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Surgical staging for endometrial cancer in the elderly — Is there a role for lymphadenectomy?
Gynecologic Oncology 126 (2012) 12–15
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Surgical staging for endometrial cancer in the elderly — Is there a role for lymphadenectomy? William J. Lowery a,⁎, Paola A. Gehrig b, Emily Ko b, Angeles Alvarez Secord a, Junzo Chino c, Laura J. Havrilesky a a b c
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
a r t i c l e
i n f o
Article history: Received 23 March 2012 Accepted 5 May 2012 Available online 12 May 2012 Keywords: Endometrial cancer Lymphadenectomy Surgery in the elderly
a b s t r a c t Objectives. We sought to evaluate the effect of systematic lymphadenectomy (LND) on endometrial cancer-specific survival in an elderly population. Methods. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2006. Women who underwent primary hysterectomy for non-serous, non-clear cell endometrial carcinoma were included. Women were stratified by age (b 70, 70–79, and ≥ 80) and disease-specific survival (DSS) was analyzed via the Kaplan–Meier method and stratified by postoperative grade. Cohorts were compared using the log-rank test. In a simulated population, the disease-specific survival of women with pre-operative grade 1 endometrial carcinoma was calculated using a weighted average survival accounting for those upgraded at final pathology. Results. Endometrial cancer was identified in 5759 women ≥ 80 years old. Disease specific survival at 5 years for the LND and no LND groups was 93.4% and 94.5% (p = 0.36) for grade 1, 84.4% and 85% (p = 0.97) for grade 2, and 65.9% and 60.9% (p = 0.002) for grade 3. In the simulated pre-operative grade 1 group, 5 year disease-specific survival (DSS) was 91% in the LND group and 92% in the no LND group. Conclusion. In women older than 80, systematic lymphadenectomy is associated with improved DSS for high grade, but similar DSS for low grade endometrial cancer, consistent with what is seen with younger women. As there is no clear survival benefit to lymphadenectomy in elderly women presenting with low grade disease, the surgeon should carefully weigh the surgical risks and benefits in this patient population, which may be at higher risk for morbidity. Published by Elsevier Inc.
Introduction Because a majority of women with endometrial cancer or its precursors develop vaginal bleeding, most cases are diagnosed in the early stages, during which surgical management is the mainstay of treatment. Many women with endometrial cancer die from other causes; Chan et al., using the SEER database, reported a 5 year disease specific survival of >98% for women with preoperative stage 1 endometrioid endometrial cancers [1]. In addition to stage, the final pathologic grade of the tumor is also recognized as an important prognostic factor and is associated with risk of lymph node metastasis as well as overall survival [2]. Controversy exists regarding the role of lymphadenectomy in the management of apparent early stage endometrial cancer. Current
⁎ Corresponding author at: Division of Gynecologic Oncology, Duke University Medical Center, Box 3079, Durham, NC 27710, USA. Fax: + 1 919 684 7048. E-mail addresses: [email protected], [email protected] (W.J. Lowery). 0090-8258/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.ygyno.2012.05.003
guidelines, set forth by the International Federation of Gynecology and Obstetrics (FIGO) in 1988 and 2009, recommend pelvic and aortic lymphadenectomy as part of the comprehensive surgical staging of all patients [3]. While most gynecologic oncologists agree that there is benefit to lymphadenectomy in patients with advanced stage disease or even early stage disease with high risk features, debate exists over the optimal surgical management. Proponents of universal staging lymphadenectomy argue that a significant proportion of patients will be upstaged or upgraded on final pathologic report, and that knowing the status of the lymph nodes will lead to a more judicious use of adjuvant therapy. Ben-Shachar et al. reported that in patients with preoperative grade 1 disease, 15% were upgraded to grade 2 and 0.5% to grade 3 at final pathologic evaluation [4]. Leitao et al. reported similar findings in preoperative grade 1 disease, with 14% of patients upgraded to grade 2 and 1% to grade 3 at final pathologic review [5]. Opponents of this strategy counter that the added risk of morbidity associated with lymphadenectomy does not justify its performance on low risk patients [6]. The American Congress of Obstetrics and Gynecology and the Society of Gynecologic Oncology recommend comprehensive
W.J. Lowery et al. / Gynecologic Oncology 126 (2012) 12–15
surgical staging including lymphadenectomy except in young or perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia and women at increased risk of mortality secondary to comorbidities [7]. The morbidity of surgical staging procedures is an important consideration in elderly women. Mariani et al. reported that in patients with Stage IA, grade 1 and 2 disease, there was no difference in 5 year survival between those who underwent lymphadenectomy and those who did not, but there was a significant increase in operating time and morbidity associated with lymphadenectomy [8]. In this and other studies, lymphadenectomy is consistently associated with longer operating time without survival benefit [9,10]. While studies have shown that age alone should not be considered a contraindication to appropriate surgical management of endometrial cancer [11,12], Turrentine et al. reported that surgical length and surgical complexity were independent risk factors for mortality in patients 80 and older [13]. Moreover, while Giannice et al. reported that lymph node dissection can be performed safely with no increase in morbidity of mortality in elderly patients, staging procedures were associated with significantly longer operating time [14]. Given the controversy surrounding the ideal clinical setting for lymph node dissection as well as the concerns about the additional morbidity in elderly women, we sought to determine the effect on disease specific survival of the inclusion or omission of a staging lymphadenectomy in women ≥80 years of age. We also sought to estimate the effect that upgrading a percentage of specimens at final pathologic evaluation might have on disease specific survival in women ≥80 years of age. Materials and methods Demographic, clinicopathologic, treatment and survival information on women who underwent primary hysterectomy for nonserous, non-clear cell endometrial carcinoma during the period of January 1, 1988 through December 31, 2006 was obtained, with permission, from the Surveillance, Epidemiology, and End Results (SEER) program of the United States National Cancer Institute. This data set is representative of approximately 26% of the population from across the United States [15]. The data are freely available to the public and include incidence, staging, pathology, initial management and survival. Data were accessed via SEERstat 6.5.2. Inclusion criteria were all women who underwent primary hysterectomy for nonserous and non-clear cell endometrial carcinoma. Also excluded were individuals with a diagnosis of uterine sarcoma, as well as those in whom staging information was not fully recorded. Grades recorded as “well-differentiated” were coded as grade 1, “moderately differentiated” as grade 2, and “poorly differentiated” or “un-differentiated” as grade 3 in order to reflect the 3 grade FIGO system. This is not a direct conversion as criteria for grading other than FIGO may have been used at participating institutions. Women were analyzed in three different age stratifications; ≤70, 70–79, and ≥80 years old. All stages of disease were evaluated together and analysis was performed for differences in 5 year disease specific survival according to surgical treatment, with specific attention to the inclusion or omission of a lymphadenectomy. To account for adverse events related to surgery, all deaths within 30 days of initial surgery were considered as death from disease in the analysis; deaths coded as being caused by any gynecological malignancy were also included as events. Statistical analysis was performed using the Kaplan–Meier method, utilizing the log-rank test for disease specific survival comparisons between cohorts. The chi square test was performed to compare the rate of adjuvant radiotherapy between cohorts. As an exploratory exercise, we simulated the disease-specific survival (DSS) of elderly women who might present with preoperative grade 1 endometrial carcinoma as follows. A weighted average survival was calculated using the assumption that approximately 20%
13
of preoperative grade 1 tumors are upgraded to grade 2, and 1% to grade 3, on final pathology [4,5,16]. Therefore the weighted average five year DSS was calculated as: 5 year DSS ðpre−operative grade 1Þ ¼ 0:79 SURVIVAL ðfinal grade 1 cohortÞ þ 0:20 SURVIVAL ðfinal grade 2 cohortÞ þ 0:01 SURVIVAL ðfinal grade 3 cohortÞ For purposes of calculating DSS, we assumed no “downgrading” to non-invasive lesions would occur at final pathology. Results From 1988 to 2006, 111,961 women with cancer arising from the uterus were identified. 12,218 were not treated with hysterectomy or were without surgical information, and were excluded. 9901 were excluded for having no grade information and 2686 for having no stage information. An additional 10,192 were excluded for serous, clear cell, or sarcoma histologies. 448 had no information recorded about performance of nodal dissection. Of the remaining 76,516 individuals, 6805 were ≥80 years of age at diagnosis. Median age of these patients was 83 years old. 2303 (33.8%) had a postoperative diagnosis of FIGO grade 1 disease, 2621 (38.5%) grade 2 disease, and 1881 (27.6%) grade 3 disease. 60 patients are excluded from DSS analysis due to lack information on cause of death. Lymphadenectomy was performed in 41.4% of the ≥80 year old population: 30.3% with grade 1 disease, 42.5% with grade 2 disease, and 53.3% with grade 3 disease (p b 0.001) (Table 1). The 5 year DSS for patients ≥80 years old with grade 1 disease was 93.9%, for those with grade 2 was 84.4%, and for those with grade 3 was 63.3% (Table 2). In women ≥80 years, 5 year DSS for grade 1 disease without lymphadenectomy was 94.5% compared to 93.4% in those with a lymphadenectomy (p = 0.36). DSS for grade 2 disease without lymphadenectomy was 85% compared to 84.4% in those with a lymphadenectomy (p = 0.97). In patients with grade 3 disease, DSS was 60.9% without a lymphadenectomy and 65.9% with a lymphadenectomy (p = 0.002) (Fig. 3). In order to determine whether the finding of improved DSS following lymphadenectomy for grade 3 disease was similar between the most elderly cohort and younger women, we examined these outcomes in women under 70 and in those aged 70–79(Figs. 1 and 2). In each younger cohort with grade 3 disease, lymphadenectomy was associated with improved 5 year DSS compared to no lymphadenectomy (b70 cohort: 79.3% vs 69.9%,p= 0.001; 70–79 cohort: 69.7% vs 65.3%, Table 1 Patients with and without lymphadenectomy and adjuvant RT, by age and grade. b 70 years (n = 52,879)
No LND G1 G2 G3 LND G1 G2 G3 RT G1 G2 G3 No RT G1 G2 G3
≥80 years (n = 6805)
70–79 years (n = 16,832)
N
%
N
%
N
%
28,171 17,368 8360 2443 24,708 9101 9802 58,05 12,739 3064 5452 4223 40,140 23,405 12,710 4025
53.3 65.6 46 29.6 46.7 34.4 54 70.4 24.1 11.6 30 51.2 75.9 88.4 70 48.8
9170 4549 3280 1341 7662 2196 3078 2388 5016 1074 2126 1816 11,816 5671 4232 1913
54.5 67.4 51.6 36 45.5 32.6 48.4 64 29.8 15.9 33.4 48.7 70.2 84.1 66.6 51.3
3991 1604 1508 879 2814 699 1113 1002 1574 295 647 632 5231 2008 1974 1249
58.6 69.7 57.5 46.7 41.4 30.3 42.5 53.3 23.1 12.8 24.7 33.6 76.9 87.2 75.3 66.4
14
W.J. Lowery et al. / Gynecologic Oncology 126 (2012) 12–15
Table 2 5 year DSS for patients with and without lymphadenectomy, by age and grade. 5 year DSS No LND Grade 1 b70 70–79 ≥80 Grade 2 b70 70–79 ≥80 Grade 3 b70 70–79 ≥80
5 year DSS LND
p
98.5% 97.2% 94.5%
97.5% 95.3% 93.4%
b 0.001 b 0.001 0.362
94.1% 91.2% 85%
93.3% 89.6% 84.4%
0.088 0.048 0.966
69.9% 65.3% 60.9%
79.3% 69.7% 65.9%
b 0.001 0.005 0.002
p = 0.005) In both of the younger cohorts, women with grade 1 disease had higher 5 year DSS without lymphadenectomy than with lymphadenectomy (b70 cohort: 98.5 vs 97.5%, p b 0.001; 70–79 cohort: 97.2 vs 95.3%,pb 0.001). Likewise, in both groups, women with grade 2 disease had higher 5 year DSS without lymphadenectomy (b70 cohort: 94.1 vs 93.3%, p b 0.088; 70–79 cohort: 91.2 vs 89.6%,p= 0.048). The overall number of women in whom lymphadenectomy was performed and adjuvant treatment was administered is shown in Table 1. In an exploratory analysis simulating the upgrading of tumors at final pathologic evaluation, we estimated the five year DSS of preoperative grade 1 disease in the over 80 cohort using a weighted average survival calculation. This provided a five year DSS of 91.3% in the lymphadenectomy group and 92.3% in the no lymphadenectomy group.
Discussion Our findings indicate that women over 80 years of age with grade 1 or 2 endometrioid endometrial cancer in whom lymphadenectomy is omitted following hysterectomy do not appear to suffer any adverse effect on cancer-specific survival. However, among women with grade 3 disease, the addition of lymphadenectomy is associated with a significantly increased 5 year DSS. Women above the age of 80 in this study whose endometrial cancer was surgically managed had a 5 year DSS that was comparable to the DSS of patients under 80 years old. Wright et al. have previously demonstrated using the SEER database that as age increases, women are less likely to undergo a hysterectomy and adjuvant treatment [17]. Our results provide evidence that age alone should not be an indication to withhold appropriate surgical management of endometrial cancer. However, the length of a surgical staging procedure for endometrial cancer is consistently higher when lymphadenectomy is performed [10,14], and this increase in surgical complexity and duration also increases the surgical risk among the elderly [13]. We propose that withholding lymphadenectomy in elderly women who are also at low risk for lymph node metastasis based on preoperative grade and gross intraoperative findings is a reasonable approach. We found a trend toward improved DSS only in the highest grade cohort in all 3 age groups examined. As with the elderly cohort, we found no DSS advantage at 5 years in either of the two younger cohorts with grade 1 and 2 disease. Although there is currently no global consensus on the role of lymphadenectomy in early stage endometrial cancer, it is accepted that there will be a number of patients in whom disease is upgraded at the time of pathologic evaluation, and that higher final grade is associated with a higher chance of nodal metastasis. To account for this in a
Fig. 1. 10 year KM survival curve in women 70 years of age or younger with and without lymphadenectomy.
Fig. 2. 10 year KM survival curves in women 70–80 years of age with and without lymphadenectomy.
W.J. Lowery et al. / Gynecologic Oncology 126 (2012) 12–15
15
Fig. 3. 10 year KM survival curves in women 80 + years of age with and without lymphadenectomy.
theoretical construct, we performed an exploratory analysis using previously published estimates of the number of specimens upgraded at final pathologic analysis [4,5,16]. Our exploratory analysis simulated DSS in the over 80 cohort who present with preoperative grade 1 disease and suggested that even after accounting for a portion of the tumors being upgraded, there may be no advantage to lymph node dissection. These findings are consistent with the ASTEC trial in which no benefit was observed when lymphadenectomy was included as part of the surgical management of women with suspected low grade endometrial cancer [9]. In our own practice we individually tailor decisions about surgical staging based on preoperative grade, intraoperative gross and frozen section findings, and each patient's co-morbid conditions. While our analysis benefits from the large number of patients included in the cohort, there are important limitations to this retrospective database study. We included only patients who were managed with primary surgical therapy; as such there was almost certainly selection bias regarding which elderly patients were offered surgical treatment. Second, even within the group receiving surgical management, there was likely a functional status-related selection bias regarding the choice of patients for lymphadenectomy. Finally, those who underwent a staging lymphadenectomy were also more likely to receive adjuvant radiation. In women with high grade disease, we were therefore unable to determine if the survival advantage associated with lymphadenectomy was driven by the procedure itself, adjuvant treatment, or by selection bias. In addition, there are inherent limitations to the SEER database. Specific to our study are the lack of reliable information regarding functional status, quality of life, and a lack of information on comorbidities. The database also lacks data on additional adjuvant therapies, such as chemotherapy or hormonal treatments, but it is unlikely that a significant number of these patients would have received these interventions. Another criticism of the SEER database is that there is no central pathologic review, but this should not necessarily be seen as a limitation, as this may more accurately reflect community practice. Even with these limitations in mind, we feel it is likely that performance of lymphadenectomy in a high preoperative risk cohort identifies women in whom adjuvant treatments are likely to improve endometrial cancer outcomes. As the elderly population increases in number and becomes more obese, and with a projected increase in the number of cases of endometrial cancer that result [18], questions regarding the optimal management of the elderly patient will continue to present a challenging dilemma. The surgical approach to endometrial cancer should continue to be tailored based on the best available evidence including preoperative and intraoperative risk factors. Our data, and that of others, suggests that women over 80 with grade 1 and 2 endometrioid lesions who exhibit no evidence of advanced stage disease at exploration may be safely spared the morbidity of lymphadenectomy. Elderly women with grade 3 endometrioid lesions and those who are appropriate candidates for
full staging to tailor adjuvant treatments may in fact derive benefit from this approach. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] Chan JK, Kapp DS, Cheung MK, Shin JY, Stieglitz D, Husain A, et al. Prognostic factors and risk of extrauterine metastases in 3867 women with grade 1 endometrioid corpus cancer. Am J Obstet Gynecol Feb 2008;198(2):216 [e1-5]. [2] Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer Oct 15 1987;60(8 Suppl):2035–41. [3] Creasman W. Revised FIGO staging for carcinoma of the endometrium. Int J Gynaecol Obstet May 2009;105(2):109. [4] Ben-Shachar I, Pavelka J, Cohn DE, Copeland LJ, Ramirez N, Manolitsas T, et al. Surgical staging for patients presenting with grade 1 endometrial carcinoma. Obstet Gynecol Mar 2005;105(3):487–93. [5] Leitao Jr MM, Kehoe S, Barakat RR, Alektiar K, Gattoc LP, Rabbitt C, et al. Accuracy of preoperative endometrial sampling diagnosis of FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol Nov 2008;111(2):244–8. [6] May K, Bryant A, Dickinson HO, Kehoe S, Morrison J. Lymphadenectomy for the management of endometrial cancer. Cochrane Database Syst Rev 2010(1):CD007585. [7] ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol Aug 2005;106(2):413–25. [8] Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol Jun 2000;182(6):1506–19. [9] Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet Jan 10 2009;373(9658):125–36. [10] Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst Dec 3 2008;100(23):1707–16. [11] Ahmed A, Zamba G, DeGeest K, Lynch CF. The impact of surgery on survival of elderly women with endometrial cancer in the SEER program from 1992-2002. Gynecol Oncol Oct 2008;111(1):35–40. [12] Vaknin Z, Ben-Ami I, Schneider D, Pansky M, Halperin R. A comparison of perioperative morbidity, perioperative mortality, and disease-specific survival in elderly women (>or=70 years) versus younger women (b70 years) with endometrioid endometrial cancer. Int J Gynecol Cancer Jul 2009;19(5):879–83. [13] Turrentine FE, Wang H, Simpson VB, Jones RS. Surgical risk factors, morbidity, and mortality in elderly patients. J Am Coll Surg Dec 2006;203(6):865–77. [14] Giannice R, Susini T, Ferrandina G, Poerio A, Margariti PA, Carminati R, et al. Systematic pelvic and aortic lymphadenectomy in elderly gynecologic oncologic patients. Cancer Nov 15 2001;92(10):2562–8. [15] National Cancer Institute. Surveillance Epidemiology and End Results. Bethesda, MD; 2010. [16] Eltabbakh GH, Shamonki J, Mount SL. Surgical stage, final grade, and survival of women with endometrial carcinoma whose preoperative endometrial biopsy shows well-differentiated tumors. Gynecol Oncol Nov 2005;99(2):309–12. [17] Wright JD, Lewin SN, Barrena Medel NI, Sun X, Burke WM, Deutsch I, et al. Endometrial cancer in the oldest old: Tumor characteristics, patterns of care, and outcome. Gynecol Oncol Jul 2011;122(1):69–74. [18] Wallace AH, Havrilesky LJ, Valea FA, Barnett JC, Berchuck A, Myers ER. Projecting the need for gynecologic oncologists for the next 40 years. Obstet Gynecol Dec 2010;116(6):1366–72.
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Surgical staging for endometrial cancer in the elderly — Is there a role for lymphadenectomy? William J. Lowery a,⁎, Paola A. Gehrig b, Emily Ko b, Angeles Alvarez Secord a, Junzo Chino c, Laura J. Havrilesky a a b c
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
a r t i c l e
i n f o
Article history: Received 23 March 2012 Accepted 5 May 2012 Available online 12 May 2012 Keywords: Endometrial cancer Lymphadenectomy Surgery in the elderly
a b s t r a c t Objectives. We sought to evaluate the effect of systematic lymphadenectomy (LND) on endometrial cancer-specific survival in an elderly population. Methods. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2006. Women who underwent primary hysterectomy for non-serous, non-clear cell endometrial carcinoma were included. Women were stratified by age (b 70, 70–79, and ≥ 80) and disease-specific survival (DSS) was analyzed via the Kaplan–Meier method and stratified by postoperative grade. Cohorts were compared using the log-rank test. In a simulated population, the disease-specific survival of women with pre-operative grade 1 endometrial carcinoma was calculated using a weighted average survival accounting for those upgraded at final pathology. Results. Endometrial cancer was identified in 5759 women ≥ 80 years old. Disease specific survival at 5 years for the LND and no LND groups was 93.4% and 94.5% (p = 0.36) for grade 1, 84.4% and 85% (p = 0.97) for grade 2, and 65.9% and 60.9% (p = 0.002) for grade 3. In the simulated pre-operative grade 1 group, 5 year disease-specific survival (DSS) was 91% in the LND group and 92% in the no LND group. Conclusion. In women older than 80, systematic lymphadenectomy is associated with improved DSS for high grade, but similar DSS for low grade endometrial cancer, consistent with what is seen with younger women. As there is no clear survival benefit to lymphadenectomy in elderly women presenting with low grade disease, the surgeon should carefully weigh the surgical risks and benefits in this patient population, which may be at higher risk for morbidity. Published by Elsevier Inc.
Introduction Because a majority of women with endometrial cancer or its precursors develop vaginal bleeding, most cases are diagnosed in the early stages, during which surgical management is the mainstay of treatment. Many women with endometrial cancer die from other causes; Chan et al., using the SEER database, reported a 5 year disease specific survival of >98% for women with preoperative stage 1 endometrioid endometrial cancers [1]. In addition to stage, the final pathologic grade of the tumor is also recognized as an important prognostic factor and is associated with risk of lymph node metastasis as well as overall survival [2]. Controversy exists regarding the role of lymphadenectomy in the management of apparent early stage endometrial cancer. Current
⁎ Corresponding author at: Division of Gynecologic Oncology, Duke University Medical Center, Box 3079, Durham, NC 27710, USA. Fax: + 1 919 684 7048. E-mail addresses: [email protected], [email protected] (W.J. Lowery). 0090-8258/$ – see front matter. Published by Elsevier Inc. doi:10.1016/j.ygyno.2012.05.003
guidelines, set forth by the International Federation of Gynecology and Obstetrics (FIGO) in 1988 and 2009, recommend pelvic and aortic lymphadenectomy as part of the comprehensive surgical staging of all patients [3]. While most gynecologic oncologists agree that there is benefit to lymphadenectomy in patients with advanced stage disease or even early stage disease with high risk features, debate exists over the optimal surgical management. Proponents of universal staging lymphadenectomy argue that a significant proportion of patients will be upstaged or upgraded on final pathologic report, and that knowing the status of the lymph nodes will lead to a more judicious use of adjuvant therapy. Ben-Shachar et al. reported that in patients with preoperative grade 1 disease, 15% were upgraded to grade 2 and 0.5% to grade 3 at final pathologic evaluation [4]. Leitao et al. reported similar findings in preoperative grade 1 disease, with 14% of patients upgraded to grade 2 and 1% to grade 3 at final pathologic review [5]. Opponents of this strategy counter that the added risk of morbidity associated with lymphadenectomy does not justify its performance on low risk patients [6]. The American Congress of Obstetrics and Gynecology and the Society of Gynecologic Oncology recommend comprehensive
W.J. Lowery et al. / Gynecologic Oncology 126 (2012) 12–15
surgical staging including lymphadenectomy except in young or perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia and women at increased risk of mortality secondary to comorbidities [7]. The morbidity of surgical staging procedures is an important consideration in elderly women. Mariani et al. reported that in patients with Stage IA, grade 1 and 2 disease, there was no difference in 5 year survival between those who underwent lymphadenectomy and those who did not, but there was a significant increase in operating time and morbidity associated with lymphadenectomy [8]. In this and other studies, lymphadenectomy is consistently associated with longer operating time without survival benefit [9,10]. While studies have shown that age alone should not be considered a contraindication to appropriate surgical management of endometrial cancer [11,12], Turrentine et al. reported that surgical length and surgical complexity were independent risk factors for mortality in patients 80 and older [13]. Moreover, while Giannice et al. reported that lymph node dissection can be performed safely with no increase in morbidity of mortality in elderly patients, staging procedures were associated with significantly longer operating time [14]. Given the controversy surrounding the ideal clinical setting for lymph node dissection as well as the concerns about the additional morbidity in elderly women, we sought to determine the effect on disease specific survival of the inclusion or omission of a staging lymphadenectomy in women ≥80 years of age. We also sought to estimate the effect that upgrading a percentage of specimens at final pathologic evaluation might have on disease specific survival in women ≥80 years of age. Materials and methods Demographic, clinicopathologic, treatment and survival information on women who underwent primary hysterectomy for nonserous, non-clear cell endometrial carcinoma during the period of January 1, 1988 through December 31, 2006 was obtained, with permission, from the Surveillance, Epidemiology, and End Results (SEER) program of the United States National Cancer Institute. This data set is representative of approximately 26% of the population from across the United States [15]. The data are freely available to the public and include incidence, staging, pathology, initial management and survival. Data were accessed via SEERstat 6.5.2. Inclusion criteria were all women who underwent primary hysterectomy for nonserous and non-clear cell endometrial carcinoma. Also excluded were individuals with a diagnosis of uterine sarcoma, as well as those in whom staging information was not fully recorded. Grades recorded as “well-differentiated” were coded as grade 1, “moderately differentiated” as grade 2, and “poorly differentiated” or “un-differentiated” as grade 3 in order to reflect the 3 grade FIGO system. This is not a direct conversion as criteria for grading other than FIGO may have been used at participating institutions. Women were analyzed in three different age stratifications; ≤70, 70–79, and ≥80 years old. All stages of disease were evaluated together and analysis was performed for differences in 5 year disease specific survival according to surgical treatment, with specific attention to the inclusion or omission of a lymphadenectomy. To account for adverse events related to surgery, all deaths within 30 days of initial surgery were considered as death from disease in the analysis; deaths coded as being caused by any gynecological malignancy were also included as events. Statistical analysis was performed using the Kaplan–Meier method, utilizing the log-rank test for disease specific survival comparisons between cohorts. The chi square test was performed to compare the rate of adjuvant radiotherapy between cohorts. As an exploratory exercise, we simulated the disease-specific survival (DSS) of elderly women who might present with preoperative grade 1 endometrial carcinoma as follows. A weighted average survival was calculated using the assumption that approximately 20%
13
of preoperative grade 1 tumors are upgraded to grade 2, and 1% to grade 3, on final pathology [4,5,16]. Therefore the weighted average five year DSS was calculated as: 5 year DSS ðpre−operative grade 1Þ ¼ 0:79 SURVIVAL ðfinal grade 1 cohortÞ þ 0:20 SURVIVAL ðfinal grade 2 cohortÞ þ 0:01 SURVIVAL ðfinal grade 3 cohortÞ For purposes of calculating DSS, we assumed no “downgrading” to non-invasive lesions would occur at final pathology. Results From 1988 to 2006, 111,961 women with cancer arising from the uterus were identified. 12,218 were not treated with hysterectomy or were without surgical information, and were excluded. 9901 were excluded for having no grade information and 2686 for having no stage information. An additional 10,192 were excluded for serous, clear cell, or sarcoma histologies. 448 had no information recorded about performance of nodal dissection. Of the remaining 76,516 individuals, 6805 were ≥80 years of age at diagnosis. Median age of these patients was 83 years old. 2303 (33.8%) had a postoperative diagnosis of FIGO grade 1 disease, 2621 (38.5%) grade 2 disease, and 1881 (27.6%) grade 3 disease. 60 patients are excluded from DSS analysis due to lack information on cause of death. Lymphadenectomy was performed in 41.4% of the ≥80 year old population: 30.3% with grade 1 disease, 42.5% with grade 2 disease, and 53.3% with grade 3 disease (p b 0.001) (Table 1). The 5 year DSS for patients ≥80 years old with grade 1 disease was 93.9%, for those with grade 2 was 84.4%, and for those with grade 3 was 63.3% (Table 2). In women ≥80 years, 5 year DSS for grade 1 disease without lymphadenectomy was 94.5% compared to 93.4% in those with a lymphadenectomy (p = 0.36). DSS for grade 2 disease without lymphadenectomy was 85% compared to 84.4% in those with a lymphadenectomy (p = 0.97). In patients with grade 3 disease, DSS was 60.9% without a lymphadenectomy and 65.9% with a lymphadenectomy (p = 0.002) (Fig. 3). In order to determine whether the finding of improved DSS following lymphadenectomy for grade 3 disease was similar between the most elderly cohort and younger women, we examined these outcomes in women under 70 and in those aged 70–79(Figs. 1 and 2). In each younger cohort with grade 3 disease, lymphadenectomy was associated with improved 5 year DSS compared to no lymphadenectomy (b70 cohort: 79.3% vs 69.9%,p= 0.001; 70–79 cohort: 69.7% vs 65.3%, Table 1 Patients with and without lymphadenectomy and adjuvant RT, by age and grade. b 70 years (n = 52,879)
No LND G1 G2 G3 LND G1 G2 G3 RT G1 G2 G3 No RT G1 G2 G3
≥80 years (n = 6805)
70–79 years (n = 16,832)
N
%
N
%
N
%
28,171 17,368 8360 2443 24,708 9101 9802 58,05 12,739 3064 5452 4223 40,140 23,405 12,710 4025
53.3 65.6 46 29.6 46.7 34.4 54 70.4 24.1 11.6 30 51.2 75.9 88.4 70 48.8
9170 4549 3280 1341 7662 2196 3078 2388 5016 1074 2126 1816 11,816 5671 4232 1913
54.5 67.4 51.6 36 45.5 32.6 48.4 64 29.8 15.9 33.4 48.7 70.2 84.1 66.6 51.3
3991 1604 1508 879 2814 699 1113 1002 1574 295 647 632 5231 2008 1974 1249
58.6 69.7 57.5 46.7 41.4 30.3 42.5 53.3 23.1 12.8 24.7 33.6 76.9 87.2 75.3 66.4
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Table 2 5 year DSS for patients with and without lymphadenectomy, by age and grade. 5 year DSS No LND Grade 1 b70 70–79 ≥80 Grade 2 b70 70–79 ≥80 Grade 3 b70 70–79 ≥80
5 year DSS LND
p
98.5% 97.2% 94.5%
97.5% 95.3% 93.4%
b 0.001 b 0.001 0.362
94.1% 91.2% 85%
93.3% 89.6% 84.4%
0.088 0.048 0.966
69.9% 65.3% 60.9%
79.3% 69.7% 65.9%
b 0.001 0.005 0.002
p = 0.005) In both of the younger cohorts, women with grade 1 disease had higher 5 year DSS without lymphadenectomy than with lymphadenectomy (b70 cohort: 98.5 vs 97.5%, p b 0.001; 70–79 cohort: 97.2 vs 95.3%,pb 0.001). Likewise, in both groups, women with grade 2 disease had higher 5 year DSS without lymphadenectomy (b70 cohort: 94.1 vs 93.3%, p b 0.088; 70–79 cohort: 91.2 vs 89.6%,p= 0.048). The overall number of women in whom lymphadenectomy was performed and adjuvant treatment was administered is shown in Table 1. In an exploratory analysis simulating the upgrading of tumors at final pathologic evaluation, we estimated the five year DSS of preoperative grade 1 disease in the over 80 cohort using a weighted average survival calculation. This provided a five year DSS of 91.3% in the lymphadenectomy group and 92.3% in the no lymphadenectomy group.
Discussion Our findings indicate that women over 80 years of age with grade 1 or 2 endometrioid endometrial cancer in whom lymphadenectomy is omitted following hysterectomy do not appear to suffer any adverse effect on cancer-specific survival. However, among women with grade 3 disease, the addition of lymphadenectomy is associated with a significantly increased 5 year DSS. Women above the age of 80 in this study whose endometrial cancer was surgically managed had a 5 year DSS that was comparable to the DSS of patients under 80 years old. Wright et al. have previously demonstrated using the SEER database that as age increases, women are less likely to undergo a hysterectomy and adjuvant treatment [17]. Our results provide evidence that age alone should not be an indication to withhold appropriate surgical management of endometrial cancer. However, the length of a surgical staging procedure for endometrial cancer is consistently higher when lymphadenectomy is performed [10,14], and this increase in surgical complexity and duration also increases the surgical risk among the elderly [13]. We propose that withholding lymphadenectomy in elderly women who are also at low risk for lymph node metastasis based on preoperative grade and gross intraoperative findings is a reasonable approach. We found a trend toward improved DSS only in the highest grade cohort in all 3 age groups examined. As with the elderly cohort, we found no DSS advantage at 5 years in either of the two younger cohorts with grade 1 and 2 disease. Although there is currently no global consensus on the role of lymphadenectomy in early stage endometrial cancer, it is accepted that there will be a number of patients in whom disease is upgraded at the time of pathologic evaluation, and that higher final grade is associated with a higher chance of nodal metastasis. To account for this in a
Fig. 1. 10 year KM survival curve in women 70 years of age or younger with and without lymphadenectomy.
Fig. 2. 10 year KM survival curves in women 70–80 years of age with and without lymphadenectomy.
W.J. Lowery et al. / Gynecologic Oncology 126 (2012) 12–15
15
Fig. 3. 10 year KM survival curves in women 80 + years of age with and without lymphadenectomy.
theoretical construct, we performed an exploratory analysis using previously published estimates of the number of specimens upgraded at final pathologic analysis [4,5,16]. Our exploratory analysis simulated DSS in the over 80 cohort who present with preoperative grade 1 disease and suggested that even after accounting for a portion of the tumors being upgraded, there may be no advantage to lymph node dissection. These findings are consistent with the ASTEC trial in which no benefit was observed when lymphadenectomy was included as part of the surgical management of women with suspected low grade endometrial cancer [9]. In our own practice we individually tailor decisions about surgical staging based on preoperative grade, intraoperative gross and frozen section findings, and each patient's co-morbid conditions. While our analysis benefits from the large number of patients included in the cohort, there are important limitations to this retrospective database study. We included only patients who were managed with primary surgical therapy; as such there was almost certainly selection bias regarding which elderly patients were offered surgical treatment. Second, even within the group receiving surgical management, there was likely a functional status-related selection bias regarding the choice of patients for lymphadenectomy. Finally, those who underwent a staging lymphadenectomy were also more likely to receive adjuvant radiation. In women with high grade disease, we were therefore unable to determine if the survival advantage associated with lymphadenectomy was driven by the procedure itself, adjuvant treatment, or by selection bias. In addition, there are inherent limitations to the SEER database. Specific to our study are the lack of reliable information regarding functional status, quality of life, and a lack of information on comorbidities. The database also lacks data on additional adjuvant therapies, such as chemotherapy or hormonal treatments, but it is unlikely that a significant number of these patients would have received these interventions. Another criticism of the SEER database is that there is no central pathologic review, but this should not necessarily be seen as a limitation, as this may more accurately reflect community practice. Even with these limitations in mind, we feel it is likely that performance of lymphadenectomy in a high preoperative risk cohort identifies women in whom adjuvant treatments are likely to improve endometrial cancer outcomes. As the elderly population increases in number and becomes more obese, and with a projected increase in the number of cases of endometrial cancer that result [18], questions regarding the optimal management of the elderly patient will continue to present a challenging dilemma. The surgical approach to endometrial cancer should continue to be tailored based on the best available evidence including preoperative and intraoperative risk factors. Our data, and that of others, suggests that women over 80 with grade 1 and 2 endometrioid lesions who exhibit no evidence of advanced stage disease at exploration may be safely spared the morbidity of lymphadenectomy. Elderly women with grade 3 endometrioid lesions and those who are appropriate candidates for
full staging to tailor adjuvant treatments may in fact derive benefit from this approach. Conflict of interest statement The authors declare that there are no conflicts of interest.
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