RAVES

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial Lancet Oncol. 2020 Oct;21(10):1331-1340. doi: 10.1016/S1470-2045(20)30456-3. [1]

Clinical Question

In Patients with High Risk Prostate cancer treated with radical prostatectomy, how does early salvage radiation treatment compared with adjuvant radiation therapy affect freedom from biochemical recurrence?

Bottom Line

Salvage radiotherapy does not appear to be an inferior treatment option to adjuvant radiotherapy following radical prostatectomy in patients with high risk disease. Salvage radiotherapy does not compromise disease control while spares some men from exposure radiotherapy.

Major Points

• Providing patients with early salvage radiotherapy was not an inferior approach to adjuvant radiotherapy disease control in post-prostatectomy patients with high risk disease. Namely, a period of observation until local recurrence is detected by PSA surveillance does not compromise disease control.
• Early salvage radiotherapy showed similar effect to standard of care adjuvant radiotherapy for 5-year freedom from biochemical progression, with a difference in freedom from biochemical progression was less than 10%.
• The effect on local eradication of disease was similar between adjuvant radiotherapy and salvage radiotherapy when PSA is 0.2ng/ml.
• However, there is not likely to be improved long-term outcomes with early salvage radiotherapy compared to adjuvant therapy.
• Salvage radiotherapy should be individualised, and the decision-making process should incorporate pathology of prostatectomy, rate of recurrence and patient wishes.
• The study suggests low-relapse risk groups have low biochemical progression rates (doubling time >1 year or Gleason score less than 8) may not require intensification of treatment; patients with Gleason scores of 7 and margin positive disease post resection may benefit from salvage therapy; and patients with high-risk of recurrence (Gleason 8-10 with rapid doubling time) may benefit from salvage therapy with ADT.

Guidelines

American (ASTRO or AUA) and European (EUA-ESTRO-SIOG) guidelines currently recommend the use of adjuvant prostate bed radiotherapy in patients with high risk features after prostatectomy. There was significant benefit in patients with extraprostatic extension and positive surgical margins compared to surgical management alone in the European Guidelines. The American guidelines reflect on the controversies of the RCT trials which have shown this, and questions in which manner radiotherapy is more effective.

Design

• Trial type: Phase 3, randomised, controlled, non-inferiority trial
• Number of patients randomized: 333 patients
  • 166 patients to adjuvant radiotherapy group
  • 167 patients to salvage radiotherapy group
• Setting: Across 32 oncology centres in Australia and New Zealand
• Enrollment: Between March 27, 2009, and Dec 31, 2015
• Mean follow-up: 6.1 years
• Analysis: Intention-to-treat analysis and per-protocol analysis
• Primary outcome: Five year Freedom from biochemical progression

Population

Inclusion Criteria

• Aged at least 18 years
• Had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as either positive surgical margins, extraprostatic extension, or * seminal vesicle invasion, as identified by local pathologists
• Postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less
• Able to start radiotherapy within 4 months of radical prostatectomy
• Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1

Exclusion Criteria

• Androgen deprivation therapy before or after radical prostatectomy
• Previous pelvic radiotherapy
• Total hip replacement
• Evidence of nodal or distant metastases
• Comorbidities that would interfere with the completion of treatment or 5 years of follow-up

Baseline Characteristics

No differences were noted between the groups. Results are for the Adjuvant treatment group:

• Mean age – 63.3 years
• ECOG 0 89%
• Mean preoperative PSA – 10.2
• Gleason 7 – 81%
• Positive margins – 66%
• Seminal vesicles involved – 19%

Interventions

Adjuvant radiotherapy was given within 6 months of radical prostatectomy; salvage radiotherapy was given within 4 months of a PSA measurement of 0.20 ng/mL or more. Use of androgen deprivation therapy with either adjuvant radiotherapy or salvage radiotherapy was not allowed.

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Freedom from biochemical recurrence

• Per protocol analysis, stratified: HR 0.97, 95% CI 0.53-1.78, non-inferiority test 0.086
• Intention To Treat analysis, stratified: HR 1.12, 95% CI 0.65-1.90.

Secondary Outcomes

• Time to starting ADT: not given results
• Time to local/regional/distal progression
• Salvage: 95% ( 92-98) freedom at 5 years
• Adjuvant: 96% (91-98) freedom at 5 years
• Overall Survival
  • Salvage: 98% (96-99)
  • Adjuvant: 99% (97-100)

Subgroup Analysis

Subgroups analysed included: seminal vesicle invasion, Pre-operative PSA, PSM, Gleason score, Extra-prostatic extension. None appear to demonstrate non-inferiority based on a HR 95% CI of 1.48.

Adverse Events

Grade 2 or worse adverse events: OR 0.34, 95% CI 0.17-0.68; lower in the salvage group.

Criticisms

• Treatment assignment was not masked to investigators or patients; investigators and subjects were aware of the group allocation to adjuvant radiotherapy or salvage radiotherapy

• Power calculation for 5-year freedom from biochemical progression rate of 74% in ART (result of EORTC trial) (SRT would be considered non-inferior if >64%) required 470 patients accrued over 4.7 years for 80% power to detect non-inferiority. Study recruited 333 and prematurely closed due to calculations that unexpectedly low event (BCR) rate (17 patients vs 113 predicted for that time) would be futile in showing non-inferiority

• The study excluded at ADT treatments, when ADT is now the standard of care in the context of Radiation therapy for prostate cancer.

Funding

• New Zealand Health Research Council
• Australian National Health Medical Research Council
• Cancer Council Victoria
• Cancer Council NSW
• Auckland Hospital Charitable Trust
• Trans-Tasman Radiation Oncology Group Seed Funding
• Cancer Research Trust New Zealand
• Royal Australian and New Zealand College of Radiologists
• Cancer Institute NSW
• Prostate Cancer Foundation Australia
• Cancer Australia

Further Reading

• Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data [2]

• Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. [3]

• Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. [4]