CUA 2018: Prostate Cancer: A Disease of Our Time

Halifax, Nova Scotia (UroToday.com) Freddie Hamdy, MD, gave an overview of prostate cancer (PC). He began with statistics regarding the United Kingdom and Canada. In the UK and Canada, 31 and 11 men die of PC every day, respectively.  Hamdy then described the paradigm changes in PC over the past century. In the 19th Century, microscopy appears and cases are increasingly described in the literature. In the early 20th century all men with PC present with advanced disease and eventually die. At this period Huggins and Hodges discover androgen dependence. In the mid-20th century, most men with PC still present with advanced disease and die, but surgery and radiation are starting to be used. In the 1980s PSA is discovered, transrectal ultrasound (TRUS) guided biopsies are developed, and the anatomical radical prostatectomy is introduced. We know today, that PC diagnosis is correlated to PSA levels, with 6.6% of patients with PSA < 0.5 ng/ml harboring cancer, and 26.9% of patients with PSA 3.1-4 ng/ml harboring cancer.

PC is a global problem with increased rates of diagnosis in all countries. However, it is clear, that we are over-detecting, over- and undertreating many cases. This led to the development of active surveillance for low-risk indolent disease. 

When looking at the ERSPC large screening trial after 13 years of follow-up, the number needed to survey to save one life was 781, with the number needed to treat is 27.1

The PROTECT trial led and published by Hamdy in the UK and published in the New England Journal of medicine2 took place between 1998-2008, encompassing 82,429 men, with 2,965 PC cases diagnosed. This is the largest randomized controlled trial comparing active monitoring, surgery, and radiotherapy for PSA-detected localized PC. The 3 compared treatment arms included active monitoring (AM), which is a surveillance program, with men followed up with PSA testing and re-evaluation of their disease. The purpose was to avoid unnecessary treatment, but keep patients in a ‘window-of-curability’ if treatment became necessary. The other two treatment arms included surgery, in the form of open radical prostatectomy with routine follow-up and additional treatments as needed; and radiotherapy with neoadjuvant androgen deprivation therapy (ADT) and 74 Gray 3-D conformal external beam, with regular follow-up and additional interventions as required. 

The CAP trial (2001-2009) is the Cluster Randomized Trial of PSA testing. This is a trial developing out of the PROTECT trial. It is an intention to treat analysis comparing standard NHS treatment to the patients in the PROTECT trial (Figure 1), with the primary outcome being PC mortality in 10 years.

Figure 1 - CAP trial:
UroToday CUA 2018 Disease specific of our time

The main results from the PROTECT trial included 1% disease-specific mortality in all arms, 10% all-cause mortality in all arms and 50% reduction in metastasis in the radical treatment arms. In the AM arm, more than 50% had received treatment by 10 years, approximately 80% of the AM arm had no sign of progression, and 44% of AM patients avoided treatment.

Significant differences were noted n the erectile dysfunction (ED) and urinary incontinence rates between the arms, with the surgery arm having significantly higher rates of ED, and urinary incontinence, and the radiotherapy arm having significantly lower bowel function score. No significant difference was demonstrated in the anxiety and depression rates between the different arms.

The most important lessons learned from the PROTECT study include:
  1. The risk of death from PC over an average of 10 years is very low – 1%.
  2. Surgery and radiotherapy reduce the risk of cancer progression and spread, but cause bothersome urinary, sexual and bowel symptoms
  3. AM avoids treatment side effects, but there is increased risk of cancer progression and spread.
  4. Longer follow-up (5-10 years) is essential in PROTECT to provide data about the ‘trade-off’ between the shorter-term effects of radical treatments, the risks of disease progression, and if any, the long-term benefits in cancer cure and survival.
The new messages given to us by the PROTECT study are:
  1. The PROTECT cohort represents patients with low and intermediate risk clinically localized disease
  2. The risk stratification at diagnosis was inaccurate and may be improved by pre-biopsy imaging, targeting, and genomics
  3. Patient-reported outcomes are like those reported by patients who receive modern treatments
  4. Patients over 65 years benefit from radical treatment
  5. The results are generalizable, and there is a place for each of the 3 treatment arms in disease management
  6. Longer follow-up (15-20 years) is essential in PROTECT and is required to fully comprehend the outcomes.
Multiparametric MRI was not used in the PROTECT study, and one often thinks what would the usage of this modality have changed in this study. It is important to remember that there is a 5-15% risk of missing significant cancer in the absence of a PI-RADS lesion. Also, there was no usage of any new molecular and genetic biomarkers, and their potential effect on the results is also unknown.

Before concluding his talk, Hamdy lastly discussed genetic diversity, which according to him, is our greatest Achilles heel in PC. Analysis of genetic phylogeny of multifocal PC identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Mutations can appear in high levels in tissue that is morphologically benign, and distant but shared by cancer.  Our knowledge in this field of genetic testing is just starting to expand. Currently, the 2017 Philadelphia consensus-driven framework for multigene testing for inherited PC recommends these genes to be factored into management considerations: BRCA 1/ BRCA 2, ATM, and HOXB13.


References:
1. Schröder FH et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014 Dec 6;384(9959):2027-35.
2. Freddie C. Hamdy, et al. N Engl J Med 2016; 375:1415-1424

Presented by: Freddie Hamdy, MD, University of Oxford, UK

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia
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