Abstract
Aim: To evaluate the feasibility of concurrent chemoradiotherapy (CCRT) in very advanced bladder cancer (stage IV) and further analyze the prognostic factors in these patients. Patients and Methods: We retrospectively reviewed the clinicopathological features and outcomes of patients with muscle-invasive bladder cancer after CCRT. Sixty-one patients with muscle-invasive bladder cancer who underwent CCRT between January 1996 and March 2011 were eligible for evaluation. Chemotherapy consisted of cisplatin (50 mg/m2) at day one, and 5-fluorouracil (500 mg/m2/day) and leucovorin (50 mg/m2/day) at days 1, 2, and 3, every three weeks, for a maximum of six cycles. The radiation dose was 44-45 Gy to the entire pelvis and 60-66 Gy to the entire bladder, with a daily fraction of 1.8-2 Gy. Results: By August 2012, the estimated median progression-free survival (PFS), cancer-specific survival, and overall survival (OS) were 25.7, 64.3 and 35.8 months, respectively; the complete response (CR) rate was 68.8%. Both clinical stage and CR following CCRT, were independent prognostic factors for PFS, cancer-specific survival, and OS. Patients with stage IV disease who achieved CR had significantly better PFS (log-rank p=0.01), cancer-specific survival (log-rank p=0.01), and OS (log-rank p=0.01) than those with stage II/III disease but no CR. The absence of hydronephrosis was the only factor predictive of CR after CCRT (odd ratio, 4.21; p=0.04). Conclusion: CR was the most important prognostic factor in muscle-invasive bladder cancer. Selected patients with stage IV bladder cancer could benefit from CCRT if a CR is achieved.
Radical cystectomy is the standard treatment for muscle-invasive bladder cancer. Bladder preservation via trimodal treatment consisting of transurethral resection of the bladder tumour (TUR-BT), radiotherapy, and chemotherapy, is an alternative treatment for muscle-invasive bladder cancer with survivals comparable to those for radical cystectomy (1). Cisplatin-based concurrent chemoradiotherapy (CCRT) has played an important role in the treatment of muscle-invasive bladder cancer (1). Recently, James et al. documented that CCRT using 5-fluorouracil (5-FU) and mitomycin C resulted in significantly better locoregional control of bladder cancer than radiotherapy alone (2). Cisplatin-sparing therapy was also an alternative CCRT option for these patients.
Previous studies of CCRT for muscle-invasive bladder cancer focused on the feasibility, efficacy, and toxicity of the treatment (3-11). The prognostic and predictive factors were seldom reported (7). Additionally, most patients in these studies had early-stage disease, which is characterized by the absence of pelvic wall and of lymph node involvement [T2-4aN0M0 according to the American Joint Committee on Cancer (AJCC) staging system, 2010] (12). The feasibility of CCRT in more advanced bladder cancer such as T4b (indicating tumour invasion to the pelvic wall and metastases to regional or para-aortic lymph nodes), is unknown.
We previously reported that CCRT with cisplatin, 5-FU, and leucovorin was a feasible treatment for muscle-invasive bladder cancer (13). Therefore, in this study, we reported the long-term results of this protocol, evaluated the feasibility in very advanced bladder cancer (stage IV), and further analyzed the prognostic factors.
Patients and Methods
Patients. We enrolled patients with muscle-invasive bladder cancer who underwent maximal TUR-BT followed by CCRT in Chang Gung Memorial Hospital (CGMH) at Linkou between January 1996 and March 2011. Patient demographics, tumour characteristics, disease status, and survival outcomes were all retrospectively collected. All patients had muscle-invasive disease and a urothelial carcinoma tumour histology. Patients with para-aortic lymph node metastasis only were also included in this study. Other inclusion criteria were no previous history of malignancy excluding superficial bladder cancer that was treated with TUR-BT, no prior chemotherapy or radiotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow function (absolute neutrophil count >1500/mm3 and platelet count>100,000/mm3), adequate renal function (creatinine <1.5 mg/dl), adequate liver function [total bilirubin <2 mg/dl and glutamate-pyruvate transaminase (GPT) less than five times the upper limit of normal], and no active infection or major concurrent diseases. The stage of the disease was based on the TUR-BT results and computed tomography (CT) or magnetic resonance imaging findings. The last follow-up was in August 2012. Our analysis was approved by the Institutional Review Board of CGMH (approval number 101-4488B).
Treatment. All patients underwent maximal TUR-BT as their initial treatment. These patients underwent CCRT two to six weeks after TUR-BT. The chemotherapy regimen consisted of cisplatin (50 mg/m2) on day 1, and 5-FU (500 mg/m2/day) and leucovorin (50 mg/day) in a continuous intravenous infusion for 72 h on days 1, 2, and 3 (12). Chemotherapy was started no more than one week before the first day of radiation, and it was repeated three times every three to four weeks. An additional three cycles of chemotherapy with the same regimen and schedule could be given by an experienced medical oncologist (13).
A total radiation dose of 44-45 Gy with 22-25 fractions (1.8-2 Gy/fraction/day, 5 days/week) was delivered to the bladder and pelvic lymphatics by parallel-opposed anteroposterior or four-field box beams. The planning target volume (PTV) was boosted to a total dose of 60-66 Gy. In the boost field, the clinical target volume (CTV) was defined as the whole bladder shown in the CT scan during simulation, and the margin between the PTV and CTV was 1.5 cm. The patients were asked to void immediately before each fraction of radiation treatment was delivered (13).
After completion of therapy, patients were to undergo cystoscopic examination every 3-4 months for the first two years and every six months thereafter. A biopsy was taken if any suspicious tumours were found. A CT scan was also performed to evaluate the tumour status every 6-12 months. Tumour response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) (14). Complete response (CR) was defined as no residual tumor found by both cystoscopy and CT scan and absence of malignant cells if a biopsy was taken. If CR was not achieved, salvage surgery and/or palliative chemotherapy would be performed based on the physician's assessment.
Statistical considerations. The description of the cohort used median and range values for categorical variables. We evaluated clinicopathological features including age, sex, tumour grade, hydronephrosis, and tumour stage based on the AJCC staging system (12). Progression-free survival (PFS) was defined as the duration from the first day of CCRT to the first evidence of recurrence or progression. Patients who died from a cause other than bladder cancer or who were lost to follow-up were censored at the date of death or last visit. Overall survival (OS) was defined as the duration from the first day of CCRT to death of any cause. Cancer-specific survival was defined as the duration from the first day of CCRT to death from bladder cancer. Prognostic factors included age, sex, tumour grade, hydronephrosis, tumour stage, and CR. Survival was analysed using the Kaplan–Meier method. Univariate and multivariate analyses of the association between the prognostic factors and survival were performed using the Cox proportional hazard model. Univariate and multivariate analyses of the odds ratio (OR) of predictive factors were performed using the binary logistic regression model. p-Values below 0.05 were considered statistically significant.
Results
Patients' characteristics. In total, 63 patients with muscle-invasive bladder cancer were treated using CCRT at CGMH in Linkou between January 1996 and March 2011. Among them, two patients were excluded because of missing data (n=1) and a non-urothelial carcinoma histology (n=1). The 61, subsequently, enrolled patients included 48 men and 13 women with a median age of 72 years. Fifty (82.0%) patients had clinical stage II/III disease, which was considered feasible for CCRT in most previous studies (3-11). Eleven (18.0%) patients with bladder cancer were staged as clinical stage IV in the initial staging. Among patients with clinical stage IV bladder cancer, one had T4b, nine had regional lymph node metastases, and six had metastases in para-aortic lymph nodes, defined as distal lymph nodes. The patients'characteristics are provided in Table I. Generally, the patients in the current study were relatively old, with tumour of high histological grade and advanced clinical stage.
Prognostic factors in patient survival. During a median follow-up of 34.6 months, there were 29 cancer-specific deaths and 46 deaths overall. Only one patient underwent salvage radical cystectomy because of local recurrence. The estimated median PFS, cancer-specific survival, and OS were 25.7, 64.3 and 35.8 months, respectively.
We performed multivariate analysis to identify the independent prognostic factors of PFS, cancer-specific survival, and OS. We found that CR, stage, and age were independent prognostic factors for PFS and OS. In addition, CR and stage were also prognostic factors for cancer-specific survival. The lack of importance of age in cancer-specific survival may be due to the fact that death from age-related causes was censored in the cancer-specific survival analysis. The details of the multivariate analysis are provided in Table II.
According to the most important prognostic factors of CR and stage, we classified these patients into four groups: stage II/III with CR, stage II/III without CR, stage IV with CR, and stage IV without CR. The survival curves for each group are shown in Figure 1. The patients with stage IV disease who achieved CR had a significantly better PFS (log-rank p=0.01), cancer-specific survival (log-rank p=0.01), and OS (log-rank p=0.01) than those with stage II/III disease but no CR. In total, five out of 11 patients with stage IV bladder cancer achieved a CR after CCRT. The characteristics and outcomes of these five patients are listed in Table III.
Factors predictive of CR. CR was the most important prognostic factor in patients with advanced bladder cancer who underwent CCRT, and thus we attempted to identify clinically predictive factors of CR in these patients. The CR rates were 88.9%, 65.6% and 45.5% for patients with stage II, III, and IV bladder cancer, respectively. In addition, the CR rates were 75.5% and 41.7% for patients without and with hydronephrosis, respectively. We found that a more advanced stage (p=0.04) and hydronephrosis (p=0.04) were significantly associated with a lower CR rate. Other factors including age, sex, and histological grade were not associated with the CR rate. The details of predictive factors for CR are provided in Table IV.
In multivariate analysis, the absence of hydronephrosis was significantly predictive of CR [OR=4.21; 95% confidence interval (CI)=1.08-16.32; p=0.04], and stage II/III displayed a trend for an association with higher CR rates (OR=3.30; 95% CI=0.81-13.45; p=0.10) (Table V).
Discussion
This study enrolled 61 patients with advanced bladder cancer who underwent CCRT. The CR rate was 68.8%, which is comparable to the one reported in previous studies (3-11). We identified that both clinical stage and CR following CCRT, were independent prognostic factors for PFS, cancer-specific survival, and OS. Additionally, we demonstrated that hydronephrosis was the sole factor predictive of CR after CCRT.
In the current study, we included patients with stage IV bladder cancer. Although these patients had a lower CR rate and a poorer prognosis than those with stage II or III bladder cancer, some of these patients could benefit from CCRT, if CR was achieved. We found that the patients with stage IV disease who achieved CR after CCRT had a significantly better prognosis than those with stage II or III disease, but with no CR. Therefore, CCRT might be an alternative treatment option for patients with stage IV bladder cancer, including T4b with regional or para-aortic lymph node involvement.
Patients who achieved CR after CCRT had a better prognosis than those who did not achieve CR (4, 5, 7). One large study analysed 415 patients with bladder cancer treated using RT or CCRT (7). Early tumour stage and complete TUR were the most important factors for predicting CR and survival. However, the study did not evaluate the role of hydronephrosis in muscle-invasive bladder cancer. Another study analyzed 77 patients with T2-4aN0M0 bladder cancer (9). The CR rate was significantly different between stage T2 and stage T3-4a disease, but no significant prognostic factors were noted for tumour-specific survival and OS.
Hydronephrosis was a prognostic factor for bladder cancer treated by radical cystectomy in previous studies (15-18), but the prognostic value of hydronephrosis had not been previously reported for CCRT-treated bladder cancer, as far as we are aware of. Although hydronephrosis was not a factor prognostic for tumour progression or survival in the current study, we found that hydronephrosis was associated with the CR rate. Patients without hydronephrosis had a significantly higher CR rate than those with hydronephrosis, although the sample size of the study was small. This finding is possibly the result of the association of hydronephrosis with advanced bladder cancer (15-17) involving structural alterations of the trigone muscle, adjacent bladder wall, and intramural ureter or interureteric ridge (Mercier's bar), via multifocal malignant transformation of the urinary epithelium (16).
Recently, biomarkers have been used as prognostic or predictive factors for muscle-invasive bladder cancer in patients treated using CCRT. Excision repair cross-complementing group-1 (ERCC1) expression is associated with resistance to cisplatin and radiotherapy, and it may predict the efficacy of CCRT in patients with bladder cancer (19). Further studies are warranted to identify candidates who would benefit from CCRT before treatment.
There are several limitations in this study. Firstly, the study was performed in a single institution using retrospective analysis. Secondly, some studies reported that complete resection (R0) of TUR was an important prognostic factor (5, 7), but we could not evaluate this factor because R0 resection was not possible in most of our patients with relatively advanced bladder cancer. Thirdly, the number of patients with stage IV bladder cancer or hydronephrosis was limited in the current study. More patients are needed to evaluate the role of CCRT in this setting.
In conclusion, CR was a prognostic factor in muscle-invasive bladder cancer treated using CCRT. Selected patients with stage IV bladder cancer could benefit from CCRT and achieve CR. A lack of hydronephrosis was predictive of CR in patients who underwent CCRT.
Footnotes
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Conflicts of Interest
None declared by the Authors.
- Received April 8, 2013.
- Revision received April 25, 2013.
- Accepted April 29, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved