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Randomized Controlled Trial
. 2020 Aug;24(37):1-176.
doi: 10.3310/hta24370.

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT

Freddie C Hamdy  1 , Jenny L Donovan  2 , J Athene Lane  2 , Malcolm Mason  3 , Chris Metcalfe  2 , Peter Holding  1 , Julia Wade  2 , Sian Noble  2 , Kirsty Garfield  2 , Grace Young  2 , Michael Davis  2 , Tim J Peters  2 , Emma L Turner  2 , Richard M Martin  2 , Jon Oxley  4 , Mary Robinson  5 , John Staffurth  6 , Eleanor Walsh  2 , Jane Blazeby  2 , Richard Bryant  1 , Prasad Bollina  7 , James Catto  8 , Andrew Doble  9 , Alan Doherty  10 , David Gillatt  11 , Vincent Gnanapragasam  9 , Owen Hughes  12 , Roger Kockelbergh  13 , Howard Kynaston  12 , Alan Paul  14 , Edgar Paez  15 , Philip Powell  15 , Stephen Prescott  14 , Derek Rosario  8 , Edward Rowe  11 , David Neal  1   16
Affiliations
Randomized Controlled Trial

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT

Freddie C Hamdy et al. Health Technol Assess. 2020 Aug.

Abstract

Background: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments.

Objectives: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years.

Design: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up.

Setting: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK.

Participants: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment.

Interventions: The interventions were active monitoring, radical prostatectomy and radical radiotherapy.

Trial primary outcome measure: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants.

Secondary outcome measures: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes.

Results: There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy).

Limitations: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed.

Conclusions: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years.

Trial registration: Current Controlled Trials ISRCTN20141297.

Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.

Keywords: ACTIVE MONITORING; PROSTATE CANCER; PROSTATE-SPECIFIC ANTIGEN TESTING; QUALITY OF LIFE; RADICAL PROSTATECTOMY; RADICAL RADIOTHERAPY; RADICAL TREATMENT; RANDOMISED CLINICAL TRIAL.

Plain language summary

Prostate cancer is the most common cancer in men and is often found through a blood test called a prostate-specific antigen test and through biopsies of the prostate. Over the years, these tests led to the detection of many small cancers that do not cause harm. Some prostate cancers are harmful, but it is difficult to recognise them early. When cancer is still inside the prostate, the conventional treatments are surgery or radiotherapy, which carry side effects including leaking urine and difficulty getting an erection, so another option is repeat investigations at regular intervals (active monitoring), with treatments given if the cancer progresses. These options needed to be compared in a study called a ‘randomised trial’ in which men agree to be allocated to one of the three treatments. In the Prostate testing for cancer and Treatment (ProtecT) study, 200,000 men aged 50–69 years were invited to have a prostate-specific antigen test. Of the 82,849 men who agreed to be tested, 1643 of whom had prostate cancer that was still contained in the prostate agreed to be allocated to one of the three treatments. After an average of 10 years of follow-up, 99% of men were alive in each of the treatment groups. However, when compared with active monitoring, surgery and radiotherapy reduced the risk of disease spreading outside the prostate by half. Patients reported that urinary leakage and sexual function were worst with surgery, and sexual and bowel functions were affected by radiotherapy. Men on active monitoring had a gradual decline in their urinary and sexual function, particularly as around half of them later had surgery or radiotherapy. Radiotherapy was the treatment that seemed to be the best value for money. The findings from the Prostate testing for cancer and Treatment (ProtecT) study can help men make decisions about being tested and which treatment to have if they are found to have cancer within the prostate. We now need to find out the longer-term effects of these treatments on how long men live and their quality of life.

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Conflict of interest statement

Malcolm Mason reports personal fees from Sanofi (Paris, France), Bayer (Leverkusen, Germany) and Janssen Pharmaceutica (Beerse, Belgium) outside the submitted work. Derek Rosario reports grants from Bayer and personal fees from Ferring Pharmaceuticals (Saint-Prex, Switzerland) outside the submitted work. Jane Blazeby was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2009–2013), HTA NIHR Obesity (2010–2012), Commissioning Board for HTA Surgery Themed Call Board and the NIHR Clinical Trials Unit (CTU) Standing Advisory Committee (2015–2019). Jenny Donovan was a member of the following during the project: HTA Commissioning Board (2006–12), Rapid Trials and Add-on Studies Board (2012), NIHR Senior Investigator panel (2009–12) and NIHR Health Services and Delivery Research board (Deputy Chairperson) (2010–11). Freddie C Hamdy was a member of the following during the project: HTA Commissioning Board (2007–12) and HTA Surgery Themed Call Board (2012–13). J Athene Lane was a member of the following during the project: CTUs funded by NIHR (2017 to present). Chris Metcalfe was a member of the following during the project: CTUs funded by NIHR (2010 to present). Tim Peters was a member of the following during the project: HTA Medicines for Children Themed Call (2005–6) and NIHR CTU Standing Advisory Committee (2008–14). John Staffurth reports support for travel to conferences and attendance on an advisory board from Bayer. Emma L Turner reports grants from Cancer Research UK (London, UK) during the conduct of the study.

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