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Surgical and oncologic outcomes of minimally invasive surgery for stage I high-grade endometrial cancer
Journal Pre-proof Surgical and oncologic outcomes of minimally invasive surgery for stage I high-grade endometrial cancer Dimitrios Nasioudis, Quetrell D. Heyward, Ashley F. Haggerty, Robert L. Giuntoli, II, Robert A. Burger, Mark A. Morgan, Emily M. Ko, Nawar A. Latif PII:
S0960-7404(19)30162-8
DOI:
https://doi.org/10.1016/j.suronc.2020.02.015
Reference:
SO 1342
To appear in:
Surgical Oncology
Received Date: 6 April 2019 Revised Date:
31 October 2019
Accepted Date: 14 February 2020
Please cite this article as: Nasioudis D, Heyward QD, Haggerty AF, Giuntoli II RL, Burger RA, Morgan MA, Ko EM, Latif NA, Surgical and oncologic outcomes of minimally invasive surgery for stage I highgrade endometrial cancer, Surgical Oncology (2020), doi: https://doi.org/10.1016/j.suronc.2020.02.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
Surgical and oncologic outcomes of minimally invasive surgery for stage I high-grade endometrial cancer.
Dimitrios Nasioudis (1), Quetrell D. Heyward (1), Ashley F. Haggerty (1), Robert L. Giuntoli II (1), Robert A. Burger (1), Mark A. Morgan (1), Emily M. Ko (1), Nawar A. Latif (1).
(1) Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
Correspondence: Dimitrios Nasioudis M.D, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 1 West Gates, Philadelphia, PA, 19104, USA. Email: [email protected], [email protected] Phone: (215) 662-2730 Fax: (215) 349-5224
Objective: To evaluate the prevalence and outcomes of minimally invasive surgery for stage I high grade endometrial cancer. We hypothesized that route of surgery is not associated with survival.
Materials: Patients diagnosed between 2010-2014, with stage I grade 3 endometrioid, serous, clear cell and carcinosarcoma endometrial carcinoma, who underwent hysterectomy with lymphadenectomy were drawn from the National Cancer Database. Patients converted to open surgery were excluded. Overall survival was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to control for confounders.
Results: A total of 12852 patients were identified. The rate of minimally invasive surgery was 62.2%. An increase in the use between 2010 and 2014 was noted (p<0.001). Open surgery was associated with longer hospital stay (median 3 vs 1 day, p<0.001), higher 30-day unplanned readmission rate (4.5% vs 2.4%, p<0.001) and 30-day mortality (0.6% vs 0.3%, p=0.008). There was no difference in overall survival between patients who had open or minimally invasive surgery, p=0.22; 3-yr overall survival rates were 83.7% and 84.4% respectively. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, the presence of comorbidities and personal history of another tumor, minimally invasive surgery was not associated with a worse survival (hazard ratio: 1.06, 95% confidence interval: 0.97, 1.15).
Conclusions: Minimally invasive surgery for patients with stage I high grade endometrial cancer, was associated with superior short-term outcomes with no difference in overall survival noted.
Keywords: endometrial neoplasms; laparoscopes; laparotomy
1. Introduction In the United States, endometrial cancer is the most common malignancy of the female reproductive system with a projected 63,230 new cases diagnosed in 2018 [1]. Compared to low-grade endometrioid carcinoma, high-grade uterine tumors (high grade endometrioid, serous, carcinosarcoma and clear cell carcinoma) are less common, and exhibit a more aggressive behavior, with higher rates of parametrial, lymphatic and distant spread [2]. Non endometrioid tumors account for approximately 20% of all uterine tumors diagnosed in the United States, while based on an analysis of the Surveillance Epidemiology and End Results database among patients with endometrioid histology 15% have grade 3 tumors [3]. Surgical staging of endometrial cancer has traditionally been performed with a midline laparotomy and included systematic lymphadenectomy [4,5]. However, with the advancement of minimally invasive surgical techniques, multiple studies have investigated the safety of minimally invasive surgery for patients with endometrial cancer [4,5]. Multiple randomized trials have demonstrated that compared to open surgery, minimally invasive surgery is associated with shorter inpatient stay, better quality of life, lower postoperative pain and equal oncologic outcomes [4,5,6,7]. In the LAP2 trial, surgical staging using laparoscopy resulted in comparable intraoperative complications with fewer postoperative complications and an overall shorter hospital stay [6]. Moreover, the Laparoscopic Approach to Carcinoma of the Endometrium (LACE) trial compared disease-free survival of patients who had total laparoscopic hysterectomy and total abdominal hysterectomy in stage I endometrial cancer; following a median follow-up of 4.5 years, disease-free rates were equivalent for both groups [7]. Furthermore, similar to the LAP2 trial, comparable intraoperative complication rates but shorter hospital stay and postoperative adverse events were noted in the laparoscopic group [7].
Even though the safety of minimally invasive staging for low-grade endometrioid uterine cancer has been clearly demonstrated in the aforementioned trials, evidence is scarce regarding the oncologic outcomes of minimally invasive surgery for high-grade tumors. The LAP2 trial included only a small number of high-grade tumors (approximately 20%), while patients with non-endometrioid histology were excluded from the Laparoscopic Approach to Carcinoma of the Endometrium trial [5,6]. The aim of the present study was to investigate the prevalence and outcomes of minimally invasive staging for patients with pathological stage I high-grade uterine carcinoma using a large hospital based database.
2. Materials and Methods In the present study a cohort of patients diagnosed between 2010 and 2014 with an invasive tumor of the uterus was selected from the National Cancer Data Base. The National Cancer Database, established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons, is a hospital-based database capturing approximately 70% of all malignancies diagnosed in the United States. Patient data are prospectively collected from participating commission-accredited cancer programs and are frequently audited to ensure their high-quality [8]. All data are de-identified and available for research purposes. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data. The present study was deemed exempt from Institutional Board Review. Based on International Classification of Diseases (ICD-O)-3 histology codes, patients who were diagnosed with a pathologically confirmed serous, clear cell, grade 3 endometrioid carcinoma or carcinosarcoma of the endometrium were identified. Those with pathological stage I, who underwent hysterectomy (as assessed from site-specific surgery codes) and known route
of surgery (open or minimally invasive) were selected for further analysis. Disease substage was determined from information available from the collaborative staging fields. The exposure of interest was the performance of minimally invasive surgery including both laparoscopic and robotic-assisted modalities. Patients who did not undergo regional lymph node dissection, or had subtotal hysterectomy were excluded from the present study. In addition, we opted to exclude patients who underwent more than one surgical procedure. Lastly, patients who had staging initiated with minimally invasive surgery and were converted to open were excluded (n=313). Demographic, clinico-pathological, and treatment variables were extracted from the deidentified dataset. For analysis purposes, insurance status was recoded into Private, Government (including Medicaid and Medicare) and Uninsured/Unknown. Age was grouped into <65 and >=65 years. Presence of co-morbidities was assessed from the Charlson-Deyo Comorbidity index and categorized as absent (score 0) and present (score >=1). Primary endpoint was overall survival defined as the months elapsed from tumor diagnosis to the date of death or last-follow up. Secondary outcomes were median hospital stay, rate of unplanned 30 day readmission, and 30-day and 90-day mortality rate. The frequency of distribution of categorical variables was compared with the chi-square test or Fisher’s exact test and continuous variables with the Mann Whitney U test. Kaplan-Meier curves were generated to determine 3-year overall survival rates while univariate analysis was performed with the log-rank test. A Cox multivariable analysis was performed to control for variables associated with overall survival by univariable analysis. All statistical analysis was performed with the Statistical Package for the Social Sciences v.24 statistical package (International Business Machines Corporation, Armonk, NY) and the alpha level of statistical significance was set at 0.05.
3. Results A total of 12852 patients who met the inclusion criteria were identified. Median patient age was 66 years (interquartile range: 13), the majority had government issued insurance (55.3%) and did not have any comorbidities (74.6%). The most common histological type was high-grade endometrioid carcinoma (46.8%), followed by serous carcinoma (27.7%), carcinosarcoma (19.8%) and clear cell carcinoma (5.6%). In the present cohort, 40.7% patients did not receive radiation therapy or chemotherapy. Higher rates of omission of adjuvant treatment were noted among those with government issued insurance compared to those with private insurance (42.5% vs 38.3%, p<0.001).
The rate of minimally invasive surgery in our cohort was 62.2% with a significant increase in rate over time from 46% in 2010 to 71.9% in 2014 (p<0.001). The majority of minimally invasive procedures were robotic-assisted (n=6090, 76.2%) while only a quarter were laparoscopic (n=1901, 23.8%). According to the reverse Kaplan-Meier method, the median follow-up for the open and minimally invasive surgery groups was 47.77 (95% confidence interval: 46.77, 48.77) and 39.69 (95% CI: 39.05, 40.34) months respectively. Patients who underwent minimally invasive surgery were more likely to have private insurance, reside in higher income areas, have stage IA disease, and endometrioid histology. Information on peritoneal cytology and lymphovascular invasion was available for 9659 and 11876 patients respectively. The rate of positive cytology was higher among patients who had minimally invasive surgery (8.5% vs 5.3%, p<0.001) while the rate of lymphovascular invasion was comparable between minimally invasive surgery (25.5%) and open (24.6%) groups, p=0.29. The median number of regional lymph nodes removed was identical in the two groups (median 15, p=0.48); 70.4% and 71.3% of patients in open and minimally invasive surgery groups had at least 10 regional lymph nodes removed (p=0.30), while 33.8% and 33.3% respectively had at least 20 lymph nodes removed
(p=0.54) . However, based on data from 12751 patients the rate of para-aortic lymph node sampling/dissection (removal of at least one para-aortic lymph node) was slightly higher in the laparotomy group (65.3% vs 60.4%, p<0.001). Neverthelss, the median number of para-aortic lymph nodes removed was higher in the minimally invasive surgery group (median 5 vs 4, p<0.001). Table 1 summarizes the clinico-pathological characteristics of patients stratified by type of surgical approach.
Among patients in the minimally invasive surgery group, patients who had robotic-assisted hysterectomy compared to laparoscopic hysterectomy were more likely to have endometrioid tumors (50.1% vs 46.6%, p=0.04). There were no differences between the two groups regarding patient age (p=0.59), disease substage (p=0.98), type of insurance (p=0.34), type of treatment facility (p=0.64), or presence of comorbidities (p=0.71). Patients who had robotic-assisted hysterectomy were more likely to have at least 10 regional lymph nodes removed (71.4% vs 68.4%, p=0.015) and para-aortic (61% vs 58.3%, p=0.036) lymph node sampling/dissection compared to those who had conventional laparoscopic hysterectomy. Rates of lymphovascular invasion (25.8% vs 24.6%, p=0.30) and positive peritoneal cytology (8.6% vs 8.0%, p=0.52) were comparable between the robotic-assisted and conventional laparoscopy groups.
Postoperative outcomes differed between the laparotomy and minimally invasive surgery groups. The rate of unplanned 30-day readmission rate was higher among patients who had open surgery (4.5%) compared to those who had minimally invasive surgery (2.4%), p<0.001. They also had longer inpatient hospital stay (median 3 vs 1 day, p<0.001). On univariate analysis, there was no difference in overall survival between patients who had open or minimally invasive surgery, p=0.22; the 3-yr overall survival rate was 83.7% and 84.4% respectively (Figure 1). There was no difference in OS between the open and MIS groups for patients with endometrioid (p=0.65; 3-yr OS rates were 87.6% and 87.8% respectively), and non-
endometriod tumors (p=0.75, 3-yr OS rates were 80.7% and 81.1% respectively). The 30-day (0.6% vs 0.3%, p=0.008) and 90-day (1.1% vs 0.6%, p=0.001) mortality rates were higher in the open surgery group. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, presence of comorbidities and personal history of another tumor, minimally invasive surgery was not associated with a worse survival (hazard ratio: 1.06, 95% confidence interval: 0.97, 1.15) (Table 2).
When analyzing patients in the minimally invasive surgery group, the rate of unplanned 30-day readmission (2.4% vs 2.1%, p=0.42), 30-day (0.3% vs 0.3%, p=0.81) and 90-day (0.6% vs 0.6%, p=0.99) mortality rates were comparable between the robotic-assisted and conventional laparoscopy groups. Similarly, by univariate analysis, there was no difference in overall survival between the robotic-assisted and conventional laparoscopy groups, p=0.98; 3-year overall survival rates were 84.2% vs 84.9% respectively. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, presence of comorbidities and personal history of another tumor, there was no difference in survival between the robotic-assisted and conventional laparoscopy groups (hazard ratio: 1.04, 95% confidence interval: 0.92, 1.18)
4. Discussion In this large cohort of stage postoperative I high-grade endometrial carcinoma, an increase in the use of minimally invasive surgery over time was observed. The use of minimally invasive surgery was associated with superior short-term outcomes (shorter hospital stay, lower re-admission and early mortality rates). There was no difference in overall survival between those who underwent minimally invasive compared to open surgery.
The staging of endometrial carcinoma has been greatly transformed over the last several decades with the introduction of minimally invasive techniques. The LAP2, and similar trials were influential in the field of gynecologic oncology for providing level I evidence on the oncologic safety of minimally invasive surgery for patients with predominantly low-grade endometrioid endometrial cancer [6,7]. Compared to laparotomy, minimally invasive surgery is associated with shorter hospital stay and a lower postoperative complications rate [4-7]. However, while minimally invasive surgery has been established as an oncologically safe approach for low-grade endometrioid carcinoma, there has been limited data supporting its use for high-grade tumors, which have been derived primarily from retrospective studies [9-14]. Given the recent concern of possible detrimental effects upon cancer recurrence and cancer specific survival related to employing minimally invasive surgery in cervical cancer, found both in retrospective as well as randomized prospective studies, we sought to evaluate the effect of minimally invasive surgery on particularly high-risk endometrial cancer patients [15]. Although our study was not prospective in nature, our sample size of over 12,000 patients in this national cohort, still did not show a trend of worse survival due to use of minimally invasive surgery. Our findings support those previously published regarding the use of minimally invasive surgery in high risk endometrial cancer. In a multicenter retrospective case-control study, 114 patients with high-risk endometrial cancer (high grade endometrioid, serous, clear cell, mixed and carcinosarcoma) who underwent minimally invasive surgery were matched for age, stage, histology and performance of lymphadenectomy to patients who had laparotomy. Those who had minimally invasive surgery were less likely to undergo para-aortic lymphadenectomy while they had less extensive lymph node dissection. However, the five-year disease free survival (60% vs 62%, p=0.71) and overall survival rates (66 vs 72%, p=0.66) were comparable between the minimally invasive surgery (the median follow up 51 months) and laparotomy (the median follow up 69 months) groups [9]. In another retrospective multicenter study that included patients with high grade endometrial cancer who had surgery at high-volume academic centers, 191
underwent laparotomy and 192 minimally invasive surgery (65% robotic, 35% laparoscopy). There were no differences between the two groups with regard to age, stage, body mass index, histology and receipt of adjuvant treatment, while the median follow-up was 44 months. After controlling for stage, no difference in overall or progression-free survival was noted between the two groups. However, the rate of complications was significantly lower in the minimally invasive surgery group (8.4% vs 31.3%, p<0.001) [10]. Monterossi et al (2017), compared the outcomes of 141 and 142 patients with high-grade tumors who had minimally invasive surgery and open surgery. A higher relapse rate was observed in the laparotomy group (33.9% vs 17.7%), however the study included a higher percentage of advanced stage disease. Among patients with stage I disease, there was no difference in overall survival based on the mode of surgery (p=0.79) [11]. In the largest cohort to date, Fader et al (2016), performed a sub-analysis of the LAP2 trial and evaluated the impact of surgical staging mode on the outcomes of 753 patients with high grade disease. Recurrence rates (25.9% versus 27.9%, respectively), patterns of recurrence, progression-free and overall survival were comparable between patients staged with laparoscopy and laparotomy [16] Para-aortic lymph node involvement can occur in approximately 7-8 % of all patients with endometrial cancer, about 50 % of patients with positive pelvic nodes and is associated with a poor prognosis [17]. In our study, almost 40% of the study population did not undergo PaLND, while patients who had MIS were less likely to undergo PaLND. Lower rates of PaLND among patients who underwent MIS were also noted in the LAP2 trial [6]. In the SEPAL study, patients with intermediate-high risk tumors who underwent PaLND had a survival benefit compared to those who did not [18]. Similarly in a recent analysis of the NCDB, for patients with serous tumors, pelvic and para-aortic LND was associated with decreased risk of death (HR=0.85, 95% CI: 0.79-0.91) compared to pelvic LND alone [19]. Further studies should investigate patterns of PaLND for patients with high-grade tumors and factors associated with its omission. Moreover,
suprisingly a large percentage of patients in our cohort did not receive any adjuvant treatment contrary to major guidelines. One of the concerns regarding the safety of minimally invasive surgery arises from the use of uterine manipulators that can theoretically precipitate tumor spillage especially when handling large tumors [20]. Indeed, in our study we noted a higher incidence of positive peritoneal cytology among patients who had minimally invasive surgery. We could not verify if the greater frequency of positive peritoneal cytology was directly associated with the use of a uterine manipulator or Tredelenburg position. Preoperative diagnosis of endometrial cancer with the use of hysteroscopy with or without distention media may have also impacted the rates of positive cytology. In a systematic review and meta-analysis, based on data from 9 studies hysteroscopy resulted in a significantly higher rate of malignant peritoneal cytology [21]. Positive cytology has been eliminated from the revised Fédération Internationale de
Gynécologie et d’Obstétrique (FIGO) staging schema of endometrial cancer but may be associated with worse outcomes based on a recent retrospective analysis of the National Cancer Database [22]. In our cohort, patients with positive peritoneal cytology (n=701) had significantly worse overall survival compared to those without (n=8958), p<0.001; 5-year overall survival rates were 63.8% versus 76% (Supplemental Figure 1). A higher rate of positive peritoneal cytology was observed among patients with lymphovascular invasion (10% vs 6.3%, p<0.001). However, it should be mentioned that following stratification by cytology status, route of surgery was not associated with survival. Moreover, the performance of colpotomy in a patient with a malignancy placed in steep Tredelenburg could potentially affect site of recurrence. For patients with cervical cancer, a laparoscopic assisted vaginal radical hysterectomy with vaginal closure of the cuff and avoidance of a uterine manipulator, has been proposed and provides excellent oncologic outcomes [23]. Further studies should investigate the role of LAVH in the management of patients with uterine cancer with a focus on patterns of
recurrence. Lastly, another theoretical concern of minimally invasive surgery is creation of artificial lymphovsascular invasion attributed to the use of a uterine manipulator [24]. In our cohort we did not observe any differences in the rate of lymphovascular invasion between the minimally invasive and open surgery groups. A major strength of the present study is the large number of patients included. In addition and contrary to other retrospective studies, we carefully selected only patients with pathological stage I who had lymph node surgery minimizing the potential bias introduced by including inadequately staged or advance stage cases. Patients who did not have LND (n=1806) had a significantly worse survival as depicted in Supplemental Figure 2 with a 3-yr OS rate of 71.6%. In a secondary analysis, we also identified 9532 patients with microscopically confirmed high grade endometrial carcinoma and clinical stage I who had hysterectomy with LND and evaluated their survival based on route of surgery. Rate of MIS was 61.8% and again there was no difference in OS between the open (n=3639) and MIS (n=5893) groups, p=0.13; 3-yr OS rates were 79.5% and 80.6% respectively (Supplemental figure 3). Several limitations of the present study should be noted. Due to the lack of central pathology report possible tumor misclassifications cannot be excluded. Also information on parameters that may have influenced surgeon choice towards minimally invasive or open surgery such as patient’s surgical history, body mass index, uterine size, and specific comorbidities, were lacking while undereporting of comorbidities may have occured. We also opted to exclude patients who had surgery initiated laparoscopically and then converted to open. Three year survival rate of these patients was 80.6% comparable to those who had MIS or open surgery (Supplemental Figure 4). In addition, the National Cancer Database does not collect information on cancer relapse or the cause of death, precluding us from analyzing differences in progression free and cause specific survival. Lastly, the median follow-up for our
cohort was less than five years, thus longitudinal data related to outcomes of laparoscopy versus laparotomy were not available. The results of the present study support the utilization of minimally invasive techniques for surgical staging of high risk endometrial histologies. Since the current evidence was mainly derived from retrospective studies with a relative short follow-up (<5 years), prospective multicenter studies with a longer follow-up are required to provide conclusive evidence on the safety of minimally invasive surgery for patients with high-grade endometrial tumors.
Conflicts of interest None to report
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Table 1. Clinico-pathological characteristics of patients with FIGO stage I high-grade endometrial cancer stratified by route of surgery. Open
MIS
Age (years) <65 >=65
2119 (43.6%) 2742 (56.4%)
3479 (43.5%) 4512 (56.5%)
Year of diagnosis 2010 2011 2012 2013 2014
1253 (25.8%) 1099 (22.6%) 927 (19.1%) 812 (16.7%) 770 (15.8%)
1066 (13.3%) 1513 (18.9%) 1553 (19.4%) 1888 (23.6%) 1971 (24.7%)
Median Income($) <38000 38000-47999 48000-62999 >=63000
949 (19.6%) 1054 (21.8%) 1252 (25.9%) 1588 (32.8%)
1245 (15.6%) 1767 (22.1%) 2116 (26.5%) 2850 (35.7%)
Comorbidities No Yes
3575 (73.5%) 1286 (26.5%)
6012 (75.2%) 1979 (24.8%)
p value 0.95
<0.001
<0.001
0.033
Open
MIS
Hx of another tumor No Yes
3794 (78%) 1067 (22%)
6474 (81%) 1517 (19%)
Insurance Private Government Uninsured/Unknown
1821 (37.5%) 2718 (55.9%) 322 (6.6%)
3338 (41.8%) 4390 (54.9%) 263 (3.3%)
Reporting facility Academic Non-academic Unknown*
2514 (51.7%) 2297 (47.3%) 50 (1%)
3670 (45.9%) 4261 (53.3%) 60 (0.8%)
Histology Endometrioid Serous Clear cell Carcinosarcoma
2083 (42.9%) 1350 (27.8%) 272 (5.6%) 1156 (23.8%)
3935 (49.2%) 2216 (27.7%) 454 (5.7%) 1386 (17.3%)
Substage IA IB I Not otherwise specified
3298 (67.8%) 1389 (28.6%) 174 (3.6%)
5602 (70.1%) 2209 (27.6%) 180 (2.3%)
Radiation therapy No Yes Unknown
2873 (59.1%) 1961 (40.3%) 27 (0.6%)
4450 (55.7%) 3493 (43.7%) 48 (0.6%)
Chemotherapy No Yes Unknown
2986 (61.4%) 1739 (35.8%) 136 (2.8%)
4856 (60.8%) 2912 (36.4%) 223 (2.8%)
p value <0.001
<0.001
<0.001
<0.001
<0.001
0.001
0.75
*type of treatment facility is suppressed for patients aged <40 years.
Table 2. Multivariate analysis of variables independently associated with overall survival.
Surgical approach Open Minimally invasive
Ref 1.06 (0.97, 1.15)
Age (yrs) <65 >=65
Ref 1.71 (1.52, 1.93)
Comorbidities No Yes
Ref 1.21 (1.11, 1.32)
History of another tumor No Yes
Ref 1.43 (1.30, 1.56)
Insurance type Private Government Uninsured/Unknown
Ref 1.25 (1.11, 1.40) 1.14 (0.90, 1.44)
Reporting facility Academic Non-academic Unknown*
Ref 1.08 (0.99, 1.17) 0.24 (0.08, 0.73)
Histology Endometrioid Serous Clear cell Carcinosarcoma
Ref 1.33 (1.22, 1.53) 1.30 (1.10, 1.61) 2.57 (2.31, 2.86)
Substage IA IB I Not otherwise specified
Ref 1.74 (1.60, 1.90) 1.34 (1.06, 1.69)
Lymph nodes removed <10 >=10 Unknown
Ref 0.81 (0.74, 0.88) 0.86 (0.59, 1.28)
Radiation therapy No Yes Unknown
Ref 0.90 (0.82, 0.98) 1.08 (0.67, 1.72)
Chemotherapy No Yes Unknown
Ref 0.62 (0.57, 0.69) 0.89 (0.70, 1.15)
*type of treatment facility is suppressed for patients aged <40 years.
Figure 1. Overall survival of patients with stage I high-grade endometrial cancer stratified by route of surgery, p=0.22 from log-rank.
Supplemental figure 1. Overall survival of patients with stage I high-grade endometrial cancer stratified by peritoneal cytology status, p<0.001 from log-rank.
Supplemental Figure 2. Overall survival of patients with stage I high-grade endometrial cancer stratified by performance of lymphadenectomy, p<0.001 from log-rank.
Supplemental Figure 3. Overall survival of patients with clinical stage I high-grade endometrial cancer stratified by route of surgery, p=0.13 from long rank.
Supplemental Figure 4. Overall survival of patients with stage I high-grade endometrial cancer who were converted from MIS to open surgery.
• Rate of MIS use for stage I high grade endometrial cancer was 62.2% • MIS was asscociated with superior short term surgical outcomes • There was no difference in 3-yr OS between MIS and open surgery.
S0960-7404(19)30162-8
DOI:
https://doi.org/10.1016/j.suronc.2020.02.015
Reference:
SO 1342
To appear in:
Surgical Oncology
Received Date: 6 April 2019 Revised Date:
31 October 2019
Accepted Date: 14 February 2020
Please cite this article as: Nasioudis D, Heyward QD, Haggerty AF, Giuntoli II RL, Burger RA, Morgan MA, Ko EM, Latif NA, Surgical and oncologic outcomes of minimally invasive surgery for stage I highgrade endometrial cancer, Surgical Oncology (2020), doi: https://doi.org/10.1016/j.suronc.2020.02.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
Surgical and oncologic outcomes of minimally invasive surgery for stage I high-grade endometrial cancer.
Dimitrios Nasioudis (1), Quetrell D. Heyward (1), Ashley F. Haggerty (1), Robert L. Giuntoli II (1), Robert A. Burger (1), Mark A. Morgan (1), Emily M. Ko (1), Nawar A. Latif (1).
(1) Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, Pennsylvania, USA
Correspondence: Dimitrios Nasioudis M.D, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 1 West Gates, Philadelphia, PA, 19104, USA. Email: [email protected], [email protected] Phone: (215) 662-2730 Fax: (215) 349-5224
Objective: To evaluate the prevalence and outcomes of minimally invasive surgery for stage I high grade endometrial cancer. We hypothesized that route of surgery is not associated with survival.
Materials: Patients diagnosed between 2010-2014, with stage I grade 3 endometrioid, serous, clear cell and carcinosarcoma endometrial carcinoma, who underwent hysterectomy with lymphadenectomy were drawn from the National Cancer Database. Patients converted to open surgery were excluded. Overall survival was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to control for confounders.
Results: A total of 12852 patients were identified. The rate of minimally invasive surgery was 62.2%. An increase in the use between 2010 and 2014 was noted (p<0.001). Open surgery was associated with longer hospital stay (median 3 vs 1 day, p<0.001), higher 30-day unplanned readmission rate (4.5% vs 2.4%, p<0.001) and 30-day mortality (0.6% vs 0.3%, p=0.008). There was no difference in overall survival between patients who had open or minimally invasive surgery, p=0.22; 3-yr overall survival rates were 83.7% and 84.4% respectively. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, the presence of comorbidities and personal history of another tumor, minimally invasive surgery was not associated with a worse survival (hazard ratio: 1.06, 95% confidence interval: 0.97, 1.15).
Conclusions: Minimally invasive surgery for patients with stage I high grade endometrial cancer, was associated with superior short-term outcomes with no difference in overall survival noted.
Keywords: endometrial neoplasms; laparoscopes; laparotomy
1. Introduction In the United States, endometrial cancer is the most common malignancy of the female reproductive system with a projected 63,230 new cases diagnosed in 2018 [1]. Compared to low-grade endometrioid carcinoma, high-grade uterine tumors (high grade endometrioid, serous, carcinosarcoma and clear cell carcinoma) are less common, and exhibit a more aggressive behavior, with higher rates of parametrial, lymphatic and distant spread [2]. Non endometrioid tumors account for approximately 20% of all uterine tumors diagnosed in the United States, while based on an analysis of the Surveillance Epidemiology and End Results database among patients with endometrioid histology 15% have grade 3 tumors [3]. Surgical staging of endometrial cancer has traditionally been performed with a midline laparotomy and included systematic lymphadenectomy [4,5]. However, with the advancement of minimally invasive surgical techniques, multiple studies have investigated the safety of minimally invasive surgery for patients with endometrial cancer [4,5]. Multiple randomized trials have demonstrated that compared to open surgery, minimally invasive surgery is associated with shorter inpatient stay, better quality of life, lower postoperative pain and equal oncologic outcomes [4,5,6,7]. In the LAP2 trial, surgical staging using laparoscopy resulted in comparable intraoperative complications with fewer postoperative complications and an overall shorter hospital stay [6]. Moreover, the Laparoscopic Approach to Carcinoma of the Endometrium (LACE) trial compared disease-free survival of patients who had total laparoscopic hysterectomy and total abdominal hysterectomy in stage I endometrial cancer; following a median follow-up of 4.5 years, disease-free rates were equivalent for both groups [7]. Furthermore, similar to the LAP2 trial, comparable intraoperative complication rates but shorter hospital stay and postoperative adverse events were noted in the laparoscopic group [7].
Even though the safety of minimally invasive staging for low-grade endometrioid uterine cancer has been clearly demonstrated in the aforementioned trials, evidence is scarce regarding the oncologic outcomes of minimally invasive surgery for high-grade tumors. The LAP2 trial included only a small number of high-grade tumors (approximately 20%), while patients with non-endometrioid histology were excluded from the Laparoscopic Approach to Carcinoma of the Endometrium trial [5,6]. The aim of the present study was to investigate the prevalence and outcomes of minimally invasive staging for patients with pathological stage I high-grade uterine carcinoma using a large hospital based database.
2. Materials and Methods In the present study a cohort of patients diagnosed between 2010 and 2014 with an invasive tumor of the uterus was selected from the National Cancer Data Base. The National Cancer Database, established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons, is a hospital-based database capturing approximately 70% of all malignancies diagnosed in the United States. Patient data are prospectively collected from participating commission-accredited cancer programs and are frequently audited to ensure their high-quality [8]. All data are de-identified and available for research purposes. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data. The present study was deemed exempt from Institutional Board Review. Based on International Classification of Diseases (ICD-O)-3 histology codes, patients who were diagnosed with a pathologically confirmed serous, clear cell, grade 3 endometrioid carcinoma or carcinosarcoma of the endometrium were identified. Those with pathological stage I, who underwent hysterectomy (as assessed from site-specific surgery codes) and known route
of surgery (open or minimally invasive) were selected for further analysis. Disease substage was determined from information available from the collaborative staging fields. The exposure of interest was the performance of minimally invasive surgery including both laparoscopic and robotic-assisted modalities. Patients who did not undergo regional lymph node dissection, or had subtotal hysterectomy were excluded from the present study. In addition, we opted to exclude patients who underwent more than one surgical procedure. Lastly, patients who had staging initiated with minimally invasive surgery and were converted to open were excluded (n=313). Demographic, clinico-pathological, and treatment variables were extracted from the deidentified dataset. For analysis purposes, insurance status was recoded into Private, Government (including Medicaid and Medicare) and Uninsured/Unknown. Age was grouped into <65 and >=65 years. Presence of co-morbidities was assessed from the Charlson-Deyo Comorbidity index and categorized as absent (score 0) and present (score >=1). Primary endpoint was overall survival defined as the months elapsed from tumor diagnosis to the date of death or last-follow up. Secondary outcomes were median hospital stay, rate of unplanned 30 day readmission, and 30-day and 90-day mortality rate. The frequency of distribution of categorical variables was compared with the chi-square test or Fisher’s exact test and continuous variables with the Mann Whitney U test. Kaplan-Meier curves were generated to determine 3-year overall survival rates while univariate analysis was performed with the log-rank test. A Cox multivariable analysis was performed to control for variables associated with overall survival by univariable analysis. All statistical analysis was performed with the Statistical Package for the Social Sciences v.24 statistical package (International Business Machines Corporation, Armonk, NY) and the alpha level of statistical significance was set at 0.05.
3. Results A total of 12852 patients who met the inclusion criteria were identified. Median patient age was 66 years (interquartile range: 13), the majority had government issued insurance (55.3%) and did not have any comorbidities (74.6%). The most common histological type was high-grade endometrioid carcinoma (46.8%), followed by serous carcinoma (27.7%), carcinosarcoma (19.8%) and clear cell carcinoma (5.6%). In the present cohort, 40.7% patients did not receive radiation therapy or chemotherapy. Higher rates of omission of adjuvant treatment were noted among those with government issued insurance compared to those with private insurance (42.5% vs 38.3%, p<0.001).
The rate of minimally invasive surgery in our cohort was 62.2% with a significant increase in rate over time from 46% in 2010 to 71.9% in 2014 (p<0.001). The majority of minimally invasive procedures were robotic-assisted (n=6090, 76.2%) while only a quarter were laparoscopic (n=1901, 23.8%). According to the reverse Kaplan-Meier method, the median follow-up for the open and minimally invasive surgery groups was 47.77 (95% confidence interval: 46.77, 48.77) and 39.69 (95% CI: 39.05, 40.34) months respectively. Patients who underwent minimally invasive surgery were more likely to have private insurance, reside in higher income areas, have stage IA disease, and endometrioid histology. Information on peritoneal cytology and lymphovascular invasion was available for 9659 and 11876 patients respectively. The rate of positive cytology was higher among patients who had minimally invasive surgery (8.5% vs 5.3%, p<0.001) while the rate of lymphovascular invasion was comparable between minimally invasive surgery (25.5%) and open (24.6%) groups, p=0.29. The median number of regional lymph nodes removed was identical in the two groups (median 15, p=0.48); 70.4% and 71.3% of patients in open and minimally invasive surgery groups had at least 10 regional lymph nodes removed (p=0.30), while 33.8% and 33.3% respectively had at least 20 lymph nodes removed
(p=0.54) . However, based on data from 12751 patients the rate of para-aortic lymph node sampling/dissection (removal of at least one para-aortic lymph node) was slightly higher in the laparotomy group (65.3% vs 60.4%, p<0.001). Neverthelss, the median number of para-aortic lymph nodes removed was higher in the minimally invasive surgery group (median 5 vs 4, p<0.001). Table 1 summarizes the clinico-pathological characteristics of patients stratified by type of surgical approach.
Among patients in the minimally invasive surgery group, patients who had robotic-assisted hysterectomy compared to laparoscopic hysterectomy were more likely to have endometrioid tumors (50.1% vs 46.6%, p=0.04). There were no differences between the two groups regarding patient age (p=0.59), disease substage (p=0.98), type of insurance (p=0.34), type of treatment facility (p=0.64), or presence of comorbidities (p=0.71). Patients who had robotic-assisted hysterectomy were more likely to have at least 10 regional lymph nodes removed (71.4% vs 68.4%, p=0.015) and para-aortic (61% vs 58.3%, p=0.036) lymph node sampling/dissection compared to those who had conventional laparoscopic hysterectomy. Rates of lymphovascular invasion (25.8% vs 24.6%, p=0.30) and positive peritoneal cytology (8.6% vs 8.0%, p=0.52) were comparable between the robotic-assisted and conventional laparoscopy groups.
Postoperative outcomes differed between the laparotomy and minimally invasive surgery groups. The rate of unplanned 30-day readmission rate was higher among patients who had open surgery (4.5%) compared to those who had minimally invasive surgery (2.4%), p<0.001. They also had longer inpatient hospital stay (median 3 vs 1 day, p<0.001). On univariate analysis, there was no difference in overall survival between patients who had open or minimally invasive surgery, p=0.22; the 3-yr overall survival rate was 83.7% and 84.4% respectively (Figure 1). There was no difference in OS between the open and MIS groups for patients with endometrioid (p=0.65; 3-yr OS rates were 87.6% and 87.8% respectively), and non-
endometriod tumors (p=0.75, 3-yr OS rates were 80.7% and 81.1% respectively). The 30-day (0.6% vs 0.3%, p=0.008) and 90-day (1.1% vs 0.6%, p=0.001) mortality rates were higher in the open surgery group. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, presence of comorbidities and personal history of another tumor, minimally invasive surgery was not associated with a worse survival (hazard ratio: 1.06, 95% confidence interval: 0.97, 1.15) (Table 2).
When analyzing patients in the minimally invasive surgery group, the rate of unplanned 30-day readmission (2.4% vs 2.1%, p=0.42), 30-day (0.3% vs 0.3%, p=0.81) and 90-day (0.6% vs 0.6%, p=0.99) mortality rates were comparable between the robotic-assisted and conventional laparoscopy groups. Similarly, by univariate analysis, there was no difference in overall survival between the robotic-assisted and conventional laparoscopy groups, p=0.98; 3-year overall survival rates were 84.2% vs 84.9% respectively. After controlling for patient age, tumor histology, substage, type of insurance, type of reporting facility, receipt of radiation therapy and chemotherapy, extent of lymphadenectomy, presence of comorbidities and personal history of another tumor, there was no difference in survival between the robotic-assisted and conventional laparoscopy groups (hazard ratio: 1.04, 95% confidence interval: 0.92, 1.18)
4. Discussion In this large cohort of stage postoperative I high-grade endometrial carcinoma, an increase in the use of minimally invasive surgery over time was observed. The use of minimally invasive surgery was associated with superior short-term outcomes (shorter hospital stay, lower re-admission and early mortality rates). There was no difference in overall survival between those who underwent minimally invasive compared to open surgery.
The staging of endometrial carcinoma has been greatly transformed over the last several decades with the introduction of minimally invasive techniques. The LAP2, and similar trials were influential in the field of gynecologic oncology for providing level I evidence on the oncologic safety of minimally invasive surgery for patients with predominantly low-grade endometrioid endometrial cancer [6,7]. Compared to laparotomy, minimally invasive surgery is associated with shorter hospital stay and a lower postoperative complications rate [4-7]. However, while minimally invasive surgery has been established as an oncologically safe approach for low-grade endometrioid carcinoma, there has been limited data supporting its use for high-grade tumors, which have been derived primarily from retrospective studies [9-14]. Given the recent concern of possible detrimental effects upon cancer recurrence and cancer specific survival related to employing minimally invasive surgery in cervical cancer, found both in retrospective as well as randomized prospective studies, we sought to evaluate the effect of minimally invasive surgery on particularly high-risk endometrial cancer patients [15]. Although our study was not prospective in nature, our sample size of over 12,000 patients in this national cohort, still did not show a trend of worse survival due to use of minimally invasive surgery. Our findings support those previously published regarding the use of minimally invasive surgery in high risk endometrial cancer. In a multicenter retrospective case-control study, 114 patients with high-risk endometrial cancer (high grade endometrioid, serous, clear cell, mixed and carcinosarcoma) who underwent minimally invasive surgery were matched for age, stage, histology and performance of lymphadenectomy to patients who had laparotomy. Those who had minimally invasive surgery were less likely to undergo para-aortic lymphadenectomy while they had less extensive lymph node dissection. However, the five-year disease free survival (60% vs 62%, p=0.71) and overall survival rates (66 vs 72%, p=0.66) were comparable between the minimally invasive surgery (the median follow up 51 months) and laparotomy (the median follow up 69 months) groups [9]. In another retrospective multicenter study that included patients with high grade endometrial cancer who had surgery at high-volume academic centers, 191
underwent laparotomy and 192 minimally invasive surgery (65% robotic, 35% laparoscopy). There were no differences between the two groups with regard to age, stage, body mass index, histology and receipt of adjuvant treatment, while the median follow-up was 44 months. After controlling for stage, no difference in overall or progression-free survival was noted between the two groups. However, the rate of complications was significantly lower in the minimally invasive surgery group (8.4% vs 31.3%, p<0.001) [10]. Monterossi et al (2017), compared the outcomes of 141 and 142 patients with high-grade tumors who had minimally invasive surgery and open surgery. A higher relapse rate was observed in the laparotomy group (33.9% vs 17.7%), however the study included a higher percentage of advanced stage disease. Among patients with stage I disease, there was no difference in overall survival based on the mode of surgery (p=0.79) [11]. In the largest cohort to date, Fader et al (2016), performed a sub-analysis of the LAP2 trial and evaluated the impact of surgical staging mode on the outcomes of 753 patients with high grade disease. Recurrence rates (25.9% versus 27.9%, respectively), patterns of recurrence, progression-free and overall survival were comparable between patients staged with laparoscopy and laparotomy [16] Para-aortic lymph node involvement can occur in approximately 7-8 % of all patients with endometrial cancer, about 50 % of patients with positive pelvic nodes and is associated with a poor prognosis [17]. In our study, almost 40% of the study population did not undergo PaLND, while patients who had MIS were less likely to undergo PaLND. Lower rates of PaLND among patients who underwent MIS were also noted in the LAP2 trial [6]. In the SEPAL study, patients with intermediate-high risk tumors who underwent PaLND had a survival benefit compared to those who did not [18]. Similarly in a recent analysis of the NCDB, for patients with serous tumors, pelvic and para-aortic LND was associated with decreased risk of death (HR=0.85, 95% CI: 0.79-0.91) compared to pelvic LND alone [19]. Further studies should investigate patterns of PaLND for patients with high-grade tumors and factors associated with its omission. Moreover,
suprisingly a large percentage of patients in our cohort did not receive any adjuvant treatment contrary to major guidelines. One of the concerns regarding the safety of minimally invasive surgery arises from the use of uterine manipulators that can theoretically precipitate tumor spillage especially when handling large tumors [20]. Indeed, in our study we noted a higher incidence of positive peritoneal cytology among patients who had minimally invasive surgery. We could not verify if the greater frequency of positive peritoneal cytology was directly associated with the use of a uterine manipulator or Tredelenburg position. Preoperative diagnosis of endometrial cancer with the use of hysteroscopy with or without distention media may have also impacted the rates of positive cytology. In a systematic review and meta-analysis, based on data from 9 studies hysteroscopy resulted in a significantly higher rate of malignant peritoneal cytology [21]. Positive cytology has been eliminated from the revised Fédération Internationale de
Gynécologie et d’Obstétrique (FIGO) staging schema of endometrial cancer but may be associated with worse outcomes based on a recent retrospective analysis of the National Cancer Database [22]. In our cohort, patients with positive peritoneal cytology (n=701) had significantly worse overall survival compared to those without (n=8958), p<0.001; 5-year overall survival rates were 63.8% versus 76% (Supplemental Figure 1). A higher rate of positive peritoneal cytology was observed among patients with lymphovascular invasion (10% vs 6.3%, p<0.001). However, it should be mentioned that following stratification by cytology status, route of surgery was not associated with survival. Moreover, the performance of colpotomy in a patient with a malignancy placed in steep Tredelenburg could potentially affect site of recurrence. For patients with cervical cancer, a laparoscopic assisted vaginal radical hysterectomy with vaginal closure of the cuff and avoidance of a uterine manipulator, has been proposed and provides excellent oncologic outcomes [23]. Further studies should investigate the role of LAVH in the management of patients with uterine cancer with a focus on patterns of
recurrence. Lastly, another theoretical concern of minimally invasive surgery is creation of artificial lymphovsascular invasion attributed to the use of a uterine manipulator [24]. In our cohort we did not observe any differences in the rate of lymphovascular invasion between the minimally invasive and open surgery groups. A major strength of the present study is the large number of patients included. In addition and contrary to other retrospective studies, we carefully selected only patients with pathological stage I who had lymph node surgery minimizing the potential bias introduced by including inadequately staged or advance stage cases. Patients who did not have LND (n=1806) had a significantly worse survival as depicted in Supplemental Figure 2 with a 3-yr OS rate of 71.6%. In a secondary analysis, we also identified 9532 patients with microscopically confirmed high grade endometrial carcinoma and clinical stage I who had hysterectomy with LND and evaluated their survival based on route of surgery. Rate of MIS was 61.8% and again there was no difference in OS between the open (n=3639) and MIS (n=5893) groups, p=0.13; 3-yr OS rates were 79.5% and 80.6% respectively (Supplemental figure 3). Several limitations of the present study should be noted. Due to the lack of central pathology report possible tumor misclassifications cannot be excluded. Also information on parameters that may have influenced surgeon choice towards minimally invasive or open surgery such as patient’s surgical history, body mass index, uterine size, and specific comorbidities, were lacking while undereporting of comorbidities may have occured. We also opted to exclude patients who had surgery initiated laparoscopically and then converted to open. Three year survival rate of these patients was 80.6% comparable to those who had MIS or open surgery (Supplemental Figure 4). In addition, the National Cancer Database does not collect information on cancer relapse or the cause of death, precluding us from analyzing differences in progression free and cause specific survival. Lastly, the median follow-up for our
cohort was less than five years, thus longitudinal data related to outcomes of laparoscopy versus laparotomy were not available. The results of the present study support the utilization of minimally invasive techniques for surgical staging of high risk endometrial histologies. Since the current evidence was mainly derived from retrospective studies with a relative short follow-up (<5 years), prospective multicenter studies with a longer follow-up are required to provide conclusive evidence on the safety of minimally invasive surgery for patients with high-grade endometrial tumors.
Conflicts of interest None to report
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Table 1. Clinico-pathological characteristics of patients with FIGO stage I high-grade endometrial cancer stratified by route of surgery. Open
MIS
Age (years) <65 >=65
2119 (43.6%) 2742 (56.4%)
3479 (43.5%) 4512 (56.5%)
Year of diagnosis 2010 2011 2012 2013 2014
1253 (25.8%) 1099 (22.6%) 927 (19.1%) 812 (16.7%) 770 (15.8%)
1066 (13.3%) 1513 (18.9%) 1553 (19.4%) 1888 (23.6%) 1971 (24.7%)
Median Income($) <38000 38000-47999 48000-62999 >=63000
949 (19.6%) 1054 (21.8%) 1252 (25.9%) 1588 (32.8%)
1245 (15.6%) 1767 (22.1%) 2116 (26.5%) 2850 (35.7%)
Comorbidities No Yes
3575 (73.5%) 1286 (26.5%)
6012 (75.2%) 1979 (24.8%)
p value 0.95
<0.001
<0.001
0.033
Open
MIS
Hx of another tumor No Yes
3794 (78%) 1067 (22%)
6474 (81%) 1517 (19%)
Insurance Private Government Uninsured/Unknown
1821 (37.5%) 2718 (55.9%) 322 (6.6%)
3338 (41.8%) 4390 (54.9%) 263 (3.3%)
Reporting facility Academic Non-academic Unknown*
2514 (51.7%) 2297 (47.3%) 50 (1%)
3670 (45.9%) 4261 (53.3%) 60 (0.8%)
Histology Endometrioid Serous Clear cell Carcinosarcoma
2083 (42.9%) 1350 (27.8%) 272 (5.6%) 1156 (23.8%)
3935 (49.2%) 2216 (27.7%) 454 (5.7%) 1386 (17.3%)
Substage IA IB I Not otherwise specified
3298 (67.8%) 1389 (28.6%) 174 (3.6%)
5602 (70.1%) 2209 (27.6%) 180 (2.3%)
Radiation therapy No Yes Unknown
2873 (59.1%) 1961 (40.3%) 27 (0.6%)
4450 (55.7%) 3493 (43.7%) 48 (0.6%)
Chemotherapy No Yes Unknown
2986 (61.4%) 1739 (35.8%) 136 (2.8%)
4856 (60.8%) 2912 (36.4%) 223 (2.8%)
p value <0.001
<0.001
<0.001
<0.001
<0.001
0.001
0.75
*type of treatment facility is suppressed for patients aged <40 years.
Table 2. Multivariate analysis of variables independently associated with overall survival.
Surgical approach Open Minimally invasive
Ref 1.06 (0.97, 1.15)
Age (yrs) <65 >=65
Ref 1.71 (1.52, 1.93)
Comorbidities No Yes
Ref 1.21 (1.11, 1.32)
History of another tumor No Yes
Ref 1.43 (1.30, 1.56)
Insurance type Private Government Uninsured/Unknown
Ref 1.25 (1.11, 1.40) 1.14 (0.90, 1.44)
Reporting facility Academic Non-academic Unknown*
Ref 1.08 (0.99, 1.17) 0.24 (0.08, 0.73)
Histology Endometrioid Serous Clear cell Carcinosarcoma
Ref 1.33 (1.22, 1.53) 1.30 (1.10, 1.61) 2.57 (2.31, 2.86)
Substage IA IB I Not otherwise specified
Ref 1.74 (1.60, 1.90) 1.34 (1.06, 1.69)
Lymph nodes removed <10 >=10 Unknown
Ref 0.81 (0.74, 0.88) 0.86 (0.59, 1.28)
Radiation therapy No Yes Unknown
Ref 0.90 (0.82, 0.98) 1.08 (0.67, 1.72)
Chemotherapy No Yes Unknown
Ref 0.62 (0.57, 0.69) 0.89 (0.70, 1.15)
*type of treatment facility is suppressed for patients aged <40 years.
Figure 1. Overall survival of patients with stage I high-grade endometrial cancer stratified by route of surgery, p=0.22 from log-rank.
Supplemental figure 1. Overall survival of patients with stage I high-grade endometrial cancer stratified by peritoneal cytology status, p<0.001 from log-rank.
Supplemental Figure 2. Overall survival of patients with stage I high-grade endometrial cancer stratified by performance of lymphadenectomy, p<0.001 from log-rank.
Supplemental Figure 3. Overall survival of patients with clinical stage I high-grade endometrial cancer stratified by route of surgery, p=0.13 from long rank.
Supplemental Figure 4. Overall survival of patients with stage I high-grade endometrial cancer who were converted from MIS to open surgery.
• Rate of MIS use for stage I high grade endometrial cancer was 62.2% • MIS was asscociated with superior short term surgical outcomes • There was no difference in 3-yr OS between MIS and open surgery.