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Long-term results confirmed that the benefit of adding chemotherapy to radiotherapy was maintained in patients with muscle-invasive bladder cancer (MIBC) in a follow-up to the phase III randomized BC2001 trial.

Over a median follow-up of about 10 years, locoregional control was significantly improved by adding 5-fluorouracil and mitomycin C to radiotherapy, with a 5-year recurrence-free rate of 63%, compared with 49% with radiotherapy alone (HR 0.61, 95% CI 0.43-0.86, P=0.004), reported Emma Hall, PhD, of the Institute of Cancer Research in London, and colleagues.

Chemoradiotherapy also improved invasive locoregional control (HR 0.55, 95% CI 0.36-0.84, P=0.006), and provided a nonsignificant benefit in disease-free survival (HR 0.78, 95% CI 0.60-1.02, P=0.069), metastasis-free survival (HR 0.78, 95% CI 0.58-1.05, P=0.089), overall survival (HR 0.88, 95% CI 0.69-1.13, P=0.3), and bladder cancer-specific survival (HR 0.79, 95% CI 0.59-1.06, P=0.11), they noted in .

"Our initial results showed that adding chemotherapy to radiotherapy almost halves the risk of bladder cancer returning and can spare some patients from surgery," said Hall in a press release. "After longer follow-up, we can now confirm that this is still the case 10 years down the line. Findings from this trial have already supported a change in clinical practice. I hope patients will feel reassured to find out that, after so many years, the risk of recurrence after treatment with chemoradiation is still lower than with radiotherapy alone."

In an , Abhishek A. Solanki, MD, of Loyola University Chicago in Maywood, Illinois, and colleagues wrote that the long-term results "should give clinicians further confidence in offering bladder-preserving therapy as a curative alternative to radical cystectomy and provides information regarding long-term sequelae and expectations for treatment success."

However, they also pointed out some unanswered questions, such as how to improve systemic disease control, suggesting that neoadjuvant chemotherapy could be a potential approach, and whether bladder tumor eradication can be further improved and the need for salvage cystectomy reduced, noting that immunotherapy studies, as well as studies evaluating adaptive radiotherapy techniques, are ongoing.

From August 2001 to August 2008, BC2001 enrolled 458 patients with T2-T4a N0M0 MIBC from 45 U.K. centers. Under a 2×2 partial factorial design, these patients were randomized to radiotherapy (n=178) or chemoradiotherapy (n=182) for a chemotherapy comparison, and/or standard whole-bladder radiotherapy (n=108) or reduced high-dose-volume radiotherapy (n=111) for a radiotherapy comparison.

According to Hall's team, the chemotherapy comparison was planned to demonstrate superiority of chemotherapy in locoregional control at 2 years, while the radiotherapy comparison was planned to show an improved toxicity profile in the reduced high-dose-volume group, with noninferior 2-year locoregional control.

In their follow-up, they also found that chemoradiotherapy was associated with a reduction in cystectomy, with a 5-year rate of 14% versus 22% in the radiotherapy group (HR 0.54, 95% CI 0.31-0.95, P=0.034). Most of these cystectomies (42 of 53) were performed due to disease recurrence, while just five were due to radiotherapy toxicity.

Overall, 69% of patients in the chemotherapy randomization died, with 5-year overall survival rates of 49% in the chemoradiotherapy group and 37% in the radiotherapy-alone group, and 10-year rates of 30% and 26%, respectively. There were no significant differences between the groups in the main model (HR 0.88, 95% CI 0.69-1.13, P=0.3) or after adjusting for significant prognostic variables (HR 0.81, 95% CI 0.62-1.04, P=0.10).

However, an analysis using time-varying effects suggested possibly improved overall survival after 2 years. "This 'delayed' effect is logical, as early survival is likely to be dominated by existing subclinical metastatic disease that is not significantly impacted by improving local control," Hall and team suggested.

They found no differences in disease control or survival endpoints between the standard whole-bladder radiotherapy and reduced high-dose-volume radiotherapy groups, nor did they find any statistically significant differences in late toxicity among the randomized groups.

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