Clinical review: Prostate cancer

An overview of the diagnosis and management of prostate cancer, including classification of prostate cancer, the role of PSA testing and NICE guidance for management.

Coloured CT scan of an enlareged prostate (SPL)
Coloured CT scan of an enlareged prostate (SPL)

Section 1: Epidemiology and aetiology
Section 2: Making the diagnosis
Section 3: Managing the condition
Section 4: Prognosis
Section 5: Case study
Section 6: Evidence base


Section 1: Epidemiology and aetiology

In the UK, there are approximately 41,700 new diagnoses of prostate cancer per year.1 It is expected that one in eight men will receive the diagnosis in their lifetime1 and this is predicted to increase.

Aetiology
The aetiology of prostate cancer is not fully understood. It is thought to be multifactorial, comprising genetic and environmental triggers.

The risk of prostate cancer is closely associated with old age. Only 1% of diagnoses in 2011 were in patients under the age of 50.1

Patients of black African or Caribbean ethnic origin have a one in four lifetime incidence of prostate cancer.2 Those with a family history (more than one affected first-degree relative) carry up to 3.5 times the RR of developing the disease.3

Modifiable risk factors should not be overlooked in disease prevention and management. A recent meta-analysis demonstrated tobacco smoking as a significant risk factor for fatal prostate cancer4 and a recent systematic review demonstrated good evidence that being overweight or obese increases the risk of developing advanced prostate cancer. 5

Although a significant proportion of men over the age of 80 are thought to demonstrate histological evidence of prostate cancer, its high prevalence does not translate directly into disease mortality rates - there were 9,632 deaths from prostate cancer in 2010.1 The increasing disease burden therefore represents a growing challenge to the healthcare system, particularly with large numbers of long-term survivors of the condition.

Classification
Prostate cancer is classified as localised, locally advanced or metastatic.

At present, disease classification indicates condition-specific mortality rates and informs treatment principles. However, optimal management of the condition remains the subject of constant evaluation, as our understanding of its pathogenesis and treatment effectiveness improves.


Section 2: Making the diagnosis

The insidious nature of prostate cancer means many patients with early disease are asymptomatic.

Symptoms of locally advanced disease may be difficult to distinguish from those associated with BPH.

Lower urinary tract symptoms (LUTS), such as increased urinary frequency, nocturia, poor stream and terminal dribbling, predominate in these commonly coexisting conditions.

The role of PSA
Diagnosis may be incidental, with a high index of suspicion generated most typically from an elevated PSA measurement, or occasionally from unrelated imaging.

A PSA <3ng/mL in patients aged under 50, and <4ng/mL for men aged 60-69, is normal. In men over 70, the normal range is extended to 5ng/mL. A PSA <10ng/mL is commonly associated with BPH and/or chronic prostatic inflammation, with only 20% of men testing positive for cancer histologically. The likelihood of malignancy increases up to 50% in men with a PSA >10ng/mL.6

Screening
Screening asymptomatic men for prostate cancer remains controversial. A recent analysis of the European Randomized Study of Screening for Prostate Cancer trial demonstrated a significant reduction in prostate cancer mortality over a 13-year study period.

However, data suggest a screening population of 781 patients is required to make one new prostate cancer diagnosis and 27 new diagnoses are needed to avoid one death from prostate cancer.7

Occasionally, clinical features of prostate cancer may only become apparent with the direct or indirect development of metastatic disease.

This may relate to systemic features of malignancy, such as general malaise/weight loss, or the site of secondary cancer involvement, for example, bony pain or pathological fractures.

In the absence of UTI, all patients with LUTS should be offered a digital rectal and external genitalia examination and counselled about a PSA test.8 If abnormal, these patients should be referred for a urological specialist opinion.

Diagnosis
The definitive diagnosis of prostate cancer is made histologically through the use of targeted biopsies.

The gold standard is the transrectal ultrasound-guided (TRUS) biopsy. However, this is associated with significant risks of infection, bleeding, pain and occasionally, acute urinary retention.

An alternative biopsy technique is via the template-guided transperineal approach. This is not yet routine practice in the UK, but may be considered for patients with previously inconclusive/negative TRUS biopsies and elevated PSA results. The roles of both techniques are under evaluation.

Many urologists now recommend imaging with multi-parametric MRI (MP-MRI) of the prostate, prior to consideration of prostate biopsy. Recent data from a large UK based randomised controlled trial, the PROMIS study, has supported this approach. Use of MP-MRI in the study resulted in 27% of patients avoiding a biopsy who would previously have had this procedure. Furthermore, if TRUS-biopsies were carried out based on MP-MRI findings, up to 18% more clinically significant cancers could be detected compared to the standard pathway without imaging prior to biopsy. NICE are planning to re-examine the role of MRI in the prostate cancer diagnostic pathway as a consequence of these findings.9

The Gleason score is used to report the histological grading of prostate biopsies. The total score may range from six (non-aggressive disease) to 10 (highly aggressive). This grading system is used as an accurate predictor of disease progression in conjunction with PSA measurement and radiological staging (TNM).


Section 3: Managing the condition

The treatment of prostate cancer is guided by patient-centred and disease-specific recommendations from specialist prostate multidisciplinary team meetings.

Current NICE guidance for the management of localised and locally advanced prostate cancer relates to risk stratification (see table 1) and centres on the patient's suitability for radical treatment.

Table 1: Risk stratification, localised prostate cancer
Level of risk PSA Gleason score Clinical stage
Low <10ng/mL and ≤6 and T1-T2a
Intermediate 10-20ng/mL or 7 or T2b
High >20ng/mL or 8-10 or ≥T2c
*High-risk localised prostate cancer is also included in the definition of locally advanced prostate cancer

Source: Adapted from NICE CG175. Prostate cancer: diagnosis and treatment10

In low-risk patients with asymptomatic localised disease, management is divided into 'watchful waiting' or 'active surveillance'.

The former involves non-invasive annual monitoring of PSA, appropriate in elderly or comorbid patients, and the latter, additional image-guided prostatic biopsies to histologically stratify potentially evolving disease. The protocol for active sur- veillance is shown in table 2.

Table 2: Protocol for active surveillance
Timing Tests*
At enrolment in active surveillance Multiparametric MRI is not previously performed
Year one
  • Every three to four months, measure PSA **
  • Throughout active surveillance, monitor PSA kinetics ***
  • Every six to 12 months, digital rectal examination
  • At 12 months, prostate re-biopsy
Years two to four
  • Every three to six months, measure PSA **
  • Throughout active surveillance, monitor PSA kinetics ***
  • Every six to twelve months, digital rectal examination
Year five and every year thereafter until active surveillance ends
  • Every six months, measure PSA **
  • Throughout active surveillance, monitor PSA kinetics ***
  • Every 12 months, digital rectal examination

Notes

*If there is concern about clinical or PSA changes at any time during active surveillance, reassess with multiparametric MRI and/or re-biopsy
** May be carried out in primary care if there are agreed shared-care protocols and recall systems
*** May include PSA doubling time and velopcity
Source: Adapted from NICE CG175. Prostate cancer: diagnosis and treatment10

Intermediate and high-risk patients may also be offered active surveillance, but are additionally considered for curative radical treatments.

These therapeutic options include radical prostatectomy (open, laparoscopic or robot-assisted laparoscopic procedures), or radiotherapy (external beam or brachytherapy).

Prostate cancer growth is stimulated by androgens. This forms the basis for androgen deprivation therapy.

This may be in the form of bilateral orchidectomies or, more commonly in the UK, gonadotrophin-releasing hormone (GnRH) agonists, which defer disease progression and act as an adjunct to surgery and/or radiotherapy.

In recent years, GnRH antagonists have also become available, offering rapid onset of action without the risk of 'tumour flare' in the early stages of treatment that can be associated with the GnRH agonists.

Metastatic disease
Patients with metastatic prostate cancer are also offered long-term hormonal manipulation.

Ultimately, hormone resistance may ensue. If patients are considered fit enough, the next step would usually be consideration of docetaxel-based chemotherapy. However, recent data has shown a significant survival benefit from using docetaxel chemotherapy at a much earlier stage in men with metastatic disease – if given  alongside hormone therapy at the time of diagnosis of metastases, docetaxel improved median survival by 10 months over standard care, to 81 months.11

Further disease progression with chemotherapy is an indication for use of enzalutamide or abiraterone. This therapy is carried out under the specialist guidance of the multidisciplinary team.

Third-line treatment for refractory metastatic prostate cancer with steroids and targeted radiotherapy for bony metastases may be advocated under the guidance of the oncology and palliative care teams, for symptom control.

As with management strategies for other cancers, in treatment for patients with prostate cancer, sociodemographic factors influence patient decision-making and play an important part in determining patient and carer satisfaction with the management plan. The involvement of specialist nurses is integral to ensure continuity of care and the patient's optimal mental and physical wellbeing throughout the process.


Section 4: Prognosis

Life expectancy data for prostate cancer are confounded by variables in evolving diagnostic and treatment modalities, comorbidities, age and stage of disease at diagnosis.

Lead-time bias, the interval between incidental disease detection and symptomatic presentation,12 adds further complexity.

Poorer prognosis is associated with younger age and tumour advancement. Age-standardised survival data (2005-2009) from Cancer Research UK and the Office for National Statistics indicate 93.5% and 81.4% of men in England with the disease will be alive for one and five years respectively from the time of diagnosis.

In spite of improvements in awareness and access to specialists, patients with metastatic prostate cancer at the time of diagnosis can expect relative survival rates of approximately 50% and 30% at three and five years.1


Section 5: Case study

Benjamin, a 65-year-old man, consulted his GP because he was troubled by a disrupted sleep pattern and its impact on daily living.

He had no past medical or family history of note. Further questioning revealed he was waking up to four times at night to pass urine.

His urinalysis was negative for infection or glycosuria and the GP identified long-standing poor urinary stream and end-micturition dribbling.

Benjamin's systems review was unremarkable. A digital rectal examination revealed a moderately enlarged, smooth, non-tender prostate.

His PSA was 5.5ng/mL. He was started on tamsulosin. A repeat PSA six months later was 6.5ng/mL.

Benjamin was referred to the urology outpatient rapid access clinic. He underwent a digital rectal examination, which was unchanged from previously. He was counselled for a TRUS biopsy, which was performed after an outpatient pelvic MRI.

His MRI scan demonstrated a small equivocal region in the central sulcus.

Benjamin's TRUS biopsy revealed a Gleason score of 3+3 in three cores. He was commenced on active surveillance in line with the recommendation of the multidisciplinary team.

Three monthly PSA measurements were performed.

A repeat TRUS biopsy was carried out one year later (PSA 11.25ng/mL). His histology was upgraded to Gleason 3+4 in two cores.

Benjamin declined the offer of radical treatment in the form of surgery or radiotherapy and continued on active surveillance. His PSA continued to rise.

Two years later, Benjamin underwent a laparoscopic prostatectomy. Unfortunately, positive margins were noted at histology. He was then referred for adjuvant radiotherapy.

His PSA was monitored for biochemical signs of recurrence and he was also referred to the erectile dysfunction service for further treatment.

Discussion
Most men presenting with LUTS are concerned about the possibility of prostate cancer - as are their partners.

NICE recommends that men should be offered the choice to have a PSA test if they have LUTS suggestive of bladder outflow obstruction by benign prostatic enlargement, or an abnormal rectal examination, or if they are worried about prostate cancer. For most men with LUTS, therefore, it is important to discuss the pros and cons of PSA testing.

Active surveillance can be a good option for men with low-risk disease and may detect progression of the disease that suggests the need for radical treatment at a later date.


Section 6: Evidence base

Clinical trials

  • European Randomized Study of Screening for Prostate Cancer (ERSPC) www.erspc.org

A long-term study of the effect of prostate cancer screening, looking at potential life-years gained.

There was no significant reduction in all cause/prostate cancer mortality in radical prostatectomy patients compared with observation.

Enzalutamide, an androgen receptor blocker, was shown to significantly reduce radiological disease progression and time to chemotherapy within this cohort.

Guidelines

This is an updated version of an article that was first published in November 2014. The article was updated by Dr Jonathan Rees, GP with an interest in urology and men’s health. The original article was written by Dr Rees and Ms Clarissa Martyn-Hemphill, core surgical trainee year two in urology, Whipps Cross University Hospital, London

Take a test on this article and claim your certificate on MIMS Learning

References

  1. Office for National Statistics. Cancer Survival in England: Adults Diagnosed, 2008 to 2012, followed up to 2013. www.ons.gov.uk Cancer Research UK. CancerStats.
  2. Prostate Cancer UK. Prostate Cancer: Who is at risk? Available at: http://prostatecanceruk.org/information/who-is-at-risk#ethnicity2 (accessed 8 Mar 2017)
  3. Johns LE, Houlston RS. A systematic review and meta-analysis of familial prostate cancer risk. BJU Intl 2003; 91: 789-94
  4. Islami F, Moreira DM, Boffetta P et al. A systematic review and meta-analysis of tobacco use and prostate cancer mortality and incidence in prospective cohort studies. Eur Urol 2014; 66: 1054-64
  5. World Cancer Research Fund International. Continuous Update Project Report: Diet, Nutrition, Physical Activity and Prostate Cancer. 2014. Available at: www.wcrf.org (accessed 8 Mar 2017)
  6. British Association of Urological Surgeons. Raised PSA. Available at: www.baus.org.uk/patients/symptoms/prostate_cancer (accessed 8 Mar 2017)
  7. Schroder FH, Hugosson J, Roobol MJ et al; for ERSPC Investigators. The European Randomized Study of Screening for Prostate Cancer – Prostate Cancer Mortality at 13 Years of Follow-up. Lancet. 2014; 384(9959): 2027–2035.
  8. NICE. Lower urinary tract symptoms: The management of lower urinary tract symptoms in men. CG97. May 2010. www.nice.org.uk/guidance/cg97
  9. Ahmed HU, El-Shater Bosaily A, Brown LC et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389(10071): 815-822
  10. NICE. Prostate cancer: diagnosis and treatment. CG175. London, NICE, January 2014. www.nice.org.uk/guidance/cg175
  11. James ND, Sydes MR, Clarke NW et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016; 387(10024): 1163-77.
  12. National Cancer Intelligence Network. Prostate Cancer Survival. NCIN Briefing. Public Health England 2010. Available at: www.ncin.org.uk/publications/data_briefings/prostate_cancer_survival (accessed 8 Mar 2017)

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