Chin 2008.

Methods	Study design: parallel randomised controlled trial Study conducted: 1999 to 2002 Setting: single institution Geographic location: Canada
Participants	Inclusion criteria: men with histologically proven prostate cancer, clinically staged as T2c, T3a or T3b based on digital rectal examination or transrectal ultrasound findings, or both, negative computerised tomography of the abdomen and pelvis, negative bone scan and serum PSA < 25 ng/mL Exclusion criteria: men with node‐positive disease and distant metastases, prior pelvic radiotherapy or hormone therapy, prostate volume > 75 mL or American Society of Anesthesiology Risk Class > 3 Total number randomly assigned: 63 Group A (whole gland cryotherapy) Number of men randomly assigned: 32 Age (years): 70.4 ± 5.5 Prostate volume (mL): 31.3 ± 16.8 PSA (ng/mL): 11.1 ± 6.8 Clinical tumour stage: T2c = 12; 3a = 17; 3b = 2 Biopsy Gleason score: < 7 = 2; 7 = 24; > 7 = 5 Group B (EBRT) Number of men randomly assigned: 31 Age (years): 70.5 ± 6.2 Prostate volume (mL): 40.9 ± 11.3 PSA (ng/mL): 8.6 ± 6.5 Clinical tumour stage: T2c = 8; 3a = 15; 3b = 8 Biopsy Gleason score: < 7 = 2; 7 = 24; > 7 = 6
Interventions	Group A (whole gland cryotherapy): Cryocare System (Endocare Inc, Irvine, CA, USA) was used under general or spinal anaesthesia using transrectal ultrasound‐guided probe placement. In most cases, 5 cryoprobes (range 2–8) were used and 2 freeze–thaw cycles were administered with the urethra protected by a urethra‐warming device (Cook Urologic Inc, Spencer, IN, USA). 3 thermocouple probes at the respective neurovascular bundles and in the midline apex were placed for monitoring purposes and to ensure that the required temperature of < −40 °C was reached. A trocar suprapubic catheter was inserted intraoperatively and kept open for 3 weeks. Group B (EBRT): 66 Gy in 33 fractions, administered at 2 Gy per day, 5 days a week for 6.5 weeks, directed at the prostate, seminal vesicles, and peri‐prostatic region. Co‐interventions: 6 months of hormonal therapy with LHRH agonists (goserelin) was administered starting 3 months before the date of cryosurgery or start of the radiotherapy sessions Follow‐up period (median): 105 months
Outcomes	Primary outcomes: overall survival or disease specific survival How measured: not reported (probably survival at follow‐up visit) Time points measured: post‐treatment follow‐up every 3 months for the first year, then every 6 months in the second year followed by annual monitoring or whenever indicated clinically Time points reported: 8 years after randomisation Subgroups: none Secondary outcomes: biochemical disease‐free survival or clinical progression How measured: American Society for Therapeutic Radiology and Oncology definition of 3 consecutive increases in PSA following nadir, or Phoenix criteria (second Radiation Treatment Oncology Group ‐ American Society for Therapeutic Radiology and Oncology Consensus Conference) definition of nadir plus PSA 2 ng/dL/ prostate biopsy Time points measured: post‐treatment follow‐up every 3 months for the first year, then every 6 months in the second year followed by annual monitoring or whenever clinically indicated. For the cryotherapy group, biopsies were done at 3, 6, 18 and 24 months, while in the EBRT arm they were performed at 18 and 24 months after treatment. Further biopsies were done if and when clinically indicated. Time points reported: 8 year after randomisation. Subgroups: none Adverse events How measured: not reported (probably assessed events at follow‐up visit) Time points measured: post‐treatment follow‐up every 3 months for the first year, then every 6 months in the second year followed by annual monitoring or whenever indicated clinically Time points of assessment: not reported Subgroups: none
Funding sources	Research grant from Astra‐Zeneca, Canada
Declarations of interest	Primary author: financial interest or relationship with US HIFU, or both
Notes	Publication status: full text publication Language of publication: English
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comments: not described
Allocation concealment (selection bias)	Unclear risk	Comments: not described
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comments: not described
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Comments: not described
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	Comments: objective outcomes were probably not affected by lack of blinding
Incomplete outcome data (attrition bias) Oncologic outcomes	Low risk	Comments: 31/32 (96.8%) and 31/31 (100.0%) men randomised to cryotherapy and EBRT were included in analysis
Incomplete outcome data (attrition bias) QoL	Unclear risk	Comments: the outcome was not measured.
Incomplete outcome data (attrition bias) Adverse events	Low risk	Comments: 31/32 (96.8%) and 31/31 (100.0%) of men randomised to cryotherapy and EBRT were included in analysis
Incomplete outcome data (attrition bias) Secondary interventions	Unclear risk	Comments: the outcome was not measured.
Selective reporting (reporting bias)	High risk	Comments: protocol was not published and treatment failure (secondary outcome of study) data were not reported
Other bias	Unclear risk	Comments: only 64 out of the planned 150 participants who planned to be randomised were accrued. Lower average prostate volumes likely favor the cryotherapy group.