Obstetrics & Gynecology:
Evaluation of Two Management Strategies for Preoperative Grade 1 Endometrial Cancer
Bernardini, Marcus Q. MD1,2; May, Taymaa MD2; Khalifa, Mahmoud A. MD, PhD3; Bland, Amy E. MD5; Nofech-Mozes, Sharon MD3; Berchuck, Andrew MD5; Covens, Al MD2,4; Havrilesky, Laura MD5
From the 1Division of Gynaecologic Oncology, University Health Network, Toronto, Ontario, Canada; 2Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; 3Department of Pathology and 4Division of Gynecologic Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada; and 5Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
See related articles on pages 2, 16, 22, and 100.
The authors thank Dr. Tony Panzarella, Statistician, for his assistance in some of the statistical analysis.
Corresponding author: Marcus Q. Bernardini, Division of Gynaecologic Oncology, University Health Network, Princess Margaret Hospital, 610 University Avenue M-700, Toronto, Ontario, M5G 2M9; e-mail: Marcus.firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To compare the practices, adjuvant treatment, and outcomes of patients with preoperatively assessed grade 1 endometrioid endometrial cancer between two academic gynecologic oncology centers that use different treatment strategies.
METHODS: A retrospective analysis was performed at Duke University Medical Center (Duke) and the Toronto Sunnybrook Regional Cancer Center (Sunnybrook) between 1991 and 2007. Patients at Duke generally underwent surgical staging unless intraoperative assessment identified a negligible risk of nodal disease. Patients at Sunnybrook generally did not undergo surgical staging.
RESULTS: A total of 494 patients (272 from Duke and 222 from Sunnybrook were identified with preoperative, central-review–confirming, grade 1, endometrioid, endometrial cancer. Groups were similar in grade, final histology, type of hysterectomy, and length of hospital stay. Patients from Sunnybrook were older (aged 62 years compared with 59 years, P=.001) and were more likely to have capillary lymphatic space involvement (18.2% compared with 8.3%, P=.003) and cervical involvement (12.2% compared with 3.7%, P<.001). Approximately 2% of cases were upgraded to high grade on final specimen. Lymphadenectomy was performed on 49.4% of patients at Duke compared with 11.7% of patients at Sunnybrook. Overall 3-year survival was 96% at Duke and 96% at Sunnybrook (P=.217). Three-year recurrence-free survival was 96% at Duke and 95% at Sunnybrook (P=.327).
CONCLUSION: Despite differences in practice and slight differences in patient populations, the recurrence-free and overall survival of women with preoperative centrally reviewed grade 1 endometrial cancer is excellent and without statistically significant difference between the two centers.
LEVEL OF EVIDENCE: III
Endometrial cancer is the most common gynecologic malignancy in the Western world. Surgical management is the mainstay of initial treatment, and the majority of cases present clinically as stage I. Since the 1980s, when the concept of modern surgical staging was originally introduced,1 there has been controversy regarding the optimal surgical management of these patients. Surgical management ranges from hysterectomy with bilateral salpingo-oophorectomy to full staging, including pelvic cytology, omentectomy, and pelvic/paraaortic lymph node dissection. Among those who surgically stage endometrial cancer, some advocate staging only patients whose tumors meet certain risk criteria at the time of intraoperative frozen section assessment,2 whereas others perform staging on all patients based on the perceived advantages of additional prognostic information as well as a possible therapeutic benefit.3 Some contend that removal of the uterus and adnexa alone are sufficient to dictate adjuvant treatment and that no prospective randomized study has identified improvement in survival for patients who have been surgically staged.4,5 Although several studies suggest that outcomes may be improved among patients who have had appropriate surgical staging in comparison with those without, this improvement is likely limited to high-risk cases.6–8 As such, one goal of surgical staging can be viewed as the reduction of unnecessary adjuvant treatment in the low-risk population, with identification of occult metastases that may improve outcome in high-risk populations.
A high number of patients continue to be managed surgically by community gynecologists, who unlike gynecologic oncologists are not trained to perform retroperitoneal lymphadenectomy. Statistics in both Canada and the United States confirm that, even in countries with a well-recognized, board-certified subspecialty in gynecologic oncology, only a minority of patients are ever seen by a gynecologic oncologist.9 One study reported that only 29.3% of patients with endometrial cancer ever saw a gynecologic oncologist as part of their care.9 Between 1996 and 2000 in Ontario, only 19.4% of patients were treated surgically by gynecologic oncologists.10 These statistics are not limited to low-risk cases. Among 900 patients with a preoperative histologic grade of 2 or higher, gynecologic oncologists operated on only 269 (30%). Subspecialty referral may be impractical due to limitations in economic resources or geographic or temporal constraints. One Canadian study investigating cost-effectiveness strategies concluded that for patients with grade 1 endometrial cancer, hysterectomy and bilateral salpingo-oophorectomy are more cost-effective than complete surgical staging.11 Other studies have found the opposite.12,13 In the setting of limited access to a gynecologic oncologist, improvements in the outcome of patients with endometrial cancer are likely to be seen if high-risk cases are triaged to gynecologic oncologists while low-risk cases, without compromise by the lack of complete surgical staging, may be managed in the community setting. The present study examines the effect of differences in practice patterns with respect to surgical staging between two programs in the United States and Canada on the use of adjuvant therapy, recurrence rates, and survival among patients with centrally reviewed preoperative grade 1 endometrial cancer.
MATERIALS AND METHODS
Analysis of 494 women with endometrial cancer treated between 1991 and 2007 was performed. The data were collected from Duke University Medical Center (Duke) and the Toronto Sunnybrook Regional Cancer Center (Sunnybrook) with appropriate Research Ethics Board approvals. All patients were required to have a pathology review of the endometrial biopsy or dilation and curettage specimen at the academic center preoperatively to confirm grade 1 disease. Data were collected through chart reviews of surgical notes, pathology reports, and clinical notes. Follow-up was obtained through the cancer registry at Duke and by letter and telephone follow-up at Sunnybrook.
Management strategies for endometrial cancer differ between Sunnybrook and Duke. Patients at Sunnybrook with central pathologic review confirming grade 1 endometrial cancer are typically not surgically staged and are often referred back to the community physician for surgical management because of resource allocation issues. Only if there is preoperative suspicion of high-risk disease, or if lymphadenopathy is found at surgery, would the patient undergo lymph node dissection by a gynecologic oncologist. At Duke, patients are usually surgically staged, with the exception of patients in whom intraoperative assessment of the primary tumor reveals no or minimal myometrial invasion (stage 1A/B grade 1) and patients with significant comorbid disease. Before reporting of the Gynecologic Oncology Group 99, patients at Duke generally did not receive adjuvant treatment if disease was confined to the uterus and the staging lymphadenectomy was negative, irrespective of uterine pathologic risk factors. Any patient who was seen preoperatively by a gynecologic oncologist, even if her surgery was done by the community physician, was included as part of the analysis.
Statistical analysis was performed using SPSS 12.0 (SPSS Inc., Chicago, IL). Parametric tests were used for continuous variables. The t test was used to compare the two centers. Categorical variables were compared with χ2 analysis. Survival analysis was performed using the Kaplan Meier method, and the log rank test was used to test for statistical significance. Statistical significance was defined as P<.05. A forward step-wise Cox regression analysis was used to identify dependent and independent prognostic variables for survival. For the calculation of recurrence-free survival, an event was defined by documentation of tumor recurrence. For overall survival, an event was defined as death from any cause. Although this was a retrospective study, we undertook a power calculation using a superiority framework. Setting the power at 0.8 and alpha error at 0.05 with n=494 women and taking into consideration a lost-to-follow-up rate of 25%, the study is powered to detect a 10% or greater difference in recurrence-free survival at 3 years.
Operative complications were defined as enterotomy, ureteral injury, vascular injury, cystotomy, nerve injury, or blood transfusion. Postoperative complications were defined as any medical event that occurred within the immediate perioperative period or any complication attributed directly to the surgery. Complications related to adjuvant treatment were classified according to the National Cancer Institute grading criteria.
Postoperative risk of recurrence was stratified into four categories: advanced stage, high risk, high intermediate risk, and low intermediate risk. These designations were established retrospectively by the authors in an attempt to better characterize the site of original disease, risk for recurrence, and administration of adjuvant treatment. A patient was classified as having advanced-stage disease if there was evidence of nodal, adnexal, or serosal involvement of tumor. High risk was defined by cervical disease, nonendometrioid histology, positive washings, or a combination of high grade, deep invasion, and positive capillary lymphatic space. High intermediate risk criteria were derived from the Gynecologic Oncology Group 99, combining age, presence of capillary lymphatic space, more than 50% myometrial invasion, and grade 2 or 3. A patient was defined as being of high intermediate risk if she was aged younger than 50 years with all three risk factors, between 50 years and 70 years with two risk factors, or older than 70 years with one risk factor. Low intermediate risk is defined as not fulfilling the criteria for high intermediate risk, but grade 2 or higher with less than 50% myometrial invasion. In an attempt to examine the patterns of adjuvant treatment according to postoperative risk, the authors assumed that patients meeting the criteria of at least high intermediate risk would potentially benefit from adjuvant treatment. Adjuvant treatment was defined as chemotherapy or radiation and did not include hormonal management.
Between 1991 and 2007, 494 patients (272 from Duke and 222 from Sunnybrook) were identified with preoperative, central review–confirming, grade 1, endometrioid, endometrial cancer. Eleven patients were excluded from the analysis because of preoperative evidence of extrauterine disease. Ten patients had preoperative suspicion of cervical involvement resulting in radical hysterectomy, and one patient underwent an anterior exenteration for stage IV disease. These patients did not fit the criteria of preoperative “low-risk.” Ten patients were excluded from the Sunnybrook group and one patient from the Duke group.
Groups were similar in grade, final histology, type of hysterectomy, and length of hospital stay (Table 1). Patients from Sunnybrook were older (aged 62 years compared with 59 years, P=.001) and more likely to have capillary lymphatic space involvement (18.2% compared with 8.3%, P=.003) and cervical involvement (12.2% compared with 3.7%, P<.001). The percentage of patients operated on by a gynecologic oncologist was higher at Duke (91% compared with 66%, P<.001).
Lymphadenectomy was performed on 49.4% of patients at Duke compared with 11.7% of patients at Sunnybrook. Operative complications were similar between centers: 12 (4.4%) at Duke and 11 (5.2%) at Sunnybrook, P=.682. Postoperative complications were also similar (33% at Duke and 30.1% at Sunnybrook, P=.748). Each center had one death within the period of 30 days after the surgical procedure. Adjuvant radiotherapy was significantly more common at Sunnybrook than at Duke (P<.001). Forty-four of 213 patients (20.7%) from the Toronto group received adjuvant radiation treatment. Twelve of the 44 women (27%) received only vaginal brachytherapy. Nineteen of 271 patients from Duke (7%) received adjuvant radiation treatment. Four of the 19 women (21%) received only vaginal brachytherapy. Six patients (2.2%) from Duke received adjuvant chemotherapy compared with 3 (1.4%) patients at Sunnybrook. The rate of grade 3 or 4 complication due to radiotherapy at Sunnybrook was 6.9%. There were no grade 3 or 4 complications due to radiotherapy at Duke. There were no complications related to chemotherapy at Sunnybrook compared with two of six patients at Duke who had grade 2 neuropathy and febrile neutropenia.
Median follow-up was 41.6 months at Duke and 38.6 months at Sunnybrook. Overall 3-year survival was 96% at Duke and 96% at Sunnybrook (P=.217). Three year recurrence-free survival was 96% at Duke and 95% at Sunnybrook (P=.327). Overall 3-year survival in the entire study population is 96%. Figure 1 shows the Kaplan Meier curve for overall survival, and Figure 2 shows the curve for recurrence-free survival.
There were 24 recurrences (5%) in the entire study population. The median time to recurrence was 22 months, with a range from 0 to 82 months. Forty-two percent of recurrences were in the pelvis. Of the seven patients with isolated vaginal vault recurrences, one died of her disease, whereas six (86%) were alive and free of disease, with a mean follow-up of 39 months from time of recurrence. There were 27 deaths (5.6%) in the entire cohort, including 15 deaths in the Duke population and 12 deaths in the Sunnybrook population. Three deaths were from unknown causes and it is unclear whether disease was present at the time of their death. Thirteen of the 27 deaths (48%) were attributed to causes apart from the disease or its related treatment.
Of the 24 patients who experienced recurrence, 13 had removal of regional lymph nodes as part of their surgical procedure (Table 2). Seven recurrences were vaginal, three were in the pelvis, 10 were distant, two were both distant and pelvic, and two were both distant and vaginal. Six of the 24 patients who experienced recurrence died of their disease, nine patients were alive with recurrent disease, and nine patients were alive without evidence of disease. Four of seven patients with lymph node metastasis experienced disease recurrence. Although surgical staging was not performed on all patients, stage of disease at the time of surgery (with or without lymphadenectomy) was the only factor that was found to be predictive of recurrence in both univariable (P<.008) and multivariable (P<.01) Cox regression analysis. Final grade did not predict recurrence.
Of 483 cases, 357 were confirmed as grade 1 in the final histologic specimen. Ninety-six cases (19.9%) were upgraded in the final specimen, 86 (17.8%) to grade 2 and 10 (2.1%) to grade 3.
Several factors were analyzed within only the Duke cohort. Of the 134 patients who underwent lymphadenectomy as part of their procedure, four (3.0%) patients were diagnosed with lymph node metastasis. All four of the patients with positive lymph nodes had positive capillary lymphatic space; one had serosal involvement of tumor, one had adnexal involvement of tumor, and one had deep myometrial invasion. All four patients received adjuvant treatment, and three of them experienced recurrence; two patients died of disease, and the third was alive with disease at last follow-up. Of 145 cases at Duke with intraoperative assessment, 20 (13.8%) were upstaged on final pathologic assessment: 13 cases were found to have less than 50% myometrial invasion after intraoperative assessment with no invasion, whereas seven cases were found to have deep myometrial invasion after six were assessed intraoperatively as less than 50% invasion, and one was assessed as no invasion. Similarly 22 of 157 (14.0%) cases were upgraded in the final histologic specimen compared with intraoperative assessment. If the intraoperative assessment was grade 1 or no cancer, 17 were upgraded to grade 2 on final histologic assessment.
For the entire study population, patients were stratified according to postoperative risk factors (Table 3). There were 120 (24.7%) women who met the criteria for at least high intermediate risk, thus potentially benefiting from adjuvant treatment. Of these 120 women, 69 received adjuvant radiation or chemotherapy. Of 50 cases from Duke who fit the criteria for adjuvant treatment, 20 received it (40%). Of 70 cases from Sunnybrook who fit the criteria, 45 received adjuvant treatment (56%).
This study addresses the management of preoperative low-risk endometrial cancer by comparing outcomes between two academic centers with different philosophies in surgical management. One of its major strengths is the exclusion of patients for whom central pathologic review to confirm grade 1 disease was not performed preoperatively. As with previous reports in low-risk endometrial cancer, we report a favorable outcome irrespective of surgical management and adjuvant therapy. Accepting the difference in follow-up between the two centers, there is no difference in recurrences or overall survival at 3 years despite their different approaches; overall 3-year survival in the entire study population was 96%. As in previous studies, medical conditions other than endometrial cancer account for a significant percentage of deaths, 48% in this study.14–16
One limitation of such a study is the inability to ensure that the groups are balanced with respect to risk factors. Although there were no statistically significant differences in grade and final histology, patients from Sunnybrook may have been of higher risk secondary to statistically significant differences in age, incidence of capillary lymphatic space, and operative stage (Table 1). The difference in stage is driven by the high percentage of stage IA cases at Duke and the higher percentage of stage II cases at Sunnybrook. Capillary lymphatic space status was unavailable in 43 of 271 (15.8%) cases at Duke compared with 5 of 213 (2.3%) cases at Sunnybrook, which may account for some of the discrepancy in this risk factor between the two centers. Capillary lymphatic space and cervical involvement are important criteria when considering the need for adjuvant treatment. As such, patients at Sunnybrook were more likely to receive adjuvant treatment when compared with those at Duke based on these factors alone. Although this potential bias might be expected to magnify any differences between the two centers, the finding of no difference in outcomes between groups reinforces the validity of each group’s treatment philosophy.
It is becoming increasingly evident that complete surgical staging with total pelvic and paraaortic lymphadenectomy is not likely to affect survival in patients with low-risk disease. Although Mariani et al17 reported on the benefits of extensive lymphadenectomy in endometrial cancer above the inferior mesenteric artery, they also found that in low-risk disease, including grade 2 lesions with less than 50% myometrial invasion, lymphadenectomy is not beneficial. Likewise, Chan et al6 reported outcomes in 27,063 women with unstaged endometrial cancer and concluded that lymphadenectomy was only likely to benefit high-risk cases. When examining the Duke cohort we found that the lymph node positivity rate in this patient population is extremely low, 4 of 134 (3.0%). The denominator in this case was patients who were both healthy enough for lymphadenectomy and at sufficient risk for lymph node metastases at the time of intraoperative assessment, such that a true estimate may be lower.
Proponents of lymphadenectomy in low-risk patients suggest that avoidance of unnecessary radiation is the main advantage in this patient population. To examine this point, the data were analyzed based on postoperative risk stratification. All four patients from Duke with lymph node metastases would have been of at least high intermediate risk even if a node dissection had not been performed. One pertinent question is whether lymphadenectomy reduced the amount of adjuvant treatment for patients who may have benefited from it. Forty percent of patients at Duke who potentially would have benefited from some adjuvant treatment based on risk factors received it compared with 56% at Sunnybrook. Lymphadenectomy itself may result in a discrepancy in administration of adjuvant therapy, or alternatively, the philosophies at each institution regarding criteria for adjuvant treatment may differ regardless of performance of lymphadenectomy. For example, the greatest difference in the administration of adjuvant treatment between institutions is in patients who meet the high intermediate risk category (Sunnybrook 55.2% compared with Duke 10.0%). Acceptance of the Gynecologic Oncology Group 99 criteria for administration of adjuvant radiotherapy is by no means universal and these criteria were published in 2004, after most of the cases examined in this study had been treated. The discrepancy in the administration of adjuvant treatment between Duke and Sunnybrook is heavily dependent on the decision not to offer adjuvant treatment to women with negative lymph nodes in the presence of uterine histologic risk factors.
Recently, three prospective randomized studies have called into question the role of both lymphadenectomy and adjuvant radiation therapy in the management of endometrial cancer.18–20 Benedetti Panici et al18 found no statistically significant difference in disease-free and overall survival at 5 years between surgery with and without lymphadenectomy. As in the current study, the group that did not have routine lymphadenectomy did have higher rates of adjuvant radiation (25% compared with 16%). A Study in the Treatment of Endometrial Cancer (ASTEC) trial similarly identified no benefit to routine lymphadenectomy.20 Finally, the combined ASTEC and National Cancer Institute of Canada (NCIC) trial has identified that there is no improvement in survival for women who receive adjuvant external beam radiation therapy and, furthermore, no difference in disease-specific recurrence-free survival.19 Our study is consistent with these trials in not suggesting a distinct advantage to either full surgical staging or more liberal use of adjuvant radiotherapy for patients at the low end of the risk spectrum; it is possible that any such advantage will only become identifiable in large studies of higher-risk subsets.
Perioperative complication rates were similar between the two centers, and thus the morbidity associated with surgical staging seems to be minimal. Although none of the patients who received radiation therapy at Duke experienced grade 3 or 4 complications, there was a 6.9% complication rate as a result of radiation therapy at Sunnybrook. In light of the recent publication showing no difference in disease-specific recurrence-free survival or overall survival in patients who did and did not receive adjuvant radiotherapy,19 efforts should be made to reasonably limit its administration in this low-risk population.
One factor that was not well-described in this study is the incidence of postoperative lymphedema. The symptom is difficult to measure and almost certainly underreported. The community of gynecologic oncologists is making a concerted effort to identify lymphedema as a consequence of lymphadenectomy; this is an important feature of a study using sentinel lymph node assessment in cervical cancer (Gynecologic Oncology Group 206. Lymphatic Mapping and Sentinel Node Identification in Patients With Cervical Cancer. National Cancer Institute–sponsored Phase II trial). It is possible that the risk of lymphedema is higher in patients who have had their staging procedure performed laparoscopically, presumably due to improved magnification and a more extensive dissection. Although not statistically significant, one study identified a trend toward increasing lymphedema in patients who underwent laparoscopic staging procedures compared with laparotomy.21 Thus, although immediate morbidity of lymphadenectomy is not increased in this study, conclusions about long-term quality-of-life issues are difficult to make and may become more relevant as minimally invasive surgery becomes more common.
An important factor in the discussion of optimal management strategies for low-risk endometrial cancer is cost. As part of this study, a formal cost analysis of the two cohorts was not undertaken, in large part because of the difference in health care costs and reimbursement between the two countries. However, an informal calculation of the cost of treatment for each cohort was performed based on standard Medicare reimbursements for surgical procedures, hospital stays, adjuvant radiotherapy modalities, and adjuvant chemotherapy treatments as previously described.13,22 Based on this reimbursement data, the average estimated treatment cost per patient is $16,551 for the Duke cohort and $17,512 for the Toronto cohort. Given the retrospective nature of the study and the imbalance in risk factors for recurrence between cohorts, we do not think this represents a significant cost difference. Prior cost-effectiveness analyses have reported the value of surgical staging even in low-risk disease12,13; these reports are influenced by the criteria for administration of adjuvant treatment, which are not universal.
There has been a change in the landscape for adjuvant treatment of endometrial cancer over the past several years. Two randomized trials have shown a survival benefit in patients with high-risk and advanced stage disease who received adjuvant chemotherapy as opposed to radiation.23,24 Thus, patients with isolated lymphatic metastases without other evidence of extrauterine disease may potentially benefit from chemotherapy. Lack of complete surgical staging would deny a patient this potential benefit even if uterine risk factors suggest the need for adjuvant radiation. This makes for a compelling argument in favor of lymphadenectomy even if the overall yield is likely to be low. Susumu et al24 included high-risk, early stage disease in their randomization of adjuvant external beam radiation compared with cisplatin, Adriamycin (Pharmacia & Upjohn, Kalamazoo, MI), and cyclophosphamide chemotherapy. Lymphadenectomy was not an inclusion criterion for the study. Although the survival benefit for chemotherapy was limited to high intermediate risk cases, it did introduce the idea that adjuvant chemotherapy as opposed to radiation may be a treatment of choice even based on uterine risk factors alone. The Gynecologic Oncology Group is currently examining the role of chemotherapy in patients with high-risk, early stage endometrial carcinoma (Gynecologic Oncology Group 249. A phase III trial of pelvic radiation therapy compared with vaginal cuff brachytherapy followed by carboplatin/Taxol).
The current study suggests that this preoperative low-risk patient population does extremely well regardless of whether lymph nodes are removed. Despite differences in practice and slight differences in patient populations, the recurrence-free and overall survival of women with preoperative centrally reviewed grade 1 endometrial cancer is excellent. Adjuvant treatment rates did vary between academic centers, in part due to a slightly higher risk population of the Sunnybrook group, but also due to a higher percentage of adjuvant treatment given to Sunnybrook patients with high intermediate risk for recurrence. The results of this study support the use of both treatment philosophies, and although there was no benefit to overall survival, lymphadenectomy may reduce the administration of adjuvant treatment.
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© 2009 by The American College of Obstetricians and Gynecologists.
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