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The significance of surgical staging in intermediate-risk endometrial cancer
Gynecologic Oncology 122 (2011) 50–54
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
The significance of surgical staging in intermediate-risk endometrial cancer Janice S. Kwon ⁎, Mona Mazgani, Dianne M. Miller, Tom Ehlen, Mark Heywood, Jessica N. McAlpine, Sarah J. Finlayson, Marie Plante, Gavin C.E. Stuart, Mark S. Carey Division of Gynecologic Oncology, University of British Columbia and BC Cancer Agency, 2775 Laurel Street, 6th Floor, Vancouver, British Columbia, Canada V5Z 1M9
a r t i c l e
i n f o
Article history: Received 8 December 2010 Available online 21 March 2011 Keywords: Endometrial cancer Surgical staging Chemotherapy Intermediate risk High risk Nodal metastases
a b s t r a c t Objective. The objective was to evaluate rates of nodal disease in endometrial cancer within risk groups based on uterine factors, and to estimate the rate of potential undertreatment and impact on survival if nodal status was unknown. Methods. This was a population-based retrospective cohort study of endometrioid-type endometrial cancer in British Columbia from 2005 to 2009. All women with a preoperative grade 2/3 cancer underwent hysterectomy, bilateral salpingo-oophorectomy (HBSO) and lymphadenectomy, and those with intermediate- or high-risk disease based on uterine factors after HBSO alone underwent secondary lymphadenectomy. We compared rates of node-positivity and potential undertreatment in each group if nodal status had been unknown (chi-square test), and estimated the survival benefit from lymphadenectomy. Results. There were 222 women who underwent primary or secondary lymphadenectomy. Median age was 65 (range 38–86) and median number of lymph nodes was 10 (range 2–39). Of the 66 women with intermediate-risk disease (grade 1 or 2 tumor, deep myometrial invasion), 6 had nodal disease (9.1%) and received adjuvant chemotherapy. They remain disease-free after 24 months (range 8–55). They would not have qualified for chemotherapy based on uterine factors alone, and would have been undertreated compared to other risk groups (chi-square p = 0.071). A 1% survival benefit was estimated from lymphadenectomy. Conclusion. Women with a grade 1 or 2 tumor and deep myometrial invasion have a 9% risk of nodal disease. Lymphadenectomy is significant for this subgroup as they would have been undertreated based on uterine risk factors alone, although the survival benefit is limited. © 2011 Elsevier Inc. All rights reserved.
Introduction From a population perspective, it is difficult to justify systematic lymphadenectomy for all women with a diagnosis of endometrial cancer, as there are approximately 4500 and 45,000 incident cases per year in Canada and the United States, respectively [1,2]. Two recent prospective randomized trials have been unable to demonstrate a survival benefit from lymphadenectomy [3,4]. The majority of women with endometrial cancer in the general population have early stage disease, and only a small percentage of women with apparent Stage I disease will actually have metastatic nodal disease [5,6]. The presence of 2 or more high-risk uterine factors such as a grade 3 tumor and deep myometrial invasion is known to be associated with a high risk of nodal disease [7]. However, these risk factors are associated with poor outcomes in endometrial cancer even in the absence of nodal disease [6]. The women most likely to benefit from lymphadenectomy are those whose treatment would change according to nodal status, and this treatment would improve survival. Chemotherapy is the only treatment modality that has been proven in the context of a prospective
⁎ Corresponding author. Fax: +1 604 875 4869. E-mail address: [email protected] (J.S. Kwon). 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.02.037
randomized trial to improve survival in endometrial cancer [8]. Therefore the greatest potential benefit of lymphadenectomy is identifying women with nodal disease who would not have received chemotherapy in the absence of this procedure. Women with apparent intermediate-risk disease (presence of only one high-risk uterine factor such as a grade 3 tumor or deep myometrial invasion) are expected to have a low rate of pelvic nodal metastases, and they may do well with vaginal vault brachytherapy alone [9]. However, if any of these women were proven to have nodal metastases, they would receive adjuvant chemotherapy for surgical Stage III disease, which may translate into a survival benefit. Although women with high-risk disease (presence of 2 or more high-risk uterine factors) are expected to have a higher rate of pelvic nodal metastases, they appear to benefit from adjuvant therapy even in the absence of nodal disease [10,11]. Therefore, lymphadenectomy may be more informative in apparent intermediate-risk disease, because only those with confirmed nodal metastases will receive chemotherapy, while those with high-risk disease may receive chemotherapy regardless of nodal status. Consequently, the rate of potential undertreatment may be greater in those with apparent intermediate-risk disease who do not undergo lymphadenectomy, compared to those with high-risk disease. The objectives of this study were: (1) to review the rate of nodal disease according to risk groups defined by uterine factors within a
J.S. Kwon et al. / Gynecologic Oncology 122 (2011) 50–54
population-based cohort; and (2) to determine what proportion of women in each risk group would have been undertreated if they did not undergo lymphadenectomy; and (3) to estimate the survival benefit from lymphadenectomy. Methods This was a retrospective cohort study of all women in British Columbia, Canada, diagnosed with endometrioid-type endometrial cancer from 2005 to 2009 who underwent a hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. This study was approved by the Office of Research Services at the University of British Columbia. All incident cases of endometrial cancer diagnosed in British Columbia were ascertained from the provincial cancer registry. During the study period, all women in British Columbia with a preoperative grade 2 or 3 cancer were referred to the Division of Gynecologic Oncology in Vancouver for consideration of a primary surgical staging procedure, which consisted of a hysterectomy, bilateral salpingooophorectomy (HBSO), and pelvic lymphadenectomy. Para-aortic lymphadenectomy was not routinely done, except in the event of suspicious pelvic and/or para-aortic nodes. For those who did not have primary surgical staging (such as those who underwent HBSO alone for a preoperative grade 1 cancer), the presence of 1 or more high-risk uterine factors on final pathology (e.g., grade 3 tumor and/or greater than 50% myometrial invasion) warranted referral to the Division of Gynecologic Oncology for a second operation (pelvic lymphadenectomy, as an outpatient laparoscopic procedure when possible, herein “secondary lymphadenectomy”). All surgical staging procedures and secondary lymphadenectomies were done by gynecologic oncologists, and all pathology specimens were reviewed by gynecologic pathologists affiliated with Vancouver General Hospital and the BC Cancer Agency. Adjuvant treatment decisions were based on risk group at final pathology after primary surgical staging or secondary lymphadenectomy. Risk groups were defined by the presence or absence of high-risk uterine factors, such as a grade 3 tumor, greater than 50% myometrial invasion (“deep myometrial invasion”), and cervical stromal involvement. Low risk included those with no risk factors (i.e., grade 1 or 2 tumor with less than 50% myometrial invasion), intermediate risk was defined as those with only 1 risk factor (i.e., either grade 3 tumor or deep myometrial invasion), and high risk was defined as those with 2 or more risk factors. Those with endocervical involvement were considered to have intermediate risk disease as long as they did not have both deep myometrial invasion and a grade 3 tumor. Adjuvant therapy was not required for those with low-risk disease, while vaginal vault brachytherapy was offered to those with intermediate-risk disease, and chemotherapy was recommended to those with 2 or more high-risk uterine factors, regardless of nodal status, as well as those with confirmed nodal metastases. We assigned women to each risk group on the basis of their uterine risk factors alone, and then assessed the proportion in each risk group who had nodal disease. To estimate the rate of potential undertreatment in each risk group, we determined the proportion of women who would not have received chemotherapy if their nodal status was unknown or negative. The chi-square test compared rates of potential undertreatment in each risk group. We then estimated the survival benefit from lymphadenectomy based on the proportion of women potentially undertreated in the absence of this procedure. Results There were 151 women with a preoperative grade 2 or 3 endometrial cancer who were referred from across British Columbia for a primary surgical staging procedure (98 and 53, respectively). There were 4 women who did not undergo lymphadenectomy at the time of surgery, because of gross metastatic disease identified intraoperatively (n = 3) or morbid obesity, and therefore, 147 women
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Table 1 Description of cohort. Subgroup
Underwent lymphadenectomy (n)
Referred for lymphadenectomy (n)
Preoperative grade 2 Preoperative grade 3 Preoperative non-endometrioid (endometrioid on final pathology) Secondary lymphadenectomy Total
98 53 12
97a 50b 12
63 226
63 222
a
Of 98 with a preoperative grade 2 tumor, 1 had gross metastatic disease at surgery. Of 53 with a preoperative grade 3 tumor, 2 had gross metastatic disease at surgery and 1 was morbidly obese and lymphadenectomy was not technically feasible. b
underwent primary surgical staging. There were another 63 women with intermediate or high-risk endometrial cancer who were referred for a secondary lymphadenectomy after HBSO alone. There were an additional 12 women who had a preoperative diagnosis of nonendometrioid histology (serous, clear cell, undifferentiated, or malignant mixed mullerian tumor) who had endometrioid histology on final pathology, for a total of 222 women in this study. This population cohort is summarized in Table 1. The median age of the study cohort was 65 years (range 38–86). There were 87 women who had laparoscopy and 60 who had a laparotomy for their primary staging procedure. All 63 women referred for secondary lymphadenectomy had the procedure completed laparoscopically. All women underwent a pelvic lymphadenectomy, for which the standard anatomic boundaries at our institution included the bifurcation of internal and external iliac vessels (superior), deep circumflex iliac vein (inferior), medial border of iliopsoas (anterior), and obturator nerve (posterior). Only 1 patient with a preoperative grade 3 tumor had a para-aortic node dissection because of intraoperative suspicious pelvic nodes. The median number of nodes resected at lymphadenectomy was 10 (range 2–39) for both primary staging by laparotomy and laparoscopy as well as secondary lymphadenectomy. There was only 1 major operative complication, which was an unrecognized small bowel perforation that occurred at the time of trocar insertion during secondary lymphadenectomy. This complication was recognized on the ward and the patient was brought back to the operating room on the 2nd postoperative day, where she underwent a laparotomy and small bowel resection. She recovered uneventfully. For the 222 women who had undergone either primary surgical staging or secondary lymphadenectomy, the rates of nodal disease are presented according to risk group in Table 2. We estimated the proportion of patients who would be undertreated had they not undergone lymphadenectomy (i.e., those with fewer than 2 high-risk uterine factors who would not qualify for adjuvant chemotherapy at our institution), and these results are summarized in Table 3. There were 95 women with apparent low-risk disease, and 2 (2.1%) of them had nodal disease. Neither of these women would have qualified for chemotherapy on the basis of their uterine risk factors, and therefore
Table 2 Risk group, final pathology, and node-positive rate. Risk group (n)
Final pathology (n)
# Node-positive (%)
Low risk (95) Intermediate risk (94)
Grade 1 or 2, superficial MI (95) Grade 3, superficial MI (28) Grade 1 or 2, deep MI (66)a Grade 3, deep MI (25) Cervical stromal involvement (8)b
2 0 6 7 3
High risk (33)
(2.1%) (9.1%) (28%) (37.5%)
MI = myometrial invasion. a Of 66 with grade 1 or 2 disease and greater than 50% myometrial invasion, 32 had grade 1 and 34 had grade 2 disease. b Of 8 with cervical stromal involvement, 6 had deep myometrial invasion, including the 3 with nodal disease.
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Table 3 Risk group, rates of treatment and undertreatment. Risk group (n)
Low risk (95) Intermediate risk, grade 3 (28) Intermediate risk, deep MI (66) High risk, grade 3 and deep MI (25) High risk (cervical stromal ± grade 3 ± deep MI (8)
# Eligible for chemotherapy based on nodepositive (%)
# Potential undertreatment if nodal status unknown (%)a
0 0
2 (2.1%) 0 (0%)
2 (2.1%) 0
0
6 (9.1%)
6 (9.1%)
25
7 (28%)
0
3 (37.5%)
0
# Eligible for chemotherapy based on uterine factors alone
8
MI = myometrial invasion. a Chi-square p = 0.071.
the rate of potential undertreatment in this subgroup was 2.1%. There were 94 women with intermediate risk disease (i.e., only 1 high-risk uterine factor), including 28 women with grade 3 tumors with superficial or no myometrial invasion, and 66 women with grade 1 or 2 tumors with deep myometrial invasion. None of the 28 women with grade 3 tumors and superficial myometrial invasion had nodal disease, however, 6 of the 66 women with a grade 1 or 2 tumor and deep myometrial invasion had nodal disease (9.1%). All 6 of these women had a normal CA125 prior to surgery (less than 35 IU/L), and all had microscopic nodal disease (i.e., unsuspected at the time of surgery). These 6 women received a combination of adjuvant chemotherapy (intravenous carboplatin and paclitaxel) and external beam pelvic radiotherapy as per institution protocol, and they remain alive and well after a median follow-up of 24 months (range 8– 55 months). The rate of potential undertreatment was 9.1% in the subgroup of women with grade 1 or 2 tumors and deep myometrial invasion, as they would have only received vault brachytherapy as per PORTEC 2 if their nodal status had been unknown. There were 25 women with a grade 3 tumor and deep myometrial invasion, and 7 had nodal disease (28%). There were 8 women with cervical stromal involvement, and 3 (37.5%) had nodal disease. All of these women would have been offered chemotherapy according to policy in British Columbia regardless of nodal status because they had at least 2 high-risk uterine factors, and therefore the rate of potential undertreatment in
these groups was 0%. The chi-square test was suggestive of a difference among these risk groups in the proportion of women who could have been undertreated in the absence of lymphadenectomy (p = 0.071). To estimate the survival benefit from lymphadenectomy in intermediate-risk disease, we evaluated a hypothetical cohort of 100 women having grade 1 or 2 tumors with deep myometrial invasion and a node-positive rate of 9% (Fig. 1). If they all undergo lymphadenectomy, 9 women will be identified as having positive nodes and will receive chemotherapy, while if they do not undergo lymphadenectomy, none will be identified as having positive nodes and they will receive vault brachytherapy alone. The magnitude of benefit from adjuvant chemotherapy for node-positive patients is estimated to be a 13% absolute difference in overall survival compared to the absence of chemotherapy, based on outcomes from GOG122 [8]. This translates into 1 additional patient alive at the end of 5 years among the 9 node-positive patients who receive chemotherapy compared to the 9 node-positive patients who do not receive chemotherapy. The 91 node-negative patients have the same survival outcomes, irrespective of lymphadenectomy. In the end, there is 1 additional life saved for every 100 women with intermediate-risk disease who undergo lymphadenectomy. Discussion The majority of women with endometrial cancer in our population will have early stage disease and will be cured with hysterectomy and bilateral salpingo-oophorectomy alone. However, about 10% of women with endometrial cancer will have nodal disease, and the challenge remains in identifying this subgroup while limiting the total number of women having to undergo lymphadenectomy. Lymphadenectomy for all endometrial cancer patients has not been shown to improve survival [1,2], and it is not necessarily practical, as these women would have to be referred to a tertiary care center to have surgery by a gynecologic oncologist. Systematic lymphadenectomy has been recommended to reduce adjuvant external beam pelvic radiotherapy rates [12–17]. However, pelvic radiotherapy does not improve survival [18–20], therefore withholding radiotherapy as a result of negative lymphadenectomy is not likely to affect survival either. Furthermore, the low pelvic recurrence rate of 3.8% in PORTEC 2 (in the vault brachytherapy group) suggests that external beam pelvic radiotherapy is unnecessary in intermediate-risk endometrial cancer, even in the absence of lymphadenectomy [9].
Intermediate risk N=100
Lymphadenectomy for all N=100
No lymphadenectomy N=100
9 Node+ (all detected)
91 Node-
9 Node+ (none detected)
91 Node-
Chemotherapy
No chemotherapy
No chemotherapy
No chemotherapy
55% survival N=5
85% survival N=77
42% survival N=4
85% survival N=77
Fig. 1. Estimated survival benefit of lymphadenectomy in apparent intermediate-risk patients (defined as those with deep myometrial invasion and grade 1 or 2 tumors). Assumptions about 5-year survival for node-positive patients receiving chemotherapy (and no chemotherapy) are based on GOG 122 [8], and for intermediate-risk patients receiving vault brachytherapy (BT) are from PORTEC 2 [9]. The flow diagram illustrates that after lymphadenectomy, a total of 82 patients (5 + 77) are alive at 5 years, while after no lymphadenectomy, a total of 81 patients (4 + 77) are still alive. This translates into 100 women undergoing lymphadenectomy in order to save 1 life.
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The rate of distant metastases in intermediate-risk patients receiving vault brachytherapy in PORTEC 2 was 8.3% [9]. This is comparable to the node-positivity rate of 9% in our study's subgroup of intermediate-risk women with grade 1 or 2 tumors and deep myometrial invasion. Similarly, this subgroup would have only received vault brachytherapy in the absence of lymphadenectomy. The node-positivity rate of 9% translates into a potential undertreatment rate of 9%, as none of them would have received chemotherapy on the basis of their uterine risk factors alone. Although this rate did not reach statistical significance, this may be a function of the limited number of women in this subgroup analysis and low rate of nodal metastases. There was a higher nodepositivity rate among those with deeply invasive grade 3 tumors and those with cervical stromal involvement, but all of them would have received adjuvant chemotherapy regardless of nodal status because of the high-risk uterine factors. Arguably, lymphadenectomy may not have been as important for this subgroup as it would not have changed adjuvant treatment recommendations. A node-positive rate of 9% may be high enough to justify lymphadenectomy as a secondary procedure for those with a grade 1 or 2 tumor and deep myometrial invasion, but this still translates into 91 unnecessary procedures for every 9 women identified with nodal disease, and the survival benefit appears to be limited. The low overall number of node-positive patients precludes further analysis of risk factors that might predict nodal metastases in apparent intermediaterisk disease. An elevated CA125 is known to be associated with extrauterine disease [21–25], but this was not a predictive factor in our study as none of the intermediate-risk patients with nodal metastases had an abnormal preoperative CA125. The sensitivity of PET/CT in detecting nodal disease is not high enough to reliably select women for lymphadenectomy, with rates ranging from only 50% to 78% [26–29]. Similarly, sentinel node detection rates of 50–86% are not sufficiently high to select women for this procedure [30–35]. Furthermore, not all health care facilities are equipped with a PET/CT, nor do they have the surgical expertise to conduct sentinel node mapping. The expansive geography of British Columbia precludes all women with endometrial cancer from having a PET/CT or sentinel node mapping because of the distance and cost required to travel to a tertiary care center for these investigations. Ideally, molecular alterations associated with lymph node metastases could be identified in preoperative tissue samples that would determine the need for lymphadenectomy. Bidus et al. found that ZIC2 overexpression is associated with node-positive endometrial cancer, but this was based on a binary comparison of grade 1 and 3 tumors [36]. This underscores the need for genomic and proteomic analyses to assist in further defining the subgroup of women who are likely to have nodal metastases and would benefit from lymphadenectomy. Until then, systematic lymphadenectomy may still be necessary for women with apparent intermediate-risk endometrial cancer to identify those with nodal disease who would potentially be undertreated, although the survival benefit will be limited.
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[23] Conflict of interest statement The authors declare that there are no conflicts of interest.
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Acknowledgment
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The authors thank the Lower Mainland Innovation and Integration Fund for financial support.
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
The significance of surgical staging in intermediate-risk endometrial cancer Janice S. Kwon ⁎, Mona Mazgani, Dianne M. Miller, Tom Ehlen, Mark Heywood, Jessica N. McAlpine, Sarah J. Finlayson, Marie Plante, Gavin C.E. Stuart, Mark S. Carey Division of Gynecologic Oncology, University of British Columbia and BC Cancer Agency, 2775 Laurel Street, 6th Floor, Vancouver, British Columbia, Canada V5Z 1M9
a r t i c l e
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Article history: Received 8 December 2010 Available online 21 March 2011 Keywords: Endometrial cancer Surgical staging Chemotherapy Intermediate risk High risk Nodal metastases
a b s t r a c t Objective. The objective was to evaluate rates of nodal disease in endometrial cancer within risk groups based on uterine factors, and to estimate the rate of potential undertreatment and impact on survival if nodal status was unknown. Methods. This was a population-based retrospective cohort study of endometrioid-type endometrial cancer in British Columbia from 2005 to 2009. All women with a preoperative grade 2/3 cancer underwent hysterectomy, bilateral salpingo-oophorectomy (HBSO) and lymphadenectomy, and those with intermediate- or high-risk disease based on uterine factors after HBSO alone underwent secondary lymphadenectomy. We compared rates of node-positivity and potential undertreatment in each group if nodal status had been unknown (chi-square test), and estimated the survival benefit from lymphadenectomy. Results. There were 222 women who underwent primary or secondary lymphadenectomy. Median age was 65 (range 38–86) and median number of lymph nodes was 10 (range 2–39). Of the 66 women with intermediate-risk disease (grade 1 or 2 tumor, deep myometrial invasion), 6 had nodal disease (9.1%) and received adjuvant chemotherapy. They remain disease-free after 24 months (range 8–55). They would not have qualified for chemotherapy based on uterine factors alone, and would have been undertreated compared to other risk groups (chi-square p = 0.071). A 1% survival benefit was estimated from lymphadenectomy. Conclusion. Women with a grade 1 or 2 tumor and deep myometrial invasion have a 9% risk of nodal disease. Lymphadenectomy is significant for this subgroup as they would have been undertreated based on uterine risk factors alone, although the survival benefit is limited. © 2011 Elsevier Inc. All rights reserved.
Introduction From a population perspective, it is difficult to justify systematic lymphadenectomy for all women with a diagnosis of endometrial cancer, as there are approximately 4500 and 45,000 incident cases per year in Canada and the United States, respectively [1,2]. Two recent prospective randomized trials have been unable to demonstrate a survival benefit from lymphadenectomy [3,4]. The majority of women with endometrial cancer in the general population have early stage disease, and only a small percentage of women with apparent Stage I disease will actually have metastatic nodal disease [5,6]. The presence of 2 or more high-risk uterine factors such as a grade 3 tumor and deep myometrial invasion is known to be associated with a high risk of nodal disease [7]. However, these risk factors are associated with poor outcomes in endometrial cancer even in the absence of nodal disease [6]. The women most likely to benefit from lymphadenectomy are those whose treatment would change according to nodal status, and this treatment would improve survival. Chemotherapy is the only treatment modality that has been proven in the context of a prospective
⁎ Corresponding author. Fax: +1 604 875 4869. E-mail address: [email protected] (J.S. Kwon). 0090-8258/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2011.02.037
randomized trial to improve survival in endometrial cancer [8]. Therefore the greatest potential benefit of lymphadenectomy is identifying women with nodal disease who would not have received chemotherapy in the absence of this procedure. Women with apparent intermediate-risk disease (presence of only one high-risk uterine factor such as a grade 3 tumor or deep myometrial invasion) are expected to have a low rate of pelvic nodal metastases, and they may do well with vaginal vault brachytherapy alone [9]. However, if any of these women were proven to have nodal metastases, they would receive adjuvant chemotherapy for surgical Stage III disease, which may translate into a survival benefit. Although women with high-risk disease (presence of 2 or more high-risk uterine factors) are expected to have a higher rate of pelvic nodal metastases, they appear to benefit from adjuvant therapy even in the absence of nodal disease [10,11]. Therefore, lymphadenectomy may be more informative in apparent intermediate-risk disease, because only those with confirmed nodal metastases will receive chemotherapy, while those with high-risk disease may receive chemotherapy regardless of nodal status. Consequently, the rate of potential undertreatment may be greater in those with apparent intermediate-risk disease who do not undergo lymphadenectomy, compared to those with high-risk disease. The objectives of this study were: (1) to review the rate of nodal disease according to risk groups defined by uterine factors within a
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population-based cohort; and (2) to determine what proportion of women in each risk group would have been undertreated if they did not undergo lymphadenectomy; and (3) to estimate the survival benefit from lymphadenectomy. Methods This was a retrospective cohort study of all women in British Columbia, Canada, diagnosed with endometrioid-type endometrial cancer from 2005 to 2009 who underwent a hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. This study was approved by the Office of Research Services at the University of British Columbia. All incident cases of endometrial cancer diagnosed in British Columbia were ascertained from the provincial cancer registry. During the study period, all women in British Columbia with a preoperative grade 2 or 3 cancer were referred to the Division of Gynecologic Oncology in Vancouver for consideration of a primary surgical staging procedure, which consisted of a hysterectomy, bilateral salpingooophorectomy (HBSO), and pelvic lymphadenectomy. Para-aortic lymphadenectomy was not routinely done, except in the event of suspicious pelvic and/or para-aortic nodes. For those who did not have primary surgical staging (such as those who underwent HBSO alone for a preoperative grade 1 cancer), the presence of 1 or more high-risk uterine factors on final pathology (e.g., grade 3 tumor and/or greater than 50% myometrial invasion) warranted referral to the Division of Gynecologic Oncology for a second operation (pelvic lymphadenectomy, as an outpatient laparoscopic procedure when possible, herein “secondary lymphadenectomy”). All surgical staging procedures and secondary lymphadenectomies were done by gynecologic oncologists, and all pathology specimens were reviewed by gynecologic pathologists affiliated with Vancouver General Hospital and the BC Cancer Agency. Adjuvant treatment decisions were based on risk group at final pathology after primary surgical staging or secondary lymphadenectomy. Risk groups were defined by the presence or absence of high-risk uterine factors, such as a grade 3 tumor, greater than 50% myometrial invasion (“deep myometrial invasion”), and cervical stromal involvement. Low risk included those with no risk factors (i.e., grade 1 or 2 tumor with less than 50% myometrial invasion), intermediate risk was defined as those with only 1 risk factor (i.e., either grade 3 tumor or deep myometrial invasion), and high risk was defined as those with 2 or more risk factors. Those with endocervical involvement were considered to have intermediate risk disease as long as they did not have both deep myometrial invasion and a grade 3 tumor. Adjuvant therapy was not required for those with low-risk disease, while vaginal vault brachytherapy was offered to those with intermediate-risk disease, and chemotherapy was recommended to those with 2 or more high-risk uterine factors, regardless of nodal status, as well as those with confirmed nodal metastases. We assigned women to each risk group on the basis of their uterine risk factors alone, and then assessed the proportion in each risk group who had nodal disease. To estimate the rate of potential undertreatment in each risk group, we determined the proportion of women who would not have received chemotherapy if their nodal status was unknown or negative. The chi-square test compared rates of potential undertreatment in each risk group. We then estimated the survival benefit from lymphadenectomy based on the proportion of women potentially undertreated in the absence of this procedure. Results There were 151 women with a preoperative grade 2 or 3 endometrial cancer who were referred from across British Columbia for a primary surgical staging procedure (98 and 53, respectively). There were 4 women who did not undergo lymphadenectomy at the time of surgery, because of gross metastatic disease identified intraoperatively (n = 3) or morbid obesity, and therefore, 147 women
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Table 1 Description of cohort. Subgroup
Underwent lymphadenectomy (n)
Referred for lymphadenectomy (n)
Preoperative grade 2 Preoperative grade 3 Preoperative non-endometrioid (endometrioid on final pathology) Secondary lymphadenectomy Total
98 53 12
97a 50b 12
63 226
63 222
a
Of 98 with a preoperative grade 2 tumor, 1 had gross metastatic disease at surgery. Of 53 with a preoperative grade 3 tumor, 2 had gross metastatic disease at surgery and 1 was morbidly obese and lymphadenectomy was not technically feasible. b
underwent primary surgical staging. There were another 63 women with intermediate or high-risk endometrial cancer who were referred for a secondary lymphadenectomy after HBSO alone. There were an additional 12 women who had a preoperative diagnosis of nonendometrioid histology (serous, clear cell, undifferentiated, or malignant mixed mullerian tumor) who had endometrioid histology on final pathology, for a total of 222 women in this study. This population cohort is summarized in Table 1. The median age of the study cohort was 65 years (range 38–86). There were 87 women who had laparoscopy and 60 who had a laparotomy for their primary staging procedure. All 63 women referred for secondary lymphadenectomy had the procedure completed laparoscopically. All women underwent a pelvic lymphadenectomy, for which the standard anatomic boundaries at our institution included the bifurcation of internal and external iliac vessels (superior), deep circumflex iliac vein (inferior), medial border of iliopsoas (anterior), and obturator nerve (posterior). Only 1 patient with a preoperative grade 3 tumor had a para-aortic node dissection because of intraoperative suspicious pelvic nodes. The median number of nodes resected at lymphadenectomy was 10 (range 2–39) for both primary staging by laparotomy and laparoscopy as well as secondary lymphadenectomy. There was only 1 major operative complication, which was an unrecognized small bowel perforation that occurred at the time of trocar insertion during secondary lymphadenectomy. This complication was recognized on the ward and the patient was brought back to the operating room on the 2nd postoperative day, where she underwent a laparotomy and small bowel resection. She recovered uneventfully. For the 222 women who had undergone either primary surgical staging or secondary lymphadenectomy, the rates of nodal disease are presented according to risk group in Table 2. We estimated the proportion of patients who would be undertreated had they not undergone lymphadenectomy (i.e., those with fewer than 2 high-risk uterine factors who would not qualify for adjuvant chemotherapy at our institution), and these results are summarized in Table 3. There were 95 women with apparent low-risk disease, and 2 (2.1%) of them had nodal disease. Neither of these women would have qualified for chemotherapy on the basis of their uterine risk factors, and therefore
Table 2 Risk group, final pathology, and node-positive rate. Risk group (n)
Final pathology (n)
# Node-positive (%)
Low risk (95) Intermediate risk (94)
Grade 1 or 2, superficial MI (95) Grade 3, superficial MI (28) Grade 1 or 2, deep MI (66)a Grade 3, deep MI (25) Cervical stromal involvement (8)b
2 0 6 7 3
High risk (33)
(2.1%) (9.1%) (28%) (37.5%)
MI = myometrial invasion. a Of 66 with grade 1 or 2 disease and greater than 50% myometrial invasion, 32 had grade 1 and 34 had grade 2 disease. b Of 8 with cervical stromal involvement, 6 had deep myometrial invasion, including the 3 with nodal disease.
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Table 3 Risk group, rates of treatment and undertreatment. Risk group (n)
Low risk (95) Intermediate risk, grade 3 (28) Intermediate risk, deep MI (66) High risk, grade 3 and deep MI (25) High risk (cervical stromal ± grade 3 ± deep MI (8)
# Eligible for chemotherapy based on nodepositive (%)
# Potential undertreatment if nodal status unknown (%)a
0 0
2 (2.1%) 0 (0%)
2 (2.1%) 0
0
6 (9.1%)
6 (9.1%)
25
7 (28%)
0
3 (37.5%)
0
# Eligible for chemotherapy based on uterine factors alone
8
MI = myometrial invasion. a Chi-square p = 0.071.
the rate of potential undertreatment in this subgroup was 2.1%. There were 94 women with intermediate risk disease (i.e., only 1 high-risk uterine factor), including 28 women with grade 3 tumors with superficial or no myometrial invasion, and 66 women with grade 1 or 2 tumors with deep myometrial invasion. None of the 28 women with grade 3 tumors and superficial myometrial invasion had nodal disease, however, 6 of the 66 women with a grade 1 or 2 tumor and deep myometrial invasion had nodal disease (9.1%). All 6 of these women had a normal CA125 prior to surgery (less than 35 IU/L), and all had microscopic nodal disease (i.e., unsuspected at the time of surgery). These 6 women received a combination of adjuvant chemotherapy (intravenous carboplatin and paclitaxel) and external beam pelvic radiotherapy as per institution protocol, and they remain alive and well after a median follow-up of 24 months (range 8– 55 months). The rate of potential undertreatment was 9.1% in the subgroup of women with grade 1 or 2 tumors and deep myometrial invasion, as they would have only received vault brachytherapy as per PORTEC 2 if their nodal status had been unknown. There were 25 women with a grade 3 tumor and deep myometrial invasion, and 7 had nodal disease (28%). There were 8 women with cervical stromal involvement, and 3 (37.5%) had nodal disease. All of these women would have been offered chemotherapy according to policy in British Columbia regardless of nodal status because they had at least 2 high-risk uterine factors, and therefore the rate of potential undertreatment in
these groups was 0%. The chi-square test was suggestive of a difference among these risk groups in the proportion of women who could have been undertreated in the absence of lymphadenectomy (p = 0.071). To estimate the survival benefit from lymphadenectomy in intermediate-risk disease, we evaluated a hypothetical cohort of 100 women having grade 1 or 2 tumors with deep myometrial invasion and a node-positive rate of 9% (Fig. 1). If they all undergo lymphadenectomy, 9 women will be identified as having positive nodes and will receive chemotherapy, while if they do not undergo lymphadenectomy, none will be identified as having positive nodes and they will receive vault brachytherapy alone. The magnitude of benefit from adjuvant chemotherapy for node-positive patients is estimated to be a 13% absolute difference in overall survival compared to the absence of chemotherapy, based on outcomes from GOG122 [8]. This translates into 1 additional patient alive at the end of 5 years among the 9 node-positive patients who receive chemotherapy compared to the 9 node-positive patients who do not receive chemotherapy. The 91 node-negative patients have the same survival outcomes, irrespective of lymphadenectomy. In the end, there is 1 additional life saved for every 100 women with intermediate-risk disease who undergo lymphadenectomy. Discussion The majority of women with endometrial cancer in our population will have early stage disease and will be cured with hysterectomy and bilateral salpingo-oophorectomy alone. However, about 10% of women with endometrial cancer will have nodal disease, and the challenge remains in identifying this subgroup while limiting the total number of women having to undergo lymphadenectomy. Lymphadenectomy for all endometrial cancer patients has not been shown to improve survival [1,2], and it is not necessarily practical, as these women would have to be referred to a tertiary care center to have surgery by a gynecologic oncologist. Systematic lymphadenectomy has been recommended to reduce adjuvant external beam pelvic radiotherapy rates [12–17]. However, pelvic radiotherapy does not improve survival [18–20], therefore withholding radiotherapy as a result of negative lymphadenectomy is not likely to affect survival either. Furthermore, the low pelvic recurrence rate of 3.8% in PORTEC 2 (in the vault brachytherapy group) suggests that external beam pelvic radiotherapy is unnecessary in intermediate-risk endometrial cancer, even in the absence of lymphadenectomy [9].
Intermediate risk N=100
Lymphadenectomy for all N=100
No lymphadenectomy N=100
9 Node+ (all detected)
91 Node-
9 Node+ (none detected)
91 Node-
Chemotherapy
No chemotherapy
No chemotherapy
No chemotherapy
55% survival N=5
85% survival N=77
42% survival N=4
85% survival N=77
Fig. 1. Estimated survival benefit of lymphadenectomy in apparent intermediate-risk patients (defined as those with deep myometrial invasion and grade 1 or 2 tumors). Assumptions about 5-year survival for node-positive patients receiving chemotherapy (and no chemotherapy) are based on GOG 122 [8], and for intermediate-risk patients receiving vault brachytherapy (BT) are from PORTEC 2 [9]. The flow diagram illustrates that after lymphadenectomy, a total of 82 patients (5 + 77) are alive at 5 years, while after no lymphadenectomy, a total of 81 patients (4 + 77) are still alive. This translates into 100 women undergoing lymphadenectomy in order to save 1 life.
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The rate of distant metastases in intermediate-risk patients receiving vault brachytherapy in PORTEC 2 was 8.3% [9]. This is comparable to the node-positivity rate of 9% in our study's subgroup of intermediate-risk women with grade 1 or 2 tumors and deep myometrial invasion. Similarly, this subgroup would have only received vault brachytherapy in the absence of lymphadenectomy. The node-positivity rate of 9% translates into a potential undertreatment rate of 9%, as none of them would have received chemotherapy on the basis of their uterine risk factors alone. Although this rate did not reach statistical significance, this may be a function of the limited number of women in this subgroup analysis and low rate of nodal metastases. There was a higher nodepositivity rate among those with deeply invasive grade 3 tumors and those with cervical stromal involvement, but all of them would have received adjuvant chemotherapy regardless of nodal status because of the high-risk uterine factors. Arguably, lymphadenectomy may not have been as important for this subgroup as it would not have changed adjuvant treatment recommendations. A node-positive rate of 9% may be high enough to justify lymphadenectomy as a secondary procedure for those with a grade 1 or 2 tumor and deep myometrial invasion, but this still translates into 91 unnecessary procedures for every 9 women identified with nodal disease, and the survival benefit appears to be limited. The low overall number of node-positive patients precludes further analysis of risk factors that might predict nodal metastases in apparent intermediaterisk disease. An elevated CA125 is known to be associated with extrauterine disease [21–25], but this was not a predictive factor in our study as none of the intermediate-risk patients with nodal metastases had an abnormal preoperative CA125. The sensitivity of PET/CT in detecting nodal disease is not high enough to reliably select women for lymphadenectomy, with rates ranging from only 50% to 78% [26–29]. Similarly, sentinel node detection rates of 50–86% are not sufficiently high to select women for this procedure [30–35]. Furthermore, not all health care facilities are equipped with a PET/CT, nor do they have the surgical expertise to conduct sentinel node mapping. The expansive geography of British Columbia precludes all women with endometrial cancer from having a PET/CT or sentinel node mapping because of the distance and cost required to travel to a tertiary care center for these investigations. Ideally, molecular alterations associated with lymph node metastases could be identified in preoperative tissue samples that would determine the need for lymphadenectomy. Bidus et al. found that ZIC2 overexpression is associated with node-positive endometrial cancer, but this was based on a binary comparison of grade 1 and 3 tumors [36]. This underscores the need for genomic and proteomic analyses to assist in further defining the subgroup of women who are likely to have nodal metastases and would benefit from lymphadenectomy. Until then, systematic lymphadenectomy may still be necessary for women with apparent intermediate-risk endometrial cancer to identify those with nodal disease who would potentially be undertreated, although the survival benefit will be limited.
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[23] Conflict of interest statement The authors declare that there are no conflicts of interest.
[24]
Acknowledgment
[25]
The authors thank the Lower Mainland Innovation and Integration Fund for financial support.
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