Oncol. 2013;131:299-303.

11. Abu-Rustum NR. Update on sentinel node mapping in uterine cancer: 10-year experience at Memorial Sloan-Kettering Cancer Center. J Obstet Gynaecol Res. 2014;40:327-34.

12. Kim CH, Soslow RA, Park KJ, et al. Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging. Int J Gynecol Cancer. 2013;23:964-70.

13. Rossi EC, Kowalski LD, Scalisi J, et al. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017;18:384-92.

14. Cormier B, Rozenholc AT, Gotlieb W, et al. Sentinel lymph node procedure in endometrial cancer: a systematic review and proposal for standardization of future research. Gynecol Oncol. 2015;138:478-85.

15. Barlin JN, Khoury-Collado F, Kim CH, et al. The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes. Gynecol Oncol. 2012;125:531-5.

16. Plante M, Touhami O, Trinh XB, et al. Sentinel node mapping with indocyanine green and endoscopic near-infrared fluorescence imaging in endometrial cancer: a pilot study and review of the literature. Gynecol Oncol. 2015;137:443-7.

17. Zahl Eriksson AG, Ducie J, Ali N, et al. Comparison of a sentinel lymph node and a selective lymphadenectomy algorithm in patients with endometrioid endometrial carcinoma and limited myometrial invasion. Gynecol Oncol. 2016;140:394-9.

18. Multinu F, Ducie JA, Zahl Eriksson AG, et al. Role of lymphadenectomy and adjuvant treatment in high-risk endometrial cancer with positive lymph nodes: comparison of an historical series with comprehensive surgical staging and a contemporary series with sentinel lymph nodes. Presented at the Society of Gynecologic Oncology (SGO) Annual Meeting; March 12-15, 2017; National Harbor, MD. Abstract 113.

19. Mariani A, Webb MJ, Keeney GL, et al. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol. 2000;182:1506-16.

 
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