Landmark Trial of Chemoradiation in Bladder Cancer

Roxanne Nelson

April 18, 2012

April 18, 2012 — Adding chemotherapy to standard-dose radiotherapy can improve survival in bladder cancer, according to research published in the April 19 issue of the New England Journal of Medicine.

Muscle-invasive bladder cancer is often treated with surgery, but radiotherapy offers an alternative to cystectomy. Now that these results show that combining chemotherapy with radiation produces even better results, "it may be time to reevaluate the relative roles of bladder preservation and surgery in the treatment of muscle-invasive bladder cancer, particularly for patients at high risk for complications from surgery," the researchers report.

The research team, headed by Nicholas James, MB BS, PhD, professor of clinical oncology at the University of Birmingham, United Kingdom, showed that chemoradiotherapy significantly improved locoregional control in bladder cancer patients. The addition of chemotherapy was associated with a relative reduction of 33% in the risk for locoregional recurrence, with a decrease of almost 50% in invasive recurrence.

This landmark study is "potentially practice changing" for patients with muscle-invasive bladder cancer, write William U. Shipley, MD, and Anthony L. Zietman, MD, in an accompanying editorial.

Drs. Shipley and Zietman, who are both from Massachusetts General Hospital and Harvard Medical School in Boston, note that the researchers report that adding a "very tolerable regimen" of chemotherapy to radiotherapy can cure significantly more patients than radiotherapy alone, and that this rate is similar to the rate observed in the best cystectomy series.

"What is more, the proportion of patients needing radical cystectomy for salvage therapy was remarkably low," they point out.

Whether or not this regimen of fluorouracil and mitomycin C should replace the cisplatin-based combinations used in the United States and elsewhere remains unclear. "We suspect that until a direct comparison is performed in patients with bladder cancer, the choice of chemotherapy drugs will be up to the physician," the editorialists write. "The tendency may be to use fluorouracil and mitomycin C in elderly patients and cisplatin in younger patients who tend to have better renal function and overall health."

Ultimately, the decision to use chemoradiotherapy, and the choice of which drugs to use, will be made by pretreatment molecular analysis of tumor tissue, they add. Although cystectomy will always "remain part of an organ-sparing approach," this study "shows that as primary treatment, it can now be regarded as one of several options for the patient," they add.

A Viable Alternative

Radiotherapy can be an alternative to cystectomy in patients with muscle-invasive bladder cancer, the researchers explain.

The survival rates in patients with muscle-invasive bladder cancer are poor; approximately 45% survive for 5 years across treatment regimens, the researchers point out. Although surgery is considered the standard of care, the considerable interest in bladder preservation has led to the use of radiotherapy as an alternative, particularly in patients who are less physically fit.

Adding chemotherapy to radiotherapy has been shown to increase local control and improve survival at many other cancer sites, so the researchers set out to investigate if it would do so in bladder cancer.

Improved Survival, Less Cystectomy

In this study, 360 patients from 43 centers were randomized from 2001 to 2008 to either chemoradiotherapy (182 patients) or radiotherapy (178 patients).

In addition, another 219 participants were randomized to either whole-bladder or modified-volume radiotherapy. A total of 121 patients underwent randomization in both comparisons.

Locoregional disease-free survival was significantly better in patients treated with chemoradiotherapy than in those treated with radiotherapy alone. The 2-year recurrence-free rate was 67% in the chemoradiotherapy group (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.48 to 0.96; P = .03) and 54% in the radiotherapy group — an estimated absolute difference of 12 percentage points.

Chemoradiotherapy was associated with a trend toward a reduction in cystectomy, the researchers note. The 2-year rate was 11.4% in the chemoradiotherapy group and 16.8% in the radiotherapy group (P = .07), although the comparison was underpowered.

Of the 51 cystectomies performed, 41 (80.4%) were done for disease recurrence (27 for invasive disease, 9 for nonmuscle-invasive disease, and 5 for an unknown type of recurrence) and 4 were performed for the late effects of radiotherapy.

Overall, there were 208 deaths (98 in the chemoradiotherapy group and 110 in the radiotherapy group). The overall 5-year survival rate was 48% in the chemoradiotherapy group and 35% in the radiotherapy group, for an estimated absolute difference of 7% (95% CI, −3 to 17). Overall, 166 deaths were specific to bladder cancer — 74 in the chemoradiotherapy group and 92 in the radiotherapy group (HR, 0.77; P = .10).

The hazard ratio for overall survival in the chemoradiotherapy group was 0.82 (95% CI, 0.63 to 1.09; P = .16), and there was little between-group difference until at least 2 years.

Higher Rate of Adverse Effects

Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs 27.5%; P = .07), but not during the follow-up period (8.3% vs 15.7%; P = .07). Grade 3 or 4 toxic effects occurred in 64 of 178 patients (36.0%) in the chemoradiotherapy group, and in 50 of 182 patients (27.5%) in the radiotherapy group (P = .07). These events were primarily gastrointestinal toxic effects, with 17 events (9.6%) in the chemoradiotherapy group and 5 (2.7%) in the radiotherapy group (P = .007).

"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, as compared with radiotherapy alone, 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," the researchers conclude.

"Thus, it may be time to reevaluate the relative roles of bladder preservation and surgery in the treatment of muscle-invasive bladder cancer, particularly for patients at high risk for complications from surgery," they add.

This study was supported by Cancer Research UK and the National Institute for Health Research.

N Engl J Med. 2012;366:1477-1488, 1540-1541. Abstract, Editorial

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