Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy?

YGYNO-977772; No. of pages: 7; 4C: Gynecologic Oncology xxx (xxxx) xxx

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Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy? Anna L. Beavis a,⁎,1, Ting-Tai Yen a,1, Rebecca L. Stone a, Stephanie L. Wethington a, Caitlin Carr b, Ji Son b, Laura Chambers b, Chad M. Michener b, Stephanie Ricci b, Wesley C. Burkett c, Debra L. Richardson k, Allison-Stuart Staley d, Susie Ahn d, Paola A. Gehrig d, Diogo Torres e, Sean C. Dowdy e, Mackenzie W. Sullivan f, Susan C. Modesitt f, Catherine Watson g, Ashely Veade g, Jessie Ehrisman g, Laura Havrilesky g, Angeles Alvarez Secord g, Amy Loreen h, Kaitlyn Griffin h, Amanda Jackson h, Akila N. Viswanathan i, Leah R. Jager j, Amanda N. Fader a a

The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH, USA Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA d Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA e Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA f Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA, USA g Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA h Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH, USA i Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA j Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA k Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA b c

H I G H L I G H T S • In this cohort of early-stage endometrioid endometrial cancer cases with LVSI, 28% who underwent observation alone recurred. • Adjuvant therapy (radiation or chemotherapy) improved progression-free survival in early-stage endometrial cancer with LVSI • In high-grade tumors with LVSI, chemotherapy +/- radiation improved PFS compared to radiation or observation

a r t i c l e

i n f o

Article history: Received 9 November 2019 Received in revised form 16 December 2019 Accepted 20 December 2019 Available online xxxx Keywords: Lymphovascular space invasion Uterine cancer Endometrial cancer Chemotherapy Radiation Adjuvant treatment

a b s t r a c t Objectives. Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/−RAD. Methods. This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/−lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/ −RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. Results. In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/ −RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/−RAD (HR = 0.18, 95% CI: 0.09–0.39) and RAD (HR = 0.31, 95% CI: 0.18–0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/−RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12–0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03–0.32). Overall survival did not differ by treatment. Conclusions. In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In

⁎ Corresponding author at: 600 North Wolfe St, Phipps 281, Baltimore, MD 21287, USA. E-mail address: [email protected] (A.L. Beavis). 1 Co-primary authors.

https://doi.org/10.1016/j.ygyno.2019.12.028 0090-8258/© 2020 Elsevier Inc. All rights reserved.

Please cite this article as: A.L. Beavis, T.-T. Yen, R.L. Stone, et al., Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.028

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those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone. © 2020 Elsevier Inc. All rights reserved.

1. Introduction The incidence and mortality rates of endometrial cancer are rising [1]. Although the prognosis is generally good for women with earlystage disease, there are a several risk factors which are associated with a higher risk of recurrence and death [2–4]. Approximately 20% of women with early-stage endometrial cancer will relapse, and though most local recurrences can be salvaged, distant recurrences are often fatal. [5,6]. As such, identifying which women with high-risk, earlystage disease who would most benefit from adjuvant therapy is of paramount importance. Several clinicopathologic prognostic factors have been identified and are used to guide decision making with regard to adjuvant treatment, including age, tumor grade, depth of myometrial invasion, and lymphovascular space invasion (LVSI) [3,7–10]. LVSI is identified in up to 34% of endometrial cancers, and in approximately 15% of patients diagnosed with FIGO stage I and II endometrial carcinoma [6,11]. LVSI is independently associated with nodal metastases, recurrence, and poor survival [4,12–16]. In a recent pooled analysis of data from the postoperative radiation therapy in endometrial cancer (PORTEC) studies 1 and 2, LVSI was classified by a three-tiered approach: none, focal, or substantial. The authors found that substantial LVSI was a strong predictor of pelvic recurrence, distant recurrence, and poor overall survival. The authors suggest that tumors with substantial LVSI may warrant systemic therapy [7]. However, there is currently no consensus on the optimal treatment and role of systemic therapy in women with LVSI positive, early-stage endometrioid endometrial cancer (EEC) [7,18]. Observation without adjuvant treatment after surgery may not be suitable for this specific population because of higher risk of recurrence [19,20]. Additionally, despite several randomized controlled trials aimed at comparing post-operative adjuvant treatments in stage I/II endometrial cancer, the role of chemotherapy in patients with LVSI positive, earlystage EEC remains unknown due to limited reporting on LVSI status, sample size limitations, and heterogeneity of disease [2,11,21–23]. While adjuvant radiotherapy has been recommended to control pelvic recurrence in this setting, it has not been shown to improve distant recurrent or overall survival. There are little data comparing outcomes among those receiving radiotherapy compared to chemotherapy in the early stage population [6,20]. Therefore, the purpose of this multi-institutional study was to compare the recurrence-free and overall survival outcomes of women with stage I or II EEC with LVSI undergoing different adjuvant therapies after surgical treatment, including observation (OBS), radiotherapy (RAD), chemotherapy with or without radiotherapy (CHEMO+/−RAD). 2. Materials and methods A multi-institutional, retrospective cohort study was conducted by incorporating prospectively-maintained data from eight medical institutions in the US. This endeavor was a collaboration with the Kelly Gynecologic Oncology Service in the Department of Gynecology and Obstetrics at Johns Hopkins School of Medicine, the Cleveland Clinic, Cleveland, OH; University of Oklahoma Health Sciences Center, Oklahoma City, OK; University of North Carolina Medical Center, Chapel Hill, NC; Mayo Clinic, Rochester, MN; University of Virginia Health System, Charlottesville, VA; Duke University Hospital, Durham, NC; and the University of Cincinnati Medical Center, Cincinnati, OH. Institutional Review Board approval was obtained from each institution. Study subjects were included who had FIGO 2009 stage IA, IB, or II endometrioid endometrial cancer (EEC) with definitive LVSI who

underwent hysterectomy with or without lymphadenectomy at the above eight institutions from January 2005 to December 2015. For women who underwent surgery from 2005 to 2008, staging was converted in accordance with the FIGO 2009 definition based on careful review of the pathology reports. Eligible patients received primary surgical treatment and post-operative follow-up at one of the 8 medical centers. Demographic data were extracted from the medical record, including age at diagnosis, body mass index (BMI), race, parity, and menopausal status. Operative reports were reviewed to collect information on the route and type of surgery, pelvic washings performed, and type of lymphadenectomy performed. Minimally invasive surgery (MIS) was defined as robotic-assisted or laparoscopic hysterectomy. Lymphadenectomy included full pelvic (and/or aortic), and/or sentinel lymph node dissection per each institution's protocol. Pathology reports were reviewed for histologic diagnosis, tumor size (cm), tumor FIGO grade (1–3), tumor location in the uterus, depth of myometrium invasion (DOI, %), number of lymph nodes removed, and result of pelvic washings, if performed. Post-operative adjuvant treatment was defined as observation/surveillance (OBS) if no further treatment was given post-operatively, radiation therapy alone (RAD) if the patient received vaginal brachytherapy (VB) and/or external beam radiation treatment (EBRT), or chemotherapy with or without radiation (CHEMO+/−RAD) if the patient received systemic chemotherapy with or without adjuvant EBRT or VB. If the patient was diagnosed with a recurrence, the location of recurrence was recorded as vaginal, pelvic, distant or multisite if both local and distant sites of recurrence were identified. Progression-free survival (PFS) was measured from the date of hysterectomy to the date of disease progression, or censored at date of last contact or death in patients who did not progress. Overall survival (OS) was measured from the date of hysterectomy to the date of death or censored at the date of last contact for patients remaining alive.

2.1. Statistical analyses Patient demographic and clinical characteristics among the 3 treatment groups were compared using Fisher's exact tests for categorical variables, and ANOVA/t-test and Kruskal-Wallis tests for continuous variables. Kaplan Meier curves and log rank tests were performed to evaluate PFS and OS in the entire cohort by treatment type received. Cox proportional hazards models were constructed to evaluate the effect of treatment type (OBS, RAD, CHEMO+/−RAD) on PFS and OS, while controlling for variables known to be associated with PFS and OS based on published literature: age (b60 and ≥60 years old), BMI (b25, 25–29.9, ≥30 kg/m2), FIGO stage (IA, IB, II), FIGO grade (1–3) and DOI (inner third, middle third, outer third), and tumor size (in cm) [2,11]. Differences between the three treatment types were evaluated with linear combinations of model coefficients; these provided estimates of the hazard ratios comparing treatment groups as well as measures of statistical significance. Additionally, an interaction between grade (high grade (grade 3) vs. low grade (grade 1 or 2)) and adjuvant therapy type (OBS, RAD, and CHEMO+/−RADS) was evaluated based on the hypothesis that the effect of treatment could differ in high grade vs low grade tumors. Grade 1 and 2 were classified as low grade and grade 3 classified as high grade based on the classification of grade 3 tumors as type II endometrial tumors, which exhibit more aggressive behavior and have a worse prognosis compared to type I tumors [24,25].

Please cite this article as: A.L. Beavis, T.-T. Yen, R.L. Stone, et al., Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.028

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Several pre-planned sensitivity analyses were performed to evaluate for the effect of heterogeneity in the cohort with regards to surgical treatment and tumor stage and grade: 1) exclusion of those without lymphadenectomy at the time of surgery, 2) exclusion of those with stage II disease, and 3) exclusion of those with grade 3 disease. Additionally, after data collection it was noted that only 7.8% (n = 8) of patients in the CHEMO+/−RAD group received chemotherapy alone, so analyses were repeated after removal of these subjects to determine if this significantly altered the conclusions of the study. STATA 15 was used to perform statistical calculations and a p-value b 0.05 was considered significant. 3. Results In sum, a total of 478 patients met inclusion criteria, with a median follow-up of 50.3 months. The median patient age was 64 years-old (range 26–92) and median BMI was 31.4 kg/m2 (range 16.3–63.5). The majority of patients were Caucasian (n = 416, 87%) and postmenopausal (n = 402, 84.1%). Eighty-four percent of patients (n = 402) underwent MIS or vaginal hysterectomy surgery while 15.9% (n = 76) had an open hysterectomy procedure. Seventy-four percent of women (n = 354) underwent a concurrent lymphadenectomy with hysterectomy, 65% (n = 95) of the OBS cohort, 78.9% (n = 183) in the RAD cohort, and 76% (n = 78) in the CHEMO+/−RAD cohort (p = 0.01). In women who underwent lymphadenectomy, 89.8% (n = 318) underwent pelvic and/or aortic lymphadenectomy, 7.1% (n = 25) underwent both pelvic and/or aortic lymphadenectomy and sentinel lymph node biopsy, and 3.1% (n = 11) patients underwent sentinel lymph node biopsy only. An average of 24.3 lymph nodes (SD = 16.0) removed. Cancer stage distribution was: stage IA (n = 196, 41%), stage IB (n = 227, 47.5%), Stage II (n = 55, 11.5%). Most women had low grade (FIGO grade 1/2) disease, while 26.2% (n = 125) had FIGO grade 3 EEC. Pelvic washings were performed in 63.4% (n = 303) of patients, of which 7.9% (n = 24) were positive for carcinoma. After surgery, 30% (n = 143) underwent OBS, 48.5% (n = 232) were treated with RAD, and 21.5% (n = 103) received CHEMO+/−RAD. In the RAD cohort, the majority underwent VB alone (68.5%, n = 159) underwent VB, 20% (n = 47) underwent EBRT alone, and 10.8% (n = 25) underwent EBRT and VB. In the CHEMO+/−RAD group, 60.2% (n = 62) received VB with the chemotherapy, 32% (n = 33) received EBRT with or without VB, and 7.8% (n = 8) received chemotherapy alone. Chemotherapy regimens were known in 97% (n = 100) of patients, and 95% received a platinum/taxane based systemic doublet. Table 1 shows the clinical and demographic characteristic distribution among the three groups. No differences were noted in patient's age, BMI, race, parity, menopausal status, pelvic washing result, tumor size, tumor location, and number of lymph nodes removed among the three cohorts. However, fewer patients underwent open hysterectomy in the CHEMO+/−RAD cohort compared with the OBS or RAD cohorts. Specifically, 22.4% (n = 32) of OBS, 15.9% (n = 37) of RAD, and 6.8% (n = 7) of CHEMO+/−RAD underwent an open surgery (p = 0.003). Additionally, 65% (n = 92) of the OBS cohort underwent a lymphadenectomy, compared to 78.9% (n = 183) of RAD and 75.7% (n = 78) of CHEMO+/−RAD (p = 0.01). There were also differences in distribution of stage with 95.1% (n = 136) of OBS with stage IA/IB disease vs. 86.2% (n = 200) of RAD vs. 84.5% (n = 87) of CHEMO+/−RAD (p b 0.001). Additionally, 14.7% (n = 21) of OBS had grade 3 disease, compared to 25.4% (n = 59) of RAD, and 43.7% (n = 45) of CHEMO+/−RAD (p b 0.001).

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Table 1 Demographics and clinical variables among treatment groups: observation (OBS), radiation (RAD), and chemotherapy with or without radiation (CHEMO+/−RAD).

Age, median (range) BMI, median (range) BMI, n (%)a Normal/underweight Overweight Obese Race, n (%) White African American Asian Hispanic Other Parity, mean ± SD Menopause status, n (%) Post-menopause Surgical approach, n (%) Laparotomy MIS Vaginal Pelvic washings, n (%) Negative result Positive result Atypical result Lymphadenectomy, n (%) Lymph nodes, mean ± SD FIGO 2009d stage, n (%) IA IB II FIGO grading, n (%) Grade 1 Grade 2 Grade 3 Tumor location, n (%) Fundus LUS Fundus and LUS DOI, %, mean (SD) DOI, n (%) Inner one third Middle one third Outer one third Tumor size, cm, mean (SD)

OBS n = 143

RADb n = 232

CHEMO ± RADc n = 103

63 (26–92) 31 (16.3–57.8)

65 (41–88) 31 (17.9–62)

64 (46–85) 33(19.6–63.5)

24 (16.8) 31 (21.7) 72 (50.3)

49 (21.1) 43 (18.5) 124 (53.4)

12 (11.7) 24 (23.3) 61 (59.2)

122 (85.3) 11 (7.7) 0 (0) 4 (2.8) 6 (4.2) 1.9 ± 1.7

201 (86.6) 15 (6.5) 6 (2.6) 3 (1.3) 7 (3.0) 2.1 ± 1.5

93 (90.3) 8 (7.8) 0 (0) 2 (1.9) 0 (0) 2.0 ± 1.4

117 (81.8)

200 (86.2)

85 (82.5)

32 (22.4) 99 (69.2) 12 (8.4) 91 (63.6) 81 (56.6) 6 (4.2) 4 (2.8) 93 (65.0) 25.4 ± 16.2

37 (15.9) 179 (77.2) 16 (6.9) 161 (69.4) 137 (59.1) 13 (5.6) 11 (4.7) 183 (78.9) 25.0 ± 16.6

7 (6.8) 93 (90.3) 3 (2.9) 51 (49.5) 44 (42.7) 5 (4.9) 1 (0.97) 78 (75.7) 21.2 ± 14.1

82 (57.3) 54 (37.8) 7 (4.9)

84 (36.2) 116 (50.0) 32 (13.8)

32 (31.1) 55 (53.4) 16 (15.5)

63 (44.1) 58 (40.6) 21 (14.7)

56 (24.1) 117 (50.4) 59 (25.4)

13 (12.6) 45 (43.7) 45 (43.7)

50 (35.0) 9 (6.3) 15 (10.5) 45.5 (27.1)

92 (39.7) 19 (8.2) 27 (11.6) 54.3 (25.6)

49 (47.6) 18 (17.5) 6 (5.8) 56.5 (24.3)

51 (35.7) 41 (28.7) 41 (28.7) 4.1 (2.5)

52 (22.4) 94 (40.5) 79 (34.1) 4.1 (2.1)

19 (18.4) 49 (47.6) 34 (33.0) 4.4 (2.3)

p value 0.21 0.49 0.25

0.16

0.68 0.28 0.003

0.003 0.65

0.01 0.16 b0.001

b0.001

0.06

0.001 0.005

0.6

BMI, body mass index. DOI, death of invasion. LUS, lower uterine segment. MIS, minimal invasive surgery. Bold indicates the p-value is b 0.05, and of statistical significance. a Data on BMI was available in 89% (n = 127) of OBS patients, 93% (n = 216) of RAD patients, and 94% (n = 97) of CHEMO+/−RAD patients. b In the RAD cohort, 68.5% (n = 159) underwent VB, 20% (n = 47) underwent EBRT alone, and 10.8% (n = 25) underwent EBRT and VB. c In the CHEMO+/−RAD group, 60.2% (n = 62) received VB with the chemotherapy, 32% (n = 33) received EBRT+/−VB, and 7.8% (n = 8) received chemotherapy alone. d 113 (24%) underwent staging prior to 2009; pathology reports were reviewed to convert their staging to FIGO 2009.

location differed by treatment modality: in patients who underwent OBS, 50% (n = 20) recurred in the vagina or pelvis compared to 20.4% (n = 9) in the RAD cohort, and 41.1% (n = 7) in the CHEMO+/−RAD cohort (p = 0.02, Supplementary Table S1). Distant or multisite recurrences were identified in 50% (n = 20) of the OBS cohort, compared to 79.5%% (n = 35) of the RAD cohort, and 58.8% (n = 10) of the CHEMO+/−RAD cohort (p = 0.02).

3.1. Recurrence location 3.2. Progression free survival In total, 21.1% (n = 101) of patients recurred: 28.0% of those in the OBS cohort, 19.0% (n = 44) of those in the RAD cohort, and 16.5% (n = 17) of those in the CHEMO+/−RAD cohort (p b 0.05). Recurrence

In the 101 patients who recurred, median time from surgery to progression was 17.9 months (95% CI 14.7–20.3). On log-rank test, PFS

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differed by adjuvant treatment group (p = 0.02; Fig. 1). Using a Cox proportional hazards model for PFS controlling for known risk factors of recurrence, both RAD (HR = 0.31, 95% CI: 0.18–0.54) and CHEMO +/−RAD (HR = 0.18, 95% CI: 0.09–0.39) showed significant improvement in PFS compared to OBS alone (Table 2). RAD was not significantly different from CHEMO+/−RAD (HR = 0.58, 95% CI: 0.29–1.15). These results were confirmed in the three sensitivity analyses (Supplementary Tables S2, S3, and S4), and when removing the 8 subjects who received chemotherapy only from the analysis. An interaction between grade (high grade: grade 3 vs. low grade: grade 1 or 2) and adjuvant treatment group was statistically significant for PFS, suggesting differences in the effect of treatment for high grade vs. low grade cancers (p = 0.04, Table 3). Estimates of hazard ratios from this interaction model for PFS show that for patients with high grade disease, patients treated with CHEMO+/−RAD had significantly longer PFS compared to RAD (HR 0.25; 95% CI: 0.12–0.52) and compared to OBS (HR 0.10; 95% CI: 0.03–0.32) (Table 3). The Kaplan Meier curve for PFS for patients with high grade disease is shown in Fig. 2, providing a visual representation of the relationship between grade and response to the different adjuvant therapies (p-value for log rank test = 0.002). 3.3. Overall survival There were 96 deaths during the median follow up time of 50.3 months. On log rank test, there was no difference in OS by treatment type (p = 0.39; Fig. 3). On Cox proportional hazards model controlling for relevant risk factors, neither CHEMO+/−RAD nor RAD was different from OBS in terms of OS (Table 2). Moreover, the test of interaction between treatment type and grade was not significant for OS (p = 0.66). These results were also confirmed in the sensitivity analyses (Supplementary Tables S2, S3, S4), and when excluding the 8 subjects who received chemotherapy alone. 4. Discussion Lymphovascular space invasion (LVSI) is one of the most important independent risk factors for disease recurrence and poor survival outcomes in women with early stage, endometrioid adenocarcinoma of the endometrium. Yet the optimal treatment for tumors with these features remains elusive. However, in this multi-institutional analysis of

Table 2 Cox proportional hazards models for progression-free survival (PFS) and OS. Variable

Adjuvant therapy OBS RAD CHEMO+/−RAD Age b60 years old N60 years old BMI Normal/underweight Overweight Obese FIGO stage IA IB II FIGO grading Grade 1 Grade 2 Grade 3 DOI Inner one third Middle one third Outer one third Tumor size

Progression-free survival

Overall survival

HR

95% CI

HR

95% CI

Ref 0.31 0.18

(0.18–0.54) (0.09–0.39)

Ref 1.20 1.07

(0.90–1.60) (0.75–1.50)

Ref 0.99

(0.59–1.67)

Ref 0.90

(0.71–1.16)

Ref 0.80 0.86

(0.39–1.67) (0.48–1.55)

Ref 1.48 1.33

(1.04–2.11) (0.99–1.78)

Ref 0.91 2.66

(0.43–1.95) (1.09–6.50)

Ref 0.87 1.12

(0.62–1.23) (0.71–1.77)

Ref 0.97 2.63

(0.52–1.80) (1.37–5.03)

Ref 1.09 1.18

(0.84–1.43) (0.85–1.64)

Ref 2.86 3.63 1.04

(1.32–6.21) (1.42–9.29) (0.94–1.15)

Ref 1.03 1.05 1.00

(0.76–1.39) (0.69–1.59) (0.94–1.06)

BMI, body mass index. DOI, depth of invasion. Bold text indicates the hazard ratio and corresponding confidence interval is of statistical significance (p b 0.05).

478 cases of LVSI positive, early-stage disease, we demonstrate that adjuvant treatment improves progression-free survival. Specifically, this study identified a subgroup of women with grade 3 disease and LVSI in whom PFS was significantly improved with CHEMO+/−RAD when compared to either RAD or OBS alone. Additionally, even when removing those women who only received chemotherapy from the analysis (the majority of whom received a platinum/taxane doublet with brachytherapy), the CHEMO+/−RAD cohort (the majority of whom received a platinum/taxane doublet in addition to brachytherapy) had a higher PFS compared to RAD alone. Our study did not show a difference in overall survival by treatment type. However, it was not powered to assess this and thus conclusions cannot be drawn on the potential impact of chemotherapy with or without radiation on overall survival in women with LVSI-positive early endometrial cancer. Previous studies have shown that adjuvant treatment can prevent recurrence and improve progression-free survival for women with early stage endometrial adenocarcinoma and high-risk uterine factors. The Gynecologic Oncology Group (GOG) 99 study identified women with high intermediate risk disease in whom adjuvant whole pelvic radiation reduced the risk of recurrence compared to observation after surgery, highlighting the prognostic significance of adverse risk factors such as LVSI, high grade tumors, and outer third myometrial invasion Table 3 Interaction model estimates progression free survival (PFS) in high-grade and low-grade endometrial endometrioid cancer (EEC) patients. Interaction between adjuvant therapy type and grade (high vs. low) was significant for PFS (p = 0.04). The CHEMO+/−RAD had superior HR compared to RAD and OBS in the high grade patients; in low grade patients CHEMO+/−RAD was only superior to OBS, but not to RAD.

Fig. 1. Kaplan-Meier curves for progression-free survival (PFS) in all patients. Using multivariable Cox proportional hazards model, both RAD (HR = 0.31, 95% CI: 0.18–0.54) and CHEMO+/−RAD (HR = 0.18, 95% CI: 0.09–0.39) showed significant improvement in PFS compared to OBS alone, but were not significantly different from each other. Estimates of survival at 36 months were 74% for OBS, 83% for RAD, and 88% for the CHEMO+/−RAD group (p = 0.02).

High grade EEC CHEMO+/−RAD vs. OBS CHEMO+/−RAD vs. RAD Low grade EEC CHEMO+/−RAD vs. OBS CHEMO+/−RAD vs. RAD

HR

95% CI

0.10 0.25

–0.32) (0.09–0.71)

0.34 1.36

(0.14–0.82) (0.57–3.28)

HR, hazard ratio. CI, confidence interval. Bold text indicates the hazard ratio and corresponding confidence interval is of statistical significance (p b 0.05).

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Fig. 2. Kaplan-Meier curves for PFS in high-grade patients only. Hazard ratios (HR) for PFS were lower for CHEMO+/−RAD compared to the RAD (HR 0.25; 95% CI: 0.12–0.52) and compared to OBS alone (HR 0.10; 95% CI: 0.03–0.32). Estimates of survival at 36 months were 39% for the OBS group, 64% for the RAD group, and 88% for the CHEMO+/−RAD group (p = 0.002).

[11]. Similarly, the PORTEC 1 European trial randomized women with early stage, uterine confined endometrial cancer to whole pelvic radiation vs. observation and identified age ≥60 years, outer third invasion, and grade 3 as risk factors for recurrence. However, they did not include LVSI in the multivariable analysis [2]. Specifically, while GOG 99 included LVSI as a risk factor for requiring adjuvant radiation, PORTEC 1 did not, making it difficult to draw firm conclusions about the optimal adjuvant treatment strategy in this setting [2,11]. PORTEC 2, a followup study evaluating the progression-free survival in women with early-stage endometrial cancer at high-intermediate risk of recurrence, compared vaginal brachytherapy to external beam radiation therapy (EBRT) and found that vaginal brachytherapy was non-inferior to EBRT [23]. However, a ten-year follow-up study of PORTEC 2 found p53 expression and extensive LVSI to be factors associated with higher rates of pelvic recurrence and distant metastases [26]. In the present study, high grade and LVSI-positive endometrioid endometrial cancers recurred less often with the administration of chemotherapy primarily in conjunction with brachytherapy, suggesting there may be a role for systemic therapy in certain populations. A recent ad hoc analysis of the PORTEC 1 and 2 trials separately examined those patients whose tumors had LVSI and quantified LVSI

Fig. 3. Kaplan-Meier curves for overall survival (OS) in all patients. There was no difference by treatment group (p = 0.39).

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degree to determine if this was prognostic of outcome [7]. Using a 3tiered approach, any degree of LVSI was identified in approximately 14% of the trial patients, and substantial LVSI was found in 4.8%. The presence of substantial LVSI had the strongest impact on the risk of distant metastasis (HR 4.5; CI 2.4–8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment), substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2; CI 2.4–16), distant metastasis (HR 3.6; CI 1.9–6.8) and overall survival (HR 2.0; CI 1.3–3.1) [7]. Interestingly, vaginal brachytherapy (as studied in PORTEC 2) did not impact the risk of recurrence in this cohort, and while whole pelvic radiation decreased the risk of pelvic relapse, it did not decrease the risk of distant recurrence or death. The study authors concluded that given the substantial risk of distant recurrence in this cohort, that it is logical to explore systemic treatment options, and that adjuvant EBRT and/or chemotherapy should be considered for patients who tumors have substantial LVSI. In women with endometrial cancers with substantial LVSI who had no adjuvant therapy, 31% had a regional recurrence and they were 2.4 times more likely to have a distant recurrence [7]. Similarly, in the present study, 28% of those in the observation cohort recurred suggesting a high recurrence rate in this at-risk population, and 50% of recurrences in the observation cohort were distant to the pelvis. While our study did not report on degree of LVSI as this is not yet routinely performed as part of pathologic evaluation, these results still suggest a substantial risk of distant recurrence in those with any LVSI, and a potential benefit for treatment of those with LVSI and high-grade disease with systemic chemotherapy, with or without locoregional therapy. GOG 249, a Phase III superiority trial, compared 3 cycles of carboplatin/paclitaxel with brachytherapy to whole pelvic radiation alone in women with high-intermediate criteria, stage II disease, or stage I and II serous or clear cell tumors [27]. While the study did not demonstrate superiority of chemotherapy with brachytherapy to EBRT, there were study limitations, including a heterogeneous patient population by tumor subtype, stage and surgical approach. Additionally, the proportion of patients with LVSI were not reported, and LVSI was not included in the Forrest plots analyzing the specific trial subgroups' response to therapy. Moreover, only three cycles of systemic therapy were administered, when the optimal number of chemotherapy cycles has not been established in those with high-intermediate risk early stage disease [27]. PORTEC 3, which compared chemoradiation to radiation alone in high-risk endometrial cancer, including those with earlystage grade 3 disease and LVSI, found that the addition of chemotherapy improved failure-free but not overall survival. Additionally, LVSI was an independent predictor of failure-free survival. However, this study included a large proportion of stage III patients and therefore the results cannot be directly compared to the present study's findings [22]. At present, based on the existing Phase III trials, it remains unresolved if there is a role for chemotherapy in patients with LVSI-positive, earlystage endometrial cancer. In the current study, only 8 patients in the systemic therapy cohort received chemotherapy alone while the remainder received chemotherapy with radiation, mostly in the form of brachytherapy. Therefore, we were not able to discern differences between the women receiving only chemotherapy and those receiving chemotherapy with locoregional radiation. Currently, the National Comprehensive Cancer Network (NCCN) guidelines for surgically treated, uterine-limited endometrioid adenocarcinoma with adverse risk factors such as LVSI recommend observation or brachytherapy for low grade (G1 and G2) tumors, and either EBRT or brachytherapy, with or without chemotherapy for high grade tumors. Similarly, for women with stage II disease, no consensus for administrating systemic adjuvant chemotherapy is reported, but chemotherapy can be considered [28]. These recommendations may require refinement as more data emerges. Ancillary analyses of US based studies could be used to validate the PORTEC ad hoc study findings and to examine the impact of chemotherapy in those with LVSI-positive tumors, in order to further elucidate the best treatment

Please cite this article as: A.L. Beavis, T.-T. Yen, R.L. Stone, et al., Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.028

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A.L. Beavis et al. / Gynecologic Oncology xxx (xxxx) xxx

options for these patients. The present study aligns with NCCN recommendations for women with early-stage, grade 1 and 2 disease. It also helps to better inform those for early-stage, grade 3 EEC patients with LVSI, where there may be a stronger role for systemic chemotherapy based on tumor-specific factors data emerges. Future treatment of endometrial cancer is likely to take into account both tumor-specific and molecular characteristics. PORTEC 4 aims to determine the potential to individualize the adjuvant treatment of women with highintermediate risk endometrial cancers by using the molecularintegrated profile of the tumor, including substantial LVSI status as well as other molecular profiling. The study is anticipated to be completed by late 2023 [29]. As those data are not available yet, clinic pathologic markers alone, such as LVSI, could currently serve as proxy. Additionally, future U.S. cooperative trial groups should consider a randomized study focused on women with high risk, early stage disease enriched with LVSI positive tumors to determine the ultimate role of systemic therapy in this population. The present study is limited by its retrospective nature and is hypothesis generating. Central pathology review and categorization of focal vs. substantial LVSI was not feasible; additionally, only those with “definitive” LVSI were included and the number of those with questionable or possible LVSI was not recorded. However, strengths include one of the largest sample sizes of women with LVSI-positive, early stage endometrioid adenocarcinoma of the endometrium, achieved through multi-institutional collaboration and a rigorous statistical design. There was heterogeneity due to varying treatment protocols at the institutions, which resulted in the treatment groups being imbalanced with respect to surgical approach, lymphadenectomy, and FIGO stage and grade. For example, women who underwent observation more often had not undergone surgical staging, and unrecognized advanced disease may have resulted in disproportionately worse outcomes in this group. However, these imbalances did not favor progression free survival in those who received chemotherapy, as more women with adverse risk factors were found in the chemotherapy-treated cohort. Additionally, we attempted to account for some of this heterogeneity through pre-planned sensitivity analyses that were consistent with the overall PFS and OS models. However, we cannot discern the impact of chemotherapy alone versus those treated with chemotherapy and radiation modalities. In this large, multisite study, we demonstrate that administering chemotherapy with or without radiation in the adjuvant setting to treat women with high grade, early stage endometrial cancer with LVSI improves PFS compared to radiation or observation alone. Future randomized studies are needed in order to confirm the potential role of adjuvant chemotherapy in the treatment of all early-stage endometrial cancers with LVSI. It is clear from the recurrence patterns and rates seen in the present study and in existing Phase III published studies that women in this setting have a high risk of distant and lethal recurrence. Given this high rate of recurrence, the results of the present study suggest that adjuvant therapy should be considered in women with early-stage endometrial endometrioid cancer with LVSI. Acknowledgements We would like to acknowledge support for the statistical analysis from Dhananjay Viadya and the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through Grant Number 1UL1TR001079. Author contribution Beavis, Yen, Jager, and Fader were responsible for the conception and analysis of the paper. Yen, Carr, Son, Chambers, Michener, Ricci, Burkett, Richardson, Staley, Ahn, Gehrig, Torres, Dowdy, Sullivan Modesitt, Watson, Veade, Ehrisman, Havrilesky, Secord, Loreen, Griffin,

Jackson, and Yen participated in data collection and management. Beavis, Jager, and Fader designed the data analysis and interpretation, with additional analytic edits from Secord, Richardson, Havrilesky, Viswanathan, Stone, Wethington, Gehrig, and Modesitt. Beavis, Yen, and Fader drafted the manuscript. All authors critically revised the manuscript, and all authors approved the manuscript in its final version prior to submission for publication. Declaration of competing interest All authors reported their potential conflicts of interest, and there were not relevant conflicts of interest disclosed. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2019.12.028.

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