Abstract
Aim: We present preliminary results from our clinical study evaluating the effectiveness of combination of radiotherapy with balloon-occluded arterial infusion (BOAI) and hemodialysis (HD) for bladder cancer. Patients and Methods: We investigated 134 patients with a median age of 67 years (range=38-88 years) and a median follow-up time of 31 months. According to the UICC classification, 89 patients were at clinical stage T2, 40 at T3, and 5 at T4. All patients received external-beam radiation therapy (EBRT) of 50 Gy to the whole pelvis with 10 Gy to the bladder as a boost. During EBRT, BOAI of cisplatin (CDDP) (100 mg/body) was administered from bilateral internal iliac arteries with simultaneous HD to prevent back-flow of CDDP into the systemic circulation. Results: Three-year local control and overall survival (OS) rates were 68% and 80%, respectively, and 3-year bladder preservation rate was 90%. Univariate and multivariate analysis showed that T stage and primary effect were significant prognostic factors for OS. In addition, primary effect was a significant prognostic factor for bladder preservation. None of the patients had grade 2 or more severe hematological toxicity. Late grade ≥3 genitourinary (GU) and gastrointestinal (GI) complications were observed in 6% and 2% of the patients, respectively. Conclusion: Combination of radiotherapy with BOAI and HD, associated with reduced hematological toxicity, may be regarded as a curative therapy for patients with bladder cancer. Late GU and GI complications were within acceptable limits. T stage is an important predictive factor for the outcome of this therapy.
Total cystectomy is a standard treatment method for locally invasive bladder cancer; however, there is a risk of cancer recurrence of approximately 30%-40% in patients with muscle-invasive disease (1). In addition, this approach decreases the quality of life (QOL), and the 5-year mortality rate for patients with clinical stage T2-T4 invasive bladder cancer is approximately 50% despite the decrease in QOL (2-8).
A trimodality therapy approach that combines radical transurethral resection of the bladder tumor (TURBT), chemotherapy, and radiation therapy has since long been applied as an alternative approach for patients who require cystectomy (9). The Radiation Therapy Oncology Group (RTOG) has completed six prospective protocols using systemic intravenous chemotherapy and radiotherapy that included more than 400 patients with T2-T4a muscle-invasive bladder cancer who were cystectomy candidates. However, the pooled analysis showed that 5-year local control and bladder-intact survival rates were 56% for both (10), which is still not satisfactory although 283 out of 468 patients were T2 stage.
Nicholas et al. assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. Two-year rates of locoregional disease–free survival were 67% in the chemoradiotherapy group and 54% in the radiotherapy group. Five-year rates for overall survival were 48% in the chemoradiotherapy and 35% in the radiotherapy group (11).
To improve treatment outcomes, high-intensity treatments may be necessary; thus, we developed a novel bladder-preservation therapy, referred to as the Osaka Medical College (OMC) regimen, that involves balloon-occluded arterial infusion (BOAI) of an anticancer agent and concurrent hemodialysis (HD). This regimen allows the anticancer agent to accumulate at very high concentrations to the tumor site, ensuring that the systemic concentration remains low, and is followed by radiation therapy.
We have previously treated 329 patients (including N+ patients) between 1988 and 2014, and reported that complete response (CR) was achieved in 84% (276 of 329) of the patients. Five-year overall survival (OS) rate was 72% with a mean follow-up of 159 weeks (12). While these results were promising, the enrolled N+ patients received additional treatments such as systemic chemotherapy. Thus, for the present study, we limited the enrolled patients to those receiving radical TURBT, BOAI, and radiation therapy without any radical treatment. In addition, late effects were another major concern, and the observation period was too short to adequately evaluate for a subset of patients. We also excluded patients who had lymph node or distant metastases and who had <12 month follow-up.
Patients and Methods
Eligibility criteria. Between 1998 and 2012, 177 patients were treated through the OMC regimen. We excluded 43 patients who had lymph node or distant metastases or were lost to follow-up <12 months after treatment; thus, 134 patients were included in the final analysis. Patients' characteristics are shown in Table I. The patients were not treated with radical therapy, such as cystectomy, systemic chemotherapy, or radiotherapy, before the OMC regimen. Eligible patients had histologically-confirmed bladder cancer without distant metastasis. All patients had an absolute neutrophil count of 1,500/l, platelets 100,000/l, creatinine 3.0, bilirubin 3-times the institutional upper limit of the normal range, aspartate transaminase 4-times the institutional upper limit of the normal range. Patients with Eastern Cooperative Oncology Group performance status 0–2 were eligible. Imaging studies, including thoracic computed tomography (CT) scan, abdominal and pelvic magnetic resonance imaging (MRI) and CT scans, and bone scintigraphy were performed at the time of diagnosis. The study was reviewed and approved by the Osaka Medical College institutional review board. Patients were informed of the investigational nature of the study and written informed consent was obtained before study enrollment.
Before study entry, patients underwent TURBT at our Institution to establish the diagnosis. Patients were first recommended total cystectomy if surgery was feasible. The OMC regimen was offered as an alternative treatment option for unfeasible cases due to advanced age or performance status, among other reasons. Patients were assigned to receive the OMC regimen 4-5 weeks after TURBT to allow for adequate wound healing.
Study design and treatment. External-beam radiation therapy (EBRT) was administered to the whole pelvis using a CT-planned three-dimensional conformal technique to a total of 60 Gy in 30 fractions: 50 Gy in 25 fractions for whole pelvis, including the bladder and pelvic lymphatics, followed by 10 Gy in five fractions for whole empty bladder only.
For the whole pelvic field, we used the 4-field box technique with an X-ray of 10 Megavolt. The empty bladder plus pelvic lymphatics (obturator and external/internal iliac lymph nodes) with a 1-cm margin was defined as the clinical target volume (CTV). CTV with a 0.5-cm margin was defined as the planning target volume (PTV). For the whole bladder field, we used the oblique 4-field technique. Likewise, the empty bladder with a 1-cm margin was defined as the CTV, and the CTV with a 0.5-cm margin was defined as the PTV.
Patients' characteristics.
The details of BOAI are described elsewhere (13). During EBRT, BOAI of cisplatin (CDDP) (50 mg per each of the bilateral internal iliac arteries) was achieved from the bilateral internal iliac arteries. For the intra-arterial infusion procedure, we used an intra-arterial catheter equipped with two occlusion balloons (size: 6 Fr., M6F-28-70-TBSB4-ST, Clinical Supply, Tokyo, Japan). The catheter was introduced into the posterior trunk of the internal iliac artery using the femoral arterial approach. Both the distal and proximal balloons were inflated and immobilized, so that the anterior trunk of the internal iliac artery, which lies upstream of the target vessels (the vesical arteries), was isolated between the balloons.
HD was simultaneously performed to prevent back-flow of CDDP into the systemic circulation, via two double-lumen catheters (size: 12 Fr., Argyle, Tyco Healthcare, Tokyo, Japan) placed in the bilateral common iliac veins for 2 h after the start of arterial infusion. The catheters were connected to a hollow-fiber dialyzer (APS150, Asahi, Tokyo, Japan) with a membrane area of 1.0-1.5 m2 according to the weight of each patient. The blood flow rate was 180-250 ml/min, and the HD fluid flow rate was 500 ml/min.
At 8 weeks post-EBRT, patients underwent a repeat TURBT of the site of the original tumor, ultrasound-guided whole-layer biopsy, and urine cytology, as well as MRI and CT scans of the pelvis, and the response of patients to this therapy was subsequently evaluated. We performed TURBT as salvage treatment if the patients did not achieve CR or recurred locally.
Statistical analysis. The life table probabilities of OS and cause-specific survival (CSS) were determined using the Kaplan–Meier analysis. Univariate analyses and maltivariate analyses using Cox proportional hazards regression were conducted to evaluate the significance of the following variables as risk factors for treatment failure: age, sex, grade, and tumor stage. Treatment responses were also evaluated. Differences of p<0.05 were considered statistically significant.
Study objectives. The primary end-points of the study were OS, CSS, and bladder preservation rates.
Results
Treatment effect. Overall, 107 out of the 134 (80%) patients achieved CR, as defined by the absence of persistent disease. Three-year local control and bladder preservation rates were 68% (95% CI=59-76) and 90% (95% CI=81-94), respectively. OS and CSS rates are shown in Figure 1. Two-year and 3-year OS rates were 89% (95%CI=82-93) and 80% (95%CI=71-87), respectively, and 2-year and 3-year CSS rates were 90% (95% CI=84-94) and 84% (95%CI=75-90), respectively. OS and CSS rates for each stage are shown in Figure 2a and 2b. Three-year OS rates were 88% (95% CI=82-94), 67% (95% CI=45-74), and 53% (95% CI=9-65) for T2, T3, and T4 (Figure 2a), respectively. Three-year CSS rates were 92% (95% CI=80-95), 70% (95% CI=62-86), and 53% (95% CI=9-65) for T2, T3, and T4 (Figure 2b). Univariate and multivariate analyses were performed (Table II), showing that the T stage and the primary effect were significant prognostic factors for the OS. Furthermore, the primary effect was a significant prognostic factor for bladder preservation.
Overall and cause-specific survival rates of all 134 patients.
Complications. To assess acute toxicity, we evaluated hematological, genitourinary (GU), and gastrointestinal (GI) toxicities using the Common Terminology Criteria for Adverse Events, version 4.0. None of the patients had severe hematological toxicity of grade 2 or more. As for the GU complications, grade 2 and 3 toxicities were observed in 14 (10%) and 12 (9%) patients, respectively. Finally, two patients (1%) had grade 2 GI toxicity. As for the late GU and GI toxicities, grade 2 and 3 late GU toxicities were observed in 17 (13%) and 8 (6%) patients, respectively. Nineteen out of 25 patients with late GU toxicity had frequent urination, 3 patients had urinary pain, 3 patients had urinary retention, and 3 patients had hematuria. Three of the 25 patients with late GU toxicity had a history of lifestyle-related diseases such as diabetes. One patient with a late GU grade 3 toxicity, and 2 patients with late GU grade 2 toxicity had diabetes mellitus. Grade 2 and 3 late GI toxicities were observed for 1 (1%) and 3 (2%) patients, respectively. Three of these 4 patients had ileus, and none had an abdominal surgical history. The other patient with the late GI toxicity had hematochezia.
Overall survival rates of patients in each stage (A). Cause-specific survival rates of patients in each stage (B).
Discussion
Combination of radiotherapy and intra-arterial chemotherapy has been investigated to improve the treatment result (14-23). This approach has a theoretical merit as the anticancer agent can be delivered at concentrations higher than those achieved by intravenous chemotherapy. Several reports showed local control rates at approximately 31%-82% and bladder preservation rates at 54%-90% (Table III).
Maebayashi et al. reported on treatment results of the Japanese Radiation Oncology Study Group (JROSG) study of 159 patients from 17 Institutes (12). They showed that 5-year bladder preservation rates were 58% for radiotherapy with intra-arterial chemotherapy and 42% for radiotherapy with systemic chemotherapy, although there was no significant difference between treatment arms: difference in radiation doses may have influenced this outcome. Thirty-six percent of patients were treated with <60 Gy in the radiotherapy with systemic chemotherapy arm compared to 61% of patients treated with the same dose in the radiotherapy with intra-arterial chemotherapy arm. Lower radiation doses may underlie the relatively lower bladder preservation rates in patients treated with radiotherapy and intra-arterial chemotherapy.
Adequate irradiation dose for each chemotherapy modality has not yet been determined. Arcangeli G et al. reported that in late-stage tumors, the highest benefit might be achieved when a total radiation equivalent dose of >60 Gy is delivered in equivalent doses of 2 Gy per fraction in combination with cisplatin-based intravenous chemotherapy, after 2-3 neoadjuvant chemotherapy cycles (24). Tsujii et al. reported that for patients treated by 50-76 Gy (4 patients) and 30-40 Gy (14 patients), local control rates were 50% and 8%, respectively (15). Some articles reported that bladder preservation rates seemed to be reduced by lower radiation doses (17, 18, 23). Against it, other ariticles reported that bladder preservation rate was almost equal in lower radiation dose (19, 20). This study showed that local control and bladder preservation rates were 69% and 95%, respectively. Based on these references, our technique (60 Gy total radiation dose with 2 Gy/fraction with intra-arterial chemotherapy) appears to be allowable. In the future, we may consider a randomized controlled trial of lower radiation dose and higher radiation dose.
The analysis of the risk factors for overall survival rate and bladder preservation rate.
Late pelvic complications that were observed in this study are within acceptable limits. Efstathiou et al. investigated the late pelvic toxicity of 4 RTOG trials (RTOG 89-03, 95-06, 97-06, 99-06) and reported late grade 3 GU and GI complications occurring in 6% and 2% of patients, respectively (25). The median duration of a late grade 3 pelvic complication was 7.1 months (range=4-33 months). Approximately 50% of the GU and 67% of the GI complications were observed for <12 months (calculated from the figure of reference 25). As the minimum and median follow-up times in our study were 12 and 30 months, respectively, our results showing 5% grade 3 GU and 2% Grade 3 GI complications appear to be reliable and within permissible range.
One other advantage of the OMC regimen is the significant reduction in systemic side-effects. CDDP exerts its anti-tumor activity via its non-protein-bound form. The most important advantage of the OMC regimen is the removal of non-protein-bound platinum immediately after CDDP administration by HD via bilateral common iliac veins, which facilitates efficient removal of CDDP immediately after its passage through the tumor. We found that >95% of serum-free platinum was efficiently eliminated by HD. Actually, no Grade ≥2 hematological complications were observed in this study. As several other reports of intra-arterial chemotherapy showed Grade ≥3 hematological complication rates of 9%-78% (16-20), we consider the OMC regimen as very efficient in limiting hematological complications.
In summary, the OMC regimen-associated local treatment effects and late pelvic complications are comparable to other bladder-preservation therapies, and this approach has lower rates of acute hematological side-effects. The OMC regimen is a useful bladder preservation strategy for patients with locally invasive bladder cancer who are not eligible for total cystectomy or systemic chemotherapy. Future studies with additional cases on long-term follow-up are warranted.
Conclusion
The OMC regimen, which delivers an extremely high concentration of anticancer agent to the tumor site by BOAI and prevents the back-flow of the agent into the systemic circulation by HD, can be regarded as a curative therapy for patients. This approach is also associated with a reduced hematological toxicity. Late GU and GI complications were within a permissible range. T-stage is an important predictive factor of the outcome for this therapy.
Combination of radiotherapy and intraarterial chemotherapy.
Acknowledgements
The Authors would like to thank the staff of the Departments of Urology, Radiology and Radiation oncology for helping us in many ways during completion of this article.
- Received November 6, 2015.
- Revision received December 18, 2015.
- Accepted January 18, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
