Orlando – The updated results of a large phase III trial support the use of chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) and confirm that this treatment regimen should be a standard of care for muscle-invasive bladder cancer (MIBC).

When comparing patients who received radiation therapy with those who received chemoradiation, there was a robust improvement in bladder cancer specific survival for the latter when adjusted for known prognostic factors (hazard ratio, 0.73; P = .043).

There was also a borderline significant improvement in metastasis-free survival (HR, 0.78) and a significant reduction in the need for salvage cystectomy in the patients treated with chemoradiation (2-year rate, chemoradiotherapy11% vs. radiation therapy:17%, HR, 0.54; P = .03).

There were no statistically significant differences between groups when it came to overall survival, but, even though overall survival did not reach significance, at 2 years, there was a hint of separation of the curves, explained study author Emma Hall, MD, from the Institute of Cancer Research, London at the 2017 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

One of the treatment arms received a reduced rate of radiation therapy to see if that would decrease toxicity. “The radiation therapy volume modification that we used did not reduce toxicity, but there is no evidence of an increase in local failure rate, suggesting it is safe to pursue clinical trials of volume sparing radiation therapy using newer technology adaptive delivery techniques,” said Dr. Hall.

The initial findings of the BC2001 study showed that adding chemotherapy (5-FU + MMC) to radiotherapy significantly improved rates of MIBC locoregional control but that reduced high-dose volume versus standard radiotherapy did not significantly reduce late side effects.

This study was a clinical trial set up to test two different questions in the treatment of MIBC, as an alternative to cystectomy. “We wanted to see if adding synchronous chemotherapy to radiotherapy would improve locoregional recurrence control and if reducing the radiation dose to uninvolved bladder would reduce toxicity and not impact local regional recurrence control,” according to Dr. Hall.

Under the 2 x 2 partial factorial design, 458 patients were randomized to radiation therapy (n = 178) or chemoradiation (n = 182) and/or to standard radiation therapy (n = 108) or reduced high-dose volume radiation therapy (n = 111).

The primary endpoint was locoregional control, and secondary endpoints included overall survival, bladder-cancer specific survival, metastasis-free survival, and salvage cystectomy rates.

The initial patients received radiation therapy instead of chemoradiation, and there was a robust improvement in bladder cancer–specific survival when adjusted for known prognostic factors (HR, 0.73; P = .043).

The analysis, presented in 2012, showed a reduction of about one-third of locoregional recurrence. The local control rates were 54% in the radiotherapy-alone arm and 67% in the chemoradiotherapy arm.

There was no significant difference in overall survival at that time.

For the radiotherapy comparison, the rate of late toxicity was low, and much lower than was anticipated, at the outset of the trial, and there was no difference in treatment groups, said Dr. Hall.

In an updated analysis, with a median of 10 years of follow-up, 70% of the patients were now deceased. “These represent robust data, and it is unlikely we will see any changes to the data,” she noted.

The findings presented now had an additional 4 years of follow-up, and while there were additional late events, the results were basically the same.

The rate of local control now showed a 40% reduction in the risk of recurrence and 5-year local control rates of 49% in the radiotherapy arm and 63% in the chemoradiotherapy arm.

“With 10 years follow up, an improvement in locoregional control and a reduced salvage cystectomy rate is confirmed with chemoradiotherapy,” Dr. Hall concluded, “and, taken together with the good quality of life data we have, this is important for this group.”

In a discussion of the paper, Dr. Jonathan Rosenberg, MD, from Memorial Sloan Kettering Cancer Center in New York, agrees with the conclusion that the data continue to support the use of chemoradiotherapy and that 5-FU + MMC is a good option.

He noted that 5-FU + MMC is a standard of care regardless of cisplatin eligibility, but he cannot draw conclusions on dose volume. “There are also other options for chemosensitization,” he said, but it is also import to determine the best way to select patients who will derive the most benefit from chemoradiation.

“There is a high need for robust predictive biomarkers, and we need novel approaches to move beyond chemotherapy,” he said.

The study was supported by Cancer Research UK. Dr Hall has received research funding from Accuray, AstraZeneca, Aventis, and Bayer. Several co-authors also have disclosed relationships with industry. Dr. Rosenberg has disclosed multiple relationships with industry.

Chemoradiation standard of care in muscle-invasive bladder cancer