Clinical trialPhase 3Bladder cancer

Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer

N Engl J Med · 2012360 patients

James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. N Engl J Med. 2012. 366:1477-1488

Study type: Clinical trial
Study name: BC2001
Phase: Phase 3
Design: Multicentre randomised phase 3 trial with a partial 2×2 factorial design (comparing radiotherapy with or without concurrent chemotherapy)
Sample size: 360 patients
Source: N Engl J Med · 2012

In plain words

In this study, patients whose bladder cancer had grown into the muscle layer and who chose radiotherapy instead of having the bladder removed were given radiotherapy alone or together with two chemotherapy drugs (fluorouracil and mitomycin C). Adding chemotherapy made it more likely that the disease stayed under control in the bladder and nearby areas. Overall survival at five years was higher in the chemoradiotherapy group, but this difference was not statistically significant. Serious side effects did not differ significantly between the two groups.

Key results

67% vs 54%

Locoregional disease-free survival at 2 years

Chemoradiotherapy versus radiotherapy; 95% CI 59 to 74 and 46 to 62

0.68

Hazard ratio for locoregional disease (median follow-up 69.9 months)

95% CI 0.48 to 0.96; P=0.03

48% vs 35%

5-year overall survival

Hazard ratio 0.82 (95% CI 0.63 to 1.09); P=0.16 (not significant)

36.0% vs 27.5%

Grade 3 or 4 adverse events during treatment

P=0.07

8.3% vs 15.7%

Grade 3 or 4 adverse events during follow-up

P=0.07

Drugs in this study:Fluorouracil (5-FU)

Dose and schedule cards

Bladder-preserving chemoradiotherapy: fluorouracil + mitomycin C (BC2001)

MIBC (T2 to T4a N0 M0) selected for trimodality therapy after maximal TURBT; in BC2001: WHO performance status 0 to 2, GFR greater than 25 mL/min, no prior pelvic radiotherapy or inflammatory bowel diseaseOn the page “Bladder cancer” · Muscle-invasive cancer (MIBC): perioperative therapy and bladder preservation

Drug	Dose	Route	Schedule
Fluorouracil	500 mg/m² per day	Continuous IV infusion	Radiotherapy fractions 1 to 5 and 16 to 20
Mitomycin C	12 mg/m²	IV	Day 1
External-beam radiotherapy to the bladder	Per institutional protocol	Daily, 5 days a week	For 4 or 6.5 weeks

Cycle length: One course, concurrent with radiotherapy
Duration: 4 or 6.5 weeks

BC2001 trial regimen; the total radiation dose is not stated in the abstract or the trial registration. Metronidazole given concurrently with fluorouracil was prohibited in the trial.

On the page “Bladder cancer” · Muscle-invasive cancer (MIBC): perioperative therapy and bladder preservation

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Radiotherapy with concurrent chemotherapy (chemoradiotherapy)

Radiotherapy daily 5 days a week for 4 or 6.5 weeks with fluorouracil 500 mg/m²/day as a continuous IV infusion during radiotherapy fractions 1 to 5 and 16 to 20, and mitomycin C 12 mg/m² IV on day 1. Metronidazole was not allowed concurrently with fluorouracil. The total radiation dose (Gy) is not stated in the sources reviewed (abstract and ClinicalTrials.gov).

2Radiotherapy alone

The same radiotherapy (5 days a week for 4 or 6.5 weeks) without concurrent chemotherapy.

Source of the regimen details: Abstract of the paper and ClinicalTrials.gov NCT00024349

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

360 patients aged 18 years or older with muscle-invasive bladder cancer (T2 to T4a, N0, M0; transitional cell, adenocarcinoma or squamous) for whom radiotherapy rather than cystectomy was planned; WHO performance status 0 to 2, white cell count above 4000 and platelets above 100,000, bilirubin and ALT/AST below 1.5 times the upper limit, GFR above 25 mL/min; no prior pelvic radiotherapy or inflammatory bowel disease. Prior neoadjuvant chemotherapy was allowed (stratification factor).

Endpoints

Primary endpoint: locoregional disease-free survival. Secondary endpoints: overall survival and toxicity. Patients were also randomised in a partial 2×2 factorial design to whole-bladder radiotherapy or modified-volume radiotherapy (reducing the volume of bladder receiving the full dose) (results not reported in this paper).

Safety and side effects

Grade 3 or 4 adverse events during treatment were slightly more common in the chemoradiotherapy group (36.0% versus 27.5%; P=0.07) but not during follow-up (8.3% versus 15.7%; P=0.07). No significant increase in adverse events was observed.

Clinical significance and place in guidelines

This trial showed that adding concurrent chemotherapy (fluorouracil and mitomycin C) to radiotherapy improves locoregional control of muscle-invasive bladder cancer compared with radiotherapy alone, without a significant increase in adverse events. From the perspective of the abstract, chemoradiotherapy is therefore an evidence-based option for bladder preservation. The status of this regimen in current guidelines should be checked separately.

Limitations

The improvement in overall survival was not statistically significant (P=0.16). The difference in grade 3 or 4 adverse events was also borderline (P=0.07). Results of the comparison of whole-bladder and modified-volume radiotherapy are not reported in this paper. This trial did not include a cystectomy comparison group.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.