In the largest randomized study to test chemoradiotherapy against radiation alone in muscle-invasive bladder cancer, chemoradiotherapy with fluorouracil (5-FU) and mitomycin was associated with a 34% reduction in risk of locoregional recurrence, according to research presented at the plenary session of the 52nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).¹ In the multicenter randomized trial conducted in the United Kingdom, 82% of patients were free of invasive bladder cancer 2 years after treatment with chemoradiotherapy, compared to 68% who received radiation alone, according to study authors led by Nicholas James, MD, an oncologist at the University of Birmingham in Birmingham, England.

UK Trial

"The hazard ratio for invasive bladder recurrence among patients receiving chemoradiotherapy in our study was 0.53-recurrences were almost halved. We feel the results of the trial should impact treatment options in the United Kingdom as well as other countries," Dr. James said. "In the U.S.A., very few patients get offered radiotherapy, and we feel these results should change that practice," he added.

In the UK trial, 459 patients with invasive bladder cancer from 45 different medical centers were were randomly assigned to receive standard-volume radiotherapy (to the tumor and whole bladder with a 1.5-cm margin) or reduced high-dose volume radiotherapy (to the tumor plus 1.5-cm margin treated to 100% [±5%] of the target dose and remaining bladder to 80% of the target dose), with and without synchronous chemotherapy with 5-FU and mitomycin. Results indicated that at 2 years the locoregional disease-free survival was 82% among those who received chemoradiotherapy, compared to 68% among those who received radiation alone (P = .008). The investigators found no significant differences in overall survival at 2 years, although they reported a trend toward improved survival after that time.

Toxicity Findings

Reducing the radiation dose to the uninvolved bladder had minimal effect on local control or toxicity. There was also no statistically significant increase in late toxicity during follow-up (starting at 6 months after treatment and up to 3 months before a recurrence). Dr. James noted that survival data are relatively immature beyond 3 years and will be revisited after longer follow-up.

"Acute toxicity was only slightly increased by the addition of chemotherapy, and there was no effect from additional chemotherapy on late toxicity," Dr. James said. "Seventy-five percent of patients reported no late side effects at all."

Dr. James noted that the investigators also measured bladder capacity after treatment, and the average fall in bladder volume was less than 10%. "That's a reduction that patients are not likely to notice. Although there's a widespread perception that radiotherapy leaves patients with a small shrunken useless bladder, this was not borne out at all by our patient-reported data," he said. "Coupled with the reduced locoregional recurrence rate seen in our trial, we feel this should make clinicians reappraise the relative roles of bladder preservation and surgery, especially in the U.S.A., where very few patients are offered bladder preservation," he added.

Therapeutic Alternatives

Dr. James noted that in the UK, radiotherapy is widely used for treatment of bladder cancer as an alternative to surgery, especially in older, frail patients. However, the failure rate from radiotherapy alone is quite high, and about 1 in 3 patients who receive radiation alone end up with a salvage cystectomy.

Dr. James and fellow investigators are now planning a randomized clinical trial that will evaluate outcomes from adding the targeted agent cetuximab (Erbitux) to chemoradiotherapy in bladder cancer treatment. "EGFR is an adverse prognostic marker in bladder cancer, and cetuximab has a proven track record as a radiosensitizer in other EGFR-positive tumor sites such as the head and neck," he said. Results of this trial should be available in several years, Dr. James added. ■

Reference

1. James N, Hussain S, Hall E, et al: Results of a 2 x 2 phase III randomized trial of synchronous chemo-radiotherapy compared to radiotherapy alone and standard versus reduced high volume RT in muscle invasive bladder cancer. 52nd ASTRO Annual Meeting. Abstract 4. Presented November 1, 2010.