There has been a longstanding controversy about the role of pelvic lymphadenectomy in the management of endometrial cancer. This practice evolved after the Gynecologic Oncology Group’s (GOG) surgical-pathologic staging study revealed a significant association between specific uterine factors (grade 3 tumor, deep myometrial invasion) and pelvic-node involvement,1 but it became widely adopted before its effectiveness as a therapeutic modality was substantiated in prospective clinical trials. Advocates of lymphadenectomy have indicated three main benefits for this procedure:1) to remove occult metastatic nodal disease that may result in a survival benefit,2 2) to reduce the need for adjuvant external beam pelvic radiotherapy for intermediate-risk to high-risk early-stage disease,3–8 and 3) to identify those with advanced-stage disease who would benefit from adjuvant chemotherapy.9 However, recent studies have forced us to rethink these paradigms because they have been unable to demonstrate a survival benefit from the use of either lymphadenectomy10,11 or adjuvant pelvic radiation,12–14 and chemotherapy may benefit some patients even in the absence of metastatic nodal disease.15 Although lymphadenectomy may reduce overall health care costs for those with intermediate-risk disease by obviating the need for adjuvant radiotherapy,16–19 the preliminary results of PORTEC 2, a randomized study comparing adjuvant pelvic radiotherapy with vault brachytherapy in intermediate-risk endometrial cancer, suggest that adjuvant pelvic radiotherapy may be omitted safely in these women even when pelvic-node status is unknown.20
Future research efforts are needed to improve survival outcomes in endometrial cancer, with particular emphasis on the role of systemic therapy in patients at high risk of relapse. It is of interest that, even in the absence of metastatic nodal disease, a subgroup of women in GOG 99 with a combination of high-risk uterine factors (high grade, deep myometrial invasion, and lymphovascular-space invasion) had relapse rates as high as 27% that often resulted in death.14 The purpose of our study was to better understand the prognostic relevance of uterine risk factors in this disease in a well-defined population of surgically staged women within a single-payer, publicly funded health care system by evaluating their association with pelvic-node status and survival. We then discuss the implications of these factors with respect to systemic therapy and improving survival outcomes in this disease.
MATERIALS AND METHODS
Ethics approval was obtained from the Research Ethics Board of the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada. All electronic records of endometrial cancer (International Classification of Diseases, 9th Revision, ClinicalModification codes 179 or 182) were identified from the Ontario Cancer Registry from 1996–2000 and linked to various administrative databases for demographic information, treatment, and vital statistics to the end of 2006, the methodology for which has been described previously.18,21 Tumor histopathology, grade, and extent of disease were obtained from pathology files at the Ontario Cancer Registry. Extent of disease included depth of myometrial invasion (none, less than 50% or superficial, more than 50% or deep), cervical involvement (none, endocervical, stromal), lymphovascular-space invasion (none, focal, extensive as per reporting pathologist), and presence or absence of metastatic disease in pelvic or paraaortic nodes. The Ontario Ministry of Health and Long-Term Care Registered Persons Database provided information on socioeconomic status based on median income per neighborhood adjusted for region in Ontario and divided into quintiles. The Canadian Institute for Health Information database provided information on comorbidities at the time of hospital admission for surgery classified using Deyo’s clinical comorbidity index for administrative databases.22 Surgical cases including total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy with or without paraaortic lymphadenectomy were identified from the Ontario Health Insurance Plan database of physician billings for services rendered. Adjuvant pelvic radiotherapy was identified from Ontario Health Insurance Plan billings for radiation oncology consultation and at least three of five weekly assessments during treatment, all within 4 months of surgery. Adjuvant chemotherapy also was ascertained through Ontario Health Insurance Plan billings. Specific details about recurrence such as timing, site, and subsequent treatment were unavailable. We included only cases of endometrioid histology in which lymphadenectomy had taken place.
Statistical analysis was performed with SAS 9.1 (SAS Institute, Inc., Cary, NC). Our primary outcome was 5-year overall survival, calculated from the date of surgery to death from any cause. Cox proportional hazards models were fitted with potential variables associated with overall survival, including age, comorbidities, socioeconomic status, tumor grade, myometrial invasion, cervical involvement, lymphovascular-space invasion, nodal status, and adjuvant pelvic radiotherapy. Effects were expressed as hazard ratios with 95% confidence intervals (CIs). A hazard ratio greater than 1.0 represents a higher risk of death compared with the reference category of each variable, whereas a hazard ratio less than 1.0 represents a lower risk of death. We generated Kaplan-Meier curves for 5-year overall survival based on nodal status and then compared patients according to nodal status stratified by number of uterine risk factors with the log-rank test.
There were 4,471 women who had a diagnosis of endometrial cancer in Ontario from 1996–2000. The province had a population of approximately 11 million during this time period.23 There was no information on treatment and pathology for 550 women, and vital statistics were unavailable for an additional 46 women who had surgery in Ontario but resided in another province or state. We had complete information on surgery, pathology, and survival for 3,875 women. Of this total, 475 had undergone lymphadenectomy (12.3%); 159 of these women had nonendometrioid histologies (eg, uterine papillary serous carcinoma, clear cell carcinoma, sarcomas). After excluding these, there were 316 cases available for analysis.
The association between pelvic-node status and uterine risk factors (grade, myometrial invasion, cervical involvement, lymphovascular-space invasion) is presented in Table 1. Women with positive pelvic nodes were more likely to have grade 3 tumors, deep myometrial invasion, cervical stromal involvement, and extensive lymphovascular-space invasion than were those with negative nodes (P<.001). There was no difference in age (P=.81) or socioeconomic status (P=.39).
There were 75 women who received adjuvant pelvic radiotherapy (23.7%)—24 node-positive (63.2%) and 51 node-negative women (18.3%). All node-negative women who received adjuvant pelvic radiotherapy had one or more of the following uterine factors: grade 3 tumor, deep myometrial invasion, and cervical stromal involvement. None of the women in this cohort received adjuvant chemotherapy.
We evaluated the association between risk factors and overall survival by univariable analysis. Age older than 60, with comorbidities, grade 3 tumor, deep myometrial invasion, cervical stromal involvement, any lymphovascular-space invasion, pelvic-node involvement, and adjuvant pelvic radiotherapy all were associated with a higher risk of death (ie, hazard ratio greater than 1.0) than the reference category for each variable (age younger than 60, no comorbidities, grade 1 tumor, no myometrial invasion, no cervical involvement, no lymphovascular-space invasion, no pelvic-node involvement, and no adjuvant pelvic radiotherapy, respectively). Women in the third and fourth income quintiles had a lower risk of death than those in the reference category (first income quintile, ie, lowest 20th percentile). However, when these significant factors from the univariable analysis were entered into a multivariable Cox regression model, the only factors associated with a higher risk of death were age older than 60, grade 3 tumor, deep myometrial invasion, and cervical stromal involvement. After adjustment for all factors, adjuvant pelvic radiotherapy was associated with a lower risk of death (hazard ratio 0.66, 95% CI 0.45–0.97). The presence of positive pelvic nodes was no longer significantly associated with a higher risk of death (hazard ratio 1.39, 95% CI 0.89–2.18). There were no significant differences in risk of death according to comorbidities, socioeconomic status, and lymphovascular-space invasion. Results of the multivariable Cox model are presented in Table 2.
The uterine factors associated with a higher risk of death in the multivariable Cox model (grade 3 tumor, deep myometrial invasion, and cervical stromal involvement) are presented according to nodal status in Table 3. Node-positive patients with two or more risk factors were younger than node-negative patients with the same number of risk factors (60.2 and 67.3 years, respectively). There were eight node-positive patients (21%) with none of the uterine risk factors and 10 node-positive patients (26%) with only one risk factor. On the other hand, 33 node-negative patients (12%) had two or more high-risk uterine factors. If those with two or more high-risk uterine factors are classified as having high-risk disease (and those with one risk factor or none as having intermediate-risk or low-risk disease, respectively), 12% of node-negative patients had high-risk disease and 47% of node-positive patients had intermediate or low-risk disease. At the end of 5 years, there were 82 deaths. Figure 1 illustrates Kaplan-Meier curves for 5-year overall survival based on nodal status (negative or positive). The 5-year overall survival rates for node-negative and node-positive patients were 81.7% and 58.8%, respectively (log-rank P<.001). Figure 2 illustrates Kaplan-Meier curves for 5-year overall survival based on nodal status stratified by number of high-risk uterine factors (0 or one compared with two or three). There was no significant difference in survival between node-negative and node-positive women with comparable uterine risk factors. With 0 or one risk factor, 5-year overall survival rates were 85.0% and 75.0% for node-negative and node-positive women, respectively (ie, top two curves). With two or three risk factors, 5-year overall survival rates were 53.1% and 44.4% for node-negative and node-positive women, respectively (ie, bottom two curves). Node-negative women with two or three risk factors had a lower 5-year overall survival rate (53.1%) than did node-positive women with 0 or only one risk factor (75.0%), although this difference did not reach statistical significance (log-rank P=.19).
Although the majority of women with endometrial cancer in the general population have a good prognosis, there is a subgroup at risk for death despite presumably early-stage or limited disease. These women must be identified if survival outcomes are to be improved. In this population-based study, uterine factors such as grade 3 tumor, deep myometrial invasion, and cervical stromal involvement were more important determinants of survival than was pelvic-node status. There are a number of important considerations in understanding this observation.
Although pelvic-node status has been considered an important determinant of survival in endometrial cancer, the presence of lymph node metastases is highly associated with uterine risk factors, as demonstrated in the original GOG surgical-pathologic staging study.1 These same associations were observed in our study, specifically, those between lymph node status and grade, depth of myometrial invasion, and cervical involvement, as seen in Table 1. More than half (53%) of the patients in this study with positive nodes also had two or more uterine risk factors. Although the association between lymph node involvement and poor prognosis has been discussed thoroughly in the literature,24,25 an additional, contrasting finding of interest was the more favorable outcome of those node-positive patients with none or only 1 risk factor. These patients had a 5-year overall survival rate of 75%, which approximates not only that of node-negative patients in our study with the same number of risk factors, but also the 5-year survival rate of 81–85% among intermediate-risk stage I patients in PORTEC.13 Although log-rank testing did not reveal a significant difference in survival between the node-positive and node-negative patients with 0 or 1 risk factor, this observation requires validation because the overall incidence of positive lymph nodes is relatively low. Larger studies will be required to confirm this result.
This population-based study also confirms previous observations relating to the substantial risk of death in node-negative women with high-risk uterine disease. Women with stage IC grade 3 disease registered to PORTEC but excluded from the study (because they were not considered intermediate-risk and all had received adjuvant pelvic radiotherapy) had a 5-year overall survival rate of only 58%,26 which is similar to the 5-year overall survival rate of 53.1% in our cohort of node-negative women with two or three risk factors. In our study, women with two or three risk factors did poorly regardless of nodal status. In the high intermediate risk subgroup of GOG 99 (defined as age older than 70 with one of three uterine risk factors, including moderate to poorly differentiated tumor, lymphovascular-space invasion, outer-third myometrial invasion, or age older than 50 with at least two of these risk factors, or any age with all three risk factors), the 4-year cumulative death rates were 12% and 26% with and without adjuvant pelvic radiotherapy, respectively.14 Thus, identifying patients with two or more uterine risk factors even in the absence of metastatic nodal disease is important for future efforts to improve outcomes in this disease.
Finally this study suggests that the identification of patients at risk of death may be improved by considering uterine factors rather than nodal status alone. If we were to rely on uterine factors alone without nodal information, we would have missed 18 patients (with low-risk or intermediate-risk disease in the node-positive group), whereas, if we relied on nodal status alone without consideration of uterine risk factors, we would have missed almost twice as many patients (33 with high-risk disease in the node-negative group). In the future, we predict that age and uterine risk factors will become increasingly important in identifying those at highest risk of death, and nodal status will be much less influential in identifying these patients.
The results of this study have important implications for adjuvant therapy in this disease. Women with two or more uterine risk factors, regardless of nodal status, should be considered for adjuvant therapy in clinical trial settings. Chemotherapy has been shown to improve survival in these patients even when they have negative nodes. Susumu et al reported a phase III Japanese GOG study in which pelvic radiotherapy was compared with cisplatin-based chemotherapy in surgically staged node-negative patients.15 For those with high-risk, early-stage disease (stage IC with deep myometrial invasion, age older than 70, or stage II or IIIA [positive cytology] with deep myometrial invasion), chemotherapy resulted in significantly higher 5-year progression-free and overall survival rates (83.6% and 89.7%, respectively) than did pelvic radiotherapy (66.2% and 73.6%, respectively). Hogberg et al reports the preliminary results of a randomized phase III study (NSGO-EC-9501/EORTC 55991) comparing adjuvant chemotherapy with pelvic radiotherapy with pelvic radiotherapy alone in high-risk, early-stage endometrial cancer.27 The majority had a grade 3 tumor with deep myometrial invasion. The combination of adjuvant chemotherapy with radiotherapy resulted in a superior 5-year progression-free survival rate (hazard ratio 0.58, 95% CI 0.34–0.99) compared with radiotherapy alone.27 Both of these studies suggest that chemotherapy improves survival in high-risk, early-stage endometrial cancer. To date, chemotherapy is the only treatment modality that has improved survival in either early-stage or advanced-stage endometrial cancer in a phase III trial.9,15,27
The major advantage of this study is that it represents an entire population within a single-payer, publicly funded health care system with detailed information on stage, grade, and other relevant prognostic factors for all women who had surgical staging for endometrial cancer. It is one of the largest known studies evaluating lymphadenectomy for endometrioid-type endometrial cancer. The 12% incidence of node positivity in our study is consistent with other large series of surgically staged patients.10,11,28 However, there were limitations of this study. We did not have details on recurrences and deaths, and, therefore, we were unable to determine when or where cancer recurred and whether patients died of endometrial cancer or unrelated causes. Secondly, because we used physician billings as surrogate indicators of adjuvant pelvic radiotherapy, we could not confirm that patients actually received radiotherapy as prescribed. According to this methodology, only 63.2% of those with positive pelvic nodes received adjuvant pelvic radiotherapy. We do not know whether the remaining 36.8% declined adjuvant radiotherapy, received hormone therapy, or died of endometrial cancer or other causes before or during adjuvant therapy. The lower risk of death associated with adjuvant pelvic radiotherapy suggests a survival benefit associated with this treatment, possibly for those with high-risk, early-stage disease (similar to the high-risk to intermediate-risk group in GOG 99) or those with occult nodal disease because it is unlikely to have improved survival in intermediate-risk, early-stage disease.12–14 There could have been unrecognized selection biases for adjuvant pelvic radiotherapy in this study. Finally, the low median number of pelvic nodes suggests that most patients actually had pelvic-node sampling instead of a complete lymphadenectomy. Several authors have reported that an adequate pelvic lymphadenectomy should consist of at least 11 to 12 nodes.29–31 Some of the patients classified as node-negative may have had unrecognized occult pelvic-node metastases, and they may have died of progressive disease in the absence of adjuvant therapy. However, total node count is dependent on the pathologist’s gross assessment, which may be highly variable.32–34 Furthermore, the benefits of lymphadenectomy may not have been as well-appreciated during the study period (1996 to 2000), such that there may have been a less meticulous effort by surgeon and pathologist to retrieve and count nodes. A higher number of retrieved nodes in more recent years has been reported in the colorectal cancer literature as the association between node count and survival has become increasingly apparent in this disease.35
Endometrial cancer remains the most common gynecologic malignancy in North America, and, over the past 20 years, there has been no significant change in survival outcomes.36 At present, the best available evidence suggests that chemotherapy may have the greatest potential to improve overall survival in endometrial cancer, especially for those with high-risk, early-stage and advanced-stage disease. PORTEC 3 is a phase III randomized trial comparing pelvic radiotherapy with chemoradiation in high-risk, early-stage and advanced-stage disease.37 GOG 604 is a phase III study designed to compare pelvic radiotherapy with chemotherapy combined with brachytherapy in high-risk, stage I disease.38 Both of these studies are timely and necessary to determine whether chemotherapy can improve survival outcomes in endometrial cancer. It remains undetermined as to what extent nodal information will contribute to selecting patients for appropriate adjuvant therapy. The results of our study suggest that a significant number of women are at risk of death despite negative nodes and that we can predict survival based on the presence or absence of high-risk uterine factors. With a paradigm shift toward systemic therapy and improving survival outcomes in endometrial cancer, the prevailing question is whether routine lymphadenectomy is sufficiently informative to influence decisions on systemic therapy or whether these decisions can be based on uterine risk factors alone.
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