Abstract
The aim of this study was to assess the pattern of failure and the outcome of endometrial cancer patients and to analyze the variables predictive of the risk of local, distant and retroperitoneal lymph node disease recurrence. Patients and Methods: The authors assessed 511 patients who underwent primary surgery. The median follow-up of survivors was 74 months. Peritoneal, hematogenous and lymph node recurrences outside retroperitoneal area were considered as distant failures. Results: Tumor relapsed in 83 (16.2%) patients. Median time to recurrence was 18.5 months (range, 3-129 months). The relapse was local in 13 cases, distant in 37, retroperitoneal in 22, and involved both distant and other sites in 11. Logistic regression showed that cervical involvement was the only independent predictor of local recurrence. Tumor grade, lymph-vascular space involvement (LVSI) and myometrial invasion were independent predictors of distant failure. Lymph node status and tumor grade were independent predictors of retroperitoneal recurrence. Five- and 10-year overall survival rates were 87.1% and 79.5%, respectively. Patient age, lymph node status, cervical involvement, tumor grade, LVSI and myometrial invasion were independent prognostic variables for overall survival. Conclusion: Cervical involvement was an independent predictor of local recurrence, LVSI and myometrial invasion were independent predictors of distant failure, lymph node status was an independent predictor of retroperitoneal relapse, and tumor grade was an independent predictor of both distant and retroperitoneal recurrence. The identification of risk factors for different patterns of failure can be useful in better tailoring adjuvant treatment.
Endometrial cancer is the most common gynecological malignancy after breast cancer in developed countries. Tumor stage, patient age, histological type, tumor grade, myometrial invasion, lymph-vascular space involvement (LVSI) and lymph node status are significant prognostic variables (1-7). The standard surgery consists of laparotomy, peritoneal washing, extra-fascial total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection, although laparoscopic or robot-assisted laparoscopic hysterectomy can represent a feasible and safe surgical approach in expert hands (8). Patients with uterine serous papillary carcinoma should undergo a comprehensive peritoneal and retroperitoneal surgical staging because of the risk of sub-clinical extra-uterine disease at presentation (9). The role of adjuvant treatment has long been debated. External pelvic radiotherapy reduces locoregional recurrences without improving survival and appears to offer a benefit in terms of clinical outcome only in patients with both deep myometrial invasion and poorly differentiated grade (10). Recent studies suggest a possible role for adjuvant platinum-based chemotherapy in association with radiotherapy for high-risk disease (11).
Data from the literature have shown that the recurrence rates range from 11 to 23%, the anatomic sites of relapse are mostly equivalently distributed between loco-regional and distant, and most of failures develop within 3 years (2, 3, 5, 12-15). A few data are currently available on the relationship between the common clinicopathological variables and the risk of recurrence in specific sites (2-5, 12, 16-18).
The aim of this retrospective study was to assess the pattern of failure and the clinical outcome of endometrial cancer patients and to analyze the variables predictive of the risk of local, distant and retroperitoneal lymph node recurrence.
Local recurrence rate according to clinical-pathological variables (21 patients).
Patients and Methods
Between May 1987 and December 2009, 523 patients underwent peritoneal washing, extra-fascial total hysterectomy and bilateral salpingo-oophorectomy, with (n=286) or without (n=237) pelvic and/or para-aortic lymphadenectomy for endometrial cancer at the Department of Gynecology and Obstetrics of the University of Pisa. Four hundred and seventy-five patients were operated on by laparotomy, 29 by laparoscopy, and 20 by robotics. An accurate exploration of the whole abdominal and pelvic cavity was performed in all cases and any suspicious lesion was biopsied. Patients who underwent vaginal hysterectomy, patients with synchronous endometrial cancer and ovarian cancer, and patients with clinical or surgicalpathological stage IV disease were excluded from the present analysis.
Patients were staged retrospectively according to the International Federation of Gynecology and Obstetrics (FIGO) classification 2009 (19). The histological classification was performed according to the World Health Organization classification (20). The architectural grade was defined: grade 1 (G1), ≤5% of non-squamous or non-morular solid growth pattern; grade 2 (G2), 6-50% of non-squamous or non-morular solid growth pattern, and grade 3 (G3), >50% of non-squamous or non-morular solid growth pattern. Notable nuclear atypia, inappropriate for the architectural grade, raised G1 or G2 tumors by one grade. LVSI was defined as the presence of tumor cells within or attached to the wall of a blood vessel or lymphatic space using morphological and immunohistochemical analysis. Postoperative management was established on the basis of histological findings on surgical specimens, patient age and general condition. Adjuvant therapy has changed since the study began, as far as both indications and types of treatment are concerned. Patients with invasion equal to or more than half of the myometrium, or grade 3 disease, or cervical involvement, usually received external pelvic beam irradiation, with addition of brachytherapy in selected cases with isthmic or stromal cervical involvement. Patients with FIGO stage III disease usually received platinum-based chemotherapy and/or external pelvic beam irradiation with or without para-aortic irradiation and with or without brachytherapy. Beginning in 1994, patients with non-endometrioid carcinoma received postoperative platinum-based chemotherapy, independently of FIGO stage or depth of myometrial invasion, with or without radiotherapy. Five-hundred and eleven patients were periodically followed-up October 2010 or until death. Periodical surveillance included physical examination, vaginal smear, and abdominal-pelvic ultrasound every 3-4 months for the first 2 years from surgery, every 6 months for the next 3 years, and every year thereafter. Chest X-ray was performed every 6 months for the first 2 years, every year for the next 3 years, and at increasing intervals thereafter. Abdominal-pelvic computed tomography (CT) scan was carried out yearly for 5 years. Further investigations were performed when appropriate. The 12 patients lost to follow-up were excluded from recurrence and survival analyses. The median follow-up of survivors was 74 months (range, 10 to 276 months).
Distant recurrence rate according to clinical-pathological variables (48 patients).
Retroperitoneal lymph node recurrence rate according to clinical-pathological variables (29 patients).
Statistical analysis. Patient age, histological type, tumor grade, myometrial invasion, LVSI, cervical involvement, FIGO stage, lymph node status and adjuvant treatment were analyzed for association with recurrence risk and overall survival. Peritoneal, hematogenous, and lymph node recurrences outside the retroperitoneal area (i.e. inguinal, or axillary and supraclavicular) were considered as distant failures. The SAS statistical package (release 8.2, SAS Institute, Cary, NC, USA) was used for the computations. The rate of recurrences was compared to the variables using Pearson's χ2 test (or two-tailed Fisher's exact test when appropriate). Multiple logistic regression was carried out to investigate the relationship between the probability of developing recurrence and the explanatory variables. The time from surgery to death or last observation was defined as overall survival. The cumulative probability of overall survival was estimated by the product-limit method. The log-rank test was used to compare the homogeneity of survival functions across strata defined by categories of prognostic variables. A multiple regression analysis based on the Cox proportional hazard model was used to jointly test the relative importance of variables as predictors of overall survival. Values of p<0.05 were considered as being significant.
Results
The median age of the 523 patients was 61 years (range, 33-92 years).
Adjuvant therapy was: no further treatment in 274 patients, external beam irradiation in 147, external beam irradiation plus brachytherapy in 18, platinum-based chemotherapy in 31, platinum-based chemotherapy followed by external beam irradiation in 50 and platinum-based chemotherapy followed by external beam irradiation plus brachytherapy in 3 .Tumor relapsed in 83 (16.2%) of 511 patients for whom follow-up data were available. The median time to recurrence was 18.5 months (range, 3-129 months). The relapse was local in 13 cases (vagina in 8, central pelvis in 5), distant in 37, retroperitoneal lymph nodal in 22 (para-aortic in 17, pelvic in 4, para-aortic and pelvic in 1), and involved both distant and other sites in 11.
On univariate analysis, local recurrence was significantly related to cervical involvement (p=0.0165) and myometrial invasion (p=0.029) (Table I). Distant failure was significantly associated with patient age (p=0.0102), tumor grade (p<0.0001), cervical involvement (p=0.0025), myometrial involvement (p<0.0001) and LVSI (p<0.0001) (Table II). Retroperitoneal recurrence was significantly related to FIGO stage (p<0.0001), histological type (p=0.0185), tumor grade (p<0.0001), cervical involvement (p=0.015), myometrial involvement (p=0.0007), LVSI (p=0.0008) and lymph node status (p<0.0001) (Table III). The median time to relapse was 18 months (range, 4 to 125 months) for local failure, 19.5 months for distant failure (range, 3 to 129 months) and 15 months for retroperitoneal recurrence (range, 3 to 73 months).
Multiple logistic regression showed that cervical involvement (p=0.0248) was the only independent predictor of local recurrence (Table IV). Poorly differentiated grade (p=0.0005), positive LVSI (p=0.0051), unknown LVSI status (p=0.0141), and deep myometrial invasion (p=0.0341) were independent predictors of distant failure. Positive lymph node status (p=0.0003) and poorly differentiated grade (p=0.0032) were independent predictors of retroperitoneal recurrence. Table V shows the sites of recurrence according to post-operative treatment. Five–year and 10-year overall survival rates were 87.1% and 79.5%, respectively. By log-rank test, overall survival was significantly associated with patient age (p<0.0001), myometrial invasion (p<0.0001), tumor grade (p<0.0001), histological type (p=0.048), LVSI (p<0.0001), cervical invasion (p<0.0001), FIGO stage (p=0.0022), and lymph node status (p<0.0001) (Table VI). The Cox proportional hazard model showed that patient age, lymph node status, cervical involvement, LVSI, tumor grade and myometrial invasion were independent prognostic variables for overall survival (Table VII).
Variables predictive of local, distant and retroperitoneal recurrence by logistic regression.
Discussion
Endometrial cancer relapses in less than one fifth of the cases, and recurrent disease may be vaginal (approximately 15% of failures), pelvic (35%) or distant (50%) (6, 13-15). A systematic review of 16 non-comparative retrospective studies on the role of follow-up assessed 2922 patients who were clinically free of disease following potentially curative treatment (6). The overall recurrence rate was 13% and the risk of failure was associated with surgical stage, histological type, myometrial invasion, tumor grade and lymph node status. Overall, 68% to 100% of relapses occurred within the first 3 years, and 61% of these (range, 38% to 86%) involved distant sites. In the series of the Mayo Clinic, tumor recurred in 142 (23%) of 610 endometrial cancer patients (2, 3, 5). Information about the site of failure was available for 131 of these patients. The relapse was peritoneal in 37 cases, hematogeneous in 60, and lymphatic in 44. As far as the 60 hematogeneous recurrences are concerned, 42 (70%) involved the lung, 9 (15%) the liver, 5 (8%) other sites, and 4 (7%) involved multiple sites (2). Of the 44 lymphatic failures, 6 (14%) were pelvic, 16 (36%) were para-aortic, 12 (27%) were both pelvic and para-aortic, and 10 (23%) involved other node-bearing areas (3). The data of the present study about the rates, times, and sites of recurrences are in agreement with the literature. A few studies investigated the risk factors for specific sites of recurrence (2-5, 12, 16-18). Poor histological differentiation, LVSI and deep myometrial invasion have been reported to be predictors of local recurrence (1, 12, 18). For instance, Elliott et al. (12) found that 10-year isolated vaginal recurrence rate was 3% for stage I G1-2 endometrial carcinomas confined to the inner third of the myometrium versus 15% for stage I tumors with G3 differentiation and/or myometrial invasion greater than one third. In our series, local recurrence rate was significantly related to cervical involvement and myometrial invasion at univariate analysis, and only to cervical involvement at multivariate analysis. Poor histological differentiation (16, 17), non-endometrioid histology (4, 5), deep myometrial invasion (1, 2, 17), LVSI (3, 18), cervical involvement (3-5), lymph node involvement (3, 17), positive peritoneal cytology (1, 5, 16), and age older than 60 years (16) have been described as significant predictors of distant failures. In the series of the Mayo Clinic, non-endometrioid histology (relative risk (RR)=11.58, p<0.001), positive peritoneal cytology (RR=6.72, p=0.009), lymph node metastasis (RR=5.10, p=0.02), and cervical involvement (RR=3.10, p=0.04) were independent predictors of peritoneal recurrence (5). In the same series, hematogeneous failure occurred in 5% of patients with myometrial invasion less than one half versus 23% of those with deeper myometrial invasion, and myometrial infiltration was found to be the only independent predictor of this type of recurrence (RR=6.0, p=0.003) (2). A further study of the same Institution reviewed 229 patients with surgical stage I endometrial cancer who had histologically proven negative pelvic and para-aortic lymph nodes (4). Multivariate analysis identified myometrial invasion greater than two thirds as the only independent predictor of distant relapse.
Sites of recurrence according to postoperative treatment.
In the present investigation, peritoneal, hematogeneous, and lymph node recurrences outside the retroperitoneal area were considered as distant failures. Multiple logistic regression showed that tumor grade, LVSI and myometrial invasion were significant predictive factors for this type of recurrence.
In the series of the Mayo Clinic, LVSI (RR=4.27, p<0.01), lymph node metastasis (RR=3.43, p=0.02) and cervical involvement (RR=2.26, p=0.04) were independent predictors of lymphatic failure, which developed within 5 years in 31% of the patients with at least one of these variables versus fewer than 1% of those patients with none of these factors (3). In our series, lymph node status and tumor grade were significantly related to retroperitoneal lymph node recurrence at multiple logistic regression. The retrospective, non-randomized nature of the study together with the many modifications that have occurred over the years in the indications and modes of adjuvant therapy do not allow us to draw conclusions regarding the impact of radiotherapy and/or chemotherapy on the pattern of recurrence. At any rate, postoperative therapy was given to patients with moderate, high-risk disease and not to those with low-risk disease. The similar local recurrence rate in patients who received and in those who did not receive radiotherapy confirms the ability of this adjuvant treatment to improve the local control of disease.
In conclusion, given the variety of postsurgical treatment modalities, clinical and pathological variables predictive of recurrence are difficult to identify. However, the present analysis appears to show that cervical involement is an independent predictor of local recurrence, LVSI and myometrial invasion are independent predictors of distant failure, lymph node status is an independent predictor of retroperitoneal lymph node relapse, and tumor grade is an independent predictor of both distant and retroperitoneal recurrence. The identification of risk factors for different patterns of failure can be useful in better tailoring adjuvant treatment. The coexistence of risk factors for different types of failure could suggest the need for concurrent and/or sequential use of chemotherapy and external beam irradiation with or without brachytherapy.
Variables prognostic of overall survival by univariate analysis.
Variables predictive of overall survival by Cox proportional hazard model.
- Received June 13, 2011.
- Revision received July 18, 2011.
- Accepted July 22, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
