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Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group
Gynecologic Oncology 115 (2009) 26–31
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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
Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group Taek Sang Lee a, Jae Weon Kim b,⁎, Tae Jin Kim c, Chi Heum Cho d, Sang Young Ryu e, Hee-Sug Ryu f, Byoung Gie Kim g, Keun Ho Lee h, Yong Man Kim i, Soon-Beom Kang b and the Korean Gynecologic Oncology Group a
Department of Obstetrics and Gynecology, Seoul Metropolitan Boramae Hospital, Republic of Korea Department of Obstetrics and Gynecology, Seoul National University Hospital, Republic of Korea c Department of Obstetrics and Gynecology, Cheil General Hospital, Republic of Korea d Department of Obstetrics and Gynecology, Keimyung University Dongsan Medical Center, Republic of Korea e Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Republic of Korea f Department of Obstetrics and Gynecology, Ajou University Hospital, Republic of Korea g Department of Obstetrics and Gynecology, Samsung Seoul Hospital, Republic of Korea h Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, Republic of Korea i Department of Obstetrics and Gynecology, Asan Medical Center, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 16 March 2009 Available online 26 July 2009 Keywords: Endometrial cancer Ovary Preservation
a b s t r a c t Objectives. The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. Methods. Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. Results. One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5 ± 8.3 years (range 25–57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2–180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. Conclusion. Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer. © 2009 Elsevier Inc. All rights reserved.
Introduction Recent clinical trials on early stage endometrial cancer have focused on well-known unsolved questions related to the survival benefit of retroperitoneal lymph node dissection, and identifying the best modality for adjuvant treatment strategies [1]. However,
⁎ Corresponding author. Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul National University, 28 Yungun-Dong Chongno-Ku, Seoul, 110-744, Republic of Korea. Fax: +82 2 762 3599. E-mail address: [email protected] (J.W. Kim). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.06.041
reappraisal of existing treatment guidelines, even those that have been accepted for decades, sometimes become necessary to determine whether they are based on reliable evidence or hold true in the face of new research. In the treatment of endometrial cancer, total abdominal hysterectomy, bilateral salpingo-oophorectomy (BSO), and surgical staging are usually performed. Further treatment is tailored according to the presence or absence of various risk factors. This treatment policy has not been changed since 1988, although numerous trials have been conducted. Accordingly, BSO is recommended routinely irrespective of the patient's age. However, although endometrial cancer is primarily regarded as a disease of post-menopausal women, more than 45% of cases occur in premenopausal patients and 10% in women
T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31 Table 1 Patient characteristics. Characteristics
Patients with a retained ovary(ies) (n = 175) No.
Age, years ≤ 30 31–35 36–40 41–45 N 45 Type of hysterectomy TAH TLH, LAVH TVH RH (MRH) Preoperative diagnosis Endometrial carcinoma Endometrial hyperplasia Leiomyoma (adenomyosis) Cervical cancer Ovarian tumor Endometrial stromal tumor Uterine prolapse Unknown Reasons for ovarian preservation Young age (b 45) and/or patient's desire Other preoperative diagnosisa Not described Saved ovaries Right ovary Left ovary Both ovaries Myometrial invasion Limited to endometrium b 1/2 ≥ 1/2 Full thickness N/A Final histology Endometrioid Non-endometrioid Adenosquamous Endometrial stromal tumor Papillary serous Mucinous Histologic grade 1 2 3 N/A Postoperative FIGO stage (incompleteb) Ia Ib Ic IIa IIb IIIa IIIc
%
31 38 44 32 30
17.7 21.7 25.1 18.3 17.2
111 31 12 21
63.4 17.7 6.9 12.0
101 31 35 2 2 1 1 2
57.7 17.8 20.0 1.1 1.1 0.6 0.6 1.1
101 69 5
57.7 39.4 2.9
45 38 92
25.7 21.7 52.6
115 43 10 4 3
65.7 24.6 5.7 2.3 1.7
162 13 3 4 3 3
92.6 7.4 1.7 2.3 1.7 1.7
121 31 6 17a
69.1 17.7 3.4 9.7
114 35 6 6 12 1 1
65.2 20.0 3.4 3.4 6.8 0.6 0.6
27
In cervical cancer patients, the incidence of ovarian metastasis in women with early stage disease has been reported to be below 1% by several large scaled retrospective studies, and thus, ovarian preservation in such patients has not been shown to increase the risk of recurrence [5,6]. This has made fertility-preserving strategies possible in young women with early stage cervical cancer, such as radical trachelectomy [7]. However, although current surgical treatment policy for endometrial cancer recommending routine BSO might almost perfectly eradicate the possibility of residual cancer, the surgical castration of young women induces an abrupt loss of estrogen, which causes climacteric symptoms and long term effects, which include its deleterious impact on cardiovascular and bone health, in addition to the loss of fertility. In this regard, we have previously reported data which showed that the risk of a coexisting malignancy is negligible in patients with minimal preoperative risk factors and no intraoperative evidence of advanced disease [8]. The present study expands upon our previous data by adding follow-up results of a significant number of patients who have undergone ovary-preserving surgeries to determine whether ovarian preservation is feasible in younger endometrial cancer patients.
TAH indicates total abdominal hysterectomy; TLH, total laparoscopic hysterectomy; LAVH, laparoscopy assisted vaginal hysterectomy; VH, vaginal hysterectomy; RH, radical hysterectomy; MRH, modified radical hysterectomy. a Diagnosis which does not require oophorectomy and incidental ovarian saving. b Unevaluated areas such as both adnexa or lymph node status were considered negative.
under the age of 40 years in Korea [2,3]. Moreover, in a recent report which has not been published in the US, changing race and ethnicity demographics, coupled with an increase in obesity, have possibly contributed the incidence of endometrial cancer to increase in younger women. Furthermore, early stage, well-differentiated endometrial cancer has been reported to be most commonly encountered in younger patients [4]. Therefore, the issue of ovarian preservation in young women should be an issue that requires further consideration.
Fig. 1. Cumulative recurrence free survival (a) and overall survival (b) in patients with retained ovarian function. ⁎Time to the date when patients were found to be alive according to the national death certificate registry.
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T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31
Materials and methods With institutional review board approval, tumor registries at fourteen tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG) were searched to identify patients with a final diagnosis of endometrial cancer whose ovaries were preserved at operation between 1993 and 2005. Thirty-five cases analyzed in our previous study published in 2007 were also included. Clinical information including age at diagnosis, preoperative diagnosis, reasons for preserving ovaries, personal and family histories of cancer, the results of preoperative and intraoperative evaluations, and follow-up results for recurrences or secondary malignancies were abstracted. Patients with disease sufficiently advanced to prevent adequate removal of all visible tumors were excluded from analysis even though BSO was not documented in their medical record. When sufficient follow-up information on recurrence or survival was unavailable from medical records, we obtained information of the cause of death and death date from death certificates obtained at the Korea National Statistical Office. We classified patients with a complete follow-up record and a disease free state as being ‘Alive without disease recurrence’, and patients with no medical records for one year prior to analysis and not registered as dead were classified as being ‘Alive with an undetermined disease status’. Pathologic information, such as histology, grade, depth of myometrial invasion, lymph-vascular space invasion, and lymph node involvement was collected from surgical pathology reports. Stage of tumor was assigned based on available pathologic findings, and unevaluated areas such as both adnexa and lymph node status were considered negative for metastatic disease. Kaplan–Meier test was used for survival analysis. All analyses were carried out using SPSS 12 software (SPSS, Chicago, IL, USA). Results One hundred and seventy five patients were evaluated. Patients' mean age was 38.5 ± 8.3 (range 25–57) and 82.3% were ≤45 years old. Approximately 60% (101/175) of the patients were initially diagnosed as having endometrial carcinoma, 31 as having endometrial hyperplasia, 35 as having benign leiomyoma or adenomyosis, and 8 as having some other preoperative diagnoses (Table 1). Of the 175 cases, 111 underwent total abdominal hysterectomy, 31 total laparoscopic or laparoscopy assisted vaginal hysterectomy, 12 total vaginal hysterectomy, and 21 radical or modified radical hysterectomy. In 15 patients, ovarian wedge resection and frozen biopsy were performed based on surgeon's judgment, and all were negative for metastasis. In 10% (10/101) of patients preoperatively diagnosed as having endometrioid adenocarcinoma, bilateral fallo-
pian tubes were removed. Lymph node dissection or biopsy was performed in 56 patients with an initial diagnosis of endometrial carcinoma, and 2 of these had lymph node metastasis in the final pathologic report. In 20 patients with high risk factors for relapse including the above two lymph node positive cases, adjuvant pelvic radiation treatment was administered without additional bilateral adnexectomy or performing ovarian transposition and tailored brachytherapy was performed in patients with cervical involvement. Two patients diagnosed with non-endometrioid histology received adjuvant cytotoxic chemotherapy. As shown in Table 1, reasons for ovarian preservation were twofold. First, in younger patients (b40 years old) preoperatively diagnosed with endometrial cancer, preservation of grossly normal looking ovaries was decided upon by the surgeon with the patient's request. Second, in premenopausal women preoperatively diagnosed as having benign disease, e.g., office-based diagnosed endometrial hyperplasia, leiomyoma, or adenomyosis, ovaries were saved incidentally and no additional surgery was undertaken to remove these ovaries. Moreover, in some post-menopausal women preoperatively diagnosed as having a benign condition, vaginal hysterectomies skipping bilateral salpingo-oophorectomy were performed without gross findings of either adnexa. One cervical cancer patient was included. No reasonable rationale for ovarian saving was obvious based on the medical record review of 5 patients. Median follow-up duration was 55.0 months (range 6.2– 180.0 months). Overall, 7 of the 175 (4.0%) had documented recurrence. Five-year recurrence free survival and overall survival for all patients were 94.3% and 93.3%, respectively (Fig. 1). Among 155 patients with disease limited to the corpus, two recurrences were detected in patients diagnosed with endometrial stromal sarcoma. No recurrences were observed in stage I patients with endometrioid histology. As shown in Table 2, recurrences were identified mainly in the pelvic side wall (in 3 cases), lung (in 3 cases), bilateral lymphatic channels (in 2 cases), vaginal vault (in 1 case), and stomach (in 1 case). All recurrent cases had several potential risk factors for recurrence that could have reasonably explained recurrence, such as a non-endometrioid histology (4/7), deep myometrial invasion (5/7), or cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). In 2 of these 7 recurrent cases, adnexal metastasis was suspected based on imaging study findings. One (No. 3) was a 44 year old woman, who rejected further postoperative adjuvant treatment despite myometrial invasion of more than 50% and frank histologic cervical stromal invasion. The other (No. 4) was a case of uterine papillary serous carcinoma that invaded the full thickness of the myometrium, and showed disease progression during postoperative adjuvant chemotherapy.
Table 2 Characteristics of patients who experienced recurrence. No.
Age
Preoperative diagnosis
Final histology
MMI
LN biopsy
Presence of extrauterine spread
Postoperative adjuvant treatment
TTP (months)
Sites of recurrencea
Patient state
1
37
Myoma uteri
UPSC
FT
Not done
Chemotherapy
10
Pelvic side wall
Death
2 3
45 44
EN Myoma uteri
EN EN
b1/2 N1/2
Yes (0/16) Not done
Cervical stroma, vagina and contralateral adnexal involvement Cervical stromal involvement Cervical stromal involvement
ERT Not done
28 26
Death Death
4
49
Myoma uteri
UPSC
FT
Not done
–
Chemotherapy
5 6 7
38 36 38
Myoma uteri Myoma uteri EN
ESS ESS EN
N1/2 N1/2 b1/2
Not done Not done Not done
– – Cervical stromal involvement
Not done Not done ERT
Pelvic side wall Vaginal vault, PEN, PAN, lung, left adnexa Bilateral PEN, PAN, left adnexab Pelvic side wall, Lung Lung Stomach
7 23 48 23
Death Alive without disease Alive with disease death
MMI indicates myometrial invasion; LN, lymph node; TTP, time to progression; UPSC, uterine papillary serous carcinoma; FT, full thickness; EN, endometrioid adenocarcinoma; ERT, external beam radiotherapy; PEN, Pelvic lymph node; PAN, Paraaortic lymph node; ESS, endometrial stromal tumor. a Sites of recurrence were based on imaging findings. b This patient showed progressive disease rather than recurrence.
T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31
There were 10 deaths (5.1%); five (2.8%) due to disease recurrence, and 5 for non-disease related causes. Fifty-five patients that had not visited hospital for at least one year were searched for in the national death certificate registry. One non-disease related death was detected and the remaining 54 were deemed to be alive during December 2007 (Table 3). No metachronous ovarian malignancies were observed during follow-up. Based on data from the gynecologic cancer registry program in Korea, we estimated the ovarian saving rate in patients under the age of 40 who underwent surgery for endometrial cancer. Approximately, 31% of patients with endometrial cancer in Korea underwent ovarypreserving surgery (Table 4). Discussion
Table 4 Estimated ovarian preservation rates for surgically treated endometrial cancer in Korea (1999–2004). Year
Newly diagnosed endometrial 862 783 709 581 425 466 3826 cancer in Korea a 338 353 298 218 186 176 1569 Patients in 14 hospitals Patients under age of 40 in Koreab 93 85 73 87 67 64 469 Estimated no. of Patients under 37 38 31 33 29 24 192 age of 40 in 14 hospitals Patients (≤ 40 yrs) whose ovaries 15 8 12 10 5 9 59 were preserved in 14 hospitals Estimated ovarian preservation rate 40.5 21.1 38.7 30.3 17.2 37.5 30.7 (≤40yrs, %) b
Table 3 Recurrence and survival of patients with retained ovarian function (n = 175).
Alive without disease recurrencea ≥ 5 year follow-up b 5 year follow-up Alive with an undetermined disease statusb ≥ 5 year follow-up b 5 year follow-up Alive with disease recurrence Total deaths Death from disease recurrences Death from other causesc
No.
%
109 52 57 54 20 34 2 10 5 5
62.3
30.8
1.1 5.8 2.9 2.9
a Patients identified to be alive without disease according to available medical records within one year of the analysis. b Patients with no medical records for one year prior to analysis. Statuses were determined by referring to the death certificate registry. c Deaths not attributed to endometrial cancer.
2004 2003 2002 2001 2000 1999 Total Number of patients
a
A review of literature using the PubMed, KoreaMed, and Scopus databases from 1970 to June 2008, using the search terms “endometrial cancer, corpus uteri, ovarian preservation, ovary, save” confirmed that this nation-wide multi-institutional study is the only analysis performed to date with an adequate follow-up of endometrial cancer patients who underwent ovary-saving surgery, although there were some loss to follow-up cases and possibility of error during the review process of older medical records. Our results show a 4.0% recurrence rate, which does not allow us to completely guarantee the safety of ovarian preservation. However, this does not necessarily mean that these 7 recurrences were associated with hormonal influences due to a residual ovary or occult metastasis. Moreover, all patients with recurrence had at least one of the following poor prognostic factors that could have reasonably explained recurrence, i.e., a non-endometrioid histology, contralateral adnexal involvement, or deep myometrial or cervical stromal invasion. In addition, sites of recurrence offered no evidence to support the suspicion that residual ovaries had influenced disease recurrence, although they were not examined histologically. Essentially, the pathologic features and outcomes of young women with endometrial cancer are reported to be similar to those of older women [9,10]. Furthermore, a recent analysis of 61,314 women in the Surveillance, Epidemiology, and End Results (SEER) cancer database from 1988 to 2003 found that younger women are more likely to be diagnosed with earlier stage disease than their older counterparts, and that their overall mean survival is significantly better [4]. Nevertheless, there has not been much debate regarding the topic of ovarian preservation in the field of surgical treatment as coexisting metastasis and synchronous ovarian tumor in patients with endometrial cancer has been thought to be ‘common’. Some reports show an incidence of
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Hospitals that provided data for this study. Data from the Korean gynecologic cancer registry program.
ovarian malignancy in subsets of young patients in the 5–29% range [11–15], which seems to be high, but these figures do not provide a rational for eradicating ovaries in all young women. Gistch et al. reported the highest ovarian synchronous malignancy rate (29%), but the total number of patients was only 17, and they noted occult metastasis in grossly normal looking ovaries in one case only (1/17, 5.9%) [12]. In addition, the crude coexisting malignancy rate in the Korean population is approximately 7% in a previous report and is not low compared with those in other countries [8]. The question that should be asked is whether saving a normal looking ovary in patients with early stage disease without predictable risk factors incurs unacceptable additional risk. To answer this question, two points should be considered. The first concerns the risk of leaving occult metastasis in situ. Evans-Metcalf et al. reported on the risk of occult malignancy in grossly normal appearing ovary (1 among 24 coexisting ovarian malignancies) in young women at time of surgery [13]. Walsh et al. reported that 15% with benign appearing ovaries at time of surgery were found to have a tumor in adnexa at final examination [15]. However, these reports failed to mention whether other evidence of extrauterine disease was present. Last year (2007), we reviewed 260 surgically treated endometrial cancer patients and found a 7.3% coexisting malignancy rate, but this was only 0.97% in patients without any evidence of intraoperative gross extrauterine disease [8]. Another separate study analyzing 160 cases conducted by a single institute in Korea also showed that staging surgery with or without BSO does not affect disease recurrence and overall survival in clinical stage I–II endometrial cancer patients [16]. The second point concerns the activation of quiescent endometrial cancer cells by endogenous estrogen. However, this theoretical relation is not supported by epidemiological studies, thus far. Although most reports were based on retrospective analysis or small prospective non-randomized studies [17–19], and the only randomized controlled trial of GOG also could not provide a definite answer regarding its safety and recommendation [20], estrogen did not appear to increase the recurrence or death rate of endometrial cancer on the basis of currently available studies. Even in breast cancer, which is closely related to estrogen, prophylactic oophorectomy is not performed in young patients who are not amenorrheic after cytotoxic therapy [21]. Thus, if castration is not routinely recommended in breast cancer, then why ovarian preservation should be prohibited in endometrial cancer patients? The consequences of surgical castration in young women are not insignificant, and the increased risks of osteoporosis and Alzheimer's disease, and the detrimental effects on the quality of life resulting from severe vasomotor instability cannot be dismissed. We are of the opinion that these issues have been overlooked due to an
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T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31
Table 5 Proposed indications for ovarian preservation in patients with endometrial cancer. Patients who want to retain ovarian function No gross intraoperative extrauterine tumor spread No gross abnormality in bilateral ovaries Negative results of frozen biopsy for lymph nodes suspicious for metastasis Endometrioid type histology in preoperative biopsy Patients who have no inherited predisposition to breast or ovarian cancer
over-focus on the eradication of the possibility of residual cancer. A recent large scale cohort study concluded that early castration is associated with higher mortality in women that had not received estrogen [22]. Some limitations of this study should be considered when interpreting our results. First, the hospital-based retrospective design used raised the problem of missing data. Accordingly, final disease state could not be evaluated in a significant number of patients, although data obtained from the national death certificate registry was also used. Second, less than a five-year disease free interval may not be sufficient to guarantee patient safety, especially with respect to the development of metachronous ovarian tumor. Third, lymph node dissection was performed in only half of the patients with a known preoperative diagnosis of endometrial cancer. Surgeries in this series were performed between 1993 and 2005. It was thought that the standard guideline at that time recommended that lymph node dissection could be omitted if G1 and no superficial myometrial invasion was suspected. Therefore, we can only guess that surgeons at that period decided to skip lymph node dissection in many patients with clinical stage Ia Grade 1 after preoperative evaluations. Nevertheless, we believe that this nation-wide study and our previous study question the validity of bilateral salpingo-oophorectomy as a standard surgical therapy for endometrial cancer in patients with disease limited to the uterus [8]. In this regard, we propose possible candidates of ovarian preservation in the surgical treatment of patients with endometrial cancer as shown in Table 5. If young women desire to retain ovarian function and meet all of the criteria, they may be candidates. If so, preserved ovaries will keep producing estrogen and can leave the door open for pregnancy from a surrogate mother. For patients approaching menopause incidentally diagnosed on hysterectomy, retention of ovarian function may be of less concern, but these women may not need additional procedures if BSO was not performed at the time of initial hysterectomy. Of course, preserving ovaries should be approached cautiously and consideration of patient's desire after providing a full explanation of the potential risks, as well as genetic tests may be necessary in patients with a family history of related malignancies. Furthermore, we suggest both fallopian tubes should be removed in these patients, although bilateral salpingectomy was performed in only a small portion of patients in our series. It should also be borne in mind that continuous follow-up of patients with preserved ovaries after hysterectomy would be necessary. We suggest that there is a need to devise a more reliable predictor than the descriptor, ‘grossly normal looking ovaries’, one which simplifies the counseling of patients and relatives regarding the risk of ovarian pathology. Although available evidence supporting the benefit of intraoperative frozen biopsy to helpfully rule out an adnexal pathology is limited, its clinical value is worthy of study [23]. Furthermore, PET/CT advancements might also provide a means of predicting occult metastasis [24,25]. However, several issues remain to be resolved, such as, its low sensitivity for small occult lesions and its false positivity due to physiologic uptake [26,27].
Given the low number of cases and ethical considerations, it is unlikely that a randomized control trial will be conducted to determine the equivalency of ovarian preservation and BSO. In this regard, the present study carries substantial weight, as it is the only study to include the follow-up results of patients that have undergone ovarian saving surgery. Nevertheless, it should be recognized that the data presented are constrained by their limited statistical power. Accordingly, more data is required and we encourage others to assist in this regard. Conflict of interest statement The authors declare that there are no conflicts of interest.
Acknowledgments The following members of the Korean Gynecologic Oncology Group also participated in this study: Won-Gyu Kim (Kosin University Gospel Hospital); Moon-Seok Cha (Dong-A University Medical Center); Ki-Tae Kim (Busan Paik Hospital); Eun-Seop Song (Inha University Hospital); Jae-Hoon Kim (Kangnam Severance Hospital); Seung-Cheol Kim (Ewha Women's University Mokdong Hospital); Kyung-Tai Kim (Hanyang University Hospital). Funding: This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412CR01-0704-0001). References [1] Ryu HS. Contemporary clinical trials in uterine corpus malignancies. Korean J Obstet Gynecol 2007;50:1299–307. [2] Annual Report of Gynecologic Cancer Registry Program in Korea for 2004. Korean J Obstet Gynecol 2007;50:28–78. [3] Lee SE, Kim JW, Park NH, Song YS, Kang SB, Lee HP. Contemporary trends of endometrial cancer in Korean women. Korean J Gynecol Oncol 2005;16:215–20. [4] Ali-Fehmi R, Cote ML, Arabi MH, Munkarah AR, Schimp VL, Bryant C, et al. Endometrial carcinoma (EC) in women 35 years of age or younger ASCO Meeting Abstracts. J Clin Oncol 2007;25:16000. [5] Shimada M, Kigawa J, Nishimura R, Yamaguchi S, Kuzuya K, Nakanishi T, et al. Ovarian metastasis in carcinoma of the uterine cervix. Gynecol Oncol 2006;101:234–7. [6] Landoni F, Zanagnolo V, Lovato-Diaz L, Maneo A, Rossi R, Gadduci A, et al. Ovarian metastases in early-stage cervical cancer (IA2–IIA): a multicenter retrospective study of 1965 patients (a Cooperative Task Force study). Int J Gynecol Cancer 2007;17:623–8. [7] Ramirez PT, Schmeler KM, Soliman PT, Frumovitz M. Fertility preservation in patients with early cervical cancer: radical trachelectomy. Gynecol Oncol 2008;110 (3 Suppl 2):S25–28. [8] Lee TS, Jung JY, Kim JW, Park NH, Song YS, Kang SB, et al. Feasibility of ovarian preservation in patients with early stage endometrial carcinoma. Gynecol Oncol 2007;104:52–7. [9] Tran BN, Connell PP, Waggoner S, Rotmensch J, Mundt AJ. Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 2000;23:476–80. [10] Kaku T, Matsuo K, Tsukamoto N, Shimamoto T, Sugihara K, Tsuruchi N, et al. Endometrial carcinoma in women aged 40 years or younger: a Japanese experience. Int J Gynecol Cancer 1993;3:147–53. [11] Duska LR, Garrett A, Rueda BR, Haas J, Chang Y, Fuller AF. Endometrial cancer in women 40 years old or younger. Gynecol Oncol 2001;83:388–93. [12] Gitsch G, Hanzal E, Jensen D, Hacker NF. Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 1995;85:504–8. [13] Evans-Metcalf ER, Brooks SE, Reale FR, Baker SP. Profile of women 45 years of age and younger with endometrial cancer. Obstet Gynecol 1998;91:349–54. [14] Zaino R, Whitney C, Brady MF, DeGeest K, Burger RA, Buller RE. Simultaneously detected endometrial and ovarian carcinomas—a prospective clinicopathologic study of 74 cases: a gynecologic oncology group study. Gynecol Oncol 2001;83:355–62. [15] Walsh C, Holschneider C, Hoang Y, Tieu K, Karlan B, Cass I. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol 2005;106:693–9. [16] Han CH, Lim SY, Kook IY, Lee KH, Namkoong SE, Park JS, et al. Prognostic outcome of patients with clinical stage I–II endometrial cancer according to bilateral salpinooophorectomy. Korean J Obstet Gynecol 2007;50:288–94. [17] Suriano KA, McHale M, McLaren CE, Li KT, Re A, DiSaia PJ. Estrogen replacement therapy in endometrial cancer patients. Obstet Gynecol 2001;97:555–60. [18] Ayhan A, Taskiran C, Simsek S, Sever A. Does immediate hormone replacement therapy affect the oncologic outcome in endometrial cancer survivors? Int J Gynecol Cancer 2006;16:805–8. [19] Tangjitgamol S, Manusirivithaya S, Hanprasertpong J, Kavanagh JJ. Hormone replacement therapy after treatment of endometrial cancer. Gynecol Obstet Invest 2008;65: 35–8.
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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
Ovarian preservation during the surgical treatment of early stage endometrial cancer: A nation-wide study conducted by the Korean Gynecologic Oncology Group Taek Sang Lee a, Jae Weon Kim b,⁎, Tae Jin Kim c, Chi Heum Cho d, Sang Young Ryu e, Hee-Sug Ryu f, Byoung Gie Kim g, Keun Ho Lee h, Yong Man Kim i, Soon-Beom Kang b and the Korean Gynecologic Oncology Group a
Department of Obstetrics and Gynecology, Seoul Metropolitan Boramae Hospital, Republic of Korea Department of Obstetrics and Gynecology, Seoul National University Hospital, Republic of Korea c Department of Obstetrics and Gynecology, Cheil General Hospital, Republic of Korea d Department of Obstetrics and Gynecology, Keimyung University Dongsan Medical Center, Republic of Korea e Department of Obstetrics and Gynecology, Korea Cancer Center Hospital, Republic of Korea f Department of Obstetrics and Gynecology, Ajou University Hospital, Republic of Korea g Department of Obstetrics and Gynecology, Samsung Seoul Hospital, Republic of Korea h Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, Republic of Korea i Department of Obstetrics and Gynecology, Asan Medical Center, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 16 March 2009 Available online 26 July 2009 Keywords: Endometrial cancer Ovary Preservation
a b s t r a c t Objectives. The objective of this study was to determine whether ovarian preservation is feasible in younger endometrial cancer patients. Methods. Endometrial cancer patients who underwent ovary-saving surgery were recruited from the tumor registries of 14 tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG). Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. Results. One hundred and seventy five patients were eligible for this study. Mean patient age at the time of surgery was 38.5 ± 8.3 years (range 25–57). Ovary-preserving surgery was performed in 101 (57.7%) patients who desired to preserve their ovaries, incidentally in 69 (39.4%) patients with preoperative diagnoses other than endometrial carcinoma, and in 5 patients (2.9%) with unknown reasons. Median duration of follow-up was 55.0 months (range 6.2–180.0 months). Recurrence free survival and overall survival rates were 94.3 and 93.3%, respectively. Seven of the 175 (4.0%) patients had documented recurrence, and no recurrences were observed in stage I patients with endometrioid histology. All 7 recurrences had risk factors that could have reasonably explained recurrence, namely, non-endometrioid histology (4/7), deep myometrial invasion (5/7), cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). No metachronous ovarian malignancy occurred during follow-up. Ten (5.8%) deaths occurred during follow-up; five resulted from disease recurrence, and 5 from non-disease related causes. Conclusion. Our findings suggest that ovarian preservation does not adversely impact the recurrence of early stage endometrial cancer. © 2009 Elsevier Inc. All rights reserved.
Introduction Recent clinical trials on early stage endometrial cancer have focused on well-known unsolved questions related to the survival benefit of retroperitoneal lymph node dissection, and identifying the best modality for adjuvant treatment strategies [1]. However,
⁎ Corresponding author. Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul National University, 28 Yungun-Dong Chongno-Ku, Seoul, 110-744, Republic of Korea. Fax: +82 2 762 3599. E-mail address: [email protected] (J.W. Kim). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.06.041
reappraisal of existing treatment guidelines, even those that have been accepted for decades, sometimes become necessary to determine whether they are based on reliable evidence or hold true in the face of new research. In the treatment of endometrial cancer, total abdominal hysterectomy, bilateral salpingo-oophorectomy (BSO), and surgical staging are usually performed. Further treatment is tailored according to the presence or absence of various risk factors. This treatment policy has not been changed since 1988, although numerous trials have been conducted. Accordingly, BSO is recommended routinely irrespective of the patient's age. However, although endometrial cancer is primarily regarded as a disease of post-menopausal women, more than 45% of cases occur in premenopausal patients and 10% in women
T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31 Table 1 Patient characteristics. Characteristics
Patients with a retained ovary(ies) (n = 175) No.
Age, years ≤ 30 31–35 36–40 41–45 N 45 Type of hysterectomy TAH TLH, LAVH TVH RH (MRH) Preoperative diagnosis Endometrial carcinoma Endometrial hyperplasia Leiomyoma (adenomyosis) Cervical cancer Ovarian tumor Endometrial stromal tumor Uterine prolapse Unknown Reasons for ovarian preservation Young age (b 45) and/or patient's desire Other preoperative diagnosisa Not described Saved ovaries Right ovary Left ovary Both ovaries Myometrial invasion Limited to endometrium b 1/2 ≥ 1/2 Full thickness N/A Final histology Endometrioid Non-endometrioid Adenosquamous Endometrial stromal tumor Papillary serous Mucinous Histologic grade 1 2 3 N/A Postoperative FIGO stage (incompleteb) Ia Ib Ic IIa IIb IIIa IIIc
%
31 38 44 32 30
17.7 21.7 25.1 18.3 17.2
111 31 12 21
63.4 17.7 6.9 12.0
101 31 35 2 2 1 1 2
57.7 17.8 20.0 1.1 1.1 0.6 0.6 1.1
101 69 5
57.7 39.4 2.9
45 38 92
25.7 21.7 52.6
115 43 10 4 3
65.7 24.6 5.7 2.3 1.7
162 13 3 4 3 3
92.6 7.4 1.7 2.3 1.7 1.7
121 31 6 17a
69.1 17.7 3.4 9.7
114 35 6 6 12 1 1
65.2 20.0 3.4 3.4 6.8 0.6 0.6
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In cervical cancer patients, the incidence of ovarian metastasis in women with early stage disease has been reported to be below 1% by several large scaled retrospective studies, and thus, ovarian preservation in such patients has not been shown to increase the risk of recurrence [5,6]. This has made fertility-preserving strategies possible in young women with early stage cervical cancer, such as radical trachelectomy [7]. However, although current surgical treatment policy for endometrial cancer recommending routine BSO might almost perfectly eradicate the possibility of residual cancer, the surgical castration of young women induces an abrupt loss of estrogen, which causes climacteric symptoms and long term effects, which include its deleterious impact on cardiovascular and bone health, in addition to the loss of fertility. In this regard, we have previously reported data which showed that the risk of a coexisting malignancy is negligible in patients with minimal preoperative risk factors and no intraoperative evidence of advanced disease [8]. The present study expands upon our previous data by adding follow-up results of a significant number of patients who have undergone ovary-preserving surgeries to determine whether ovarian preservation is feasible in younger endometrial cancer patients.
TAH indicates total abdominal hysterectomy; TLH, total laparoscopic hysterectomy; LAVH, laparoscopy assisted vaginal hysterectomy; VH, vaginal hysterectomy; RH, radical hysterectomy; MRH, modified radical hysterectomy. a Diagnosis which does not require oophorectomy and incidental ovarian saving. b Unevaluated areas such as both adnexa or lymph node status were considered negative.
under the age of 40 years in Korea [2,3]. Moreover, in a recent report which has not been published in the US, changing race and ethnicity demographics, coupled with an increase in obesity, have possibly contributed the incidence of endometrial cancer to increase in younger women. Furthermore, early stage, well-differentiated endometrial cancer has been reported to be most commonly encountered in younger patients [4]. Therefore, the issue of ovarian preservation in young women should be an issue that requires further consideration.
Fig. 1. Cumulative recurrence free survival (a) and overall survival (b) in patients with retained ovarian function. ⁎Time to the date when patients were found to be alive according to the national death certificate registry.
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T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31
Materials and methods With institutional review board approval, tumor registries at fourteen tertiary hospitals under the influence of the Korean Gynecologic Oncology Group (KGOG) were searched to identify patients with a final diagnosis of endometrial cancer whose ovaries were preserved at operation between 1993 and 2005. Thirty-five cases analyzed in our previous study published in 2007 were also included. Clinical information including age at diagnosis, preoperative diagnosis, reasons for preserving ovaries, personal and family histories of cancer, the results of preoperative and intraoperative evaluations, and follow-up results for recurrences or secondary malignancies were abstracted. Patients with disease sufficiently advanced to prevent adequate removal of all visible tumors were excluded from analysis even though BSO was not documented in their medical record. When sufficient follow-up information on recurrence or survival was unavailable from medical records, we obtained information of the cause of death and death date from death certificates obtained at the Korea National Statistical Office. We classified patients with a complete follow-up record and a disease free state as being ‘Alive without disease recurrence’, and patients with no medical records for one year prior to analysis and not registered as dead were classified as being ‘Alive with an undetermined disease status’. Pathologic information, such as histology, grade, depth of myometrial invasion, lymph-vascular space invasion, and lymph node involvement was collected from surgical pathology reports. Stage of tumor was assigned based on available pathologic findings, and unevaluated areas such as both adnexa and lymph node status were considered negative for metastatic disease. Kaplan–Meier test was used for survival analysis. All analyses were carried out using SPSS 12 software (SPSS, Chicago, IL, USA). Results One hundred and seventy five patients were evaluated. Patients' mean age was 38.5 ± 8.3 (range 25–57) and 82.3% were ≤45 years old. Approximately 60% (101/175) of the patients were initially diagnosed as having endometrial carcinoma, 31 as having endometrial hyperplasia, 35 as having benign leiomyoma or adenomyosis, and 8 as having some other preoperative diagnoses (Table 1). Of the 175 cases, 111 underwent total abdominal hysterectomy, 31 total laparoscopic or laparoscopy assisted vaginal hysterectomy, 12 total vaginal hysterectomy, and 21 radical or modified radical hysterectomy. In 15 patients, ovarian wedge resection and frozen biopsy were performed based on surgeon's judgment, and all were negative for metastasis. In 10% (10/101) of patients preoperatively diagnosed as having endometrioid adenocarcinoma, bilateral fallo-
pian tubes were removed. Lymph node dissection or biopsy was performed in 56 patients with an initial diagnosis of endometrial carcinoma, and 2 of these had lymph node metastasis in the final pathologic report. In 20 patients with high risk factors for relapse including the above two lymph node positive cases, adjuvant pelvic radiation treatment was administered without additional bilateral adnexectomy or performing ovarian transposition and tailored brachytherapy was performed in patients with cervical involvement. Two patients diagnosed with non-endometrioid histology received adjuvant cytotoxic chemotherapy. As shown in Table 1, reasons for ovarian preservation were twofold. First, in younger patients (b40 years old) preoperatively diagnosed with endometrial cancer, preservation of grossly normal looking ovaries was decided upon by the surgeon with the patient's request. Second, in premenopausal women preoperatively diagnosed as having benign disease, e.g., office-based diagnosed endometrial hyperplasia, leiomyoma, or adenomyosis, ovaries were saved incidentally and no additional surgery was undertaken to remove these ovaries. Moreover, in some post-menopausal women preoperatively diagnosed as having a benign condition, vaginal hysterectomies skipping bilateral salpingo-oophorectomy were performed without gross findings of either adnexa. One cervical cancer patient was included. No reasonable rationale for ovarian saving was obvious based on the medical record review of 5 patients. Median follow-up duration was 55.0 months (range 6.2– 180.0 months). Overall, 7 of the 175 (4.0%) had documented recurrence. Five-year recurrence free survival and overall survival for all patients were 94.3% and 93.3%, respectively (Fig. 1). Among 155 patients with disease limited to the corpus, two recurrences were detected in patients diagnosed with endometrial stromal sarcoma. No recurrences were observed in stage I patients with endometrioid histology. As shown in Table 2, recurrences were identified mainly in the pelvic side wall (in 3 cases), lung (in 3 cases), bilateral lymphatic channels (in 2 cases), vaginal vault (in 1 case), and stomach (in 1 case). All recurrent cases had several potential risk factors for recurrence that could have reasonably explained recurrence, such as a non-endometrioid histology (4/7), deep myometrial invasion (5/7), or cervical stromal invasion (4/7), and inadequate adjuvant treatment (4/7). In 2 of these 7 recurrent cases, adnexal metastasis was suspected based on imaging study findings. One (No. 3) was a 44 year old woman, who rejected further postoperative adjuvant treatment despite myometrial invasion of more than 50% and frank histologic cervical stromal invasion. The other (No. 4) was a case of uterine papillary serous carcinoma that invaded the full thickness of the myometrium, and showed disease progression during postoperative adjuvant chemotherapy.
Table 2 Characteristics of patients who experienced recurrence. No.
Age
Preoperative diagnosis
Final histology
MMI
LN biopsy
Presence of extrauterine spread
Postoperative adjuvant treatment
TTP (months)
Sites of recurrencea
Patient state
1
37
Myoma uteri
UPSC
FT
Not done
Chemotherapy
10
Pelvic side wall
Death
2 3
45 44
EN Myoma uteri
EN EN
b1/2 N1/2
Yes (0/16) Not done
Cervical stroma, vagina and contralateral adnexal involvement Cervical stromal involvement Cervical stromal involvement
ERT Not done
28 26
Death Death
4
49
Myoma uteri
UPSC
FT
Not done
–
Chemotherapy
5 6 7
38 36 38
Myoma uteri Myoma uteri EN
ESS ESS EN
N1/2 N1/2 b1/2
Not done Not done Not done
– – Cervical stromal involvement
Not done Not done ERT
Pelvic side wall Vaginal vault, PEN, PAN, lung, left adnexa Bilateral PEN, PAN, left adnexab Pelvic side wall, Lung Lung Stomach
7 23 48 23
Death Alive without disease Alive with disease death
MMI indicates myometrial invasion; LN, lymph node; TTP, time to progression; UPSC, uterine papillary serous carcinoma; FT, full thickness; EN, endometrioid adenocarcinoma; ERT, external beam radiotherapy; PEN, Pelvic lymph node; PAN, Paraaortic lymph node; ESS, endometrial stromal tumor. a Sites of recurrence were based on imaging findings. b This patient showed progressive disease rather than recurrence.
T.S. Lee et al. / Gynecologic Oncology 115 (2009) 26–31
There were 10 deaths (5.1%); five (2.8%) due to disease recurrence, and 5 for non-disease related causes. Fifty-five patients that had not visited hospital for at least one year were searched for in the national death certificate registry. One non-disease related death was detected and the remaining 54 were deemed to be alive during December 2007 (Table 3). No metachronous ovarian malignancies were observed during follow-up. Based on data from the gynecologic cancer registry program in Korea, we estimated the ovarian saving rate in patients under the age of 40 who underwent surgery for endometrial cancer. Approximately, 31% of patients with endometrial cancer in Korea underwent ovarypreserving surgery (Table 4). Discussion
Table 4 Estimated ovarian preservation rates for surgically treated endometrial cancer in Korea (1999–2004). Year
Newly diagnosed endometrial 862 783 709 581 425 466 3826 cancer in Korea a 338 353 298 218 186 176 1569 Patients in 14 hospitals Patients under age of 40 in Koreab 93 85 73 87 67 64 469 Estimated no. of Patients under 37 38 31 33 29 24 192 age of 40 in 14 hospitals Patients (≤ 40 yrs) whose ovaries 15 8 12 10 5 9 59 were preserved in 14 hospitals Estimated ovarian preservation rate 40.5 21.1 38.7 30.3 17.2 37.5 30.7 (≤40yrs, %) b
Table 3 Recurrence and survival of patients with retained ovarian function (n = 175).
Alive without disease recurrencea ≥ 5 year follow-up b 5 year follow-up Alive with an undetermined disease statusb ≥ 5 year follow-up b 5 year follow-up Alive with disease recurrence Total deaths Death from disease recurrences Death from other causesc
No.
%
109 52 57 54 20 34 2 10 5 5
62.3
30.8
1.1 5.8 2.9 2.9
a Patients identified to be alive without disease according to available medical records within one year of the analysis. b Patients with no medical records for one year prior to analysis. Statuses were determined by referring to the death certificate registry. c Deaths not attributed to endometrial cancer.
2004 2003 2002 2001 2000 1999 Total Number of patients
a
A review of literature using the PubMed, KoreaMed, and Scopus databases from 1970 to June 2008, using the search terms “endometrial cancer, corpus uteri, ovarian preservation, ovary, save” confirmed that this nation-wide multi-institutional study is the only analysis performed to date with an adequate follow-up of endometrial cancer patients who underwent ovary-saving surgery, although there were some loss to follow-up cases and possibility of error during the review process of older medical records. Our results show a 4.0% recurrence rate, which does not allow us to completely guarantee the safety of ovarian preservation. However, this does not necessarily mean that these 7 recurrences were associated with hormonal influences due to a residual ovary or occult metastasis. Moreover, all patients with recurrence had at least one of the following poor prognostic factors that could have reasonably explained recurrence, i.e., a non-endometrioid histology, contralateral adnexal involvement, or deep myometrial or cervical stromal invasion. In addition, sites of recurrence offered no evidence to support the suspicion that residual ovaries had influenced disease recurrence, although they were not examined histologically. Essentially, the pathologic features and outcomes of young women with endometrial cancer are reported to be similar to those of older women [9,10]. Furthermore, a recent analysis of 61,314 women in the Surveillance, Epidemiology, and End Results (SEER) cancer database from 1988 to 2003 found that younger women are more likely to be diagnosed with earlier stage disease than their older counterparts, and that their overall mean survival is significantly better [4]. Nevertheless, there has not been much debate regarding the topic of ovarian preservation in the field of surgical treatment as coexisting metastasis and synchronous ovarian tumor in patients with endometrial cancer has been thought to be ‘common’. Some reports show an incidence of
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Hospitals that provided data for this study. Data from the Korean gynecologic cancer registry program.
ovarian malignancy in subsets of young patients in the 5–29% range [11–15], which seems to be high, but these figures do not provide a rational for eradicating ovaries in all young women. Gistch et al. reported the highest ovarian synchronous malignancy rate (29%), but the total number of patients was only 17, and they noted occult metastasis in grossly normal looking ovaries in one case only (1/17, 5.9%) [12]. In addition, the crude coexisting malignancy rate in the Korean population is approximately 7% in a previous report and is not low compared with those in other countries [8]. The question that should be asked is whether saving a normal looking ovary in patients with early stage disease without predictable risk factors incurs unacceptable additional risk. To answer this question, two points should be considered. The first concerns the risk of leaving occult metastasis in situ. Evans-Metcalf et al. reported on the risk of occult malignancy in grossly normal appearing ovary (1 among 24 coexisting ovarian malignancies) in young women at time of surgery [13]. Walsh et al. reported that 15% with benign appearing ovaries at time of surgery were found to have a tumor in adnexa at final examination [15]. However, these reports failed to mention whether other evidence of extrauterine disease was present. Last year (2007), we reviewed 260 surgically treated endometrial cancer patients and found a 7.3% coexisting malignancy rate, but this was only 0.97% in patients without any evidence of intraoperative gross extrauterine disease [8]. Another separate study analyzing 160 cases conducted by a single institute in Korea also showed that staging surgery with or without BSO does not affect disease recurrence and overall survival in clinical stage I–II endometrial cancer patients [16]. The second point concerns the activation of quiescent endometrial cancer cells by endogenous estrogen. However, this theoretical relation is not supported by epidemiological studies, thus far. Although most reports were based on retrospective analysis or small prospective non-randomized studies [17–19], and the only randomized controlled trial of GOG also could not provide a definite answer regarding its safety and recommendation [20], estrogen did not appear to increase the recurrence or death rate of endometrial cancer on the basis of currently available studies. Even in breast cancer, which is closely related to estrogen, prophylactic oophorectomy is not performed in young patients who are not amenorrheic after cytotoxic therapy [21]. Thus, if castration is not routinely recommended in breast cancer, then why ovarian preservation should be prohibited in endometrial cancer patients? The consequences of surgical castration in young women are not insignificant, and the increased risks of osteoporosis and Alzheimer's disease, and the detrimental effects on the quality of life resulting from severe vasomotor instability cannot be dismissed. We are of the opinion that these issues have been overlooked due to an
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Table 5 Proposed indications for ovarian preservation in patients with endometrial cancer. Patients who want to retain ovarian function No gross intraoperative extrauterine tumor spread No gross abnormality in bilateral ovaries Negative results of frozen biopsy for lymph nodes suspicious for metastasis Endometrioid type histology in preoperative biopsy Patients who have no inherited predisposition to breast or ovarian cancer
over-focus on the eradication of the possibility of residual cancer. A recent large scale cohort study concluded that early castration is associated with higher mortality in women that had not received estrogen [22]. Some limitations of this study should be considered when interpreting our results. First, the hospital-based retrospective design used raised the problem of missing data. Accordingly, final disease state could not be evaluated in a significant number of patients, although data obtained from the national death certificate registry was also used. Second, less than a five-year disease free interval may not be sufficient to guarantee patient safety, especially with respect to the development of metachronous ovarian tumor. Third, lymph node dissection was performed in only half of the patients with a known preoperative diagnosis of endometrial cancer. Surgeries in this series were performed between 1993 and 2005. It was thought that the standard guideline at that time recommended that lymph node dissection could be omitted if G1 and no superficial myometrial invasion was suspected. Therefore, we can only guess that surgeons at that period decided to skip lymph node dissection in many patients with clinical stage Ia Grade 1 after preoperative evaluations. Nevertheless, we believe that this nation-wide study and our previous study question the validity of bilateral salpingo-oophorectomy as a standard surgical therapy for endometrial cancer in patients with disease limited to the uterus [8]. In this regard, we propose possible candidates of ovarian preservation in the surgical treatment of patients with endometrial cancer as shown in Table 5. If young women desire to retain ovarian function and meet all of the criteria, they may be candidates. If so, preserved ovaries will keep producing estrogen and can leave the door open for pregnancy from a surrogate mother. For patients approaching menopause incidentally diagnosed on hysterectomy, retention of ovarian function may be of less concern, but these women may not need additional procedures if BSO was not performed at the time of initial hysterectomy. Of course, preserving ovaries should be approached cautiously and consideration of patient's desire after providing a full explanation of the potential risks, as well as genetic tests may be necessary in patients with a family history of related malignancies. Furthermore, we suggest both fallopian tubes should be removed in these patients, although bilateral salpingectomy was performed in only a small portion of patients in our series. It should also be borne in mind that continuous follow-up of patients with preserved ovaries after hysterectomy would be necessary. We suggest that there is a need to devise a more reliable predictor than the descriptor, ‘grossly normal looking ovaries’, one which simplifies the counseling of patients and relatives regarding the risk of ovarian pathology. Although available evidence supporting the benefit of intraoperative frozen biopsy to helpfully rule out an adnexal pathology is limited, its clinical value is worthy of study [23]. Furthermore, PET/CT advancements might also provide a means of predicting occult metastasis [24,25]. However, several issues remain to be resolved, such as, its low sensitivity for small occult lesions and its false positivity due to physiologic uptake [26,27].
Given the low number of cases and ethical considerations, it is unlikely that a randomized control trial will be conducted to determine the equivalency of ovarian preservation and BSO. In this regard, the present study carries substantial weight, as it is the only study to include the follow-up results of patients that have undergone ovarian saving surgery. Nevertheless, it should be recognized that the data presented are constrained by their limited statistical power. Accordingly, more data is required and we encourage others to assist in this regard. Conflict of interest statement The authors declare that there are no conflicts of interest.
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