Chemoradiation with Fluorouracil and Mitomycin Reduces Recurrence of Muscle-invasive Bladder Cancer


Get Permission

Radiotherapy is an alternative to surgery in muscle-invasive bladder cancer, particularly in less-fit patients. However, it is associated with high rates of incomplete response or recurrence, with salvage surgery often being required. Although synchronous chemoradiotherapy has improved local control and survival in some cancers, there are few data from randomized trials of this approach in bladder cancer. One relatively small trial of chemoradiotherapy with cisplatin in this setting showed improved survival without pelvic disease progression.1 However, cisplatin as a radiosensitizer may not be optimal for patients with bladder cancer, since many patients undergoing radiotherapy have renal impairment or poor performance status. As recently reported in The New England Journal of Medicine by James and colleagues for the BC2001 investigators, the UK phase III Bladder Cancer 2001 (BC2001) trial showed that the addition of chemotherapy with fluorouracil (5-FU) plus mitomycin to radiotherapy significantly improved locoregional control of bladder cancer without significantly increasing adverse events.2

Design and Patient Population

In this unblinded trial, 360 patients with muscle-invasive bladder cancer from 45 centers in the United Kingdom were randomly assigned to receive radiotherapy at 55 Gy in 20 fractions over 4 weeks or 64 Gy in 32 fractions over 6.5 weeks, with (n = 182) or without (n = 178) chemotherapy consisting of 5-FU at 500 mg/m2 per day given as a continuous infusion during fractions 1 to 5 and 16 to 20 (10 days total) plus mitomycin at 12 mg/m2 given as IV bolus on day 1.2 The primary endpoint was locoregional disease-free survival (defined as survival free of recurrence in the pelvic nodes or bladder), a second primary tumor, or death.

Patients had to have histologically confirmed stage T2 to T4a adenocarcinoma or transitional or squamous cell carcinoma with no lymph node involvement or metastasis, WHO performance status of 0 to 2, white blood cell count > 4,000/mm3, platelet count > 100,000/mm3, glomerular filtration rate > 25 mL/min, and serum bilirubin and aminotransferase levels < 1.5 times the upper limit of normal. (In a separate randomization, patients were allocated to whole-bladder or modified-volume radiotherapy; results of this comparison were not reported in the current analysis.)

Patients had a median age of 72 years. For the chemoradiotherapy group vs the radiotherapy group, 82% vs 79% were male, 63% vs 66% had performance status of 0, 85% vs 80% had pathologic stage 2 disease, 97% vs 98% had transitional cell carcinoma, 57% vs 53% had complete cystoscopic resection, 26% vs 38% had incomplete resection, 3% vs 2% had no resection, 12% vs 5% had biopsy (P = .01), 26% vs 29% had residual mass after cystoscopic resection, 31% vs 34% had planned neoadjuvant therapy, and 39% vs 40% were planned to have the radiotherapy schedule consisting of 55 Gy in 20 fractions.

Key Results

Patients were followed for a median of 69.9 months. Two-year recurrence-free survival was 67% with chemoradiotherapy vs 54% with radiotherapy, representing a 32% reduction in risk of recurrence with chemoradiotherapy (HR = 0.68, P = .03). Over 72 months of follow-up, risk of recurrence was reduced by 34% with chemoradiotherapy (HR = 0.66, P = .03), after adjustment for neoadjuvant chemotherapy, age, radiotherapy dose, tumor stage, performance status, and tumor grade.

Relapses consisted of invasive bladder cancer in 11% of patients in the chemoradiotherapy group vs 19% in radiotherapy group, noninvasive bladder cancer in 14% vs 17%, and pelvic node relapse in 5% vs 7%. Over 72 months, chemoradiotherapy was also associated with a significant 43% reduction in risk for invasive recurrence (HR = 0.57, P = .01), and a nonsignificant reduction in risk for death (HR = 0.82, P = .16), with separation of the overall survival curves starting at approximately 2 years. Five-year overall survival was 48% in the chemoradiotherapy group and 35% in the radiotherapy group. Chemoradiotherapy was associated with a trend toward a reduction in performance of salvage cystectomy, with 2-year rates of 11% vs 17% (P = .07).

Adverse Events

Acute grade 3 or 4 adverse events (assessed by NCI criteria) were somewhat more common with chemoradiotherapy, occurring in 36% vs 27.5% of the radiotherapy group (P = .07). Acute adverse events were primarily genitourinary and gastrointestinal side effects, with the latter occurring more frequently with chemoradiotherapy (10% vs 3%, P = .007). Late grade 3 or 4 adverse events, assessed by Radiation Therapy Oncology Group (RTOG) criteria over 6 months to 5 years after randomization in 120 patients in the chemoradiotherapy group and 108 in the radiotherapy group, were somewhat more common in the radiotherapy group (8% vs 16%, P = .07). Data on bladder volume were available for 78 patients at 1 year and 51 patents at 2 years. Reductions in bladder volume were 1.3 mL greater in the radiotherapy group at 1 year and 55.6 mL greater at 2 years, although the differences between groups were not significant at either time point.

Primary Conclusions

Thus, the study showed that synchronous chemoradiotherapy resulted in reduced recurrence of cancer, with the benefit occurring irrespective of history of neoadjuvant chemotherapy and without any marked increase in adverse events. Chemoradiotherapy did not appear to be associated with late impairment of bladder function, a concern with more intensive therapy, particularly when given after neoadjuvant chemotherapy. As noted by the authors, reduced rates of invasive relapse might result in improved survival that would be expected to become evident after relatively long-term follow-up. The more frequent use of salvage surgery—which would also be expected to improve survival—in the radiotherapy group may have contributed to the absence of a significant overall survival benefit with chemoradiotherapy in the study.

As stated by the authors, “Although further clinical trials to refine and improve chemoradiotherapy schedules are warranted, our study shows that the addition of chemotherapy to radiotherapy improved local control, particularly freedom from invasive recurrence … and resulted in good long-term bladder function and low rates of salvage cystectomy, all of which are of major importance in this elderly, relatively frail group of patients.” ■

Disclosure: The authors of the paper published in The New England Journal of Medicine reported no potential conflict of interest.

Expert Point of View: Chemoradiation with Fluorouracil and Mitomycin Reduces Recurrence of Muscle-invasive Bladder Cancer

References

1. Coppin CM, Gospodarowicz MK, James K, et al: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol 14:2901-2907, 1996.

2. James ND, Hussain SA, Hall E, et al: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366:1477-1488, 2012.


Related Articles

Expert Point of View: Chemoradiation Reduces Recurrence of Muscle-invasive Bladder Cancer

In an editorial accompanying the recently reported UK phase III Bladder Cancer 2001 (BC2001) trial, Shipley and Zietman, from Massachusetts General Hospital and Harvard Medical School, point out that this trial shows that “the addition of a very tolerable regimen of chemotherapy to radiotherapy...


Advertisement

Advertisement



Advertisement