Cancer - prostate
Description
- Adenocarcinoma of the peripheral zone in >95% (BPH is transition zone - different problem)
- Androgen-driven throughout its natural history - every systemic therapy targets the androgen axis until it fails
Disease states - the organising framework
| State | Definition |
|---|---|
| Localised | Confined to prostate; risk-stratified low/intermediate/high |
| Locally advanced | T3-4 or node-positive |
| Biochemical recurrence | Rising PSA after definitive therapy, no visible disease |
| mHSPC (hormone/castration-sensitive) | Metastatic, not yet treated with ADT |
| nmCRPC | Rising PSA on castrate testosterone, no metastases on conventional imaging |
| mCRPC | Progression despite castrate testosterone (<1.7 nmol/L) - by PSA, symptoms, or imaging |
Grading - ISUP Grade Group
| Grade Group | Gleason |
|---|---|
| 1 | <=6 (indolent; many never need treatment) |
| 2 | 3+4 = 7 |
| 3 | 4+3 = 7 (worse than 3+4 - the majority pattern matters) |
| 4 | 8 |
| 5 | 9-10 |
Variant histology
- Ductal, intraductal - aggressive, often PSA-low
- Neuroendocrine / small cell transformation - emerges under prolonged AR blockade; low PSA with rapidly growing visceral disease, treat as small cell
Epidemiology
- Commonest cancer in Australian men (~26,000/yr); 2nd commonest cancer death in men
- Lifetime risk ~1 in 6; median age at diagnosis ~69
- Incidence follows PSA testing intensity, not biology - large reservoir of indolent disease
- Autopsy prevalence >50% in men over 70 (most die with it, not of it)
- African ancestry: higher incidence, earlier onset, more aggressive
Aetiopathogenesis
Risk factors
- Age - dominant
- Family history (FDR doubles risk); African ancestry
- Germline DNA repair defects
Germline predisposition
| Gene | Prostate cancer risk by 80 |
|---|---|
| BRCA2 | ~19-61% (aggressive, early, poor prognosis) |
| BRCA1 | ~7-26% |
| CHEK2, ATM, PALB2 | Moderate |
| Lynch (MMR) | Small increase, possibly non-causal |
- BRCA2, CHEK2, ATM are the commonest germline HRR defects in mCRPC
- Test germline + somatic HRR in all metastatic disease - predicts PARP inhibitor benefit
Androgen biology
- Testosterone (testis, LH-driven) + adrenal androgens -> 5-alpha-reductase -> DHT
- DHT binds AR -> dimerisation -> nuclear translocation -> transcription
- -> inc PSA, inc proliferation, inc survival
How castration resistance arises
Castration-resistant does NOT mean androgen-independent - the AR axis is still on
- AR gene amplification and gain-of-function mutation
- AR splice variants (AR-V7) - constitutively active, lack ligand-binding domain
- Predicts resistance to abiraterone/enzalutamide, not to taxanes
- Intratumoural de novo androgen synthesis
- AR co-activator changes, bypass kinase signalling (PI3K/AKT after PTEN loss)
- Lineage plasticity -> neuroendocrine transformation
Diagnosis
PSA
- Organ-specific, not cancer-specific - raised by BPH, prostatitis, instrumentation, ejaculation, cycling
- *PSA >4 ng/mL yields cancer on biopsy in only ~21%* - ~75% of men over the threshold are biopsied without cancer
- Improve specificity with age-specific ranges, PSA density, free:total ratio, velocity
- No Australian population screening program; shared decision-making, offer testing 50-69 (earlier if family history or BRCA2)
Diagnostic pathway
- Multiparametric MRI BEFORE biopsy - PI-RADS 1-2 may avoid biopsy entirely; 3-5 -> targeted biopsy
- Transperineal biopsy preferred over transrectal (far lower sepsis rate)
- Histology -> ISUP Grade Group
Staging by risk
- Low risk (PSA <10, GG1, <=T2a) - no staging imaging needed
- Intermediate/high risk - PSMA PET/CT (superseded CT + bone scan; higher sensitivity and specificity, changes management in ~1 in 4)
- MRI/CT brain not routine
Castration-resistant prostate cancer - definition
- Progression despite castrate testosterone <1.7 nmol/L, by any of:
- Rising PSA (2 consecutive rises, >=2 ng/mL)
- Radiographic progression
- Clinical/symptomatic progression
- Always confirm testosterone is actually castrate before calling it resistant
PSMA
- Overexpressed on prostate cancer, increasing with progression to mCRPC
- Theranostic pair: 68Ga/18F-PSMA PET for imaging, 177Lu-PSMA-617 for therapy
Management
A. Localised disease - by risk
- Low risk -> active surveillance
- Serial PSA, mpMRI, repeat biopsy; treat only on progression
- Avoids over-treatment of a disease that would never have caused harm
- Intermediate risk -> radical prostatectomy or radiotherapy (EBRT or brachytherapy) +/- short-course ADT (4-6 mo)
- High risk / locally advanced -> dose-escalated radiotherapy + long-course ADT (18-36 mo), or surgery with adjuvant therapy
- Add abiraterone to RT + ADT in very high-risk/node-positive (STAMPEDE)
- Prostatectomy generally offered under ~74 yr / >10 yr life expectancy
- Toxicity trade-off: surgery -> incontinence and erectile dysfunction early; RT -> bowel/urinary irritation later, small second malignancy risk
B. Biochemical recurrence
- Post-prostatectomy: PSA should be undetectable; any detectable and rising PSA (>=0.2, or earlier) warrants action
- PSMA PET to exclude systemic disease - salvage radiotherapy is futile if disease is already distant
- Salvage RT + 24 months ADT > salvage RT alone for overall survival
- Post-radiotherapy: Phoenix definition = nadir + 2 ng/mL
C. Metastatic hormone-sensitive (mHSPC)
ADT alone is no longer adequate - most progress within 18-24 months
- Backbone: ADT
- GnRH agonist (goserelin, leuprolide) = surgical castration in efficacy
- *Testosterone flare* - cover with an anti-androgen for 2-4 weeks; avoid in cord compression/severe obstruction
- GnRH antagonist (degarelix, oral relugolix) - castrate levels in days, no flare, possibly fewer cardiac events
- GnRH agonist (goserelin, leuprolide) = surgical castration in efficacy
- Always intensify with at least one of:
- AR pathway inhibitor - abiraterone + prednisolone, enzalutamide, apalutamide, darolutamide
- Docetaxel x6 - benefit greatest in high-volume disease (CHAARTED, STAMPEDE)
- Triplet (ADT + docetaxel + darolutamide or abiraterone) for high-volume/de novo disease - OS benefit (ARASENS, PEACE-1)
- Add prostate radiotherapy in low-volume metastatic disease (STAMPEDE arm H)
- 177Lu-PSMA-617 added to ADT + ARPI is moving into the hormone-sensitive setting (PSMAddition)
D. Castration-resistant (mCRPC)
Continue ADT lifelong through all subsequent lines - never stop it
| Option | Note |
|---|---|
| Abiraterone + prednisolone | CYP17 inhibitor |
| Enzalutamide | AR antagonist |
| Docetaxel | Then cabazitaxel (better than a 2nd AR agent after docetaxel + one ARPI) |
| Olaparib / talazoparib | HRR/BRCA-mutant only; combined with abiraterone in some settings |
| 177Lu-PSMA-617 | PSMA-avid disease after ARPI +/- taxane (VISION); OS benefit |
| Radium-223 | Alpha emitter, bone-only symptomatic disease; OS benefit. Do not combine with abiraterone - fractures |
| Pembrolizumab | Only if MSI-H/dMMR or high TMB |
| Sipuleucel-T | Not available in Australia |
- Bone-modifying agents (denosumab, zoledronic acid) reduce skeletal-related events; *no overall survival benefit* - and require dental review first
- Do not sequence abiraterone -> enzalutamide (or the reverse) - cross-resistance, minimal benefit
- Non-metastatic CRPC: apalutamide, enzalutamide or darolutamide delay metastasis and improve OS
E. Drug mechanisms and toxicity
- Abiraterone - blocks CYP17 (17-alpha-hydroxylase + 17,20-lyase) -> blocks adrenal/intratumoural androgen synthesis
- dec cortisol -> inc ACTH -> accumulation of mineralocorticoid precursors
- -> hypertension, hypokalaemia, oedema - hence mandatory prednisolone co-administration
- Also transaminitis (monitor LFTs); take on an empty stomach
- Enzalutamide - competitive AR antagonist; blocks binding, nuclear translocation and AR-mediated transcription
- Fatigue, cognitive impairment/falls, hypertension; *lowers seizure threshold - avoid with a seizure history*
- Bicalutamide/nilutamide (1st generation) - block DHT-AR binding; used for flare cover and as adjuncts; gynaecomastia, hepatotoxicity
- ADT class effects - hot flushes, loss of libido/ED, fatigue, sarcopenia, osteoporosis (DEXA + calcium/vitD +/- antiresorptive), metabolic syndrome, insulin resistance, cardiovascular risk, mood and cognitive change, anaemia, gynaecomastia
- Exercise programs are a genuine intervention here, not advice
Associations
- BRCA2 kindreds - breast, ovarian, pancreatic cancer, melanoma
- Lynch syndrome
- Androgen deprivation -> osteoporosis, metabolic syndrome, cardiovascular disease, depression, cognitive decline
- Bone metastases -> osteoblastic/sclerotic (contrast with the lytic lesions of myeloma and most other solid tumours)
- Neuroendocrine transformation under prolonged AR blockade
- Prior pelvic radiotherapy -> secondary bladder and rectal malignancy
Natural history & complications
- Highly variable: from indolent disease requiring no treatment, to rapid lethality
- Localised disease 5-yr survival ~100%; metastatic ~35%
- PSA doubling time is the key prognostic tool in biochemical recurrence - <6-9 months predicts metastasis and cancer death
- mHSPC: median OS now >5 years with intensified therapy (was ~3 yr with ADT alone)
- mCRPC: median OS ~3 years across sequential lines
Metastatic pattern
- Bone (axial skeleton, via Batson venous plexus) - sclerotic
- Pelvic and retroperitoneal nodes
- Visceral (liver, lung) late - suggests neuroendocrine transformation, worse prognosis
Complications
- Bladder outlet obstruction, ureteric obstruction -> renal failure
- Spinal cord compression (a medical emergency - dexamethasone + urgent MRI whole spine + RT/surgery)
- Pathological fracture, bone pain
- Anaemia, marrow infiltration
- Treatment-related: incontinence, erectile dysfunction, radiation proctitis, ADT metabolic and skeletal effects
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