ORIGINAL STUDY
Bone Metastasis in Primary Endometrial Carcinoma Features, Outcomes, and Predictors Aera Yoon, MD, Chel Hun Choi, MD, Tae-Hyun Kim, MD, June-Kuk Choi, MD, Jin-Young Park, MD, Yoo-Young Lee, MD, PhD, Tae-Joong Kim, MD, Jeong-Won Lee, MD, PhD, Duk-Soo Bae, MD, PhD, and Byoung-Gie Kim, MD, PhD
Objectives: This study aimed to describe the clinicopathologic characteristics and outcomes and to assess the predictors associated with prognosis in endometrial carcinoma that developed bone metastasis. Methods: A retrospective review of medical records was performed to identify the patients with endometrial carcinoma who developed bone metastasis between October 1994 and May 2012. Results: Of the 1185 patients with endometrial carcinoma, 22 (1.8%) were identified with bone metastasis, and 21 patients were analyzed in the study. Seventeen (80.9%) patients had advanced-stage disease (2009 International Federation of Gynecologists and Obstetricians stages III-IV). Four (19.0%) patients had a bone lesion at the diagnosis of endometrial cancer. The median time of recurrence to the bone in 17 patients was 9 months (range, 2Y43 months). The median overall survival (OS) and survival after bone metastasis of the entire cohort were 33 months (range, 9Y57 months) and 15 months (range, 12Y17 months), respectively. The patients with bone metastasis at recurrence had significantly longer OS than those patients with bone metastasis at diagnosis of endometrial cancer (36 vs 13 months; P = 0.042). Metastasis to extrapelvic bone was significantly associated with longer OS (46 vs 19 months; P = 0.001) and longer survival after bone metastasis (25 vs 12 months; P = 0.002). Isolated bone recurrence without extraosseous metastases and extrapelvic bone metastasis revealed independent predictors for survival after bone metastasis (hazard ratio, 0.09; 95% confidence interval, 0.01Y0.67; P = 0.019 and hazard ratio, 0.07; 95% confidence interval, 0.01Y0.53; P = 0.01). Conclusions: In endometrial carcinoma that develops bone metastasis, isolated bone recurrence and extrapelvic bone metastasis are significant predictors of prolonged survival after the diagnosis of bone metastasis. Further researches on the optimal treatment modality and factors that have the clinical implications are warranted. Key Words: Endometrial cancer, Bone metastasis, Outcome, Survival Received August 16, 2013, and in revised form September 2, 2013. Accepted for publication September 3, 2013. (Int J Gynecol Cancer 2014;24: 107Y112)
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Copyright * 2013 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000015 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Byoung-Gie Kim, MD, PhD, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea. E-mail: [email protected]. The authors did not receive funding for this work. The authors declare no conflicts of interest.
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cancer is the most common gynecologic maE ndometrial lignancy in developed countries. The incidence rates of 1
endometrial cancer are steadily rising from 2.6% in 2000 to 5.0% in 2010 in South Korea, accounting for an estimated 1752 new cases and 222 deaths in 2010.2 Endometrial cancer with early-stage disease was diagnosed in more than 75% of the patients because most patients have obvious symptoms, including abnormal vaginal bleeding. The 5-year overall survival (OS) rate is 80% to 85%.3 However, for patients with advanced-stage disease and those with recurrent endometrial cancer, the prognosis remains poor. Endometrial cancer recurrence mostly occurs within the pelvis. Most distant recurrences develop within lymph nodes, lung, or liver.4,5 Bone involvement in endometrial cancer is rare and the prevalence is variously reported (0%Y15%).6Y8 Although metastases to the bone are thought to result from hematologic dissemination, the mechanism of bone metastasis is not clearly understood. It can be associated with primary tumor behavior, vascular supply, immune system, and bone environment.9 Once bone metastasis develops, neoplastic progress becomes incurable and the chances of survival of the patients are decreased. Moreover, bone metastases cause suffering because of severe pain, pathologic fracture, and disability. Therefore, early diagnosis and proper treatment could lead to better quality of life in patients with bone metastasis. There is some research on patients with endometrial cancer who developed bone metastasis. However, because of its rarity, almost all the published studies are case reports describing unusual cases of bone metastasis. In this study, we describe the clinical characteristics and outcomes of 21 patients with endometrial cancer who developed bone metastasis. In addition, we investigate the prognostic factors associated with disease-related survival, which provide further understanding of bone metastasis in endometrial cancer.
METHODS This was a retrospective study of patients with endometrial cancer who developed bone metastasis using the electronic medical records. With institutional review board approval, we identified patients whose conditions were diagnosed with endometrial cancer between October 1994 and May 2012 at the Department of Obstetrics and Gynecology at Samsung Medical Center. Of the patients with endometrial cancer, this study included the patients whose conditions were diagnosed to have bone metastasis either at the time of diagnosis or at recurrence, as the primary site, with or without concomitant lesions. Bone metastasis was diagnosed with histologic confirmation by a bone biopsy or with positive results on more than 2 radiographic imaging investigations without a biopsy. Patients with any history of malignancy and with uterine sarcomas or carcinosarcomas were excluded in this study. With a comprehensive review of the medical records, clinicopathologic data and clinical outcomes of the patients with endometrial carcinoma who developed bone metastasis were evaluated. Staging was determined according to the
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2009 FIGO (International Federation of Gynecology and Oncology) staging system.10 The number of bone metastases was categorized as being either single or multiple according to the location of the involved bone. Clinical characteristics were summarized using descriptive statistics. Survival was calculated as the number of months, and survival probabilities were estimated using the Kaplan-Meier method. Log-rank test was used to identify the predictors of disease-related survival, and Cox proportional hazards model was used for the multivariate analysis. Overall survival was defined as the time from diagnosis of endometrial cancer to death or last follow-up. Survival after bone metastasis was defined as the time from diagnosis of bone metastasis to death or last follow-up. All P values were 2 tailed and considered significant if less than 0.05. All statistical analyses were performed using SPSS software (version 18.0; SPSS, Chicago, Ill).
RESULTS Patient Characteristics Endometrial cancer was diagnosed in 1185 patients during the study period. Of these patients, 22 (1.8%) had bone metastasis. One patient was excluded because of a history of breast cancer. Therefore, 21 patients were included in the study. The characteristics of these patients are summarized in Table 1. The median age at diagnosis of endometrial cancer in 21 patients was 59 years (range, 28Y72 years). Although bone metastasis occurred in all stages, most patients had advancedstage disease (2009 FIGO stages III-IV, 17/21 [80.9%]). Of the 3 patients who had the early-stage disease (IB), 1 patient had serous adenocarcinoma with lymphovascular space invasion, 1 patient had grade 2 and 4-cm endometrioid adenocarcinoma, and 1 patient had grade 3 endometrioid adenocarcinoma with lymph-vascular space invasion. Eight (38.1%) patients had endometrioid carcinoma, and 13 (61.9%) patients showed nonendometrioid histology including serous adenocarcinoma (n = 5), clear cell carcinoma (n = 1), poorly differentiated carcinoma (n = 2), villoglandular adenocarcinoma (n = 1), and adenocarcinoma not otherwise specified (n = 4). Most of the tumors had grade 2 or 3 differentiation, and in the 18 patients who underwent a surgery, 12 (12/18, 66.7%) showed deep myometrial invasion (Q 1/2 invasions to the myometrium). Three patients with clinical stage IVB received chemotherapy or concurrent chemoradiotherapy (CCRT) without surgery as a primary treatment. As postoperative adjuvant treatment, radiotherapy, chemotherapy, or CCRT was performed. Most patients received platinumcontaining combination chemotherapy. Chemotherapeutic regimens included the combinations of taxane and platinum in 4 patients and cyclophosphamide, doxorubicin, and platinum in 2 patients. During the CCRT, platinum-based chemotherapy was used in all patients.
Characteristics of Bone Metastasis Most patients presented symptoms with pain (81%) or fracture (9.5%) at the time of diagnosis of bone metastasis. The conditions of the 2 patients were diagnosed on routine recurrent work-up. Bone metastasis was diagnosed in * 2013 IGCS and ESGO
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& Volume 24, Number 1, January 2014 Bone Metastasis in Endometrial Carcinoma
TABLE 1. Patient characteristics (n = 21) Characteristic
n (%)
Age, median (range), y BMI, median (range), kg/m2 2009 FIGO stage IB II IIIA IIIC1 IIIC2 IVB Histology Endometrioid Nonendometrioid Tumor size, median (range), cm FIGO grade 1 2 3 Unknown Depth of myometrial invasion G2 Q2 Unknown Primary treatment Surgery and radiotherapy Surgery and chemotherapy Surgery and CCRT Chemotherapy CCRT
59 (28Y72) 24.1 (20.9Y31.7) 3 1 1 3 6 7
(14.3) (4.8) (4.8) (14.3) (28.5) (33.3)
8 (38.1) 13 (61.9) 4.2 (2.3Y14) 1 4 10 6
(4.8) (19.0) (47.6) (28.6)
1 (4.8) 12 (57.1) 8 (38.1) 10 4 4 2 1
(47.6) (19.0) (19.0) (9.5) (4.8)
BMI, body mass index.
3 (14.3%) patients by bone biopsy, and the most commonly used imaging modality was positron emission tomography scan (47.6%) followed by bone scan (23.8%). Of the 21 patients, 4 (19%) had their bone metastasis identified simultaneously with the primary diagnosis of endometrial cancer, and 17 (81%) patients developed bone metastasis as a recurrence. The median time of recurrence to the bone in these 17 patients was 9 months (range, 2Y43 months). Ten (47.6%) patients had a single bone lesion, and 11 (52.4%) patients had multiple bone metastases at more than 2 sites (Table 2). At the diagnosis of bone metastasis, 13 (61.9%) patients had a coexisting extraosseous metastatic lesion, and the lung (8/13, 61.5%) was the most common coexisting visceral metastatic site. Other sites were the liver, brain, and lymph nodes including the supraclavicular and para-aortic lymph nodes. Ten (47.6%) patients had only extrapelvic bone metastasis (Table 2). The distribution of bone metastases was predominantly to the axial skeleton. The total locations of bone metastases were 36 in the 21 patients. The most
common locations of bone metastasis were the vertebral spine (16/36, 44.4%) and pelvis (10/36, 27.8%). Additional unusual locations of bone metastasis were as follows: rib (n = 2), femur (n = 2), acetabulum (n = 2), clavicle (n = 1), parietal bone (n = 1), scapula (n = 1), and humerus (n = 1). There were no patients with hypercalcemia (reference, 8.4Y10.2 mg/dL) because of the bone metastasis.
Salvage Treatments Patients received treatment with surgical resection (n = 2, 9.5%), radiotherapy (n = 4, 19%), chemotherapy (n = 6, 28.6%), or both (n = 7, 33.3%) as the salvage therapy after bone metastasis. Two (9.5%) patients received supportive care because of a predicted short life expectancy and unfavorable performance status (Table 2). These 2 patients died of the disease 9 days and 22 days after the diagnosis of bone metastasis. Of the 2 patients who underwent surgical resection, cranioplasty was performed in 1 patient with parietal bone metastasis, and laminectomy with fixation was performed in
TABLE 2. Characteristics of bone metastasis (n = 21) Characteristic Symptom Pain Fracture None Diagnosis of bone metastasis Bone biopsy PET Bone scan MRI Bone metastasis at diagnosis Bone metastasis at recurrence No. bone metastasis Single Multiple Coexisting extraosseous metastasis Yes No Sites of bone metastasis Pelvis T extrapelvic Extrapelvic only Salvage treatment Surgical resection Radiotherapy Chemotherapy Sequential radiotherapy and chemotherapy Supportive care
n (%) 17 (81.0) 2 (9.5) 2 (9.5) 3 10 5 3 4 17
(14.3) (47.6) (23.8) (14.3) (19.0) (81.0)
10 (47.6) 11 (52.4) 13 (61.9) 8 (38.1) 11 (52.4) 10 (47.6) 2 4 6 7 2
(9.5) (19.0) (28.6) (33.3) (9.5)
MRI, magnetic resonance imaging; PET, positron emission tomography.
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FIGURE 1. The OS in patients with bone metastasis at primary diagnosis of endometrial cancer vs patients with bone metastasis at recurrence (A) and according to the sites of bone metastases: extrapelvic only vs pelvis T extrapelvic (B). 1 patient who developed gait disturbance by compressive fracture of the thoracic spine metastasis.
Survival and Prognostic Factors The median follow-up time was 21 months (range, 2Y78 months). At the date of data analysis, a total of 15 patients died of the disease. The median OS and median survival after bone metastasis of the entire cohort were 33 months (range, 9Y57 months) and 15 months (range, 12Y17 months), respectively. The OS of patients with bone metastasis at recurrence was significantly longer than that of patients with bone metastasis at the primary diagnosis of endometrial cancer (36 vs 13 months; P = 0.042; Fig. 1A). Metastasis only to the extrapelvic bone was significantly associated with longer OS (46 vs 19 months; P = 0.001) and longer survival after bone metastasis (25 vs 12 months; P = 0.002; Fig. 1B and Fig. 2). In the multivariate analysis, isolated bone recurrence without extraosseous metastases and extrapelvic bone metastasis revealed independent predictors for survival after bone metastasis (HR, 0.09; 95% confidence interval [CI], 0.01Y0.67; P = 0.019 and HR, 0.07; 95% CI, 0.01Y0.53; P = 0.01; Table 3). Age, initial stage, histology, and number of bone metastasis were not associated with the OS and survival after bone metastasis.
therapy in endometrial cancer. In the study, most patients (15/ 21, 71%) received pelvic radiation. In recurrent or metastatic endometrial cancer, the relapse of the disease within the previous radiation demonstrated a prognostic factor for poor survival in the previous literature.5 Similar results have been reported in cervical cancer, where a lower therapeutic response was shown in patients with relapse within the radiotherapy field.11 The reason for this is not fully understood, and this may reflect biologic differences. Radioresistant endometrial cancers may have unfavorable biologic factors, and the aggressiveness of these cancers may be associated with a lower response to treatment and rapid progression of disease. Another finding of the study is that OS was significantly shorter in patients who had bone dissemination at the diagnosis of endometrial cancer than those patients with bone metastasis at disease recurrence. Kehoe et al6 reported similar results. They showed that the OS of those patients with bone metastases at primary diagnosis was 17 months (95%
DISCUSSION The principal findings of this study are that extrapelvic bone metastasis and isolated bone recurrence are the prognostic factors for prolonged survival after bone metastasis in patients with endometrial carcinoma who developed bone metastases. Another finding of our study is that the patients with bone metastasis as a recurrence have longer survival than patients with endometrial carcinoma who developed bone metastasis at presentation. In addition, our study is one of the largest cohorts of bone metastasis in endometrial carcinoma that describes the clinical features and outcomes. On the basis of our results, the patients with pelvic bone metastasis showed poor prognosis compared with patients with extrapelvic bone metastasis. Irradiation to the pelvic area such as whole pelvic radiotherapy and brachytherapy is the standard treatment for postoperative adjuvant or primary
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FIGURE 2. The survival after the diagnosis of bone metastasis according to the sites of bone metastases: extrapelvic only vs pelvis T extrapelvic. * 2013 IGCS and ESGO
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& Volume 24, Number 1, January 2014 Bone Metastasis in Endometrial Carcinoma
TABLE 3. Prognostic factors for survival after bone metastasis (n = 21) Univariate Analysis Factor Age, y e60 960 Stage I-II III-IV Histology Endometrioid Nonendometrioid No. bone metastasis Single Multiple Coexisting extraosseous metastasis Yes No Sites of bone metastasis Pelvis T extrapelvic Extrapelvic only
Multivariate Analysis
No.
Median, mo
P
HR (95% CI)
P
11 10
15 13
0.354
1 0.26 (0.03Y2.29)
0.226
4 17
15 14
0.958
1 3.8 (0.71Y20.2)
0.117
8 13
15 14
0.309
1 0.24 (0.04Y1.32)
0.101
11 13
15 12
0.102
1 14.32 (0.9Y227.9)
0.059
13 8
15 15
0.288
1 0.09 (0.01Y0.67)
0.019
11 10
12 25
0.002
1 0.07 (0.01Y0.53)
0.01
CI, 2Y32) compared with 32 months (95% CI, 14Y49) for those with recurrent bone metastasis. In addition, the authors reported that survival after bone metastasis is longer in patients with disease recurrence in the bone. The occurrence of bone metastases secondary to endometrial cancer is very rare and is variously reported. Recently, Uccella et al7 reported that the exact frequency of bone metastases in endometrial cancer is less than 1% through the review of published literatures. In their series, the overall incidence of bone dissemination was presented in 0.8%, and the incidence of bone metastases at presentation with endometrial cancer was presented in 0.12%. In our series, the former was in 1.8% (22/1185) and the later was in 0.3% (4/1185). In another large series, only 21 patients were identified to have a bone metastasis among 6144 patients with endometrial cancer.6 The difference of diagnostic methods for bone metastasis or incidence of endometrial cancer may be associated with this distinction. Tumor histology is a known prognostic factor in endometrial cancer. Some literatures reported that nonendometrioid histology is associated with poor prognosis in recurrent endometrial cancer5,12 and is a predictor of hematogenous dissemination in endometrial cancer.13 Similar result was reported in patients with endometrial cancer who developed bone metastasis. The authors found that the survival after bone metastasis is significantly longer in patients with endometrioid histology than those patients with nonendometrioid histology. In addition, this study showed that the patients with single bone metastasis have a better prognosis.7 However, in our results, tumor histology and number of involved bones were not associated with
the outcomes of the patients. Further studies are warranted to identify the clinical implications of tumor histology and the number of involved bones in endometrial cancer that developed bone metastasis. Similar to previous studies,6,7 the axial skeleton (vertebral spine, pelvic bone, and rib) was the predominant metastatic sites in the study. Metastasis to the spine account for 44.4%, and the most common site was thoracic spine followed by lumbar spine. In this study, the median survival after diagnosis of bone metastasis was 15 months, which is comparable with the 12 months and 10 months reported previous literatures.6,7 The median OS of patients with bone metastasis was 33 months in our result. This result was a relatively good outcome compared with the previous studies; the authors reported the median OS as 18 months and 25 months.6,7 Currently, there is no standard treatment for the patients with endometrial cancer who developed bone metastasis because of the limited number of studies with small cases due to their rarity. Treatment options include directed radiation therapy, systemic chemotherapy, surgical resection, and hormonal therapy. The selection of therapy is based on the sites and number of involved bones, concomitant extraosseous metastasis, type of previous treatment, and patients’ performance status. According to the literatures from other solid tumors (ie, prostate or breast cancer), bisphosphonate could be considered as the treatment modality.14,15 Furthermore, further studies are required regarding the bone-targeting agents such as denosumab in breast and prostate cancers with bone metastasis.16
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Our study is limited by its retrospective design and by the heterogeneity of patients and treatment strategies because of the long-term follow-up study. The study has the small number of patients, although it is the largest case series regarding patients with endometrial cancer who developed bone metastasis. In conclusion, the median OS and median survival after bone metastasis are 33 months and 15 months in patients with endometrial cancer who developed bone metastasis, respectively. Recurrence to extrapelvic bone has a more favorable outcome than recurrence to the pelvic bone, and isolated bone recurrence without visceral metastasis is a predictor for survival after the diagnosis of bone metastasis. In addition, patients with bone involvement that occurred as a recurrence have a longer survival than those patients with bone involvement at presentation with endometrial cancer. Further researches on the optimal treatment modality and factors that have clinical implications are required.
REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69Y90. 2. Jung KW, Won YJ, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013;45:1Y14. 3. Sant M, Aareleid T, Berrino F, et al. EUROCARE-3: survival of cancer patients diagnosed 1990-94Yresults and commentary. Ann Oncol. 2003;14:v61Yv118. 4. Fujimoto T, Nanjyo H, Fukuda J, et al. Endometrioid uterine cancer: histopathological risk factors of local and distant recurrence. Gynecol Oncol. 2009;112:342Y347. 5. Mountzios G, Bamias A, Voulgaris Z, et al. Prognostic factors in patients treated with taxane-based chemotherapy for recurrent or metastatic endometrial cancer: proposal for a new prognostic model. Gynecol Oncol. 2008;108:130Y135.
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6. Kehoe SM, Zivanovic O, Ferguson SE, et al. Clinicopathologic features of bone metastases and outcomes in patients with primary endometrial cancer. Gynecol Oncol. 2010;117:229Y233. 7. Uccella S, Morris JM, Bakkum-Gamez JN, et al. Bone metastases in endometrial cancer: report on 19 patients and review of the medical literature. Gynecol Oncol. 2013;130:474Y482. 8. Kaya A, Olmezoglu A, Eren CS, et al. Solitary bone metastasis in the tibia as a presenting sign of endometrial adenocarcinoma: a case report and the review of the literature. Clin Exp Metastasis. 2007;24:87Y92. 9. Mackiewicz-Wysocka M, Pankowska M, Wysocki PJ. Progress in the treatment of bone metastases in cancer patients. Expert Opin Investig Drugs. 2012;21:785Y795. 10. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105:103Y104. 11. Kastritis E, Bamias A, Efstathiou E, et al. The outcome of advanced or recurrent non-squamous carcinoma of the uterine cervix after platinum-based combination chemotherapy. Gynecol Oncol. 2005;99:376Y382. 12. Mariani A, Webb MJ, Keeney GL, et al. Surgical stage I endometrial cancer: predictors of distant failure and death. Gynecol Oncol. 2002;87:274Y280. 13. Mariani A, Webb MJ, Keeney GL, et al. Hematogenous dissemination in corpus cancer. Gynecol Oncol. 2001;80:233Y238. 14. Solomayer EF, Gebauer G, Hirnle P, et al. Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol. 2012;23:2271Y2277. 15. Rove KO, Crawford ED. Evolution of treatment options for patients with CRPC and bone metastases: bone-targeted agents that go beyond palliation of symptoms to improve overall survival. Oncology (Williston Park). 2011;25:1362Y1370, 1375Y1381, 1387. 16. Coleman RE. Bone cancer in 2011: prevention and treatment of bone metastases. Nat Rev Clin Oncol. 2012;9:76Y78.
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Bone Metastasis in Primary Endometrial Carcinoma Features, Outcomes, and Predictors Aera Yoon, MD, Chel Hun Choi, MD, Tae-Hyun Kim, MD, June-Kuk Choi, MD, Jin-Young Park, MD, Yoo-Young Lee, MD, PhD, Tae-Joong Kim, MD, Jeong-Won Lee, MD, PhD, Duk-Soo Bae, MD, PhD, and Byoung-Gie Kim, MD, PhD
Objectives: This study aimed to describe the clinicopathologic characteristics and outcomes and to assess the predictors associated with prognosis in endometrial carcinoma that developed bone metastasis. Methods: A retrospective review of medical records was performed to identify the patients with endometrial carcinoma who developed bone metastasis between October 1994 and May 2012. Results: Of the 1185 patients with endometrial carcinoma, 22 (1.8%) were identified with bone metastasis, and 21 patients were analyzed in the study. Seventeen (80.9%) patients had advanced-stage disease (2009 International Federation of Gynecologists and Obstetricians stages III-IV). Four (19.0%) patients had a bone lesion at the diagnosis of endometrial cancer. The median time of recurrence to the bone in 17 patients was 9 months (range, 2Y43 months). The median overall survival (OS) and survival after bone metastasis of the entire cohort were 33 months (range, 9Y57 months) and 15 months (range, 12Y17 months), respectively. The patients with bone metastasis at recurrence had significantly longer OS than those patients with bone metastasis at diagnosis of endometrial cancer (36 vs 13 months; P = 0.042). Metastasis to extrapelvic bone was significantly associated with longer OS (46 vs 19 months; P = 0.001) and longer survival after bone metastasis (25 vs 12 months; P = 0.002). Isolated bone recurrence without extraosseous metastases and extrapelvic bone metastasis revealed independent predictors for survival after bone metastasis (hazard ratio, 0.09; 95% confidence interval, 0.01Y0.67; P = 0.019 and hazard ratio, 0.07; 95% confidence interval, 0.01Y0.53; P = 0.01). Conclusions: In endometrial carcinoma that develops bone metastasis, isolated bone recurrence and extrapelvic bone metastasis are significant predictors of prolonged survival after the diagnosis of bone metastasis. Further researches on the optimal treatment modality and factors that have the clinical implications are warranted. Key Words: Endometrial cancer, Bone metastasis, Outcome, Survival Received August 16, 2013, and in revised form September 2, 2013. Accepted for publication September 3, 2013. (Int J Gynecol Cancer 2014;24: 107Y112)
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Copyright * 2013 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000015 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Byoung-Gie Kim, MD, PhD, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, South Korea. E-mail: [email protected]. The authors did not receive funding for this work. The authors declare no conflicts of interest.
& Volume 24, Number 1, January 2014
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International Journal of Gynecological Cancer
Yoon et al
cancer is the most common gynecologic maE ndometrial lignancy in developed countries. The incidence rates of 1
endometrial cancer are steadily rising from 2.6% in 2000 to 5.0% in 2010 in South Korea, accounting for an estimated 1752 new cases and 222 deaths in 2010.2 Endometrial cancer with early-stage disease was diagnosed in more than 75% of the patients because most patients have obvious symptoms, including abnormal vaginal bleeding. The 5-year overall survival (OS) rate is 80% to 85%.3 However, for patients with advanced-stage disease and those with recurrent endometrial cancer, the prognosis remains poor. Endometrial cancer recurrence mostly occurs within the pelvis. Most distant recurrences develop within lymph nodes, lung, or liver.4,5 Bone involvement in endometrial cancer is rare and the prevalence is variously reported (0%Y15%).6Y8 Although metastases to the bone are thought to result from hematologic dissemination, the mechanism of bone metastasis is not clearly understood. It can be associated with primary tumor behavior, vascular supply, immune system, and bone environment.9 Once bone metastasis develops, neoplastic progress becomes incurable and the chances of survival of the patients are decreased. Moreover, bone metastases cause suffering because of severe pain, pathologic fracture, and disability. Therefore, early diagnosis and proper treatment could lead to better quality of life in patients with bone metastasis. There is some research on patients with endometrial cancer who developed bone metastasis. However, because of its rarity, almost all the published studies are case reports describing unusual cases of bone metastasis. In this study, we describe the clinical characteristics and outcomes of 21 patients with endometrial cancer who developed bone metastasis. In addition, we investigate the prognostic factors associated with disease-related survival, which provide further understanding of bone metastasis in endometrial cancer.
METHODS This was a retrospective study of patients with endometrial cancer who developed bone metastasis using the electronic medical records. With institutional review board approval, we identified patients whose conditions were diagnosed with endometrial cancer between October 1994 and May 2012 at the Department of Obstetrics and Gynecology at Samsung Medical Center. Of the patients with endometrial cancer, this study included the patients whose conditions were diagnosed to have bone metastasis either at the time of diagnosis or at recurrence, as the primary site, with or without concomitant lesions. Bone metastasis was diagnosed with histologic confirmation by a bone biopsy or with positive results on more than 2 radiographic imaging investigations without a biopsy. Patients with any history of malignancy and with uterine sarcomas or carcinosarcomas were excluded in this study. With a comprehensive review of the medical records, clinicopathologic data and clinical outcomes of the patients with endometrial carcinoma who developed bone metastasis were evaluated. Staging was determined according to the
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2009 FIGO (International Federation of Gynecology and Oncology) staging system.10 The number of bone metastases was categorized as being either single or multiple according to the location of the involved bone. Clinical characteristics were summarized using descriptive statistics. Survival was calculated as the number of months, and survival probabilities were estimated using the Kaplan-Meier method. Log-rank test was used to identify the predictors of disease-related survival, and Cox proportional hazards model was used for the multivariate analysis. Overall survival was defined as the time from diagnosis of endometrial cancer to death or last follow-up. Survival after bone metastasis was defined as the time from diagnosis of bone metastasis to death or last follow-up. All P values were 2 tailed and considered significant if less than 0.05. All statistical analyses were performed using SPSS software (version 18.0; SPSS, Chicago, Ill).
RESULTS Patient Characteristics Endometrial cancer was diagnosed in 1185 patients during the study period. Of these patients, 22 (1.8%) had bone metastasis. One patient was excluded because of a history of breast cancer. Therefore, 21 patients were included in the study. The characteristics of these patients are summarized in Table 1. The median age at diagnosis of endometrial cancer in 21 patients was 59 years (range, 28Y72 years). Although bone metastasis occurred in all stages, most patients had advancedstage disease (2009 FIGO stages III-IV, 17/21 [80.9%]). Of the 3 patients who had the early-stage disease (IB), 1 patient had serous adenocarcinoma with lymphovascular space invasion, 1 patient had grade 2 and 4-cm endometrioid adenocarcinoma, and 1 patient had grade 3 endometrioid adenocarcinoma with lymph-vascular space invasion. Eight (38.1%) patients had endometrioid carcinoma, and 13 (61.9%) patients showed nonendometrioid histology including serous adenocarcinoma (n = 5), clear cell carcinoma (n = 1), poorly differentiated carcinoma (n = 2), villoglandular adenocarcinoma (n = 1), and adenocarcinoma not otherwise specified (n = 4). Most of the tumors had grade 2 or 3 differentiation, and in the 18 patients who underwent a surgery, 12 (12/18, 66.7%) showed deep myometrial invasion (Q 1/2 invasions to the myometrium). Three patients with clinical stage IVB received chemotherapy or concurrent chemoradiotherapy (CCRT) without surgery as a primary treatment. As postoperative adjuvant treatment, radiotherapy, chemotherapy, or CCRT was performed. Most patients received platinumcontaining combination chemotherapy. Chemotherapeutic regimens included the combinations of taxane and platinum in 4 patients and cyclophosphamide, doxorubicin, and platinum in 2 patients. During the CCRT, platinum-based chemotherapy was used in all patients.
Characteristics of Bone Metastasis Most patients presented symptoms with pain (81%) or fracture (9.5%) at the time of diagnosis of bone metastasis. The conditions of the 2 patients were diagnosed on routine recurrent work-up. Bone metastasis was diagnosed in * 2013 IGCS and ESGO
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International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014 Bone Metastasis in Endometrial Carcinoma
TABLE 1. Patient characteristics (n = 21) Characteristic
n (%)
Age, median (range), y BMI, median (range), kg/m2 2009 FIGO stage IB II IIIA IIIC1 IIIC2 IVB Histology Endometrioid Nonendometrioid Tumor size, median (range), cm FIGO grade 1 2 3 Unknown Depth of myometrial invasion G2 Q2 Unknown Primary treatment Surgery and radiotherapy Surgery and chemotherapy Surgery and CCRT Chemotherapy CCRT
59 (28Y72) 24.1 (20.9Y31.7) 3 1 1 3 6 7
(14.3) (4.8) (4.8) (14.3) (28.5) (33.3)
8 (38.1) 13 (61.9) 4.2 (2.3Y14) 1 4 10 6
(4.8) (19.0) (47.6) (28.6)
1 (4.8) 12 (57.1) 8 (38.1) 10 4 4 2 1
(47.6) (19.0) (19.0) (9.5) (4.8)
BMI, body mass index.
3 (14.3%) patients by bone biopsy, and the most commonly used imaging modality was positron emission tomography scan (47.6%) followed by bone scan (23.8%). Of the 21 patients, 4 (19%) had their bone metastasis identified simultaneously with the primary diagnosis of endometrial cancer, and 17 (81%) patients developed bone metastasis as a recurrence. The median time of recurrence to the bone in these 17 patients was 9 months (range, 2Y43 months). Ten (47.6%) patients had a single bone lesion, and 11 (52.4%) patients had multiple bone metastases at more than 2 sites (Table 2). At the diagnosis of bone metastasis, 13 (61.9%) patients had a coexisting extraosseous metastatic lesion, and the lung (8/13, 61.5%) was the most common coexisting visceral metastatic site. Other sites were the liver, brain, and lymph nodes including the supraclavicular and para-aortic lymph nodes. Ten (47.6%) patients had only extrapelvic bone metastasis (Table 2). The distribution of bone metastases was predominantly to the axial skeleton. The total locations of bone metastases were 36 in the 21 patients. The most
common locations of bone metastasis were the vertebral spine (16/36, 44.4%) and pelvis (10/36, 27.8%). Additional unusual locations of bone metastasis were as follows: rib (n = 2), femur (n = 2), acetabulum (n = 2), clavicle (n = 1), parietal bone (n = 1), scapula (n = 1), and humerus (n = 1). There were no patients with hypercalcemia (reference, 8.4Y10.2 mg/dL) because of the bone metastasis.
Salvage Treatments Patients received treatment with surgical resection (n = 2, 9.5%), radiotherapy (n = 4, 19%), chemotherapy (n = 6, 28.6%), or both (n = 7, 33.3%) as the salvage therapy after bone metastasis. Two (9.5%) patients received supportive care because of a predicted short life expectancy and unfavorable performance status (Table 2). These 2 patients died of the disease 9 days and 22 days after the diagnosis of bone metastasis. Of the 2 patients who underwent surgical resection, cranioplasty was performed in 1 patient with parietal bone metastasis, and laminectomy with fixation was performed in
TABLE 2. Characteristics of bone metastasis (n = 21) Characteristic Symptom Pain Fracture None Diagnosis of bone metastasis Bone biopsy PET Bone scan MRI Bone metastasis at diagnosis Bone metastasis at recurrence No. bone metastasis Single Multiple Coexisting extraosseous metastasis Yes No Sites of bone metastasis Pelvis T extrapelvic Extrapelvic only Salvage treatment Surgical resection Radiotherapy Chemotherapy Sequential radiotherapy and chemotherapy Supportive care
n (%) 17 (81.0) 2 (9.5) 2 (9.5) 3 10 5 3 4 17
(14.3) (47.6) (23.8) (14.3) (19.0) (81.0)
10 (47.6) 11 (52.4) 13 (61.9) 8 (38.1) 11 (52.4) 10 (47.6) 2 4 6 7 2
(9.5) (19.0) (28.6) (33.3) (9.5)
MRI, magnetic resonance imaging; PET, positron emission tomography.
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& Volume 24, Number 1, January 2014
FIGURE 1. The OS in patients with bone metastasis at primary diagnosis of endometrial cancer vs patients with bone metastasis at recurrence (A) and according to the sites of bone metastases: extrapelvic only vs pelvis T extrapelvic (B). 1 patient who developed gait disturbance by compressive fracture of the thoracic spine metastasis.
Survival and Prognostic Factors The median follow-up time was 21 months (range, 2Y78 months). At the date of data analysis, a total of 15 patients died of the disease. The median OS and median survival after bone metastasis of the entire cohort were 33 months (range, 9Y57 months) and 15 months (range, 12Y17 months), respectively. The OS of patients with bone metastasis at recurrence was significantly longer than that of patients with bone metastasis at the primary diagnosis of endometrial cancer (36 vs 13 months; P = 0.042; Fig. 1A). Metastasis only to the extrapelvic bone was significantly associated with longer OS (46 vs 19 months; P = 0.001) and longer survival after bone metastasis (25 vs 12 months; P = 0.002; Fig. 1B and Fig. 2). In the multivariate analysis, isolated bone recurrence without extraosseous metastases and extrapelvic bone metastasis revealed independent predictors for survival after bone metastasis (HR, 0.09; 95% confidence interval [CI], 0.01Y0.67; P = 0.019 and HR, 0.07; 95% CI, 0.01Y0.53; P = 0.01; Table 3). Age, initial stage, histology, and number of bone metastasis were not associated with the OS and survival after bone metastasis.
therapy in endometrial cancer. In the study, most patients (15/ 21, 71%) received pelvic radiation. In recurrent or metastatic endometrial cancer, the relapse of the disease within the previous radiation demonstrated a prognostic factor for poor survival in the previous literature.5 Similar results have been reported in cervical cancer, where a lower therapeutic response was shown in patients with relapse within the radiotherapy field.11 The reason for this is not fully understood, and this may reflect biologic differences. Radioresistant endometrial cancers may have unfavorable biologic factors, and the aggressiveness of these cancers may be associated with a lower response to treatment and rapid progression of disease. Another finding of the study is that OS was significantly shorter in patients who had bone dissemination at the diagnosis of endometrial cancer than those patients with bone metastasis at disease recurrence. Kehoe et al6 reported similar results. They showed that the OS of those patients with bone metastases at primary diagnosis was 17 months (95%
DISCUSSION The principal findings of this study are that extrapelvic bone metastasis and isolated bone recurrence are the prognostic factors for prolonged survival after bone metastasis in patients with endometrial carcinoma who developed bone metastases. Another finding of our study is that the patients with bone metastasis as a recurrence have longer survival than patients with endometrial carcinoma who developed bone metastasis at presentation. In addition, our study is one of the largest cohorts of bone metastasis in endometrial carcinoma that describes the clinical features and outcomes. On the basis of our results, the patients with pelvic bone metastasis showed poor prognosis compared with patients with extrapelvic bone metastasis. Irradiation to the pelvic area such as whole pelvic radiotherapy and brachytherapy is the standard treatment for postoperative adjuvant or primary
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FIGURE 2. The survival after the diagnosis of bone metastasis according to the sites of bone metastases: extrapelvic only vs pelvis T extrapelvic. * 2013 IGCS and ESGO
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International Journal of Gynecological Cancer
& Volume 24, Number 1, January 2014 Bone Metastasis in Endometrial Carcinoma
TABLE 3. Prognostic factors for survival after bone metastasis (n = 21) Univariate Analysis Factor Age, y e60 960 Stage I-II III-IV Histology Endometrioid Nonendometrioid No. bone metastasis Single Multiple Coexisting extraosseous metastasis Yes No Sites of bone metastasis Pelvis T extrapelvic Extrapelvic only
Multivariate Analysis
No.
Median, mo
P
HR (95% CI)
P
11 10
15 13
0.354
1 0.26 (0.03Y2.29)
0.226
4 17
15 14
0.958
1 3.8 (0.71Y20.2)
0.117
8 13
15 14
0.309
1 0.24 (0.04Y1.32)
0.101
11 13
15 12
0.102
1 14.32 (0.9Y227.9)
0.059
13 8
15 15
0.288
1 0.09 (0.01Y0.67)
0.019
11 10
12 25
0.002
1 0.07 (0.01Y0.53)
0.01
CI, 2Y32) compared with 32 months (95% CI, 14Y49) for those with recurrent bone metastasis. In addition, the authors reported that survival after bone metastasis is longer in patients with disease recurrence in the bone. The occurrence of bone metastases secondary to endometrial cancer is very rare and is variously reported. Recently, Uccella et al7 reported that the exact frequency of bone metastases in endometrial cancer is less than 1% through the review of published literatures. In their series, the overall incidence of bone dissemination was presented in 0.8%, and the incidence of bone metastases at presentation with endometrial cancer was presented in 0.12%. In our series, the former was in 1.8% (22/1185) and the later was in 0.3% (4/1185). In another large series, only 21 patients were identified to have a bone metastasis among 6144 patients with endometrial cancer.6 The difference of diagnostic methods for bone metastasis or incidence of endometrial cancer may be associated with this distinction. Tumor histology is a known prognostic factor in endometrial cancer. Some literatures reported that nonendometrioid histology is associated with poor prognosis in recurrent endometrial cancer5,12 and is a predictor of hematogenous dissemination in endometrial cancer.13 Similar result was reported in patients with endometrial cancer who developed bone metastasis. The authors found that the survival after bone metastasis is significantly longer in patients with endometrioid histology than those patients with nonendometrioid histology. In addition, this study showed that the patients with single bone metastasis have a better prognosis.7 However, in our results, tumor histology and number of involved bones were not associated with
the outcomes of the patients. Further studies are warranted to identify the clinical implications of tumor histology and the number of involved bones in endometrial cancer that developed bone metastasis. Similar to previous studies,6,7 the axial skeleton (vertebral spine, pelvic bone, and rib) was the predominant metastatic sites in the study. Metastasis to the spine account for 44.4%, and the most common site was thoracic spine followed by lumbar spine. In this study, the median survival after diagnosis of bone metastasis was 15 months, which is comparable with the 12 months and 10 months reported previous literatures.6,7 The median OS of patients with bone metastasis was 33 months in our result. This result was a relatively good outcome compared with the previous studies; the authors reported the median OS as 18 months and 25 months.6,7 Currently, there is no standard treatment for the patients with endometrial cancer who developed bone metastasis because of the limited number of studies with small cases due to their rarity. Treatment options include directed radiation therapy, systemic chemotherapy, surgical resection, and hormonal therapy. The selection of therapy is based on the sites and number of involved bones, concomitant extraosseous metastasis, type of previous treatment, and patients’ performance status. According to the literatures from other solid tumors (ie, prostate or breast cancer), bisphosphonate could be considered as the treatment modality.14,15 Furthermore, further studies are required regarding the bone-targeting agents such as denosumab in breast and prostate cancers with bone metastasis.16
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Our study is limited by its retrospective design and by the heterogeneity of patients and treatment strategies because of the long-term follow-up study. The study has the small number of patients, although it is the largest case series regarding patients with endometrial cancer who developed bone metastasis. In conclusion, the median OS and median survival after bone metastasis are 33 months and 15 months in patients with endometrial cancer who developed bone metastasis, respectively. Recurrence to extrapelvic bone has a more favorable outcome than recurrence to the pelvic bone, and isolated bone recurrence without visceral metastasis is a predictor for survival after the diagnosis of bone metastasis. In addition, patients with bone involvement that occurred as a recurrence have a longer survival than those patients with bone involvement at presentation with endometrial cancer. Further researches on the optimal treatment modality and factors that have clinical implications are required.
REFERENCES 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69Y90. 2. Jung KW, Won YJ, Kong HJ, et al. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013;45:1Y14. 3. Sant M, Aareleid T, Berrino F, et al. EUROCARE-3: survival of cancer patients diagnosed 1990-94Yresults and commentary. Ann Oncol. 2003;14:v61Yv118. 4. Fujimoto T, Nanjyo H, Fukuda J, et al. Endometrioid uterine cancer: histopathological risk factors of local and distant recurrence. Gynecol Oncol. 2009;112:342Y347. 5. Mountzios G, Bamias A, Voulgaris Z, et al. Prognostic factors in patients treated with taxane-based chemotherapy for recurrent or metastatic endometrial cancer: proposal for a new prognostic model. Gynecol Oncol. 2008;108:130Y135.
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6. Kehoe SM, Zivanovic O, Ferguson SE, et al. Clinicopathologic features of bone metastases and outcomes in patients with primary endometrial cancer. Gynecol Oncol. 2010;117:229Y233. 7. Uccella S, Morris JM, Bakkum-Gamez JN, et al. Bone metastases in endometrial cancer: report on 19 patients and review of the medical literature. Gynecol Oncol. 2013;130:474Y482. 8. Kaya A, Olmezoglu A, Eren CS, et al. Solitary bone metastasis in the tibia as a presenting sign of endometrial adenocarcinoma: a case report and the review of the literature. Clin Exp Metastasis. 2007;24:87Y92. 9. Mackiewicz-Wysocka M, Pankowska M, Wysocki PJ. Progress in the treatment of bone metastases in cancer patients. Expert Opin Investig Drugs. 2012;21:785Y795. 10. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105:103Y104. 11. Kastritis E, Bamias A, Efstathiou E, et al. The outcome of advanced or recurrent non-squamous carcinoma of the uterine cervix after platinum-based combination chemotherapy. Gynecol Oncol. 2005;99:376Y382. 12. Mariani A, Webb MJ, Keeney GL, et al. Surgical stage I endometrial cancer: predictors of distant failure and death. Gynecol Oncol. 2002;87:274Y280. 13. Mariani A, Webb MJ, Keeney GL, et al. Hematogenous dissemination in corpus cancer. Gynecol Oncol. 2001;80:233Y238. 14. Solomayer EF, Gebauer G, Hirnle P, et al. Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol. 2012;23:2271Y2277. 15. Rove KO, Crawford ED. Evolution of treatment options for patients with CRPC and bone metastases: bone-targeted agents that go beyond palliation of symptoms to improve overall survival. Oncology (Williston Park). 2011;25:1362Y1370, 1375Y1381, 1387. 16. Coleman RE. Bone cancer in 2011: prevention and treatment of bone metastases. Nat Rev Clin Oncol. 2012;9:76Y78.
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