Does Brachytherapy Improve Survival in Addition to External Beam Radiation Therapy in Patients With High Risk Stage I and II Endometrial Carcinoma?

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1 ORIGINAL ARTICLE Does Brachytherapy Improve Survival in Addition to External Beam Radiation Therapy in Patients With High Risk Stage I and II Endometrial Carcinoma? Marcus A. Crosby, MD,* Jonathan D. Tward, MD, PhD, Aniko Szabo, PhD, Christopher M. Lee, MD, and David K. Gaffney, MD, PhD Introduction: The benefit of adjuvant external beam radiation therapy (EBRT) in combination with intravaginal brachytherapy (BT) in stage I and II endometrial adenocarcinoma remains controversial. We evaluated the effect of adjuvant EBRT and combined EBRT BT on overall survival and relative survival within a large US population database. Methods: We performed an analysis of retrospective data from the Surveillance, Epidemiology, and End Results (SEER) program of the US National Cancer Institute from January 1, 1998 to December 31, A total of 3395 patients with stages IB, IC, and II node-negative endometrial adenocarcinoma comprised the population. Overall survival (OS) and relative survival (RS) curves were constructed via the Kaplan-Meier method and subgroups were compared via stratified log-rank test within T stage/grade combinations. Cox proportional hazards modeling was performed to evaluate the effect of multiple variables. Results: EBRT alone was used in 2128 patients (62.7%) and 1267 patients (37.3%) received a combination of EBRT BT. Higher grade, black race, older age at diagnosis, and later year of diagnosis are associated with worse overall survival, while lymphadenectomy is associated statistically with improved survival. The addition of BT revealed no statistically significant effect on OS. Conclusions: This large population-based study revealed no improvement in OS or RS with the addition of BT to EBRT in high risk stage I and stage II endometrial cancer. Although specific patient cohorts may benefit from combined EBRT and BT, additional analysis is warranted to further elucidate optimal treatment strategies for adjuvant radiotherapy based on specific clinical and pathologic features. Key Words: endometrial cancer, radiation therapy, brachytherapy (Am J Clin Oncol 2010;33: ) Endometrial cancer is the most common gynecologic malignancy in the United States and the second leading cause of gynecologic cancer mortality. As of 2005, there were approximately 572,626 women with endometrial cancer in the United States. It is expected that 1 in 40 women will develop the disease in her lifetime. 1 The optimal role for adjuvant radiation therapy (RT) in the treatment of this common malignancy remains controversial. Adjuvant RT is commonly recommended for specific patient subgroups after a total abdominal hysterectomy with bilateral salpingo oophorectomy (TAH/BSO) with the goal of treating residual From the *Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, UT; Department of Population Health, Medical College of Wisconsin, Milwaukee, WI; and Department of Radiation Oncology, Cancer Care Northwest, Spokane, WA. Reprints: David K. Gaffney, MD, PhD, Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle of Hope, Rm 1570, Salt Lake City, UT David.Gaffney@hci.utah.edu. Copyright 2010 by Lippincott Williams & Wilkins ISSN: /10/ DOI: /COC.0b013e3181b0c266 microscopic locoregional disease in surrounding soft tissues or lymph nodes. Local recurrences remain the most common area of recurrence and the incidence in 1 study was 13.7% after TAH/BSO. 2 The most common site for local recurrences is at the vaginal cuff (at the surgical scar used to close the upper vagina). Even after external beam radiation therapy (EBRT), the vaginal cuff continues to be a site of failure affecting 1% to 3% of patients. 2 The largest patterns of care analysis to date of stage I and II patients from 1988 to shows that the rate of combined EBRT BT use increases with stage and varies by geographic region. The number of patients receiving combined EBRT BT has increased since 1994 compared with those receiving EBRT alone. EBRT BT was given to 27% of stage II patients and was the most common form of adjuvant radiation for that stage group. A more recent survey conducted by the American Brachytherapy Society indicated that combined EBRT BT had become the most frequently recommended adjuvant treatment by radiation oncologists for stage 1B grade 3 and all higher stages. 4 In stage II patients, combined adjuvant therapy was recommended by 75.6% of respondents. Despite the popularity of this combined therapy among practitioners, several retrospective studies have failed to show a consistent local control or survival advantage in patients treated with combined EBRT BT over EBRT alone in stage I and II patients. 5 9 Direct comparisons are often difficult in these retrospective studies as patients receiving both modes of RT frequently have independent risk factors for local recurrence. Evidence shows that combined EBRT BT treatment may lead to increased morbidity. 7 9 Furthermore, a study comparing the cost effectiveness of RT options in surgical stage I endometrial cancer showed combined EBRT BT to be the least cost-effective form of adjuvant RT for stage I patients. 10 Although RT has been consistently shown to reduce local recurrence in intermediate stage endometrial cancer patients compared with patients not receiving radiation, adjuvant RT has not shown an overall survival (OS) benefit despite 4 phase III trials. Although each showed a significant advantage in reducing local regional recurrences, none of the studies showed an OS benefit. 2,11 13 The GOG-99 trial did show an increase in recurrence-free interval and a trend toward improved OS with RT. 12 However, as the manuscript states, the study was not powered to detect a significant survival difference. In the high intermediate risk group, a 14% improvement in overall survival was seen. In the recently reported ASTEC trial, there was no survival benefit for any subgroup that received EBRT. In this important trial, approximately one-half of patients in both arms of the trial did receive BT. In a large retrospective study including 21,249 stage 1 endometrial cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, a significant survival advantage was seen in patients with stage 1C grades 1 and 3 of To better assess the potential survival benefit of combined EBRT BT over EBRT alone in stages I and II endometrial cancer patients post TAH/BSO, we performed a large retrospective analysis American Journal of Clinical Oncology Volume 33, Number 4, August 2010

2 American Journal of Clinical Oncology Volume 33, Number 4, August 2010 EBRT in Addition to BT in Patients using the updated SEER-17 database. We also assessed the role of adjuvant RT on relative survival in patients treated with EBRT alone, EBRT BT. MATERIALS AND METHODS Data were obtained from the SEER program of the United States National Cancer Institute (NCI) using the SEER 17-Registries plus the limited use hurricane Katrina impacted Louisiana cases and the Alaska data set (April 2008 edition). The SEER database is the authoritative source of population-based information on cancer incidence and survival in the United States and is composed of a set of geographically defined, population-based, central cancer registries in the United States. This database contains data from Connecticut, Iowa, New Mexico, Utah, Hawaii, Louisiana, New Jersey, Kentucky, California, Puerto Rico, the metropolitan areas of Detroit and Atlanta, as well as several rural counties of Georgia, several counties in the Seattle, Washington area, American Indians residing in Arizona, and Alaska Native populations residing in Alaska. Twenty-six percent of the US population is represented in the current database. The SEER program is operated by local nonprofit organizations under contract with the NCI. Serial registry data are submitted electronically without personal identifiers (deidentified) to the NCI on a biannual basis and the NCI thereafter makes the data available to the public for research purposes. Because all SEER database information remains deidentified, approval by an ethics committee and informed consent by the study participants were not necessary to perform the analyses. The analyzed study population included women diagnosed with International Federation of Gynecology and Obstetrics stages IB, IC, IIA, and IIB endometrial adenocarcinoma, who underwent TAH/BSO followed by EBRT or combined EBRT BT. Histologic classification was based on the International Classification of Diseases for Oncology codes (ICD: 8380). Patients included were those diagnosed between January 1, 1988, and December 31, 2005 and for whom complete data sets were available. The following prognostic factors were included in the analysis: age, race, stage, grade, extent of surgery (whether pelvic or paraaortic lymph nodes were sampled in addition to TAH/BSO), and whether postoperative adjuvant RT was administered. Sampling of pelvic and/or paraaortic lymph nodes at the time of TAH/BSO was designated as surgical lymph node examination. Information on race was used as entered in the SEER database (self-determined). This information was analyzed to evaluate known differences in prognosis according to race. The following were causes for patient exclusion from the analysis: clinical or pathologic lymph node involvement (N1 disease), distant spread (M1 disease), other primary malignancies, surgery did not include TAH-BSO, preoperative RT, lack of pathologic staging, and cases with missing variables. All participants in the SEER program routinely link patient files with vital records (ie, death certificates) in their respective areas of coverage to identify patients with cancer who have died (regardless of cause of death); therefore, death certificates are the source for information regarding underlying cause of death as recorded in the SEER program database. The National Center for Health Statistics conducts routine reviews of death certificates to ensure quality of data. Cox proportional hazards regression was the main modeling tool used. The considered predictors were RT (external beam or combination), stage, grade, age at diagnosis, year of diagnosis, race, and whether lymph node surgery was performed at the time of TAH/BSO. The functional form of the continuous variables (age and year of diagnosis) was estimated using martingale residuals plotted against the covariate. A linear form was found to be appropriate for both variables. Preliminary investigations showed lack of proportionality for the effect of grade. The model was stratified by grade to remove the proportional hazards assumption for it; subsequently a global test of proportionality showed no evidence of nonproportionality ( , P 0.45). For the initial model, all main effects and all 2-way interactions (including interactions with grade) were included. A global test of interactions was not significant ( , P 0.17), thus all the interactions were removed for the final model. Relative survival curves were also calculated. These measure the survival with respect to a population unaffected by endometrial cancer. This analysis adjusts for the fact that people of different ages and races have different overall survival experience even without the disease. The modeling strategy was similar to that for overall survival. The expected survival for each patient was obtained matched by age, year, and race (for this analysis, only patients whose race could be classified as black or white were used). An offset term quantifying the log of the expected hazard was added to the Cox model -this approach provides proportional hazards regression for relative survival. The results are similar to those for overall survival. After stratifying by grade, the proportional hazards assumption was reasonable for all covariates ( , P 0.12). None of the 2-way interactions were significant ( , P 0.10). RESULTS A total of 3395 women were included in our analysis. The mean age at diagnosis was 63.0 years. EBRT alone was used in 2128 patients (62.7%) and 1267 (37.3%) received a combination of EBRT BT. The frequency of EBRT versus EBRT BT use by stage, grade, race, lymphadenectomy, age at diagnosis, and year of diagnosis is shown in Table 1. Balance was seen between the 2 groups for the frequency of lymphadenectomy and race, while imbalance between the 2 adjuvant strategies was seen for stage, grade, age of diagnosis and year of diagnosis. The median follow-up for the entire cohort was 39 months (range: 1 211). Figure 1 shows Kaplan-Meier survival curves for OS within each treatment group compared via stratified log-rank test within each stage/grade combination. No significant differences were seen in any of the stage/grade classification survival curves between EBRT and EBRT BT. The overall 5 year survivals for EBRT and TABLE 1. Patient Characteristics Beam N 2128 Combination N 1267 Test Statistic Stage IB 32% (678) 23% (288) P IC 43% (916) 36% (451) IIC 25% (534) 42% (528) Grade I 26% (548) 24% (310) P II 43% (912) 47% (600) III/IV 31% (668) 28% (357) Race White 87% (1857) 88% (1119) P Black 6% (135) 5% (67) Other 6% (136) 6% (81) Lymph Yes 62% (1311) 63% (796) P Age at diagnosis 56, 64, 72* 55, 62, 71* P Year of diagnosis 1999, 2001, 2004* 1999, 2001, 2003* P *a, b, c, represent the lower quartile a, the median b, and the upper quartile c for continuous variables. Tests used: Pearson test; Wilcoxon test. Numbers after percents are frequencies Lippincott Williams & Wilkins 365

3 Crosby et al American Journal of Clinical Oncology Volume 33, Number 4, August 2010 FIGURE 1. Overall survival by stage and grade for EBRT compared with EBRT BT. The number of patients at risk in each cohort are shown below each figure. P values for the comparison are inset for each figure. EBRT BT are 84.5% and 84.7%, respectively. Respective overall 10-year survivals are 68.6% and 68.9%. Figure 2 illustrates the estimated relative survival for treatment groups within each stage/grade combination. Survival can go above or below 1 as the selected population could have better or worse survival than the overall reference population (the reference population has a relative survival defined as 1). As expected, patients in this analysis generally had a worse survival than the overall United States population, and prognosis worsened with increased stage and grade. Cox proportional hazards regression modeling was performed to assess the impact of independent variables on overall survival and relative survival and to diminish the effect of confounding factors Lippincott Williams & Wilkins

4 American Journal of Clinical Oncology Volume 33, Number 4, August 2010 EBRT in Addition to BT in Patients FIGURE 2. Relative survival by stage and grade for EBRT compared with EBRT BT. TABLE 2. Multivariate Analysis for Overall Survival HR 95% CI P Radiation Beam 1 Reference Combination Stage IB 1 Reference IC II Race White 1 Reference Black Other Lymph No 1 Reference Yes Age at diagnosis Year of diagnosis Higher grade, black race, older age at diagnosis, and later year of diagnosis are associated with a statistically significant decrease in overall survival, while lymphadenectomy is associated with statistically significant improvement in overall survival. The addition of brachytherapy did not have a statistically significant effect on OS (Table 2). For relative survival, higher grade and later year of diagnosis correlated with a statistically significant decrease in relative survival, while lymphadenectomy, was associated with statistically significant improvement in relative survival. Neither the addition of brachytherapy, nor black race has a significant effect on relative survival (Table 3). DISCUSSION The present study was not able to detect a survival difference in patients who received additional BT with EBRT for intermediatehigh risk stage I and stage II endometrial cancer patients compared with those who received EBRT alone. This finding is consistent with previous studies comparing these treatment options. Table 4 contains a literature summary of selected articles comparing survival and recurrence data in stage I and II patients receiving EBRT or EBRT RT. Out of 6 studies which directly compare survival or local recurrence rates among these 2 treatment options, no significant difference was observed. 5 9,15 This study is the largest retrospective analysis comparing EBRT BT to EBRT. It is also unique in that comparisons are made within specific stage/grade combinations. This study also includes a higher-risk population than the majority of the previous studies Lippincott Williams & Wilkins 367

5 Crosby et al American Journal of Clinical Oncology Volume 33, Number 4, August 2010 TABLE 3. Multivariate Analysis for Relative Survival HR Low High P Radiation Beam 1 Reference Combination Stage IB 1 Reference IC II Race White 1 Reference Black Lymph No 1 Reference Yes Age at diagnosis Year of diagnosis We purposely focused on the survival impact of the addition of BT to EBRT. We have previously described a survival benefit for adjuvant RT in the SEER data for stage IC, grade 1 and grade 3 to 4 compared with no further treatment. 14 With an updated version of the SEER registry, we have corroborated and expanded our previous findings. The updated analysis now includes 6 additional registries and 4 additional years of data acquisition than the version available to Lee et al. 14 A statistically significant improvement in overall survival was seen in the cohort receiving adjuvant RT in all grades of stage IC, as well as stage II grade 2 compared with those receiving no further treatment (P , data not shown). Although, given proper technique, the overall incidence of severe late toxicity is low, the addition of BT to EBRT may result in an increased incidence of injuries to the rectum and bladder as well as a variety of vaginal complications such as adhesions, necrosis, stenosis, and vesicovaginal fistulae. Irwin et al saw late radiation complications in 25% of patients treated with combined EBRT BT compared with 12% of those in the EBRT only group (P 0.014). 7 Randall et al observed an increase in late complications including rectal bleeding/proctitis in 18.6% of patients treated with combined therapies as opposed to 3.8% of EBRT only patients (P 0.01). Randall et al also noted an overall trend for increased grade 2 complications (P 0.09). 9 Greven et al, likewise saw a trend toward more vaginal and small bowel complications with the addition of BT to EBRT. 6 These side effects occur more frequently when BT is combined with EBRT than when BT is administered alone. 17 Lachance et al compared the cost effectiveness of adjuvant therapies in treatment of stage 1 endometrial carcinoma. 10 Cost data are obtained and compared with complication and recurrence rates for treatment options including BT, EBRT, EBRT BT, or observation. They show that EBRT BT treatment results in fewer survivors and/or greater costs when compared with EBRT alone or observation. The current available evidence does not suggest a survival, quality of life, or financial advantage to the use of EBRT BT over EBRT alone in early-stage patients. Consequently, clinical judgment is required when recommending this treatment. A recent survey of radiation oncologists found EBRT BT was recommended by 16.6% of respondents for stage 1A grade 3, 39.9% for stage 1B grade 3, and 61.3% for stage 1C grade 3 endometrial carcinoma. 4 No other adjuvant treatment option was more recommended for stage 1B grade 3 or higher stages. The percentage of patients who actually receive combined treatment after TAH/BSO is much lower. A SEER database analysis TABLE 4. Literature Review Showing 5-Year Survivals and Local Control Rates of EBRT or EBRT BT EBRT EBRT BT EBRT vs. EBRT RT Survival P Value(s) Local Control P Value 5 (yr) Survival 5 (yr) Local Control No. Patients 5 (yr) Survival 5 (yr) Local Control No. Patients Stages Included Study/Type Irwin et al 7 retrospective I 97 94% OS: 79% DFS: 77% % OS: 82% DFS: 77% Not significant Not significant Randall et al 9 retrospective I % NR % NR 0.74 NR Greven et al 6 retrospective I, II % DFS: 88% 97 94% DFS: 83% Stryker et al 15 I, II (occult) 69 NR NR % NR NR Not significant Pitson et al 8 retrospective II % DFS: 82% % DFS: 68% NR Not significant Cozad 5 retrospective II % OS: 70.5% CSS: 78.8% % OS: 75.8% CSS: 82.9% 0.27 OS: 0.58 CSS: 0.53 Portec-1 2 prospective IB (G2 3), IC (G1 2) % OS: 81% NR NR NR NR NR Creutzberg et al 16 prospective IC (G3) 99 86% OS: 58% NR NR NR NR NR GOG prospective IB, IC, II (occult) % (4 yr) OS: 92% (4 yr) NR NR NR NR NR Aalders et al 11 prospective IB, IC NR NR NR % OS: 89% NR NR Kucera et al 17 prospective IC NR NR NR % OS: 87.8% NR NR Current report retrospective IB, IC, II 2129 NR OS: 84.5% 1267 NR OS: 84.7% Not significant Not significant EBRT indicates external beam radiation therapy; BT, intravaginal brachytherapy; NR, not reported; OS, overall survival; DFS, disease free survival; CSS, cause specific survival Lippincott Williams & Wilkins

6 American Journal of Clinical Oncology Volume 33, Number 4, August 2010 EBRT in Addition to BT in Patients shows that from 1988 to 2002, among stage I and II patients, the highest rate of EBRT BT use was in stage II grade 2 at a rate of 30%, with rates increasing since 1994 compared with EBRT alone. 3 Although not addressed in our analysis, it is important to consider BT alone as a treatment option that may provide a similar benefit to EBRT or EBRT BT with less side effects and less financial burden. Lachance et al show BT alone to be the only cost effective adjuvant treatment choice for stage 1 patients. Several nonrandomized retrospective case studies have shown BT alone to have high rates of survival and local control with few side effects in appropriately selected low and intermediate risk stage I and II patients The PORTEC-2 trial tested if vaginal brachytherapy could replace EBRT while providing equal local control and similar quality of life. 22 The study included patients with stage IB grade 3, IC grade 2 to 3, and 2A. No difference was observed in vaginal recurrence rate, cause specific survival, or overall survival between treatment groups; however, there was a greater risk for pelvic nodal recurrence in the brachytherapy group which did not translate to a survival decrement. There was also a significant quality-of-life advantage to patients receiving brachytherapy with a decreased incidence of activity-limiting diarrhea and decreased skin reaction. Several limitations of this US population-based study must be considered. Specific clinical and pathologic data of prognostic significance are not readily available, including information regarding lymphovascular invasion, precise depth of myometrial invasion, lower uterine segment involvement, tumor size, positive surgical margins, or the specifics of RT, such as radiation dose, field sizes, BR applicator type, whether high-dose-rate or low-dose-rate BT was used, and compliance with therapy. Therefore, we were unable to adjust for these factors in these analyses. Results of this study reveal no difference in survival between the EBRT and EBRT BT groups, but this does not prove that certain subgroups within these stage/grade cohorts would not benefit from the combined therapy. We agree with the ASTEC investigators that the testing of specific therapeutic modalities is best accomplished by phase III randomized trials. The SEER database does not record history of treatment failure (whether local-regional or distant spread) or time of relapse. The lack of these data prevents a SEER population analyses from containing an event-free survival component. In addition, the SEER database does not adequately record quality-of-life information, and we are unable to assess the possible increase in radiation side effects for different treatment regimens. Individual data on socioeconomic status were not analyzed in this study and may play a role in patient outcomes. Also, the analysis of stage II patients was not stratified to differentiate stage IIA from IIB as 31% of stage II patients were reported in SEER as stage II NOS. Nevertheless, multiple articles have failed to show a difference in prognosis between substages IIA and IIB. 6,16,23 25 The use of adjuvant radiation in early-stage endometrial cancer remains controversial and further studies will help define its optimal role. In this analysis of 3395 patients with high-risk stage I and stage II endometrial cancer, we did not observe a benefit in overall or relative survival for the addition of BT to EBRT. Physicians should select treatment options, which maximize survival and quality of life while minimizing cost. ACKNOWLEDGMENTS The authors thank the editorial assistance of Jakob K. Rinderknecht. REFERENCES 1. Ries LAG, Melbert D, Krapcho M, et al, eds. SEER Cancer Statistics Review, Bethesda, MD: National Cancer Institute. Available at: seer.cancer.gov/statfacts/html/corp.html. Accessed February 9, 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: Lee CM, Szabo A, Shrieve DC, et al. 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