Prostatic Carcinoma

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

• Prostate cancer is the second commonest malignancy in men.
• It is estimated that the lifetime risk of developing microscopic prostate cancer is about 30%, developing clinical disease 10% and dying from prostate cancer 3%.

Risk factors

• It is particularly common in older men. Two thirds of those who die from prostate cancer are over 75. 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.¹
• Race is an important risk factor with a higher incidence in North America and Europe especially amongst black African or black Caribbean groups.² China and Japan have low rates.
• Familial prostate cancer: risk increase 2-3 times if first degree relative 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 (anti-oxidant found in tomatoes) appear to have a protective effect.
• Occupation: increased risk with farming and exposure to radiation or cadmium.

• 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.³ 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.⁴
• 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 prostate specific antigen. 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.⁵
• 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.⁴

Also see separate article on Urological History and Examination.
Lower urinary symptoms, e.g. urinary frequency, hesitancy, nocturia, and slow stream do not increase prostate cancer risk but are associated with higher PSA values.⁴

• Local disease:
  • Raised prostate specific antigen (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

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

The serum PSA level alone should not decide whether a prostate biopsy is necessary.²

• A standard normal range is less than 4 ng/ml, but age-specific ranges are more useful:^6,7,8
  • Age under 50 years: PSA below 2.5
  • Age 50-59 years: PSA below 3.0
  • Age 60-69 years: PSA below 4.0
  • Age 70 years and over: PSA below 5.0
• Correlating PSA with a digital rectal examination improves the sensitivity.
• Prostate specific antigen is largely bound to one of two inhibitors in the serum. The proportion of free, unbound PSA is lower in patients with prostate cancer than in those with benign prostatic hyperplasia.⁹
• Other causes of a raised PSA include:
  • Urinary tract infections
  • Prostatitis
  • Benign prostatic hypertrophy
  • Any procedure traumatising the prostate eg. catheterisation, cystoscopy, biopsy
  • Cycling
• PSA is normal in 30% of small cancers and is raised in about 25% of men with benign prostatic hyperplasia.
• Digital rectal examination does not have significant effects on PSA. Finasteride (5 alpha reductase inhibitor used in benign prostatic hypertrophy) approximately halves the value of 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 prostate specific antigen, 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.¹⁰
• Uroflow measurement, measurement of post micturition 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.

TNM Staging For Prostate Cancer

• Primary tumour (T):
  • TX: Primary tumour cannot be assessed
  • T0: No evidence of primary tumour
  • T1: Clinically inapparent tumour not 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 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.¹¹
• The Gleason score has been used as the best prognostic indicator for prostate cancer but other molecular indicators are being evaluated.
  • Gleason score 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%

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

• Low risk: PSA < 10, and Gleason score 6 or below, and clinical stage T1–T2a
• Intermediate risk: PSA 10–20, or Gleason score 7, or clinical stage T2b–T2c
• High risk: PSA > 20, or Gleason score 8–10, or clinical stage T3–T4

Localised prostate cancer²

• Watchful waiting; if show evidence of disease progression.
• Active surveillance: 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.
• 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 cancer²

• Neoadjuvant and concurrent luteinising hormone-releasing hormone agonist (LHRHa) therapy for 3–6 months to men receiving radiotherapy.
• 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,² radical prostatectomy (retropubic or perineal), external beam radiation therapy, brachytherapy, androgen deprivation therapy (drugs or surgical removal of testicles) and cryoablation.⁴

• Watchful waiting: if the tumour is small and well differentiated (Gleason score of six or lower) watchful waiting may be appropriate, especially for older patients with significant other diseases. In younger men, or when there is evidence of local tumour extension or an incremental rise in concentration of prostate specific antigen, more invasive treatment should be considered.¹²
• 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.¹³
• 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.¹⁴
• Brachytherapy (transperineal implantation of radioactive seeds into the prostate). Brachytherapy is usually recommended for patients whose glands are less than 50 g.¹⁵ Low dose rate brachytherapy may be used alone or in combination with external-beam radiotherapy.¹⁶
• Cryotherapy: cryotherapy can used as a primary treatment for patients with localised or locally advanced prostate cancer.¹⁷ 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.¹⁸
• 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. Starting patients on androgen suppression early improves their survival compared with deferring treatment.¹⁹

Metastatic prostate cancer²

• 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:²
  • Symptomatic local disease progression
  • Any proven metastases
  • A doubling of PSA within 3 months
• Treatment often involves monthly or three-monthly depot injections of luteinising hormone releasing hormone agonists. 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 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.
• There is some evidence that combining an anti-androgen (e.g.bicalutamide or flutamide) with androgen suppression (luteinising hormone releasing hormone agonist or orchidectomy) improves long-term survival compared with androgen suppression alone.²⁰

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.²
• New chemotherapy agents (e.g. mitoxantrone and suramin), combined with corticosteroids, can reduce pain, lengthen palliation, and improve quality of life.
• 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 Karnofsky score is 60% or above (see Internet and Further Reading below). Stop treatment after 10 planned cycles or if severe adverse events occur or if disease progresses (clinical, laboratory or imaging criteria). Do not repeat treatment cycles if disease recurs.²¹
• Corticosteroid (e.g. dexamethasone 0.5 mg daily) as a third-line therapy after androgen withdrawal and anti-androgen therapy.²
• Spinal MRI if spinal metastases are found and spine-related symptoms develop.²
• Decompression of the urinary tract by percutaneous nephrostomy or insertion of a double J stent to men with obstructive uropathy.²

Palliative care

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

• Urinary tract obstruction, renal failure
• Sexual dysfunction: erectile dysfunction, loss of libido²²
• Metastatic spread: bone pain, pathological fractures
• Complications of hormonal therapy:²
  • 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 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.