Abstract
Aim: To evaluate the clinical results of external-beam radiotherapy (EBRT) for muscle-invasive bladder cancer (MIBC) in elderly or medically-fragile patients. Patients and Methods: Twenty-five consecutive patients with MIBC (cT2-4N0-1M0) receiving EBRT were retrospectively analyzed. Their median age was 82 years. Radiotherapy median dose was 60 Gy administered in 30 fractions. Results: Median follow-up period was 14.7 months. Median overall survival (OS) and progression-free survival (PFS) were 14.7 months and 7.8 months, respectively. The OS, cause-specific survival (CSS), and PFS rates at 1-year were 56.0%, 68.5%, and 40.0%, respectively. The local progression-free rates (LPFR) at 6 months and 1 year were 89.3% and 59.5%, respectively. Performance status 3 was a significantly unfavorable factor for OS, CSS, and progression-free survival; clinical N stage was a significantly unfavorable factor for progression-free survival; and lower irradiation dose (≤50.4 Gy) was a significantly unfavorable factor for LPFR. Conclusion: EBRT for elderly or medically-fragile patients is feasible, and achieves acceptable local progression-free status.
In Japan, more than 20,000 cases of bladder cancer are diagnosed every year (1). Approximately 30% are muscle-invasive bladder cancer (MIBC) (2), a type of refractory cancer. The standard of care for MIBC is radical cystectomy. Incidence of bladder cancer is higher among the elderly (median age at diagnosis is reportedly 73 years) and can be related to smoking (2). Elderly patients with MIBC are frequently in poor general health condition, with several concomitant illnesses. Although a radical surgical approach is standard, most of these patients are not candidates for this type of surgery. When patients are medically unfit for surgery, few treatment options are available and prognosis is poor. External-beam radiotherapy (EBRT) is an alternative treatment option, with both curative and palliative applications (3-15).
There have been several clinical trials and retrospective analyses of EBRT for MIBC, most published by researchers in Western countries (3-7). These reports describe EBRT performed to preserve the bladder in T2-3 disease. EBRT can be combined with other modalities such as transurethral resection of bladder tumor (TURBT) and chemotherapy. These have been established as alternative therapeutic options for organ preservation. However, very elderly patients or patients in poor general health condition are often not eligible for clinical trials, and, to the best of our knowledge, no prospective study evaluating the efficacy of EBRT for MIBC in medically fragile patients has been published. Even considering retrospective studies, reports of EBRT use in this population are limited (9-13).
We performed a retrospective analysis to evaluate the feasibility, tolerability, and efficacy of EBRT for MIBC in very elderly or medically-fragile patients. We also sought to determine prognostic factors that affect clinical outcomes in this population.
Patients and Methods
This report follows the Declaration of Helsinki, and our institutional Ethics Review Board approved the research.
We conducted a retrospective medical record review of 26 consecutive patients with bladder cancer who were considered unfit for surgery, or with high surgical risk, and subsequently treated with EBRT at our Institution between January 2004 and July 2015. All patients were initially evaluated for their operability by urologists at our Institution and thereafter, introduced to our Department for EBRT. The radiotherapy chart of 46 patients treated in our Department for urinary tumor during this period was reviewed to identify this subgroup.
Inclusion criteria were as follows: (i) clinical diagnosis of bladder cancer without distant metastases. (ii) Histological confirmation of carcinoma of the urinary bladder. (iii) Advanced age (≥75 years) or considered inoperable. Inoperable patients included those who were unfit for surgery because of poor general health condition, advanced age, or advanced tumor stage (T4b). Although some patients with advanced age were theoretically operable, surgical risks were retrospectively considered to be very high. (iv) We included patients with primary tumor sites at the ureterovesical junction in whom ureteral cancer was difficult to rule out. Patients with recurrent cancer after radical cystectomy were excluded.
Transitional cell carcinoma or urothelial cell carcinoma was histologically confirmed in all patients. Two radiologists reviewed all available pretreatment computed tomography (CT) and magnetic resonance imaging (MRI) images, according to Union for International Cancer Control (International Union Against cancer) ver.7 guidelines (16), to confirm clinical staging.
All patients were treated with three-dimensional conformal radiotherapy. The 10-MV photon beam of the Precise Treatment SystemTM (Elekta Inc., Crawley, UK) was used until April 2015. Thereafter we used the 6-MV photon beam of the Vero4DRT system (formerly called MHI-TM2000; Mitsubishi Heavy Industries, Tokyo, Japan, and BrainLab, Feldkirchen, Germany). Target delineations and treatment planning were performed using Pinnacle3 (Philips Radiation Oncology Systems, Fitchburg, WI, USA) until April 2015, and thereafter iPlan (BrainLab, Feldkirchen, Germany). The final dose distributions for the treatment plans were calculated using a collapsed cones convolution superposition algorithm until April 2015. Since then, we have used the X-ray voxel Monte Carlo algorithm.
Outcome evaluation and statistical analyses. Overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and local progression-free rate (LPFR) were calculated from the last date of EBRT using Kaplan–Meier estimates. We estimated survival curve differences using a log-rank test. A p-value of less than 0.05 denoted statistical significance. Patients who were lost to follow-up because of disease progression were categorized as ‘dead from bladder cancer’ at the time of their last follow-up visit. We performed univariate analyses using the log-rank test to identify factors that potentially affected OS, CSS, PFS, and LPFR. Factors, including performance status (PS) (≤2 vs. 3), age, clinical T stage (≤3 vs. 4), clinical N stage (0 vs. 1), chemotherapy, and irradiation dose (≤50.4 Gy vs. ≥59.4 Gy) were evaluated with regard to OS, CSS, PFS, and LPFR. Adverse events were retrospectively re-evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) ver. 4 (17). All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna Austria) (18).
Patients demographic and treatment characteristics.
Results
Patient characteristics. Distant metastasis was found on re-evaluation in one patient, subsequently excluded from further analyses. A total of 25 patients were analyzed, consisting of 15 men and 10 women, with median age of 82 (range=68-92) years. Fifteen patients (60%) had PS scores of 2 or 3. Nineteen patients (76%) were classified as inoperable, four were operable, and operability could not be determined from the medical records for two patients. One patient was retrospectively determined to be inoperable because chemotherapy for pancreatic cancer was concurrently performed. Twenty-one patients (84%) had tumors that included grade 3 histology. Before EBRT, total tumor resection with TURBT was performed only in three patients, whereas 20 patients underwent subtotal tumor resection or biopsy only, and TURBT was not performed in two patients. Patient characteristics are summarized in Table I.
Characteristics of six patients treated with concurrent or sequential chemotherapy.
T-Stage classification was determined based on CT or MRI findings. The clinical T stage was cT2-4N0-1M0. T-Stages were distributed as follows: T2, nine; T3, seven; T4a, five; T4b, four cases. The N-stage was N0 in 23 cases and N1 in two cases. Clinical TNM stage was stage II in nine, III in 10, and IV in six cases.
Radiotherapy. EBRT was delivered to a dose of 60 (range=50-66) Gy in 30 (range=25-35) fractions for 5 days per week. Of the total 25 patients, 19 received pelvic irradiation. The pelvic lymphatics were initially treated with a four-field box or an anteroposterior opposing field technique to a median of 50 (range=39.6-50.4) Gy in 25 (range=22-28) fractions. The superior border was at the L4-L5 interspace in four cases, at the L5-S1 interspace in 13, and at the S1-S2 interspace in two. The inferior border was just below the lower pole of the obturator foramen, sometimes extending to the lower ischial bone. The lateral border was 0.5-2 cm lateral to the bony margin of the pelvis at its widest point. Seventeen out of these 19 patients received boost irradiation doses at the bladder, the tumor site or both after pelvic irradiation, whereas, six patients did not receive pelvic irradiation. In five patients, the entire bladder was irradiated with a median of 40 (range=40-50.4) Gy in 20 (range=20-25) fractions, with or without boost irradiation to local tumor site. In one patient, only the tumor site was irradiated. Treatment details are summarized in Table I.
Chemotherapy or other treatment. In total, 19 patients received radiotherapy alone and six received concurrent or sequential chemoradiotherapy. In one patient, S1 was concurrently used as adjuvant chemotherapy for a previously resected pancreatic cancer. Hyperthermia treatment was used concurrently with EBRT for two patients. Chemotherapy details are described in Table II.
Patient follow-up. Patient follow-up consisted of routine physical examination, CT, MRI, ultrasonography, or cystoscopic examination. Following EBRT, 23 patients were followed-up at 1- to 4-month intervals; two patients were lost to follow-up after the completion of EBRT.
Oncological and survival outcomes. The median follow-up period after EBRT completion was 14.7 (range=1.6-134.6) months. The median OS was 14.7 [95% confidence interval (CI)=5.5-20.7] months. Twenty-three patients died during follow-up, 17 of bladder cancer. The OS and CSS rates (95% CI) at 1 year were 56.0% (34.8-72.7%) and 68.5% (45.0-83.6%), respectively (Figure 1). The median PFS (95% CI) was 7.8 (4.3-14.7) months. The PFS (95% CI) rates at 6 months and 1 year were 64.0% (42.2-79.4%) and 40.0% (21.3-58.1%), respectively (Figure 2).
Post-EBRT evaluations of local disease status with CT, MRI, ultrasonography or cystoscopy were conducted in 24 patients. During the follow-up period, 10 patients experienced local failure, and the median interval between EBRT completion and the date of local recurrence or disease progression was 7.3 (range=1.5-133.1) months. The LPFRs (95% CI) at 6 months and 1 year were 89.3% (63.2-97.2) and 59.5% (33.2-78.4), respectively (Figure 2).
Toxicity. Adverse events, defined as grade 3 or more according to CTCAE ver. 4 (17), were observed in three patients (12%); grade 3 rectal bleeding (8.5 months after EBRT), grade 3 hemorrhagic cystitis (19.4 months after EBRT), and grade 3 diarrhea (during EBRT) in one patient each. The cause of grade 3 diarrhea was determined to be pseudomembranous enterocolitis secondary to antibiotic therapy and the event resolved with conservative vancomycin therapy.
Factors affecting the oncological outcomes. The results of univariate analysis are as follows. PS3 was a significantly unfavorable factor for OS (p=0.0011), CSS (p=0.0498), and PFS (p=0.0132). Clinical N-stage (N1) was a significantly unfavorable factor for PFS (p=0.044), and lower irradiation dose (≤50.4 Gy) was a significantly unfavorable factor for LPFR (p=0.0209).
The Kaplan–Meier estimate of overall survival (OS) and cause-specific survival (CSS) rates after external-beam radiotherapy (EBRT).
Discussion
We retrospectively evaluated clinical outcomes of EBRT for MIBC without distant metastasis. The study population consisted of patients who were deemed inoperable, or at high risk for surgical adverse events because of advanced age or low general health condition. The OS rate, CSS rate, PFS rate, and LPFR at 1-year were 56.0%, 68.5%, 40.0%, and 59.5%, respectively. Three patients (12%) had ≥grade-3 adverse events were observed. Although survival outcomes were relatively low, EBRT was feasible and effective at achieving local progression-free status in a majority of patients.
There are several clinical trials and retrospective analyses of EBRT for MIBC. Most describe bladder preserving, combined-modality approaches mainly for T2-3 diseases. The OS rates in these prior reports were 20%-70% at 5 years (3, 5-7), which were higher than the survival outcomes in our study. There are several potential explanations for this disparity. First, our study sample consisted of very elderly patients or patients with low general health condition. Our patients' median age (82 years) was approximately 10 years older than the median age of patients included in earlier reports. Additionally, 15 (60%) of our patients had low PS (PS 2 or 3), whereas the PS scores of patients in previous reports were mostly 0-1. Most of the patients in our study were treated with radiotherapy alone, and very few underwent total tumor resection via TURBT (n=3, 12%). These treatment limitations may explain our poor survival outcomes (3, 4, 7, 15). Second, our study included more patients with advanced-stage cancers than previous reports. Nine (36%) of our patients had T4 disease. An earlier report of definitive EBRT following TURBT for bladder cancer described that all patients with T4 disease died within 17 months after EBRT (15).
The Kaplan–Meier estimate of progression-free survival (PFS) and local progression-free rates (LPFR) after external-beam radiotherapy.
Our treatment protocol specified administration of 39.6-50.4 Gy to the pelvis or the whole bladder, followed by boost irradiation with approximately 10-20 Gy. In five of our patients (20%), total doses of up to 50-50.4 Gy were administered. These doses were lower than those recommended in the guidelines (19), and LPFRs were significantly lower for these patients (≤50.4 Gy). Previous studies reported that higher doses with curative intent produced superior LPFRs (5). In four out of the five patients who received 50-50.4 Gy low doses, boost irradiation using conventional irradiation techniques (secondary to multifocal or bulky lesions) was precluded because dose constraints of the bladder would have exceeded in these patients. Recently, high-precision radiotherapy, for example image-guided radiotherapy or intensity-modulated radiotherapy (IMRT), has been safely applied for dose delivery (20, 21).
Survival outcomes (OS, CSS, and PFS) of patients with low general health condition (PS3) were significantly worse. Although these were the products of univariate analysis, these poor survival results suggest that a palliative approach is appropriate for use with these patients. Our patients were treated with conventional fractions over 4-6 weeks. Given the constrained life expectancies of these patients, irradiation with lower palliative doses and shorter durations may be preferable (8). In four out of six patients (66.7%) with PS3, pelvic irradiation was performed. According to the reports of adverse events in EBRT for uterine cervical cancer, radiation-induced gastrointestinal complications were frequent in patients in whom large volume of the small bowel was irradiated (22). Especially for frail patients, irradiation with smaller fields (for example, limited to the bladder or the tumor), may help decrease adverse events (22).
Severe adverse events related to EBRT are relatively rare (3, 4, 7, 9-11, 13-15). In an earlier report of EBRT for MIBC in very elderly or frail patients, Santacaterina et al. (11) reported that no cases showed ≥grade 3 late toxicity. We observed ≥grade 3 acute and late toxicity in only three patients (12%). Of these, one case (grade 3 diarrhea) was attributed to pseudomembranous enterocolitis, likely caused by antibiotic therapy rather than EBRT courses. In our investigation, EBRT was well tolerated.
Our study had several limitations because of its retrospective nature of analysis. Our conclusions depend on the accuracy of information recorded in the past, and not research protocols. Follow-up periods were relatively short. Furthermore, we were unable to perform multivariate analyses because of the small sample size. Due to these limitations, our study does not allow for the definite conclusions in regards to the optimal treatment option for MIBC. Nevertheless, we believe that our results provide baseline data supporting the merit of EBRT and deciding the treatment policy for these patients' group because prospective studies in patients with such special backgrounds are considered difficult.
In conclusion, EBRT for MIBC in very elderly or medically-fragile patients was feasible and well tolerated. Most our patients achieved acceptable local progression-free status, although our survival outcomes were lower than those previously reported. EBRT should be considered as a therapeutic option in such patients, for whom treatment options are limited.
Footnotes
Funding
None.
Conflicts of Interest
The Authors report no conflict of interests regarding the publication of this article.
- Received August 13, 2017.
- Revision received September 8, 2017.
- Accepted September 13, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
