ProtectT - 10-year outcomes after monitoring, surgery, or radiotherapy for localised prostate cancer

Incomplete

Hamdy FC, et al. "10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer". The New England Journal of Medicine. 2016. 375:1415-1424.
PubMed • Full text • PDF

Clinical Question

In men with PSA screening detected prostate cancer, how do survival and progression outcomes compare ten years after monitoring, surgery or radiotherapy?

Bottom Line

After a median of ten years, prostate cancer specific mortality (PCSM) is low irrespective of the treatment assigned. There were no significant differences in PCSM between the treatment groups. surgery and radiotherapy had lower rates of progression that active monitoring

Major Points

• In this cohort, prostate cancer specific survival was similar between observation, surgery and radiotherapy
• Men managed under monitoring appeared to have a higher rate of progression and metastases
• PIVOT
• SPCG-4

Guidelines

EAU

• Localised prostate cancer is assigned to a risk grouping and then treatment recommended based on the grouping. The patients included in this trial fall across the spectrum of risk groups (low-risk, intermediate-risk and high-risk), meaning that many treatment options are available including Active surveillance, radical prostatectomy and radiotherapy.

NCCN

• Similar in concept to the EAU guidelines, NCCN uses a risk stratification to group patients for treatment recommendations. The patients included in this trial fall across a series of strata and could be recommended for many treatment types.

In both guidelines, patients included in this trial with Gleason >7 would not be eligible for active surveillance (monitoring).

Design

• Trial type: randomised, multicentre
• N=number of patients randomized (often different from number of patients enrolled)
• Radical prostatectomy : n= 553
  • Active monitoring: n=545
  • Radiotherapy: n= 545
• Setting: UK, nine sites
• Enrolment: 1999-2009
• Median follow-up: 10 years
• Analysis: intention to treat, cox proportional hazards model with adjustment for confounders
• Primary outcome: prostate cancer specific mortality

Population

Inclusion Criteria

• Men aged 50-69 years, diagnosed with localised prostate cancer after a PSA screening test, agreed to undergo randomisation.

Exclusion Criteria

• Advanced disease.

Baseline Characteristics

From the active monitoring group.

• Age: 62 years
• White ethnic origin: 99%
• Married or living with partner: 84%
• Managerial/professional occupation: 43%
• Known family history of prostate cancer: 8%
• Median PSA in ng/mL: 4.7
• PSA 10+: 10%
• Gleason 6: 77%
• Gleason 7: 20%
• Gleason 8-10: 2%
• Missing Gleason: 0%
• Clinical stage – T1c: 75%
• Clinical stage T2: 25%

Interventions

• Patients were randomized to a group:
  • Active monitoring: PSA measured 3 monthly for the first year and then every 6-12 months thereafter. A change of 50% in a 12 month period triggered a review, with continued monitoring or radical intervention possible.
  • Radical prostatectomy: PSA monitoring every 3 months after surgery for 12 months, 6 monthly for two years and then annually. Adjuvant or salvage radiotherapy for those with positive surgical margins, extracapsular disease or a postoperative PSA 0.2ng or higher.
• Radiotherapy: neoadjuvant ADT for 3-6 months, then 3D confocal radiotherapy, 74Gy, 37 fractions.

Outcomes

Primary Outcomes

Prostate cancer specific mortality

RP vs AM – HR 0.63 (95% CI 0.21-1.93)

RT vs AM – HR 0.51 (95% CI 0.15-1.69)

Log rank test between three groups – p=0.48

Secondary Outcomes

Clinical progression of prostate cancer

RP vs AM - HR 0.39 (95% CI 0.27-0.54)

RT vs AM - HR 0.39 (95% CI 0.27-0.55)

Log rank test between three groups – p<0.001

All cause mortality

RP vs AM - HR 0.93 (95% CI 0.65-1.35)

RT vs AM - HR 0.94 (95% CI 0.65-1.36)

Log rank test between three groups – p=0.92

Subgroup Analysis

• Sensitivity analysis using competing risks regression showed similar results to the Cox proportional hazards model.

Adverse Events

• The sister paper describing the PROMS of the same cohort includes detailed descriptions of the Patient Reported Outcomes Measures for each arm of this trial.

Additional complications

Surgery – Nine men had thromboembolic or cardiac events, 14 required transfusion of more than three units of blood, one had rectal injury, nine required intervention for anastomotic problems.

Radiotherapy – three deaths within 90 days, unrelated to prostate cancer.

Criticisms

• Allocation to Active Monitoring was higher risk than recommended in current guidelines
• MRI and transperineal biopsy are now standard of care for monitoring
• The mortality in was low
• There is a low rate of men agreeing to be randomised from the initial cohort
• The average man randomised is somewhat younger than the typical man diagnosed with prostate cancer
• While prostate cancer specific mortality rates are comparable between the groups, this is likely to change given further follow-up, based on the increased observation of metastases in the active monitoring group
• It is now accepted that localised disease is not always low risk disease

Funding

Supported by the U.K. National Institute for Health Research Health Technology Assessment Programme (NIHR HTA: projects 96/20/06, 96/20/99, with the University of Oxford as sponsor). Dr. Donovan is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West, hosted by University Hospitals Bristol NHS Foundation Trust, and Dr. Hamdy is supported by the Oxford NIHR Biomedical Research Centre Surgical Innovation and Evaluation Theme and the Cancer Research U.K. Oxford Centre.