Concurrent cisplatin, 5-fluorouracil, leucovorin, and radiotherapy for invasive bladder cancer

Abstract

Purpose

To investigate the tolerance and efficacy of a modified concurrent chemoradiation (CCRT) protocol for patients with invasive bladder cancer “unfit” for radical cystectomy.

Methods and materials

Twenty-three muscle-invasive bladder cancer patients who were unfit for or unwilling to receive radical cystectomy were enrolled in this study. All patients had transitional cell carcinoma of bladder, and distribution of stage was 14 (61%), 1 (4%), and 8 (35%) for T3a, T3b, and T4, respectively. This study included a relatively old-age population, with the median age being 75 and 70% of patients over 70 years old. Patients were treated with maximal transurethral resection of the bladder tumor followed by curative CCRT. The chemotherapy (C/T) regimen was comprised of cisplatin, 50 mg/m² intravenously (i.v.) on Day 1; 5-fluorouracil (5-FU), 500 mg/m²/day by continuous i.v. infusion on Days 1–3; and leucovorin, 50 mg/day by continuous i.v. infusion on Days 1–3. Chemotherapy course was repeated at 21-day intervals. The radiation dose was 44–45 Gy to whole pelvis and 60–61.2 Gy to bladder, with a daily fraction of 1.8–2 Gy. The completeness of the CCRT protocol was defined as patients receiving at least 55 Gy of radiotherapy to the whole bladder and at least three courses C/T.

Results

Seventy-four percent of patients (17/23) completed the CCRT protocol. Radiation Therapy Oncology Group (RTOG) Grade 3 acute toxicities were observed in 4 patients, which included leucopenia, vomiting, genitourinary (GU) tract infection, and diarrhea. No treatment-related deaths occurred during the CCRT period. RTOG Grade 3 or more late complications were observed in 3 patients; one of them died of radiation cystitis superimposed with GU infection. Of the 18 patients whose response to CCRT was evaluated, a complete tumor response was documented in 16 patients (89%). With a median follow-up of 3 years, the 3-year overall survival (OS) and disease-free survival (DFS) for all patients was 69% and 65% respectively. Meanwhile, the 3-year overall and DFS rates for patients who completed CCRT vs. those who did not complete CCRT were 82% vs. 33% and 75% vs. 33%, respectively (p = 0.18 for OS and p = 0.04 for DFS).

Conclusions

Concurrent cisplatin, 5-FU, leucovorin, and radiotherapy for treatment of invasive bladder cancer is a feasible and promising treatment even for relatively old patients. Our results are comparable to those in recent studies by using combined modality treatment or neoadjuvant chemotherapy plus radical cystectomy. Consequently, this novel protocol warrants a prospective clinical trial and may be a safe, effective alternative to radical cystectomy.

Introduction

Radical cystectomy is a conventional means of treating muscle-invasive bladder cancer. Local recurrence and perioperative mortality rates after radical cystectomy can be as low as 5% to 10% and below 5%, respectively 1, 2, 3, 4. However, bladder cancer is generally diagnosed after age 65, and rarely before 40 (5), and thus 15% or more of patients with invasive bladder cancer are judged “unfit” for radical cystectomy. For this group of patients, radiotherapy (RT) is an alternative, but the local control rate with RT alone is unsatisfactory (6). On the other hand, half of the patients who received radical surgery succumb to distant metastasis after good local control. To enhance both local and systemic control, a combination of chemotherapy (C/T) and RT is an attractive modality for patients unfit for radical surgery.

In an investigation by Housset et al., pathologically complete remission was noted in all patients who received transurethral resection followed by concurrent chemoradiation (CCRT) with cisplatin, 5-fluorouracil (5-FU), and accelerated RT as a precystectomy regimen and were judged to achieve clinically complete remission by cystoscopy (7). Several studies that aimed to preserve a functioning bladder by CCRT after transurethral resection of bladder tumor (TUR-BT), demonstrated that overall survival with CCRT is comparable to that with radical cystectomy 8, 9, 10, 11, 12. More importantly, 80% of patients achieving long-term survival after CCRT maintained normal bladder function. These studies found that cisplatin/carboplatin with or without 5-FU were effective agents concurrently used with RT, and some of them included neoadjuvant C/T with methotrexate, cisplatin, and vinblastine as part of the treatment protocols. Although bladder preservation by CCRT might not be universally considered the optimum treatment for patients with invasive bladder cancer, these studies suggested that cisplatin-based CCRT should be employed for patients unfit for surgery.

This study reports our initial experience in administering a modified CCRT protocol with lower dosages of cisplatin, 5-FU, and leucovorin to bladder cancer patients. Although the combination of leucovorin and 5-FU was demonstrated to enhance the therapeutic effects of 5-FU and was used to treat many types of tumor, such as head-and-neck cancer and colon cancer 13, 14, its effectiveness as an agent for CCRT in invasive bladder cancer has not yet been tested. This study found that this CCRT protocol could be completed in 73% of our old-age patients, and found a 3-year disease-free survival (DFS) rate of 75% for patients completing CCRT. These findings suggest that this CCRT protocol is a tolerable and effective modality even for relatively old patients, and furthermore is a promising modality worthy of testing in future clinical trials for all patients with invasive bladder cancer.