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

Oncology (Williston Park). 31(5):390, 400-401.

Emma Rossi, MD

Comprehensive Lymphadenectomy Increases Morbidity and Provides No Survival Benefit in Clinical Stage I Endometrial Cancer

The staging of endometrial cancer creates some interesting challenges and controversies, with none more significant than the topic of whether or not to perform lymphadenectomy, and on whom. Historically the staging of endometrial cancer was performed clinically. However, in 1988 the International Federation of Gynecology and Obstetrics, or FIGO, adjusted the staging of endometrial cancer,[1] from clinical- to surgical-based staging; this occurred after surgical studies demonstrated that, when comprehensive surgical staging was performed, approximately 22% of patients with clinical stage I endometrial cancer had metastatic disease detected, with lymph node metastases found in 11%.[2] Advocates of lymphadenectomy endorse the procedure because it serves to guide their prescription of adjuvant therapy. The primary goal of adjuvant therapy should be to improve patient survival-yet, to date, no survival advantage has been associated with the performance of lymphadenectomy in endometrial cancer.

In 2009, two seminal randomized controlled trials were published that questioned whether routine lymphadenectomy at the time of endometrial cancer staging is associated with improved survival.[3,4] In the two trials, a total of 1,922 patients were randomly assigned to treatment with hysterectomy and bilateral salpingo-oophorectomy (with sampling of suspicious lymph nodes) or hysterectomy and bilateral salpingo-oophorectomy plus obligatory complete pelvic lymphadenectomy. Neither trial found a difference in overall survival between the two study groups (hazard ratio [HR], 1.2, 95% CI, 0.86–1.54; and HR, 1.16, 95% CI, 0.67–2.02). In response to the publication of this level I evidence from the two studies, the Cochrane Database Systematic Review summarized its conclusions about lymphadenectomy for endometrial cancer by stating: “We found no evidence that lymphadenectomy decreases the risk of death or disease recurrence compared with no lymphadenectomy in women with presumed stage I disease. The evidence on serious adverse events suggests that women who receive lymphadenectomy are more likely to experience surgically related systemic morbidity or lymphoedema/lymphocyst formation.”[5]

In fact, while level I evidence has not shown an improvement in survival with lymphadenectomy, an increase in patient morbidity has been observed. Increased rates of lymphadenectomy yielding higher numbers of node counts were observed after surgical staging, and were linked to higher rates of identifying patients with lymph node metastases; as a result, lymphadenectomy for the surgical treatment of endometrial cancer was advocated by FIGO and the American Congress of Obstetricians and Gynecologists.[6] This trend of lymph node removal at initial surgery was coupled with increased rates of lymphedema.[7] Lymphedema in the lower extremities has been conservatively estimated to occur in approximately 20% of patients undergoing complete pelvic and para-aortic lymphadenectomy for gynecologic cancers,[8] particularly when associated with higher node counts and circumflex iliac nodal removal.[9] Lymphedema is a major iatrogenic complication, and has the potential to significantly impact the survivorship experience.

Morbidity following lymphadenectomy is not restricted to the incidence of lymphedema. In recent decades, minimally invasive surgery has emerged as the preferred modality for the surgical management of endometrial cancer, because it achieves clinical outcomes similar to those observed with more invasive approaches but with lower rates of postoperative morbidity and improved quality of life.[10,11] However, comprehensive lymphadenectomy is difficult to perform in a minimally invasive fashion, particularly in morbidly obese women, a patient population in which there can be high rates of conversion from laparoscopy to laparotomy, a surgical approach associated with greater morbidity.[12] As the rates and degree of obesity in our populations rise, will we accept moving away from the proven patient-centered advantages of minimally invasive surgery in order to preserve the more questionable benefits of lymphadenectomy? Given that the majority of patients diagnosed with endometrial cancer will survive their cancer, it is important that surgeons do not introduce lifelong comorbidities that will erode quality of life, unless these approaches convey a substantial and measurable clinical benefit.

Those who would rely on surgical pathology results to guide the adjuvant therapy prescription can look to the uterine specimen itself, to inform their treatment decisions. Identification of high/intermediate risk factors through evaluation of uterine specimens (high-grade tumors, deep myometrial invasion, lymphovascular space invasion), further categorized by prognostic factors such as the patient’s age, has been shown to be useful in determining which patients will experience improved local control by the addition of adjuvant radiation.[13,14] In the Gynecologic Oncology Group study GOG-99, patients were randomized to surgery alone or surgery with postoperative radiation, and were included only if they were comprehensively staged with lymphadenectomy; once again, however, adjunctive radiation therapy provided no overall survival advantage in this stage I population who had undergone lymphadenectomy.[13]

The question that should be posed to those who advocate for lymphadenectomy as a tool to guide the adjuvant therapy of endometrial cancer is: At what cost to the patient is lymphadenectomy performed? If we do not see survival improvements associated with complete, comprehensive pelvic and/or para-aortic lymphadenectomy, and instead the procedure serves purely to prognosticate and categorize, is it acceptable to increase patient morbidity in the process? If surgeons do subject patients to extirpation of lymph nodes as a way of prognosticating risk and guiding adjuvant therapy in endometrial cancer, they should strongly consider “patient-selective” approaches (algorithms that restrict lymphadenectomy to only patients at the highest risk of harboring metastatic disease[15,16]) and/or “node-selective” approaches, such as sentinel lymph node biopsy, in which lymph node retrieval is limited to a low volume of high-yield tissue.[17-19]

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

References:

1. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol. 1989;96:889-92.

2. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group Study. Cancer. 1987;60:2035-41.

3. 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.

4. 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.

5. May K, Bryant A, Dickinson HO, et al. Lymphadenectomy for the management of endometrial cancer. Cochrane Database Syst Rev. 2010;1:CD007585.

6. American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol. 2005;106:413-25.

7. Abu-Rustum NR, Alektiar K, Iasonos A, et al. The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center. Gynecol Oncol. 2006;103:714-8.

8. Hareyama H, Hada K, Goto K, et al. Prevalence, classification, and risk factors for postoperative lower extremity lymphedema in women with gynecologic malignancies: a retrospective study. Int J Gynecol Cancer. 2015;25:751-7.

9. Lindqvist E, Wedin M, Fredrikson M, Kjolhede P. Lymphedema after treatment for endometrial cancer: a review of prevalence and risk factors. Eur J Obstet Gynecol Reprod Biol. 2017;211:112-21.

10. Kornblith AB, Huang HQ, Walker JL, et al. Quality of life of patients with endometrial cancer undergoing laparoscopic International Federation of Gynecology and Obstetrics staging compared with laparotomy: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:5337-42.

11. Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 study. J Clin Oncol. 2012;30:695-700.

12. Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group study LAP2. J Clin Oncol. 2009;27:5331-6.

13. Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92:744-51.

14. Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet. 2000;355:1404-11.

15. Mariani A, Dowdy SC, Cliby WA, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008;109:11-8.

16. Kang S, Nam JH, Bae DS, et al. Preoperative assessment of lymph node metastasis in endometrial cancer: a Korean Gynecologic Oncology Group study. Cancer. 2017;123:263-72.

17. Darai E, Dubernard G, Bats AS, et al. Sentinel node biopsy for the management of early stage endometrial cancer: long-term results of the SENTI-ENDO study. Gynecol Oncol. 2015;136:54-9.

18. Khoury-Collado F, Murray MP, Hensley ML, et al. Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes. Gynecol Oncol. 2011;122:251-4.

19. Rossi EC, Kowalski LD, Scalici 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.