Retrospective Analysis of Selective Lymphadenectomy in Apparent Early-Stage Endometrial Cancer
http://www.100md.com
《临床肿瘤学》
the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cancer Prevention, Detection, and Control Research Program, Duke University Medical Center, Durham, NC
ABSTRACT
PURPOSE: Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy.
PATIENTS AND METHODS: Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model.
RESULTS: Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence.
CONCLUSION: These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.
INTRODUCTION
Endometrial cancer is the most common gynecologic malignancy, with 40,100 new cases and 6,800 deaths reported each year.1 Seventy-five percent of endometrial cancers do not have evidence of extrauterine disease preoperatively (clinical stage I). Regional lymph nodes are the most common site of occult metastatic disease in apparent early-stage cancers.2 Since the establishment of surgical staging criteria by the International Federation of Gynecology and Obstetrics (FIGO) in 1988, complete staging has included abdominal exploration, pelvic peritoneal cytology, hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic selective lymphadenectomy.
The rationale underlying selective lymphadenectomy is that a more accurate assessment of the extent of disease allows for better individualization of adjuvant therapy. Adjuvant radiation can be prescribed for the fraction of patients found to have lymph node metastases or other high-risk features such as deep myometrial invasion, as they are most likely to benefit. Conversely, the vast majority of patients without lymph node metastases can be spared radiation. Some have suggested that there may be a direct therapeutic benefit to removing occult metastatic disease in lymph nodes.3 The benefits of selective lymphadenectomy in early endometrial cancer have not been examined in the context of prospective randomized trials, however. Pelvic lymph nodes are the most common site of extrauterine metastasis of endometrial cancer at initial presentation and can usually be sampled through the same incision used for hysterectomy. Aortic node metastases are less common, and aortic selective lymphadenectomy usually requires a larger incision and more extensive dissection. Therefore, the addition of aortic selective lymphadenectomy may lengthen operative time and increase blood loss and perioperative morbidity. The goals of this study were to assess the effect on survival and morbidity of the extent of selective lymphadenectomy in women thought at surgery to have endometrial cancer confined to the uterus.
PATIENTS AND METHODS
Following institutional review board approval, the Duke University Tumor Registry was reviewed in order to identify all patients with endometrial cancer who received primary surgical treatment at Duke University Medical Center between 1973 and 2002. Inclusion criteria were preoperative clinical stage I or occult stage II disease, and an initial procedure that included hysterectomy and selective lymphadenectomy (pelvic or pelvic and aortic). Patients who had at least one lymph node identified by final pathology report were included. The decision to perform lymphadenectomy and the extent of lymphadenectomy varied by surgeon preference and was typically decided with consideration of the grade, depth of invasion, size, and location of the primary tumor at the time of hysterectomy, as well as each patient’s medical comorbidities. At our institution, selective pelvic lymphadenectomy for endometrial cancer typically involves removing lymphatic tissue from the anterior and medial surfaces of the iliac vessels and from the obturator fossa superior to the obturator nerve. Aortic selective lymphadenectomy usually consists of removal of precaval and lower right and left aortic lymphatic tissue to the level of the inferior mesenteric artery. Exclusion criteria included preoperative radiation, clinical stage IIB and above, lymph node sampling not performed, coexisting second primary cancer, and visible metastatic disease (including grossly positive lymph nodes at laparotomy).
Clinical data were abstracted by review of patient medical records. Medical adverse events were recorded, including small bowel obstruction or prolonged ileus managed conservatively, deep venous thrombus, pneumonia, pulmonary embolus, stroke, congestive heart failure, myocardial infarction, pyelonephritis, and unanticipated intensive care unit stay. Surgical adverse events included lymphocyst requiring drainage, small bowel obstruction requiring surgery, return to the operating room within 30 days, wound dehiscence, pelvic hematoma or abscess requiring drainage, nerve injury, urinary obstruction, and death within 30 days of surgery. Original pathology reports were reviewed for histologic type, depth of myometrial invasion, FIGO grade, FIGO stage, number, location, status of retroperitoneal nodes, and sites of metastasis.
Statistical analyses were performed using SAS version 8.2 (Statistical Analysis Software, Cary, NC). Pearson 2 and Fisher’s exact tests were used for categorical variables. Because anesthesia time, hospital stay, and estimated blood loss were highly skewed, we reported medians and used the Wilcoxon rank sum test. The Kaplan-Meier method was used to generate survival curves and calculate 5-year overall and progression-free (events include recurrence or death from any cause) survival. The log-rank test was used to test for survival differences. Stratified analyses were performed to examine possible effect modification by clinical risk factors (histology, grade, and myometrial invasion).
Multivariate analysis was performed using the Cox proportional hazards model to assess the impact of the quantity and location of nodes removed on survival while controlling for known prognostic factors. Number of pelvic nodes was included as a dichotomous variable ( 11 v > 11), and an indicator variable was used to identify whether patients had aortic nodes removed in addition to pelvic nodes. Models were developed using stepwise forward selection, retaining variables for quantity and location of nodes removed as well as variables significant at the two-sided = .05 level. Variables tested for inclusion in the multivariate model were depth of myometrial invasion (inner/outer), histologic type (papillary serous/clear-cell versus other), grade (< 3 v 3), cervical invasion, adjuvant radiation, year of surgery (coded as year 1973), age at surgery (continuous), race (white/other), and separate variables indicating presence of metastasis in pelvic and aortic lymph nodes. For the continuous variables age and year of surgery, quadratic and cubic terms were assessed. Interaction terms between number of pelvic nodes removed and each of the other variables were created and tested for significance. A significant interaction was found between number of pelvic nodes removed and grade.
RESULTS
Of 1,656 patients treated for endometrial cancer between 1973 and 2002, 619 underwent hysterectomy and selective lymphadenectomy for primary treatment of clinical stage I endometrial cancer. After exclusion of 110 patients in whom extrauterine disease was identified grossly at laparotomy (93 with abnormal lymph nodes), 509 met inclusion criteria. One hundred thirty-six patients underwent selective pelvic lymphadenectomy, and 373 underwent selective pelvic and aortic lymphadenectomy. The mean age was 63 years (range, 30 to 93 years); 81% were white. Median number of lymph nodes removed was 15; median number of pelvic nodes removed was 11 (interquartile range, 7 to 17 nodes), and median number of aortic nodes removed was three. The median number of lymph nodes removed increased from nine between 1973 and 1987 to 14 between 1988 and 2002 (P < .0001). Clinical and pathologic characteristics are listed in Table 1. The rates of pelvic and aortic lymph node metastasis were 25 (5%) of 509 and 11 (3%) of 373, respectively. Adjuvant radiotherapy was administered to 137 (27%) of 509 patients. Of patients receiving adjuvant radiotherapy, 87 (64%) of 137 had a final surgical stage of II to IV. Among 137 patients who received adjuvant radiotherapy, retroperitoneal lymph node metastasis was found in 28 (20%), and other occult metastatic disease was identified in 54 (39%). Fifty patients with surgical stage I disease received adjuvant radiotherapy, of whom 34 (68%) had outer-half myometrial invasion, poorly differentiated carcinoma, or papillary serous or clear-cell histologic type. The overall cancer recurrence rate was 48 (9.4%) of 509. Five-year overall survival and progression-free survival rates were 83% and 80%, respectively.
We performed a multivariate analysis to determine the impact of the number and location of lymph nodes removed, on overall and progression-free survival while controlling for clinical prognostic factors and adjuvant treatment (Table 2). More than 11 pelvic lymph nodes were removed in 246 (48.3%) of 509 patients. Patients with grade 3 cancers who had more than 11 pelvic lymph nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients with grade 3 cancers who had 11 or fewer nodes removed. Patients with grade 1 to 2 cancers did not have a difference in survival based on the number of pelvic nodes removed and had virtually the same HR as patients with grade 3 cancers who had more than 11 nodes removed. Removal of aortic lymph nodes was not independently associated with survival (overall survival HR, 1.29; 95% CI, 0.74 to 2.22; progression-free survival HR, 1.32; 95% CI, 0.80 to 2.19). Factors associated with lower survival were aortic node metastasis, older age, high histologic grade, papillary serous or clear-cell histologic type, nonwhite race, and adjuvant radiotherapy. Year of surgery was also associated with survival but had a quadratic relationship, with the hazard ratio increasing between 1973 and 1981, then decreasing gradually. To test whether the possible therapeutic effect of lymphadenectomy was due to adjuvant treatment of those with identified metastasis, or rather an effect of the surgical removal of occult metastasis, we removed from the analysis patients with aortic or pelvic nodal metastasis as identified on final pathology report. Again, the removal of more than 11 lymph nodes was associated with improved survival among patients with poorly differentiated cancers and without identified nodal metastasis (HR, 0.20; P < .0001).
Using the Kaplan-Meier method and the log-rank test we found that patients who had more than 11 pelvic lymph nodes removed had better overall survival (P = .013) and progression-free survival (P = .010) than those who had 11 or fewer pelvic nodes removed. Five-year overall survival was 88% for those with more than 11 pelvic lymph nodes removed compared to 79% with 11 or fewer (Fig 1A), and progression-free survival was 86% compared to 75%. Patients were stratified into high-risk (poorly differentiated, greater than 1/2 myometrial invasion, or papillary serous or clear-cell histologic type, n = 234) and low-risk (well or moderately differentiated, inner 1/2 myometrial invasion, and all other histologic types, n = 275) groups. High-risk patients who had more than 11 pelvic nodes removed (n = 123) had better overall (P = .001) and progression-free survival (P = .001) than those with 11 or fewer pelvic nodes removed (n = 111). Among high-risk patients, 5-year overall survival was 82% for those with more than 11 pelvic nodes removed compared with 64% in those with 11 or fewer nodes removed (Fig 1B); progression-free survival was 80% compared with 60%, respectively. The addition of selective aortic lymphadenectomy was not associated with improved survival in the high-risk group. Among low-risk patients, removal of more than 11 pelvic lymph nodes (n = 123) was associated with a non–statistically significant progression-free (92% v 86%) and overall (94% v 89%; Fig 1C) 5-year survival advantage compared with those in whom fewer nodes were removed (n = 152). After excluding patients with retroperitoneal node metastasis, patients who had more than 11 pelvic lymph nodes removed had significantly better overall survival (90% v 80%; P = .016). Patients having more than 11 pelvic lymph nodes removed had a lower rate of pelvic recurrence (1% v 5%; P = .020) and a similar rate of vaginal recurrence (2% v 3%; P = .385) compared with patients who had 11 or fewer nodes removed.
Adverse events were observed in 18% of patients (Table 3). There was no significant difference in overall, surgical, or medical adverse events between patients undergoing selective pelvic and aortic lymphadenectomy and those undergoing selective pelvic lymphadenectomy alone. The most common medical complications were small bowel obstruction or prolonged ileus treated medically (2.6%) and deep venous thrombus (2.6%). The most common surgical complications were lymphocyst requiring drainage (2.4%) and small bowel obstruction requiring exploration (1.8%). Patients undergoing selective pelvic and aortic lymphadenectomy had longer anesthesia time (median, 220 v 204 minutes; P = .011), longer hospital stay (8 v 5 days; P < .0001), and higher estimated blood loss (500 v 300 mL; P < .0001) than those undergoing selective pelvic lymphadenectomy alone. Blood transfusion was given in 23% of the selective pelvic and aortic lymphadenectomy group and in 5% of the selective pelvic lymphadenectomy group (P < .0001).
Patients with retroperitoneal lymph node metastasis had a 5-year overall survival of 55% and a progression-free survival of 48%. Among patients with aortic node metastasis, 5-year overall survival was 31%, and progression-free survival, 27%. Table 4 examines outcomes of the 11 patients with aortic lymph node metastases. Three of 11 patients are alive with no evidence of recurrence more than 5 years postsurgery. Four have died of disease. One died of unrelated medical illness 24 months after diagnosis. Three died of medical illness without evidence of recurrent disease at 1, 2, and 8 months: one died of gastrointestinal bleeding following whole abdominal radiotherapy 8 months after diagnosis, one died from subarachnoid hemorrhage after anticoagulation for a deep venous thrombosis 2 months after surgery, and one died at an outside hospital from unknown causes within 1 month after surgery.
DISCUSSION
In this study of patients with endometrial cancer that appeared to be confined to the uterus at laparotomy, 5% had pelvic node metastasis, and 3% had aortic node metastasis. This is lower than the 9% and 6% incidences of pelvic and aortic node metastasis reported in the large Gynecologic Oncology Group study among patients with clinical stage I cancers.2 The lower incidence of nodal metastasis in our population likely is attributable to the exclusion of patients in whom enlarged nodes or other extrauterine cancer were identified intraoperatively. The objective of this study was to examine the value of selective lymphadenectomy in patients thought to have disease confined to the uterus at surgery, rather than the effect of debulking lymph nodes obviously involved with metastatic cancer.
We found that more extensive selective lymphadenectomy (> 11 pelvic lymph nodes) is associated with improved survival in women with grade 3 cancers without gross evidence of metastatic endometrial cancer at the time of hysterectomy. Although our use of a cutoff at the median number of nodes removed is relatively arbitrary, it is supported by statistical analysis of residuals. Our findings are consistent with those of Kilgore et al from the University of Alabama, Birmingham, who retrospectively reviewed 649 patients treated surgically for clinical stage I endometrial cancer and found that patients undergoing multiple site selective lymphadenectomy (median number of nodes removed, 11) had improved survival over those who did not have lymph node sampling performed.3 The survival difference persisted after patients were separated into pathologic risk groups and by adjuvant treatment. Several other authors have reported series in which complete pelvic lymphadenectomy was performed without adjuvant external beam radiotherapy, with excellent long-term results, suggesting a therapeutic benefit to the surgical procedure.4-6 One possible explanation for the potential beneficial effect of more extensive lymphadenectomy is the identification of patients with nodal metastases who are potentially curable with adjuvant treatment. In our study, patients with positive pelvic or aortic lymph nodes had a 5-year progression-free survival of 48% and overall survival of 55%. When controlling for administration of adjuvant radiotherapy in multivariate analysis, we found that the association between extent of lymphadenectomy and improved survival remained. This finding suggests that improved survival cannot be solely attributed to adjuvant therapy among patients having more extensive lymphadenectomy.
Another factor that may contribute to the therapeutic benefit of more extensive selective lymphadenectomy is the removal of occult small-volume metastatic disease that remains undiagnosed by the pathologist. Our finding that a more extensive lymphadenectomy was associated with improved survival after removing from the analysis patients reported to have pelvic or aortic nodal metastasis, is supportive of this hypothesis. Likewise, McMeekin et al7 hypothesized that the favorable 70% to 87% 3-year survival rate observed in their patients with lymph node metastases was due to the performance of complete lymphadenectomy in most cases.
A potential limitation of our study and others that use lymph node count as a surrogate for completeness of lymphadenectomy is that the total lymph node count may vary not only with the extent of the surgical dissection, but also due to differences in the pathologist’s evaluation of the surgical specimen. Because total node count is partially dependent on the pathologist’s gross assessment, it is not possible to perform a verifying independent pathology review. However, we believe that the number of nodes reported at our institution is generally reflective of the extent of lymphadenectomy. All surgical specimens in this study were processed at a single institution with relatively stable gross dissection procedures. The number of lymph nodes removed increased over time, possibly reflecting the formal institution by FIGO in 1988 of a surgical staging system for endometrial cancer that incorporates the results of lymph node sampling. The number of lymph nodes removed retained prognostic significance when controlling for the year surgery was performed.
Another potential limitation is selection bias, which is inherent in any retrospective study. Because we wished to focus on the outcomes of patients who underwent selective lymphadenectomy, we did not include in our survival analysis patients who did not have any lymph nodes removed. Table 1 shows that patients who did not undergo lymphadenectomy had primarily low-grade (59% grade 1), minimally invasive (90% less than half invasive), and low-risk histologic type (94% endometrioid or mucinous) cancers. Selection bias may also affect the analysis of the number of lymph nodes removed. As presented in Table 1, most prognostic factors seem to be fairly well balanced among patients who had greater than 11 v 11 or fewer pelvic lymph nodes removed. Those with more than 11 nodes removed were more likely to have a higher FIGO grade (P = .022). The decision to administer adjuvant therapy was also at the oncologist’s discretion and therefore subject to selection bias. We did control for the administration of adjuvant radiotherapy in multivariate analysis.
The addition of selective aortic lymphadenectomy to hysterectomy and selective pelvic lymphadenectomy was not associated with a survival benefit in our study. Since the incidence of aortic node metastasis in our series was only 3%, any overall survival benefit of selective aortic lymphadenectomy would likely be small and difficult to detect. Other authors have reported improved survival and lower retroperitoneal recurrence rates among high-risk patients who had aortic lymphadenectomy as part of their surgical staging procedure.8,9 While we were not able to demonstrate a direct benefit to aortic node sampling, these studies in combination with our findings suggest that more extensive lymphadenectomy may be beneficial.
We identified 11 patients with microscopic aortic node metastasis. Aortic node metastasis was strongly associated with lower overall (HR, 11.6) and progression-free (HR, 9.8) survival in multivariate analysis. This finding may be biased by the lack of performance of aortic lymphadenectomy in every patient. Because patients who did not undergo aortic lymphadenectomy were coded as "negative" for aortic node metastasis, the actual hazard ratio for aortic node metastasis may be higher than what we report. Among patients we identified with aortic node metastasis, three (27%) of eleven are without evidence of disease and all are more than 5 years from the date of diagnosis. Prior studies report 5-year survival rates of 36% to 67% for patients with aortic nodal metastasis,10-13and both extended-field radiotherapy and surgical resection have been associated with improved survival among these patients.14,15 The potential therapeutic benefit of aortic lymphadenectomy and radiation in a small subset of patients with metastatic disease must be weighed against the potential for increased morbidity and mortality in all patients who undergo this procedure. Extended-field radiotherapy following selective aortic lymphadenectomy has been associated with radiation enteritis and bowel obstruction.14 Although selective aortic lymphadenectomy did not significantly increase the frequency of perioperative adverse events, one patient with aortic nodal metastases died within 1 month of surgery, and another died at 2 months with a hemorrhagic complication of anticoagulation for a deep venous thrombus.
Previous work by our group and others indicated that the addition of selective pelvic and aortic lymphadenectomy to hysterectomy alone was associated with increased blood loss and hospital stay, but not an increase in postoperative complications.16,17 In the present study, the addition of aortic lymphadenectomy to pelvic lymphadenectomy was also associated with increased blood loss (200 mL), transfusion rates, hospital stay, and anesthesia time. The higher transfusion rate and longer hospital stay may be partially explained by the different proportions of each surgical group who were treated before 1985. Eighteen percent of patients undergoing selective pelvic lymphadenectomy alone were treated before 1985 compared with 47% of patients undergoing selective pelvic and aortic lymphadenectomy. Hospital stays and blood transfusion rates have decreased during the last 30 years with the advent of managed health care and concerns regarding blood-borne pathogens. This trend will likely accelerate with the increasing use of minimally invasive laparoscopic approaches for surgical management of endometrial cancer.
Given the low rate of aortic lymph node metastases in women with endometrial cancer that appears to be confined to the uterus at the time of laparotomy (3%), some have proposed that aortic lymphadenectomy should be limited to patients with high-risk features such as deep myometrial invasion and higher histologic grade.18 Unfortunately there is no risk factor profile that reliably identifies all patients with aortic nodal metastasis. Among 11 patients in our series with aortic node metastasis, four (36%) had only inner-half myometrial invasion, and one had grade 1 cancer preoperatively. Only six (55%) of 11 were grade 3 preoperatively, and the grade was increased to 3 postoperatively in four (36%) cases. Preoperative and frozen section diagnoses of tumor grade are sometimes inconsistent with the final pathologic grade.19 Finally, isolated aortic node metastasis is fairly common7; in our series, five of the 11 patients (45%) with positive aortic nodes had negative pelvic nodes and would not have received aortic radiation had selective pelvic lymphadenectomy alone been performed.
The finding that a more extensive pelvic lymphadenectomy is associated with improved survival suggests that there is value in performing this procedure in a systematic and thorough manner when feasible. At our institution, selective pelvic lymphadenectomy for patients with apparent early-stage endometrial cancer typically involves removing lymphatic tissue from the anterior and medial surfaces of the iliac vessels and from the obturator fossa superior to the obturator nerve. Aortic selective lymphadenectomy usually consists of removal of the precaval and lower right and left aortic lymphatic tissue to the level of the inferior mesenteric artery. The potential benefit of selective aortic lymphadenectomy should be weighed along with known prognostic factors and medical fitness in determining the suitability of individual patients for this procedure. These data add to the growing literature documenting the possible therapeutic benefit of selective lymphadenectomy in the management of patients with early-stage endometrial cancer.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Main plenary presentation, Society of Gynecologic Oncologists 35th Annual Meeting, San Diego, CA, February 7-11, 2004.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003
Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer: A Gynecologic Oncology Group Study. Cancer 60:2035-2041, 1987
Kilgore LC, Partridge EE, Alvarez RD, et al: Adenocarcinoma of the endometrium: Survival comparisons of patients with and without pelvic node sampling. Gynecol Oncol 56:29-33, 1995
Orr JW Jr, Holimon JL, Orr PF: Stage I corpus cancer: Is teletherapy necessary Am J Obstet Gynecol 176:777-789, 1997
Mohan DS, Samuels MA, Selim MA, et al: Long-term outcomes of therapeutic pelvic lymphadenectomy for stage I endometrial adenocarcinoma. Gynecol Oncol 70:165-171, 1998
Fanning J: Long-term survival of intermediate risk endometrial cancer (stage IG3, IC, II) treated with full lymphadenectomy and brachytherapy without teletherapy. Gynecol Oncol 82:371-374, 2001
McMeekin DS, Lashbrook D, Gold M, et al: Nodal distribution and its significance in FIGO stage IIIc endometrial cancer. Gynecol Oncol 82:375-379, 2001
Mariani A, Webb MJ, Galli L, et al: Potential therapeutic role of para-aortic lymphadenectomy in node-positive endometrial cancer. Gynecol Oncol 76:348-356, 2000
Chuang L, Burke TW, Tornos C, et al: Staging laparotomy for endometrial carcinoma: Assessment of retroperitoneal lymph nodes. Gynecol Oncol 58:189-193, 1995
McMeekin DS, Lashbrook D, Gold M, et al: Analysis of FIGO Stage IIIc endometrial cancer patients. Gynecol Oncol 81:273-278, 2001
Morrow CP, Bundy BN, Kurman RJ, et al: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group study. Gynecol Oncol 40:55-65, 1991
Hirahatake K, Hareyama H, Sakuragi N, et al: A clinical and pathologic study on para-aortic lymph node metastasis in endometrial carcinoma. J Surg Oncol 65:82-87, 1997
Grigsby PW, Perez CA, Kuske RR, et al: Results of therapy, analysis of failures, and prognostic factors for clinical and pathologic stage III adenocarcinoma of the endometrium. Gynecol Oncol 27:44-57, 1987
Rose PG, Cha SD, Tak WK, et al: Radiation therapy for surgically proven para-aortic node metastasis in endometrial carcinoma. Int J Radiat Oncol Biol Phys 24:229-233, 1992
Corn BW, Lanciano RM, Greven KM, et al: Endometrial cancer with para-aortic adenopathy: Patterns of failure and opportunities for cure. Int J Radiat Oncol Biol Phys 24:223-227, 1992
Larson DM, Johnson K, Olson KA: Pelvic and para-aortic lymphadenectomy for surgical staging of endometrial cancer: Morbidity and mortality. Obstet Gynecol 79:998-1001, 1992
Cliby WA, Clarke-Pearson DL, Dodge R, et al: Acute morbidity and mortality associated with selective pelvic and para-aortic lymphadenectomy in the surgical staging of endometrial adenocarcinoma. J Gynecol Tech 1:19-25, 1995
Kim YB, Niloff JM: Endometrial carcinoma: Analysis of recurrence in patients treated with a strategy minimizing lymph node sampling and radiation therapy. Obstet Gynecol 82:175-180, 1993
Kucera E, Kainz C, Reinthaller A, et al: Accuracy of intraoperative frozen-section diagnosis in stage I endometrial adenocarcinoma. Gynecol Obstet Invest 49:62-66, 2000(Janiel M. Cragun, Laura J)
ABSTRACT
PURPOSE: Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy.
PATIENTS AND METHODS: Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model.
RESULTS: Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence.
CONCLUSION: These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.
INTRODUCTION
Endometrial cancer is the most common gynecologic malignancy, with 40,100 new cases and 6,800 deaths reported each year.1 Seventy-five percent of endometrial cancers do not have evidence of extrauterine disease preoperatively (clinical stage I). Regional lymph nodes are the most common site of occult metastatic disease in apparent early-stage cancers.2 Since the establishment of surgical staging criteria by the International Federation of Gynecology and Obstetrics (FIGO) in 1988, complete staging has included abdominal exploration, pelvic peritoneal cytology, hysterectomy, bilateral salpingo-oophorectomy, and pelvic and aortic selective lymphadenectomy.
The rationale underlying selective lymphadenectomy is that a more accurate assessment of the extent of disease allows for better individualization of adjuvant therapy. Adjuvant radiation can be prescribed for the fraction of patients found to have lymph node metastases or other high-risk features such as deep myometrial invasion, as they are most likely to benefit. Conversely, the vast majority of patients without lymph node metastases can be spared radiation. Some have suggested that there may be a direct therapeutic benefit to removing occult metastatic disease in lymph nodes.3 The benefits of selective lymphadenectomy in early endometrial cancer have not been examined in the context of prospective randomized trials, however. Pelvic lymph nodes are the most common site of extrauterine metastasis of endometrial cancer at initial presentation and can usually be sampled through the same incision used for hysterectomy. Aortic node metastases are less common, and aortic selective lymphadenectomy usually requires a larger incision and more extensive dissection. Therefore, the addition of aortic selective lymphadenectomy may lengthen operative time and increase blood loss and perioperative morbidity. The goals of this study were to assess the effect on survival and morbidity of the extent of selective lymphadenectomy in women thought at surgery to have endometrial cancer confined to the uterus.
PATIENTS AND METHODS
Following institutional review board approval, the Duke University Tumor Registry was reviewed in order to identify all patients with endometrial cancer who received primary surgical treatment at Duke University Medical Center between 1973 and 2002. Inclusion criteria were preoperative clinical stage I or occult stage II disease, and an initial procedure that included hysterectomy and selective lymphadenectomy (pelvic or pelvic and aortic). Patients who had at least one lymph node identified by final pathology report were included. The decision to perform lymphadenectomy and the extent of lymphadenectomy varied by surgeon preference and was typically decided with consideration of the grade, depth of invasion, size, and location of the primary tumor at the time of hysterectomy, as well as each patient’s medical comorbidities. At our institution, selective pelvic lymphadenectomy for endometrial cancer typically involves removing lymphatic tissue from the anterior and medial surfaces of the iliac vessels and from the obturator fossa superior to the obturator nerve. Aortic selective lymphadenectomy usually consists of removal of precaval and lower right and left aortic lymphatic tissue to the level of the inferior mesenteric artery. Exclusion criteria included preoperative radiation, clinical stage IIB and above, lymph node sampling not performed, coexisting second primary cancer, and visible metastatic disease (including grossly positive lymph nodes at laparotomy).
Clinical data were abstracted by review of patient medical records. Medical adverse events were recorded, including small bowel obstruction or prolonged ileus managed conservatively, deep venous thrombus, pneumonia, pulmonary embolus, stroke, congestive heart failure, myocardial infarction, pyelonephritis, and unanticipated intensive care unit stay. Surgical adverse events included lymphocyst requiring drainage, small bowel obstruction requiring surgery, return to the operating room within 30 days, wound dehiscence, pelvic hematoma or abscess requiring drainage, nerve injury, urinary obstruction, and death within 30 days of surgery. Original pathology reports were reviewed for histologic type, depth of myometrial invasion, FIGO grade, FIGO stage, number, location, status of retroperitoneal nodes, and sites of metastasis.
Statistical analyses were performed using SAS version 8.2 (Statistical Analysis Software, Cary, NC). Pearson 2 and Fisher’s exact tests were used for categorical variables. Because anesthesia time, hospital stay, and estimated blood loss were highly skewed, we reported medians and used the Wilcoxon rank sum test. The Kaplan-Meier method was used to generate survival curves and calculate 5-year overall and progression-free (events include recurrence or death from any cause) survival. The log-rank test was used to test for survival differences. Stratified analyses were performed to examine possible effect modification by clinical risk factors (histology, grade, and myometrial invasion).
Multivariate analysis was performed using the Cox proportional hazards model to assess the impact of the quantity and location of nodes removed on survival while controlling for known prognostic factors. Number of pelvic nodes was included as a dichotomous variable ( 11 v > 11), and an indicator variable was used to identify whether patients had aortic nodes removed in addition to pelvic nodes. Models were developed using stepwise forward selection, retaining variables for quantity and location of nodes removed as well as variables significant at the two-sided = .05 level. Variables tested for inclusion in the multivariate model were depth of myometrial invasion (inner/outer), histologic type (papillary serous/clear-cell versus other), grade (< 3 v 3), cervical invasion, adjuvant radiation, year of surgery (coded as year 1973), age at surgery (continuous), race (white/other), and separate variables indicating presence of metastasis in pelvic and aortic lymph nodes. For the continuous variables age and year of surgery, quadratic and cubic terms were assessed. Interaction terms between number of pelvic nodes removed and each of the other variables were created and tested for significance. A significant interaction was found between number of pelvic nodes removed and grade.
RESULTS
Of 1,656 patients treated for endometrial cancer between 1973 and 2002, 619 underwent hysterectomy and selective lymphadenectomy for primary treatment of clinical stage I endometrial cancer. After exclusion of 110 patients in whom extrauterine disease was identified grossly at laparotomy (93 with abnormal lymph nodes), 509 met inclusion criteria. One hundred thirty-six patients underwent selective pelvic lymphadenectomy, and 373 underwent selective pelvic and aortic lymphadenectomy. The mean age was 63 years (range, 30 to 93 years); 81% were white. Median number of lymph nodes removed was 15; median number of pelvic nodes removed was 11 (interquartile range, 7 to 17 nodes), and median number of aortic nodes removed was three. The median number of lymph nodes removed increased from nine between 1973 and 1987 to 14 between 1988 and 2002 (P < .0001). Clinical and pathologic characteristics are listed in Table 1. The rates of pelvic and aortic lymph node metastasis were 25 (5%) of 509 and 11 (3%) of 373, respectively. Adjuvant radiotherapy was administered to 137 (27%) of 509 patients. Of patients receiving adjuvant radiotherapy, 87 (64%) of 137 had a final surgical stage of II to IV. Among 137 patients who received adjuvant radiotherapy, retroperitoneal lymph node metastasis was found in 28 (20%), and other occult metastatic disease was identified in 54 (39%). Fifty patients with surgical stage I disease received adjuvant radiotherapy, of whom 34 (68%) had outer-half myometrial invasion, poorly differentiated carcinoma, or papillary serous or clear-cell histologic type. The overall cancer recurrence rate was 48 (9.4%) of 509. Five-year overall survival and progression-free survival rates were 83% and 80%, respectively.
We performed a multivariate analysis to determine the impact of the number and location of lymph nodes removed, on overall and progression-free survival while controlling for clinical prognostic factors and adjuvant treatment (Table 2). More than 11 pelvic lymph nodes were removed in 246 (48.3%) of 509 patients. Patients with grade 3 cancers who had more than 11 pelvic lymph nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients with grade 3 cancers who had 11 or fewer nodes removed. Patients with grade 1 to 2 cancers did not have a difference in survival based on the number of pelvic nodes removed and had virtually the same HR as patients with grade 3 cancers who had more than 11 nodes removed. Removal of aortic lymph nodes was not independently associated with survival (overall survival HR, 1.29; 95% CI, 0.74 to 2.22; progression-free survival HR, 1.32; 95% CI, 0.80 to 2.19). Factors associated with lower survival were aortic node metastasis, older age, high histologic grade, papillary serous or clear-cell histologic type, nonwhite race, and adjuvant radiotherapy. Year of surgery was also associated with survival but had a quadratic relationship, with the hazard ratio increasing between 1973 and 1981, then decreasing gradually. To test whether the possible therapeutic effect of lymphadenectomy was due to adjuvant treatment of those with identified metastasis, or rather an effect of the surgical removal of occult metastasis, we removed from the analysis patients with aortic or pelvic nodal metastasis as identified on final pathology report. Again, the removal of more than 11 lymph nodes was associated with improved survival among patients with poorly differentiated cancers and without identified nodal metastasis (HR, 0.20; P < .0001).
Using the Kaplan-Meier method and the log-rank test we found that patients who had more than 11 pelvic lymph nodes removed had better overall survival (P = .013) and progression-free survival (P = .010) than those who had 11 or fewer pelvic nodes removed. Five-year overall survival was 88% for those with more than 11 pelvic lymph nodes removed compared to 79% with 11 or fewer (Fig 1A), and progression-free survival was 86% compared to 75%. Patients were stratified into high-risk (poorly differentiated, greater than 1/2 myometrial invasion, or papillary serous or clear-cell histologic type, n = 234) and low-risk (well or moderately differentiated, inner 1/2 myometrial invasion, and all other histologic types, n = 275) groups. High-risk patients who had more than 11 pelvic nodes removed (n = 123) had better overall (P = .001) and progression-free survival (P = .001) than those with 11 or fewer pelvic nodes removed (n = 111). Among high-risk patients, 5-year overall survival was 82% for those with more than 11 pelvic nodes removed compared with 64% in those with 11 or fewer nodes removed (Fig 1B); progression-free survival was 80% compared with 60%, respectively. The addition of selective aortic lymphadenectomy was not associated with improved survival in the high-risk group. Among low-risk patients, removal of more than 11 pelvic lymph nodes (n = 123) was associated with a non–statistically significant progression-free (92% v 86%) and overall (94% v 89%; Fig 1C) 5-year survival advantage compared with those in whom fewer nodes were removed (n = 152). After excluding patients with retroperitoneal node metastasis, patients who had more than 11 pelvic lymph nodes removed had significantly better overall survival (90% v 80%; P = .016). Patients having more than 11 pelvic lymph nodes removed had a lower rate of pelvic recurrence (1% v 5%; P = .020) and a similar rate of vaginal recurrence (2% v 3%; P = .385) compared with patients who had 11 or fewer nodes removed.
Adverse events were observed in 18% of patients (Table 3). There was no significant difference in overall, surgical, or medical adverse events between patients undergoing selective pelvic and aortic lymphadenectomy and those undergoing selective pelvic lymphadenectomy alone. The most common medical complications were small bowel obstruction or prolonged ileus treated medically (2.6%) and deep venous thrombus (2.6%). The most common surgical complications were lymphocyst requiring drainage (2.4%) and small bowel obstruction requiring exploration (1.8%). Patients undergoing selective pelvic and aortic lymphadenectomy had longer anesthesia time (median, 220 v 204 minutes; P = .011), longer hospital stay (8 v 5 days; P < .0001), and higher estimated blood loss (500 v 300 mL; P < .0001) than those undergoing selective pelvic lymphadenectomy alone. Blood transfusion was given in 23% of the selective pelvic and aortic lymphadenectomy group and in 5% of the selective pelvic lymphadenectomy group (P < .0001).
Patients with retroperitoneal lymph node metastasis had a 5-year overall survival of 55% and a progression-free survival of 48%. Among patients with aortic node metastasis, 5-year overall survival was 31%, and progression-free survival, 27%. Table 4 examines outcomes of the 11 patients with aortic lymph node metastases. Three of 11 patients are alive with no evidence of recurrence more than 5 years postsurgery. Four have died of disease. One died of unrelated medical illness 24 months after diagnosis. Three died of medical illness without evidence of recurrent disease at 1, 2, and 8 months: one died of gastrointestinal bleeding following whole abdominal radiotherapy 8 months after diagnosis, one died from subarachnoid hemorrhage after anticoagulation for a deep venous thrombosis 2 months after surgery, and one died at an outside hospital from unknown causes within 1 month after surgery.
DISCUSSION
In this study of patients with endometrial cancer that appeared to be confined to the uterus at laparotomy, 5% had pelvic node metastasis, and 3% had aortic node metastasis. This is lower than the 9% and 6% incidences of pelvic and aortic node metastasis reported in the large Gynecologic Oncology Group study among patients with clinical stage I cancers.2 The lower incidence of nodal metastasis in our population likely is attributable to the exclusion of patients in whom enlarged nodes or other extrauterine cancer were identified intraoperatively. The objective of this study was to examine the value of selective lymphadenectomy in patients thought to have disease confined to the uterus at surgery, rather than the effect of debulking lymph nodes obviously involved with metastatic cancer.
We found that more extensive selective lymphadenectomy (> 11 pelvic lymph nodes) is associated with improved survival in women with grade 3 cancers without gross evidence of metastatic endometrial cancer at the time of hysterectomy. Although our use of a cutoff at the median number of nodes removed is relatively arbitrary, it is supported by statistical analysis of residuals. Our findings are consistent with those of Kilgore et al from the University of Alabama, Birmingham, who retrospectively reviewed 649 patients treated surgically for clinical stage I endometrial cancer and found that patients undergoing multiple site selective lymphadenectomy (median number of nodes removed, 11) had improved survival over those who did not have lymph node sampling performed.3 The survival difference persisted after patients were separated into pathologic risk groups and by adjuvant treatment. Several other authors have reported series in which complete pelvic lymphadenectomy was performed without adjuvant external beam radiotherapy, with excellent long-term results, suggesting a therapeutic benefit to the surgical procedure.4-6 One possible explanation for the potential beneficial effect of more extensive lymphadenectomy is the identification of patients with nodal metastases who are potentially curable with adjuvant treatment. In our study, patients with positive pelvic or aortic lymph nodes had a 5-year progression-free survival of 48% and overall survival of 55%. When controlling for administration of adjuvant radiotherapy in multivariate analysis, we found that the association between extent of lymphadenectomy and improved survival remained. This finding suggests that improved survival cannot be solely attributed to adjuvant therapy among patients having more extensive lymphadenectomy.
Another factor that may contribute to the therapeutic benefit of more extensive selective lymphadenectomy is the removal of occult small-volume metastatic disease that remains undiagnosed by the pathologist. Our finding that a more extensive lymphadenectomy was associated with improved survival after removing from the analysis patients reported to have pelvic or aortic nodal metastasis, is supportive of this hypothesis. Likewise, McMeekin et al7 hypothesized that the favorable 70% to 87% 3-year survival rate observed in their patients with lymph node metastases was due to the performance of complete lymphadenectomy in most cases.
A potential limitation of our study and others that use lymph node count as a surrogate for completeness of lymphadenectomy is that the total lymph node count may vary not only with the extent of the surgical dissection, but also due to differences in the pathologist’s evaluation of the surgical specimen. Because total node count is partially dependent on the pathologist’s gross assessment, it is not possible to perform a verifying independent pathology review. However, we believe that the number of nodes reported at our institution is generally reflective of the extent of lymphadenectomy. All surgical specimens in this study were processed at a single institution with relatively stable gross dissection procedures. The number of lymph nodes removed increased over time, possibly reflecting the formal institution by FIGO in 1988 of a surgical staging system for endometrial cancer that incorporates the results of lymph node sampling. The number of lymph nodes removed retained prognostic significance when controlling for the year surgery was performed.
Another potential limitation is selection bias, which is inherent in any retrospective study. Because we wished to focus on the outcomes of patients who underwent selective lymphadenectomy, we did not include in our survival analysis patients who did not have any lymph nodes removed. Table 1 shows that patients who did not undergo lymphadenectomy had primarily low-grade (59% grade 1), minimally invasive (90% less than half invasive), and low-risk histologic type (94% endometrioid or mucinous) cancers. Selection bias may also affect the analysis of the number of lymph nodes removed. As presented in Table 1, most prognostic factors seem to be fairly well balanced among patients who had greater than 11 v 11 or fewer pelvic lymph nodes removed. Those with more than 11 nodes removed were more likely to have a higher FIGO grade (P = .022). The decision to administer adjuvant therapy was also at the oncologist’s discretion and therefore subject to selection bias. We did control for the administration of adjuvant radiotherapy in multivariate analysis.
The addition of selective aortic lymphadenectomy to hysterectomy and selective pelvic lymphadenectomy was not associated with a survival benefit in our study. Since the incidence of aortic node metastasis in our series was only 3%, any overall survival benefit of selective aortic lymphadenectomy would likely be small and difficult to detect. Other authors have reported improved survival and lower retroperitoneal recurrence rates among high-risk patients who had aortic lymphadenectomy as part of their surgical staging procedure.8,9 While we were not able to demonstrate a direct benefit to aortic node sampling, these studies in combination with our findings suggest that more extensive lymphadenectomy may be beneficial.
We identified 11 patients with microscopic aortic node metastasis. Aortic node metastasis was strongly associated with lower overall (HR, 11.6) and progression-free (HR, 9.8) survival in multivariate analysis. This finding may be biased by the lack of performance of aortic lymphadenectomy in every patient. Because patients who did not undergo aortic lymphadenectomy were coded as "negative" for aortic node metastasis, the actual hazard ratio for aortic node metastasis may be higher than what we report. Among patients we identified with aortic node metastasis, three (27%) of eleven are without evidence of disease and all are more than 5 years from the date of diagnosis. Prior studies report 5-year survival rates of 36% to 67% for patients with aortic nodal metastasis,10-13and both extended-field radiotherapy and surgical resection have been associated with improved survival among these patients.14,15 The potential therapeutic benefit of aortic lymphadenectomy and radiation in a small subset of patients with metastatic disease must be weighed against the potential for increased morbidity and mortality in all patients who undergo this procedure. Extended-field radiotherapy following selective aortic lymphadenectomy has been associated with radiation enteritis and bowel obstruction.14 Although selective aortic lymphadenectomy did not significantly increase the frequency of perioperative adverse events, one patient with aortic nodal metastases died within 1 month of surgery, and another died at 2 months with a hemorrhagic complication of anticoagulation for a deep venous thrombus.
Previous work by our group and others indicated that the addition of selective pelvic and aortic lymphadenectomy to hysterectomy alone was associated with increased blood loss and hospital stay, but not an increase in postoperative complications.16,17 In the present study, the addition of aortic lymphadenectomy to pelvic lymphadenectomy was also associated with increased blood loss (200 mL), transfusion rates, hospital stay, and anesthesia time. The higher transfusion rate and longer hospital stay may be partially explained by the different proportions of each surgical group who were treated before 1985. Eighteen percent of patients undergoing selective pelvic lymphadenectomy alone were treated before 1985 compared with 47% of patients undergoing selective pelvic and aortic lymphadenectomy. Hospital stays and blood transfusion rates have decreased during the last 30 years with the advent of managed health care and concerns regarding blood-borne pathogens. This trend will likely accelerate with the increasing use of minimally invasive laparoscopic approaches for surgical management of endometrial cancer.
Given the low rate of aortic lymph node metastases in women with endometrial cancer that appears to be confined to the uterus at the time of laparotomy (3%), some have proposed that aortic lymphadenectomy should be limited to patients with high-risk features such as deep myometrial invasion and higher histologic grade.18 Unfortunately there is no risk factor profile that reliably identifies all patients with aortic nodal metastasis. Among 11 patients in our series with aortic node metastasis, four (36%) had only inner-half myometrial invasion, and one had grade 1 cancer preoperatively. Only six (55%) of 11 were grade 3 preoperatively, and the grade was increased to 3 postoperatively in four (36%) cases. Preoperative and frozen section diagnoses of tumor grade are sometimes inconsistent with the final pathologic grade.19 Finally, isolated aortic node metastasis is fairly common7; in our series, five of the 11 patients (45%) with positive aortic nodes had negative pelvic nodes and would not have received aortic radiation had selective pelvic lymphadenectomy alone been performed.
The finding that a more extensive pelvic lymphadenectomy is associated with improved survival suggests that there is value in performing this procedure in a systematic and thorough manner when feasible. At our institution, selective pelvic lymphadenectomy for patients with apparent early-stage endometrial cancer typically involves removing lymphatic tissue from the anterior and medial surfaces of the iliac vessels and from the obturator fossa superior to the obturator nerve. Aortic selective lymphadenectomy usually consists of removal of the precaval and lower right and left aortic lymphatic tissue to the level of the inferior mesenteric artery. The potential benefit of selective aortic lymphadenectomy should be weighed along with known prognostic factors and medical fitness in determining the suitability of individual patients for this procedure. These data add to the growing literature documenting the possible therapeutic benefit of selective lymphadenectomy in the management of patients with early-stage endometrial cancer.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Main plenary presentation, Society of Gynecologic Oncologists 35th Annual Meeting, San Diego, CA, February 7-11, 2004.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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