Prostate Advances in Comparative Evidence (PACE)

• Toxicity assessment for surgical and SBRT arm [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  CTCAEv4.03 and RTOG for acute and late toxicity. Clavien scale used to assess acute post surgical complications for surgical patients only.
• Toxicity assessment for conventionally fractionated and SBRT arm [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  CTCAEv4.03 and RTOG acute and late toxicity scoring. During the treatment period of conventional radiation therapy and SBRT, treatment associated toxicities are assessed using RTOG scoring only.
• Patient reported outcomes and quality of life assessment for all treatment arms [ Time Frame: 10 years ] [ Designated as safety issue: Yes ]
  International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), Vaizey score (UK and US patients only) Expanded Prostate Index Composite-26 (EPIC-26) and PR-25 (PR-25 is optional)
• Disease-specific and overall survival [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  Disease-specific and overall survival
• Progression-free survival [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  Radiographic, clinical or biochemical evidence of local or distant failure
• Commencement of androgen deprivation therapy [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  LHRH analogues, anti-androgens, orchidectomy

• Cause-specific and overall survival [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  Cause-specific survival will include deaths from prostate cancer only. Overall survival will include deaths from any cause.
• Progression-free survival [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  Radiographic or clinical evidence of local, regional or distant failure.
• Toxicities associated with surgery, radiotherapy and radiosurgery [ Time Frame: 10 years ] [ Designated as safety issue: Yes ]
  Assessed by CTCAE version 4
• Quality of Life [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  Using EORTC Quality of Life Questionnaire PR-25

• Procedure: Laproscopic Prostatectomy
• Radiation: Conventionally Fractionated Prostate Radiotherapy
  Conventional fractionation delivered to a dose of 78 Gy in 2 Gy fractions.
• Radiation: Prostate SBRT
  Prostate SBRT delivered to a dose of 36.25 Gy in 5 fractions.

• Active Comparator: Laparoscopic Prostatectomy vs prostate SBRT
  Patients for whom surgery is considered will be randomised to laparoscopic prostatectomy or prostate SBRT delivered with 36.25 Gy in 5 fractions.
  Interventions:

  • Procedure: Laproscopic Prostatectomy
  • Radiation: Prostate SBRT
• Active Comparator: Conventionally Fractionated RT vs Prostate SBRT
  Patients for whom surgery is not considered or who refuse surgery will be randomised to either conventionally fractionated radiotherapy delivered to a dose of 78 Gy in 2 Gy fractions or SBRT delivered with 36.25 Gy in 5 fractions.
  Interventions:

  • Radiation: Conventionally Fractionated Prostate Radiotherapy
  • Radiation: Prostate SBRT

Inclusion Criteria: All of the following criteria are mandatory for inclusion:

• Histological confirmation of prostate adenocarcinoma with a minimum of 10 biopsy cores taken within 18 months of randomisation.
• Gleason score ≤ 3+4
• Men aged ≥18
• Clinical and MRI stage T1c -T2c, N0-X, M0-X (TNM 6th Edition [72], See Appendix 1)
• PSA ≤ 20 ng/ml
• Pre-enrollment PSA must be completed within 60 days of randomisation

• Patients belonging in one of the following risk groups according to the National Comprehensive Cancer Network (www.nccn.org):

  • Low risk: Clinical stage T1-T2a and Gleason ≤ 6 and PSA < 10 ng/ml, or
  • Intermediate risk includes any one of the following:
  • Clinical stage T2b orT2c
  • PSA 10-20 ng/ml or
  • Gleason 3+4
• WHO performance status 0 - 2
• Prostate volume ≤ 90 cc measured within 6 months of randomisation (height*width*length *π/6)
• Ability of the research subject to understand and the willingness to sign a written informed consent document

Exclusion criteria: One of the following criteria is sufficient for exclusion:

• Clinical stage T3 or greater
• Gleason score ≥ 4 + 3
• High risk disease defined by National Comprehensive Cancer Network (www.nccn.org)
• Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival
• Prior pelvic radiotherapy
• Prior androgen deprivation therapy (including LHRH agonists and antagonists and anti-androgens)
• Any prior active treatment for prostate cancer. Patients previously on active surveillance are eligible if they continue to meet all other eligibility criteria.
• Life expectancy <5 years
• Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artifacts
• Medical conditions likely to make radiotherapy inadvisable eg inflammatory bowel disease, significant urinary symptoms
• Anticoagulation with warfarin/ bleeding tendency making fiducial placement or surgery unsafe in the opinion of the clinician (see section 11, Treatment).
• Participation in another concurrent treatment protocol for prostate cancer