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12 March 2018
Jenny Donovan, Professor of Social Medicine, University of Bristol and Director of the NIHR Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West) on the recent findings from two large prostate cancer trials that she has led.
Last week, it was announced that deaths from prostate cancer exceeded those from breast cancer in England and Wales for the first time – 11,800 per year. Yet screening for prostate cancer is a controversial public health topic. There are strong advocates for or against screening for prostate cancer who draw on the same evidence to reach opposite conclusions.
This week the third and largest ever randomised trial of prostate cancer screening was published, the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP), funded by Cancer Research UK and the Department of Health and Social Care. The NIHR-funded Prostate testing for cancer and Treatment (ProtecT) trial – the largest of its type – was embedded in CAP. Will these two interlinked trials provide the evidence that finally ends the controversies?
The idea of screening for prostate cancer gained momentum when the prostate specific antigen (PSA) blood test became widely available from the mid-1980s. A PSA result over a particular threshold followed by trans-rectal ultrasound-guided (TRUS) prostate biopsies could lead to the detection of many cancers, mostly still confined within the prostate. At the same time, surgeons in the US and Europe perfected the technique of radical prostatectomy – removal of the prostate gland and any cancer within it.
It seemed like an ideal situation for screening: men could have a simple blood test and prostate cancers localised in the gland could be cured. But over time, concerns were raised: PSA could be raised by infections, benign prostate enlargement or other factors, not just cancer; and biopsies could cause complications including bleeding and infection. While many small low-grade cancers were found, some lethal cancers were missed. In addition, it became clear that radical treatments aiming for cure (surgery and radiotherapy) had side effects, including damage to sexual, urinary and bowel function. Meanwhile, PSA testing and radical treatment spread widely.
NIHR’s precursor, the Department of Health R&D Health Technology Assessment panel, commissioned two groups to undertake systematic reviews of the diagnosis, management, treatment and costs of prostate cancer and of screening of early localised prostate cancer. The NIHR Health Technology Assessment (HTA) Programme then commissioned the ProtecT feasibility study.
The ProtecT feasibility study investigated whether it was possible to recruit men aged 50-69 in general practices to have a prostate check and consider having a PSA test, with recruitment to a trial of treatment if they had localised prostate cancer. This feasibility study was successful, so the main NIHR-funded ProtecT trial of monitoring, surgery, or radiotherapy for prostate cancer began recruitment in nine UK centres from May 2001.
At this point, the NIHR HTA Programme supported a feasibility study of creating an over-arching screening trial to provide a way of recruiting men to ProtecT. In 2003, Cancer Research UK agreed to support the CAP trial. CAP published median 10-year outcomes in the Journal of the American Medical Association this week.
In total, 415,582 men aged 50-69 years in 573 general practices in the UK were involved in the CAP trial. In the intervention group, men were invited to screening with a one-off PSA test to see if they had prostate cancer, with a view to then taking part in the ProtecT treatment trial comparing surgery, radiotherapy and active monitoring if they were diagnosed with clinically localised disease.
In the control group, practices provided standard NHS management, with information about PSA testing provided only to those who requested it. Data were collected for all participants on deaths, cancer registrations, and prostate cancer stage and grade at diagnosis.
The main finding of the CAP screening trial was that after a median of 10 years’ follow up, while the number of cases of prostate cancer was higher in men who underwent screening than in the control group, screening had no effect on prostate cancer-specific or all-cause mortality.
Meanwhile in the ProtecT treatment trial, published in the New England Journal of Medicine in 2016, prostate cancer mortality was extremely low at around 1% at a median of 10 years. There was no difference in mortality between the groups allocated to surgery, radiotherapy or active monitoring. However, men who underwent radical treatments were half as likely to develop metastases or local disease progression compared with men who underwent active monitoring (2-3% versus 6%). And, for the first time, ProtecT showed that surgery and radiotherapy were equally effective at treating localised prostate cancer.
ProtecT also showed the impact of each of the treatment options on quality of life: urinary incontinence and erectile dysfunction were highest in the surgery group, and erectile dysfunction and bowel problems were found in the radiotherapy group. Although these adverse effects were much less common in the active monitoring group initially, they increased gradually over time as men aged and received radical treatments (by 10 years 50% had undergone radical treatment).
The goal of the CAP trial, with its low-intensity one-off PSA testing, was to try to avoid unnecessary detection of low-risk cancers while still identifying men with dangerous disease for whom screening and early treatment could be beneficial.
A previous trial, the European Randomised Study of Screening for Prostate Cancer (ERSPC), had shown a 20% reduction in mortality after 13 years with repeated PSA testing, but with unacceptable levels of over-detection and over-treatment. However, the larger CAP trial found that after an average of 10-years of follow-up, a single PSA test still detected too many low-risk prostate cancers. Although the study did detect some dangerous cancers that could benefit from treatment, the approach of one-off PSA testing and TRUS biopsy missed a number of lethal cancers.
The ProtecT trial showed that radical treatments were effective in reducing cancer spread, but each treatment carried a particular burden of adverse effects. Longer follow-up is needed to see if a difference in mortality develops in ProtecT or CAP after 15 or 20 years, and to assess the longer-term impact of treatments.
It is now clear that screening the whole population of men for prostate cancer using the PSA test is too blunt an approach. There is a need for new tests to determine the risk of aggressive disease, perhaps using genetic information, and a new diagnostic pathway that includes imaging in the form of multiparametric MRI. Another study funded by the NIHR HTA Programme, the Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS) study, has shown that multiparametric MRI may be a useful tool to identify and target visible cancers and perhaps reduce over-detection of low-risk disease.
The outcomes of the CAP and ProtecT trials provide a great deal of information to facilitate individual decision-making and to guide policy and further research. Men with localised prostate cancer do not need to rush to decide their management strategy but can now weigh up the risks and benefits of each of the treatments in the context of their lives and wishes. The findings should also spur us on to strengthen our efforts to find better tests and methods to detect aggressive prostate cancer as early as possible, in order to give the right treatment to the right patient at the right time.
Jenny Donovan
Professor of Social Medicine, University of Bristol
Director of the NIHR Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West)
NIHR Senior Investigator
Freddie Hamdy
Professor of Surgery, University of Oxford
NIHR Oxford Biomedical Research Centre, Surgical Innovation and Evaluation Theme and the Cancer Research UK Oxford Centre
NIHR Senior Investigator
Richard Martin
Professor of Clinical Epidemiology, University of Bristol
NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
David Neal
Professor of Surgical Oncology, University of Oxford
NIHR Senior Investigator