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The emerging role of active surveillance for low-risk prostate cancer

Newly-diagnosed prostate cancer

Once a patient is diagnosed with prostate cancer (PCa), it is important to discuss the implications of all management options with him. Treatment of the condition may or may not be appropriate, depending on the stage and grade of the disease. NICE guidelines recommend that any patient who is being considered for treatment should be aware that it may result in:

  • Altered physical appearance.
  • Altered sexual experience.
  • Loss of sexual function, ejaculation and fertility.
  • Altered urinary and/or bowel function.
  • Other common side-effects or complications.
  • In addition, the patient should be offered:
  • Support in the decision-making process, with access to written material and a specialist nurse service.
  • Ongoing access to erectile dysfunction services, if necessary.
  • Ongoing access to specialist psychosexual services, if necessary.
  • A urological assessment if lower urinary tract symptoms are present.
  • The option of sperm storage (if appropriate).

Rationale for active surveillance

Traditionally, the majority of men with newly-diagnosed PCa underwent aggressive treatment in the form of radical radiotherapy or radical surgery, regardless of risk.

However, a greater understanding of the natural history of PCa has led to concerns regarding over-diagnosis and over-treatment in male patients with newly-diagnosed, low-risk PCa [Table 1]. Active surveillance (AS), as opposed to immediate, definitive therapy, has emerged as a potential option in the treatment of low-risk disease. It is not recommended for men with high-risk disease and all men who are being considered for AS should have a minimum of a 10-core prostate biopsy protocol. [Table 1]

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Table 1: Risk stratification system for prostate cancer based on NICE guidelines (2008)

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Table 2: Natural history of localised prostate cancer without treatmentBiopsy Gleasongrade% Risk of metastasis(10 years)% Risk of PCa death(15 years)Estimated

The aim of AS is to avoid treatment in male patients with indolent prostate cancer. However, the patient should be suitable for radical treatment in the form of radiotherapy or surgery if there is evidence of disease progression. Identification of low-risk disease can be difficult, as the presence of occult, higher-risk disease can be missed during the investigation process.

Therefore, patients on AS protocols require regular reassessment of their risk category.

It has been suggested that AS may prevent the need for radical intervention in up to 80 per cent of patients with newly-diagnosed PCa. Table 2 demonstrates the natural history of localised PCa in patients managed with no initial treatment.

Criteria for active surveillance

Globally, a number of institutions have varying criteria for enrolment into AS programmes. For example, the Royal Marsden Criteria include the following parameters, however other AS protocols may have more stringent entrance criteria:

  • Age: 50-to-80 years.
  • Fitness for radical treatment.
  • PSA level <15ng/ml.
  • Stage: T1-2a.
  • Gleason score ≤3+4.
  • Total positive cores ≤50 per cent.

A typical AS protocol involves performing a confirmatory repeat TRUS biopsy at approximately three-to-six months to confirm the risk category for the disease. The aim of an early confirmatory biopsy is to reduce the risk of under-sampling. Investigators from the Memorial Sloan-Kettering Cancer Centre have used a strategy of a confirmatory biopsy within three months in their AS cohort.

Twenty-seven per cent of male patients were identified with adverse pathological features on a 12-core confirmatory biopsy and this rendered them unsuitable for AS, based on their protocol. In addition, 26 per cent of men demonstrated negative histology on confirmatory biopsy.

These findings demonstrate that patients deciding whether to commit to an AS protocol should undergo a confirmatory biopsy to decrease the possibility that they may harbour occult, higher-risk disease.

After a confirmatory biopsy is performed, the Royal Marsden regimen involves a PSA blood test every month for the first year, every six months for the second year, and every six months thereafter.

A repeat TRUS biopsy is performed at 18-to-24 months and every two years thereafter. Imaging with MRI is only performed in the setting of disease progression. Indicators for disease progression and initiation of treatment include the following:

  • PSA doubling time <2 years.
  • Re-biopsy primary Gleason ≥4.
  • >50 per cent positive cores.

The role of imaging in active surveillance

The lack of adequate imaging modalities for early-stage PCa has been an important issue for AS. Most men with low-risk PCa have non-contributory ultrasound findings and serial transrectal ultrasonography has not proved beneficial in monitoring for disease progression.

Multiple investigators have evaluated magnetic resonance imaging (MRI) for PCa, as this imaging modality offers advantages over other imaging modalities, including enhanced delineation of pelvic anatomy, as well as the opportunity for functional assessment. Disadvantages with MRI include a significant burden on resources and cost-effectiveness issues.

MRI with spectroscopic imaging was performed at the time of cancer diagnosis on 114 men at the University of California, San Francisco, who were being considered for AS.

Seventy-five per cent of men had either concerning lesions or metabolic activity suggestive of cancer. When comparing visible anatomical lesions to spectroscopically-functional lesions only, the anatomical MRI was associated with biopsy progression and receipt of treatment. More recently, diffusion-weighted MRI techniques have been applied to prostate imaging and may improve tumour imaging over standard MRI in due course.

Long-term data on active surveillance

A potential disadvantage of AS is that long-term data remain relatively limited and are only beginning to be published. It is also arguable that a young male patient with a long life expectancy may miss the opportunity for curative treatment.

Importantly, it has been demonstrated that a delay of several months or even years from diagnosis to definitive therapy in men with low-risk PCa is very unlikely to have any unfavourable impact on morbidity or PCa mortality. This is not surprising, considering the favourable natural history of low-risk PCa with long lead times. However, in patients with high-risk or even intermediate-risk disease, a delay of 2.5-to-nine months might unfavourably affect long-term outcomes in terms of morbidity and mortality after radical treatment.

AS series are now beginning to mature and published data show that disease-specific mortality remains low, with moderate rates of intervention over the first few years. The original Canadian AS group from 2005 showed an overall survival of 85 per cent and disease-specific survival of 99 per cent at eight years of follow-up.

In total, 34 per cent of patients discontinued AS because of biochemical progression (15 per cent); clinical progression (3 per cent); histological progression (4 per cent); or patient preference.

These findings emphasise that decisions regarding the management of organ-confined PCa, including AS, should be made with an individualised approach after careful risk assessment. Male patients with newly-diagnosed PCa should be counselled on the need for long-term surveillance, as well as the definitions of progression that may lead to intervention.

The latest update from the longest series of patients on active surveillance was recently presented. Over a period of up to 20 years after PCa diagnosis, 993 men have been enrolled, with a median follow-up of 8.1 years. Within this group, 15 patients (1.5 per cent) have died from PCa, however death was 10 times more likely from another medical cause.

At five, 10, 15, and 20 years after diagnosis, 76 per cent, 64 per cent, 55 per cent and 55 per cent of patients, respectively, remain on AS. These results highlight that there are risks associated with AS and that difficulties remain in defining and diagnosing the exact cohort of patients who are good candidates for this type of management.

Notably, 95 per cent of patients in this study group have been managed appropriately and avoided all forms of complications that are related to early treatment.

Conclusion

Data on AS demonstrate that disease-specific mortality remains low, with moderate rates of intervention after diagnosing low-grade PCa. Decisions regarding management of localised PCa should be made with an individualised approach and after careful risk assessment.

Men with newly-diagnosed PCa should be counselled up-front on the need for long-term follow-up with AS, including the potential for invasive treatment over time. A confirmatory biopsy is necessary to limit the risk of under-grading for newly-diagnosed PCa.

References on request

Case study

A 56-year-old male is referred to the urology outpatient department with two elevated PSA levels that were taken six weeks apart. His first PSA measured 5.6ng/ml and his second PSA measured 5.8ng/ml. He does not complain of lower urinary tract symptoms and has no relevant past medical or surgical history. His family history is non-contributory and he is on no medications. His digital rectal exam reveals a 30g benign prostate.

He is counselled about the risks and benefits of proceeding to a transrectal ultrasound-guided prostate biopsy and has this investigation performed, after being appropriately consented. He returns to the outpatient department three weeks later for his biopsy results and is diagnosed with Gleason 3+3=6 prostate adenocarcinoma in 2/6 core biopsies from the left side of the prostate gland, with both positive samples occupying <5 per cent of the core volume. The six biopsies taken from the right side of the prostate were benign.

The patient reports that one of his work colleagues is on an active surveillance programme for prostate cancer and asks if this management strategy could also be suitable for him. He also asks about the risks and benefits of active surveillance programmes for prostate cancer.

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