Abstract
Aim: In order to define the role of adjuvant radiotherapy (RT), the clinical outcomes of patients with stage III/IV urothelial carcinoma of the upper urinary tract (UTUC) were reviewed. Patients and Methods: Clinical data from a total of 127 patients who underwent radical nephroureterectomy with bladder cuff were analyzed. While 36 patients underwent adjuvant RT following surgery, 91 were treated with surgery-alone. Differences in risk-adjusted treatment outcomes between the two groups were assessed using a multivariable Cox proportional-hazards model and inverse probability of treatment weighting with propensity score for balancing covariates including use of chemotherapy between the two groups was estimated. Results: With a median follow-up of 38.3 months, 3-year actuarial locoregional recurrence-free survival rates were 89% vs. 61% in the RT vs. non-RT groups, respectively (p=0.01). Three-year bladder recurrence-free survival rates were 73% and 52% in favor of the RT group (p=0.02). After adjustment for differences in covariates, the risks of locoregional, bladder, and disease recurrence were found significantly lower in the RT group. Conclusion: Adjuvant RT may be beneficial in terms of locoregional and bladder control in patients with stage III/IV UTUC. Further prospective studied are needed to verify these findings.
Urothelial carcinoma of the upper urinary tract (UTUC) is an uncommon malignancy, accounting for 5% of all urothelial tumors, although evidence suggests that its incidence is increasing (1). Radical nephroureterectomy (RNU) with bladder cuff is the recommended standard treatment for patients with UTUC (1). However, the prognosis of patients with locally advanced disease (i.e. stage III or IV) is poor despite radical surgery. The 5-year cancer-specific survival rate is 75-94% after surgical management of organ-confined disease (T2 or less), and it decreases to 12-54% in patients with primary tumor stage pT3-4 or 10-35% in those with nodal disease (2). As a result, the value of adjuvant treatment has been a subject of debate, and a diverse range of clinical outcomes has been reported. The role of adjuvant radiotherapy (RT) has not been clearly defined and studies have reported contradictory findings (3-10). Because of the rarity of UTUC, previous studies have been limited by the inclusion of a small number of patients in different disease stages and the use of old RT techniques, insufficient RT doses, and various surgical approaches. Since 2007, RT has been used as an adjuvant treatment in patients with locally advanced (i.e. pT3/4 or pN+) UTUC following RNU plus bladder cuff at our institution. Therefore, we designed a retrospective case–control study to investigate the efficacy and toxicity of adjuvant RT following radical surgery in this population and in patients treated with radical surgery as a historical control group.
Patients and Methods
Patients with a pathological diagnosis of stage III or IV (i.e. pT3/4 or pN+) UTUC who underwent RNU and bladder cuff were included in this study. Patients were excluded from this analysis if they had distant metastasis or a prior history of any malignancies including bladder cancer, or had previously received RT. The RT group comprised 36 consecutive patients who received adjuvant RT between 2007 and 2012. As a historic control group, a series of 91 patients treated with surgery with or without chemotherapy for stage III/IV UTUC from 2000 to 2010 were enrolled. Pathological staging was based on the 2010 American Joint Committee on Cancer classification (11). Clinical data were obtained by review of all pertinent medical records with the approval of the Institutional Review Board (AMC IRB 2013-0699).
Adjuvant RT was performed using three-dimensional conformal techniques with 15-megavolt (MV) x-rays within six weeks after surgery. Before RT, 36 patients underwent CT simulation in the supine position with arms on the chest using intravenous contrast agents and free breathing (Light Speed RT; GE Healthcare, St Giles, UK). Patients were treated with external beam RT with a median dose of 46 (range=45-60) Gy and a fraction size of 2.0 (range=1.8-2.2) Gy five-times per week. The target volume generally encompassed the tumor bed and regional lymph nodes (LNs). A bladder cuff bed was included in the RT field if the tumor was located in the distal ureter. Systemic chemotherapy was administered in 21 (58%) and 26 (29%) patients in the RT and non-RT groups, respectively (p<0.01, Table I). The chemotherapy regimen consisted of gemcitabine and cisplatin in all patients of both groups, except for two patients in the non-RT group who were treated with methotrexate, vinblastine, doxorubicin, and cisplatin. Regarding the sequence of RT and chemotherapy, cisplatin was administered concurrently with RT followed by four cycles of gemcitabine and cisplatin in six out of the 21 patients. One patient was treated with chemotherapy followed by RT, and 14 were treated in the opposite order.
Baseline characteristics.
During RT, patients were evaluated weekly for potential toxicity. After completion of therapy, patients were evaluated every three months for two years, every six months for the next three years, and then annually thereafter. History taking and physical examination were performed on every visit, whereas urine cytology, cystoscopy, abdominopelvic computed tomographic (CT) scan, chest X-ray, and bone scan were performed every six months for the first three years, and then once per year thereafter. Additional tests were performed if clinically indicated. Toxicity was assessed by reviewing medical records and graded according to the Common Terminology Criteria for Adverse Events version 4.03 (12). Acute toxicity was defined as any toxicity occurring during or within 90 days after RT, and late toxicity was defined as that occurring after more than 90 days since the completion of RT.
The prevalence rates of risk factors and characteristics of the patients in the two treatment groups were compared using the Student's t-test (for continuous variables) and the chi-square test or Fisher's exact test (for categorical variables). Locoregional recurrence was defined as any recurrence within the radiation field irrespective of field size, and distant metastasis was defined as relapse outside the field excluding the bladder. Bladder recurrence was defined as any recurrence within the bladder not included in the RT field and confirmed histologically. The survival time was counted from the date of the surgery to the date of death or last follow-up. Survival curves were constructed using the Kaplan–Meier method and compared by the log–rank test. Differences in risk-adjusted rates of treatment outcomes between patients who did or did not receive adjuvant RT were assessed using a multivariable Cox proportional-hazards model. Adjusted covariates were selected by backward elimination in the final model. To reduce the impact of treatment selection bias and potential confounding in an observational study, we adjusted for significant differences in the characteristics of patients using inverse probability of treatment weighting (IPTW) (13). With that technique, weights for patients receiving RT were the inverse of the propensity score, and weights for patients not receiving RT were the inverse of 1–propensity score. Propensity scores reflect the probability that a patient will receive therapy based on observed covariates. The bias inherent in retrospective nonrandomized regression analyses is reduced using IPTW with thpropensity score (14). The propensity score was estimated with RT as the dependent variable by multiple logistic regression analysis. A full nonparsimonious model was developed that included all the variables listed in Table I. Model discrimination was assessed with c-statistics (c-index=0.85) and model calibration was assessed with Hosmer–Lemeshow statistics (Chi-square=4.69, df=8, p=0.79). To assess treatment effect, IPTW was incorporated into weighted Cox regression models. All reported p-values are two-sided, and p<0.05 was considered statistically significant. No adjustment was performed for multiple testing in several subgroups. SAS version 9.2 (SAS Institute, Cary, NC, USA) and SPSS version 13.0 (SPSS Inc., Chicago, IL, USA) were used for statistical analyses.
Results
The patients' characteristics are summarized in Table I. No significant differences in age, gender, or stage were detected between the two groups. Patients in the RT group had a significantly higher tumor grade and a higher incidence of ureter cancer and residual disease than those in the non-RT group.
Patterns of failure in the adjuvant (n=36) (a) and in the non-adjuvant radiotherapy (n=91) (b) group.
Hazard ratios by radiotherapy or chemotherapy in terms of clinical outcome.
The median follow-up was 38.3 (range=7.3-154.3) months for the entire cohort. The median follow-up was 27.0 (range=9.9-65.2) months for patients in the RT group versus 44.3 (range=7.3-154.3) months in the non-RT group. Overall, 65 (51%) patients died, of whom 63 died of disease progression during the period of the study. A total of 40 (32%) patients had locoregional recurrence, 51 (40%) had bladder recurrence, and 57 (45%) had distant metastasis. The sites of metastasis included lungs in 27 patients, bones in 16, liver in 14, distant LN in 12, peritoneal seeding in five, and contralateral ureter in one. Recurrence patterns are shown in Figure 1. Both locoregional and bladder recurrences were reduced significantly in the RT group, while distant failure probability was similar. Three-year locoregional and bladder recurrence-free survival rates for the RT group were 89% and 73%, respectively, and the corresponding values for the non-RT group were 61% and 52%. The differences in locoregional and bladder recurrence-free survival rates were statistically significant (locoregional recurrence-free survival, p=0.01; bladder recurrence-free survival, p=0.02, Figure 2A). Distant metastasis control and overall survival were similar between the two groups (3-year distant metastasis-free survival, 60% for the RT group vs. 57% for the non-RT group, p=0.59; 3-year overall survival, 66% vs. 62%, p=0.78, Figure 2B), whereas the 3-year disease-free survival rate was 49% for the RT group and 33% for the non-RT group (p=0.05, Figure 2B). After adjustment for baseline differences using multivariable-adjusted Cox regression analysis and the IPTW, the risk of locoregional, bladder, and disease recurrence remained significantly lower in favor of the RT group as shown in Table II. Univariate and multivariate analyses revealed that only bladder recurrence was influenced by the use of chemotherapy (Table II). Regarding the bladder recurrence site, recurrence near the bladder cuff site was most commonly observed in three and 24 patients in the RT and non-RT groups, respectively (p=0.44).
(a) Locoregional and bladder recurrence-free survival curve for each treatment group. (b) Overall and disease-free survival curve for each treatment group.
Eleven patients (31%) in the RT group had acute severe hematological toxicity, including one with grade 4 and 10 with grade 3 neutropenia. All of them received chemotherapy and recovered after completion of chemotherapy with supportive care. In the RT group, 16 and 14 patients each developed grade 1 and 2 acute gastrointestinal (GI) toxicities, including nausea, indigestion, and diarrhea. Eight patients who received RT developed grade 1 (n=3) and 2 (n=5) acute genitourinary (GU) toxicities, such as frequency, nocturia, urinary retention, and hematuria. None experienced grade 3 or higher acute GI or GU toxicities. In the RT group, late toxicities included grade 2 urinary frequencies in two patients, and three patients presented with hand-foot syndrome and one complained of peripheral neuropathy. These four had received systemic chemotherapy.
Discussion
This study showed that locoregional and bladder recurrence rates were significantly lower in patients with locally advanced UTUC receiving adjuvant RT than in patients who did not receive RT. Advanced-stage UTUC has a poor prognosis, with high locoregional recurrence and/or distant metastasis rates even after radical surgery (15). To improve the prognosis of these patients, the role of postoperative RT has been investigated in several retrospective studies in the last two decades. However, these small retrospective studies have shown inconsistent findings. Some studies reported a low rate of locoregional recurrence after adjuvant RT following surgery (3, 5, 6, 10), whereas others showed similar locoregional recurrence rates between adjuvant-RT and surgery-alone groups, or even lower rates in the surgery-alone group (4, 7-9). These studies included patients with heterogeneous stages from I to IV who underwent several types of surgery, including RNU with or without bladder cuff, nephrectomy, ureterectomy, or endoscopic resection. Several patients received total doses below 45-50 Gy administered using old RT techniques, and information on radiation field or the technique used was lacking in some series. Moreover, the effect of unmeasured confounding related to case selection and different or ambiguous definitions of locoregional failure may explain the discordance between these published results.
In the present study and in previous trials (3, 5, 6, 10), enhanced locoregional control in the RT group did not result in a reduction in distant metastasis or survival gain. There are two possible explanations for this outcome: i) disseminated occult disease outside the RT field already existed at the commencement of RT, and ii) without a significant effect of chemotherapy on distant control, the improvement of locoregional control by RT has inherent limitations. Nevertheless, a high distant metastasis rate despite adjuvant RT and radical surgery promoted the use of adjuvant systemic chemotherapy. Although large prospective studies examining the role of perioperative chemotherapy are not feasible because of the paucity of UTUC, results from extensive studies on perioperative chemotherapy in bladder cancer have been extrapolated to UTUC in view of the similar disease biology and stage-adjusted behavior of the two diseases (16). However, retrospective data from these clinical trials failed to draw concrete evidence supporting the routine use of chemotherapy considering different treatment outcomes (17-19). In our study, univariate and multivariate analyses showed no beneficial effect of chemotherapy on treatment outcomes except for bladder recurrence. Therefore, the benefit of chemotherapy and an optimal sequence of adjuvant treatments in patients with stage III/IV UTUC who underwent RNU with RT remain to be elucidated through further prospective studies.
The reported recurrence rate within the bladder after treatment of a primary UTUC reaches values of up to 50% (1). Currently, two main concepts explain synchronous/metachronous multi-focal urothelial tumor growth. The ‘field cancerization’ hypothesis suggests that exposure of the entire urothelial layer to carcinogens can lead to independent multi-focal (and thus multi-clonal) tumor development (20). However, there is increasing evidence from molecular studies supporting intra-luminal tumor seeding, in which multiple tumors develop as a consequence of clonal evolution from a single transformed cell, as the predominant mechanism (21). Both mechanisms might co-exist and also explain the incidence of bladder recurrence after treatment of UTUC. Kang et al. showed that most intra-vesical tumor recurrences occurred on the same side of the previous UTUC and on the wound from bladder cuff, for which our results are in agreement with (22). These studies may partially explain the lower adjusted rate of bladder recurrence after adjuvant RT determined in the present study; however, it remains largely unaccountable and needs to be validated through randomized study. Various methods have been proposed to reduce bladder recurrence. Chen et al. reported a reduction in bladder recurrence rate after whole-bladder irradiation (5), while Sakamoto et al. showed a trend towards a change in bladder recurrence rates favoring intravesical instillation of chemotherapy (23). The reduction of bladder relapse using systemic chemotherapy is controversial (18).
The present study included a homogeneous group of patients with stage III or IV UTUC who initially received the same surgical treatment at a single institution. Furthermore, an adequate (median 46 Gy, range 45-60Gy) radiation dose was delivered using sophisticated techniques such as three-dimensional conformal RT with 15MV of energy. In addition, two-stage adjustments using the multivariable Cox model with IPTW were performed to overcome the limitations of an observational study. IPTW can prevent the overestimation of the benefits of RT as a result of residual confounding related to the selection of a lower-risk population by propensity score matching. Despite these strengths, limitations inherent to a retrospective study such as its non-randomized nature, small number of patients, and a relatively shorter follow-up period of patients in the RT group than that of patients in the surgery-alone group suggest that a conclusion on the definite beneficial effect of postoperative RT must be made with caution.
Footnotes
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Conflicts of Interest
None to declare.
- Received November 11, 2013.
- Revision received November 29, 2013.
- Accepted December 2, 2013.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
