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Lymphadenectomy influences the utilization of adjuvant radiation treatment for endometrial cancer

  • Charu Sharma
    Affiliations
    Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY
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  • Israel Deutsch
    Affiliations
    Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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  • Sharyn N. Lewin
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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  • William M. Burke
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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  • Yaming Qiao
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY
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  • Xuming Sun
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY
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  • Clifford K. Chao
    Affiliations
    Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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  • Thomas J. Herzog
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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  • Jason D. Wright
    Correspondence
    Reprints: Jason D. Wright, MD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 161 Fort Washington Ave., Eighth Flr., New York, NY. 10032
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, NY

    Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY
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Published:September 16, 2011DOI:https://doi.org/10.1016/j.ajog.2011.09.001

      Objective

      We analyzed the effect of lymphadenectomy on the use of adjuvant radiation treatment for women with stage I-II endometrial cancer.

      Study Design

      Women with stage I-II endometrioid adenocarcinomas treated between 1988 and 2006 and recorded in the Surveillance, Epidemiology, and End Results database were identified. The influence of lymphadenectomy (LND) on receipt of external beam radiation and brachytherapy stratified was examined.

      Results

      We identified 58,776 women including 26,043 who underwent LND (44.3%). Among women younger than 60 years of age with stage IA (grades 1, 2, and 3) tumors, LND had no impact on the use of radiation. Patients with stage IB (grade 2 or 3) and stage IC (grade 1 or 2) tumors who underwent lymph node dissection were less likely to undergo external beam radiation and more likely to receive vaginal brachytherapy (P < .05 for all). Furthermore, the extent of lymphadenectomy influenced the receipt of radiation.

      Conclusion

      Women who undergo lymphadenectomy are less likely to receive whole pelvic radiotherapy.

      Key words

      Endometrial cancer is the most common gynecologic malignancy. In the United States, it is estimated that 43,470 women will be diagnosed with the endometrial cancer in 2010 and that 7950 will die from the disease.
      • Jemal A.
      • Siegel R.
      • Xu J.
      • Ward E.
      Cancer statistics, 2010.
      Although the majority of women are diagnosed at an early stage and have a favorable outcome, a number of clinicopathologic risk factors predispose to a poorer prognosis. Age, stage, tumor grade, histologic type, depth of myometrial invasion, and metastasis to the regional lymph nodes are all established prognostic factors.
      • Aalders J.
      • Abeler V.
      • Kolstad P.
      • Onsrud M.
      Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients.
      • Creasman W.T.
      • Morrow C.P.
      • Bundy B.N.
      • Homesley H.D.
      • Graham J.E.
      • Heller P.B.
      Surgical pathologic spread patterns of endometrial cancer A Gynecologic Oncology Group study.
      • Morrow C.P.
      • Bundy B.N.
      • Kurman R.J.
      • et al.
      Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study.
      For Editors' Commentary, see Table of Contents
      See related editorial, page 509
      Metastasis to the pelvic and paraaortic lymph nodes is widely recognized as the most important prognostic factor for endometrial cancer.
      • Creasman W.T.
      • Morrow C.P.
      • Bundy B.N.
      • Homesley H.D.
      • Graham J.E.
      • Heller P.B.
      Surgical pathologic spread patterns of endometrial cancer A Gynecologic Oncology Group study.
      • Morrow C.P.
      • Bundy B.N.
      • Kurman R.J.
      • et al.
      Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study.
      The Gynecologic Oncology Group (GOG) demonstrated the importance of nodal metastasis in a landmark surgicopathology study of 621 patients with clinical stage I tumors. In this report the investigators noted that regional lymph nodes were the most common site of extrauterine disease and that the frequency of nodal dissemination correlated with tumor grade and depth of myometrial invasion. Five year recurrence-free survival for patients with pelvic nodal involvement was 58% and decreased to 41% for women with paraaortic metastases.
      • Morrow C.P.
      • Bundy B.N.
      • Kurman R.J.
      • et al.
      Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study.
      The importance of nodal disease was further acknowledged in 1988 when a surgical staging system that included pathologic assessment of the regional nodes was adopted.
      • Creasman W.
      Revised FIGO staging for carcinoma of the endometrium.
      With the recognition of the importance of the status of the regional lymphatics, lymphadenectomy was incorporated into the primary surgical management of women with endometrial cancer.
      • Barakat R.R.
      • Lev G.
      • Hummer A.J.
      • et al.
      Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.
      • Chan J.K.
      • Wu H.
      • Cheung M.K.
      • Shin J.Y.
      • Osann K.
      • Kapp D.S.
      The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
      • Cragun J.M.
      • Havrilesky L.J.
      • Calingaert B.
      • et al.
      Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer.
      • Chan J.K.
      • Cheung M.K.
      • Huh W.K.
      • et al.
      Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients.
      Proponents of the procedure argue that it provides important prognostic information and helps to guide adjuvant treatment planning.
      • Barakat R.R.
      • Lev G.
      • Hummer A.J.
      • et al.
      Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.
      • Chan J.K.
      • Wu H.
      • Cheung M.K.
      • Shin J.Y.
      • Osann K.
      • Kapp D.S.
      The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
      As the use of lymphadenectomy increased, data emerged that the procedure may provide a therapeutic benefit in and of itself; those patients who underwent a more extensive dissection had improved survival.
      • Cragun J.M.
      • Havrilesky L.J.
      • Calingaert B.
      • et al.
      Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer.
      • Chan J.K.
      • Cheung M.K.
      • Huh W.K.
      • et al.
      Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients.
      • Kilgore L.C.
      • Partridge E.E.
      • Alvarez R.D.
      • et al.
      Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling.
      However, 2 recent randomized trials cast doubt on the role of nodal dissection. Both of these studies found that lymphadenectomy had no effect on survival and that the procedure was associated with a small, but statistically significant, increase in morbidity.
      • Kitchener H.
      • Swart A.M.
      • Qian Q.
      • Amos C.
      • Parmar M.K.
      Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study.
      • Benedetti Panici P.
      • Basile S.
      • Maneschi F.
      • et al.
      Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial.
      Given the conflicting data on lymphadenectomy, performance of the procedure is now actively debated.

      Creasman WT, Mutch DE, Herzog TJ. ASTEC lymphadenectomy and radiation therapy studies: are conclusions valid? Gynecol Oncol;116:293-4.

      Although it appears that lymphadenectomy does not directly influence survival, the procedure may be important in guiding adjuvant treatment planning. Although small institutional studies have suggested that nodal dissection effects the allocation of adjuvant treatment, the population-based effect of lymphadenectomy on influencing patterns of care remains unknown.
      • Barakat R.R.
      • Lev G.
      • Hummer A.J.
      • et al.
      Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.
      • Cragun J.M.
      • Havrilesky L.J.
      • Calingaert B.
      • et al.
      Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer.
      • Goudge C.
      • Bernhard S.
      • Cloven N.G.
      • Morris P.
      The impact of complete surgical staging on adjuvant treatment decisions in endometrial cancer.
      Even if lymphadenectomy does not alter survival, the procedure may be worthwhile in subsets of patients if it can spare women unnecessary additional treatment. Surgically staged patients may avoid adjuvant radiation altogether or opt for brachytherapy, which is associated with survival that is comparable with whole pelvic radiation.
      • Lin L.L.
      • Mutch D.G.
      • Rader J.S.
      • Powell M.A.
      • Grigsby P.W.
      External radiotherapy versus vaginal brachytherapy for patients with intermediate risk endometrial cancer.
      • Seago D.P.
      • Raman A.
      • Lele S.
      Potential benefit of lymphadenectomy for the treatment of node-negative locally advanced uterine cancers.
      • Straughn J.M.
      • Huh W.K.
      • Orr Jr, J.W.
      • et al.
      Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy.
      The goal of our study was to perform a population-based analysis to determine the effect of lymphadenectomy on influencing the use of adjuvant radiation treatment for women with stage I-II endometrial cancer.

      Materials and Methods

      Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was utilized. SEER is a population-based tumor registry that captures data on approximately 26% of the US population.
      The Surveillance, Epidemiology, and End Results (SEER) program: data quality.
      SEER comprises several geographically distinct tumor registries. Data from SEER 17 registries was utilized.
      Surveillance, Epidemiology, and End Results, SEER*Stat Database: incidence-SEER 9 regs limited-use, Nov 2006 Sub (1973-2004), National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Cancer Statistics Branch, released April 2007, based on the November 2006 submission.
      All data were publicly available, deidentified, and exempt from institutional review board review.
      Women with stage I-II endometrioid adenocarcinomas of the uterine corpus treated between 1988 and 2006 were included in the analysis. The clinical and pathologic date including age at diagnosis (<60 or ≥60 years old), tumor grade (1, 2, or 3), and marital status were collected. The year of diagnosis was classified as 1988-1994, 1995-2000, or 2001-2006.
      Patients were categorized based on the geographic area of residence at the time of diagnosis: central (Detroit, MI; Iowa; Kentucky; Louisiana; Utah), eastern (Connecticut; New Jersey; Atlanta, GA; rural Georgia), and western (Alaska; California; Hawaii; Los Angeles, CA; New Mexico; San Francisco, CA; San Jose, CA; Seattle, WA) United States.
      Use of adjuvant radiation therapy (external beam or brachytherapy) was collected. Patients who received both external beam and vaginal brachytherapy were included in the external beam radiation group.
      Patients who had any lymph nodes removed were classified as having undergone lymphadenectomy. To assess the effect of the extent of lymphadenectomy on the use of adjuvant therapy, a second analysis was performed among women who underwent lymphadenectomy comparing those with 1-9 nodes removed with those who had 10 or more nodes removed.
      • Miller D.S.
      Advanced endometrial cancer: is lymphadenectomy necessary or sufficient?.
      Staging information was determined for each patient using the extent of disease codes and was based on the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system.
      Clinical and demographic characteristics of the cohort were compared based on the performance of lymphadenectomy and compared using the χ2 test. Use of external beam and vaginal brachytherapy was then compared based on the performance of lymphadenectomy. These analyses were stratified by stage, grade, and age at diagnosis. P < .05 was considered statistically significant. All analyses were performed with SAS version 9.2 (SAS Institute Inc, Cary, NC).

      Results

      A total of 58,776 women including 26,043 who underwent lymph node sampling (44.3%) and 32,733 who did not undergo lymphadenectomy (55.7%) were identified. The clinical and demographic characteristics of the cohort are displayed in Table 1. Patients who underwent lymphadenectomy were more often nonwhite, were diagnosed from 2001 to 2006, and resided in the western United States (P < .0001 for all). Women with high-grade tumors and patients with more advanced-stage disease were also more likely to undergo lymphadenectomy (P < .0001 for both).
      TABLE 1Clinical and demographic characteristics of the cohort
      CharacteristicNo lymphadenectomyLymphadenectomyP value
      32,733 (55.7)26,043 (44.3)
      Age, y.16
       <6013,718 (41.9)10,766 (41.3)
       ≥6019,015 (58.1)15,277 (58.7)
      Race< .0001
       White29,371 (89.7)22,707 (87.2)
       Black1243 (3.8)1251 (4.8)
       Other2007 (6.1)1980 (7.6)
       Unknown112 (0.3)105 (0.4)
      Year of diagnosis< .0001
       1988-19948572 (26.2)3451 (13.3)
       1995-200010,032 (30.7)6631 (25.5)
       2001-200614,129 (43.2)15,961 (61.3)
      SEER registry< .0001
       West16,530 (50.5)14,134 (54.3)
       Central9352 (28.6)6199 (23.8)
       East6851 (20.9)5710 (21.9)
      Marital status.47
       Married18,125 (55.4)14,387 (55.2)
       Single13,540 (41.4)10,848 (41.7)
       Unknown1068 (3.3)808 (3.1)
      Tumor grade< .0001
       119,347 (59.1)9695 (37.2)
       29609 (29.4)10,124 (38.9)
       32187 (6.7)4880 (18.7)
       Unknown1590 (4.9)1344 (5.2)
      Radiation< .0001
       External beam3727 (11.4)4598 (17.7)
       Brachytherapy875 (2.7)1954 (7.5)
       Other165 (0.5)222 (0.9)
       None27,966 (85.4)19,269 (74.0)
      Stage< .0001
       IA12,129 (37.1)6042 (23.2)
       IB16,127 (49.3)13,006 (49.9)
       IC3447 (10.5)4898 (18.8)
       IIA570 (1.7)1008 (3.9)
       IIB460 (1.4)1089 (4.2)
      SEER, Surveillance, Epidemiology, and End Results.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.
      Table 2 displays the use of radiation (external beam and vaginal brachytherapy) in women younger than 60 years of age stratified by stage and grade. Among the women with stage IA tumors (grades 1, 2, and 3), lymph node dissection had no impact on the use of radiation. Patients with stage IB tumors (grade 2 or 3) who underwent lymph node dissection were less likely to undergo external beam radiation and were more likely to receive vaginal brachytherapy (Figure). For example, among the women with stage IB grade 3 tumors, external beam radiation was administered to 30.0% of those who underwent lymphadenectomy compared with 36.5% of those who did not undergo lymphadenectomy (P = .04), whereas brachytherapy was given to 13.8% of those who underwent nodal dissection and to 4.5% of those who did not (P < .0001).
      TABLE 2Effect of lymphadenectomy on use of radiation in women younger than 60 years of age
      VariableTotalLymph nodesNo lymph nodesExternal beam radiationVaginal brachytherapy
      Lymph node dissection, n (%)No lymph node dissection, n (%)P valueLymph node dissection, n (%)No lymph node dissection, n (%)P value
      IA
       All IA98613316654575 (2.3)68 (1.0)< .000152 (1.6)53 (0.8).0005
       Grade 165961849474717 (0.9)31 (0.7).2515 (0.8)29 (0.6).37
       Grade 22231978125327 (2.8)23 (1.8).1415 (1.5)15 (1.2).49
       Grade 341427913527 (9.7)10 (7.4).4513 (4.7)2 (1.5).10
      IB
       All IB11,60654156191574 (10.6)457 (7.4)< .0001397 (7.3)217 (3.5)< .0001
       Grade 160642179388589 (4.1)135 (3.5).2378 (3.6)95 (2.5).01
       Grade 2384220841758183 (8.9)200 (11.4).008164 (7.9)100 (5.7).008
       Grade 31177889288267 (30.0)105 (36.5).04123 (13.8)13 (4.5)< .0001
      IC
       All IC16911107584469 (42.4)311 (53.3)< .0001130 (11.7)24 (4.1)< .0001
       Grade 157832025887 (27.2)116 (45.0)< .000142 (13.1)16 (6.2).006
       Grade 2650438212177 (40.4)129 (60.9)< .000146 (10.5)4 (1.9).0001
       Grade 338829791192 (64.7)61 (67.0).6821 (7.1)3 (3.3).19
      IIA
       All IIA666428238153 (35.8)99 (41.6).1483 (19.4)20 (8.4).0002
       Grade 129016212842 (25.9)43 (33.6).1531 (19.1)13 (10.2).03
       Grade 22581689068 (40.5)45 (50.0).1433 (19.6)6 (6.7).006
       Grade 379661332 (48.5)9 (69.2).179 (13.6)0 (—).16
      IIB
       All IIB660500160282 (56.4)103 (64.4).0753 (10.6)13 (8.1).36
       Grade 12031366762 (45.6)38 (56.7).1421 (15.4)4 (6.0).05
       Grade 228221270121 (57.1)48 (68.6).0924 (11.3)9 (12.9).73
       Grade 31361201679 (65.8)13 (81.3).227 (5.8)0 (—).32
      Total number of patients for each substage includes patients with unknown tumor grade.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.
      Figure thumbnail gr1
      FIGUREUse of external beam radiation and vaginal brachytherapy
      A, Use of external beam radiation in women younger than 60 years of age with stage IB or IC tumors stratified by performance of lymphadenectomy. B, Use of external beam radiation in women 60 years of age or older. C, Use of vaginal brachytherapy in women younger than 60 years of age. D, Use of vaginal brachytherapy in women 60 years of age or older. Solid blue line represents women who underwent lymphadenectomy, dashed red line represents women who did not undergo nodal dissection.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.
      Similar trends were noted for women with stage IC (grade 1 and 2) tumors. Among those with stage IC grade 2 neoplasms, 40.4% of women who had a lymph node dissection received external beam radiotherapy vs 60.9% of those who did not (P < .0001). In addition, 10.5% of those who underwent lymph node dissection received vaginal brachytherapy compared with 1.9% with no lymph node dissection (P = .0001).
      These findings were similar for patients 60 years of age or older (Table 3). Patients with stage IA (grade 3), stage IB (grade 2), stage IC (grades 1 and 2), and stage IIA (grade 2) tumors were less likely to receive pelvic radiotherapy if they underwent lymphadenectomy (P < .05 for all). Patients with stage IB (all grades), stage IC (all grades), and stage IIA (grade 2) who underwent lymphadenectomy were more likely to receive adjuvant vaginal brachytherapy than those who did not undergo lymphadenectomy.
      TABLE 3Effect of lymphadenectomy on use of radiation in women 60 years of age or older
      VariableTotalLymph nodesNo lymph nodesExternal beam radiationVaginal brachytherapy
      Lymph node dissection, n (%)No lymph node dissection, n (%)P valueLymph node dissection, n (%)No lymph node dissection, n (%)P value
      IA
       All IA831027265584102 (3.7)141 (2.5).00252 (1.9)67 (1.2).01
       Grade 148601196366425 (2.1)43 (1.2).026 (0.5)31 (0.9).23
       Grade 22225912131336 (4.0)52 (4.0).9920 (2.2)19 (1.5).19
       Grade 372745427332 (7.1)35 (12.8).00919 (4.2)13 (4.8).71
      IB
       All IB17,52775919936890 (11.7)857 (8.6)< .0001578 (7.6)337 (3.4)< .0001
       Grade 1791625725344120 (4.7)187 (3.5).0189 (3.5)127 (2.4).006
       Grade 2662831883440294 (9.2)392 (11.4).004250 (7.8)157 (4.6)< .0001
       Grade 322421485757429 (28.9)237 (31.3).24183 (12.3)32 (4.2)< .0001
      IC
       All IC6654379128631551 (40.9)1409 (49.2)< .0001423 (11.2)92 (3.2)< .0001
       Grade 120299901039290 (29.3)461 (44.4)< .0001103 (10.4)37 (3.6).0001
       Grade 2289516591236693 (41.8)646 (52.3)< .0001184 (11.1)36 (2.9)< .0001
       Grade 31452981471515 (52.5)254 (53.9).6190 (9.2)13 (2.8)< .0001
      IIA
       All IIA912580332187 (32.2)131 (39.5).03117 (20.2)37 (11.1).0005
       Grade 128516112435 (21.7)36 (29.0).1634 (21.1)18 (14.5).15
       Grade 236724212576 (31.4)52 (41.6).0555 (22.7)13 (10.4).004
       Grade 32101407070 (50.0)36 (51.4).8515 (10.7)5 (7.1).41
      IIB
       All IIB889315151315 (53.5)151 (50.3).3769 (11.7)15 (5.0).001
       Grade 12211309168 (52.3)50 (55.0).7017 (13.1)6 (6.6).12
       Grade 2355243112120 (49.4)63 (56.3).2327 (11.1)6 (5.4).08
       Grade 32421697397 (57.4)29 (39.7).0118 (10.7)1 (1.4).01
      Total number of patients for each substage includes patients with unknown tumor grade.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.
      The influence of extent of lymphadenectomy on the use of radiation was then examined (Tables 4 and 5). Patients who underwent lymphadenectomy were stratified based on the number of nodes removed (1-9 vs ≥10 nodes). Patients younger than 60 years of age with stage IB (grades 2 and 3), IC (all grades), IIA (grade 1), and IIB (grade 2) tumors who underwent a more extensive lymphadenectomy (10 or more nodes) were less likely to receive external beam radiation and more likely to receive vaginal brachytherapy than those patients who underwent less extensive nodal sampling (1-9 nodes) (P < .05 for all). For example, among women with stage IC grade 2 neoplasms, 54.8% of women who had 1-9 nodes removed received pelvic radiation compared with 31.0% of those who had 10 or more nodes removed (P < .0001). Similar trends were noted when the extent of lymphadenectomy was examined in patients 60 years of age or older.
      TABLE 4Effect of extent of lymphadenectomy (1-9 vs ≥10 nodes) on use of radiation in women younger than 60 years of age who underwent nodal evaluation
      VariableTotal1-9 lymph nodes≥10 lymph nodesExternal beam radiationVaginal brachytherapy
      1-9 nodes, n (%)≥10 nodes, n (%)P value1-9 nodes, n (%)≥10 nodes, n (%)P value
      IA
       All IA29981351164730 (2.2)33 (2.0).6821 (1.6)28 (1.7).75
       Grade 116828068766 (0.7)6 (0.7).888 (1.0)6 (0.7).49
       Grade 287637550112 (3.2)13 (2.6).595 (1.3)8 (1.6).75
       Grade 32429514711 (11.6)11 (7.5).285 (5.3)8 (5.4).95
      IB
       All IB494721012846259 (12.3)264 (9.3).0006128 (6.1)247 (8.7).0007
       Grade 12008931107743 (4.6)39 (3.6).2631 (3.3)45 (4.2).32
       Grade 21894781111389 (11.4)78 (7.0).000955 (7.0)99 (8.9).15
       Grade 3801303498117 (38.6)123 (24.7)< .000134 (11.2)80 (16.1).06
      IC
       All IC1016393623212 (53.9)212 (34.0)< .000132 (8.1)94 (15.1).001
       Grade 129712417347 (37.9)29 (16.8)< .000113 (10.5)28 (16.2).16
       Grade 240215724586 (54.8)76 (31.0)< .000111 (7.0)33 (13.5).04
       Grade 32689916974 (74.8)101 (59.8).015 (5.1)15 (8.9).25
      IIA
       All IIA40113127055 (42.0)87 (32.2).0620 (15.3)59 (22.9).12
       Grade 1149519820 (39.2)20 (20.4).019 (17.7)20 (20.4).69
       Grade 21615310823 (43.4)40 (37.0).447 (13.2)26 (24.1).11
       Grade 35918419 (50.0)19 (46.3).801 (5.6)6 (14.6).32
      IIB
       All IIB46514532094 (64.8)165 (51.6).0088 (5.5)42 (13.1).01
       Grade 1130379319 (51.4)42 (45.2).523 (8.1)17 (18.3).15
       Grade 21966613046 (69.7)62 (47.7).0033 (4.6)19 (14.6).03
       Grade 3108327622 (68.8)49 (64.5).672 (6.3)5 (6.6).95
      Total number of patients for each substage includes patients with unknown tumor grade.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.
      TABLE 5Effect of extent of lymphadenectomy (1-9 vs ≥10 nodes) on use of radiation in women 60 years of age or older who underwent nodal evaluation
      VariableTotal1-9 lymph nodes≥10 lymph nodesExternal beam radiationVaginal brachytherapy
      1-9 nodes, n (%)≥10 nodes, n (%)P value1-9 nodes, n (%)≥10 nodes, n (%)P value
      IA
       All IA24121136127649 (4.3)45 (3.5).3224 (2.1)27 (2.1)1.00
       Grade 1106453453015 (2.8)9 (1.7).225 (0.9)1 (0.2).10
       Grade 279937542418 (4.8)15 (3.5).3711 (2.9)9 (2.1).46
       Grade 339915424512 (7.8)17 (6.9).755 (3.3)13 (5.3).33
      IB
       All IB679330833710410 (13.3)394 (10.6).0007195 (6.3)352 (9.5)< .0001
       Grade 123121132118060 (5.3)46 (3.9).1142 (3.7)43 (3.6).93
       Grade 2283012941536142 (11.0)120 (7.8).00492 (7.1)140 (9.1).05
       Grade 31325529796190 (35.9)200 (25.1)< .000140 (7.6)134 (16.8)
      IC
       All IC341615391877744 (48.3)646 (34.4)< .0001100 (6.5)294 (15.7)< .0001
       Grade 1901426475169 (39.7)90 (19.0)< .000135 (8.2)66 (13.9).007
       Grade 21496695801340 (48.9)286 (35.7)< .000145 (6.5)125 (15.6)< .0001
       Grade 3869370499219 (59.2)238 (47.7).000812 (3.2)68 (13.6)< .0001
      IIA
       All IIA539214325102 (47.7)71 (21.9)< .000129 (13.6)83 (25.5).0008
       Grade 1152658722 (33.9)12 (13.8).00310 (15.4)22 (25.3).14
       Grade 22218114038 (46.9)30 (21.4)< .000110 (12.4)43 (30.7).002
       Grade 3132537939 (73.6)28 (35.4)< .00014 (7.6)10 (12.7).35
      IIB
       All IIB558213345115 (54.0)183 (53.0).8318 (8.5)49 (14.2).04
       Grade 1121437823 (53.5)39 (50.0).714 (9.3)13 (16.7).26
       Grade 22349913555 (55.6)60 (44.4).097 (7.1)18 (13.3).13
       Grade 3157629533 (53.2)59 (62.1).276 (9.7)12 (12.6).57
      Total number of patients for each substage includes patients with unknown tumor grade.
      Sharma. Lymphadenectomy for endometrial cancer. Am J Obstet Gynecol 2011.

      Comment

      The role of lymphadenectomy in endometrial cancer is rapidly evolving. Randomized trials of lymphadenectomy have failed to show a survival advantage for the procedure and have not convincingly demonstrated that lymphadenectomy influences adjuvant treatment planning.
      • Kitchener H.
      • Swart A.M.
      • Qian Q.
      • Amos C.
      • Parmar M.K.
      Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study.
      • Benedetti Panici P.
      • Basile S.
      • Maneschi F.
      • et al.
      Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial.
      Our population-based analysis of patients treated across the United States clearly demonstrates that the performance of lymphadenectomy effects the allocation of adjuvant treatment. The effects appear to be the most pronounced for women with intermediate risk tumors and suggest that those women who undergo lymphadenectomy are less likely to receive external beam radiation.
      The difficulty in extrapolating the role of lymphadenectomy is due in large part to the fact that the optimal adjuvant treatment for most women with endometrial cancer is unknown. Among patients with tumors confined to the uterine corpus, radiation improves local control without having an impact on overall survival.
      • Aalders J.
      • Abeler V.
      • Kolstad P.
      • Onsrud M.
      Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients.
      • Blake P.
      • Swart A.M.
      • Orton J.
      • et al.
      Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis.
      • Creutzberg C.L.
      • van Putten W.L.
      • Koper P.C.
      • et al.
      PORTEC Study Group
      Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial Post Operative Radiation Therapy in Endometrial Carcinoma.
      • Keys H.M.
      • Roberts J.A.
      • Brunetto V.L.
      • 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.
      Those patients with high-grade, deeply invasive tumors, so-called high intermediate risk, appear to derive the most benefit from radiation.
      • Keys H.M.
      • Roberts J.A.
      • Brunetto V.L.
      • 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.
      Evidence-based guidelines for the treatment of women with corpus-confined disease endorse a variety of possible treatments from observation to radiation in combination with chemotherapy.
      National Comprehensive Cancer Network physician clinical practice guidelines in oncology: uterine neoplasms. v. 2.2009.
      Among women with nodal disease, controversy also exists with regard to optimal management. Although chemotherapy has been shown to be superior to radiation, a substantial number of women in the United States are treated with a combination of chemotherapy and radiation.
      National Comprehensive Cancer Network physician clinical practice guidelines in oncology: uterine neoplasms. v. 2.2009.
      • Randall M.E.
      • Filiaci V.L.
      • Muss H.
      • et al.
      Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study.
      • Secord A.A.
      • Havrilesky L.J.
      • O'Malley D.M.
      • et al.
      A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer.
      Given the uncertain role of radiation in women with cancer confined to the uterus, the most important rationale for pelvic radiation in women with unstaged endometrial cancer is for the treatment of occult nodal disease.
      • Parthasarathy A.
      • Kapp D.S.
      • Cheung M.K.
      • Shin J.Y.
      • Osann K.
      • Chan J.K.
      Adjuvant radiotherapy in incompletely staged IC and II endometrioid uterine cancer.
      Although it is widely hypothesized that lymphadenectomy influences adjuvant treatment planning, there are relatively few data describing how nodal sampling has an impact on the allocation of treatment.
      • Barakat R.R.
      • Lev G.
      • Hummer A.J.
      • et al.
      Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.
      • Chan J.K.
      • Wu H.
      • Cheung M.K.
      • Shin J.Y.
      • Osann K.
      • Kapp D.S.
      The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
      • Goudge C.
      • Bernhard S.
      • Cloven N.G.
      • Morris P.
      The impact of complete surgical staging on adjuvant treatment decisions in endometrial cancer.
      Barakat et al
      • Barakat R.R.
      • Lev G.
      • Hummer A.J.
      • et al.
      Twelve-year experience in the management of endometrial cancer: a change in surgical and postoperative radiation approaches.
      examined the effect of increased use of surgical staging in women with endometrial cancer over a 12 year period. The authors noted that the use of whole pelvic radiation decreased from 16% to 9%. In an evaluation of women with all stages of endometrial cancer, it was noted that unstaged patients were twice as likely to receive some form of adjuvant radiation as those who underwent lymph node evaluation.
      • Chan J.K.
      • Wu H.
      • Cheung M.K.
      • Shin J.Y.
      • Osann K.
      • Kapp D.S.
      The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
      Our findings suggest that patients with stage I-II endometrial cancer who undergo lymphadenectomy are less likely to receive external pelvic radiotherapy and more likely to undergo treatment with vaginal brachytherapy. These findings are most pronounced for patients with intermediate risk (stage IB grades 2 and 3 and IC grades 1 and 2) tumors.
      Among women without nodal metastases, the primary rationale for radiation is to prevent locoregional recurrence.
      • Nout R.A.
      • Smit V.T.
      • Putter H.
      • et al.
      Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.
      • Horowitz N.S.
      • Peters 3rd, W.A.
      • Smith M.R.
      • Drescher C.W.
      • Atwood M.
      • Mate T.P.
      Adjuvant high dose rate vaginal brachytherapy as treatment of stage I and II endometrial carcinoma.
      A recent randomized trial of women with apparent stage I-IIA endometrial cancer (Post-Operative Radiation Therapy for Endometrial Carcinoma [PORTEC]-2) demonstrated that vaginal brachytherapy was not inferior to whole pelvic radiation.
      • Nout R.A.
      • Smit V.T.
      • Putter H.
      • et al.
      Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.
      These data suggest that whole pelvic radiation can safely be omitted in favor of brachytherapy in those patients with corpus-confined disease in whom radiation is elected.
      Patients with unstaged endometrial cancer present a difficult dilemma in that vaginal brachytherapy is inadequate treatment for women with unrecognized nodal disease. Although lymphadenectomy was not required for entry into the PORTEC-2 trial, it is unclear whether clinicians in the United States would consider vaginal brachytherapy adequate treatment for women with unstaged high-intermediate risk disease. A survey of US gynecologic oncologists reported that these physicians were 23% less likely to administer radiation to women with grade 1 tumors with 50-66% myoinvasion in women who underwent lymphadenectomy compared with patients who had not undergone nodal evaluation.
      • Gretz H. Fr
      • Economos K.
      • Husain A.
      • et al.
      The practice of surgical staging and its impact on adjuvant treatment recommendations in patients with stage I endometrial carcinoma.
      Whereas pelvic radiation is generally well tolerated, treatment is associated with an increased risk of both acute and late toxicities
      • Aalders J.
      • Abeler V.
      • Kolstad P.
      • Onsrud M.
      Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients.
      • Creutzberg C.L.
      • van Putten W.L.
      • Koper P.C.
      • et al.
      PORTEC Study Group
      Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial Post Operative Radiation Therapy in Endometrial Carcinoma.
      • Keys H.M.
      • Roberts J.A.
      • Brunetto V.L.
      • 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.
      • Nout R.A.
      • Smit V.T.
      • Putter H.
      • et al.
      Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.
      In the GOG's evaluation of pelvic radiation for intermediate-risk endometrial cancer, treatment was associated with an increased risk of hematologic, gastrointestinal, genitourinary, and cutaneous complications.
      • Keys H.M.
      • Roberts J.A.
      • Brunetto V.L.
      • 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.
      The side effect profile of radiation is improved when vaginal brachytherapy is substituted for external beam treatment. The PORTEC-2 investigators noted that the rate of gastrointestinal toxicity was 4-fold lower in patients treated with brachytherapy compared with those who received external beam radiation.
      • Nout R.A.
      • Smit V.T.
      • Putter H.
      • et al.
      Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.
      In addition to toxicity, pelvic radiotherapy is associated with significant costs to the health care system.
      • Lachance J.A.
      • Stukenborg G.J.
      • Schneider B.F.
      • Rice L.W.
      • Jazaeri A.A.
      A cost-effective analysis of adjuvant therapies for the treatment of stage I endometrial adenocarcinoma.
      • Rankins N.C.
      • Secord A.A.
      • Jewell E.
      • Havrilesky L.J.
      • Soper J.T.
      • Myers E.
      Cost-effectiveness of adjuvant radiotherapy in intermediate risk endometrial cancer.
      A recent decision analysis reported the mean cost of external beam pelvic radiation as more than $9000.
      • Lachance J.A.
      • Stukenborg G.J.
      • Schneider B.F.
      • Rice L.W.
      • Jazaeri A.A.
      A cost-effective analysis of adjuvant therapies for the treatment of stage I endometrial adenocarcinoma.
      In addition to direct costs, pelvic radiotherapy is typically administered over a course of 5-6 weeks and requires a significant time commitment from patients. In our analysis, performance of lymphadenectomy in only 5 patients younger than 60 years of age or 7 patients older than 60 years of age with stage IC grade 2 tumors would be required to avoid 1 course of pelvic radiation.
      The most important question addressed by our study is which patients derive the most benefit from lymphadenectomy. Our findings suggest that patients with stage IB and IC tumors are most likely to have their adjuvant treatment influenced by lymphadenectomy. Although prior work has demonstrated the difficulty in predicting final tumor grade and depth of invasion based on preoperative biopsy and intraoperative inspection, we noted that even women with low-grade, superficially invasive tumors were less likely to receive pelvic radiation if they underwent lymphadenectomy.
      • Goff B.A.
      • Rice L.W.
      Assessment of depth of myometrial invasion in endometrial adenocarcinoma.
      • Frumovitz M.
      • Singh D.K.
      • Meyer L.
      • et al.
      Predictors of final histology in patients with endometrial cancer.
      • Traen K.
      • Holund B.
      • Mogensen O.
      Accuracy of preoperative tumor grade and intraoperative gross examination of myometrial invasion in patients with endometrial cancer.
      • Ben-Shachar I.
      • Pavelka J.
      • Cohn D.E.
      • et al.
      Surgical staging for patients presenting with grade 1 endometrial carcinoma.
      We also noted that the extent of lymphadenectomy performed appeared to influence treatment allocation. The reduced use of external beam radiation among patients with intermediate risk tumors was most pronounced in patients who had 10 or more nodes removed. Although prior studies of endometrial cancer have suggested that the extent of lymphadenectomy influences survival, our data suggest that node count also has a direct impact on the allocation of adjuvant treatment.
      Although our analysis benefits from the inclusion of a large number of patients, we recognize several important limitations. Because SEER lacks data on chemotherapy, our study was limited to examining the influence of lymphadenctomy on the prescription of radiotherapy. Although uncommon during the years of study, adjuvant chemotherapy for women with early-stage endometrial cancer is now more frequently utilized.
      • Susumu N.
      • Sagae S.
      • Udagawa Y.
      • et al.
      Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study.
      • Maggi R.
      • Lissoni A.
      • Spina F.
      • et al.
      Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial.
      Although SEER captures data on the type of radiation administered, the database lacks details on total dose of radiation, treatment fields, and duration of treatment.
      Given these limitations, we restricted our analysis to simply determining whether external beam radiation or brachytherapy was administered. Our study utilized the 1988 FIGO staging criteria. FIGO has recently implemented a revised staging schema, and our findings may have differed somewhat using the updated system. Finally, although we stratified our analysis by 3 of the factors most important in the use of adjuvant treatment (age, stage, and grade), a number of individual patient and physician factors have an impact on the allocation of treatment and may have influenced our results.
      Our findings suggest that lymphadenectomy plays an important role in the allocation of adjuvant treatment for women with stage I and II endometrial cancer. Those women who undergo lymphadenectomy are less likely to receive whole pelvic radiotherapy. The effects of lymphadenectomy are most pronounced in women with high-intermediate risk tumors and greatest for patients who have 10 or more nodes removed. In aggregate are data support lymphadenectomy for the majority of women with endometrial cancer. Those women who undergo lymphadenectomy should have at least 10 nodes removed as specified by the GOG.
      • Miller D.S.
      Advanced endometrial cancer: is lymphadenectomy necessary or sufficient?.

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      Linked Article

      • Lymphadenectomy in endometrial cancer: what's the right question?
        American Journal of Obstetrics & GynecologyVol. 206Issue 5
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          We read, with great interest, the article by Sharma et al,1 in which, in a large retrospective study on data from the National Cancer Institute's Surveillance, Epidemiology, and End Results database, the authors analyzed women with stages I-II endometrioid adenocarcinomas of the uterine corpus treated between 1988 and 2006. Findings suggest that, especially among women with high- to intermediate-risk tumors, patients who undergo lymphadenectomy are less likely to receive external-beam radiation.
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