Jean Tremlett

Radiotherapy with or without Chemotherapy in Muscle-Invasive Bladder Cancer

BACKGROUND Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. METHODS In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). 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=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). CONCLUSIONS Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

Summary Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. Methods CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. Findings Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015).

BACKGROUND AND PURPOSE Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Randomized Noninferiority Trial of Reduced High-Dose Volume Versus Standard Volume Radiation Therapy for Muscle-Invasive Bladder Cancer: Results of the BC2001 Trial (CRUK/01/004)

Purpose To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. Methods and Materials In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Results Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population. Conclusions In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015): The FAST Trialists group

BACKGROUND AND PURPOSE Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.