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Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma
European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 309–316
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Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma Zhang Gong-yi, Wu Ling-ying*, Li Bin, Huang Man-ni, Zhang Rong, Li Xiao-guang Department of Gynecological Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 July 2012 Received in revised form 10 December 2012 Accepted 27 February 2013
Objective: To identify independent prognostic variables for surgically staged intermediate risk endometrial carcinoma as defined by the Gynecologic Oncology Group 99 (GOG99) criteria. Study design: Retrospective study of 239 patients with FIGO stage IB-occult IIB endometrioid type endometrial cancer, who were primarily treated with comprehensive staging surgery. Data were collected on clinicopathological variables, extent of primary surgery, postoperative adjuvant treatment, and patterns of recurrences. Kaplan–Meier survival curves were used to estimate disease free survival (DFS) and overall survival (OS), and multivariate Cox regression models were used to identify independent prognostic variables. The median follow-up time was 67 months (range, 12–183 months). Results: The 5-year DFS and OS were 91.0% and 93.0%, respectively. On univariate Kaplan–Meier analysis, age > 60 years, deep myometrial invasion (MI), presence of lymph vascular invasion (LVSI), and negative progesterone receptor (PR) status were significantly associated with diminished 5-year DFS and OS. The univariate analysis on patterns of failures demonstrated that patients with older age or positive LVSI were more inclined to develop locoregional recurrence, while PR status and the depth of MI had a statistically significant impact on distant failure. On multivariate analysis, PR status, age, and the depth of MI were independent prognostic variables for 5-year DFS, and age was the only independent prognostic variable for 5-year OS. LVSI and age were independent prognostic variables for locoregional recurrence, while PR status and depth of MI were independent prognostic variables for distant recurrence. Conclusions: Age, depth of MI, PR status and presence of LVSI are of independent prognostic value for intermediate risk endometrial cancer. The presence of these variables warrants consideration when deciding upon treatment strategies. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometrial carcinoma Age Prognosis Factors analysis Survival
1. Introduction Endometrial cancer is the most common gynecologic malignancy in western countries and every year approximately 40,000 women are newly diagnosed in the United States [1]. The incidence of endometrial cancer is also increasing in developing countries in the past decades [2,3]. Fortunately, due to the early manifestations such as abnormal vaginal bleeding, the majority of patients have early stage disease with a favorable prognosis at the time of diagnosis. Although consensus has been reached that stage IA patients seldom relapse and are classified as low-risk, the definition of intermediate risk patients was inconsistent among various studies [4–12]. This lack of consistency continued until a Gynecologic Oncology Group (GOG) study defined
* Corresponding author at: Department of Gynecological Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 17 Panjiayuan, Chaoyang District, Beijing, China. Tel.: +86 13522057759. E-mail address: [email protected] (L.-y. Wu). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.02.025
endometrioid-type International Federation of Gynecology and Obstetrics (FIGO) stages IB, IC, and II occult diseases as intermediate risk endometrial carcinoma in 2004 [13], and this definition was widely adopted thereafter [14–17]. Nearly 15–20% of this subset of patients would develop recurrence if no adjuvant treatment is administered. Identifying prognostic factors which might lead to a more accurate recognition of these 15–20% patients is important, thus the rest of patients would be spared unnecessary adjuvant treatment and related complications. Previously, the GOG99 study had stratified intermediate risk patients into high-intermediate risk (HIR) and lowintermediate risk (LIR) groups based on age, tumor grade, lymphvascular space invasion (LVSI), and depth of myometrial invasion (MI) [13]. These variables, however, display strong interrelationships, and it is not clear if there is an independent prognostic variable. Moreover, steroid receptor status, which is supposed to be a main prognostic variable for endometrial cancer, was not considered in that trial. Several previous studies had identified various independent prognostic factors for endometrial cancer, but few of them examined their prognostic value in the subset patients
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Table 1 Baseline data for patients lost to follow up. Variable Age 60 60 Stage IB IC IIA IIB Grade G1 G2 G3 Depth of MIa 1/2 1/2 Cervical involvement No Yes PR (+) ( ) ER (+) ( ) Comorbid diseasesb Yes No LVSI ( ) (+) BMIc 25 25 a b c
N
Percentage
20 9
69.0% 31.0%
20 6 3 0
69.0% 20.7% 10.3% 0%
14 10 5
48.3% 34.5% 17.2%
22 7
75.9% 24.1%
26 3
89.7% 10.3%
17 12
58.6% 41.4%
20 9
69.0% 31.0%
4 25
13.8% 86.2%
27 2
93.1% 6.9%
13 16
44.8% 55.2%
Myometrial invasion. Diabetes or hypertension. Body mass index.
of intermediate risk [18–24]. In addition, most of those articles did not require comprehensive surgical staging. This lack of data prompted us to review our patients in order to clarify the independent prognostic variables for intermediate risk patients. The aim of the present retrospective study was to evaluate the association of the various clinicopathological features such as age, depth of MI, tumor grade and stage, LVSI, cervical involvement (CI), body mass index (BMI) and steroid receptor status with the oncologic outcomes in surgically staged endometrial cancer patients of intermediate risk. 2. Materials and methods From July 1995 to July 2007, a total of 329 consecutive patients diagnosed with intermediate risk endometrial carcinoma as defined in the GOG99 trial were managed surgically at the Cancer Hospital of China Academy of Medical Science. The institutional review boards approved the retrospective study. Patients with papillary serous, clear cell, or squamous type were excluded. Patients with a history of another primary cancer were not eligible, as well as patients with previous history of radiation therapy or chemotherapy. Follow-up information was retrieved from the patients’ medical records first. If no out-patient clinic interview was documented within the past 3 months in the medical records, a telephone interview was made to the patient or her family members requesting information about recurrence and survival status. If a treatment failure was reported, the sites and subsequent treatments of the recurrence were inquired about. In those cases where cancer-related or unrelated deaths were reported, the causes and time of deaths
would also be investigated. In total, 76 (23.1%) patients received an additional telephone interview, a follow-up strategy which had been validated by and applied to several previous studies [22,25– 28]. Owing to the rapid urbanization and industrialization during the past two decades, however, change of residence address or telephone number is common, which made follow-up quite a challenging task. Moreover, some rural patients did not have phone number in the mid-1990s. As a result, 29 (8.8%) patients were lost to follow-up during the long time span encompassed in this analysis. The baseline data for patients who were lost to follow-up are provided in Table 1. Of the remaining 300 patients, 239 received comprehensive surgical staging according to the FIGO staging system (1988) and comprised our study population. All pathological sections were initially reviewed by a board-certified pathologist specializing in gynecologic pathology, and the diagnoses were confirmed at a multidisciplinary oncology tumor board. Histological types were evaluated according to the criteria of the WHO International Histological Classification of Tumors. Depth of MI was categorized as superficial (1/2) or deep (1/2). LVSI was defined as the
Table 2 Patient characteristics and treatment outcomes for the study cohort. Variable
N
Age 177 60 60 62 Stage IB 139 IC 32 IIA 42 IIB 26 Grade G1 80 G2 116 G3 43 Depth of MIa 1/2 183 1/2 56 Cervical involvement No 171 Yes 68 PR status (+) 173 ( ) 66 ER status (+) 150 ( ) 89 Comorbid diseasesb Yes 62 No 177 LVSI ( ) 225 (+) 14 BMIc 25 82 25 157 Types of hysterectomy Type I 39 Type II 160 Type III 40 Adjuvant radiotherapy Yes 85 No 154 Chemotherapy Yes 28 No 211 Endocrine therapy Yes 58 No 181 a b c
5-year DFS
p-Value
5-year OS
p-Value
94.0% 81.7%
0.005
96.3% 85.8%
0.004
94.1% 87.3% 87.0% 84.3%
0.413
95.6% 90.6% 94.9% 84.0%
0.219
92.2% 92.1% 85.4%
0.604
94.4% 94.4% 90.2%
0.506
95.0% 77.0%
0.0001
96.3% 84.4%
0.001
92.8% 85.9%
0.252
94.6% 90.8%
0.209
93.2% 84.8%
0.008
96.2% 86.6%
0.024
90.2% 88.8%
0.637
95.1% 90.1%
0.492
91.7% 90.6%
0.572
96.3% 92.6%
0.379
92.1% 71.4%
0.010
94.5% 78.6%
0.032
93.4% 89.6%
0.188
95.0% 92.8%
0.592
87.1% 92.2% 88.9%
0.279
91.9% 94.7% 91.8%
0.807
85.1% 94.1%
0.093
88.7% 96.2%
0.009
96.0% 88.8%
0.631
95.7% 92.8%
0.557
89.3% 91.4%
0.730
92.9% 93.8%
0.519
Myometrial invasion. Diabetes or hypertension. Body mass index.
G-y. Zhang / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 309–316 Table 3 Potential risk factors by adjuvant therapy. Variable
RTa
Age 62 60 60 23 Stage IB 17 IC 27 IIA 25 16 IIB LVSI (+) 7 ( ) 78 ER status (+) 52 ( ) 33 PR status (+) 58 ( ) 27 Grade G1 18 G2 36 31 G3 Depth of MI 1/2 39 1/2 46 a b c d e f
NRTb
p-Value
CTc
NCTd
p-Value
ETe
NETf
p-Value
115 39
0.761
20 8
157 54
0.735
45 13
132 49
0.481
122 5 17 10
<0.0001
13 2 4 9
126 30 38 17
0.201
35 6 10 7
104 26 32 19
0.874
7 147
0.261
4 24
10 201
0.043
2 56
12 169
0.527
98 56
0.706
13 15
137 74
0.057
47 11
103 78
0.001
115 39
0.286
17 11
156 55
0.142
51 7
122 59
0.002
62 80 12
<0.0001
2 6 20
78 110 23
<0.0001
22 29 7
58 87 36
0.371
144 10
<0.0001
20 8
163 48
0.494
48 10
135 46
0.201
Radiotherapy. No radiotherapy. Chemotherapy. No chemotherapy. Endocrine therapy. No endocrine therapy.
presence of tumor cells within or attached to the wall of a blood vessel or lymphatic space. The steroid receptor status was assessed immunohistochemically and evaluated according to the Allred scoring system [29]. Primary surgery consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with routine systematic pelvic lymphadenectomy, including a thorough and complete dissection
311
of the lymphatics of the common iliac, internal iliac, external iliac, and obturator nodal groups. Piver type I, type II, or type III hysterectomy was performed depending on the patient’s status and doctor’s preference. A peritoneal cytology specimen was obtained during the surgical procedure for cytological review. Postoperatively, some patients received external beam radiotherapy (EBRT), and the prescription was usually based on the presence of adverse risk factors such as deep MI, cervical involvement or poor tumor differentiation. EBRT was delivered by a 6 MV linear accelerator using anterior–posterior opposed two-field technique, the superior margin being the upper border of L4 and the lower margin being inferior to the obturator foramen. No vaginal brachytherapy was applied during the radiation treatment. Oral medroxyprogesterone acetate (MPA) 250–500 mg daily or megestrol 160 mg daily were prescribed for at least 6 months in some of the patients with positive steroid receptor status. Additionally, a proportion of patients with poorly differentiated tumor or LVSI received adjuvant chemotherapy with an adriamycin and cisplatin (AP) regimen or paclitaxcel and carboplatin (TC) regimen postoperatively, since several articles had suggested that tumor grade and LVSI might be prognostic factors for distant recurrence [21,30,31]. The patterns of first recurrences were classified as locoregional or distant according to the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) study protocol [12]. Locoregional recurrence was defined as any recurrence that was localized in the vagina and/or pelvic region, including pelvic lymph nodes. All other recurrences were defined as distant, including para-aortic lymph-nodes, abdominal cavity, liver, lung, bone metastases, and diffuse metastatic disease. Statistical evaluation was performed using SPSS 16.0 (SPSS, Inc., Chicago, IL). OS, DFS, locoregional recurrence (LRR) and distant recurrence (DR) referred to the date of initial diagnosis and were calculated actuarially according to Kaplan–Meier statistics. Survival curves were determined by the Kaplan–Meier product-limit method. Analysis of the differences between survival curves was performed using the log-rank test. The Cox proportional hazards model was used to determine which variables were independent
Table 4 Initial sites of recurrences and clinico-pathological factors. No.
Site of recurrence
TTRa
Age
Depth of MI
Grade
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Hilar LNb Liver Pelvic LN Liver, abdomen Liver, omentum Bile duct Vaginal apex Bile duct Vaginal apex Lung, bone Vaginal apex Lung Pelvic side wall Liver Pelvic LN Paraaortic, mediastinnm and supraclavicular LN Lung Mediastinnm and supraclavicular LN Paraaortic and axillary LN Lung Pelvic side wall and LN Vaginal apex Vaginal apex
108 96 48 20 30 37 13 60 22 12 27 31 11 8 24 9
49 54 61 64 62 50 53 52 64 67 65 51 69 68 71 27
1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2
G1 G2 G1 G3 G1 G3 G2 G3 G2 G3 G2 G1 G3 G3 G2 G2
22 9 16 33 36 33 8
51 53 58 62 63 50 81
1/2 1/2 1/2 1/2 1/2 1/2 1/2
G2 G2 G2 G1 G1 G1 G2
17 18 19 20 21 22 23 a b
Time to recurrence. Lymph node.
PR status
LVSI
+ + + + + +
+
+ +
+
+ + + + +
Stage
Cervical involvement
EBRT
Vital status
Ib Ib Ib Ic IIb IIb Ib IIa Ib Ic Ib IIa Ib IIb Ib Ic
No No No No Yes Yes No Yes No No No Yes No Yes No No
No No Yes Yes Yes Yes No Yes No Yes No Yes No Yes No Yes
Die Alive Die Die Die Die Die Die Alive Alive Die Die Alive Die Die Die
Ic Ic IIa IIa Ib IIa IIb
No No Yes Yes No Yes Yes
Yes No Yes Yes No No No
Alive Alive Die Alive Die Alive Die
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G-y. Zhang / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 309–316 Age 1.0 60 years or younger over 60 years 60 years or younger-censored over 60 years-censored
Cum Survival
0.8
0.6
0.4
0.2
P=0.0002
0.0 0
50
100
150
200
Locoregional Recurrence Free Survival Time (months) Fig. 1. Locoregional recurrence free survival by age.
prognostic factors. All tests were two-sided and differences between groups were considered statistically significant at p 0.05. 3. Results The median age of the 239 eligible patients was 54 years (range, 26–82 years). Table 2 shows the characteristics of the patients included in this study. All patients received systematic pelvic lymphadenectomy, and a total of 5821 lymph nodes were removed, with a median number of 23 (range, 8–64) nodes. Postoperative EBRT was administered to a total of 85 (35.6%) patients with an average dose of 44.3 Gy (range, 40–45 Gy) given in fractions of 1.8–2.0 Gy. The distribution of patients receiving EBRT was biased toward those with increased depth of MI, worse histological differentiation, and/or presence of cervical invasion (Table 3). In addition, a total of 58 (24.3%) patients received
adjuvant endocrine therapy, and 28 (11.7%) patients received adjuvant chemotherapy. The distribution of patients receiving chemotherapy was biased toward those with worse histological differentiation, and/or presence of LVSI (Table 3). After a mean follow-up period of 67 (range, 12–183) months, a total of 23 (9.0%) patients developed recurrence. The accumulated 5-year DFS was 91.0%. The median time to recurrence was 24 (range, 8–108) months, and most recurrences (78.3%) occurred within the first 36 months after primary surgery. Of the 23 recurrences, 9 were classified as locoregional and 14 as distant. The detailed sites of recurrence are described in Table 4. A total of 15 patients succumbed to disease progression at the time of last follow-up, while two other patients died from causes unrelated to endometrial cancer or treatment. The accumulated 5-year OS was 93.0%. On univariate analysis, patients with younger age exhibited a higher 5-year DFS and OS than older patients. Five-year DFS and OS
LVSI
1.0
LVSI (-) LVSI (+) LVSI (-)-censored LVSI (+)-censored
Cum Survival
0.8
0.6
0.4
0.2
P=0.0003 0.0 0
50
100
150
Locoregional Recurrence Free Survival Time (months) Fig. 2. Locoregional recurrence free survival by LVSI.
200
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PR
1.0
PR (-) PR (+) PR (-)-censored PR (+)-censored
0.8
Cum Survival
313
0.6
0.4
0.2
P=0.003 0.0 0
50
100
150
200
Distant Recurrence Free Survival Time (months) Fig. 3. Distant recurrence free survival by PR.
were 94.0% and 96.3% in the patients 60 years old or younger, compared with 81.7% and 85.8% in the patients aged > 60 years (p < 0.05). Moreover, we found that compared with patients with deep MI, those with superficial MI demonstrated a significant survival advantage both on 5-year DFS (95.0% vs. 77.0%, p = 0.0001) and 5-year OS (96.3% vs. 84.4%, p = 0.001). Univariate analysis also indicated that the presence of LVSI was associated with a compromised 5-year DFS (71.4% vs. 92.1%, p = 0.01) and OS (78.6% vs.94.5%, p = 0.032). The treatment outcomes were similar between patients with distinct ER status, whereas the 5-year DFS and OS were compromised by the presence of negative PR status. Five-year DFS and OS were 84.8% and 86.6% in PR negative patients, compared with 93.2% and 96.2% in PR positive patients, p < 0.05. The results of univariate analysis for prognostic factors are shown in Table 2. Meanwhile, univariate analysis of the relationship
between patients’ outcomes and treatment variables demonstrated that various types of hysterectomy, postoperative adjuvant EBRT, chemotherapy, or endocrine therapy had no impact on DFS or OS (Table 2). The correlations between treatment failure patterns and the prognostic variables mentioned above were further investigated (Figs. 1–4). Age and LVSI were strongly correlated with LRR on univariate analysis. LRR were observed in 2 out of the 177 (1.1%) patients aged 60 years, compared with 7 out of the 62 (11.3%) patients aged > 60 years (p = 0.0002). Six out of 225 (2.7%) LVSI ( ) patients developed LRR, while 3 out of 14 (21.4%) LVSI (+) patients experienced LRR (p = 0.0003). Moreover, our investigation revealed that patients with negative PR status or deep MI were more likely to have distant recurrence. Ten of the 56 (17.9%) patients with deep MI experienced distant recurrence, compared with 4 (2.2%) of the
Depth of MI 1.0 superficial MI deep MI superficial MI-censored deep MI-censored
Cum Survival
0.8
0.6
0.4
0.2
P<0.0001 0.0 0
50
100
150
200
Distant Recurrence Free Survival Time (months) Fig. 4. Distant recurrence free survival by depth of MI.
314
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183 patients with superficial MI (p < 0.0001). Similarly, patients with negative PR status developed more distant recurrence than those with positive PR status (13.6% vs. 2.9%, p = 0.003). Our investigation, however, failed to demonstrate the efficacy of chemotherapy on distant recurrence. Approximately 7% of patients who received chemotherapy developed distant recurrence, while 5.3% patients who did not receive chemotherapy experienced distant recurrence (p = 0.693). All the above variables which were predictive of treatment outcomes were entered in a Cox regression model to determine the independent significance. Since several previous articles have shown that the extent of surgery or postoperative adjuvant therapy might affect treatment outcomes, these factors were also taken into account. Because of the small number of patients to whom chemotherapy was administered, the impact of chemotherapy was not accounted for. In the Cox model, older age still predicted a higher risk of developing LRR (HR = 10.550 (95%CI: 2.101–52.969), p = 0.004), disease free survival events (HR = 3.605 (95%CI: 1.516–8.577), p = 0.004), and mortality (HR = 4.719 (95%CI: 1.661–13.404), p = 0.004). We also found that deep MI conferred a 3.7-fold increase in the risk of recurrence (HR = 3.692 (95%CI: 1.614–8.448), p = 0.002), especially the risk of distant metastasis (1HR = 4.286 (95%CI: 1.103–16.665), p = 0.036). The estimated risk of recurrence among patients with positive PR status was 58% (HR = 0.421 (95%CI: 0.179–0.992), p = 0.048) less than patients with negative PR status, and the event-free benefit was also contributed by the 67% (HR = 0.331 (95%CI: 0.115–0.955), p = 0.041) decrease in distant metastasis. Multivariate analysis also indicated that LVSI was an independent prognostic factor for locoregional recurrence (HR = 7.649 (95%CI: 1.504–38.886), p = 0.014). 4. Comments To the best of our knowledge, this represents the first retrospective study investigating specifically the prognostic variables for stages IB–IIB (occult) endometrioid-type disease in patients who received comprehensive surgical staging. Moreover, because our institution is a tertiary-care cancer center, all the patients in our series were treated by qualified gynecologic oncologists, as recommended by the American College of Obstetricians and Gynecologists (ACOG) and justified by several previous studies [32–34]. During the time period over which our study was conducted, nearly 80% of apparently early stage patients admitted in our hospital received comprehensive surgical staging with a median number of 24 removed lymph nodes, which was above average. The median number of nodes removed in most previous studies ranged from 9 to 14, and only two studies harvested a median number of over 20 nodes [32,35–39]. The adequacy of the staging procedure in our series provided a precise staging and minimized the bias caused by stage migration, which was confirmed by a previous study conducted by Lutman et al. In that article, the author revealed that patients with over 12 nodes removed were more rigorously staged to exclude occult lymph node metastases [35]. The prognostic value of age for patients with endometrial cancer has been previously discussed in several articles, most of which agreed that increasing age represent an adverse prognostic parameter. Jolly et al., however, noted that the impact of age on patients with stage I–II disease is minor [18,19,40]. The interpretation of these results was compromised either by the inclusion of papillary serous or clear cell type tumor with more unfavorable prognosis, or by potential stage migration due to the incomplete surgical staging procedure. We restricted our study cohort exclusively to patients with stage IB-occult stage IIB endometrioid-type diseases, and found that older age is still an
independent adverse prognostic factor. Older age predicted a 10-fold higher risk of developing loco-regional recurrences, a threefold higher risk in disease-free survival events, and a nearly 5fold higher mortality after accounting for other potential confounding factors including LVSI, depth of MI, cervical involvement, and treatment variables. It was presumed that the adverse effect of increasing age may be related to differences between younger and older patients in tumor biology, immunologic response, tumor neovascularization, and the patient’s capability to produce and stimulate proteolytic enzymes [20]. Relatively few studies have been conducted of the association between steroid receptor status and treatment outcomes in early stage endometrial cancer previously. As far as we know, only one preceding study conducted by Kadar et al. had evaluated such relationship in surgically staged patients and showed that PR status affected survival independently. When the analysis was restricted to women with stage I–II disease, however, the effect lost its statistical significance [41]. In contrast, we found that the PR status affected both 5-year DFS and OS independently, and PR negative patients were associated with an increased risk of distant metastasis. This discrepancy might be related to the unequal sample sizes. In Kadar’s article, a total of 107 stage IA–IIB patients were examined, while our series was composed of 239 stage IBoccult IIB patients. With a larger sample size, we might detect some minor survival advantage that may be unobservable in Kadar’s article. Furthermore, we find that the prognostic value of ER was less significant than that of PR, which was consistent with several previous studies. In Fukuda’s analysis of 92 patients with endometrioid adenocarcinoma, PR status was found to be the most significant predictor of survival, whereas ER status demonstrated less prognostic significance [23]. In another study, Palmer et al. noted that if only one receptor could be obtained, PR status might provide the most helpful information for the majority of patients [42]. The underlying mechanism of the stronger prognostic power of PR over ER has not been clearly illustrated yet, and further molecular biological study is warranted. We also identified deep MI as an independent prognostic factor for impaired 5-year OS and DFS in intermediate risk patients, and the adverse effects were mainly contributed by distant failure. This result is consistent with a previous report by Gadducci et al. which indicated that deep MI was a strong predictor for distant haematogenous metastasis in patients with stage I–II endometrioid-type endometrial cancer [21]. Similarly, in a report of 229 stage I endometrial cancer patients, Marini et al. identified deep MI as the only independent predictor of disease related survival, DFS, and distant failure [22]. Graesslin et al. revealed that the aggressive behavior of cancer with deep MI was related to a lower expression of tissue inhibitors of metalloproteinase-2, a member of zincdependent endopeptidases [43]. The previous published prevalence of LVSI in apparently early stage endometrial cancer ranged from 2% to 37% [44–48], whereas 5% patients were LVSI positive in our series. It is noteworthy that few previous studies were restricted to surgically staged patients, and occult stage III disease with positive nodes might inevitably be included in those studies. Panggid et al. found that 87% patients with lymph node involvement had LVSI, while only 32% patients without lymph node involvement were LVSI positive [49]. From this perspective, our result might reflect the comparatively low frequency of LVSI associated with pathologically confirmed nodenegative patients. Despite the relatively low frequency, we still observed that LVSI exerted an independent adverse impact on locoregional recurrence, although the majority of previous studies demonstrated that LVSI was mainly associated with lymph node metastasis or distant recurrence. Little is known about the mechanism by which tumor with LVSI is prone to invade the normal tissues bordering on tumors. Only one previous study on
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endometrial cancer reached a similar result, which indicated that the presence of LVSI was a significant predictor for locoregional relapse when analyzed separately [50]. We are aware that there are several limitations to the present study. Firstly, given the retrospective nature of this study, the distribution of postoperative adjuvant treatment was unbalanced and patients with more adverse factors were treated more aggressively, thus the prognostic effect of some adverse factors might be masked. Secondly, the incidences of recurrence and death are small and affected the statistical power of the study. Thirdly, the number of patients who were prescribed adjuvant chemotherapy in the current investigation was too small to arrive at a definite conclusion. Although several previous articles had suggested that the risk of recurrence (especially distant recurrence) could be reduced by chemotherapy [51–53], our data failed to confirm the efficacy of chemotherapy in this respect. Further study exploring the role of systematic adjuvant chemotherapy in intermediate-risk patients is necessary. Finally, few patients received paraaortic lymph node resection in our series. The previously reported prevalence of paraaortic lymph node metastasis ranged from 4.0% to 20.0%, and the National Comprehensive Cancer Network Clinical Practice Guidelines have recommended that paraaortic lymph node resection should be an indispensable component of surgical staging for endometrial cancer [54–59]. It is noteworthy, however, that the diagnostic and therapeutic value of paraaortic lymph node resection was more definite in patients with stage IIIC disease than those with I–II disease, since nearly 28.6–66.7% of patients with positive pelvic lymph nodes had concomitant positive paraaortic lymph nodes [54–58]. In contrast, according to a recently reported result by Abu-Rustum et al., isolated paraaortic nodal metastasis occurs in approximately 1% of endometrial cancer cases [60]. Therefore, the negative impact of the lack of paraaortic lymph node resection could be neglected. In summary, age, PR status, depth of MI and LVSI are independent prognostic variables for intermediate-risk endometrial cancer. Age > 60 years and positive LVSI were associated with increased locoregional recurrence, while PR status and the depth of MI had significant impacts on distant failure. These variables should be incorporated in treatment decisions to achieve better tumor control. References [1] Greenlee RT, Murray T, Bolden S, et al. Cancer statistics 2000. CA A Cancer Journal for Clinicians 2000;50:7–35. [2] Yang Dan, Han L-M. Year 1969–2003 study on evolution of endometrial cancer. Fudan University Journal of Medical Sciences 2005;32:479–83. [3] Xiang YB, Zhang W, Gao LF, et al. Methods for time trend analysis of cancer incidence rates. Zhonghua Liu Xing Bing Xue Za Zhi 2004;25:173–7. [4] Salani R, Nagel CI, Drennen E, et al. Recurrence patterns and surveillance for patients with early stage endometrial cancer. Gynecologic Oncology 2011;123: 205–7. [5] Song T, Lee JW, Kim HJ, et al. Prognostic significance of DNA ploidy in stage I endometrial cancer. Gynecologic Oncology 2011;122:79–82. [6] Abu-Rustum NR, Zhou Q, Iasonos A, et al. The revised 2009 FIGO staging system for endometrial cancer: should the 1988 FIGO stages IA and IB be altered. International Journal of Gynecological Cancer 2011;21:511–6. [7] Cardenes H, Randall ME. Is observation and salvage (when necessary) an appropriate approach to intermediate risk endometrial cancer. Gynecologic Oncology 2003;89:199–200. [8] Pellizzon AC, Fogarolli RC, Miziara M, et al. Morbidity of adjuvant high-doserate brachytherapy for low to intermediate risk endometrial adenocarcinoma completely resected. International Journal of Cancer 2001;96(Suppl.):105–8. [9] Ampil FL, Caldito G, Unger J, et al. Can intermediate-risk node-negative patients with stage I corpus cancer do without posthysterectomy radiotherapy? Review of a 13-year experience. European Journal of Gynaecological Oncology 2001;22:269–72. [10] Fanning J. Long-term survival of intermediate risk endometrial cancer (stage IG3, IC, II) treated with full lymphadenectomy and brachytherapy without teletherapy. Gynecologic Oncology 2001;82:371–4. [11] Corn BW. Intermediate-risk endometrial cancer. A management approach. American Journal of Clinical Oncology 1996;19:631–5.
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A Gynecologic Oncology Group Study. Cancer 1987;60: 2035–41. [32] Macdonald OK, Sause WT, Lee RJ, et al. Adjuvant radiotherapy and survival outcomes in early-stage endometrial cancer: a multi-institutional analysis of 608 women. Gynecologic Oncology 2006;103:661–6. [33] Roland PY, Kelly FJ, Kulwicki CY, et al. The benefits of a gynecologic oncologist: a pattern of care study for endometrial cancer treatment. Gynecologic Oncology 2004;93:125–30. [34] Chan JK, Sherman AE, Kapp DS, et al. Influence of gynecologic oncologists on the survival of patients with endometrial cancer. Journal of Clinical Oncology 2011;29:832–8. [35] Lutman CV, Havrilesky LJ, Cragun JM, et al. Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecologic Oncology 2006;102:92–7. [36] ASTEC Study Group, Kitchener H, Swart AM, et al. 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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma Zhang Gong-yi, Wu Ling-ying*, Li Bin, Huang Man-ni, Zhang Rong, Li Xiao-guang Department of Gynecological Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 8 July 2012 Received in revised form 10 December 2012 Accepted 27 February 2013
Objective: To identify independent prognostic variables for surgically staged intermediate risk endometrial carcinoma as defined by the Gynecologic Oncology Group 99 (GOG99) criteria. Study design: Retrospective study of 239 patients with FIGO stage IB-occult IIB endometrioid type endometrial cancer, who were primarily treated with comprehensive staging surgery. Data were collected on clinicopathological variables, extent of primary surgery, postoperative adjuvant treatment, and patterns of recurrences. Kaplan–Meier survival curves were used to estimate disease free survival (DFS) and overall survival (OS), and multivariate Cox regression models were used to identify independent prognostic variables. The median follow-up time was 67 months (range, 12–183 months). Results: The 5-year DFS and OS were 91.0% and 93.0%, respectively. On univariate Kaplan–Meier analysis, age > 60 years, deep myometrial invasion (MI), presence of lymph vascular invasion (LVSI), and negative progesterone receptor (PR) status were significantly associated with diminished 5-year DFS and OS. The univariate analysis on patterns of failures demonstrated that patients with older age or positive LVSI were more inclined to develop locoregional recurrence, while PR status and the depth of MI had a statistically significant impact on distant failure. On multivariate analysis, PR status, age, and the depth of MI were independent prognostic variables for 5-year DFS, and age was the only independent prognostic variable for 5-year OS. LVSI and age were independent prognostic variables for locoregional recurrence, while PR status and depth of MI were independent prognostic variables for distant recurrence. Conclusions: Age, depth of MI, PR status and presence of LVSI are of independent prognostic value for intermediate risk endometrial cancer. The presence of these variables warrants consideration when deciding upon treatment strategies. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometrial carcinoma Age Prognosis Factors analysis Survival
1. Introduction Endometrial cancer is the most common gynecologic malignancy in western countries and every year approximately 40,000 women are newly diagnosed in the United States [1]. The incidence of endometrial cancer is also increasing in developing countries in the past decades [2,3]. Fortunately, due to the early manifestations such as abnormal vaginal bleeding, the majority of patients have early stage disease with a favorable prognosis at the time of diagnosis. Although consensus has been reached that stage IA patients seldom relapse and are classified as low-risk, the definition of intermediate risk patients was inconsistent among various studies [4–12]. This lack of consistency continued until a Gynecologic Oncology Group (GOG) study defined
* Corresponding author at: Department of Gynecological Oncology, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 17 Panjiayuan, Chaoyang District, Beijing, China. Tel.: +86 13522057759. E-mail address: [email protected] (L.-y. Wu). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.02.025
endometrioid-type International Federation of Gynecology and Obstetrics (FIGO) stages IB, IC, and II occult diseases as intermediate risk endometrial carcinoma in 2004 [13], and this definition was widely adopted thereafter [14–17]. Nearly 15–20% of this subset of patients would develop recurrence if no adjuvant treatment is administered. Identifying prognostic factors which might lead to a more accurate recognition of these 15–20% patients is important, thus the rest of patients would be spared unnecessary adjuvant treatment and related complications. Previously, the GOG99 study had stratified intermediate risk patients into high-intermediate risk (HIR) and lowintermediate risk (LIR) groups based on age, tumor grade, lymphvascular space invasion (LVSI), and depth of myometrial invasion (MI) [13]. These variables, however, display strong interrelationships, and it is not clear if there is an independent prognostic variable. Moreover, steroid receptor status, which is supposed to be a main prognostic variable for endometrial cancer, was not considered in that trial. Several previous studies had identified various independent prognostic factors for endometrial cancer, but few of them examined their prognostic value in the subset patients
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310
Table 1 Baseline data for patients lost to follow up. Variable Age 60 60 Stage IB IC IIA IIB Grade G1 G2 G3 Depth of MIa 1/2 1/2 Cervical involvement No Yes PR (+) ( ) ER (+) ( ) Comorbid diseasesb Yes No LVSI ( ) (+) BMIc 25 25 a b c
N
Percentage
20 9
69.0% 31.0%
20 6 3 0
69.0% 20.7% 10.3% 0%
14 10 5
48.3% 34.5% 17.2%
22 7
75.9% 24.1%
26 3
89.7% 10.3%
17 12
58.6% 41.4%
20 9
69.0% 31.0%
4 25
13.8% 86.2%
27 2
93.1% 6.9%
13 16
44.8% 55.2%
Myometrial invasion. Diabetes or hypertension. Body mass index.
of intermediate risk [18–24]. In addition, most of those articles did not require comprehensive surgical staging. This lack of data prompted us to review our patients in order to clarify the independent prognostic variables for intermediate risk patients. The aim of the present retrospective study was to evaluate the association of the various clinicopathological features such as age, depth of MI, tumor grade and stage, LVSI, cervical involvement (CI), body mass index (BMI) and steroid receptor status with the oncologic outcomes in surgically staged endometrial cancer patients of intermediate risk. 2. Materials and methods From July 1995 to July 2007, a total of 329 consecutive patients diagnosed with intermediate risk endometrial carcinoma as defined in the GOG99 trial were managed surgically at the Cancer Hospital of China Academy of Medical Science. The institutional review boards approved the retrospective study. Patients with papillary serous, clear cell, or squamous type were excluded. Patients with a history of another primary cancer were not eligible, as well as patients with previous history of radiation therapy or chemotherapy. Follow-up information was retrieved from the patients’ medical records first. If no out-patient clinic interview was documented within the past 3 months in the medical records, a telephone interview was made to the patient or her family members requesting information about recurrence and survival status. If a treatment failure was reported, the sites and subsequent treatments of the recurrence were inquired about. In those cases where cancer-related or unrelated deaths were reported, the causes and time of deaths
would also be investigated. In total, 76 (23.1%) patients received an additional telephone interview, a follow-up strategy which had been validated by and applied to several previous studies [22,25– 28]. Owing to the rapid urbanization and industrialization during the past two decades, however, change of residence address or telephone number is common, which made follow-up quite a challenging task. Moreover, some rural patients did not have phone number in the mid-1990s. As a result, 29 (8.8%) patients were lost to follow-up during the long time span encompassed in this analysis. The baseline data for patients who were lost to follow-up are provided in Table 1. Of the remaining 300 patients, 239 received comprehensive surgical staging according to the FIGO staging system (1988) and comprised our study population. All pathological sections were initially reviewed by a board-certified pathologist specializing in gynecologic pathology, and the diagnoses were confirmed at a multidisciplinary oncology tumor board. Histological types were evaluated according to the criteria of the WHO International Histological Classification of Tumors. Depth of MI was categorized as superficial (1/2) or deep (1/2). LVSI was defined as the
Table 2 Patient characteristics and treatment outcomes for the study cohort. Variable
N
Age 177 60 60 62 Stage IB 139 IC 32 IIA 42 IIB 26 Grade G1 80 G2 116 G3 43 Depth of MIa 1/2 183 1/2 56 Cervical involvement No 171 Yes 68 PR status (+) 173 ( ) 66 ER status (+) 150 ( ) 89 Comorbid diseasesb Yes 62 No 177 LVSI ( ) 225 (+) 14 BMIc 25 82 25 157 Types of hysterectomy Type I 39 Type II 160 Type III 40 Adjuvant radiotherapy Yes 85 No 154 Chemotherapy Yes 28 No 211 Endocrine therapy Yes 58 No 181 a b c
5-year DFS
p-Value
5-year OS
p-Value
94.0% 81.7%
0.005
96.3% 85.8%
0.004
94.1% 87.3% 87.0% 84.3%
0.413
95.6% 90.6% 94.9% 84.0%
0.219
92.2% 92.1% 85.4%
0.604
94.4% 94.4% 90.2%
0.506
95.0% 77.0%
0.0001
96.3% 84.4%
0.001
92.8% 85.9%
0.252
94.6% 90.8%
0.209
93.2% 84.8%
0.008
96.2% 86.6%
0.024
90.2% 88.8%
0.637
95.1% 90.1%
0.492
91.7% 90.6%
0.572
96.3% 92.6%
0.379
92.1% 71.4%
0.010
94.5% 78.6%
0.032
93.4% 89.6%
0.188
95.0% 92.8%
0.592
87.1% 92.2% 88.9%
0.279
91.9% 94.7% 91.8%
0.807
85.1% 94.1%
0.093
88.7% 96.2%
0.009
96.0% 88.8%
0.631
95.7% 92.8%
0.557
89.3% 91.4%
0.730
92.9% 93.8%
0.519
Myometrial invasion. Diabetes or hypertension. Body mass index.
G-y. Zhang / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 309–316 Table 3 Potential risk factors by adjuvant therapy. Variable
RTa
Age 62 60 60 23 Stage IB 17 IC 27 IIA 25 16 IIB LVSI (+) 7 ( ) 78 ER status (+) 52 ( ) 33 PR status (+) 58 ( ) 27 Grade G1 18 G2 36 31 G3 Depth of MI 1/2 39 1/2 46 a b c d e f
NRTb
p-Value
CTc
NCTd
p-Value
ETe
NETf
p-Value
115 39
0.761
20 8
157 54
0.735
45 13
132 49
0.481
122 5 17 10
<0.0001
13 2 4 9
126 30 38 17
0.201
35 6 10 7
104 26 32 19
0.874
7 147
0.261
4 24
10 201
0.043
2 56
12 169
0.527
98 56
0.706
13 15
137 74
0.057
47 11
103 78
0.001
115 39
0.286
17 11
156 55
0.142
51 7
122 59
0.002
62 80 12
<0.0001
2 6 20
78 110 23
<0.0001
22 29 7
58 87 36
0.371
144 10
<0.0001
20 8
163 48
0.494
48 10
135 46
0.201
Radiotherapy. No radiotherapy. Chemotherapy. No chemotherapy. Endocrine therapy. No endocrine therapy.
presence of tumor cells within or attached to the wall of a blood vessel or lymphatic space. The steroid receptor status was assessed immunohistochemically and evaluated according to the Allred scoring system [29]. Primary surgery consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with routine systematic pelvic lymphadenectomy, including a thorough and complete dissection
311
of the lymphatics of the common iliac, internal iliac, external iliac, and obturator nodal groups. Piver type I, type II, or type III hysterectomy was performed depending on the patient’s status and doctor’s preference. A peritoneal cytology specimen was obtained during the surgical procedure for cytological review. Postoperatively, some patients received external beam radiotherapy (EBRT), and the prescription was usually based on the presence of adverse risk factors such as deep MI, cervical involvement or poor tumor differentiation. EBRT was delivered by a 6 MV linear accelerator using anterior–posterior opposed two-field technique, the superior margin being the upper border of L4 and the lower margin being inferior to the obturator foramen. No vaginal brachytherapy was applied during the radiation treatment. Oral medroxyprogesterone acetate (MPA) 250–500 mg daily or megestrol 160 mg daily were prescribed for at least 6 months in some of the patients with positive steroid receptor status. Additionally, a proportion of patients with poorly differentiated tumor or LVSI received adjuvant chemotherapy with an adriamycin and cisplatin (AP) regimen or paclitaxcel and carboplatin (TC) regimen postoperatively, since several articles had suggested that tumor grade and LVSI might be prognostic factors for distant recurrence [21,30,31]. The patterns of first recurrences were classified as locoregional or distant according to the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) study protocol [12]. Locoregional recurrence was defined as any recurrence that was localized in the vagina and/or pelvic region, including pelvic lymph nodes. All other recurrences were defined as distant, including para-aortic lymph-nodes, abdominal cavity, liver, lung, bone metastases, and diffuse metastatic disease. Statistical evaluation was performed using SPSS 16.0 (SPSS, Inc., Chicago, IL). OS, DFS, locoregional recurrence (LRR) and distant recurrence (DR) referred to the date of initial diagnosis and were calculated actuarially according to Kaplan–Meier statistics. Survival curves were determined by the Kaplan–Meier product-limit method. Analysis of the differences between survival curves was performed using the log-rank test. The Cox proportional hazards model was used to determine which variables were independent
Table 4 Initial sites of recurrences and clinico-pathological factors. No.
Site of recurrence
TTRa
Age
Depth of MI
Grade
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Hilar LNb Liver Pelvic LN Liver, abdomen Liver, omentum Bile duct Vaginal apex Bile duct Vaginal apex Lung, bone Vaginal apex Lung Pelvic side wall Liver Pelvic LN Paraaortic, mediastinnm and supraclavicular LN Lung Mediastinnm and supraclavicular LN Paraaortic and axillary LN Lung Pelvic side wall and LN Vaginal apex Vaginal apex
108 96 48 20 30 37 13 60 22 12 27 31 11 8 24 9
49 54 61 64 62 50 53 52 64 67 65 51 69 68 71 27
1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2 1/2
G1 G2 G1 G3 G1 G3 G2 G3 G2 G3 G2 G1 G3 G3 G2 G2
22 9 16 33 36 33 8
51 53 58 62 63 50 81
1/2 1/2 1/2 1/2 1/2 1/2 1/2
G2 G2 G2 G1 G1 G1 G2
17 18 19 20 21 22 23 a b
Time to recurrence. Lymph node.
PR status
LVSI
+ + + + + +
+
+ +
+
+ + + + +
Stage
Cervical involvement
EBRT
Vital status
Ib Ib Ib Ic IIb IIb Ib IIa Ib Ic Ib IIa Ib IIb Ib Ic
No No No No Yes Yes No Yes No No No Yes No Yes No No
No No Yes Yes Yes Yes No Yes No Yes No Yes No Yes No Yes
Die Alive Die Die Die Die Die Die Alive Alive Die Die Alive Die Die Die
Ic Ic IIa IIa Ib IIa IIb
No No Yes Yes No Yes Yes
Yes No Yes Yes No No No
Alive Alive Die Alive Die Alive Die
312
G-y. Zhang / European Journal of Obstetrics & Gynecology and Reproductive Biology 169 (2013) 309–316 Age 1.0 60 years or younger over 60 years 60 years or younger-censored over 60 years-censored
Cum Survival
0.8
0.6
0.4
0.2
P=0.0002
0.0 0
50
100
150
200
Locoregional Recurrence Free Survival Time (months) Fig. 1. Locoregional recurrence free survival by age.
prognostic factors. All tests were two-sided and differences between groups were considered statistically significant at p 0.05. 3. Results The median age of the 239 eligible patients was 54 years (range, 26–82 years). Table 2 shows the characteristics of the patients included in this study. All patients received systematic pelvic lymphadenectomy, and a total of 5821 lymph nodes were removed, with a median number of 23 (range, 8–64) nodes. Postoperative EBRT was administered to a total of 85 (35.6%) patients with an average dose of 44.3 Gy (range, 40–45 Gy) given in fractions of 1.8–2.0 Gy. The distribution of patients receiving EBRT was biased toward those with increased depth of MI, worse histological differentiation, and/or presence of cervical invasion (Table 3). In addition, a total of 58 (24.3%) patients received
adjuvant endocrine therapy, and 28 (11.7%) patients received adjuvant chemotherapy. The distribution of patients receiving chemotherapy was biased toward those with worse histological differentiation, and/or presence of LVSI (Table 3). After a mean follow-up period of 67 (range, 12–183) months, a total of 23 (9.0%) patients developed recurrence. The accumulated 5-year DFS was 91.0%. The median time to recurrence was 24 (range, 8–108) months, and most recurrences (78.3%) occurred within the first 36 months after primary surgery. Of the 23 recurrences, 9 were classified as locoregional and 14 as distant. The detailed sites of recurrence are described in Table 4. A total of 15 patients succumbed to disease progression at the time of last follow-up, while two other patients died from causes unrelated to endometrial cancer or treatment. The accumulated 5-year OS was 93.0%. On univariate analysis, patients with younger age exhibited a higher 5-year DFS and OS than older patients. Five-year DFS and OS
LVSI
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Locoregional Recurrence Free Survival Time (months) Fig. 2. Locoregional recurrence free survival by LVSI.
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PR
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Distant Recurrence Free Survival Time (months) Fig. 3. Distant recurrence free survival by PR.
were 94.0% and 96.3% in the patients 60 years old or younger, compared with 81.7% and 85.8% in the patients aged > 60 years (p < 0.05). Moreover, we found that compared with patients with deep MI, those with superficial MI demonstrated a significant survival advantage both on 5-year DFS (95.0% vs. 77.0%, p = 0.0001) and 5-year OS (96.3% vs. 84.4%, p = 0.001). Univariate analysis also indicated that the presence of LVSI was associated with a compromised 5-year DFS (71.4% vs. 92.1%, p = 0.01) and OS (78.6% vs.94.5%, p = 0.032). The treatment outcomes were similar between patients with distinct ER status, whereas the 5-year DFS and OS were compromised by the presence of negative PR status. Five-year DFS and OS were 84.8% and 86.6% in PR negative patients, compared with 93.2% and 96.2% in PR positive patients, p < 0.05. The results of univariate analysis for prognostic factors are shown in Table 2. Meanwhile, univariate analysis of the relationship
between patients’ outcomes and treatment variables demonstrated that various types of hysterectomy, postoperative adjuvant EBRT, chemotherapy, or endocrine therapy had no impact on DFS or OS (Table 2). The correlations between treatment failure patterns and the prognostic variables mentioned above were further investigated (Figs. 1–4). Age and LVSI were strongly correlated with LRR on univariate analysis. LRR were observed in 2 out of the 177 (1.1%) patients aged 60 years, compared with 7 out of the 62 (11.3%) patients aged > 60 years (p = 0.0002). Six out of 225 (2.7%) LVSI ( ) patients developed LRR, while 3 out of 14 (21.4%) LVSI (+) patients experienced LRR (p = 0.0003). Moreover, our investigation revealed that patients with negative PR status or deep MI were more likely to have distant recurrence. Ten of the 56 (17.9%) patients with deep MI experienced distant recurrence, compared with 4 (2.2%) of the
Depth of MI 1.0 superficial MI deep MI superficial MI-censored deep MI-censored
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183 patients with superficial MI (p < 0.0001). Similarly, patients with negative PR status developed more distant recurrence than those with positive PR status (13.6% vs. 2.9%, p = 0.003). Our investigation, however, failed to demonstrate the efficacy of chemotherapy on distant recurrence. Approximately 7% of patients who received chemotherapy developed distant recurrence, while 5.3% patients who did not receive chemotherapy experienced distant recurrence (p = 0.693). All the above variables which were predictive of treatment outcomes were entered in a Cox regression model to determine the independent significance. Since several previous articles have shown that the extent of surgery or postoperative adjuvant therapy might affect treatment outcomes, these factors were also taken into account. Because of the small number of patients to whom chemotherapy was administered, the impact of chemotherapy was not accounted for. In the Cox model, older age still predicted a higher risk of developing LRR (HR = 10.550 (95%CI: 2.101–52.969), p = 0.004), disease free survival events (HR = 3.605 (95%CI: 1.516–8.577), p = 0.004), and mortality (HR = 4.719 (95%CI: 1.661–13.404), p = 0.004). We also found that deep MI conferred a 3.7-fold increase in the risk of recurrence (HR = 3.692 (95%CI: 1.614–8.448), p = 0.002), especially the risk of distant metastasis (1HR = 4.286 (95%CI: 1.103–16.665), p = 0.036). The estimated risk of recurrence among patients with positive PR status was 58% (HR = 0.421 (95%CI: 0.179–0.992), p = 0.048) less than patients with negative PR status, and the event-free benefit was also contributed by the 67% (HR = 0.331 (95%CI: 0.115–0.955), p = 0.041) decrease in distant metastasis. Multivariate analysis also indicated that LVSI was an independent prognostic factor for locoregional recurrence (HR = 7.649 (95%CI: 1.504–38.886), p = 0.014). 4. Comments To the best of our knowledge, this represents the first retrospective study investigating specifically the prognostic variables for stages IB–IIB (occult) endometrioid-type disease in patients who received comprehensive surgical staging. Moreover, because our institution is a tertiary-care cancer center, all the patients in our series were treated by qualified gynecologic oncologists, as recommended by the American College of Obstetricians and Gynecologists (ACOG) and justified by several previous studies [32–34]. During the time period over which our study was conducted, nearly 80% of apparently early stage patients admitted in our hospital received comprehensive surgical staging with a median number of 24 removed lymph nodes, which was above average. The median number of nodes removed in most previous studies ranged from 9 to 14, and only two studies harvested a median number of over 20 nodes [32,35–39]. The adequacy of the staging procedure in our series provided a precise staging and minimized the bias caused by stage migration, which was confirmed by a previous study conducted by Lutman et al. In that article, the author revealed that patients with over 12 nodes removed were more rigorously staged to exclude occult lymph node metastases [35]. The prognostic value of age for patients with endometrial cancer has been previously discussed in several articles, most of which agreed that increasing age represent an adverse prognostic parameter. Jolly et al., however, noted that the impact of age on patients with stage I–II disease is minor [18,19,40]. The interpretation of these results was compromised either by the inclusion of papillary serous or clear cell type tumor with more unfavorable prognosis, or by potential stage migration due to the incomplete surgical staging procedure. We restricted our study cohort exclusively to patients with stage IB-occult stage IIB endometrioid-type diseases, and found that older age is still an
independent adverse prognostic factor. Older age predicted a 10-fold higher risk of developing loco-regional recurrences, a threefold higher risk in disease-free survival events, and a nearly 5fold higher mortality after accounting for other potential confounding factors including LVSI, depth of MI, cervical involvement, and treatment variables. It was presumed that the adverse effect of increasing age may be related to differences between younger and older patients in tumor biology, immunologic response, tumor neovascularization, and the patient’s capability to produce and stimulate proteolytic enzymes [20]. Relatively few studies have been conducted of the association between steroid receptor status and treatment outcomes in early stage endometrial cancer previously. As far as we know, only one preceding study conducted by Kadar et al. had evaluated such relationship in surgically staged patients and showed that PR status affected survival independently. When the analysis was restricted to women with stage I–II disease, however, the effect lost its statistical significance [41]. In contrast, we found that the PR status affected both 5-year DFS and OS independently, and PR negative patients were associated with an increased risk of distant metastasis. This discrepancy might be related to the unequal sample sizes. In Kadar’s article, a total of 107 stage IA–IIB patients were examined, while our series was composed of 239 stage IBoccult IIB patients. With a larger sample size, we might detect some minor survival advantage that may be unobservable in Kadar’s article. Furthermore, we find that the prognostic value of ER was less significant than that of PR, which was consistent with several previous studies. In Fukuda’s analysis of 92 patients with endometrioid adenocarcinoma, PR status was found to be the most significant predictor of survival, whereas ER status demonstrated less prognostic significance [23]. In another study, Palmer et al. noted that if only one receptor could be obtained, PR status might provide the most helpful information for the majority of patients [42]. The underlying mechanism of the stronger prognostic power of PR over ER has not been clearly illustrated yet, and further molecular biological study is warranted. We also identified deep MI as an independent prognostic factor for impaired 5-year OS and DFS in intermediate risk patients, and the adverse effects were mainly contributed by distant failure. This result is consistent with a previous report by Gadducci et al. which indicated that deep MI was a strong predictor for distant haematogenous metastasis in patients with stage I–II endometrioid-type endometrial cancer [21]. Similarly, in a report of 229 stage I endometrial cancer patients, Marini et al. identified deep MI as the only independent predictor of disease related survival, DFS, and distant failure [22]. Graesslin et al. revealed that the aggressive behavior of cancer with deep MI was related to a lower expression of tissue inhibitors of metalloproteinase-2, a member of zincdependent endopeptidases [43]. The previous published prevalence of LVSI in apparently early stage endometrial cancer ranged from 2% to 37% [44–48], whereas 5% patients were LVSI positive in our series. It is noteworthy that few previous studies were restricted to surgically staged patients, and occult stage III disease with positive nodes might inevitably be included in those studies. Panggid et al. found that 87% patients with lymph node involvement had LVSI, while only 32% patients without lymph node involvement were LVSI positive [49]. From this perspective, our result might reflect the comparatively low frequency of LVSI associated with pathologically confirmed nodenegative patients. Despite the relatively low frequency, we still observed that LVSI exerted an independent adverse impact on locoregional recurrence, although the majority of previous studies demonstrated that LVSI was mainly associated with lymph node metastasis or distant recurrence. Little is known about the mechanism by which tumor with LVSI is prone to invade the normal tissues bordering on tumors. Only one previous study on
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endometrial cancer reached a similar result, which indicated that the presence of LVSI was a significant predictor for locoregional relapse when analyzed separately [50]. We are aware that there are several limitations to the present study. Firstly, given the retrospective nature of this study, the distribution of postoperative adjuvant treatment was unbalanced and patients with more adverse factors were treated more aggressively, thus the prognostic effect of some adverse factors might be masked. Secondly, the incidences of recurrence and death are small and affected the statistical power of the study. Thirdly, the number of patients who were prescribed adjuvant chemotherapy in the current investigation was too small to arrive at a definite conclusion. Although several previous articles had suggested that the risk of recurrence (especially distant recurrence) could be reduced by chemotherapy [51–53], our data failed to confirm the efficacy of chemotherapy in this respect. Further study exploring the role of systematic adjuvant chemotherapy in intermediate-risk patients is necessary. Finally, few patients received paraaortic lymph node resection in our series. The previously reported prevalence of paraaortic lymph node metastasis ranged from 4.0% to 20.0%, and the National Comprehensive Cancer Network Clinical Practice Guidelines have recommended that paraaortic lymph node resection should be an indispensable component of surgical staging for endometrial cancer [54–59]. It is noteworthy, however, that the diagnostic and therapeutic value of paraaortic lymph node resection was more definite in patients with stage IIIC disease than those with I–II disease, since nearly 28.6–66.7% of patients with positive pelvic lymph nodes had concomitant positive paraaortic lymph nodes [54–58]. In contrast, according to a recently reported result by Abu-Rustum et al., isolated paraaortic nodal metastasis occurs in approximately 1% of endometrial cancer cases [60]. Therefore, the negative impact of the lack of paraaortic lymph node resection could be neglected. In summary, age, PR status, depth of MI and LVSI are independent prognostic variables for intermediate-risk endometrial cancer. Age > 60 years and positive LVSI were associated with increased locoregional recurrence, while PR status and the depth of MI had significant impacts on distant failure. These variables should be incorporated in treatment decisions to achieve better tumor control. References [1] Greenlee RT, Murray T, Bolden S, et al. Cancer statistics 2000. CA A Cancer Journal for Clinicians 2000;50:7–35. [2] Yang Dan, Han L-M. Year 1969–2003 study on evolution of endometrial cancer. Fudan University Journal of Medical Sciences 2005;32:479–83. [3] Xiang YB, Zhang W, Gao LF, et al. Methods for time trend analysis of cancer incidence rates. Zhonghua Liu Xing Bing Xue Za Zhi 2004;25:173–7. [4] Salani R, Nagel CI, Drennen E, et al. Recurrence patterns and surveillance for patients with early stage endometrial cancer. Gynecologic Oncology 2011;123: 205–7. [5] Song T, Lee JW, Kim HJ, et al. Prognostic significance of DNA ploidy in stage I endometrial cancer. Gynecologic Oncology 2011;122:79–82. [6] Abu-Rustum NR, Zhou Q, Iasonos A, et al. The revised 2009 FIGO staging system for endometrial cancer: should the 1988 FIGO stages IA and IB be altered. International Journal of Gynecological Cancer 2011;21:511–6. [7] Cardenes H, Randall ME. Is observation and salvage (when necessary) an appropriate approach to intermediate risk endometrial cancer. Gynecologic Oncology 2003;89:199–200. [8] Pellizzon AC, Fogarolli RC, Miziara M, et al. Morbidity of adjuvant high-doserate brachytherapy for low to intermediate risk endometrial adenocarcinoma completely resected. International Journal of Cancer 2001;96(Suppl.):105–8. [9] Ampil FL, Caldito G, Unger J, et al. Can intermediate-risk node-negative patients with stage I corpus cancer do without posthysterectomy radiotherapy? Review of a 13-year experience. European Journal of Gynaecological Oncology 2001;22:269–72. [10] Fanning J. Long-term survival of intermediate risk endometrial cancer (stage IG3, IC, II) treated with full lymphadenectomy and brachytherapy without teletherapy. Gynecologic Oncology 2001;82:371–4. [11] Corn BW. Intermediate-risk endometrial cancer. A management approach. American Journal of Clinical Oncology 1996;19:631–5.
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