Case 14.6 – Prostate Cancer

History

• Age (prostate cancer is predominantly a disease of the elderly, over 50's. Younger men rarely get prostate cancer)
• Family history of prostate cancer (first degree relative with disease or family history of breast cancer)
• Past medical history: UTI
• Symptoms of benign prostatic hypertrophy (BPH): hesitancy, frequency, urgency, nocturia, poor stream, terminal dribbling, sensation of incomplete emptying
• Haematuria
• Symptoms that may suggest advanced disease: weight loss, bone pain (back pain), symptoms of anaemia

Examination

• General examination: pallor, cachexia
• Abdominal examination: palpable bladder, masses, lymphadenopathy
• Digital rectal examination (DRE): assess prostate size, consistency, symmetry, nodules, tenderness
  • Normal prostate: smooth, symmetrical, firm, non-tender, about 3cm in diameter
  • BPH: enlarged, smooth, symmetrical, firm/rubbery
  • Prostate cancer: hard, irregular, asymmetrical, may have palpable nodules
  • Prostatitis: tender, boggy
• Neurological examination of lower limbs if symptoms suggest spinal cord compression

• PSA (Prostate Specific Antigen) is a glycoprotein enzyme produced by the prostate gland
• PSA is organ-specific but not cancer-specific – can be elevated in BPH, prostatitis, UTI, after instrumentation or DRE, and in prostate cancer
• PSA levels increase with age – age-specific reference ranges should be used
• Normal PSA: generally <4 ng/mL, but this varies with age:
  • 40-49 years: <2.5 ng/mL
  • 50-59 years: <3.5 ng/mL
  • 60-69 years: <4.5 ng/mL
  • 70-79 years: <6.5 ng/mL
• PSA >10 ng/mL is associated with significantly increased risk of prostate cancer
• PSA is not recommended as a screening test for prostate cancer in asymptomatic men (controversial):
  • Low specificity – many false positives (elevated PSA without cancer)
  • PSA screening may lead to detection of clinically insignificant cancers (overdiagnosis)
  • No clear evidence that PSA screening reduces mortality from prostate cancer
  • Potential harms: anxiety, unnecessary biopsies, overtreatment of indolent cancers
• PSA testing may be offered to men >50 years (\>45 if African ancestry or family history) who request it after informed discussion of risks and benefits
• PSA is useful for:
  • Assessment of men with symptoms suggestive of prostate cancer
  • Monitoring response to treatment in men with diagnosed prostate cancer
  • Detecting recurrence after treatment
• PSA velocity (rate of change over time) may be more useful than single values
• Free PSA:total PSA ratio may help distinguish BPH from cancer (lower ratio suggests cancer)

Epidemiology

• Most common cancer in men in Ireland and UK
• Second most common cause of cancer death in men (after lung cancer)
• Incidence increases with age – rare under 50, most cases occur in men >65 years
• Lifetime risk approximately 1 in 8 men
• Geographical variation: highest rates in Western countries, lowest in Asia
• Incidence has increased due to PSA testing and ageing population
• Mortality has decreased due to earlier detection and improved treatments
• Many prostate cancers are slow-growing and may not cause problems during a man's lifetime (indolent disease)

Aetiology and risk factors

• Age: strongest risk factor – incidence increases markedly after 50
• Family history: 2-3 fold increased risk if first-degree relative affected. Risk increases with number of affected relatives and younger age at diagnosis. Hereditary prostate cancer accounts for 5-10% of cases
• Ethnicity: highest incidence in African-Caribbean men, lowest in Asian men
• Genetic factors: mutations in BRCA1 and BRCA2 genes increase risk
• Hormonal factors: androgens (testosterone) are required for prostate cancer development and growth
• Dietary factors: high fat diet, low fruit and vegetable intake may increase risk (weak evidence). Obesity may be associated with more aggressive disease
• Environmental factors: occupational exposure to cadmium, pesticides (weak evidence)

• Histology: 95% are adenocarcinomas arising from the peripheral zone of the prostate (70% peripheral zone, 20% transition zone, 10% central zone)
• Grading – Gleason score:
  • Based on histological pattern/architecture of the tumour
  • Graded from 1 (well-differentiated) to 5 (poorly differentiated)
  • Two most common patterns are added together to give Gleason score (range 2-10)
  • Gleason score 6 (3+3): low grade, well-differentiated
  • Gleason score 7 (3+4 or 4+3): intermediate grade
  • Gleason score 8-10: high grade, poorly differentiated
  • Higher Gleason scores associated with more aggressive disease and poorer prognosis
• Spread:
  • Local invasion: through prostatic capsule to seminal vesicles, bladder neck, rectum
  • Lymphatic spread: to pelvic and para-aortic lymph nodes
  • Haematogenous spread: to bone (osteoblastic metastases – most common site), lung, liver

• Asymptomatic: detected by elevated PSA or abnormal DRE in asymptomatic men
• Lower urinary tract symptoms (LUTS):
  • Hesitancy, weak stream, frequency, urgency, nocturia
  • Usually due to coexistent BPH rather than cancer itself
  • Cancer in peripheral zone less likely to cause LUTS until advanced
• Haematuria or haematospermia
• Symptoms of locally advanced disease:
  • Acute urinary retention
  • Pelvic pain, perineal pain
  • Erectile dysfunction
  • Rectal symptoms (tenesmus, bleeding) – rare
  • Hydronephrosis (due to ureteric obstruction) – loin pain, renal failure
• Symptoms of metastatic disease:
  • Bone pain (especially back pain from vertebral metastases) – most common presentation of metastatic disease
  • Pathological fractures
  • Spinal cord compression – back pain, leg weakness, sensory loss, urinary retention, faecal incontinence (urological emergency)
  • Weight loss, fatigue, anaemia
  • Lymphoedema (due to lymph node involvement)

• Serum PSA: elevated in majority of cases, but can be normal
• Digital rectal examination (DRE): palpable abnormality in ~50% of cases
• Transrectal ultrasound (TRUS) guided biopsy:
  • Definitive diagnostic test
  • Multiple cores (10-12) taken from different areas of prostate
  • Provides histological diagnosis and Gleason score
  • Complications: bleeding (haematuria, haematospermia, rectal bleeding), infection (sepsis), urinary retention
• Multiparametric MRI prostate:
  • Increasingly used before biopsy to identify suspicious areas
  • Can help target biopsies (MRI-fusion biopsy)
  • May reduce unnecessary biopsies in men with low-risk abnormalities
• Staging investigations (if cancer confirmed):
  • Bone scan: to detect bone metastases (if PSA >10, high Gleason score, or bone pain)
  • CT or MRI pelvis: to assess local extent and lymph node involvement
  • Chest X-ray or CT chest: if suspicion of lung metastases
• Other investigations:
  • FBC: anaemia (chronic disease, bone marrow infiltration)
  • Renal function: obstructive uropathy
  • Liver function tests
  • Bone profile: alkaline phosphatase (elevated in bone metastases), calcium

TNM staging

• T (Tumour):
  • T1: Clinically inapparent tumour (not palpable or visible on imaging)
    • T1a: ≤5% of resected tissue (incidental finding at TURP)
    • T1b: >5% of resected tissue
    • T1c: Tumour identified by needle biopsy (e.g. elevated PSA)
  • T2: Tumour confined within prostate
    • T2a: Involves ≤50% of one lobe
    • T2b: Involves >50% of one lobe
    • T2c: Involves both lobes
  • T3: Tumour extends through prostatic capsule
    • T3a: Extracapsular extension
    • T3b: Invades seminal vesicles
  • T4: Tumour invades adjacent structures (bladder neck, rectum, pelvic wall)
• N (Nodes):
  • N0: No regional lymph node metastases
  • N1: Regional lymph node metastases
• M (Metastases):
  • M0: No distant metastases
  • M1: Distant metastases
    • M1a: Non-regional lymph nodes
    • M1b: Bone
    • M1c: Other sites

Risk stratification (for localized disease)

Based on PSA, Gleason score, and clinical stage:

• Low risk: PSA <10, Gleason ≤6, stage T1-T2a
• Intermediate risk: PSA 10-20, or Gleason 7, or stage T2b
• High risk: PSA >20, or Gleason 8-10, or stage T2c-T3

Risk stratification helps guide treatment decisions and predict prognosis

Treatment depends on stage, grade, patient age, comorbidities and patient preference

Localized disease (T1-T2, N0, M0)

• Active surveillance:
  • Appropriate for low-risk, slow-growing cancers
  • Regular monitoring with PSA, DRE, repeat biopsies
  • Treatment initiated if disease progresses
  • Avoids side effects of treatment for indolent cancers
  • Suitable for elderly men with limited life expectancy or significant comorbidities
• Radical prostatectomy:
  • Surgical removal of entire prostate and seminal vesicles
  • Can be open, laparoscopic, or robotic-assisted
  • Curative intent for localized disease
  • Side effects: erectile dysfunction (30-70%), urinary incontinence (5-20%), risk of anastomotic stricture
  • PSA should become undetectable after surgery
• External beam radiotherapy (EBRT):
  • Curative intent for localized disease
  • Typically 7-8 weeks of daily treatment
  • Side effects: urinary symptoms (frequency, urgency), bowel symptoms (diarrhoea, rectal bleeding), erectile dysfunction (develops gradually over months-years)
  • Can be combined with androgen deprivation therapy (ADT) for higher-risk disease
• Brachytherapy:
  • Radioactive seeds implanted directly into prostate
  • Low dose rate (LDR) – permanent seeds
  • High dose rate (HDR) – temporary implants
  • Can be used alone or in combination with EBRT
  • Suitable for low-intermediate risk disease

Locally advanced disease (T3-T4)

• Radiotherapy (EBRT) + androgen deprivation therapy (ADT) for 2-3 years
• Radical prostatectomy may be considered in selected cases

Metastatic disease (N1 or M1)

• Androgen deprivation therapy (ADT):
  • Mainstay of treatment for metastatic disease
  • Prostate cancer is androgen-dependent
  • Methods:
    • LHRH agonists (goserelin, leuprorelin) – cause initial testosterone surge then suppression
    • LHRH antagonists (degarelix) – immediate testosterone suppression, no surge
    • Anti-androgens (bicalutamide, enzalutamide)
    • Bilateral orchidectomy (surgical castration) – rarely used now
  • Side effects: hot flushes, loss of libido, erectile dysfunction, fatigue, osteoporosis, weight gain, gynaecomastia, anaemia, increased cardiovascular risk
  • Most patients initially respond well (months-years)
  • Eventually disease becomes castration-resistant (CRPC)
• Chemotherapy:
  • Docetaxel – first-line for metastatic CRPC
  • Cabazitaxel – second-line
  • May be combined with ADT in newly diagnosed high-volume metastatic disease
• Novel hormonal agents for CRPC:
  • Abiraterone (CYP17 inhibitor – blocks androgen synthesis)
  • Enzalutamide (androgen receptor antagonist)
• Radium-223:
  • Targeted alpha therapy for bone metastases
  • Improves survival and reduces skeletal events in CRPC with bone metastases
• Bisphosphonates or denosumab:
  • Reduce skeletal-related events in bone metastases
  • Treatment of osteoporosis in men on ADT
• Palliative radiotherapy:
  • For painful bone metastases
  • For spinal cord compression

Emergency treatments

• Spinal cord compression: High-dose dexamethasone + urgent radiotherapy or surgical decompression
• Acute urinary retention: Catheterization, TURP if persistent, ADT may help

Prognosis

• Overall 5-year survival >90%
• Localized disease: 5-year survival ~100%
• Locally advanced: 5-year survival ~95%
• Metastatic disease: 5-year survival ~30%
• Many men with prostate cancer die with the disease rather than from it