In this trial, men age 50-69 underwent PSA screening at centers in England or Wales, including 8,556 men that had a PSA from 3-19.9 ng/mL. There were 7,414 that men had a 10-core biopsy, which resulted in 2,896 patients diagnosed with prostate cancer. Subsequently, 1,643 patients were randomized to active monitoring, radical prostatectomy (open), or radiotherapy (74 Gy with 3-6 months of ADT). As Dr. D’Amico notes, ~75% of men had T1c and ~25% had T2 disease. Furthermore, 77% of men had Gleason 6 prostate cancer, 20% Gleason 7, and 2% had Gleason 8-10 disease.
A couple of points that Dr. D’Amico raises about the patient population and the exclusion criteria. First, there were <1% of the patients that were black, and only 7% of the patients had a family history of prostate cancer. Second, 20% had Gleason 7 disease, however we do not have the breakdown of 3+4 vs 4+3 disease. Third, important exclusion criteria included men that had a PSA >20 ng/mL, as well as men <50 and >70 years of ages. The above factors are important, considering that the patient profile of those included in the study may not reflect current practice demographics.
Dr. D’Amico also notes that disease characteristics included in ProtecT have important implications compared to other large randomized prostate cancer trials. As mentioned, there were 77% of patients in ProtecT that had Gleason 6 disease, compared to 52% in PIVOT and 60% in SPCG-4. Importantly, active monitoring vs watchful waiting and more favorable prostate cancer indices make it less likely to see a difference in metastasis in ProtecT compared to PIVOT/SPCG-4 according to Dr. D’Amico.
Given the long accrual period for the trial, certainly there have been advances in detection of prostate cancer since ProtecT. Our practice patterns have changed, particularly with regards to detection of occult high grade disease: (i) extended TRUS biopsy sampling, (ii) multiparametric MRI and TRUS-MRI fusion biopsies, and (iii) the addition of biomarkers, such as Phi and 4Kscore. However, Dr. D’Amico notes that further study is necessary to assess if advanced imaging/biomarkers can reduce the risk of metastasis in men opting for active surveillance vs immediate treatment.
With a primary end point of prostate cancer specific mortality, Dr. D’Amico states that there are a number of concerns with this study design. First, the study was powered for 10% of patients to die of prostate cancer, whereas only 1% of patients in the trial actually suffered prostate cancer specific mortality. Second, there are competing risks for prostate specific mortality, given the prevalence of cardiovascular disease, diabetes, etc. As Dr. D’Amico also mentions, even in patients with metastases, for which patients may still live for many years, competing risks is still a major concern when powering a study on long-term outcome.
In conclusion, Dr. D’Amico states that we need to consider stratification when designing trials and treating patients, specifically with regards to comorbidities, race and disease aggressiveness. Furthermore, how we design clinical trial endpoints can have a significant downstream effect during the period of data analysis and knowledge translation.
1. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016;375(15):1415-1424.
Presented by: Anthony D’Amico, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Boston, MA, USA
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA