To treat or not to treat: is the way forward clearer in low-risk prostate cancer?


  • Vincent J. Gnanapragasam

    1. Translational Prostate Cancer Group, Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
    2. Department of Urology, Addenbrookes Hospital, Cambridge, UK
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The recent Prostate Cancer Intervention Versus Observation Trial (PIVOT) has reported that for men with low-risk prostate cancer (LRPC) radical prostatectomy (RP) conveys no benefit compared with surveillance alone. These results add to the growing body of evidence that most men with low-risk disease will not benefit from active treatment; however, there are major issues to consider before there can be widespread adoption of active surveillance (AS). The present editorial considers the shortcomings in current methods of grading and staging prostate cancer and of being able to robustly assign risk. It also discusses the implications of widespread adoption of AS and the effects on resources and for health services. Finally, it highlights the urgent need for debate and consensus on defining the criteria and mechanism of an AS programme and the fact that these need to be determined before a radical change in management of low-risk disease is implemented.

The management of LRPC is an ongoing conundrum for clinicians and patients. Perhaps in no other context is there such a dilemma in consulting rooms when patients ask for advice, and clinicians can only quote papers and figures on the options available. The recent reporting of the PIVOT trial is another important piece of evidence which will no doubt be discussed in these consultations [1]. That study failed to reach its original recruitment target, and treatment crossover occurred in 12–20% of the cohorts. Despite this, at a median follow-up of 10 years, the study found that, compared with observation, RP did not confer any benefit in terms of prostate-cancer-specific or overall survival in men with LRPC (D'Amico risk criteria). These findings are not surprising. Data from long-term studies of the natural history of prostate cancer have previously shown good outcomes from conservative management of LRPC [2]. This is also supported by data on intermediate follow-up of AS which have shown good outcomes from a number of different series, albeit with different regimes [3]. Taken together, these different strands of evidence make a compelling case that LRPC can be safely managed by AS and without the risk of treatment-related side effects. Indeed this is one of the main recommendations from the authors of the PIVOT trial [1]. The findings are also likely to be equally applicable for other treatments currently used for LRPC, including external beam radiotherapy, brachytherapy and the range of focal therapies which are currently being evaluated. Notably, none of these have been compared with AS in a head-to-head randomized controlled trial; however, if RP cannot show a disease-specific or overall survival benefit in LRPC then it is very unlikely that these other therapies will do so.

There are, however, major caveats in considering widespread adoption of AS for LRPC in the UK and indeed in other health systems. Firstly, it is well recognized that many men with ostensibly low-risk disease at first presentation will be upgraded or upstaged at subsequent RP [4]. Data from early repeat biopsies in men on AS have also shown disease upgrading in over a third of men. This is particularly apparent when template biopsy approaches have been used and where higher-risk disease has been found in up to 40% of re-investigated men [5]. There is thus a significant potential to miss higher-risk disease in maintaining the current diagnostic method of an elevated PSA level, DRE and a single 10–12 core transrectal biopsy episode, which remains the current standard for grading and staging men with prostate cancer in most hospitals and is the basis on which treatment decisions are made. Prostate imaging is not mandatory for LRPC and many cancer networks do not include this as a requirement in their staging guidelines [6]. Recent improvements in MRI and functional MRI, however, have shown that they may be important tools for both improving initial staging as well as monitoring in AS programmes [7, 8]. There are therefore reasonable grounds to support the notion that men with LRPC should be first intensively re-assessed by rigorous initial repeat biopsies as well as good quality imaging before being counselled about AS in preference to other treatment options.

Secondly, there is a lack of consensus on what an AS regime should consist of. Whereas there are national and international guidelines on standards for surgery and radiotherapy for prostate cancer, these are conspicuously lacking for AS [3, 6]. The timing of PSA checks, repeat examinations, place and role of imaging, repeat biopsies and triggers for intervention vary considerably from centre to centre and even from clinician to clinician. Furthermore, AS requires well-structured, -resourced and -supported clinics for regular patient reviews which will be required for many years. Inconsistency in advice and overdue clinic reviews are a significant source of anxiety for many patients and indeed clinicians. Analyses of contemporary UK prostate cancers that present to referral clinics have shown that LRPC accounts for 20% of all cancers and up to 36% of men aged 50–69 years [9]. AS for all men with LRPC would therefore be a significant resource implication for any health service let alone an already overstretched NHS. A move to a wider implementation of AS will require a national consensus on a uniform protocol, on the resource and service requirements in setting this up and on the likely cost implications for what will be a long-term programme. This would provide much needed reassurance to clinicians and patients of the robustness of an AS programme alongside standard therapeutic options which offer the prospect of immediate ‘cure’. Notably, the PIVOT study did not report on the regime used in the observation cohort. Perhaps, if a standardized, validated and robust AS programme was available then recruitment to this and other treatment vs surveillance trials would have been much improved.

Finally, there remain no universally accepted inclusion criteria for AS. The definition of low-risk disease itself remains open to debate. The D'Amico criteria for instance do not consider the numbers of biopsy cores involved or percentage of core involvement. The UK National Institute for Health and Clinical Excellence (NICE) guidelines define men suitable for AS as having the following characteristics: clinical stage T1c; a Gleason score 3+3; a PSA density <0.15 ng/mL/mL; and cancer in <50% of their total number of biopsy cores with <10 mm of any core involved ( Yet other groups use different criteria in their cohorts [10]. There are also groups of patients for whom clinicians may be uncomfortable about recommending AS. These include men diagnosed at an early age and/or those with a strong family history. Indeed, in the PIVOT trial the inclusion criteria included men aged up to 75 years and the majority recruited were >65 years. Thus, the study findings are primarily based on an older population compared with most surgically treated cohorts. The outcome of AS for younger men and those at risk is therefore as yet unknown and early radical intervention may be more appropriate. Of paramount importance of course remains the patients own preference and choice of treatment.

The PIVOT trial has served to reinforce what many have already known, i.e. that the majority of men with LRPC are unlikely to benefit from active treatment. The critical question, however, is how to be as sure as possible (and reassure our patients) that we are dealing with truly low-risk disease. Furthermore, we must be sure that we have robust mechanisms in place, not only locally but nationally, to manage men on AS programmes for the long term. There is good evidence for best practice in these areas but the resource requirements are likely to be very significant and are not currently in place across the UK. These issues need urgent resolution and it is now timely for a national discussion and debate on achieving consensus and planning resources for AS as a mainstream therapeutic strategy. Thus, to answer the question posed, the way forward is clearer but the road appears to be still under construction.

Conflict of Interest

None declared.