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Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 5, pp. 1438–1445, 2007Copyright © 2007 Elsevier Inc.
Printed in the USA. All rights reserved0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.02.003
LINICAL INVESTIGATION Endometrium
ANALYSIS OF PROGNOSTIC FACTORS AND PATTERNS OF RECURRENCEIN PATIENTS WITH PATHOLOGIC STAGE III ENDOMETRIAL CANCER
SAMIR PATEL, M.D.,* LORRAINE PORTELANCE, M.D.,* LUCY GILBERT, M.D.,† LEONARD TAN, B.SC.,†
GERALD STANIMIR, M.D.,† MARIE DUCLOS, M.D.,* AND LUIS SOUHAMI, M.D.*
*Division of Radiation Oncology, Department of Oncology, and †Department of Obstetrics and Gynecology, McGill University,Montreal, Quebec, Canada
Purpose: To retrospectively assess prognostic factors and patterns of recurrence in patients with pathologic StageIII endometrial cancer.Methods and Materials: Between 1989 and 2003, 107 patients with pathologic International Federation ofGynecology and Obstetrics Stage III endometrial adenocarcinoma confined to the pelvis were treated at ourinstitution. Adjuvant radiotherapy (RT) was delivered to 68 patients (64%). The influence of multiple patient-and treatment-related factors on pelvic and distant control and overall survival (OS) was evaluated.Results: Median follow-up for patients at risk was 41 months. Five-year actuarial OS was significantly improvedin patients treated with adjuvant RT (68%) compared with those with resection alone (50%; p � 0.029). Age,histology, grade, uterine serosal invasion, adnexal involvement, number of extrauterine sites, and treatment withadjuvant RT predicted for improved survival in univariate analysis. Multivariate analysis revealed that grade,uterine serosal invasion, and treatment with adjuvant RT were independent predictors of survival. Five-yearactuarial pelvic control was improved significantly with the delivery of adjuvant RT (74% vs. 49%; p � 0.011).Depth of myometrial invasion and treatment with adjuvant RT were independent predictors of pelvic control inmultivariate analysis.Conclusions: Multiple prognostic factors predicting for the outcome of pathologic Stage III endometrial cancerpatients were identified in this analysis. In particular, delivery of adjuvant RT seems to be a significantindependent predictor for improved survival and pelvic control, suggesting that pelvic RT should be routinelyconsidered in the management of these patients. © 2007 Elsevier Inc.
Endometrial cancer, Stage III, Radiotherapy, Prognostic factors, Patterns of failure.
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INTRODUCTION
ndometrial cancer is the most commonly diagnosed gyne-ologic malignancy in North America (1, 2). The majorityf patients present with disease limited to the uterus andave an overall 5-year survival rate of �80% (3). Patientsith disease involving the serosa, adnexa, peritoneal wash-
ng cytology (Stage IIIA), vagina (Stage IIIB), or pelvic orara-aortic lymph nodes (Stage IIIC) at diagnosis are un-ommon, with an incidence of 10–15% (4). Experienceegarding the optimal management of these women is lim-ted, and clinical outcomes are poor. Adjuvant pelvic radio-herapy (RT) has the potential to decrease the incidence ofelvic recurrence (5–7) and is typically offered to patients.Age of the patient, high-risk histology (serous papillary and
lear cell adenocarcinoma), high grade, lymphovascular inva-ion (LVI), depth of myometrial invasion, and number ofxtrauterine sites have been identified as predictors of clinical
Reprint requests to: Lorraine Portelance, M.D., Montreal Gen-ral Hospital, Suite D5.400, 1650 Cedar Avenue, Montreal, Que-ec H3G 1A4, Canada. Tel: (514) 934-8040; Fax: (514) 934-8392;-mail: [email protected]
Presented in part at the Forty Seventh Annual Meeting of the A1438
utcome in multivariate analyses (8, 9). Given the uncommonresentation of this stage of disease, however, the publishediterature has been largely based on small sample sizes orooled data from multiple institutions. These analyses havelso included patients with extrapelvic metastases (involvedara-aortic nodes). Data regarding factors predicting clinicalutcomes in patients with Stage III endometrial cancer whoave disease confined to the pelvis are limited. This retrospec-ive analysis examines prognostic factors and patterns of fail-re in patients with Stage III endometrial cancer confined tohe pelvis treated at a single institution, to guide the appropriatese of adjuvant therapy in these patients.
METHODS AND MATERIALS
atient populationBetween 1989 and 2003, 1,461 patients were treated for endo-etrial cancer at the McGill University Health Centre. One hun-
merican Society for Therapeutic Radiology and OncologyASTRO), October 16 –20, 2005, Denver, CO.
Conflict of interest: none.Received Dec 6, 2006, and in revised form Jan 30, 2007.
ccepted for publication Feb 1, 2007.
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1439Stage III endometrial cancer ● S. PATEL et al.
red thirty patients (9%) had Stage III disease according to the998 International Federation of Gynecology and ObstetricsFIGO) system (10). Excluded from the analysis were 10 casesith nonadenocarcinoma histology, 9 cases with extrapelvic dis-
ase (including patients with involved para-aortic nodes), and 4ases treated with definitive or preoperative RT. Data from 107atients were analyzed. Written consent to review patient infor-ation was obtained from the institutional ethics committee.
reatmentAll patients underwent exploratory laparotomy and total abdom-
nal hysterectomy with bilateral salpingo-oophorectomy. Patho-ogic assessments of peritoneal cytologic findings were performedn 104 patients (97%). It has been our practice to surgicallyvaluate lymph nodes in all clinically Stage III patients. In clini-ally Stage I–II patients, however, nodal evaluation is performednly in patients with FIGO Grade 3 tumors, high-risk histology,1/2 myometrial invasion on frozen section, suspiciously enlarged
ymph nodes, or where specified by research protocol. On the basisf these criteria, pathologic lymph node evaluations were per-ormed in 62 patients (58%), and a total of 2 to 35 nodes weressessed. The median numbers of pelvic and para-aortic lymphodes evaluated were 6 and 2, respectively.Adjuvant RT was delivered to only 68 patients (64%) because of
hysician’s preference or lack of referral. It typically consisted ofxternal beam RT (EBRT) and high-dose-rate (HDR) vaginal cuffrachytherapy. External beam RT was delivered to 66 patientsith a median dose of 45 Gy (range, 45–50.4 Gy). Fifty-nine of
hese patients (89%) were treated with a four-field box technique,patients (8%) with a two-field parallel-opposed pair, and 2
atients (3%) with intensity-modulated RT in the later years. Theuperior border of the radiation portals was defined at the L4/L5 or5/S1 interspace, the inferior border was defined at the lowerorder of the ischial tuberosity, and the lateral borders wereefined at 1.5–2 cm beyond the lateral bony margins of the pelvicnlet. Field borders of the lateral fields, in the case of a four-fieldeld box technique, were the S2/S3 interspace posteriorly and theubic symphysis anteriorly. None of these patients received treat-ent with whole abdominal irradiation.The dose to the vaginal cuff was boosted with HDR brachyther-
py using two colpostats in 50 of the 66 patients (76%) whoeceived EBRT. The median brachytherapy dose was 6 Gy pre-cribed to 2 cm from the center of the ovoids in one session. Oneatient (2%) was treated with adjuvant HDR brachytherapy alonefter hysterectomy. In this patient, brachytherapy was deliveredsing two colpostats with a total dose of 16 Gy prescribed to 2 cmrom the center of the ovoids, in two sessions.
Adjuvant chemotherapy was delivered to 27 patients (25%).hemotherapy regimens included cyclophosphamide, doxorubi-in, and cisplatin in 17 patients, carboplatin and paclitaxel in 5atients, and were unknown in 5 patients. In those patients whoeceived both adjuvant RT and chemotherapy (n � 9), chemother-py was delivered sequentially (either before or after RT). Proges-in hormonal therapy was delivered to 8 patients (7%) in thedjuvant setting using megestrol (n � 7) or medroxyprogesteronen � 1). Seven patients who were treated with adjuvant hormonalherapy (88%) also received treatment with adjuvant RT, but noneeceived treatment with adjuvant chemotherapy.
tatistical designThe time to censorship in all survival analyses was determined
rom the date of hysterectomy. Pelvic failure was scored as relapse a
n the vaginal vault or distal vagina, paracervical tissues, centralelvis, lateral pelvic walls, bladder, rectum, or pelvic lymph nodes.istant failure was defined as an extrapelvic relapse, includingeritoneal implants, involved para-aortic nodes, and distant metas-ases. Relapse-free survival (RFS) was calculated as the time torst pelvic or distant failure. Actuarial estimates of pelvic andistant control, RFS, and overall survival (OS) were evaluatedsing the Kaplan-Meier method (11). The influence on outcome ofge at diagnosis, histology, FIGO grade, LVI, depth of myometrialnvasion, involvement of the lower uterine segment, cervix, uterineerosa, and adnexa, number of extrauterine sites involved, lymphode involvement, and treatment with adjuvant RT, chemotherapy,nd hormonal therapy were evaluated. Associations between con-inuous and categoric variables were examined using the Student’s
test and Fisher’s exact (or chi-squared) test as appropriate,espectively. Differences in survival rates for each factor weressessed using the Mantel-Cox log–rank test (12). The Cox pro-ortional hazards regression model was used to identify prognosticactors in univariate and multivariate analyses (13). A two-sided palue of �0.05 was considered to indicate statistical significance.ll analyses were performed using SPSS 13.0 for Windows
SPSS, Chicago, IL).Radiation-related complications were scored using the European
rganization for Research and Treatment of Cancer/Radiationherapy Oncology Group grading system for treatment-relateddverse events. Acute adverse events were defined as those occur-ing within 90 days of the completion of RT. Complicationsccurring thereafter were recorded as late adverse events.
RESULTS
atient demographicsThe median age at diagnosis was 65 years (35–87 years).
urther patient demographics are given in Table 1. Patientsresented clinically with postmenopausal bleeding in 86ases (80%), premenopausal or irregular bleeding in 15ases (14%), abdominal cramps in 9 cases (8%), pelvic painn 7 cases (7%), a pelvic mass in 3 cases (3%), or assymptomatic in 1 case (1%). Three patients (3%) hadicroscopically positive resection margins after total ab-
ominal hysterectomy with bilateral salpingo-oophorec-omy, and all were treated with adjuvant RT.
The prognostic value of positive results on cytologicvaluation alone is controversial, and some studies supporthe fact that positive cytology by itself does not impact onlinical outcome (14). For this reason, 21 patients staged asIGO Stage IIIA owing to the presence of isolated positiveeritoneal cytology were included in the analysis. Patientnd disease characteristics were not significantly different inatients treated with or without adjuvant RT (p � 0.05). Ofote, significantly more patients in the surgery-alone groupompared with the adjuvant RT group were treated withhemotherapy (p � 0.001).
linical outcomesThe median follow-up time was 41 months (range, 1.3–
63 months) for patients at risk. Five-year actuarial esti-ates of OS and RFS were 61% and 51%, respectively, for
ll patients. Pelvic and distant control and OS rates accord-
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1440 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 5, 2007
ng to patient and treatment-related factors are given inable 2. Five-year OS (Fig. 1) was significantly improved inatients treated with adjuvant RT (68%) compared withhose treated with resection alone (50%; p � 0.029). The-year RFS rate in patients treated with or without adjuvantT was 67% and 37%, respectively (p � 0.004). Because ofn inadequate number of cases of Stage IIIB disease, resultsre not reported for these patients.
Patient age �70 years, serous papillary histology, FIGOrade 3, uterine serosal invasion, adnexal involvement, num-er of extrauterine sites involved �3, and absence of treatmentith adjuvant RT predicted for reduced OS in univariate anal-sis (Table 3). In addition, a trend for reduced OS was ob-erved with the presence of LVI (p � 0.092). Multivariatenalysis (Table 4) revealed that FIGO Grade 3, uterine serosalnvasion, and treatment with adjuvant RT were independentrognostic factors of OS (all p � 0.05).
Five-year actuarial pelvic control (Fig. 2) improved sig-ificantly with the delivery of adjuvant RT (74% vs. 49%;� 0.011). Predictors of reduced pelvic control in univar-
Table 1. Pretreatment patient characteristics
Surgery Surgery � RTCharacteristic (n � 39) (n � 68)
ge, median (range) (y) 68 62istologyEndometrioid 26 (67) 53 (78)Serous papillary 11 (28) 10 (15)Clear cell 2 (5) 5 (7)
IGO Grade1 13 (33) 26 (38)2 8 (21) 24 (35)3 18 (46) 18 (26)
ymphovascular invasion 26 (67) 48 (71)terine serosal invasion 16 (41) 24 (35)epth of myometrial
invasion �1/217 (44) 36 (53)
ower segment extension 9 (24) 25 (37)ervical stromal extension 17 (44) 21 (31)terine serosal invasion 16 (41) 24 (35)dnexal invasion 22 (56) 32 (47)o. of extrauterine sites
involved1 16 (41) 41 (60)2 11 (28) 19 (28)3 8 (21) 6 (9)4 3 (8) 2 (3)5 1 (3) 0
ositive peritoneal cytology 21 (54) 27 (40)IGO StageIIIA 26 (67) 43 (63)IIIB 2 (5) 2 (3)IIIC 11 (28) 23 (34)
hemotherapy 18 (36) 9 (13)ormonal therapy 1 (3) 7 (10)ollow-up time, median (mo) 48 39
Abbreviations: RT � radiotherapy; FIGO � International Fed-ration of Gynecology and Obstetrics.
Values are number (percentage), unless otherwise noted.
ate analysis included serous papillary histology, depth of t
yometrial invasion �1/2, uterine serosal invasion, adnexalnvolvement, number of extrauterine sites involved �3, andbsence of treatment with adjuvant RT (Table 3). Depth ofyometrial invasion and treatment with adjuvant RT onlyere independent prognostic factors of pelvic control inultivariate analysis (p � 0.05; Table 4). The overall 5-year
ctuarial distant control rate was 65% and did not signifi-antly differ according to treatment with adjuvant RT (p �.663). Patients with high-risk histology, FIGO Grade 3,terine serosal invasion, or number of extrauterine sitesnvolved �3 had reduced distant control according to uni-ariate analysis. Multivariate analysis determined that onlyistology and uterine serosal invasion were independentrognostic factors of distant control (p � 0.05).
The median times to first pelvic and distant failure were5.4 months (range, 1.6–81.9 months) and 17.3 monthsrange, 1.8–71.3 months), respectively. Pelvic failure (Ta-le 5) was observed in 9 patients (13%) treated with adju-ant RT, compared with 13 patients (33%) not treated withdjuvant RT (p � 0.024). Treatment with adjuvant RTesulted in fewer pelvic recurrences in the vaginal vault,aracervical tissues, other central pelvis sites, and pelvicidewall. Of 22 patients with pelvic failure, 10 (45%) had aomponent of vaginal recurrence, including 6 of 9 patients67%) treated with RT. Distant failure occurred in 21 pa-ients (20%), and 15 of these 21 patients (71%) had anbdominal component of recurrence (Table 5).
dverse eventsThe observed incidence of acute radiation-related adverse
vents was low. Acute upper gastrointestinal (GI) toxicityas limited to Grade 2 events and observed in 6 patients
9%) of those treated with RT. Grades 2, 3, and 4 lower GIoxicity was observed in 32 patients (47%), 1 patient (1%),nd 1 patient (1%), respectively. Grades 2, 3, and 4 geni-ourinary toxicity was observed in 3 patients (4%), 2 pa-ients (3%), and no patients, respectively. Acute hemato-ogic toxicity was limited to Grade 2 events and observed asnemia in 2 patients (3%), leukocytopenia in 4 patients6%), and neutropenia in 1 patient (1%). Thrombocytopeniaas not observed. Three patients required hospitalizationuring or immediately after completion of adjuvant RT formall bowel obstruction, radiation cystitis, and persistentrinary tract infection, and all were medically managed.Late events were limited to GI toxicity and were observed inpatients (4%) as Grade 2 events and in 2 patients (3%) asrade 4 events. Late genitourinary and hematologic toxicityas not observed. One patient suffered a rectal perforationith formation of a presacral abscess requiring surgical drain-
ge after adjuvant RT. She developed a rectovaginal fistula 28onths after RT and was managed with a colostomy and
ttempted surgical repair. Another patient developed a recto-aginal fistula requiring a colostomy 19 months after comple-ion of adjuvant RT. Both patients with rectovaginal fistulasere treated with EBRT of 45 Gy in 25 fractions and HDRrachytherapy of 6 and 8 Gy, respectively, in one session. No
reatment-related deaths were observed.
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1441Stage III endometrial cancer ● S. PATEL et al.
DISCUSSION
This report describes the largest experience of patients withathologic FIGO Stage III endometrial cancer with diseaseonfined to the pelvis. All patients were prospectively stagedccording to 1988 FIGO surgical staging criteria and treated atsingle institution. Limited information exists on the prognosis
Table 2. Five-year actuarial pelvic control, distant control, and
Factor No. Pelvic control (%) p
ge (y)�70 71 68 N�70 36 53
istologyndometrioid 79 75 0.0erous papillary 21 28lear cell 7 60IGO Grade1 39 85 N2 32 593 36 53
ymphovascular invasionAbsent 33 63 NPresent 74 66
epth of myometrial invasion�1/2 40 86 0.0�1/2 67 59
ower segment extensionAbsent 73 61 NPresent 34 71
ervical extensionAbsent 69 63 NPresent 38 61
terine serosal invasionAbsent 67 68 0.0Present 40 56
dnexal involvementAbsent 53 74 0.0Present 54 55
o. of ovaries involved0 84 69 N1 9 532 14 0
o. of extrauterine sites1 57 74 0.02 30 67�3 20 34
eritoneal cytologyNegative 58 68 NPositive 49 61
IGO StageIIIA 69 67 NIIIC 34 51
djuvant RTll stagesAbsent 39 49 0.0Present 68 74
IGO Stage IIIAAbsent 26 62 NPresent 43 70
IGO Stage IIICAbsent 11 15 0.0Present 23 78
Abbreviations: FIGO � International Federation of Gynecolog
f patients with Stage III disease confined to the pelvis. In a i
eview of 17 patients with pelvic nodal metastases, Nelson etl. (15) reported positive peritoneal cytology as a predictor ofurvival. Other investigators included patients with involvedara-aortic nodes (4, 8, 16–21).
In a large study, Greven et al. (8) reported prognosticactors in 105 Stage III endometrial cancer patients, includ-
l survival estimates according to patient and treatment factors
istant control (%) p Overall survival (%) p
68 NS 69 0.02257 47
74 �0.001 70 �0.00147 4020 56
77 0.037 78 0.07867 6945 47
67 NS 76 0.08463 55
73 NS 69 NS59 65
70 NS 63 NS58 57
63 NS 67 NS67 52
75 0.030 69 0.02350 47
63 NS 78 0.00369 46
64 NS 70 0.01588 4433 22
74 0.013 70 0.00169 7027 23
78 NS 64 NS54 64
67 NS 61 NS54 58
67 NS 50 0.02962 68
80 NS 53 NS66 67
35 NS 41 0.04867 60
bstetrics; NS � not significant (p � 0.05); RT � radiotherapy.
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1442 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 5, 2007
reated at three institutions. High-risk histology predictedor reduced pelvic control in univariate analysis. Multivar-ate analysis did not identify independent predictors ofelvic control, although the predictive value of tumor gradeor local control approached significance (p � 0.06). Theresent report indicates that depth of myometrial invasionnd treatment with adjuvant pelvic RT are significant pre-ictors of pelvic control in multivariate analysis. Theseesults are consistent with randomized data demonstratingignificantly improved pelvic control in Stage I–II endome-
ig. 1. Actuarial estimates of overall survival according to treat-ent with adjuvant radiotherapy (RT).
Table 3. Univariate analysis of prognostic factors
Factor
Pelvic control
HR 95% CI p
ge �70 y 1.23 0.50–3.02 NSistology (vs.
endometrioid)Serous papillary 3.69 1.50–9.09 0.004Clear cell 3.40 0.72–15.9 NS
IGO Grade (vs. Grade 1)2 2.32 0.72–7.41 NS3 1.96 0.59–6.48 NS
ymphovascular invasion 1.62 0.59–4.40 NSepth of myometrial
invasion �1/24.91 1.11–21.7 0.036
ower segment extension 1.12 0.47–2.68 NServical extension 1.69 0.73–3.93 NSterine serosal invasion 2.30 1.00–5.35 0.049dnexal involvement 2.55 1.04–6.28 0.042umber of ovaries
involved (vs. 0)1 1.61 0.47–5.55 NS2 1.79 0.52–6.23 NS
umber of extrauterinesites (vs. 1)
2 1.47 0.53–4.08 NS�3 3.87 1.39–10.8 0.009
ositive peritonealcytology
1.02 0.43–2.41 NS
djuvant RT 0.35 0.15–0.82 0.016
Abbreviations: HR � hazard ratio; CI � confidence interval; FI
ignificant (p � 0.05); RT � radiotherapy.rial cancer patients treated with adjuvant RT (5–7). Serousapillary histology (but not clear cell carcinoma), uterineerosal invasion, adnexal involvement, and number of ex-rauterine sites �3 predicted for pelvic control in univariatenalyses. The increase in pelvic relapse predicted by theseactors, except depth of myometrial invasion, resulted ineduced survival in univariate analysis.
Histology, depth of myometrial invasion, and number ofxtrauterine sites were reported by Greven et al. (8) asignificant predictors of distant control in multivariate anal-sis. The number of extrauterine sites approached signifi-ance in predicting disease-free survival (p � 0.09) (8, 9).ur results confirm the independent predictive value ofistology and also identifies uterine serosal invasion as anndependent predictor of distant control. Number of extra-terine sites was a significant predictor of distant control innivariate analysis but was not included in the multivariatenalysis owing to interaction with uterine serosal, adnexal,nd nodal involvement that we evaluated as predictive fac-ors. All factors predicting increased distant failure alsoredicted for reduced survival in univariate analysis.No prospective Phase III trial has been performed com-
aring surgery vs. surgery plus postoperative RT in anyubgroup of Stage III endometrium carcinoma. Thus, theenefit of any form of adjuvant RT in this group of patientsemains unclear and is based on indirect evidence from
lvic control, distant control, and overall survival
Distant control Overall survival
95% CI p HR 95% CI p
1 0.49–2.98 NS 2.21 1.10–4.44 0.026
5 1.14–7.66 0.026 2.81 1.31–6.01 0.0083.17–36.2 �0.001 1.47 0.34–6.39 NS
0 0.22–3.78 NS 1.87 0.65–5.41 NS5 1.04–8.95 0.042 2.97 1.11–7.93 0.0301 0.41–2.49 NS 2.16 0.88–5.26 0.0929 0.48–4.01 NS 1.63 0.64–4.17 NS
3 0.57–3.11 NS 1.05 0.51–2.18 NS6 0.62–3.42 NS 1.71 0.85–3.43 NS6 1.06–5.72 0.036 2.20 1.09–4.41 0.0273 0.62–3.31 NS 3.03 1.40–6.56 0.005
2 0.06–3.18 NS 1.52 0.52–4.49 NS9 0.43–5.09 NS 3.19 1.39–7.30 0.006
4 0.40–3.21 NS 0.85 0.34–2.12 NS7 1.40–10.2 0.009 3.37 1.52–7.47 0.0039 0.57–3.35 NS 0.77 0.37–1.61 NS
3 0.35–1.95 NS 0.47 0.23–0.94 0.033
International Federation of Gynecology and Obstetrics; NS � not
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1443Stage III endometrial cancer ● S. PATEL et al.
onrandomized reports. To our knowledge this is the firstuch report that suggests pelvic EBRT independently pre-icts for improved OS in multivariate analysis. Treatmentith pelvic EBRT resulted in improved OS, from 50% to8% (p � 0.029), with a hazard ratio of 0.66 (95% confi-ence interval 0.22–0.98; p � 0.046). Schorge et al. (20)eported the effect of adjuvant therapy in 86 pathologictage III endometrial cancer patients. Pelvic EBRT did not
mprove survival in patients with Stage IIIA–IIIB disease.n patients with Stage IIIC disease, 5-year disease-freeurvival was improved from 20% to 50% with treatmentith pelvic EBRT (p � 0.05). Pelvic EBRT was predictivef improved disease-free survival in Stage IIIC patients inultivariate analysis (p � 0.05), with a trend toward in-
reased OS. This report confirms the survival benefit ofelvic EBRT in Stage IIIC patients (p � 0.048) but not intage IIIA–IIIB disease. The lack of benefit observed intage IIIA–IIIB patients may result from inadequate sampleize in these subgroups. Larger numbers of these patientsould be required to adequately address this issue.More recently, the importance of EBRT in the manage-ent of advanced-stage disease has been questioned since
ig. 2. Actuarial estimates of pelvic control according to treatment
Table 4. Multivariate analysis of prognostic factor
Pelvic control
Factor HR 95% CI
ge �70 y —istology (vs. endometrioid)erous papillary 2.39 0.65–8.82 Nlear cell 3.13 0.36–27.4 NIGO Grade (vs. Grade 1)2 —3 —
ymphovascular invasion —epth of myometrial invasion �1/2 5.17 1.17–22.9 0.terine serosal invasion 1.65 0.58–4.67 Ndnexal invasion 1.88 0.61–5.78 Ndjuvant RT 0.28 0.10–0.75 0.
Abbreviations: HR � hazard ratio; CI � confidence interval; FIignificant (p � 0.05); RT � radiotherapy.
ith adjuvant radiotherapy (RT).
he publication of results from Gynecologic Oncologyroup (GOG) study 122 by Randall et al. (22). This trial
andomized 396 eligible patients with Stage III or IV endo-etrial carcinoma (50% endometrioid) with maximal resid-
al disease �2 cm after surgery to whole abdominal irra-iation (WAI) or chemotherapy of doxorubicin and cisplatinvery 3 weeks. Whole abdominal irradiation consisted of 30y in 20 fractions followed by a 15-Gy boost to the pelvis
nd, in selected cases, the para-aortic nodes. Planned ther-py was completed in 84% of patients treated with WAI andnly 63% treated with chemotherapy, mostly owing to tox-city and progression. With a median follow-up of 74onths, the hazard ratio for stage-adjusted progression was
elvic control, distant control, and overall survival
Distant control Overall survival
HR 95% CI p HR 95% CI p
— 1.43 0.49–4.15 NS
3.28 0.95–11.4 0.060 1.24 0.26–5.83 NS14.9 3.39–65.8 �0.001 3.25 0.35–30.4 NS
1.07 0.25–4.56 NS 2.45 0.55–11.2 NS1.99 0.60–6.63 NS 3.01 1.18–10.3 0.030— 2.62 0.67–10.3 NS— —
4.08 1.44–11.5 0.008 1.84 1.12–5.47 0.028— 3.58 1.16–11.0 0.027— 0.66 0.22–0.98 0.046
International Federation of Gynecology and Obstetrics; NS � not
Table 5. Patterns of failure according to treatment with adjuvantRT
No adjuvantRT
AdjuvantRT Total
Site of first failure (n � 39) (n � 68) (n � 107)
elvic failureVaginal vault 3 (8) 3 (4) 6 (6)Distal vagina 1 (3) 3 (4) 4 (4)Paracervical tissues 1 (3) 0 (0) 1 (1)Other central pelvis
failure*7 (18) 0 (0) 7 (7)
Pelvic side wall 5 (13) 1 (1) 6 (6)Pelvic lymph nodes 1 (3) 2 (3) 3 (3)Total pelvic failure 13 (33) 9 (13) 22 (21)
istant failurePeritoneal implants 1 (3) 2 (3) 3 (3)Para-aortic lymph nodes 1 (3) 3 (4) 4 (4)Other abdominal failure 3 (8) 7 (10) 10 (9)Inguinal lymph nodes 1 (3) 2 (3) 3 (3)Other distant metastasis† 5 (13) 9 (13) 14 (13)Total distant failure 9 (23) 12 (18) 21 (20)
Abbreviation: RT � radiotherapy.Values are number (percentage).* Includes recurrences in the bladder or rectum.
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1444 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 5, 2007
.71 in favor of the chemotherapy arm (p � 0.01). At 60onths, the stage-adjusted hazard ratio for death was 0.68
avoring chemotherapy (p � 0.01). For patients with StageII disease, 5-year PFS improved from 48% with WAI to4% with chemotherapy, and OS improved from 52% withAI to 63% with chemotherapy (from survival curves).espite the survival benefit achieved with chemotherapy,
he results of GOG 122 do not necessarily eliminate EBRTs a treatment modality for such patients. High recurrenceates were observed in both arms (54% with WAI and 50%ith chemotherapy), including limited pelvic disease as
nitial recurrence in 13% of patients treated with WAI and8% treated with chemotherapy. The patterns of subsequentailure were not reported. Furthermore, the radiation tech-ique was not optimal: radiation doses of 30–45 Gy may benadequate to control gross disease up to 2 cm that wasncluded. Whole abdominal irradiation may not be the mostffective radiation technique, and more tailored (pelvic orelvic and para-aortic) fields when treated with higher dosesay produce a higher therapeutic ratio. Many centers con-
inue to use EBRT in the management of Stage III endo-etrial carcinoma. In fact, in the recently closed GOG 0184
ECOG-G0184/RTOG-EN0130) prospective randomizedtudy of Stage III disease comparing two chemotherapyegimens (doxorubicin and cisplatin with or without pacli-axel), all patients on both arms were treated with adjuvantT (with or without para-aortic RT) after surgery.Tumor grade, uterine serosal invasion, and adnexal invasion
ere also identified as independent predictors of overall sur-ival, which to our knowledge has not been previously re-orted. Although depth of myometrial invasion and LVI wereot found to be independent predictors of survival, these fac-ors are significant predictors of survival in patients treatedith adjuvant chemotherapy (18). Interestingly, depth of myo-etrial invasion and LVI are also independent predictors of
ara-aortic lymph node involvement in Stage I–IV disease23), possibly explaining why nodal involvement does notndependently predict for survival in multivariate analyses thatnclude these factors. Risk groups of Stage III endometrialancer that have been defined according to identified prognos-ic factors (8) may be refined on the basis of our results. Grevent al. (8) suggested that optimal local treatment is the goal inatients at low risk for distant relapse (low tumor grade,uperficial myometrial penetration, and only one extrauterineite). Our results suggest that pelvic EBRT should be consid-red in all patients with Stage III endometrial cancer confined
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ith high-risk histology, high tumor grade, deep myometrialenetration, or two or more extrauterine sites (8). These patientsay benefit from systemic therapy in addition to pelvic RT.The retrospective nature of our report is the major study
imitation that precludes definitive conclusions that alter clin-cal practice from being made. Patient assignment to surgery orurgery plus adjuvant RT was not randomized but was ratherased on physician’s preference or referral bias. This certainlyaises the possibility of patient selection bias, although treat-ent groups were not significantly imbalanced in terms of
retreatment patient characteristics (Table 1). The use of aonstandardized treatment protocol also raises the question ofhether the magnitude of the benefit of adjuvant RT was
ffected by use of adjuvant chemotherapy or hormonal therapyn each group. However, chemotherapy was delivered to only
limited number of patients (25% of patients). Of note, sig-ificantly fewer patients received chemotherapy after adjuvantT (n � 9) compared with after surgery alone (n � 18; p �.001), indicating that it is unlikely that chemotherapy couldccount for the survival benefit observed in the patient groupreated with adjuvant RT. Hormonal therapy use was alsoimited (7% of patients), and its benefit in endometrial canceremains unproven (20). Because it remains unlikely that arospective, randomized, Phase III trial comparing surgeryith surgery plus postoperative RT will be conducted, owing
o limited patient populations and heterogeneity of patientsith Stage III endometrial carcinoma, analysis of prospectively
ollected data in the future will help to better define the role ofdjuvant RT for these patients.
CONCLUSIONS
Multiple prognostic factors predicting for clinical outcomesn pathologic Stage III endometrial cancer patients with diseaseonfined to the pelvis were identified in this report. This reportescribed the largest experience of Stage III endometrial can-er patients without extrapelvic metastases treated at a singlenstitution. In particular, delivery of adjuvant pelvic RT seemso be a significant independent predictor for improved survivalnd pelvic control. Risk groups for pelvic and distant failureased on known prognostic factors may aid in selecting pa-ients most likely to benefit from adjuvant systemic therapy inddition to pelvic RT. Given that the major limitation of thiseport is its retrospective nature, analysis of prospectivelyollected data and future randomized controlled trials remainsmportant to better define the role of adjuvant RT for Stage III
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