Abstract
Background: While radical nephroureterectomy is the treatment of choice for localized or regional urothelial carcinoma of the upper urinary tract (UTUC), the role of adjuvant radiotherapy is unclear, with conflicting data from various small studies. Patients and Methods: We sought to study the impact of adjuvant radiotherapy on UTUC by utilizing the Survelliance, Epidemiolgy, and End Results (SEER) 9 database from 1998-2011. Results: Of 2,572 identified cases, 113 patients (4.4%) received adjuvant radiotherapy, with a median age of 74 years (range=22-100 years). In univariate analysis, patients treated with adjuvant radiation therapy seemed to have a lower survival time than those without radiation therapy (19 months versus 31 months, p<0.05). However, after adjusting for covariates, including age at diagnosis, gender, race, year of diagnosis, stage, histological grade and surgery, radiation therapy did not seem to influence survival (hazard ratio=0.68; 95% confidence interval=0.68-1.06, p=0.85). Conclusion: This hypothesis-generating, population-based analysis shows that adjuvant radiotherapy may not influence survival among patients with locoregional UTUC.
Upper tract urothelial carcinoma (UTUC) can arise from the urothelial lining of the renal pelvis or ureters. UTUC is a rare genitourinary malignancy with increasing incidence that accounts for about 5% of all urothelial malignancies and 10% of all renal malignancies (1-3). Radical nephroureterectomy (RNU) with ipsilateral bladder cuff and retroperitoneal lymph node dissection is the gold-standard treatment for UTUC, with the highest cancer-free survival rates (1-3). Despite treatment with RNU, locally advanced UTUC (pT3-4, NO or N+) has dismal 5-year survival rates of 12-54% (3, 4). Additionally, UTUC is frequently a multifocal disease, with many patients developing bladder UC after RNU (5, 6). The poor overall survival rates and multifocal nature of locally advanced UTUC has prompted questions regarding the need for adjuvant therapy, such as radiotherapy or chemotherapy.
Many small clinical series have been published over the years regarding the role of radiotherapy as an adjuvant therapy for UTUC; however, these series have shown widely varying results (7-15). These small case series have had heterogeneous patient populations, often at single institutions, have different radiotherapy approaches, and have measured different clinical outcomes to create a blurry recommendation for adjuvant radiotherapy in the treatment of UTUC. Most importantly, contemporary studies on adjuvant radiotherapy have been limited by small sample sizes due to the rarity of UTUC. Here, we present a US population-based analysis of the role of adjuvant radiotherapy in the treatment of UTUC utilizing the NCI's robust Surveillance, Epidemiology, and End Results (SEER) database.
Patients and Methods
Our study utilized case listings from the NCI's SEER 9 public database. The SEER 9 registry is comprised of regional cancer registries from 9 diverse geographic and socioeconomic areas within the United States. The SEER 9 registry accounts for 10% of the US population. SEER registries maintain data including patient demographics, incidence, mortality, primary site, tumor structure, and follow-up information, including radiation status. Cases within SEER are associated with one of three racial groups: White, Black, or other. The SEER database classifies cancer histology and topography information on the basis of the third edition of the International Classifications of Diseases for Oncology (ICD-O-3) (16).
We identified patients with microscopically confirmed cases of urothelial malignancies of the upper urinary tract from 1998 to 2011 using the appropriate ICD-O-3 codes, C65.9 for the renal pelvis and C66.9 for the ureter. Cases were limited to those with locoregional stage, known radiation status, and who underwent partial, total, or radical nephroureterectomy. In the SEER summary staging system, a localized tumor is confined to the organ of origin without extension beyond the primary organ, whereas regional tumors include direct extension to adjacent organs or structures or spread to regional lymph nodes.
Median overall (OS) survival, 3-year and 5-year survival were calculated using actuarial (Kaplan–Meier) methods, and compared using Z-test for comparison of population proportions. Kaplan–Meier survival curves were drawn for patients with and without radiation therapy and compared using log-rank test. Cox multivariate regression model was used to adjust for the presence of other covariates affecting survival including age, year of diagnosis, gender, stage, grade and the type of surgery. In addition, a propensity score for receiving radiation therapy was developed using a logistic regression model including age, year of diagnosis, gender, race, stage, grade and the type of surgery as the covariates. The calculated propensity score was then used as an additional covariate in the outcome modeling to control for the propensity to receive radiation therapy in the study population. Statistical analysis was carried out using SEER*Stat 8.1.2 and STATA 13.0 software (Stata Corp., College Station, TX, USA). All p-values were based on two-sided hypothesis tests and the level of significance was chosen at 0.05.
Results
A total of 2,572 cases were identified within the SEER registry using the study criteria, of which 113 (4.4%) received adjuvant radiotherapy. The median age was 74 years (range=22-100 years), and the majority of patients were white (90%, n=2315) and male (57%, n=1464). Among these patients, localized tumors comprised 30% (n=780) of the cases by stage, and the majority of patients had poorly differentiated (45%, n=1172) or undifferentiated (40%, n=1019) high-grade tumors. Overall, 42% of patients underwent RNU (n=1084). The basic demographic characteristics of the study population are summarized in Table I.
On calculation of actuarial survival rates, patients treated with adjuvant radiotherapy seemed to have a lower survival time than those without radiation therapy (19 months versus 31 months; 1-year survival 64% versus 73%; 3-year survival 46% versus 31%; and 5-year survival 44% versus 24.2%; all p<0.05). Similarly, review of the Kaplan–Meier survival curves (Figure 1) for the two groups showed a significantly lower overall survival among patients treated with radiation therapy as compared to those not (p<0.01).
Table II shows summary results of the Cox proportional hazard regression model designed to assess the survival benefit of radiotherapy while adjusting for covariates, including age, sex, year of diagnosis, tumor grade, tumor stage, and surgery type. Additionally, it includes a propensity-adjusted analysis for the impact of radiotherapy on UTUC. After controlling for covariates, radiotherapy was not associated with a survival benefit among surgically treated patients (hazard ratio=0.85, 95% confidence interval=0.68-1.06; p=0.16). This was further confirmed with propensity score adjusted multivariate regression analysis where adjuvant radiation therapy was not associated with a survival benefit (hazard ratio=0.88, 95% confidence interval=0.71-1.11; p=0.30).
Discussion
Due to the rarity of UTUC, outcomes for adjuvant radiotherapy are limited to a number of small, single institution studies that have produced contrasting results. Our analysis of a large unselected population-based cohort suggests that adjuvant radiotherapy may not have a survival benefit among patients with locoregional UTUC treated with surgery. Our observations are consistent with some of the prior clinical series performed (12-14). Additionally, multivariate analysis confirmed that advanced stage and poorly differentiated tumor grade are risk factors for poor OS in UTUC (5, 8, 10).
Adjuvant radiotherapy has been reserved for patients with locally advanced UTUC as their 5-year survival rates are poor despite treatment with RNU (3, 4). The most recent and robust single-institution study of adjuvant radiotherapy by Jwa et al. also found it to have no effect on OS in patients with locally advanced UTUC, but they did report decreased local and bladder recurrences of UC (15). Bladder recurrences are common in UTUC and thought to occur by one of two mechanisms: field cancerization or intraluminal tumor seeding (5, 17-19). Conceptually, we believe that demonstrating improvements in OS is essential for supporting the use of radiotherapy alone as adjuvant therapy.
Our finding that adjuvant radiotherapy does not influence OS in locoregional UTUC align with those of two retrospective, single-institution studies (12, 13). In a study of 49 patients with stage III UTUC, Hall et al. found no significant difference in survival regardless of administration of adjuvant radiotherapy (12). They found that patients who received adjuvant radiotherapy had a 5-year disease-specific survival of 45% and survival for those who did not receive radiotherapy was 40%. Furthermore, they found that the major clinical feature of disease relapse in locally advanced UTUC was distant failure, which could explain the disparity noted in survival and local recurrence in the recent study by Jwa et al. (15). A unique study of 26 patients with invasive UTUC treated with adjuvant radiotherapy was performed by Maulard-Durdux et al., in which outcomes for 5-year OS were compared to those of a surgical series (13). They found no OS benefit between the two groups. Our population-based findings support these studies in suggesting that adjuvant radiotherapy does not improve survival for patients with locally advanced UTUC.
The poor clinical outcomes seen in locally advanced UTUC imply a need for adjuvant therapy in addition to RNU. While our study brings into question the use of radiotherapy alone as an adjuvant therapy, further studies need to explore other modalities of adjuvant therapy, such as chemotherapy or combination therapy. Studies of adjuvant chemotherapy for UTUC have had negative results in general (20-22). However, these studies have focused on the use of very traditional chemotherapeutic regimens, such as methotrexate, vinblastine, doxorubicin, cisplatin or gemcitabine and cisplatin. Studies have shown that the biology of UTUC can be extrapolated from UC of the bladder, a much more common malignancy (23). Hence, targeted therapies for locally advanced UTUC based on molecular alterations present need further investigation. Another option with some promise is the concurrent use of adjuvant radiation with targeted therapies for both local and distant control (11).
The principle strength of our study is the large sample size in a population-based setting that is highly representative of practice within the US. Large population databases, such as SEER, can provide answers to questions regarding incidence and outcome for rare malignancies that collaborative or single institutions may not have the power to answer. In addition, the use of OS as an indicator of outcomes with adjuvant radiotherapy may be more meaningful than other outcome measures, such as local recurrence. Our study has several limitations. By using SEER, we were unable to access the specific details of radiotherapy dosage, frequency and modality used, which have varied significantly by institution and time period in different studies. However, by showing no association between OS and the year of diagnosis on multivariate analysis, it appears less likely that the use of different radiation modalities affected our findings. We cannot assess for the concurrent use of adjuvant chemotherapy with radiotherapy or tumor size due to limitations with the SEER database. SEER also does not allow us to account for many prognostic clinical characteristics and how they would differ between the two groups. Finally, many patients with UTUC have a high degree of co-morbidities, and SEER does not allow us to stipulate cancer-specific survival rates.
In conclusion, our population-based analysis suggests that adjuvant radiotherapy may not influence OS for patients with locoregional UTUC. It also confirms that advanced tumor stage and poorly differentiated tumor grades are associated with worse OS. The current study demonstrates a need for improved adjuvant treatment options for locoregional UTUC. Finally, this study illustrates the value of population-based registries in providing clinical outcome data for rare malignancies.
Footnotes
Conflicts of Interest
The Authors have no conflicts of interests to declare.
- Received May 18, 2016.
- Revision received June 12, 2016.
- Accepted June 13, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved