NIHR Signal Large ten-year trial on treatment of localised prostate cancer will aid management decisions
Published on 15 September 2016
New, long-term research indicates that active monitoring, with prompt treatment if needed, may be a better option than radical surgery or radiotherapy for many men who have prostate cancer if it’s confined to the prostate gland. In the ProtecT trial, after an average of ten years, few men died of prostate cancer and there was no difference in survival between men receiving active monitoring and those who had radical treatments (which caused unpleasant side effects). But active monitoring did increase the risk of cancer progressing or spreading to other parts of the body. Longer follow-up will help to fully understand the balance between treatments.
Surgery caused incontinence and sexual function problems in some men, which were worse in the first year. Radiotherapy caused more bowel problems, and problems with sexual function and bladder emptying, also worse for the first year.
This NIHR-funded study provides information about the effects of the different treatments for men and their families, as well as clinicians, when deciding whether to have a prostate specific antigen (PSA) test or what treatment to have if localised prostate cancer is diagnosed.
- Cancers, Surgery
Why was this study needed?
Prostate cancer is the most common cancer in men, being diagnosed in over 47,000 individuals in the UK every year. It mainly affects men over 50, and risk increases with age. It can be detected by a blood test for PSA. The trouble with PSA is that it can also be raised in non-cancerous conditions and cancer can be present at low PSA levels. This is one of the reasons why screening using the PSA test has not yet been introduced, alongside the fact that many localised cancers (confined to the prostate) may not require detection or treatment.
Management of localised prostate cancer is controversial because it’s difficult to predict which cancers will behave aggressively. Most will be slow-growing and unlikely to cause many symptoms or affect life-expectancy. Therefore, radical treatments such as surgery or radiotherapy which can have significant side effects may not be necessary, but adopting a “wait and see” policy risks cancer spreading, and so possibly reducing the likelihood of cure.
Currently, these decisions are based on a combination of the level of PSA in the blood, degree of prostate cell abnormality on biopsy (Gleason score) and individual factors such as general health. Higher Gleason scores are associated with more aggressive cancer.
Previous trials such as the Scandinavian SPCG-4 trial and US PIVOT trial had compared the outcomes of surgery with ‘watchful waiting’ or observation. Unlike ProtecT, they did not include radiotherapy or modern forms of active monitoring or surveillance which involves more frequent checks of the cancer. Active monitoring in ProtecT aimed to avoid unnecessary treatment without increasing the risk of cancer spread or progression.
What did this study do?
The UK ProtecT trial invited men aged 50 to 69 in general practices in and around nine cities across the UK to have a PSA test between 1999 and 2009. Of the 82,429 men who had the test, 11% were offered a biopsy as their PSA level was 3µg/L or more. Prostate cancer was diagnosed in 3% of those who had blood tests. The researchers recruited 1,643 of those men with localised prostate cancer to be randomly allocated to receive:
- Active monitoring – PSA level was checked every three months in the first year, and every six to 12 months thereafter. If the PSA level increased by more than 50%, a decision was made on whether to perform further tests and stay on active monitoring or commence surgery, radiotherapy or other treatments.
- Radical prostatectomy – surgery to remove the prostate gland. If cancer cells were left behind, or PSA rose above 0.2µg/L, radiotherapy was offered.
- Radiotherapy – directed at the prostate from outside the body, in tandem with hormone therapy to reduce the cancer (External Beam 3-D conformal).
During follow-up, each group was offered further curative or palliative treatments as required, including hormone therapy.
The men were, on average, aged 62 and mostly at low risk of progression. Around 77% had a Gleason score of 6, 20% were at intermediate risk with a Gleason score of 7 and 2% were at high risk of progression with a Gleason score of 8 to 10.
This was a well-constructed large randomised trial. Strengths of the study include the similarity of the groups at the start of the trial, full analysis of all participants and multicentre involvement. Further strengths include the contemporary radiotherapy and active monitoring treatments, integration of patient-reported outcome assessment of symptoms, quality of life, and long follow-up with high response rates. However, the length of follow-up also means that some treatments have changed over the course of the study. For example, surgical techniques have developed with laparoscopic and robotic approaches, and there are other radiotherapy options such as implanting radioactive seeds into the prostate. However, the three treatments in the trial remain the most commonly-used approaches approved by NICE.
It should be noted that some men in each intervention group did not receive the management that had been allocated to them within the first nine months of study participation. In the radiotherapy and surgery groups, some took up active monitoring initially, but by the end of follow up, most had received a radical intervention. In addition, while active monitoring was taken up by most initially allocated to it, one half had changed to a radical treatment by the end of follow up.
Men were recruited to the study from the general population and had to be fit enough to undergo radical treatment, so are likely to represent more health-conscious men undergoing such treatments.
What did it find?
Mortality and disease progression over a median of ten years follow-up
- There were fewer deaths from prostate cancer than expected, 1% in total with no difference between each group (8/545 active monitoring, 5/553 surgical group and 4/545 radiotherapy group).
- Death rate from other causes was the same in each group at 9%.
- Almost half the men in the active monitoring group (254/545) did not receive a radical treatment. A change to radical treatment occurred in 10% (56/545) within the first nine months of the study, 25% within three years and 53% by ten years.
- Metastases were uncommon, but twice as likely in the active monitoring group (33/545) compared to the surgical group (13/553) or radiotherapy group (16/545). To prevent metastases in one man, 27 men would need surgery and 33 men would need radiotherapy.
- More than twice as many men experienced cancer progression in the active monitoring group (112/545) compared to those allocated to surgery (46/553) or radiotherapy (46/545). However, this was difficult to compare between groups, as progression included a range of different definitions including local spread, increased PSA level, commencement of hormone therapy and metastases.
- The Gleason score, PSA level or clinical stage did not affect death rate, though there were low numbers of men at high risk.
Quality of life assessed over a six year follow-up period
- Surgery had the greatest negative impact on sexual function and urinary incontinence, particularly in the first year, and although there was some recovery, both remained worse than radiotherapy and active monitoring throughout follow up.
- Radiotherapy’s impact on sexual function was only a little less than surgery’s at six months, and bowel problems, bladder emptying and nocturia were worse in the radiotherapy group at six months. However most men recovered from these side-effects over the next two to three years, except for increasing blood in stools.
- Sexual and urinary functions were better in men receiving active monitoring initially, but declined gradually over time as radical treatments were taken up.
- Symptoms experienced by men bothered them, but overall quality of life, including anxiety and depression, were not affected.
What does current guidance say on this issue?
NICE guidance published in 2014 recommends active surveillance or radical treatments for men with localised prostate cancer at low to intermediate risk of progression. NICE recommends that active surveillance involves an MRI scan followed by PSA tests every three to four months for the first year and then a repeat biopsy, followed by PSA tests every three to six months for the next two years, then every six months. If there are concerns at any point, a further biopsy or MRI scan is recommended. Radical treatments are recommended for men with localised prostate cancer at high risk of progression. Options include radical prostatectomy, external radiotherapy with hormone therapy or brachytherapy (insertion of radioactive implants into the prostate). Newer treatments such as high intensity ultrasound or cryotherapy (use of extreme cold during surgery) are not recommended unless part of a clinical trial. Throughout, it is recommended that men are well-informed of their options, taking account of their preferences.
Public Health England, through the UK Prostate Cancer Risk Management Programme provides resources to help men and their clinicians weigh up the pros and cons of having a PSA test to screen for prostate cancer. The UK National Screening Committee does not currently recommend a screening program for men with no symptoms, though men aged 50 and over can have a PSA test if they wish.
What are the implications?
This major trial greatly strengthened the evidence base about short and medium term outcomes of active monitoring compared to radical surgery and radiotherapy treatments for localised prostate cancer, compared to what was previously known from earlier trials in Europe and the US.
ProtecT used a more intensive monitoring approach - active monitoring, rather than watchful waiting, and this was more inclusive, less selective and less invasive (without routine re-biopsy) than most current active surveillance programmes. Diagnosis and treatment options have developed in the two decades since the ProtecT trial was planned; this is inevitable, and while it limits the relevance of some of the findings, the three treatments compared remain the major ones recommended for use today.
The evidence from ProtecT will help men with prostate cancer and their clinicians make better decisions about treatment, not only concerning likelihood of cancer progression and treatment effectiveness but also weighing up the risk of troublesome symptoms and treatment side effects. It’s clear from this study that localised cancer is slow-growing and that men can, at least, safely take their time to consider whether to have radical treatment.
The results of this study will be taken into account by the National Screening Committee. Further details of this study are due to be published in the coming months.
Citation and Funding
Donovan J, Hamdy F, Lane JA, et al; ProtecT Study Group. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Eng J Med. 2016. [Epub ahead of print].
Hamdy F, Donovan J, Lane JA, et al; ProtecT Study Group. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Eng J Med. 2016. [Epub ahead of print].
The ProtecT trial is funded by the UK National Institute for Health Research Health Technology Assessment Programme (project numbers 96/20/06, 96/20/99), with the University of Oxford as sponsor.
Holmberg L, Bill-Axelson A, Steineck G, et al. Results from the Scandinavian Prostate Cancer Group Trial Number 4: a randomized controlled trial of radical prostatectomy versus watchful waiting. Journal of the National Cancer Institute. Monographs. 2012;2012(45):230-33.
Lane JA, Donovan JL, Davis M, et al. Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial. Lancet Oncol. 2014;15(10):1109-18.
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NICE. Prostate cancer: diagnosis and management. CG175. London: National Institute for Health and Care Excellence; 2014.
Public Health England. Prostate cancer risk management programme (PCRMP): benefits and risks of PSA testing. London: Public Health England; 2016.
Prostate Cancer UK. About prostate cancer. London: Prostate Cancer UK; 2016.
Schröder FH, Hugosson J, Roobol MJ, 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;384(9959):2027-35.
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ProtecT is extremely important when considering treatment for men with small prostate cancers, but it leaves some critical screening questions unanswered. While clinicians can now have a more informed discussion with their patients to help them reach a decision on treatment strategy, the study’s implications for UK screening policy are not straightforward. Despite an effect on the development of metastatic disease, further follow-up is required to reveal whether there is a mortality benefit from early definitive treatment, and whether overtreatment can be reduced. Results are also awaited from the CAP study, which directly addresses screening, and PROMIS is due to report on diagnostic strategies. It is to be hoped that, put together, these trials will allow us to confidently recommend a strategy that will reduce the burden of prostate cancer in the UK. The UKNSC is in close contact with the trialists in each of these studies and will discuss the findings and their significance as the results become available.
Professor Robert JC Steele, Independent Chair, UK National Screening Committee (UK NSC)
The world has awaited the results of the ProtecT Trial with huge anticipation and all those with an interest in finding the best way to treat men with localised prostate cancer can now examine the outcomes from their various perspectives. Conclusion of the trial is a testament to the desire and willingness of all those who collaborated in its delivery including the men who agreed to be randomised, the primary and secondary care clinicians caring for them, trial teams and the funders, all under the umbrella of the UK NHS. ProtecT is the first treatment trial set in the ‘PSA era’ to include the option of radiotherapy, which is the active treatment option chosen by about 50% of men undergoing treatment with curative intent in the UK.
The results show that the primary outcome, prostate cancer-related death, is too infrequent, at ten years, to judge any possible differences between the treatments. However, it is shown that the active surveillance strategy used in the trial is not a satisfactory way to prevent progression compared to prostatectomy or radiotherapy. This is of major importance as active surveillance is currently recommended as a suitable option for men with low risk disease, a group who comprised a relatively large proportion of the men participating in ProtecT.
The trial also provides robust data on the relative occurrence of the main harms of treatment particularly urinary incontinence and sexual dysfunction, both being common overall and more prevalent in men who underwent prostatectomy. This will add robust detail to information given to men who are deciding their preferred treatment option.
A number of factors including changing diagnostic criteria, improved imaging, improved treatment delivery and more rigorous active surveillance strategies mean that detection and management of men with localised prostate cancer has become more refined since ProtecT was started. However, the successful completion and results of ProtecT argue for more investment in such trials perhaps most urgently to define the role and optimum strategy of active surveillance.
Robert Pickard, Professor of Urology and Consultant Urologist, Newcastle upon Tyne
Prostate cancer can be divided into three groups, based on how far it has spread in the body.
Localised prostate cancer has not spread outside the prostate gland. Some tumours at this stage may have characteristics that suggest they may grow quickly, or they may remain small and localised. Symptoms are unlikely at this stage – difficulty urinating in men over 50 years old is commonly due to enlargement of the prostate gland that is unrelated to cancer.
Locally advanced prostate cancer has broken through the outer covering (capsule) of the prostate gland. There may not be symptoms at this stage.
Metastatic prostate cancer has spread to other parts of the body, most commonly lymph nodes or bones. Symptoms may include pain in the bones.
Gleason score is used to grade the cancer by looking at how abnormal the glands are within the prostate. The glands are graded from 1 to 5. Grades 1 and 2 are close to normality, whereas 3 to 5 are cancerous, with 5 being the most abnormal. The overall Gleason score is calculated from adding together the most common types of abnormal glands seen within the patient’s prostate. This then gives an idea of whether the cancer is of low (6), intermediate (7) or high (8 to 10) risk of spreading, but it is only a guide.
Watchful waiting and active monitoring are different approaches to monitoring localised prostate cancer, with the aim of avoiding invasive treatment until absolutely necessary.
Watchful waiting involves checks, usually at the GP’s surgery, and only having invasive treatment to control cancer rather than cure it. It is most suitable for people with other health problems, for whom surgery might be relatively risky.
Active monitoring involves more frequent blood tests with checks, and active surveillance involves repeat biopsies and imaging, usually at a hospital. The aim of these options is to avoid radical treatments but retain men in a ‘window of curability’ so that the aim when intervening would be to cure the cancer.