Epidemiology¹

• The incidence of prostate cancer in Europe is 214 cases per 1,000 men. It is the most common solid tumour and now outnumbers lung and colorectal cancer.
• It is the second most common cause of cancer death in men (lung being the most common).
• There has been a global slight increase in deaths since 1985, even in countries in which prostate cancer is not common. There are however notable exceptions, including the UK, the USA and Austria. The reasons for this are not clear but may be related to increased awareness and earlier detection of disease.

Most prostate cancers are adenocarcinomas arising in the peripheral zone of the prostate gland.

Risk factors

• It is particularly common in older men. Two thirds of those who die from prostate cancer are aged over 75 years. When prostate cancer occurs in younger men it is often more aggressive. Relatively few men aged below 50 years are affected but these men have the highest mortality rate.²
• Race is an important risk factor with a higher incidence in North America and Europe, especially amongst black African or black Caribbean groups.³ China and Japan have low rates.
• Familial prostate cancer: risk increase 2-3 times if a first-degree relative is diagnosed at an early age. There is also an increased risk with a family history of breast cancer. Possible responsible genes have been localised to short arm of chromosome 1q and also on the X-chromosome. About 9% of all cases of prostate cancer have a genetic basis.
• Diet may also be important. Red meat and unsaturated fats increase risk while Vitamin E, selenium and lycopene (antioxidant found in tomatoes) appear to have a protective effect.
• Occupation: there is increased risk with farming and exposure to radiation or cadmium.
• Links to alcohol consumption, sexual behaviour and exposure to ultraviolet light have been investigated but further research is needed.

Screening

• There is currently no strong evidence from randomised controlled trials (RCTs) regarding the impact of screening on quality of life, harms of screening, or its economic value.^1,4 Early detection and treatment may prevent future cancer-related illness and extend life but prostate cancer screening can have false-positive and false-negative results and detects many cancers that would never cause symptoms.⁵
• Suggested methods of prostate cancer screening are digital rectal examination, prostate specific antigen (PSA) and transrectal ultrasonography.
• The most sensitive screening tests for prostate cancer are based on levels of PSA. However, the PSA test is not a specific test for prostate cancer. Only about 30% of men with a raised PSA level will have prostate cancer and the PSA may be normal in a patient who does have prostate cancer.
• Screening may lead to physical and psychological harm resulting from testing, biopsy and treatment. It is therefore not known whether screening for prostate cancer does more good than harm.⁶
• Wide publicity regarding PSA testing leads to many requests to have the test. It is very important to discuss the issues thoroughly and to support this with written information for patients.
• Men with a life expectancy of less than 10-15 years (due to advanced age or a serious coexisting condition) are unlikely to benefit from routine testing.⁵

Presentation

See related article Genitourinary History and Examination (Male).
Lower urinary symptoms, e.g. urinary frequency, hesitancy, nocturia and slow stream do not increase prostate cancer risk but are associated with higher prostate specific antigen (PSA) values.⁵

• Local disease:
  • Raised PSA on screening
  • Weak stream, hesitancy, sensation of incomplete emptying, urinary frequency, urgency, urge incontinence. The severity of urinary symptoms can be assessed with the International Prostate Symptom Score (IPSS)
  • Urinary tract infection
• Locally invasive disease:
  • Haematuria, dysuria, incontinence
  • Haematospermia
  • Perineal and suprapubic pain
  • Obstruction of ureters causing loin pain, anuria, symptoms of renal failure
  • Impotence
  • Rectal symptoms, e.g. tenesmus
• Metastatic disease:
  • Bone pain or sciatica
  • Paraplegia secondary to spinal cord compression
  • Lymph node enlargement
  • Loin pain or anuria due to ureteric obstruction by lymph nodes
  • Lethargy (anaemia, uraemia)
  • Weight loss, cachexia

Signs

• Advanced disease: general malaise, bone pain, anorexia, weight loss, obstructive nephropathy, paralysis due to cord compression.
• Abdominal palpation may demonstrate a palpable bladder due to outflow obstruction.
• Digital rectal examination may reveal a hard, irregular prostate gland. Indications of possible prostate cancer are:
  • Asymmetry of the gland
  • A nodule within one lobe
  • Induration of part or all of the prostate
  • Lack of mobility - adhesion to surrounding tissue
  • Palpable seminal vesicles

Differential diagnosis

• All other causes of haematuria (e.g. urinary tract infection) and urinary tract obstruction
• Benign prostatic hypertrophy
• Prostatitis
• Bladder tumours

Investigations¹

• The PSA Test is dealt with in the separate article Prostate Specific Antigen (PSA).
• Urinalysis to exclude renal and bladder pathology. Urine sent for microscopy, culture and sensitivities.
• Serum creatinine level to exclude renal disease.
• Transrectal ultrasound and biopsy: in men with a raised concentration of PSA, biopsy will miss 10% to 30% of clinically significant prostate cancers. It may be appropriate to repeat the biopsy if you have a high index of suspicion for cancer.⁷
• Uroflow measurement, measurement of postmicturition residual urine, cystoscopy and imaging of the upper urinary tract (if you suspect upper tract dilatation or bladder outlet obstruction).
• MRI, CT scan and a bone scan to stage the disease.

Staging

Prostate cancer is divided into:

• Non-metastatic prostate cancer: either clinically localised disease (confined to the prostate gland) or locally advanced disease (spread outside the capsule of the gland but has not spread to organs, other than the seminal vesicles).
• Metastatic disease: spread beyond the prostate to local, regional, or systemic lymph nodes, or to other body organs (such as bone, liver, or brain). Bone metastases are particularly common.

Tumour, node, metastases (TNM) staging for prostate cancer

• Primary tumour (T):
  • TX: primary tumour cannot be assessed
  • T0: no evidence of primary tumour
  • T1: clinically inapparent tumour neither palpable nor visible by imaging
  • T1a: tumour incidental histologic finding in 5% or less of tissue resected
  • T1b: tumour incidental histologic finding in more than 5% of tissue resected
  • T1c: tumour identified by needle biopsy (e.g. because of elevated prostate specific antigen (PSA))
  • T2: tumour confined within prostate
  • T2a: tumour involves 1 lobe
  • T2b: tumour involves both lobes
  • T3: tumour extends through the prostatic capsule
  • T3a: extracapsular extension (unilateral or bilateral)
  • T3b: tumour invades seminal vesicle(s)
  • T4: tumour is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles and/or pelvic wall
• Regional lymph nodes (N):
  • NX: regional lymph nodes cannot be assessed
  • N0: no regional lymph node metastasis
  • N1: metastasis in regional lymph node or nodes
• Distant metastasis (M); when more than 1 site of metastasis is present, the most advanced category (pM1c) is used:
  • MX: distant metastasis cannot be assessed
  • M0: no distant metastasis
  • M1: distant metastasis
  • M1a: non-regional lymph node(s)
  • M1b: bone(s)
  • M1c: other site(s)

Histological grading

• There are several systems for grading the histology. The most commonly used is the Gleason grading system. It estimates the grade of prostate cancer according to its differentiation. A score of two is the most well differentiated tumour and 10 is the most poorly differentiated. Higher scores are associated with a worse prognosis than lower scores.
  • Grade 1: small, uniform glands with minimal nuclear changes
  • Grade 2: medium-sized acinii, separated by stromal tissue but more closely arranged
  • Grade 3: marked variation in glandular size and organisation and infiltration of stromal and neighbouring tissues
  • Grade 4: marked atypical cytology with extensive infiltration
  • Grade 5: sheets of undifferentiated cells
• Prostate cancers are often heterogeneous and the Gleason score is the sum of the two most prominent grades.
• Combining PSA, clinical stage and Gleason score has been used to predict the pathological stage of localised prostate cancer.⁸
• The Gleason score has been used as the best prognostic indicator for prostate cancer but other molecular indicators are being evaluated.
  • Gleason score of 4 or less: well differentiated; ten-year risk of local progression 25%
  • Gleason score 5-7: moderately differentiated; ten-year risk of local progression 50%
  • Gleason score over 7: poorly differentiated; ten-year risk of local progression 75%

Risk stratification criteria for men with localised prostate cancer³

Several factors have been shown to predict the risk of recurrence after treatment of localised prostate cancer:

• Low risk: prostate specific antigen (PSA) <10 ng/ml and Gleason score 6 or below and clinical stage T1–T2a
• Intermediate risk: PSA 10–20 ng/ml, or Gleason score 7, or clinical stage T2b–T2c
• High risk: PSA >20 ng/ml, or Gleason score 8–10, or clinical stage T3–T4

Management^1,3

• Men and their partners should be made aware of the effects of prostate cancer and its treatment on their sexual function and appearance. They should be offered specialist erectile dysfunction services at an early stage.
• Urinary problems, including incontinence, may require bladder retraining, pelvic floor exercises, pharmacotherapy and construction of an artificial urinary sphincter.
• Palliative care services should be offered when needed and not reserved for the time of hospice care or at the end of life.

Localised prostate cancer

• Watchful waiting; if show evidence of disease progression, refer to urological cancer multidisciplinary team.
• Active surveillance: the preferred option for low-risk men who are candidates for radical treatment, especially for men with clinical stage T1c, Gleason score 3 + 3 and PSA density <0.15 ng/ml/ml who have cancer in less than 50% of their biopsy cores, with <10 mm of any core involved. PSA density is derived by dividing the PSA value by the volume of the prostate measured by trans-rectal ultrasound.
• If men on active surveillance show evidence of disease progression, offer radical treatment.
• Radical treatments: adjuvant hormonal therapy should be offered for a minimum of 2 years to men receiving radiotherapy who have a Gleason score of 8 or above.

Locally advanced prostate cancer

• Luteinising hormone-releasing hormone agonist (LHRHa) therapy before (=neoadjuvant) and during radiotherapy for 3–6 months.
• Adjuvant hormonal therapy for a minimum of 2 years to men receiving radiotherapy who have a Gleason score of 8 or above.
• Consider pelvic radiotherapy for men with >15% risk of pelvic lymph node involvement who are to receive neoadjuvant hormonal therapy and radiotherapy. The risk is estimated using the Roach formula: 2/3 PSA + (10 x (Gleason score – 6)).

Treatment options for non-metastatic disease

Treatment options for clinically localised prostate cancer include watchful waiting,³ radical prostatectomy (retropubic or perineal), external beam radiation therapy, brachytherapy, androgen deprivation therapy (drugs or surgical removal of testicles) and cryoablation.⁵

• Watchful waiting: if the tumour is small and well differentiated (Gleason score of 6 or lower), watchful waiting may be appropriate, especially for older patients with significant other diseases.
• Radical prostatectomy: radical surgery is appropriate for patients with extra-prostatic extension but no evidence of distant metastases. Drawbacks include erectile dysfunction (in up to 80% of men), incontinence (in up to 20% of men) and mortality rate is 0.2% to 1.2%. 40% have positive surgical margins.
• Radiotherapy using external beam radiation: usually the preferred option if there are distant metastases. Erectile dysfunction occurs in up to 60% of men, incontinence in up to 5% of men and long-term bowel problems (such as diarrhoea) occur in up to 10% of men.¹⁰
• Brachytherapy (transperineal implantation of radioactive seeds into the prostate). A decision to use this technique takes into account several prognostic factors, including Gleason score, PSA level and TNM classification . Low-dose rate brachytherapy may be used alone or in combination with external beam radiotherapy.
• Cryotherapy: cryotherapy can be used as a primary treatment for patients with localised or locally advanced prostate cancer.¹¹ Cryotherapy may also be used to treat locally recurrent carcinoma of the prostate that has been refractory to other treatments, such as radiotherapy or hormone therapy.¹²
• High-intensity focused ultrasound (HIFU) may be used to treat carcinoma of the prostate, either as a primary or salvage therapy.¹³
• There is evidence that for locally advanced disease, adding androgen suppression to standard treatments (radiation, prostatectomy) can prolong survival. Starting patients on androgen suppression early improves their survival compared with deferring treatment.¹⁴

Metastatic prostate cancer

• Patients with androgen-dependent metastatic disease are generally managed with androgen suppression, which can improve survival.
• Hormonal therapy is not routinely recommended for men with prostate cancer who have a biochemical relapse unless they have:³
  • Symptomatic local disease progression
  • Any proven metastases
  • A doubling of PSA within 3 months
• Treatment often involves monthly or three-monthly depot injections of LHRHa. Evidence supports starting treatment at the diagnosis rather than when symptoms develop.
• Bilateral orchidectomy as an alternative to continuous LHRHa therapy should be offered.
• Monotherapy with bicalutamide (150 mg) if the man hopes to retain sexual function and is willing to accept gynaecomastia and reduced survival.
• Androgen withdrawal (using luteinising hormone-releasing hormone agonists) in place of bicalutamide, if bicalutamide is not successful in retaining sexual function.
• Consider offering intermittent androgen withdrawal, providing the man is informed about the lack of long-term effectiveness evidence.

Hormone-refractory prostate cancer

• Treatment options include chemotherapy, external beam radiation therapy and radionuclides. All are proven to be valuable for palliation but there is no good evidence that they improve survival.³
• Palliative treatments are usually given for bone pain or anaemia. They include blood transfusions, corticosteroids, chemotherapy, local radiotherapy and radionuclides (e.g. strontium-89). Radionuclide therapy appears to be superior to radiotherapy for pain relief.
• Docetaxel should be offered only if the Karnofsky score is 60% or above.¹⁵ Stop treatment after 10 planned cycles or if severe adverse events occur or if the disease progresses (clinical, laboratory or imaging criteria). Do not repeat treatment cycles if disease recurs.¹⁶
• Corticosteroid (e.g. dexamethasone 0.5 mg daily) as a third-line therapy after androgen withdrawal and antiandrogen therapy.
• Spinal MRI if spinal metastases are found and spine-related symptoms develop.³
• Decompression of the urinary tract by percutaneous nephrostomy or insertion of a double J stent to men with obstructive uropathy.

Palliative care

See separate articles Palliative Care, Pain Control in Terminal Care, Helping Patients Face Death and Dying and Looking After People With Cancer.

Complications

• Urinary tract obstruction, renal failure
• Sexual dysfunction: erectile dysfunction, loss of libido
• Metastatic spread: bone pain, pathological fractures
• Complications of hormonal therapy:³
  • Hot flushes: synthetic progestogens are recommended as first-line therapy for troublesome hot flushes.
  • Gynaecomastia is a common, troublesome complication of long-term bicalutamide monotherapy: men starting long-term bicalutamide monotherapy (>6 months) should receive prophylactic radiotherapy to both breast buds within the first month of treatment.

Prognosis¹⁷

• Prognosis is related to the histology and stage of the malignancy.
• When the cancer is confined to the prostate gland, median survival is in excess of 5 years.
• Patients with locally advanced cancer are not usually curable. A substantial proportion of these patients will eventually die of prostate cancer, although median survival may be as long as 5 years.
• If prostate cancer has spread to distant organs, current therapy will not cure it and median survival is usually 1 to 3 years and most of these patients will die of prostate cancer. Even in this group of patients, however, survival for many years may be observed.

Document references

1. Guidelines on prostate cancer, European Association of Urology (2009)
2. Majeed A, Babb P, Jones J, et al; Trends in prostate cancer incidence, mortality and survival in England and Wales 1971-1998. BJU Int. 2000 Jun;85(9):1058-62. [abstract]
3. Prostate cancer, NICE Clinical Guideline (February 2008)
4. Ilic D, O'Connor D, Green S, et al; Screening for prostate cancer. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004720. [abstract]
5. Wilt TJ, Thompson IM; Clinically localised prostate cancer. BMJ. 2006 Nov 25;333(7578):1102-6.
6. Effectiveness Matters; Screening for Prostate Cancer. February 1997.
7. Djavan B, Remzi M, Schulman CC, et al; Repeat prostate biopsy: who, how and when?. a review. Eur Urol. 2002 Aug;42(2):93-103. [abstract]
8. Partin AW, Kattan MW, Subong EN, et al; Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA. 1997 May 14;277(18):1445-51. [abstract]
9. Referral for suspected cancer, NICE Clinical Guideline (2005)
10. Duchesne GM; Radiation for prostate cancer. Lancet Oncol. 2001 Feb;2(2):73-81. [abstract]
11. Cryotherapy as a primary treatment for prostate cancer, NICE Technology Appraisal (2005)
12. Cryotherapy for recurrent prostate cancer, NICE Technology Appraisal (2005)
13. High-intensity focused ultrasound for prostate cancer, NICE Technology Appraisal (2005)
14. Bolla M, Collette L, Blank L, et al; Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002 Jul 13;360(9327):103-6. [abstract]
15. Karnofsky Performance Scale Index
16. Docetaxel for the treatment of hormone refractory prostate cancer, NICE Technology Appraisal (2006)
17. Statistics and outlook for prostate cancer; Cancer Research UK 2009.

Internet and further reading

• Macmillan Cancer Support (Cancerbackup); Prostate cancer.
• National Cancer Institute; Prostate Cancer

Acknowledgements