Comparison 1. Hypofraction versus conventional fractionation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Prostate cancer‐specific survival (PC‐SS)	8	7946	Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
2 PC‐SS 3‐dimensional conformal radiation therapy (3DCRT) vs intensity‐modulated radiation therapy (IMRT)	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
2.1 3DCRT	3		Hazard Ratio (Random, 95% CI)	0.99 [0.42, 2.32]
2.2 IMRT	5		Hazard Ratio (Random, 95% CI)	1.03 [0.69, 1.56]
3 PC‐SS subgroup analysis (SGA) by dose 74 Gy or greater control arm	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
3.1 > 74 Gy	5		Hazard Ratio (Random, 95% CI)	1.17 [0.79, 1.73]
3.2 ≤ 74 Gy	3		Hazard Ratio (Random, 95% CI)	0.67 [0.36, 1.25]
4 PC‐SS < 4 Gy equivalent dose in 2 Gy fractions (EQD2) vs ≥ 4 Gy	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
4.1 EQD2 difference < 4Gy	4		Hazard Ratio (Random, 95% CI)	1.11 [0.66, 1.87]
4.2 EQD2 difference ≥ 4 Gy	4		Hazard Ratio (Random, 95% CI)	0.90 [0.56, 1.43]
5 PC‐SS androgen deprivation (AD) versus no AD	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
5.1 AD	3		Hazard Ratio (Random, 95% CI)	1.29 [0.81, 2.04]
5.2 No AD	5		Hazard Ratio (Random, 95% CI)	0.76 [0.47, 1.23]
6 PC‐SS quality assurance (QA) versus no QA	8		Hazard Ratio (Random, 95% CI)	Subtotals only
6.1 Radiation therapy (RT) QA process described	4		Hazard Ratio (Random, 95% CI)	0.88 [0.57, 1.34]
6.2 No RT QA process reported	4		Hazard Ratio (Random, 95% CI)	1.22 [0.72, 2.07]
7 ≥ Grade II late gastrointestinal (GI) Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG/EORTC) toxicity at 60 months	4	3843	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.68, 1.78]
8 Late GI RT toxicity by dose ≥ 4 Gy difference between arms	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 EQD2 differs > 4 Gy between study arms	2	985	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.79, 2.14]
8.2 EQD2 differs by < 4 Gy between arms	2	2858	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.38, 2.34]
9 SGA ≥ Grade II late GI RTOG/EORTC toxicity AD vs no AD	4	3843	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.68, 1.78]
9.1 AD	3	2637	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.96, 1.56]
9.2 No AD	1	1206	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.46, 0.88]
10 Late GI RT toxicity by QA vs no QA	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
10.1 QA process reported	2	2858	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.38, 2.34]
10.2 No QA process reported	1	203	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.78, 6.05]
11 Late genitourinary (GU) ≥ Grade II RTOG/EORTC toxicity at 60 months	4	3843	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.93, 1.18]
12 Late GU RT toxicity by dose ≥ 4 Gy difference between arms	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
12.1 EQD2 differs by > 4 Gy between study arms	2	985	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.93, 1.25]
12.2 EQD2 differs by < 4 Gy between study arms	3	3026	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.71, 2.18]
13 SGA late GU ≥ Grade II RTOG/EORTC toxicity: AD vs no AD	5	4011	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.93, 1.22]
13.1 AD	4	2805	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.85, 1.52]
13.2 No AD	1	1206	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.81, 1.23]
14 Late GU RT toxicity by QA vs no QA	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
14.1 QA process described	2	2858	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.82, 1.23]
14.2 No QA process described	2	371	Risk Ratio (M‐H, Random, 95% CI)	1.70 [0.48, 6.04]
15 Overall survival	10	8243	Hazard Ratio (Random, 95% CI)	0.94 [0.83, 1.07]
16 Metastasis‐free survival	5	4985	Hazard Ratio (Random, 95% CI)	1.07 [0.65, 1.76]
17 Biochemical relapse‐free survival Phoenix	5	2889	Hazard Ratio (Random, 95% CI)	0.88 [0.68, 1.13]
18 Acute GI ≥ Grade II RTOG/EORTC	4	4174	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.19, 1.75]
19 Acute GU ≥ Grade II RTOG/EORTC toxicity	4	4174	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.95, 1.11]
20 Health‐related quality of life (HRQoL): ≥ Grade II sexual 'bother' (participant reported) at 60 months	1	1084	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.88, 1.12]
21 HRQoL: ≥ bowel 'bother'	1	1258	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.84, 1.56]
22 HRQoL: ≥ Grade II sexual 'bother' (doctor reported) at 60 months	1	1416	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.90, 1.05]
23 HRQoL: erectile function	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.55, 1.40]
24 PC‐SS sensitivity analysis (SA) dose ≥ 74 Gy conventional (α/β 4.14)	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
24.1 ≥ 74 Gy	5		Hazard Ratio (Random, 95% CI)	1.17 [0.79, 1.73]
24.2 < 74 Gy	3		Hazard Ratio (Random, 95% CI)	0.67 [0.36, 1.25]
25 PC‐SS SA dose control arm ≥ 74 Gy (α/β 0.58)	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
25.1 Dose ≥ 74 Gy	5		Hazard Ratio (Random, 95% CI)	1.17 [0.79, 1.73]
25.2 Dose < 74 Gy	3		Hazard Ratio (Random, 95% CI)	0.67 [0.36, 1.25]
26 PC‐SS SA < 4 Gy EQD2 vs ≥ 4 Gy (α/β 4.14) to 4 Gy	8		Hazard Ratio (Random, 95% CI)	1.00 [0.72, 1.39]
26.1 EQD2 difference ≥ 4 Gy	5		Hazard Ratio (Random, 95% CI)	0.99 [0.66, 1.49]
26.2 EQD2 difference < 4 Gy	3		Hazard Ratio (Random, 95% CI)	1.01 [0.55, 1.84]
27 PC‐SS SA EQD2 < 4 Gy vs ≥ 4 Gy (α/β 0.58))	7		Hazard Ratio (Random, 95% CI)	1.03 [0.73, 1.44]
27.1 EQD2 difference ≥ 4 Gy	6		Hazard Ratio (Random, 95% CI)	1.14 [0.77, 1.68]
27.2 EQD2 difference < 4 Gy	1		Hazard Ratio (Random, 95% CI)	0.73 [0.36, 1.47]