Adjuvant radiotherapy in Stage II endometrial carcinoma: Is brachytherapy alone sufficient for local control?

Brachytherapy

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(2015)

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Adjuvant radiotherapy in Stage II endometrial carcinoma: Is brachytherapy alone sufficient for local control? Ima Paydar1, Todd DeWees1, Matthew Powell2,3, David G. Mutch2,3, Perry W. Grigsby1,2,3,4, Julie K. Schwarz1,3,* 2

1 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 3 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 4 Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO

ABSTRACT

OBJECTIVE: To evaluate recurrence patterns and overall survival in patients treated with adjuvant radiation after surgical staging for Stage II endometrial carcinoma. Secondary goals include identification of prognostic factors for recurrence and toxicity assessment. METHODS/MATERIALS: The medical records of 41 patients treated with adjuvant radiotherapy at Washington University School of Medicine after surgical staging for endometrial cancer (total abdominal hysterectomy and bilateral salpingo-oophorectomy, peritoneal cytology, lymph node dissection) were reviewed. Nineteen were treated with a combination of external beam radiotherapy and vaginal brachytherapy (VB), and 22 patients were treated with postoperative VB alone. Median followup for all patients was 41 months. RESULTS: Median patient age was 59 years (range, 42e87 years). All tumors were of endometrioid histology. There were 20 Grade 1 tumors, 13 Grade 2 tumors, and 8 Grade 3 tumors. For all patients, the 5-year overall survival was 69.8%, and the 5-year recurrence-free survival was 89.0%. There was no statistically significant difference in overall survival ( p 5 0.510) or freedom from vaginal ( p 5 0.840), distant ( p 5 0.133), or any recurrence ( p 5 0.275) with respect to modality of treatment (external beam radiotherapy and VB vs. VB alone). There were no pelvic lymph node recurrences. In the univariate analysis, there were no risk factors influencing overall survival or recurrences. One patient experienced a toxicity requiring hospital admission. She was treated with pelvic external beam radiation plus brachytherapy. CONCLUSIONS: VB alone results in excellent local control for patients with Stage II endometrial cancer after surgical staging. Long-term toxicities are rare and more common in the group of patients who were treated with pelvic external beam plus brachytherapy. Ó 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Key words:

Adjuvant radiation; Endometrial adenocarcinoma; Gynecologic malignancy

Introduction Endometrial adenocarcinoma is the most common gynecologic malignancy in North America, with approximately 12% of surgically staged patients presenting with Stage II disease (1). The current International Federation

Received 21 October 2014; received in revised form 28 January 2015; accepted 17 February 2015. * Corresponding author. Department of Radiation Oncology, Washington University School of Medicine, Campus Box 8224, Mallinckrodt Institute of Radiology, St. Louis, MO 63110. Tel.: (314) 362-8502. E-mail address: [email protected] (J.K. Schwarz).

of Gynecologic Oncology (FIGO) 2009 staging system defines Stage II endometrial cancer as tumor invading the stromal connective tissue of the cervix without extension beyond the uterus (2). Involvement of the endocervical glandular portion of the cervix only is no longer classified as Stage II. Presentation with Stage I disease is far more common; hence, research on risk stratification techniques and treatment approaches for Stage II cancer are controversial, limited, and often extrapolated from radiation therapy guidelines for cancer limited to the uterus. For instance, a randomized prospective trial by the Gynecologic Oncology Group (GOG-99) has shown that adjuvant pelvic radiation, when compared with no additional

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therapy, results in significant reduction of locoregional recurrence (vaginal, pelvic, or both) with no overall survival advantage (3) in patients with Stage IB-II (occult) disease. More recent results from PORTEC-2 have further shown that patients with Stage I or IIa cancer who receive vaginal cuff brachytherapy (VB) have similar rates of locoregional relapse with no overall survival difference and with significantly lower rates of gastrointestinal toxicity when compared with pelvic external beam radiotherapy (EBRT) (4). Such findings have altered the treatment paradigm of Stage I cancer toward more conservative management. Growing evidence in the literature further supports such conservative use of radiation in the setting of Stage II endometrial cancer (5e10). One of the largest retrospective analyses by Cannon et al. (7), which included 71 patients with Stage II disease (23 Stage IIA, 48 Stage IIB) has shown that VB alone resulted in fewer toxicities without an increased recurrence risk compared with the combination of EBRT and VB, suggesting that VB alone provides adequate control in patients with low-risk histopathologic features and comprehensive surgical staging with complete lymphadenectomy. The purpose of our study was to perform a retrospective review of patients treated at Washington University in St. Louis with adjuvant radiotherapy after surgical staging for pathologic Stage II endometrial cancer. The primary goal was to evaluate recurrence patterns and overall survival in patients who received various forms of postoperative radiation. Secondary goals included identification of risk factors for recurrence as well as assessment of radiation toxicity.

Materials and methods After approval by the Washington University Institutional Review Board/Human Studies Committee, a retrospective review was carried out of 106 patients with clinical or pathologic Stage II endometrial cancer who were referred to the Radiation Oncology Department of Washington University in St. Louis between 1988 and 2012. A total of 99 patients underwent surgical staging, which included a total abdominal hysterectomyebilateral salpingo-oophorectomy and pelvic washings. Surgeries were performed at Washington University or at regional community hospitals; however, all surgical specimens were reviewed by the Surgical Pathology Department at Washington University. Patients who were clinically Stage II before the 1988 FIGO staging system were excluded from the study. Patients treated between 1988 and 2009 were staged by the 1988 FIGO staging system and were included only if surgical pathology showed extension of disease to the cervical stroma (Stage IIB). Stage IIA patients were excluded from the final analysis. After 2009, only patients with cervical stromal extension were included in our study. Patients

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who were found at the time of surgery to have no cervical involvement or tumor involvement beyond the cervix were excluded. Patients also were excluded if they underwent definitive radiotherapy only or preoperative pelvic radiotherapy (RT) or intracavitary radiation with afterloading tandems, ovoids, and Simon-Heyman capsules. Patients who received chemotherapy in addition to adjuvant radiation were excluded from this analysis. Two patients were treated with EBRT alone due to patient refusal of VB, and these 2 patients were also excluded from this analysis. Patients who did not undergo a pelvic þ/ para-aortic lymphadenectomy at the time of surgical staging were excluded. Range of dissected lymph nodes was 12e64 with a median of 24 lymph nodes removed in 37 cases. In the remaining cases, quantification of the number of lymph nodes removed was not possible using information from archived pathology reports. In an effort to have uniform surgical treatment in our patient population, patients who underwent radical hysterectomy were excluded from our analysis. Patients with nonendometrioid histology (papillary serous, clear cell, mixed, and carcinosarcoma) also were excluded. Our final group included 41 patients, which included 36 patients with Stage IIB cancer per FIGO 1988 and 5 Stage II patients per FIGO 2009. Data were obtained from the electronic and written medical records at Washington University Mallinckrodt Institute of Radiology, Department of Radiation Oncology, and Department of Gynecologic Oncology. Details collected and analyzed included age at diagnosis, date of surgery, radical hysterectomy, inclusion of lymph node dissection, histology, grade, depth of myometrial invasion, presence of lymphovascular space invasion (LVSI), type of adjuvant radiation, dose of radiation, dates of radiation, type of recurrence (vaginal, pelvic, distant), date of recurrence, treatment for recurrence (chemotherapy, radiation, or both), date of last followup, and date of death (if applicable). The median age at diagnosis was 59 years (range, 42e87). Patient and tumor characteristics at the time of initial treatment are listed in Table 1. Forty-one patients were included in the final analysis. VB alone was administered to 22 patients and EBRT þ VB was administered to 19 patients. Of the 41 patients who received VB, 8 patients were treated with low dose rate brachytherapy and 33 were treated with high dose rate (HDR) brachytherapy. Postoperative radiotherapy was generally initiated 6e8 weeks after surgery (range, 3 weekse4 months). For patients receiving HDR VB alone, a Nucletron HDR unit with Iridium-192 as the source was used to prescribe 4200 cGy to 0.5 cm depth. A dose prescription of 2400 cGy was most commonly used when administering VB in addition to EBRT. A 2.5-cm vaginal cylinder was used for most patients (range, 2.5e3.0 cm). For the patients receiving low dose rate VB, Cesium-137 sources with two 2.0- or 2.5-cm ovoids were used, and 6500 cGy was prescribed to the surface. The proximal one-third of the vagina was treated. Using a biologically

I. Paydar et al. / Brachytherapy Table 1 Characteristics of 41 patients with Stage II endometrial cancer stratified with respect to treatment modality Characteristic Age, y !50 50e69 $70 Stage IIB II (after 2010) Grade 1 2 3 Lymphovascular space invasion Yes No No data Depth of myometrial disease None First third Middle third Deep third No data Radiation type EBRT þ VB (5040 cGy þ 2400 cGy) VB alone (4200 cGy)

VB

VB þ EBRT

No. of patients (%)

2 15 5

3 10 6

5 (12.2) 25 (61.0) 11 (26.8)

18 4

18 1

36 (87.8) 5 (12.2)

15 6 1

5 7 7

20 (48.8) 13 (31.7) 8 (19.5)

7 15 0

10 6 3

17 (41.5) 21 (51.2) 3 (7.3)

1 7 9 5 0

1 4 6 6 2

0

19

19 (46.3)

22

0

22 (53.7)

p Value 0.5932

0.3499

0.0074

0.0990

0.8812 2 11 15 11 2

(4.9) (26.8) (36.6) (26.8) (4.9)

Abbreviations: EBRT, external beam radiotherapy; VB, vaginal brachytherapy.

effective dose calculation, HDR brachytherapy fractional dose was converted to equivalent 2-Gy fractions assuming an a/b of 10 for tumor and 3 for normal tissue. For patients receiving HDR brachytherapy and pelvic RT, the mean EQD2 was 79.4 Gy (range, 66.5e99.6 Gy). For patients receiving HDR brachytherapy alone, the mean EQD2 was 55.6 Gy (range, 22.2e77.7 Gy). Patients receiving EBRT were treated using either anterior-posterior opposed fields or a four field box technique with megavoltage beams. The most common prescription for EBRT was 1980 cGy to the whole pelvis followed by an additional 3060 cGy with a midline block in place for a total dose of 5040 cGy. Daily fractions of 160 or 180 cGy were used.

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Beginning in 2005, intensity modulated EBRT was used to treat the pelvis. Details of our contouring practices, dose prescriptions, and combination with HDR brachytherapy have been previously published (11). Patients were generally examined at 3-month intervals for the first 2 years after treatment, then at 6-month intervals for the next 3 years, then yearly afterward. Patients were censored at the time of death or date of last followup. Toxicities were retrospectively assessed based on the Common Terminology Criteria for Adverse Events v4.0. Acute toxicities were obtained from details recorded in the treatment summaries, and late toxicities were extracted from followup records and further surgical and procedural interventions. Time to recurrence was calculated from the completion of radiation treatment to the time of histological or radiographic confirmation of recurrence. Overall survival was calculated using Kaplan-Meier estimates (12). The Cox proportional hazards model was used for univariate analysis (13). The Fisher’s exact test was used to assess the association between clinical variables and type of adjuvant radiation treatment. The Wilcoxon rank sum test was used for age as a continuous covariate.

Results Median followup for all patients after completion of surgery was 41 months. Overall, there were 5 (12.2%) patients who developed a relapse. Two (4.9%) of these patients acquired a vaginal recurrence, and 3 (7.3%) developed a distant metastasis. There were no pelvic metastases. One of these 5 patients was treated with VB alone, and the rest were treated with VB þ EBRT. The characteristics and sites of failure for each patient who developed a relapse are shown in Table 2. The 5-year overall survival and freedom from any recurrence for all patients were 69.8% and 89.0%, respectively. The 5-year freedom from vaginal recurrence and distant metastasis was 96.9% and 91.9%, respectively. In the Cox proportional hazards model, there was no statistically

Table 2 Details for patients with recurrence Patient

Age

Grade

Depth invasion

LVSI

Adjuvant radiation

Site of recurrence

Cause of death

1 2 3

68 46 72

1 3 3

!1/3 O2/3 O2/3

No Yes Unknown

VB VB þ EBRT VB þ EBRT

Other Metastasis Metastasis

4

74

3

1/3e2/3

Yes

VB þ EBRT

5

50

2

!1/3

Yes

VB þ EBRT

Vagina Vagina Distant Para-aortic LNs Liver Vertebral body Distant Peritoneal/ omental Distant Abdominal wall

Abbreviations: EBRT, external beam radiotherapy; LN, lymph node; LVSI, lymphovascular space invasion; VB, vaginal brachytherapy.

Metastasis

Alive

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Figure 1. Kaplan-Meier curves for (a) overall survival, (b) freedom from any recurrence, (c) freedom from vaginal recurrence, (d) freedom from distant metastasis, stratified by adjuvant treatment modality. No pelvic recurrences occurred.

significant difference in overall survival ( p 5 0.510) or freedom from vaginal ( p 5 0.840), distant ( p 5 0.133), or any recurrence ( p 5 0.275) with respect to modality of treatment (VB vs. VB þ EBRT). Kaplan-Meier curves for overall survival and freedom from recurrence separated by treatment modality are shown in Fig 1. The univariate Cox proportional hazards model found no statistically significant risk factors associated with recurrence or overall survival (data not shown). No patient experienced a greater than Grade 2 acute toxicity or required discontinuation of therapy due to radiation therapy. All vaginal discharge and changes in bowel and bladder function were medically managed. One patient experienced a Grade 3 or greater radiation toxicity. Specifically, she acquired chronic radiation enteritis requiring multiple hospital admissions. She was treated with both VB and EBRT. Discussion Radiation therapy guidelines for early-stage endometrial cancer are based on four randomized prospective trials (3, 14e16). The conclusion drawn from these trials is that for early-stage endometrial cancer, pelvic RT confers significant improvement in local control but no overall survival advantage. In the GOG-99, a high intermediate risk subgroup of patients was defined as those with (1) moderate to poorly differentiated tumor, presence of LVSI, and outer third myometrial invasion; (2) age 50 or older with any two

risk factors listed previously; or (3) age of at least 70 with any risk factor listed previously. All other patients were considered to be in the low intermediate risk group. Although no survival benefit was observed either group, in the high intermediate risk group, pelvic RT resulted in a reduction of the 2-year cumulative incidence of recurrence from 26% to 6% when compared with observation alone. Based on such results, pelvic radiation is reserved for older patients with high-risk histopathologic features. Although a small subset of patients in two of these trials had Stage II disease (GOG-99 included 37 patients with Stage II [occult] disease, and the ASTEC/EN5 included 40 patients with Stage II disease), no randomized prospective trials exist to guide therapy for such patients. However, growing evidence in literature, albeit retrospective, does support the use of more conservative adjuvant radiation management for FIGO Stage II endometrial cancer. Ng et al. (5), for example, showed that in 15 patients with Stage II (occult) endometrial cancer, VB alone resulted in no recurrence after 36 months of followup. In another retrospective analysis of 20 patients with node-negative Stage II endometrial cancer, Rittenberg et al. (6) showed no recurrences or deaths in patients who received either VB alone or combined with EBRT. Further analysis by Cannon et al. (7) also has shown that in 71 patients with Stage II disease (23 Stage IIA, 48 Stage IIB), treatment with VB alone when compared with VB plus EBRT results in fewer toxicities and no increased risk of recurrence, suggesting

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that VB without EBRT may be sufficient in patients with low-risk histopathologic features and extensive surgical staging. More recently, a retrospective multi-institutional study by Elshaikh et al. (10) reported that in 130 patients with 2009 FIGO Stage II disease, 99 (76%) of whom received adjuvant radiation, there was no statistically significant difference in recurrence-free, disease-specific, or overall survival for women who received VB alone vs. pelvic EBRT alone or in combination with brachytherapy. Similar to our study, the overall recurrence rate in patients who had received radiotherapy was low (11 of 99 patients, 11.1%). Although some aspects of the inclusion criteria and radiation schema varied from our study (median pelvic dose of 45 Gy in 25 fractions; median brachytherapy dose of 21 Gy in three fractions of 7 Gy prescribed to the 5-mm depth when used alone; median two fractions of 5 Gy prescribed to the surface when used in combination with pelvic RT), and although no toxicities were reported, the outcomes of the study compare favorably with ours. A summary of these studies is provided in Table 3. In contrast, preliminary results from GOG 0249, which included patients with Stage II disease, did not demonstrate superiority of vaginal cuff brachytherapy plus concurrent chemotherapy to pelvic RT (17). Similar to our study, at a median followup of 2 years, there was no statistically significant difference in recurrence-free survival or overall survival between VB and chemotherapy vs. pelvic radiation. In contrast to our study, however, GOG 0249 demonstrated a higher rate of pelvic recurrences in the brachytherapy and chemotherapy arm (19 vs. 2 recurrences) compared with our study (no pelvic recurrences). Acute toxicity, moreover, was higher in the brachytherapy and chemotherapy arm and may have been a result of combining systemic

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chemotherapy with radiation. Final analysis from GOG 0249 will better define adjuvant treatment in this patient population. Our treatment policies at Washington University for patients with Stage II endometrial cancer have evolved over the past few decades. We were interested in examining the failure patterns with VB compared with pelvic RT and VB in our group of surgically staged patients. To eliminate heterogeneity in patient characteristics and generate more clinically generalizable results, we excluded patients with nonendometrioid histology as well as patients who received a radical hysterectomy or did not undergo a lymphadenectomy. We also excluded patients treated before the 1988 FIGO surgical staging and patients treated for Stage IIA disease before the current staging system. This resulted in a subset analysis of 41 patients with Stage IIB or II (after 2009) disease. Thus, to our knowledge, this is one of the largest retrospective studies assessing the role of adjuvant radiotherapy and addressing differences in radiotherapy technique in patients with Stage II endometrial cancer according to the current staging system. Our results show that there was no statistically significant difference in overall survival or freedom from vaginal, distant, or any recurrence when comparing VB alone with VB and external beam pelvic RT. As expected, the likely explanation is that patients with isolated local failures can be salvaged with radiotherapy. Additionally, endometrial cancer tends to affect an older population with other comorbid illnesses, thus making a survival benefit difficult to detect. Our univariate analysis identified no statistically significant risk factors for recurrence or survival, an effect that may be related to the overall low rate of recurrences or to our small sample size. However, previous studies have identified many features, including age, stage, high grade,

Table 3 Review of retrospective reviews for Stage II disease treated with VB Study

IIA

IIB

II

Ng et al. (5) Rittenberg et al. (6)

5 6 0 23

10 6 5 48

N/A VB only N/A VB only VB þ EBRT N/A VB  EBRTb

Cannon et al. (7)

Elshaikh et al. (9) Elshaikh M. et al. (10) Gadducci et al. (8) Paydar et al.

N/A N/A 89c N/A N/A 99 N/A N/A 30e N/A 18 4c N/A 18 1c

Adjuvant RT

VB  EBRTb VB þ/ EBRT or EBRT alone VB  EBRTb VB only VB þ EBRT

Median No. of recurrences (%) followup, mo (treatment specifics)

Acute toxicity

Chronic toxicity

36 34

0 0

6.7% NRa

0% 0%

62.4

16% O grade 2 (EBRT), 18% (EBRT), 5% (VB) 0% (VB alone)

52 44

IIB: 7 (2 VB alone, 5 VB þ EBRT) IIA: 2 (both VB þ EBRT) 32 (13%)d 11 (11.1%)

NRa NRa

NRa NRa

57 41

11 (36.7%)f 5 (1 VB; 4 VB þ EBRT)

NRa 0

NRa 2.4% (VB þ EBRT)

Abbreviations: EBRT, external beam radiotherapy; N/A, not applicable; RT, radiotherapy; VB, vaginal brachytherapy. a Not reported. b Does not specify subset of Stage IIA or IIB patients who received VB or VB þ EBRT. c Stage II (after 2010). d Percentage of patients who received any RT. Recurrences based on RT type not specified. e Number of patients with Stage II disease. Breakdown of Stage IIA and IIB patients not provided. f Percentage of Stage II patients with recurrence. Details of VB vs VB þ EBRT in this subset not provided.

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presence of LVSI, deep myometrial invasion, and atypical histology as indicators of poor prognosis(7, 18, 19). Radiation treatment was well tolerated in most individuals, with only 1 patient (2.4%) experiencing a Grade 3 or greater toxicity that required multiple hospitalizations. No patient required procedures or surgical management. As expected, this patient had undergone treatment with pelvic EBRT in addition to VB. Given that no pelvic recurrences occurred in our study group, one must balance the risk of long-term toxicity when considering pelvic EBRT plus brachytherapy for this group. There are a number of limitations in our study. This was a retrospective analysis, and as such there may be inherent selection bias. Patients receiving VB alone had more lowrisk histopathologic features, such as low grade, although the two groups were otherwise well balanced. Despite these limitations, we conclude that, for most patients with pathologic Stage II endometrial cancer, VB alone appears to be adequate adjuvant local treatment after surgical staging. Although the addition of pelvic RT to VB may confer a trend toward improved recurrence rates and overall survival, these results are not statistically significant and must be balanced with an increased risk of long-term toxicity. Thus, our single-institution, hypothesis-generating study indicates that brachytherapy alone may be sufficient for Stage II disease presenting in the absence of other high-risk features. This concept could be investigated more thoroughly in a multi-institutional prospective clinical trial.

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[5] Ng TY, Nicklin JL, Perrin LC, et al. Postoperative vaginal vault brachytherapy for node-negative Stage II (occult) endometrial carcinoma. Gynecol Oncol 2001;81:193e195. [6] Rittenberg PV, Lotocki RJ, Heywood MS, Krepart GV. Stage II endometrial carcinoma: limiting post-operative radiotherapy to the vaginal vault in node-negative tumors. Gynecol Oncol 2005;98:434e438. [7] Cannon GM, Geye H, Terakedis BE, et al. Outcomes following surgery and adjuvant radiation in stage II endometrial adenocarcinoma. Gynecol Oncol 2009;113:176e180. [8] Gadducci A, Cosio S, Landoni F, et al. Adjuvant treatment and analysis of failures in patients with high-risk FIGO stage Ib-II endometrial cancer: an Italian multicenter retrospective study (CTF study). Gynecol Oncol 2014;134:29e35. [9] Elshaikh M, Vance S, Suri J, et al. Improved survival endpoints with adjuvant radiation treatment in patients with high-risk early stage endometrial carcinoma. Int J Radiat Oncol Biol Phys 2014;88: 351e356. [10] Elshaikh MA, Al-Wahab Z, Mahdi H, et al. Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: a multi-institution study. Gynecol Oncol 2015;136:235e239. [11] Schwarz JK, Wahab S, Grigsby PW. Prospective phase I-II trial of helical tomotherapy with or without chemotherapy for postoperative cervical cancer patients. Int J Radiat Oncol Biol Phys 2011;81: 1258e1263. [12] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457e481. [13] COX DR. Regression models and life tables. J R Stat Soc 1972;34: 187e220. [14] Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980;56:419e427. [15] Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000;355:1404e1411. [16] Blake P, Swart AM, Orton J, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 2009;373:137e146. [17] McMeekin DS, Filiaci VL, Aghajani C, et al. A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial. Gynecol Oncol 2014; 134:438. [18] Jobsen JJ, Lybeert ML, van der Steen-Banasik EM, et al. Multicenter cohort study on treatment results and risk factors in stage II endometrial carcinoma. Int J Gynecol Cancer 2008;18:1071e1078. [19] Pitson G, Colgan T, Levin W, et al. Stage II endometrial carcinoma: prognostic factors and risk classification in 170 patients. Int J Radiat Oncol Biol Phys 2002;53:862e867.