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.

Methods

Study design: parallel randomised controlled trial

Study conducted: December 1997 to February 2003

Setting: single institution

Geographic location: Canada

Participants

Inclusion criteria: men with histologically proven adenocarcinoma of the prostate, a biopsy tumour classification of T2 or T3, no evidence of lymph node or distant metastases, a pretreatment PSA level < 20 ng/mL, and a gland volume < 60 cm³

Exclusion criteria: men were ineligible if they had: clinically bulky T3 tumour; received prior pelvic radiation; received previous androgen‐deprivation therapy (ADT) at any time; or had undergone transurethral resection of prostate within the previous 3 months

Total number randomly assigned: 244

Group A (whole gland cryotherapy)

• Number of men randomly assigned: 122

• Age (years, range): 69.4 (52.8‐81.4)

• Prostate volume (mL): not reported

• PSA (ng/mL, range): 8.1 (0.7‐19.9)

• Clinical tumour stage: T2a = 22; 2b = 28; 2c = 49; 3a = 17; 3b = 6

• Biopsy Gleason score: < 7 = 42; 7 = 69; > 7 = 11

Group B (EBRT)

• Number of men randomly assigned: 122

• Age (years, range): 68.6 (53.2‐78.6)

• Prostate volume (mL): not reported

• PSA (ng/mL, range): 9.0 (2.5‐23.3)

• Clinical tumour stage: T2a = 20; 2b = 23; 2c = 57; 3a = 18; 3b = 4

• Biopsy Gleason score: < 7 = 44; 7 = 65; > 7 = 13

Interventions

Group A (whole gland cryotherapy): transrectal ultrasound guidance with argon/helium third‐generation equipment was used in all participants. The investigators routinely applied thermosensor monitoring, urethral warming, and saline injections to separate the anterior rectal wall from the posterior prostate. 2 freeze‐thaw cycles were used in all men.

Group B (EBRT): 4‐field box technique, received 2 Gy daily (5 days per week) using high‐energy mega‐voltage X‐rays (> 10 MV), prescribed dose was 68 Gy initially then increased to 70 Gy in 2000 and 73.5 Gy in 2002 based on standard practice. Clinical target volume included prostate gland and seminal vesicle base (if biopsy tumour classification < T3c) or entirety (if biopsy tumour classification T3c).

Co‐interventions: all participants received ADT using LHRH agonist therapy. A single 3‐month depot of LHRH agonist was given followed by local treatment between 90 days and 120 days after the injection. In 2001, the local standard care changed to include 6 months of ADT before EBRT using 2 consecutive 3‐month depots of LHRH, and the protocol was amended accordingly to reflect this change with local treatment commencing between 180 days and 210 days after the first injection.

Follow‐up period (median, range): 100 months (53‐128)

Outcomes

Primary outcomes: treatment failure

• How measured: defined as any of the following: biochemical failure; radiologic evidence of disease; or the initiation of further prostate cancer treatment

• Time points measured: every 6 months for 3 years and annually thereafter

• Time points reported: 36, 60, and 84 months

• Subgroups: none

Secondary outcomes: overall survival or disease‐specific survival or prevalence of positive biopsies

• How measured: no survival data or biopsy results were reported.

• Time points measured: survival measured every 6 months for 3 years and annually thereafter; biopsy at 36 months

• Time points reported: survival at 5 years; biopsy at 36 months

• Subgroups: none

QoL

• How measured: European Organisation for Research and Treatment core QoL questionnaire and the Prostate Cancer Index

• Time points measured: before treatment and at 1.5, 3, 6, 12, 18, 24, and 36 months post‐treatment

• Time points reported: same as above

• Subgroups: none

Adverse events

• How measured: reported by National Cancer Institute of Canada Common Toxicity Criteria (version 2.0)

• Time points measured: every 6 months for 3 years and annually thereafter

• Time points reported: cumulative adverse events rates reported (not detailed by time‐point)

• Subgroups: none

Funding sources

Grant from the National Cancer Institute of Canada and the Calgary Health Region

Declarations of interest

Supported by the National Cancer Institute of Canada, and the Alberta Cancer Board.

One of coauthor (Dr Rewcastle) was research director for Endocare, Inc

Notes

Publication status: full text publication

Language of publication: English

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The study biostatistician (P.M.A.B.) randomly assigned eligible patients to receive 1 of 2 treatments, with stratification according to biopsy tumor classification (bT2 vs bT3), Gleason score (2‐4 vs 5‐7 vs 8‐10), and PSA (7.5 ng/mL vs >7.5 ng/mL) with use of dynamic randomization with a biased coin".

Allocation concealment (selection bias)

Unclear risk

Comments: not described

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: Study reported as "Open Label" in protocol

Blinding of outcome assessment (detection bias)
Subjective outcomes

High risk

Quote: Study reported as "Open Label" in protocol; outcome assessment not explicitly reported but judged to have been unlikely

Blinding of outcome assessment (detection bias)
Objective outcomes

Low risk

Comments: objective outcomes were not likely to be affected by lack of blinding

Incomplete outcome data (attrition bias)
Oncologic outcomes

Low risk

Comments: 117/122 (95.9%) and 114/122 (93.4%) men randomised to cryotherapy and EBRT were included in analysis

Incomplete outcome data (attrition bias)
QoL

High risk

Comments:

Short term: 106/122 (86.8%) and 88/122 (72.1%) men randomised to cryotherapy and EBRT were included in analysis

Long term: 98/122 (80.3%) and 97/122 (79.5%) men randomised to cryotherapy and EBRT were included in analysis

Incomplete outcome data (attrition bias)
Adverse events

Low risk

Comments: 117/122 (95.9%) and 114/122 (93.4%) 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)

Low risk

Protocol (NCT00489060) was published and all review outcomes were well described

Other bias

Unclear risk

Quote: "Trial was closed prematurely because of diminishing patient accrual, and not because of adverse events", "One interim analysis was planned"; some participants with PSA > 20 ng/mL were included in EBRT group.