Epidemiology^[2]

• The age-standardised incidence of prostate cancer in the UK in 2008 was 97.9 per 100,000 population.
• It was estimated that the lifetime risk of being diagnosed with prostate cancer in 2008 was 1 in 9 for men in the UK.
• In developed countries prostate cancer accounts for 15% of male cancers compared with 4% of male cancers in developing countries.^[1]

Risk factors

• It is particularly common in older men.^[3] 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.
• Race is an important risk factor with a higher incidence in North America and Europe, especially amongst black African or black Caribbean groups.^[4] China and Japan have low rates.
• Familial prostate cancer: risk increases 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 no organised screening programme for prostate cancer in the UK but there is an NHS Prostate Cancer Risk Management Programme.^[5]

• Suggested methods of prostate cancer screening are digital rectal examination (DRE), prostate specific antigen (PSA) and transrectal ultrasonography (TRUS). 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.
• There is currently no strong evidence from randomised controlled trials regarding the impact of screening on quality of life, harms of screening, or its economic value.^[6]
• 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.^[7]
• A large European randomised study of screening for prostate cancer found that 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. Harms included high rates of false-positive results for the PSA test (up to 75.9%), infection, bleeding, and pain associated with subsequent biopsy.^[8]
• 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.^[7]

Presentation

See related separate article Genitourinary History and Examination (Male).

Lower urinary symptoms, eg urinary frequency, hesitancy, nocturia and slow stream do not increase prostate cancer risk but are associated with higher PSA values.^[7]

• 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, eg 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.
• DRE 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 (eg urinary tract infection) and urinary tract obstruction.
• Benign prostatic hypertrophy.
• Prostatitis.
• Bladder tumours.

Investigations^[1]

• The PSA Test is dealt with in the separate article Prostate Specific Antigen (PSA). PSA density is derived by dividing the PSA value by the volume of the prostate measured by TRUS.
• Urinalysis to exclude renal and bladder pathology. Urine sent for microscopy, culture and sensitivities.
• Serum creatinine level to exclude renal disease.
• Prostate biopsy:
  • Prostate biopsy in patients with suspected prostate cancer is usually carried out by a transrectal needle biopsy. TRUS and biopsy: in men with a raised concentration of PSA, biopsy will miss 10% to 30% of clinically significant prostate cancers.
  • Transperineal template biopsy may be used for patients with suspected prostate cancer who have had a negative or inconclusive transrectal biopsy. Other proposed indications for transperineal template biopsy include mapping to determine the location and extent of prostate cancer as a guide to focal treatment (eg ablation), and as part of active surveillance of low-risk localised prostate cancer with the aim of reducing the number of biopsies.^[9]
• 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 histological finding in 5% or less of tissue resected.
  • T1b: tumour incidental histological finding in more than 5% of tissue resected.
  • T1c: tumour identified by needle biopsy (eg because of elevated PSA).
  • T2: tumour confined within prostate.
  • T2a: tumour involves one 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 one 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.
• 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 cancer^[4]

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

• Low risk: 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][4]

• 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.

Treatment options for non-metastatic disease

Treatment options for clinically localised prostate cancer include watchful waiting,^[4] radical prostatectomy (retropubic or perineal), external beam radiation therapy, brachytherapy, androgen deprivation therapy (drugs or surgical removal of testicles) and cryoablation.^[7]

• Watchful waiting: if the tumour is small and well differentiated (Gleason score of 6 or lower), watchful waiting may be appropriate, especially for patients with less than 10-year life expectancy.
• 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 of 0.2% to 1.2%. 40% have positive surgical margins. Laparoscopic radical prostatectomy is indicated for localised prostate cancer with no evidence of spread beyond the prostate or of distant metastases.^[11]
• Radiotherapy may be an option for younger patients with a long life expectancy, especially for poorly differentiated tumours.
• 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. High-dose rate brachytherapy in combination with external beam radiotherapy, and low-dose rate brachytherapy are recommended as a treatment option for localised prostate cancer.^[12][13]
• Cryotherapy: cryotherapy can be used as a primary treatment for patients with localised or locally advanced prostate cancer.^[14] 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.^[15]
• High-intensity focused ultrasound (HIFU) may be used to treat carcinoma of the prostate, either as a primary or salvage therapy.^[16]
• There is evidence that, for locally advanced disease, adding androgen suppression to standard treatments (radiation, prostatectomy) can prolong survival.

Localised prostate cancer

• Watchful waiting: standard treatment for T1a, Gleason score <7 adenocarcinomas and less than 10-year life expectancy. If showing evidence of disease progression, refer to the urological cancer multidisciplinary team.
• Active surveillance:
  • For patients with T1a and >10-year life expectancy: re-staging with TRUS and biopsy is recommended.
  • Treatment option in patients with cT1c-cT2a, PSA <10 ng/mL, biopsy Gleason score <6, <2 biopsies positive, <50% cancer involvement of each biopsy.
  • Patients with T1b-T2b cancer and a life expectancy <10 years.
  • Patients who do not accept treatment-related complications.
• If men on active surveillance show evidence of disease progression, offer radical treatment.

Radical treatments

• T1a:
  • Radical prostatectomy: option for younger patients with a long life expectancy, especially for Gleason score >7 adenocarcinomas.
  • Radiotherapy: optional in younger patients with a long life expectancy, in particular in poorly differentiated tumours.
• T1b-T2c:
  • Radical prostatectomy: standard treatment for patients with a life expectancy >10 years who accept treatment-related complications.
  • Radiotherapy:
    • Patients with a life expectancy >10 years who accept treatment-related complications.
    • Patients with contra-indications for surgery.
    • Unfit patients with 5-10 years of life expectancy and poorly differentiated tumours (adjuvant hormonal therapy should be offered for a minimum of two years to men receiving radiotherapy who have a Gleason score of 8 or above).
  • Brachytherapy: low-dose rate brachytherapy can be considered for low-risk prostate cancer patients with a prostate volume <50 mL and an International Prostate Symptom Score (IPSS) <12.
  • Hormonal: symptomatic patients, who need palliation of symptoms, unfit for curative treatment. Anti-androgens are associated with a poorer outcome compared to 'active surveillance' and are not recommended.
  • Combination: for high-risk patients, neoadjuvant hormonal treatment and concomitant hormonal therapy plus radiotherapy results in increased overall survival.

Locally advanced prostate cancer (T3-T4)

• Watchful waiting: option in asymptomatic patients with T3, well differentiated and moderately differentiated tumours, and a life expectancy <10 years, who are unfit for local treatment.
• Radical prostatectomy (adjuvant or salvage therapy such as radiation therapy or androgen deprivation might be indicated):
  • Optional for selected patients with T3a, PSA <20 ng/mL, biopsy Gleason score <8 and a life expectancy >10 years.
  • Radical prostatectomy is associated with an increased risk of positive surgical margins, unfavourable histology and positive lymph nodes, and so further treatment, eg radiation therapy or androgen deprivation, may be required.
• Radiotherapy:
  • T3 with >5-10 years of life expectancy. Dose escalation of >74 Gy seems to be of benefit. A combination with hormonal therapy can be recommended (adjuvant hormonal therapy for a minimum of two years is recommended for 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)).
• Hormonal:
  • Symptomatic patients, extensive T3-T4, high PSA level (>25-50 ng/mL), PSA doubling time (DT) <1 year.
  • Hormone monotherapy is not an option for patients who are fit enough for radiotherapy.
• Combination: overall survival is improved by concomitant and adjuvant hormonal therapy (three years) combined with external beam radiation.

Metastatic prostate cancer

N+, M0

• Watchful waiting: asymptomatic patients, PSA <20-50 ng/mL, PSA DT >12 months. Requires very close follow-up.
• Radical prostatectomy: optional for selected patients with a life expectancy of >10 years as part of a multimodal treatment approach.
• Radiotherapy: optional in selected patients with a life expectancy of >10 years. Combination therapy with adjuvant androgen deprivation for three years is mandatory.
• Hormonal:
  • Standard adjuvant therapy in more than one positive node to radiation therapy or radical prostatectomy as primary local therapy.
  • Hormonal therapy should only be used as monotherapy in patients who are unfit for any type of local therapy.

M+

Patients with androgen-dependent metastatic disease are generally managed with hormonal treatment aimed at androgen depletion, which usually includes either bilateral subcapsular orchidectomy or use of a gonadorelin analogue (buserelin, goserelin, histrelin, leuprorelin or triptorelin). The anti-androgens cyproterone acetate, flutamide and bicalutamide inhibit the tumour 'flare' which may occur after commencing gonadorelin analogue administration. Cyproterone acetate and flutamide are also licensed for use alone in patients with metastatic prostate cancer refractory to gonadorelin analogue therapy. Degarelix is a gonadotrophin-releasing hormone antagonist used to treat advanced hormone-dependent prostate cancer. It does not induce a testosterone surge or tumour 'flare' and so anti-androgen therapy is not required.^[17]

• Hormonal therapy is not routinely recommended for men with prostate cancer who have a biochemical relapse unless they have:^[4]
  • Symptomatic local disease progression.
  • Any proven metastases.
  • A doubling of PSA within three 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.
• Radiotherapy is a therapeutic option in combination with androgen deprivation for treatment of local cancer-derived symptoms.

Hormone-refractory prostate cancer

Also called castrate-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.^[4]
• Palliative treatments are usually given for bone pain or anaemia. They include blood transfusions, corticosteroids, chemotherapy, local radiotherapy and radionuclides (eg strontium-89). Radionuclide therapy appears to be superior to radiotherapy for pain relief.
• In patients with symptomatic bone metastases, either docetaxel or mitoxantrone with prednisone or hydrocortisone are therapeutic options. Docetaxel is the preferred agent based on the significant advantage in pain relief.^[1] Docetaxel should be offered only if the Karnofsky score is 60% or above.^[18] 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.^[19]
• In patients with relapse following first-line docetaxel chemotherapy, then cabazitaxel and abiraterone are regarded as first-choice option for second-line treatment. If patients are not eligible for cabazitaxel or abiraterone, then docetaxel is an option.^[1]
• The inhibition of androgen biosynthesis by abiraterone acetate has been shown to prolong overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.^[20]
• Cabazitaxel, in combination with prednisone or prednisolone, is licensed for the treatment of hormone refractory metastatic prostate cancer in patients who have previously been treated with a docetaxel-containing regimen. Routine premedication with a corticosteroid, an antihistamine, and a histamine H₂-receptor antagonist is recommended to prevent severe hypersensitivity reactions.
• Corticosteroid (eg 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.^[4]
• Decompression of the urinary tract by percutaneous nephrostomy or insertion of a double J stent to men with obstructive uropathy.

Follow-up after treatment^[1]

• In asymptomatic patients, a disease-specific history and a serum PSA measurement supplemented by DRE are the recommended tests for routine follow-up. These should be performed at three, six and twelve months after treatment, and then every six months until three years, and then annually.
• After radical prostatectomy, a serum PSA level >0.2 ng/mL can be associated with residual or recurrent disease.
• After radiation therapy, a rising PSA level >2 ng/mL above the baseline PSA is the most reliable sign of persistent or recurrent disease.
• Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan. In most cases, TRUS and biopsy are not necessary before second-line therapy.
• Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level is <20 ng/mL (but research data on this topic are sparse). If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level.
• Routine bone scans and other imaging studies are not recommended in asymptomatic patients.

Following hormone treatment^[1]

• Patients should first be evaluated at three and six months after treatment initiation. Tests should at least include serum PSA measurement, DRE, serum testosterone and careful evaluation of symptoms in order to assess the treatment response and side-effects.
• If patients undergo intermittent androgen deprivation, PSA and testosterone should be monitored at three-month intervals during the treatment pause.

Palliative care^[1]

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

• Bisphosphonates should be considered for patients with skeletal masses, to prevent osseous complications.
• Palliative treatments, such as radionuclides, external beam radiotherapy and adequate use of analgesics, should be considered early on in the management of painful bone metastases.
• Emergency spinal surgery or decompressive radiotherapy should be considered for patients with neurological symptoms thought to be critical.

Complications

• Urinary tract obstruction, acute kidney injury, chronic kidney disease.
• Sexual dysfunction: erectile dysfunction, loss of libido.
• Metastatic spread: bone pain, pathological fractures, spinal cord compression.
• Complications of hormonal therapy:^[4]
  • 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.

Prognosis^[2]

• Survival from prostate cancer is strongly related to the stage of the disease at diagnosis.
• Five-year relative survival rates for men diagnosed with prostate cancer in their 60s are higher than rates for either younger or older men.