In the United States, it is estimated that over 42,000 women are diagnosed each year with endometrial cancer and that 7,700 women die from the disease.1 Worldwide, nearly 200,000 cases of uterine cancer are diagnosed annually.2 Surgery remains the mainstay of treatment for most women with endometrial cancer.
In the 1970s and early 1980s, endometrial cancer was staged clinically.3 A number of surgical-pathology studies carried out by the Gynecologic Oncology Group revealed the association between uterine factors such as grade and depth of invasion and the risk of lymph node metastasis in women with apparent early-stage tumors.4–6 The importance of nodal disease as a prognostic factor was recognized in 1988 when the International Federation of Gynecologists and Obstetricians (FIGO) determined that tumors of the corpus uteri should be staged surgically. The 1988 FIGO system incorporated three substages for women with uterine confined cancer, whereas those with pelvic and paraaortic nodal disease were classified as stage IIIC.3
In 2009, FIGO proposed a revised staging classification system for endometrial cancer. The revised staging systems contained a number of changes. First, women with stage IA and IB tumors were combined into a single stage, stage IA. Second, cervical glandular involvement was eliminated from the staging criteria; only women with cervical stromal invasion were classified as stage II. Third, peritoneal cytology has been removed as a staging criterion. Finally, patients with nodal metastasis have been stratified into those with pelvic nodal disease (stage IIIC1) and those with paraaortic nodal involvement (stage IIIC2).3
Given the importance of tumor stage on both prognosis as well as adjuvant treatment selection, we sought to examine the performance of the 2009 FIGO staging system in a population-based data set. The objective of our study was to compare the performance of the 1988 and 2009 FIGO staging systems for women with uterine corpus cancer diagnosed and treated throughout the United States.
MATERIALS AND METHODS
Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results database was obtained. Surveillance, Epidemiology, and End Results is population-based registry that incorporates approximately 26% of the US population.7 Surveillance, Epidemiology, and End Results comprises several geographically distinct tumor registries. Data from Surveillance, Epidemiology, and End Results' 17 registries were analyzed.8 All data were publicly available, deidentified, and exempt from Institutional Review Board review.
Patients with endometrioid adenocarcinomas of the uterine corpus treated between 1988 and 2006 were included in the analysis. Clinical and pathologic data, including age at diagnosis (younger than 40, 40–65, older than 65 years), tumor grade (1, 2, or 3), and marital status, were collected. Year of diagnosis was classified as 1988–1994, 1995–2000, or 2001–2006. Patients were categorized based on the geographic area of residence at the time of diagnosis: central (Detroit, Iowa, Kentucky, Louisiana, Utah), eastern (Connecticut, New Jersey, Atlanta, rural Georgia), and western (Alaska, California, Hawaii, Los Angeles, New Mexico, San Francisco, San Jose, Seattle) United States. Use of adjuvant radiation therapy (external beam or intracavitary implants) was collected. Whether or not lymphadenectomy was performed at the initial operative procedure was documented as was the presence or absence of nodal metastases.
Staging information was derived from the recorded extent of disease codes. Based on extent of disease, each patient's stage was determined based on the 1988 FIGO staging criteria as well as the revised 2009 FIGO staging criteria.3 Major changes in the 2009 system include: 1) classification of patients with stage IA and IB tumors as stage IA; 2) elimination of stage IIA; and 3) stratification of stage IIIC into pelvic nodes only (IIIC1) or paraaortic nodal (IIIC2) involvement. The entire cohort was analyzed and a separate analysis performed in the subset of women who underwent lymphadenectomy.
The vital status of each patient was recorded. Survival was calculated as the number of months from cancer diagnosis to date of death. Five-year survival was calculated for each patient based on stage. For women with early-stage (stage I and II) tumors, a separate analysis was performed after stratification by tumor grade. For each group, survival was reported with 95% confidence intervals (CIs). Cox proportional hazards models were constructed to determine the prognostic significance of each staging system while controlling for other covariates. Separate Cox models were generated for both staging systems. Survival was examined further using Kaplan-Meier curves, which were compared using the log rank test. Patients alive at last follow-up were censored. All analyses were performed with SAS 9.2.
A total 81,902 women with endometrioid adenocarcinomas of the uterus treated between 1988 and 2006 were identified. The stage distribution for the FIGO 1988 and FIGO 2009 staging systems is highlighted in Table 1. According to the FIGO 1988 system, 18,960 (23.2%) patients were classified as stage IA, 29,393 (35.9%) as stage IB, and 8,404 (10.3%) as stage IC. In the FIGO 2009 staging system, 48,353 (59.0%) patients shifted to stage IA, whereas 8,404 (10.3%) patients were classified as stage IB. The new FIGO 2009 stage II had 1,618 (2%) patients, the same as stage IIB in the FIGO 1988 system. With the absence of stage IIIA positive cytology only, the number of patients in the FIGO 2009 stage IIIA decreased to 2,137 (2.6%) compared with 3,003 (3.7%) in FIGO 1988. The number of patients in stage IIIC was 3,120 (3.8%) patients in FIGO 1988. The FIGO 2009 system classified 1,842 (2.3%) women as stage IIIC1 and 1,010 (1.2%) as stage IIIC2. Adequate pathologic data to accurately assign a stage were not available for 11,928 (14.6%) women for the FIGO 1988 system and 14,722 (18.0%) for the FIGO 2009 criteria.
As illustrated in Table 1, 37,278 (45.5%) patients underwent lymph node sampling. According to the FIGO 1988 staging system, 6,075 (16.3%) patients were classified as stage IA, 13,049 (35.0%) as stage IB, and 4,920 (13.2%) as stage IC. In the FIGO 2009 staging system, 19,124 (51.3%) patients shifted to stage IA, whereas 4,920 (13.2%) patients had stage IB disease. The new FIGO 2009 stage II had 1,094 (2.9%), the same as stage IIB in the FIGO 1988 system. With the absence of stage IIIA positive cytology only, the number of patients in the FIGO 2009 stage IIIA decreased to 1,084 (2.9%) compared with 1,695 (4.5%) in FIGO 1988. The number of with stage IIIC tumors was 2,971 (8%) in FIGO 1988. FIGO 2009 classified 1,780 (4.8%) as stage IIIC1 and 948 (2.5%) as stage IIIC2.
Overall 5-year survival rates of each stage according to the FIGO 1988 and FIGO 2009 staging systems are shown in Table 2. Data are further stratified based on the presence of lymph node sampling. Based on the FIGO 1988 system, survival for stage IA was 90.7% (95% CI 90–91%), 88.9% (95% CI 88–89%) for stage IB, and 77.6% (95% CI 76–79%) for stage IC. In the FIGO 2009 system, there was a more clear delineation in survival among the substages for stage I patients; survival was 89.6% (95% CI 89–90%) for stage IA and 77.6% (95% CI 76–79%) for stage IB. In the FIGO 1988 system, survival for stage IIA (78.9%; 95% CI 76–81%) was superior to that of stage IC (77.6%; 95% CI 76–79%). In the FIGO 2009 system, survival for stage II (73.5%; 95% CI 71–76%) was inferior to all stage I patients, including those women with deep myometrial invasion (77.6%; 95% CI 76–79%). The newly defined stage IIIC substages were prognostically different. Survival for stage IIIC1 was 57.0% (95% CI 54–60%) compared with 49.4% (95% CI 46–53%) for stage IIIC2.
Similar trends were noted for women who underwent lymphadenectomy; survival for FIGO 1988 stage IA was 91.9% (95% CI 91–93%) compared with 89.6% (95% CI 89–90%) for stage IB. In the FIGO 2009 system, survival for stage IA was 90.3% (95% CI 90–91%) compared with 80.0% (95% CI 78–81%) for stage IB. Again, based on the FIGO 1988 schema, survival for stage IIA (84.7%; 95% CI 82–87%) was higher than that of stage IC (80.0%; 95% CI 79–81%). The newly defined stage IIIC substages were prognostically different; survival for stage IIIC1 was 58.3% (95% CI 55–61%) compared with 51.2 (95% CI 47–55%) for stage IIIC2.
Patients with early-stage tumors were then stratified by grade (Table 3). Matched by grade and stage, survival between stage IA and IB based on the FIGO 1988 system overlapped. For example, survival for FIGO stage IA grade 2 was 89.0% (95% CI 88–90%) compared with 87.9% (95% CI 87–89%) for stage IB grade 2. Survival was 78.9% (95% CI 76–81%) for FIGO 1988 stage IA grade 3 compared with 80.6% for stage IB grade 3. Less overlap was noted for stage I tumors based on the FIGO 2009 system. It was again noted that survival for FIGO 1988 stage IIA was often superior to stage IC in the FIGO 1988 schema. Similar trends for stage I and II tumors were noted when the analysis was limited to women who had undergone nodal sampling.
Cox proportional hazards models of cancer-specific survival were developed to examine the performance of each staging system while accounting for the influence of other prognostic variables (Table 4). Both the FIGO 1988 system and the FIGO 2009 staging schema were highly correlated with cancer-specific survival. The hazard ratio for death increased incrementally with stage for both systems. It was again noted that the FIGO 2009 stages IIIC1 and IIIC2 were prognostically distinct.
The Kaplan-Meier analysis for survival by stage for the FIGO 1988 and FIGO 2009 staging systems are illustrated in Figures 1 and 2. Again, stage was highly prognostic for both staging systems (P<.001 for both). Among women with early-stage disease, survival was similar for FIGO stage IA and IB. For women with advanced-stage tumors, there was a clear difference in survival between stage IIIC1 and IIIC2 tumors.
Use of adjuvant radiotherapy by stage is shown in Table 5. A total of 4.3% of women with FIGO 1988 stage IA, 15.0% with IB, and 52.8% with stage IC received radiotherapy. Based on the FIGO 2009 criteria, 10.7% of stage IA patients received radiation. Among women who underwent lymphadenectomy, 1.4% of patients with FIGO 1988 stage IA tumors and 8.3% with FIGO stage IB tumors were treated with radiation. Over 60% of women with stage IIIC tumors in the FIGO 1988 system and stage IIIC1 and IIIC2 tumors based on FIGO 2009 criteria received adjuvant radiotherapy.
Our findings suggest that the 2009 FIGO staging system for uterine corpus cancer is highly prognostic for women with endometrioid adenocarcinomas. Removal of women with cervical glandular involvement from stage II and stratification of patients with stage IIIC disease improved the correlation of stage with survival. Because survival is very similar for patients with tumors confined to the endometrium and women with superficial myometrial invasion, combining FIGO 1988 stages IA and IB provided a reduction in the number of stage I substages without reducing prognostic discrimination.
The prognosis for most women with uterine-confined endometrial cancer is excellent.9–11 We noted that for patients with tumors limited to the endometrium, 5-year survival was 91% compared with 89% for those with early myometrial invasion. Even among women with high-grade tumors, survival was very similar between FIGO 1988 stage IA grade 3 and stage IB grade 3 tumors (80% compared with 81%, respectively). Given the similar prognosis of these subgroups, it appears reasonable to combine FIGO 1988 stages IA and IB into a single substage (FIGO 2009 stage IA).
The prognostic significance of cervical glandular involvement (FIGO 1988 stage IIA) for endometrial cancer has been questioned.12–15 Although there is a clear difference in survival for women with cervical glandular and cervical stromal invasion, it appears that tumor grade and depth of myometrial invasion are more significant prognostic factors than cervical glandular involvement.12–15 In our series, we noted that the median 5-year survival for FIGO 1988 stage IIA disease was similar to that of FIGO 1988 stage IC tumors. When stratified by grade, survival for stage IIA grade 1 tumors approached that of stage IA disease. These findings strongly support the decision to eliminate cervical glandular involvement from the 2009 staging system. With inclusion of only women with cervical stromal invasion as stage II in the FIGO 2009 scheme, the survival for stage II disease is inferior to that of all stage I substages.
Metastasis to the regional lymph nodes is one of the most important prognostic factors for women with endometrial cancer.4,6,16,17 In the Gynecologic Oncology Group's surgical–pathology study of women with clinical stage I and II endometrial cancer, there was a clear differential in survival between women with pelvic and paraaortic nodal metastases.4 We noted similar trends: 5-year survival was 58% for women with only pelvic nodal metastases (stage IIIC1) compared with 51% for those with paraaortic nodal disease (stage IIIC2). In addition to important prognostic information, the stratification of stage IIIC tumors has important implications for treatment planning because multimodality therapy with both radiation and chemotherapy is now frequently used for women with nodal metastases.18,19
In addition to the changes described, the revised FIGO staging system has eliminated peritoneal cytology from the staging criteria. Whether positive peritoneal cytology is an independent risk factor for endometrial cancer is actively debated.20–23 Although our group and others have found that positive pelvic washings are an independent predictor of decreased survival, other investigators have suggested that cytologic disease just potentiates the effects of other poor prognostic factors.20–23 Although peritoneal washings are not a part of the new staging guidelines, it is recommended that peritoneal cytology be reported separately.
Although our study benefits from the inclusion of a large number of women, we acknowledge several limitations. Most importantly, Surveillance, Epidemiology, and End Results lacks some pathologic data. For example, for those women with cervical glandular involvement, it is not possible to assess depth of tumor invasion. As such, there was a small number of patients that could not be completely staged in both the FIGO 1988 and FIGO 2009 systems. We cannot exclude the possibility that exclusion of these patients may have biased our outcomes. Second, not all women underwent comprehensive surgical staging. To overcome this limitation we performed separate analyses that included only those women who had lymph node dissection. It should be noted that the number of nodes removed was highly variable and not standardized. Although this reflects treatment patterns of women with endometrial cancer, we cannot exclude the possibility that a small number of women with occult stage IIIC disease were not detected. Although data on radiation is available, Surveillance, Epidemiology, and End Results does not record the use of either chemotherapy or hormonal therapy. Although chemotherapy was not in widespread use for endometrial cancer during the majority of the years of our study, chemotherapy has now become an increasingly important modality in the management of uterine cancer.24 Finally, Surveillance, Epidemiology, and End Results lacks data on recurrences, and as such, we were only able to analyze survival.
Although our data suggest that the revised FIGO staging system is highly prognostic, a number of controversies remain. Perhaps most important is the lack of agreement regarding the extent of staging that is required for women with endometrial cancer.25 Currently there is no consensus on which patients require lymphadenectomy and what defines an adequate lymph node dissection in those women who undergo the procedure.25,26 Recently two large, randomized European trials have both reported that lymphadenectomy had no effect on survival for women with apparent early-stage endometrial cancer.27,28 Although significant methodologic issues have been raised regarding both trials, the fact remains that a large number of women with endometrial cancer do not undergo staging lymphadenectomy.26,29 In our cohort, 46% of patients underwent some form of nodal evaluation. Although survival clearly differed by stage when the nodal status was known, the general performance characteristics of the revised FIGO system were similar regardless of whether the nodal status was known.
In conclusion, our findings suggest that the revised FIGO 2009 staging system for uterine corpus cancer is highly prognostic in women with endometrioid tumors. The reduction in stage I substages, the elimination of cervical glandular involvement, and the stratification of women with nodal disease all improved the performance of the staging system.
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