For men with biopsy-diagnosed prostate cancer, for which patients (based on diagnostic, clinical and other criteria) does active surveillance achieve equivalent or better outcomes in terms of length and quality of life than definitive treatment? (PICOi question 9)
For men with biopsy-diagnosed prostate cancer following an active surveillance protocol, which combination of monitoring tests, testing frequency and clinical or other criteria for intervention achieve the best outcomes in terms of length and quality of life? (PICO questioni 10)
Guidelines developed in partnership with
Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Clinical practice guidelines PSA Testing and Early Management of Test-Detected Prostate Cancer. Sydney: Cancer Council Australia. [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=122836, cited 2018 Jan 19]. Available from: https://wiki.cancer.org.au/australia/Guidelines:PSA_Testing/Active_surveillance.
National Health and Medical Research Council
In approving the guidelines (recommendations), NHMRC considers that they meet the NHMRC standard for clinical practice guidelines. This approval is valid for a period of five years. NHMRC is satisfied that the guidelines (recommendations) are systematically derived, based on the identification and synthesis of the best available scientific evidence, and developed for health professionals practising in an Australian health care setting.This publication reflects the views of the authors and not necessarily the views of the Australian Government.
Management options for low-risk biopsy-diagnosed prostate cancer include immediate definitive treatment and active surveillance. Developing an effective management approach therefore involves:
- determining the appropriate criteria for choosing active surveillance in preference to definitive treatment for men with biopsy-diagnosed prostate cancer
- identifying the optimal monitoring protocol for active surveillance, including criteria for intervention.
Conservative strategies for managing biopsy-diagnosed prostate cancer when cure is not the goal (watchful waiting) are discussed in Chapter 5 Watchful waiting.
Active surveillanceii entails close follow-up of patients diagnosed with low-risk prostate cancer. The objective is to avoid unnecessary treatment of men with indolent cancer and treat only those who show signs of disease progression, so as to avoid treatment-related effects that may reduce quality of life. Definitive treatment is offered at a time when disease progression is detected and cure is deemed possible.
The optimal protocol for active surveillance is uncertain. Monitoring usually involves prostate-specific antigen (PSA) testing, digital rectal examination (DRE), prostate biopsies, and, in specialised centres, consideration of multiparametric prostate magnetic resonance imaging (MRI). There is a lack of evidence about the optimal frequency of monitoring and the most appropriate triggers for intervention. Whilst many active surveillance protocols have been reported in the literature, these vary in their inclusion criteria and monitoring procedures. To date, these active surveillance protocols have not been validated in randomised controlled trials. More importantly, they have not been examined with respect to overall and/or prostate cancer-specific mortality rates.
Criteria for selecting active surveillance
No published randomised controlled trials were identified that compared immediate definitive treatment with active surveillance and met inclusion criteria. However, several relevant randomised controlled trials are currently underway (see Studies currently underway, below). The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Three cohort studies at high risk of bias reported mortality and quality-of-life outcomes in men who underwent either surveillance or immediate treatment. These studies demonstrated similar prostate cancer-specific survival rates for men with prostate cancer managed by active surveillance. In all but one study, men were aged greater than 50 years.
In a prospective cohort study in men aged 50–80 years with PSA ≤ 20 ng/mL, clinical stage T1c prostate cancer, 1–2 cores involved and Gleason score ≤ 6,iii no difference in prostate cancer-specific mortality rate was demonstrated between the immediate treatment and active surveillance groups after 2.8–4.8 years of follow-up. In a prostate cancer register cohort of men with PSA < 20 ng/mL, Gleason score ≤ 6, and T1–2 cancer, a slightly higher prostate cancer-specific mortality rate was observed after a median follow-up period of 8.2 years in those who underwent active surveillance than in those who received immediate treatment (0.9% versus 0.7%, p > 0.05). Prostate cancer-specific mortality rates were low, both overall (13.6%) and among those men aged ≥ 66 years with Gleason score ≤ 6, and clinical stage T1–2 tumours.
A systematic review of prognostic factors that may identify men most suitable for active surveillance was undertaken by the UK National Collaborating Centre for Cancer during the development of the 2014 clinical guideline for prostate cancer published by the National Institute for Health and Care Excellence (NICE). The NICE review included four analyses from three studies, all of which reported results with end points of cessation of active surveillance but did not report overall survival rates, prostate cancer-specific mortality rates or quality-of-life outcomes. Factors analysed included PSA velocity, PSA doubling time, PSA level at diagnosis, PSA density, free PSA to total PSA percentage (free-to-total PSA%), total cancer length at biopsy, tumour volume, Gleason score at diagnosis, clinical stage at diagnosis, and expression of the biomarker Ki67. The single study that measured PSA velocity reported that a PSA velocity greater than 1 ng/mL/year was predictive of progression (p < 0.001). Of the three studies that reported PSA doubling time, two found it to be a significant predictor of progression. One study found that a PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical progression after definitive treatment, compared with a doubling time of more than 3 years. Conflicting and inconsistent results were reported for all the other parameters.
Active surveillance protocols
Three cohort studies at high risk of bias were identified that compared immediate treatment with delayed treatment. These studies reported outcomes for different combinations of prognostic and outcome variables, but did not directly compare different active surveillance protocols. Findings were inconsistent between studies.
It was not possible to make evidence-based recommendations about specific protocols for active surveillance monitoring, or triggers for intervention (see Unresolved issues).
Evidence summary and recommendations
| Three cohort studies reported similar prostate cancer-specific survival rates for men aged 41–80 years with prostate cancer managed by active surveillance.
In men aged ≥ 66 years with early prostate cancer with PSA ≤ 20 ng/mL, clinical stage T1–2, and Gleason score ≤ 6,iii active surveillance was associated with a similarly low risk of death due to prostate cancer as immediate definitive treatment.
|III-2||, , , , , , |
|A systematic review of studies that followed men undergoing active surveillance found conflicting and inconsistent results for the effects of various baseline parameters including PSA velocity, PSA level at diagnosis, PSA density, free-to-total PSA%, PSA doubling time, total cancer length at biopsy, tumour volume, Gleason score at diagnosis, clinical stage at diagnosis, and Ki67 expression. However, PSA velocity > 1.0 ng/mL/year predicted progression from active surveillance to definitive treatment (p < 0.001) in one study.||II, III-3||, , , , |
|No studies were found that compared different active surveillance monitoring protocols.||N/A|
Offer active surveillance to men with prostate cancer if all the following criteria are met:
Consider offering active surveillance to men with prostate cancer if all the following criteria are met:
For men aged less than 60 years, consider offering active surveillance based on the above criteria, provided that the man understands that treatment in these circumstances may be delayed rather than avoided.
Consider offering definitive treatment for:
If the man strongly prefers active surveillance, offer repeat biopsy to ensure that disease classification is accurate.
Consider offering definitive treatment to men aged less than 60 years with either of the following:
If the man strongly prefers active surveillance, offer repeat biopsy.
For men with prostate cancer managed by an active surveillance protocol, offer monitoring with PSA measurements every 3 months, and a physical examination, including digital rectal examination, every 6 months.
Offer a reclassification repeat prostate biopsy within 6–12 months of starting an active surveillance protocol.
Offer repeat biopsies every 2–3 years, or earlier as needed to investigate suspected disease progression: offer repeat biopsy and/or multiparametric MRI (in specialised centres) if PSA doubling time is less than 2–3 years or clinical progression is detected on digital rectal examination.
During active surveillance, offer definitive treatment if pathological progression is detected on biopsy, or if the patient prefers to proceed to intervention.
Advise men with low-risk prostate cancer that, if they choose active surveillance, their risk of death due to prostate cancer over the next 10 years would be low, and would probably be no greater than if they were to choose immediate definitive treatment.
When considering active surveillance, take into account other factors that may be associated with risk of future pathological progression but for which evidence is inconsistent (e.g. total cancer length at biopsy, tumour volume, PSA doubling time < 3 years and PSA density).
In centres where staff have skills and experience in the use of multiparametric MRI for prostate examination, consider using it to help identify foci of potentially higher-grade disease, aid targeting at reclassification biopsies and aid determination of interval tumour growth. Clinicians and other staff performing multiparametric MRI should refer to appropriate standards and guidelines for its use (Moore CM et al 2013).
Health system implications
No changes to the way care is currently organised would be required for implementation of the recommendations about which men with early prostate cancer should be offered active surveillance. If this results in more men being offered active surveillance, increased capacity for follow-up clinics and PSA testing facilities may be required.
Implementation of the recommendations for monitoring protocols during active surveillance may result in an increase in biopsies.
The use of multiparametric MRI would be associated with additional costs.
Biopsies performed within monitoring protocols may be associated with indirect additional costs, including the cost of pathological examination, given that the recommendation for biopsy (see Chapter 3 Prostate biopsy and multiparametric MRI) requires a taking higher number of cores than is current practice for some urologists. However, biopsy-related costs may be offset if the monitoring protocol were to result in fewer biopsies.
Barriers to implementation
No barriers to the implementation of this recommendation are envisaged.
i Clinical questions were translated into the PICO framework: population, intervention, comparator and outcome (see 'Appendix 3'.)
ii Active surveillance involves PSA tests every 3 months, rectal examination every 6 months, biopsies from time to time, and (in specialised centres) multiparametric MRI. If the cancer shows signs of growing, the man can have surgery or radiotherapy. In general, men with low-risk prostate cancer who choose this option instead of immediate prostate cancer treatment do not have a higher risk of dying from prostate cancer within the next 10 years. For men younger than 60 years, choosing active surveillance might just delay surgery or radiotherapy rather than avoid it.
iii Gleason scores less than 6 are no longer reported for prostate cancer detected in core biopsy specimens. See the Prostate Cancer (core/needle biopsy) Structured Reporting Protocol (1st edition 2014), Royal College of Pathologists of Australasia.
- Holmström B, Holmberg E, Egevad L, Adolfsson J, Johansson JE, Hugosson J, et al. Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden Follow-Up Study. J Urol 2010 Oct;184(4):1322-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20723940.
- Kakehi Y, Kamoto T, Shiraishi T, Ogawa O, Suzukamo Y, Fukuhara S, et al. Prospective evaluation of selection criteria for active surveillance in Japanese patients with stage T1cN0M0 prostate cancer. Jpn J Clin Oncol 2008 Feb;38(2):122-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18272471.
- Sun M, Abdollah F, Hansen J, Trinh QD, Bianchi M, Tian Z, et al. Is a treatment delay in radical prostatectomy safe in individuals with low-risk prostate cancer? J Sex Med 2012 Nov;9(11):2961-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22672479.
- National Collaborating Centre for Cancer. Prostate cancer: diagnosis and treatment. London (UK): National Institute for Health and Care Excellence; 2014 Jan. Report No.: Clinical guideline; no. 175. Available from: http://www.nice.org.uk/guidance/cg175/chapter/the-guideline-development-group-national-collaborating-centre-and-nice-project-team.
- Selvadurai ED, Singhera M, Thomas K, Mohammed K, Woode-Amissah R, Horwich A, et al. Medium-term outcomes of active surveillance for localised prostate cancer. Eur Urol 2013 Dec;64(6):981-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23473579.
- Khatami A, Aus G, Damber JE, Lilja H, Lodding P, Hugosson J. PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: results from the European randomized study of screening for prostate cancer, Sweden section. Int J Cancer 2007 Jan 1;120(1):170-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17013897.
- Khatami A, Hugosson J, Wang W, Damber JE. Ki-67 in screen-detected, low-grade, low-stage prostate cancer, relation to prostate-specific antigen doubling time, Gleason score and prostate-specific antigen relapse after radical prostatectomy. Scand J Urol Nephrol 2009;43(1):12-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18949633.
- Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010 Jan 1;28(1):126-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19917860.