CHHiP 2016.

Methods	Parallel RCT Setting: cancer centers, UK Dates: Aug 2002–June 2011 Follow‐up: median 62.4 months Randomization ratio: 1:1:1 Non‐inferiority design: 1‐sided confidence interval
Participants	3216 men Inclusion criteria: > 16 years, T1B–T3A N0 M0 prostate cancer, PSA < 30 ng/mL, estimated risk of lymph‐node involvement < 30% (prior to 2006, when 454 men had been recruited, PSA < 40 ng/mL and risk of node involvement < 30% were eligible), WHO performance status 0–1. Exclusion criteria: T3 + Gleason score ≥ 8, life expectancy < 10 years, previous pelvic RT, previous androgen suppression, another active malignancy in the past 5 years (other than cutaneous basal‐cell carcinoma), comorbid conditions precluding radical RT, full anticoagulation treatment or hip prosthesis. Diagnostic criteria: histologically confirmed prostate cancer
Interventions	Number of study centers: 71 Run‐in period: not stated Extension period: no Experimental arm: 2151/2151 participants Conventional arm: 1065/1065 participants Complex interventions: Hypofractionation arm: Group 1 (n = 1074): 60 Gy in 20 fractions in 4.0 weeks (3 Gy per fraction) Group 2 (n = 1077): 57 Gy in 19 fractions in 3.8 weeks (3 Gy per fraction) Conventional arm (n = 1065): 74 Gy in 37 fractions (2 Gy per fraction) over 7.4 weeks (see Table 8)
Outcomes	Primary outcomes: Biochemical failure or prostate cancer recurrence Secondary outcomes: ≥ Grade II GI/GU/sexual late toxicities at 2 years Quality of life (UCLA‐PCI, EPIC, FACT‐P) Complete outcome measures reported: yes
Funding sources	Institute of Cancer Research UK
Declarations of interest	CP reported grants and personal fees from Bayer, personal fees from Janssen and personal fees from BNIT. JS reported personal fees from Janssen‐Cilag Limited and personal fees from Bayer. DD reported grants from Cancer Research UK, during the conduct of the study. EH reported grants from Cancer Research UK, during the conduct of the study; and a grant from Accuracy Inc. to the Institute of Cancer Research to support independent statistical analysis of a phase 3 trial of stereotactic body RT in prostate cancer, outside the submitted work. VK reported advisory and educational fees and non‐financial support from Astellas, educational fees from Bayer, non‐financial educational support from Janssen, advisory and educational fees and non‐financial support from Ipsen, and educational fees from Tolmar. All other authors declared no competing interests.
Notes	All men received short‐course androgen suppression (3–6 months) before and during RT (optional for men with low‐risk disease). Treatment technique: IMTRT (integrated simultaneous boost used) AD: all had 3–6 months AD Pelvic nodes not treated Margins: 59 Gy PTV 1.0 cm isotropically (0.5 cm posteriorly), 74 Gy PTV, margin 0.5 cm isotropically, with 0 cm posterior margin Target volumes covered by 95% isodose IGRT portal imaging films daily A national quality assurance program was used in CHHiP 2016. Note: this is a 3‐phase study. Phase 1: n = 150 designed to evaluate and exclude unacceptable toxicity Phase 2: n = 300 to refine estimates of acute and late toxicity, this data was necessary to gain approval for phase 3 Phase 3: n = 1713 Total n = 3216
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "Computer‐generated random permuted blocks were used, with block sizes of six and nine", page 3, 2016. Randomization and masking. Comment: we deemed at low risk of bias
Allocation concealment (selection bias)	Low risk	Quote from publication: "Randomisation was done centrally via telephone calls to the ICR‐CTSU [Institute of Cancer Research Clinical Trials and Statistics Unit]", page 3, 2016. Randomization and masking. Comment: we deemed this at low risk of bias.
Blinding of participants and personnel (performance bias) Subjective outcomes	High risk	Quote from publication: "it was not possible to mask patients or clinicians to treatment allocation", page 3, 2016. Randomization and masking. Comment: we deemed this domain at high risk of bias.
Blinding of participants and personnel (performance bias) Objective outcomes	Low risk	Quote from publication: "it was not possible to mask patients or clinicians to treatment allocation", page 3, 2016. Randomization and masking. Comment: we deemed this domain at low of bias because of the nature of the outcome. OS: low risk of bias Second malignancy: not reported
Blinding of outcome assessment (detection bias) Subjective outcomes	High risk	Quote from publication: "Treatment allocation was not masked and, because of the trial's size, assessors could not be blinded to toxicity or clinical assessments", page 44. Randomization and masking. Comment: PC‐SS: cause of death was centrally reviewed by masked panel of trial investigators, so for this outcome we deemed this study at be at low risk of bias. The following outcomes were at high risk of bias for lack of blinding, physicians were not blinded, both participant and physician‐reported outcomes were combined. Late GI RT toxicity Late GU RT toxicity The following outcomes were at high risk of bias for lack of blinding. DM‐FS BR‐FS Acute GI RT toxicity Acute GU RT toxicity Health‐related quality of life
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Quote from publication: "Neither treatment allocation nor clinical assessment were masked because sham radiotherapy was not given", page 1606. Randomization and masking. Comment: although outcome assessors for objective outcomes were not blinded, we deemed it was not a source of bias for OS
Incomplete outcome data (attrition bias)	Low risk	Attrition and exclusions were clearly described by study arm, with reasons given (see Figure 1, page 45), so we deemed this at low risk of bias. 3216/3216 men enrolled were reported on for efficacy. They gave details of how many men had a complete set of follow‐up forms for toxicity reporting, so we deemed this at low risk of bias. Number of participants reported on by outcome PC‐SS: reported in 3216/3216 participants Late EORTC/RTOG GI RT toxicity: 1652/3216 assessable participants (51%). Deemed at high risk of attrition bias. Late EORTC/RTOG GU RT toxicity: 1652/3216 assessable participants (51%). Deemed at high risk of attrition bias. OS: reported in 3216/3216 participants DM‐FS: reported in 3216/3216 participants BR‐FS: not reported Quote from publication: "Acute toxicity data was collected for the first 2163 … patients. When the sample size was increased, it was felt that sufficient data had been collected on acute toxicity to all robust conclusions to be drawn about acute toxicity", Dearnaley 2016, page 4. Acute EORTC/RTOG GI RT toxicity: 2148/2163 (99%). Deemed at low risk of attrition bias in view of above statement. Acute EORTC/RTOG GU RT toxicity: 2148/2163 (99%). Deemed at low risk of attrition bias in view of above statement. Second malignancy: not reported Quality of life Self‐reported bowel bother: 1258/3163 assessable participants (40%). Deemed at high risk of attrition bias. Self‐reported sexual bother: 1084/3216 assessable participants (34%). Deemed at high risk of attrition bias.
Selective reporting (reporting bias)	Unclear risk	Outcomes specified in methods: time to biochemical or clinical failure, disease‐free survival, OS, DM, starting AD, acute and late GI and GU toxicity (participant and physician reported), and quality of life. All the outcomes specified were reported. We did not have access to the study protocol. We deemed this domain at unclear risk of bias.
Other bias	Low risk	We did not identify other sources of bias.