Treatment of Vaginal Recurrences in Endometrial Carcinoma by High-dose-rate Brachytherapy

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1 Treatment of Vaginal Recurrences in Endometrial Carcinoma by High-dose-rate Brachytherapy BENGT SORBE 1 and KARIN SÖDERSTRÖM 2 1 Department of Oncology, University Hospital, Örebro, Sweden; 2 Department of Oncology, University Hospital, Umeå, Sweden Abstract. Aim: The aim of the present study was to evaluate the efficacy and safety of high-dose-rate brachytherapy alone or in combination with external pelvic irradiation in treatment of vaginal recurrences in endometrial carcinomas. Predictive and prognostic factors were also evaluated. Patients and Methods: Between 1990 and 2005, forty patients were consecutively treated for vaginal recurrences with or without extravaginal tumoral spread from endometrial carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stages IA-IIIA. Thirtyfive patients were treated primarily with surgery and five patients with primary radiotherapy. Six patients were treated with adjuvant external beam irradiation and seven patients with vaginal brachytherapy upfront. The medium time from diagnosis to recurrence was 17 months. The recurrences were treated with a combination of high-dose-rate brachytherapy (mean 25.8 Gy) and external beam pelvic irradiation (mean 46.7 Gy) in 24 cases (60%) and with external therapy-alone or brachytherapy-alone in 12 cases. Results: The local control of vaginal recurrences treated with a combination of external beam therapy and brachytherapy was 92%. The local control rate was lower for external beam therapy-alone. In eleven patients (28%), a second recurrence occurred (five vaginal and six distant metastases). The overall 5-year survival rate was 50%. Age, FIGO grade and time from diagnosis to recurrence were the only independent and significant prognostic factors. Upfront external beam therapy was associated with a worse overall survival rate. Site of recurrence was significant only in univariate analysis. Late gastrointestinal toxicity (grade 3-4) was recorded in 11% of irradiated patients. Conclusion: Combined highdose-rate brachytherapy and external beam therapy was an Correspondence to: Bengt Sorbe, MD, Ph.D., Department of Oncology, University Hospital, S Örebro, Sweden. Tel: , mob: , b.sorbe@telia.com Key Words: Endometrial carcinoma, vaginal recurrence, radiotherapy, brachytherapy. effective treatment for vaginal recurrences. Age, FIGO grade, and time-to-recurrence were significant and independent prognostic factors. Upfront radiotherapy was an unfavorable prognostic factor in univariate analysis. Endometrial cancer is the most common gynecological malignancy in developed countries (1). Most endometrial carcinomas are diagnosed in early stages (FIGO I-II) and have an inherent good prognosis and are cured by primary surgery and adjuvant radiotherapy. However, 10-20% of the tumors will recur and mainly (80-90%) within three years (2). Treatment of recurrences is a challenge; local vaginal recurrences are curable if diagnosed early, but pelvic and distant recurrences have a poor prognosis. A number of predictive and prognostic factors are discussed in the literature, e.g. age, time from primary treatment to recurrence (3), prior radiotherapy (4), histology, International Federation of Gynecology and Obstetrics (FIGO) grade, tumor size (5), type of therapy for the recurrence (6), radiation dose to target (7). The impact of many of these factors is controversial. In the present retrospective study of 40 endometrial cancer recurrences, a number of predictive and prognostic factors were analyzed; the type of therapy was the main topic and high-dose-rate brachytherapy was a cornerstone in the treatment of the recurrences in this series. All patients had vaginal recurrences and five patients had also pelvic and/or distant metastases. Materials and Methods Patients. During the period from October 1990 to July 2005, 40 patients with recurrent endometrial carcinoma at the vaginal site were consecutively registered and treated at the Department of Gynecological Oncology, University Hospital, Örebro. Thirty-five patients were treated primarily with abdominal hysterectomy and bilateral salpingo-oophorectomy and five patients with radiotherapy alone. In 10 patients, lymph node sampling (n=7) or lymphadenectomy (n=3) were performed. External radiotherapy. External beam pelvic irradiation was given to six patients upfront. The total external dose ranged between /2013 $

2 30.0 Gy and 50.0 Gy (mean=46.7 Gy). The dose per fraction was 2.0 Gy, with five fractions per week, and a four-field box-technique was used. The external treatment equipment was linear accelerators with 18 MV energy. Brachytherapy. Thirteen patients were treated by intrauterine irradiation as preoperative therapy (n=8) or definitive primary therapy (n=5). The total brachytherapy dose ranged between 8.0 Gy and 48.0 Gy (mean=25.8 Gy). The dose per fraction ranged between 2.5 Gy and 6.0 Gy. Brachytherapy was given by a high dose-rate technique (MicroSelectron, Ir-192, Nucletron, Veenendaal, Netherlands). The intrauterine treatment (upfront) was given by twin-applicators. Seven patients had adjuvant vaginal treatment using plastic cylinders (20 mm, 25 mm or 30 mm in diameter) and the dose was specified at 5 mm from the surface of the applicator. The upper two-thirds of the vaginal walls were defined as the target in adjuvant treatment. Treatment of recurrences. All patients in this series had vaginal recurrences and in five cases there were recurrences at other extravaginal sites. Radiotherapy was the treatment option for these patients, mainly with a combination of external beam therapy and vaginal brachytherapy (n=24). In 12 cases, external irradiation-alone or brachytherapy-alone was chosen due to prior treatment, tumor localization, or the physical status of the patient. In one case, vaginal surgery and brachytherapy were used in combination. The treatment technique was the same as presented above for the upfront primary and adjuvant therapy, but target prescriptions and doses were more individualized and the whole vagina was included in the treatment of recurrent disease. Statistical methods. For comparison of proportions, the Pearson chisquare test was used, and for continuous variables, the t-test for independent groups. For variables with dichotomous outcome, logistic regression analysis was used with univariate and multivariate technique. The Kaplan-Meier method was used for the survival analyses. Cox proportional regression analysis was used to analyze prognostic factors, with overall survival rate as the endpoint. p-values <0.05 were regarded as statistically significant. The Statistica software (version 10; StatSoft, Inc., Tulsa, USA) was used for the statistical analyses. Follow-up. All patients were treated and followed-up at the Örebro University Department of Gynecological Oncology. During the first year after treatment, the patients came to regular follow-up visits every three months; during the second and third years, every four months; then every six months up to five years, and after that annually up to 10 years. The median follow-up time at the end of the study for patients who were alive was 66 months (range= months). Results The median age of the complete series was 75 years (range=55-87 years). In 35 cases (87.5%), a single vaginal recurrence was diagnosed as the first recurrence. In two cases, a vaginal and pelvic recurrence were diagnosed, in one case a combined vaginal, pelvic and abdominal recurrence occurred, and in another two cases the sites of relapse were vagina, pelvis and the lungs. In 30 cases (75%), the tumoral lesions were localized in the upper third of the vagina, and in the remaining 10 cases, the middle and distal thirds of the vagina were also involved. In one case, the whole length of the vagina was infiltrated by the tumor. In 3 out of 40 recurrences (7.5%) the site was extrapelvic. Tumor size ranged from 2 to 70 mm (mean=18.5 mm). The median time from diagnosis to the first sign of the recurrence was 17.1 months (range=2-207 months). In 11 patients (27.5%) a second recurrence was diagnosed, in five cases a new vaginal recurrence, and in the six other cases at distant sites (lungs, peripheral lymph nodes and bone). The median time between the first and the second recurrence was 18.6 months (range= months). In one patient, a third relapse was recorded at the vaginal site. The original FIGO stage distribution is presented in Table I. Thirty-four tumors were stage I (85%), and six tumors stages II-IIIA. The type of histology was endometrioid in the majority of cases (92.5%). Fourteen carcinomas were welldifferentiated, 18 moderately to well-differentiated, and 8 (20%) poorly-differentiated. In 27 cases (68%) the tumor infiltrated less than 50% of the myometrial thickness and in 13 cases more than 50% (deep infiltration). DNA ploidy showed a diploid pattern in 34 cases (85%) and aneuploid in 6 cases (15%). Lymphovascular space invasion (LVSI) was not regularly reported in this series of endometrial carcinomas. In all, 18 carcinomas (45%) were allotted to a low-risk group, 16 carcinomas (40%) to an intermediate risk group, and 6 carcinomas (15%) to a high-risk group upfront. Thirty-five patients (87.5%) underwent primary surgery with total abdominal hysterectomy and bilateral salpingooophorectomy upfront. Five patients were treated with primary radiotherapy. Lymph node sampling was performed in seven patients and pelvic lymphadenectomy in three patients. In 25 patients no surgery was performed on the lymph nodes. Six patients (15%) received external beam pelvic radiotherapy and 20 patients (50%) vaginal brachytherapy as primary therapy or as postoperative adjuvant therapy. All patients, except one, achieved primary cure (97.5%) of their endometrial carcinoma. At the time of follow-up (December 2011) nine patients (22.5%) were alive, 17 were dead of disease, and 14 patients were dead of intercurrent diseases. The 5-year local control rate was 75%. The overall 5-year survival rate of the complete series was 49.5% (95% confidence interval, %) and the cancer-specific survival 64.8% (95% confidence interval, %). Women with vaginal recurrences alone had a significantly (log-rank test; p=0.039) superior overall survival rate (56.7%) than women with vaginal recurrences concomitant with recurrences at other sites (0% at 5 years) (Figure 1). The site of the vaginal recurrence (upper onethird versus distant two-thirds of the vaginal walls) was not 242

3 Sorbe et al: Brachytherapy in Treatment of Vaginal Recurrences Table I. Original International Federation of Gynecology and Obstetrics (FIGO) stage distribution and histopathological characteristics of the tumors. Number Percentage FIGO stage IA IB IC IIA IIB IIIA Histology Endometrioid Serous carcinoma Undifferentiated FIGO grade Well-differentiated Moderately well-differentiated Poorly differentiated DNA ploidy Diploid Aneuploid Unknown S-phase fraction (%) 6.3 (mean) (range) Myometrial invasion Superficial (<50%) Deep ( 50%) Risk groups Low risk Medium risk High risk associated with the overall survival rate (log-rank test; p=0.377). On the other hand, patients who achieved complete remission of their vaginal relapse had significantly (log-rank test; p=0.011) better overall survival than patients with residual vaginal tumor lesions after treatment. In univariate Cox proportional regression analysis, the FIGO grade of the tumor, DNA ploidy, and the risk group the tumor was allotted to were significantly associated with the overall survival rate. All patients with FIGO grade 3 tumors (n=8) were dead by 4.2 years. However, myometrial infiltration and surgery with lymph node sampling or lymphadenectomy were not associated with the survival rate in this series of recurrent carcinomas (Table II). Age of the patient (p=0.002), FIGO grade of the tumor (p=0.003), and time interval to recurrence (TTR) (p=0.005) were significant prognostic factors in multivariate Cox analysis with regard to overall and cancer-specific survival rates. Site of recurrence was significant in univariate analysis (p=0.003) but not in multivariate analysis (p=0.935). Patients who had external beam therapy as part of their primary treatment had a significantly (Wald statistics; p=0.014; risk ratio=3.33) worse overall survival rate than Figure 1. Overall survival rate according to site of recurrences (vaginalalone or vaginal plus other sites). A statistically significant difference was noted (log-rank test; p=0.039). patients treated with surgery alone or surgery plus vaginal brachytherapy. On the other hand, adjuvant vaginal brachytherapy was not associated (Wald statistics; p=0.332) with the overall survival rate. However, the probability of achieving complete vaginal remission was higher (logistic regression analysis; odds ratio=1.714, p=0.013) in the group who had had no adjuvant brachytherapy as part of the firstline treatment. In treatment of the first vaginal recurrence, 36 patients received radiotherapy, external beam irradiation (n=29), vaginal brachytherapy (n=31) or a combination of both types of radiotherapy (n=24). Brachytherapy-alone was given to seven patients and external beam therapy-alone to five patients. In one patient, vaginal surgery and brachytherapy were used in combination and the recurrence was cured despite use of a very low radiation dose. Four patients were treated with chemotherapy or hormonal therapy (Table III). In the group treated with external beam irradiation and vaginal brachytherapy in combination, 92% (23/25) of the vaginal recurrences were cured, but in the group treated with external irradiation-alone or vaginal brachytherapy-alone, primary cure was achieved in only 64% (7/11) (Pearson chisquare; p=0.035). In the group of seven patients treated with vaginal brachytherapy-alone, 86% (6/7) achieved complete vaginal remission and in the group with external beam therapy-alone, 40% (2/5). In all patients with local cure of the vaginal recurrence, 93% were treated with brachytherapy and in the group with residual vaginal tumor, only 30% of the patients were treated with brachytherapy (Pearson chisquare; p= ). Patients treated with external beam irradiation plus vaginal brachytherapy or vaginal brachytherapy-alone (n=32) had a significantly (log-rank test=2.161; p=0.031) superior cancer- 243

4 Table II. Univariate Cox proportional regression analyses. Prognostic factors of the primary tumor and the recurrence for overall survival rate. Prognostic factor Beta SE Risk ratio 95% CI p-value Age Primary tumor FIGO-grade DNA ploidy Infiltration Risk groups Lymph node surgery Recurrence Tumor size (mm) Tumor thickness (mm) Localization* *Upper third versus distal two-thirds of the vagina. SE: standard error; CI: confidence interval; FIGO: International Federation of Gynecology and Obstetrics. specific survival rate than patients treated with external beam irradiation-alone or chemotherapy-hormonal therapy (Figure 2). Among patients achieving cure of their first recurrence, six (17.1%) developed a second or third vaginal recurrence and a further six patients distant recurrences. The mean total equivalent dose in 2 Gy fractions (EQD2 dose) (α/β=10) was 67.2 Gy in the group with primary cure of the vaginal recurrence, and 58.1 Gy in the group with residual vaginal tumor (t-test; p=0.353). A dose 80 Gy to the relapse site did not discriminate between primary cure or not in this series of vaginal recurrences (p=0.473). In univariate logistic regression analyses, the EQD2 brachytherapy dose (odds ratio=1.054; p=0.0018) and the total external pelvic dose (odds ratio=1.038; p=0.0010) were significantly associated with complete eradication of the vaginal tumor lesions. The primary risk group of the tumor was also significantly (logistic regression analysis) associated with the outcome of the treatment of the vaginal recurrence. Patients with tumors belonging to the low-risk group had five times higher probability (p=0.011) of achieving complete remission and those with medium-risk tumors three times higher probability (p=0.057) than women with high-risk cancer (Table IV). Patients treated with a combination of external beam irradiation and vaginal brachytherapy had eleven times higher probability (p=0.007) of local control of the vaginal recurrence than patients treated with single-modality therapy. TTR was significantly (Cox univariate analysis; p=0.012) associated with the overall survival rate. The risk of death decreased by 4% per month of increased TTR. This was also true for cancer-specific survival rate and for locoregional recurrences in a separate analysis. Among 36 patients receiving radiotherapy, seven cases (19%) of grade 2-3 vaginal toxicity were recorded. Only one case of grade 3 bladder toxicity was recorded. Nine cases Table III. Treatment of the vaginal recurrences of the complete series (n=40). Treatment technique Number Percent Radiotherapy External beam therapy Vaginal brachytherapy Combination Surgery Chemotherapy/hormonal therapy Table IV. Logistic regression analysis of the primary cure of the vaginal recurrence versus the primary risk group of the tumor. Risk group* Odds ratio 95% CI p-value High risk Medium risk Low risk *High risk: Presence of two or more high-risk factors (FIGO grade 3, nuclear grade 3, deep myometrial infiltration, DNA aneuploidy, nonendometrioid histology); medium risk: presence of one high-risk factor (FIGO grade 3, deep myometrial infiltration, DNA aneuploidy); Low risk: no high-risk factors present. (25%) with grade 2-4 intestinal reactions occurred and four cases (11%) were grade 3-4. Intestinal side-effects were significantly (Pearson chi-square=10.041; p=0.040) more common after combined radiotherapy (external beam therapy plus vaginal brachytherapy) than after single modality therapy, with 34.8% grade 2-4 reactions compared with 9.1% grade 2-4 intestinal reactions, respectively. 244

5 Sorbe et al: Brachytherapy in Treatment of Vaginal Recurrences Figure 2. Cancer-specific survival rate according to the type of therapy [external beam irradiation (EBRT) plus vaginal brachytherapy (VBT) or vaginal brachytherapy alone versus external beam irradiation alone or chemotherapy (CT) or hormonal therapy (HT)]. A statistically significant difference was noted (log-rank test; p=0.031). Discussion Endometrial carcinoma in general has a rather favorable prognosis, but 10-20% of patients will experience relapse (8) and the 5-year overall survival rate is 80% (9). It has become common to define three risk groups among endometrial carcinomas with highly different survival and recurrence rate and pattern of recurrences. Vaginal recurrences are the most frequent type of recurrence in all risk groups and also the type of relapse that is possible to cure if diagnosed early (10). The majority (90%) of all recurrences occur within three years (11). There has been intense debate during the past decades about postoperative prophylactic therapy (radiotherapy and/or chemotherapy). For low-risk cases, a wait-and-see philosophy has been advocated and recurrences will be treated when they occur. Most of these recurrences are vaginal relapses, mainly in the vaginal vault. For medium and high-risk cases, pelvic and distant recurrences will also be common, often in multiple sites (12). Prognosis is poor when extravaginal metastases are diagnosed. Even pelvic recurrences are difficult to treat and to achieve cure and long-term survival. In the present study, 40 consecutive recurrences of endometrial carcinoma were studied with regard to type of therapy, predictive and prognostic factors and survival rate. Vaginal brachytherapy-alone or in combination with external beam pelvic irradiation were the most important parts of the treatment. Only four patients were treated with chemotherapy or hormonal therapy. The risk group distribution for high, medium and low-risk groups was 15%, 40%, and 45%, respectively, which is a normal distribution for an unselected series of endometrial carcinomas. The endometrioid type constituted 93% of the cases, and 20% were poorly differentiated. Twenty patients (50%) received postoperative adjuvant brachytherapy, and six patients (15%) external beam irradiation of the pelvic region. In 35 cases, single vaginal recurrences were diagnosed and in five cases vaginal relapse in combination with pelvic, abdominal or lung metastases. In 30 cases (75%) the tumor lesions were localized in the upper third of the vagina with a mean size of 18 mm. The median TTR was 17 months, which is in agreement with other published series (3). A second recurrence was recorded in 11 patients (27.5%), five vaginal and six distant, and in one patient a third recurrence (vaginal). The median time between the first and the second recurrence was 19 months. In the complete series 30 out of 40 (75%) vaginal recurrences achieved primary cure, after brachytherapy-alone 86% were cured and after a combination of brachytherapy and external beam therapy a cure rate of 92% was achieved. However, in the group with only one type of therapy, only 50% achieved local control and this was significantly inferior to the combination group (Pearson chi-square=8.889; p=0.0029). Hasbini et al. reported the same local control rate in a series of 23 patients (13). Among six patients with a second or third vaginal recurrence, combination radiotherapy was used for three, brachytherapy-alone or external beam therapy-alone for two, and chemotherapy for one. In the complete series, the 5-year cumulative local control rate was 75%. This is comparable to the results of 90% complete response and 74% 10-year cumulative local control rate reported in a series of 20 patients by Pai et al. (14). Jhingran et al. (6) reported on a series of 91 patients from M.D. Anderson Cancer Center and found a 69% 5-year local control rate. In the PORTEC-1 trial, 35 isolated vaginal recurrences were treated with curative intent and 89% achieved complete remission and 77% long-term remission (4). In a small series of 22 patients with isolated vaginal recurrences, Petignat et al. (15) reported a 100% complete response rate, and no patient had locoregional recurrence. However, in a series from Detroit, Hart et al. (16) reported a 54% failure rate after radiotherapy in 26 cases of tumor recurrence. Brachytherapy was not used as a routine therapy in the treatment of these patients. External beam therapy can probably not replace vaginal brachytherapy in the treatment of vaginal relapse. In our series, five cases of distant metastasis (12.5%) were present together with the vaginal recurrence as the first recurrence, and during follow-up after treatment another six distant recurrences (15%) appeared. All six recurrences at distant sites had an isolated vaginal recurrence as the first recurrence. This means that 6/35 (17.1%) isolated vaginal recurrences recurred distantly after locoregional treatment with radiotherapy (17). 245

6 The overall 5-year survival rate of the complete series was 50% and the cancer-specific survival was 65%. In a series of 58 recurrences from Princess Margaret Hospital Wylie et al. (18) reported an overall survival rate of 53% and a local control rate of 65%. Lin et al. (5) also reported overall survival of 53% in a series of 50 patients. Colombo et al. (19) reported 57% alive without evidence of disease at 3 to 11 years following treatment. On the other hand, Blecharz et al. (20) reported only 42% 5-year overall survival rate after treatment of 47 patients with vaginal recurrences. The corresponding figure in their series for pelvic recurrences was 13%. A similar survival rate was reported by Jhingran et al. (6), with 43% overall survival at 5 years. Creutzberg et al. (4) found a difference in survival after treatment of vaginal relapses in the group treated with compared to those treated without prior external radiotherapy (PORTEC-1 study), with 43% versus 65% at 5 years, respectively. In our series, we did not find such a difference, the survival rate was 50% in both groups. TTR for all recurrences was a significant prognostic factor for both cancerspecific and overall survival rate as for the locoregional relapses. Robbins et al. (3) reported that a TTR <18 months was associated with shorter overall and cancer-specific survival, but only for patients with extrapelvic recurrence. In univariate Cox analyses, FIGO grade, DNA ploidy, and the original risk group of the tumor (low, medium or high), as well as age of the patients were statistically significant prognostic factors for overall survival rate. However, in multivariate analysis, only age and FIGO grade were independent and significant prognostic factors. This was also true for the cancer-specific survival rate. In a number of studies, other predictive and prognostic factors have been identified. In the study by Lin et al. (5) age, FIGO grade, and size of the recurrence were significant predictors of overall survival. Blecharz et al. (20) found the site of recurrence (vaginal versus pelvic recurrences) to be the only independent prognostic factor for 5-year overall survival. Hasbini et al. (13) found that extravaginal extension, tumor size, and stage of initial disease had a significant impact on the prognosis. Smaniotto et al. (21) presented a scoring system (time between surgery and recurrence, pelvic wall site, positive lymph nodes, hemoglobin <11 g/dl) to identify patients benefitting from treatment. Patients with a low score (<2) had significantly better outcome, better local control of the disease and better overall survival than patients with a score 2. Jhingran et al. (6) found in their study that external beam irradiation plus brachytherapy versus single modality therapy was significant in univariate analysis with regard to the overall survival rate. In a series of 73 endometrial cancer recurrences from Poland, Jereczek et al. (7) reported in a multivariate analysis that only stage of recurrent disease and high total irradiation dose correlated with better survival. In our series five cases (14%) with grade 3 vaginal toxicity, one case with grade 3 bladder toxicity, and four cases (11%) with grade 3-4 gastrointestinal toxicity were recorded. Pai et al. (14) reported a late complication rate of 15% and no grade 3 or 4 late complications. Petignat et al. (15) reported 18% late grade 3-4 gastrointestinal toxicity and 50% grade 3 vaginal toxicity. Nag et al. (22) presented a small series of 13 patients with interstitial brachytherapy for salvage of vaginal recurrences. 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7 Sorbe et al: Brachytherapy in Treatment of Vaginal Recurrences 10 Ng TY, Perrin LC, Nicklin JL, Cheuk R and Crandon AJ: Local recurrence in high-risk node-negative stage I endometrial carcinoma treated with postoperative vaginal vault brachytherapy. Gynecol Oncol 79: , Sohaib SA, Houghton SL, Meroni R, Rockall AG, Blake P and Reznek RH: Recurrent endometrial cancer: patterns of recurrent disease and assessment of prognosis. Clin Radiol 62: 28-34, Sorbe B, Horvath G, Andersson H, Boman K, Lundgren C and Pettersson B: External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma A prospective randomized study. Int J Radiat Oncol Biol Phys 82: , Hasbini A, Haie-Meder C, Morice P, Chirat E, Duvillard P, Lhommé C, Delapierre M and Gerbaulet A: Outcome after salvage radiotherapy (brachytherapy ± external) in patients with a vaginal recurrence from endometrial carcinomas. Radiother Oncol 65: 23-28, Pai HH, Souhami L, Clark BG and Roman T: Isolated vaginal recurrences in endometrial carcinoma: Treatment results using high-dose-rate intracavitary brachytherapy and external beam radiotherapy. Gynecol Oncol 66: , Petignat P, Jolicoeur M, Alobaid A, Drouin P, Gauthier P, Provencher D, Donath D and Van Nguyen T: Salvage treatment with high-dose-rate brachytherapy for isolated vaginal endometrial cancer recurrence. Gynecol Oncol 101: , Hart KB, Han I, Shamsa F, Court WS, Chuba P, Deppe G, Malone J, Christensen C and Porter AT: Radiation therapy for endometrial cancer in patients treated for postoperative recurrence. Int J Radiat Oncol Biol Phys 41: 7-11, Corn BW, Lanciano RM, D agostino R, Kiggundu E, Dunton CJ, Purser P and Greven KM: The relationship of local and distant failure from endometrial cancer: Defining a clinical paradigm. Gynecol Oncol 66: , Wylie J, Irwin C, Pintilie M, Levin W, Manchul L, Milosevic M and Fyles A: Results of radical radiotherapy for recurrent endometrial cancer. Gynecol Oncol 77: 66-72, Colombo A, Cormio G, Placa F, Landoni F, Ardizzoia A, Gabriele A and Lissoni A: Brachytherapy for isolated vaginal recurrences from endometrial carcinoma. Tumori 84: , Blecharz P, Brandys P, Urbanski K, Reinfuss M and Patla A: Vaginal and pelvic recurrences in stage I and II endometrial carcinoma survival and prognostic factors. Eur J Gynaecol Oncol 32: , Smaniotto D, D Agostino G, Luzi S, Valentini V, Macchia G, Mangiacotti MG, Margariti PA, Ferrandina G and Scambia G: Concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, in recurrent endometrial cancer: A scoring system to predict clinical response and outcome. Tumori 91: , Nag S, Yacoub S, Copeland LJ and Fowler JM: Interstitial brachytherapy for salvage treatment of vaginal recurrences in previously unirradiated endometrial cancer patients. Int Radiat Oncol Biol Phys 54: , Received November 6, 2012 Revised November 17, 2012 Accepted November 19,