Gynecologic Oncology 131 (2013) 581–585

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Gynecologic Oncology

j ourna l homepage: www.e lsev ie r .com/ locate /ygyno

The importance of adjuvant chemotherapy and pelvic radiotherapy inhigh-risk early stage endometrial carcinoma

Leah Jutzi a, Paul Hoskins b, Peter Lim c, Christina Aquino-Parsons c, Anna Tinker b, Janice S. Kwon d,⁎a Division of Gynecologic Oncology, University of British Columbia and British Columbia Cancer Agency, Diamond Health Care Centre, 2775 Laurel Street, Vancouver,British Columbia V5Z 1M9, Canadab Department of Medical Oncology, British Columbia Cancer Agency, Vancouver Clinic, 600 West 10 Ave., Vancouver, British Columbia V5Z 4E6, Canadac Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver Clinic, 600 West 10 Ave., Vancouver, British Columbia V5Z 4E6, Canadad Division of Gynecologic Oncology, University of British Columbia and British Columbia Cancer Agency, Diamond Health Care Centre, 2775 Laurel Street, Vancouver,British Columbia V5Z 1M9, Canada

H I G H L I G H T S

• High-risk early stage endometrial cancer recurs in 29% with no adjuvant therapy.• The recurrence rate with adjuvant chemotherapy and pelvic radiation is 7%.

⁎ Corresponding author. Fax: +1 604 875 4869.E-mail addresses: leah.jutzi@vch.ca (L. Jutzi), phoskins

plim@bccancer.bc.ca (P. Lim), cparsons@bccancer.bc.ca (Catinker@bccancer.bc.ca (A. Tinker), janice.kwon@vch.ca (

0090-8258/$ – see front matter © 2013 Elsevier Inc. All rihttp://dx.doi.org/10.1016/j.ygyno.2013.09.012

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 29 July 2013Accepted 11 September 2013Available online 19 September 2013

Keywords:Endometrial cancerLymphadenectomyChemotherapyRadiation therapy

Objective. To determine the impact of a policy change inwhichwomenwith high-risk early stage endometrioidendometrial cancer (EEC) received adjuvant chemoradiotherapy.

Methods. This is a population-based retrospective cohort study of British Columbia Cancer Registry patientsdiagnosed from 2008 to 2012 with high-risk early stage EEC, who received adjuvant chemoradiotherapy afterprimary surgery. High-risk early stage was defined as the presence of two or more high-risk uterine factors:grade 3 tumor, more than 50% myometrial invasion, and/or cervical stromal involvement. Adjuvant therapyconsisted of 3 or 4 cycles of carboplatin and paclitaxel chemotherapy, followed by pelvic radiotherapy. Sites andrate of recurrencewere compared to a historical cohort diagnosed from2005 to 2008 inwhich none of the patientsreceived adjuvant chemoradiotherapy. Five-year progression-free and overall survival rates were calculated.

Results. The study includes 55 patients. All patients except for 2 received at least 3 cycles of chemotherapy. Allpatients received pelvic radiotherapy except for 2 who received brachytherapy only. Median follow-up was27 months (7–56 months). Four patients (7.3%) recurred, including three with distant recurrence only and onewith both a pelvic and paraaortic nodal recurrence. The historical cohort had a 29.4% recurrence rate, and thereforethe hazard ratio for recurrence was 0.27 (95% CI 0.02–4.11). Five-year progression-free and overall survival rateswere 88.6% and 97.3%, respectively.

Conclusion. Patientswithhigh-risk early stage endometrial carcinoma treatedwith adjuvant chemoradiotherapyhave a low rate of recurrence compared to those not receiving such therapy.

© 2013 Elsevier Inc. All rights reserved.

Introduction

Mostwomenwith endometrioid endometrial carcinoma (EEC) havea good prognosis andwill be cured by surgery. However, a proportion ofwomenwith apparent early stage disease have an increased risk of can-cer recurrence and death. Several factors have been associated with thepotential for extrauterine disease and worse prognosis and these are

@bccancer.bc.ca (P. Hoskins),. Aquino-Parsons),J.S. Kwon).

ghts reserved.

older age, higher grade, deep myometrial invasion, lymphovascularspace invasion (LVI) and involvement of the cervical stroma [1–3].

It is evident that even when the pelvic lymph nodes are uninvolved,high-risk uterine factors predict for a risk of recurrence and death in theabsence of adjuvant therapy. In GOG99, the addition of postoperativepelvic radiotherapy for women with intermediate risk disease reducedrecurrence compared to no adjuvant treatment (relative hazard 0.42,90%CI 0.25–0.73). Of particular relevance to this study is that in the sub-group of patients with high-intermediate risk disease, the risk of anyrecurrence without adjuvant treatment was 27%, predominantly dueto distant recurrence (19%). Adjuvant radiotherapy reduced the overalldeath rate in this high-intermediate risk group compared to no adjuvant

Table 1Pathologic characteristics of the study population.

2005–2008 2008–2012

n % n %

Grade2 0 0 6 10.93 15 88.2 47 85.4Other 2 11.7 2 3.6

Myometrial invasionNone 0 0 1 1.8b50% 1 5.9 2 3.6N50% 16 94.1 52 94.5

Lymphovascular space invasion (LVI)Yes 7 41.2 46 83.6No 9 52.9 8 14.5Not reported 1 5.9 1 1.8

StageIB 14 82.4 38 69.1II 3 17.6 17 30.9

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treatment (relative hazard 0.73, 90% CI 0.43–1.26). Although this resultwas not significant, it suggests that some form of adjuvant therapyshould be considered for these patients, even when lymph nodes arenegative. However, radiotherapy alone is not sufficient as even amongthose who received adjuvant pelvic radiotherapy, the 4-year risk ofdistant recurrence was still 10%, comprising more than half of all recur-rences in this subgroup [4]. This high rate of distant recurrenceprompted evaluation of adjuvant chemotherapy in high-risk earlystage disease. The combined results of two phase III randomized studiescomparing a combination of chemotherapy and radiotherapy to radio-therapy alone in the adjuvant setting demonstrated an improvementin cancer-related survival with a hazard ratio of 0.55 (95% CI 0.35–0.88), and overall survival that approached significance (HR 0.69 95%CI 0.46–1.03) [5].

In British Columbia (BC), all women with gynecologic cancers aremanaged according to provincially applied policies. Between 2005 and2008, women in BC with high grade (grade 2 or 3), deeply invasiveendometrial cancer underwent surgical staging including pelvic lymph-adenectomy either at the time of hysterectomy or as a subsequent stag-ing operation.Womenwith confirmed negative pelvic lymph nodes didnot routinely receive adjuvant therapy. The recurrence rate in thiscohort was 29.4% (5 of 17 women), and two of these recurrences weredistant. As a result, starting in 2008, women with high-risk early stagedisease have been treated with three or four cycles of carboplatin andpaclitaxel chemotherapy followed by pelvic radiotherapy, regardlessof their nodal status.

The objective of this studywas to determine the impact of this policychange on the rate and sites of recurrence and to estimate the five-yearprogression-free and overall survival rates of women with high-riskearly stage endometrioid endometrial carcinoma.

Methods

This was a population-based, retrospective cohort study of womenin British Columbia diagnosed with endometrial cancer between 2008and 2012. Patients were identified from the British Columbia CancerAgency database and included if they received primary surgical treat-ment with a minimum of a hysterectomy. Additional inclusion criteriawere endometrioid histology and at least two of three uterine riskfactors including grade 3 tumor, more than 50% myometrial invasion,and/or cervical stromal involvement. Patients were thus surgical stageIB or II according to the 2009 FIGO staging system. If lymph node sam-pling was performed, lymph nodes were negative. The protocol foradjuvant therapy included three cycles of carboplatinum (AUC 6) andpaclitaxel (175 mg/m2) chemotherapy at 3–4 week intervals. This wasfollowed by external beam pelvic radiotherapy, most commonly at adose of 4500 cGy in 25 fractions prescribed to the isocenter. Vaultbrachytherapy was delivered using an HDR vaginal cylinder to theupper 3.5 cm of the vagina with the prescription point being 0.5 cmfrom vaginal mucosal surface and at a dose of 300–500 cGy. Externalbeam radiotherapy was delivered with a standard conventional 4 fieldbox technique, or with 7 field or RapidArc IMRT with defined volumesof interest and organs at risk parameters according to RTOG guidelines.

Data extracted from the electronic patient record included age atdiagnosis, date of diagnosis, surgical procedure, surgical stage, tumorgrade, type and number of cycles of chemotherapy and radiation dose.Treatment-related toxicities were evaluated, although they were notsystematically recorded. Follow-up visits consisted of a history andphysical examination. Symptoms or physical findings suggestive of re-currence prompted further evaluation with imaging, lab investigationsand/or biopsies. The date of recurrence represented the first objectivedocumentation of disease using either imaging or tissue biopsy. If pa-tients recurred, the date, site and treatment for recurrence, and whereapplicable, the date of death, were recorded.

Progression-free survival was calculated as the time from diagnosisto recurrence or death from any cause in the absence of known

recurrence. Patients not recurring were censored at the time of lastfollow-up. Overall survival was calculated as the time from diagnosisto the date of death or last known follow-up. Kaplan–Meier curveswere calculated for both progression-free and overall survival at5 years. The hazard ratio for progression-free survival for the con-temporary cohort receiving combined adjuvant therapy comparedto the high-risk node negative historical cohort without such treat-ment, was estimated according to the method of Parmar et al. [6].

Results

There were 55 patients in the contemporary cohort. Themedian agewas 58 (range 38–81), and median follow-up was 27 months (range7–56 months). In the historic cohort, there were 17 patients with amedian age of 66 (range 48–80) and median follow-up of 48 months(range 20–62 months).

In the contemporary cohort, 27 patients underwent a laparotomyand 26 had laparoscopic or robotic surgery. All patients had aminimumof a hysterectomy and bilateral salpingo-oophorectomy. Two patientshad a vaginal hysterectomy with no salpingo-oophorectomy becauseof morbid obesity (BMI 43 and 62). Thirty-three (60%) had pelviclymphadenectomy or pelvic lymph node sampling, with a mediannode count of 9 (range 1–23). Three patients had sampling of paraaorticlymph nodes. The frequency of node dissection decreased over the timeperiod. In 2008 and 2009, 18 of 26 patients (69.2%) had a pelvic lymph-adenectomy compared to 13 of 29 (44.8%) in 2010 and 2011. All womenin the historic cohort had a pelvic lymphadenectomy and confirmednegative nodes.

The pathologic characteristics of both cohorts are described inTable 1. Only patients with endometrioid tumors were included. Allpathologywas reviewed by a gynecologic pathologist. In the contempo-rary cohort, 39 (70.9%) had high-risk disease based on a grade 3tumor with deep myometrial invasion. Nine (16.4%) had a grade 3tumor, deep myometrial invasion and involvement of the cervicalstroma. The remaining 7 (12.7%) had cervical stromal involvementplus one additional risk factor (grade 3 tumor or deep myometrialinvasion).

In the contemporary cohort, all patients were treated withcarboplatinum (AUC 6) and paclitaxel (175 mg/m2) chemotherapy.Fifty-three women (96.4%) received at least three cycles. Four women(7.3%) received four cycles. One of these women received an additionalcycle because she received a lower dose of radiotherapy due to priorsurgery for rectal cancer. For the remaining three patients, 4 cycleswere given as this is the preference in one of the five health authorityregions in BC. One patient canceled her chemotherapy after one cycle.Another patient had her chemotherapy canceled after two cycles due

Table 2Patients with disease recurrence.

Pathology Site(s) recurrence Time to recurrence(months)

Investigations at recurrence Treatment of recurrence Outcome

1 Stage IBgrade 3+ LVI

PelvisParaaortic lymph nodesLiver

11 CT chest/abdomen/pelvis 6 cycles carboplatin/paclitaxelRadiotherapyDoxorubicinTamoxifen

AED*28 months

2 Stage IIgrade 2+ LVI

Paraaortic lymph nodes 15 CT abdomen/pelvisPET/CT

Radiotherapy AED*17 months

3 Stage IBgrade 3+ LVI

Bone, orbit 19 CT lumbar spineBone scanCT headMRI head

Radiotherapy DOD**21 months

4 Stage IIgrade 2+ LVI

Lung 37 CT chest bronchoscopy MegaceLetrozole

AED*47 months

LVI = lymphovascular space invasion; AED* = alive with evidence of disease, DOD** = died of disease.

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to severe facial acne from the pre-paclitaxel dexamethasone. In thehistoric cohort, none of the patients received chemotherapy.

All patients received pelvic radiotherapy and 54 were treated onemonth after the completion of chemotherapy. One patient had a6 month delay to radiotherapy because of a hip fracture. Forty-two pa-tients (76.3%) had 4500 cGy of external beam radiotherapy to the pelviswith a vaginal vault brachytherapy boost (37 patients received 300 cGyand 5 received 500 cGy); six patients (10.9%) received 4500 cGy withbrachytherapy and an external beam boost because of concern regard-ing the cervical stromal disease, (range 900–1500 cGy) and five re-ceived pelvic radiation (4500 cGy) only. Two patients were treatedwith vault brachytherapy only (2100 cGy in 3 fractions), one patient be-cause of previous surgery for rectal cancer and one because of a pelvickidney. Overall, 80% of patients received vault brachytherapy. In the his-toric cohort, two patients received vault brachytherapy only (2100 cGyin 3 fractions), and another two patients with stage II disease received4500 cGy of external beam radiotherapy to the pelvis with a 300 cGyvaginal vault brachytherapy boost. Radiation doses and volumes wereat the discretion of the treating radiation oncologist.

Forty-two patients (76.4%) had no record of toxicity that resultedtreatment alteration, additional therapy or hospital admission. Three pa-tients (5.5%) had grade 2 neuropathy, and one patient had grade 1 neu-ropathy. Two patients (3.6%) had grade 2 myalgia. Four patients (7.3%)had grade 4 neutropenia, including one who required hospital admissionfor febrile neutropenia. Two patients had grade 2 radiation enteritis,resulting in a 10 day gap in the radiotherapy for one patient. One patienthad grade 3 radiation enteritis that required hospital admission.

In the contemporary cohort, fourwomen recurred (7.3%). Themedi-an time to recurrence was 17 months (11–37 months). All patients haddistant recurrence and one had a synchronous pelvic recurrence(Table 2). All patients were diagnosed on imaging, and one patient

Fig. 1. Five year progression-free survival, 2008–2012 cohort.

also had a bronchoscopy and biopsies because of a history of colon cancer.The locoregional recurrence risk was 1.9%, and the distant recurrence riskwas 7.3%. The estimated five-year progression-free survival was 88.6%(Fig. 1) and the five-year overall survival was 97.1% (Fig. 2).

In the historic cohort, five patients recurred (29.4%) at a median of17 months (6–17 months), including 3 pelvic and 2 distant (bone,abdomen) recurrences. The locoregional recurrence risk was 17.6%,and the distant recurrence risk was 11.7%. The estimated five yearprogression-free survival was 61.3% (Fig. 3) and the five year overallsurvival was 55% (Fig. 4). The contemporary cohort had a relative riskreduction of 73% (HR 0.27, 95% CI 0.02–4.11), and an absolute riskreduction in recurrences of 22.1% compared to the historic cohort.

Discussion

The objective of this study was to determine the impact of a policychange in which women with high-risk early stage endometrial cancerdetermined by adverse uterine pathologic factors were to be treatedwith adjuvant chemoradiotherapy, regardless of whether nodal statuswas negative or unknown. Previously (2005 to 2008), nodal statusalone was used to guide adjuvant therapy. Women with negative nodeswere not routinely offered adjuvant therapy, and had a high rate ofrecurrence (29.4%, three pelvic and two distant). A similar recurrencerate was noted in the untreated high-intermediate risk group in GOG99,defined as those with a grade 2 or 3 tumor, LVI and deep invasion, olderthan 50with twoof these risk factors or older than 70with one risk factor.Despite all patients being node-negative, the risk of recurrence was 27%without adjuvant therapy. Thosewho received adjuvant pelvic radiother-apy had a lower recurrence risk at 19%, butmore than half of these recur-rences were distant [4]. These findings are consistent with the results ofanother population-based study that demonstrated that women with

Fig. 2. Five year overall survival, 2008–2012 cohort.

Fig. 3. Five year progression-free survival, 2005–2008 cohort.

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2–3 uterine risk factors and negative pelvic lymph nodes had a worseprognosis than those with 0–1 risk factors and positive lymph nodes. Inthat study, 5-year survival for those with negative nodes but high-riskuterine featureswas 53%. None of the patients in that study received che-motherapy, and only 23.7% received pelvic radiotherapy, including 63.2%of thosewithpositive nodes and18.3% of thosewithnegativenodes [7]. InPORTEC1, there were 104 women with deep myometrial invasion andgrade 3 tumors who were not eligible for randomization because oftheir high-risk disease, and therefore received adjuvant radiotherapy[8]. They did not undergo full surgical staging (including lymphadenecto-my), which limits comparability to GOG99, but there was an importantobservation. Distant recurrences comprised the majority of recurrencesin this high-risk subgroup, with 31% and 14% having distant andlocoregional recurrences, respectively [8]. These studies suggest thatwhile radiotherapy reduces locoregional recurrence risk, there is still asignificant distant recurrence risk, which provides the rationale for sys-temic therapy. As a result of the high recurrence rates observed inwomen with high-risk early stage disease, particularly distant recur-rences, there was a treatment policy change in British Columbia in2008, such that all women with 2 or more high-risk uterine factorswould receive adjuvant chemotherapy and radiation, regardless ofnodal status. In keeping with this policy change, there was a downwardtrend in lymph node sampling during the contemporary time period.

Other studies have evaluated chemotherapy in the context of high-risk early stage endometrial cancer. In a randomized trial by theJapanese Gynecologic Oncology Group, there were 120 patients withhigh-intermediate risk disease who had: (1) deep myometrial invasionand grade 3 tumors or age over 70 or (2) deepmyometrial invasion andcervical involvement or positive cytology. In this group, cyclophospha-mide, doxorubicin and cisplatin chemotherapy was associated withan improved overall survival compared to pelvic radiotherapy alone(89.7% vs. 73.6%, HR 0.24, 95% CI 0.09–0.69). Although the pelvic recur-rence rate in the chemotherapy groupwas 7.3%, this study included 190

Fig. 4. Five year overall survival, 2005–2008 cohort.

womenwith low-intermediate risk disease (deep myometrial invasion,grade 1 or 2 tumor, and age under 70) [9]. It is well recognized thatchemotherapy alone for early stage high-risk and advanced stage pa-tients is associatedwith a high rate of pelvic recurrence, which providesthe rationale for combined modality adjuvant therapy [10,11].

The feasibility and outcomes of combined modality adjuvant thera-py for early stage, high-risk endometrial cancer were investigated inRTOG 9708. This study included 46 patients with grade 2 or 3 tumorsand deep myometrial invasion, cervical stromal involvement or extra-uterine disease confined to the pelvis. Patients received pelvic radio-therapy with concurrent cisplatin (50 mg/m2) followed by vaginalbrachytherapy and four cycles of cisplatin (50 mg/m2) and paclitaxel(175 mg/m2). 17 patients had stage I or II disease, and none of these pa-tients recurred at a median follow-up of 4.3 years [12]. The benefit ofchemotherapy in addition to pelvic radiotherapy for early stage diseasehas also been demonstrated in two European phase III randomized trials(EORTC/MANGO). Since neither trial was large enough to show a statis-tically significant benefit, the results were combined for a total of 534patients randomized to receive pelvic radiotherapy with or withoutchemotherapy [5]. All patients had disease confined to the pelvis, butcould be stages I–III, and some had non-endometrioid histology. Radio-therapywas followed by chemotherapy.With radiotherapy alone, 26.2%of patients recurred compared to 16% in the combination therapy group.The adjusted hazard ratio for recurrence was 0.65 (95% CI 0.43–0.99) infavor of combination therapy. The higher rates of recurrence in thosegroups compared to our cohort are likely the result of the inclusion ofhigher stage (78% stage I or II) and non-endometrioid histology (29%)patients.

Our study represents a large series of patients with high-risk, earlystage endometrial cancer who received adjuvant therapy based on aconsistent set of uterine risk factors. All patients had endometrioid his-tology and stage I or II disease. Lymph nodes were negative in 60% andunknown in 40%. One of the major limitations inherent to our study isthat there were only 17 patients evaluable in the earlier cohort beforeour treatment policy changed. The reduced rate of recurrence (29.4%vs. 7.3%, HR 0.27 95% CI 0.02–4.11) was not statistically significant,which is related to the small number of patients, particularly in theearlier cohort. This study was underpowered to detect a significant dif-ference in recurrence. Another limitation is that there was no contem-porary control group, since the policy change impacted all patientstreated in British Columbia between 2008 and 2012. However, therates of recurrence in patients with high-risk disease in the absence ofadjuvant therapy are known from GOG99 and PORTEC1, and they aresimilar to our own data from 2005 to 2008 [4,8]. It is unlikely that theimproved outcomes observed in our study are due to factors otherthan the addition of adjuvant therapy. These patients are from thesame population and are treated in the same centers. The only otherdifference was that all patients in the earlier cohort had undergone sur-gical staging, compared to 60% in the current cohort. It is possible thatsome of the unstaged patients in the current cohortmayhave had occultnodal disease, but this if anything should artificially inflate the recur-rence rate compared to the earlier staged cohort. This study is alsolimited somewhat by themedian follow-up being 27 months. However,it is well documented that most recurrences of endometrial canceroccur within 18 months of treatment [4].

Conclusion

The use of adjuvant chemoradiotherapy in patients with high-riskearly stage endometrioid endometrial cancer defined by uterine riskfactors is associated with a lower rate of recurrence compared tothose not receiving this treatment. The use of chemotherapy for high-risk early stage disease remains somewhat controversial, even thougha survival benefit was reported in the EORTC/MANGO trials as well asin the high-intermediate risk subgroup of the Japanese GOG study[5,9]. Further comparison of adjuvant chemotherapy and radiotherapy

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to radiotherapy alone is the subject of two ongoing clinical trials.PORTEC3 is amulticentre phase III randomized trial evaluating the com-bination of chemotherapy and radiotherapy compared to radiotherapyalone for these high-risk patients [13]. GOG 249 is a randomizedphase III trial comparing pelvic radiotherapy alone to vault brachyther-apy plus paclitaxel and carboplatin [14]. Our study is small compared topreviously published trials and the targeted accrual in ongoing trials(670 and 562 patients in PORTEC3 andGOG249, respectively). Althoughunderpowered, our study does provide insight into the utility of chemo-therapy for this high-risk subgroup of women, particularly from a pop-ulation perspective in which there is standardized treatment andadequate follow-up. The results of PORTEC3 and GOG249 will furtherdefine the role of chemotherapy in the adjuvant treatment of womenwith high-risk early stage endometrial cancer.

Conflict of interest statement

The authors disclose no potential conflict of interest with regard to this work.

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