SEARCH

SEARCH BY CITATION

Abbreviations
WW

watchful waiting

AS

active surveillance

RP

radical prostatectomy

PCA3

prostate cancer antigen 3

PSAV

PSA velocity

PSADT

PSA doubling time

PSAD

PSA density

START

Standard Treatment Against Restricted Treatment.

INTRODUCTION

  1. Top of page
  2. INTRODUCTION
  3. ACTIVE SURVEILLANCE (AS)
  4. ADVANTAGES OF AS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

Almost 32 000 men are diagnosed with prostate cancer every year in the UK, yet only 10 000 die because of it. The vast increase in diagnosis and radical treatments in recent years has not been followed by a significant change in mortality, indicating that clinicians are over-detecting and over-treating insignificant disease, while making little impact on fatal disease. PSA screening will increase these problems, with the (anticipated) benefit of improved disease-specific survival.

It is accepted that men with truly low-grade (Gleason score 2–4) localized prostate cancer are at little risk of death from their cancer in the long term, and can be managed by watchful waiting (WW) [1] rather than with radical treatment [2]. However, low-grade disease has become rare, as pathologists rarely assign a Gleason score of <6 to needle biopsies.

ACTIVE SURVEILLANCE (AS)

  1. Top of page
  2. INTRODUCTION
  3. ACTIVE SURVEILLANCE (AS)
  4. ADVANTAGES OF AS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

AS differs from WW, as the intention remains curative for those patients who might need it, while it is hoped that most will safely avoid the morbidity of treatment. WW aims only to palliate; Table 1 compares and contrasts WW with AS.

Table 1.  A comparison of WW with AS
 WWAS
No initial treatment;YesYes
No treatment morbidity
Ideal patient with localized diseaseUnsuitable for curative treatment: elderly, unfitSuitable for curative treatment: younger, fit
Treatment IntentionPalliativeCurative
Typical follow-up protocol6-monthly clinical/PSA; bone scans, etc. as required3-monthly PSA, with kinetics, 6-monthly clinical review
Repeat prostate biopsy?NoYes, every 1–2 years and if indicated

The categorization of the risk of localized prostate cancer was introduced by D'Amico et al.[3] on the basis of an extensive review of published outcomes of radical surgery and radiotherapy. ‘Low-risk’ tumours were associated with a <25% 5-year risk of PSA failure and comprised patients with T1–2a disease, a PSA level of <10 ng/mL and biopsy Gleason score of ≤6. It is important to appreciate that little is known about the risk of these patients' disease without treatment.

There are currently no randomized data to inform decisions about the best management for low-risk disease between radical prostatectomy (RP), radiotherapy or AS with delayed intervention on progression. The Swedish randomized trial of RP vs WW showed a 5.8% overall survival benefit for surgery in men with clinically detected disease (of whom ≥60% were Gleason score ≤6) at a median follow-up of 8.2 years [4]. Therefore, WW cannot be the appropriate management for all men with localized prostate cancer. However, it is estimated that the long-term overall survival benefit for radical treatment, compared with conservative management, of men with screen-detected Gleason score ≤6 disease, is only 1–2%[5].

While AS is gaining popularity in the UK, Europe and some centres in the USA, there are relatively few published studies. Table 2[6–10] shows five studies, all relatively small and immature, non-randomized, lacking standardized inclusion criteria and follow-up, and with no consensus on triggers for intervention triggers. Nevertheless, within these limitations, most (60–85%) patients avoid intervention, and deaths from prostate cancer are rare.

Table 2.  The inclusion criteria, follow-up protocols, intervention triggers and outcomes of five published studies of AS
Variable[6][7][8][9][10]
  1. GS, Gleason score.

N patients29940799326270
InclusionAge < 70: GS ≥6, PSA < 10; age > 70: GS ≤7, PSA < 15Age 45–81 T1c;PSAD ≤0.15 favourable biopsy featuresStage ≤T2GS ≤6, <50% in 2 biopsies PSA < 15Stage ≤T2GS ≤6, PSA < 15 <half biopsies positiveScreened age 50–70PSA 3–27.8 total cancer length <2 mm comorbidity
Follow-up protocol/ evaluations3-monthlyPSA/DRE; biopsy 1 year then 3–5 years to age 806-monthlyPSA/DRE annual biopsy3-monthlyPSA/DRE for 2 years; biopsy 6–12 months, then as indicated3-monthlyPSA/DRE for 2 years; biopsy 18–24 months6-monthly PSA/DRE for 2 years, then annual no routine re-biopsy only progression
Median follow-up, years5.33.4 (0.4–12.5)3.8 (1–14)1.85.25
Intervention triggersPatient choice; PSADT <3/year; clinical or biopsy GS progressionPatient choice; unfavourable biopsy features Not PSA changePatient choice; unfavourable biopsy features PSA changePatient choice; unfavourable biopsy features PSADT <4/year; PSAV >1 ng/mLPatient choice PSA, T stage or grade progression
N (%) on AS198 (66)239 (59)85 (85)238 (73)156 (58) (78% aged 65–70)
N (%) delayed intervention101 (34)103 (25) 8 (8) 65 (20)104 (39) – 10% of these palliative
Cancer deaths 3 (1%) 0 0 0 0

ADVANTAGES OF AS

  1. Top of page
  2. INTRODUCTION
  3. ACTIVE SURVEILLANCE (AS)
  4. ADVANTAGES OF AS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

AS is a coping strategy for over-detection of pathologically insignificant disease, defined as organ-confined cancer of <0.5 mL and with no Gleason pattern 4 or 5. The prevalence increases from 20% in the clinical setting to 49% in screened men [11,12]. AS reduces over-treatment of non-aggressive disease; while the Swedish randomized study [4] showed significant overall and disease-specific survival advantages for RP over WW, the number needed to treat was 17 to prevent one death from prostate cancer [6]. AS maintains the quality of life by avoiding or delaying treatment-related morbidity, especially urinary and bowel toxicity, and erectile dysfunction. It might also reduce healthcare spending, although there are no published data on this topic. However, the AS evidence-base raises some important questions.

CAN MEN WITH INSIGNIFICANT DISEASE BE ACCURATELY AND SAFELY SELECTED?

Nomograms incorporating pretreatment variables (Fig. 1) have been developed to predict the chance that an individual's cancer is pathologically insignificant [11]. It is conceded that the tool rarely predicts with very high probability, and was insufficient by itself to direct an individual towards observation; it would be more useful to ‘rule out’ rather than ‘rule in’ insignificant disease. Nomograms have recently been validated and updated using a relatively small (247 men) screen-detected population undergoing RP [12]. Depending on the threshold percentage probability of insignificance chosen, for which there is no consensus, it is claimed AS can be offered with a <15% risk of including potentially aggressive cancers [13].

image

Figure 1. A nomogram predicting the risk of insignificant disease at RP. From [11].

Download figure to PowerPoint

As well as the potential shortcomings of nomograms, studies of RP specimens in men diagnosed with just one microscopic focus of cancer report significant disease (pT3 or Gleason score >7, or tumour >0.5 mL) in 33–70% of RP specimens [14–16].

In a study of 96 men undergoing RP, multivariate analysis of preoperative variables showed that the urinary biomarker prostate cancer antigen 3 (PCA3) mRNA score was the best predictor of total cancer volume, and could discriminate low (<0.5 mL) cancer volumes well [17]. There remains uncertainty about the reliable and safe selection of men with ‘insignificant’ disease, which cannot be assumed for all with low-risk disease.

DOES DELAYING TREATMENT REDUCE THE CHANCE OF CURE?

A small study compared the outcomes of 38 men with small low-grade prostate cancers who had RP after a period of AS (median 26.5 months) with 150 similar patients who had immediate RP. By a local definition of incurable disease, delayed prostate cancer surgery did not appear to compromise curability [18]. However, the Toronto AS study reported on 24 patients who had delayed RP, of whom 14 (58%) had pT3a-c and two (8%) had N1 disease. Klotz commented: ‘For a group of patients with favourable clinical characteristics, this is a high rate of locally advanced disease’[6]. Further studies reporting pathological and long-term outcomes after delayed RP will be of interest, as the answer to this question remains uncertain.

CAN PROGRESSION BE PREDICTED IN PATIENTS ON AS?

Apart from the DRE and frequent PSA evaluations, most of the published study protocols use PSA kinetics or density. Biopsy features, e.g. the number of positive cores, core cancer length and other biomarkers in biopsy material (e.g. p53, DNA arrays) and urine (e.g. PCA3, TMPRSS2-ETS gene fusions) are also under investigation.

PSA kinetics

PSA velocity (PSAV): whilst a PSAV of >2 ng/mL in the year before RP is associated with a greater risk of treatment failure and shorter survival [19], it is often unknown at diagnosis and the optimum threshold triggering intervention during AS is uncertain.

PSA doubling time (PSADT): The Toronto AS series reported a median PSADT of 7.0 years, with a wide range (42% >10 years; 20% >100 years; 20% <3 years) [6]. Thresholds for recommending active treatment vary, with < 3 or <4 years being suggested. In the study of Swedish screen-detected disease a PSADT of <2 years was associated with frequent relapse (seven of nine men) after delayed treatment in 70 patients, whereas >4 years carried no risk of relapse at a mean follow-up of 37 months [10].

PSA density (PSAD): calculated as the PSA level/TRUS-derived prostate volume. Diagnostically, a PSAD of >0.15 is associated with a greater risk of cancer diagnosis [20] and correlates with prostate cancer aggressiveness. It can be calculated easily at the time of diagnosis. In a study of 54 patients with microfocal prostate cancer undergoing RP, a PSAD of <0.15 predicted insignificant disease at RP in 83%[14]. During AS, a PSAD at initial biopsy of >0.9 predicts a more rapid PSAV during the follow-up, which might help to inform decision-making [21]. At present there is no consensus that can confidently be used to predict progression in patients on AS, before it is ‘too late’.

HOW DO PATIENTS TOLERATE AS PSYCHOLOGICALLY?

In a self-administered questionnaire study of 2365 men with clinically localized disease in the USA Surveillance, Epidemiology and End Results registries from mid-1990s, those receiving active treatment were significantly more satisfied than those receiving no treatment (230 men) [22]. In that study it is likely that ‘no treatment’ was WW rather than AS. A non-randomized study of 329 men showed no difference in the Hospital Anxiety and Depression scale scores between patients on AS (100 men) and those receiving or having received radiotherapy [23]. Psychosocial barriers to AS might be alleviated by good communication, education, empowerment and peer-support [24]. Further investigation into this aspect of AS is required before conclusions can be drawn.

The 2008 UK National Institute for Clinical Excellence Guidance [25] recommendation, that AS is the ‘preferred’ option for men with low-risk disease, has been criticised for its lack of consensus and evaluation [26]. Little evidence shows superiority of one treatment option over another on the basis of disease-risk status. So can clinicians recommend AS to, e.g. a 55-year-old man with a PSA level of 8.5 ng/mL and cT2a Gleason 3 + 3 = 6 cancer in six cores, after explaining there is up to a 25% chance that immediate treatment will not cure him?

Three randomized trials are in progress, but only the Canada-based Standard Treatment Against Restricted Treatment (START) trial rigorously tests AS vs immediate radical treatment in a phase III randomized setting [6,27]. START aims to recruit >2000 men to compare disease-specific survival, overall survival and quality of life, completing in 2023. The US PIVOT [28] and UK ProtecT [29] trials contain observation arms, but do not set out to treat all patients with curative intent.

CONCLUSIONS

  1. Top of page
  2. INTRODUCTION
  3. ACTIVE SURVEILLANCE (AS)
  4. ADVANTAGES OF AS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES

With all its advantages, AS appears to be safe for most men with low-risk localized prostate cancer, and is a management option, but on the available evidence it cannot yet be heralded as the ‘preferred’ treatment for everyone in this category. Patients should be informed of the present uncertainties and offered all options. Careful selection and follow-up is important to minimize risk of disease progression during surveillance. Consensus over early predictors of significant disease or progression will facilitate decision-making and minimize the risk of harm. AS will probably become more prevalent in the future if population-based screening programmes are developed. Finally, randomized trials are awaited to confirm that AS with delayed intervention is as oncologically safe as immediate treatment.

REFERENCES

  1. Top of page
  2. INTRODUCTION
  3. ACTIVE SURVEILLANCE (AS)
  4. ADVANTAGES OF AS
  5. CONCLUSIONS
  6. CONFLICT OF INTEREST
  7. REFERENCES