Prostate Cancer

Pathology & Pre-Cancerous Lesions

PIN

• Low-grade or unifocal high-grade — no increased risk of developing prostate cancer; monitor PSA + DRE (biopsy only if suspicion)
  • Unifocal HGPIN → reassess at 12 months; cancer yield on re-biopsy within 1 year is 26.4% — not significantly higher than after a benign biopsy (10–25%)
  • A single core of PIN needs no re-biopsy — just monitor PSA and DRE
• Multifocal high-grade (2 or more cores) — cancer risk ≈ 30%; monitor PSA + DRE and repeat biopsy in 1–3 years
  • Exam answer: multifocal HGPIN warrants further evaluation — biomarkers, MRI (if not already done) or repeat biopsy within 1 year
  • It matters to distinguish PIN from ductal or intraductal carcinoma — a uropathologist's call
• In an elderly patient with HGPIN found on TURP, often no further workup is instituted; in a younger man a more aggressive workup to exclude clinically significant tumor may be warranted

AAH (Adenosis)

• Atypical adenomatous hyperplasia — no risk of cancer

ASAP

• HMWCK positive
• Suspicious but non-diagnostic
  • Found in about 5% of needle biopsies
• Does not alter PSA
• → Re-biopsy in 3–6 months, focusing on the atypical regions
  • Re-biopsy regardless of PSA
  • Before re-biopsy, consider expert pathology review — atypia is the diagnosis most often changed on review
  • Sample the whole gland, with extra cores at and around the ASAP site
• Cancer risk: 40–60%
  • Exam answer: 30–50% show cancer on re-biopsy — far more than high-grade PIN

Prostate Cancer Histology

• HMWCK negative
• Types:
  • Acinar (most common — > 95% of adenocarcinomas; 85% arise in the peripheral zone, multifocal in >85%)
  • Ductal (normal PSA) CI to AS
  • Intraductal — a rare and aggressive variant (Gleason 4+4); grows into the urethral lumen and usually presents with obstructive voiding symptoms + hematuria; does not alter PSA. CI to AS
  • Non-adenocarcinoma is < 5%, of which transitional cell is the most common

Why HMWCK staining answers the question

• Prostate adenocarcinoma arises from prostate epithelial cells, which stain positive for prostatic acid phosphatase (PAP) and PSA
• Normal prostate has a basal cell layer, which stains positive for HMWCK and negative for PAP and PSA
• Prostate adenocarcinoma NEVER has a basal cell layer
  • Basal cell loss disrupts the basement membrane — this defines adenocarcinoma on biopsy, not epithelial crowding or prominent nucleoli
• So: stain with HMWCK → positive = basal layer present = benign; negative = no basal layer = malignant, and it will stain positive for PAP and PSA
  • p63 also marks basal cells — absent HMWCK/p63 staining in an atypical focus confirms carcinoma; positive staining excludes it
• Cancer mimics — partial atrophy, adenosis and HGPIN may also lack basal cells → small lesions may need HMWCK/p63 + AMACR staining to settle the diagnosis

---

Risk Factors

• African ancestry (incidence Black > White > Hispanic > Asian)
• Age >40
• Germline mutations: BRCA2 (most aggressive), BRCA1, CHEK2, Lynch (MLH1/MSH2/MSH6/PMS2)
• TMPRSS2:ERG fusion in ~50% sporadic PCa
• Mets pattern: LN → bone (osteoblastic) → lung → bladder → liver

Family history — relative risk

• A brother affected carries higher risk than a father affected
• One affected first-degree relative → risk 2–3 fold; risk rises with the number of affected relatives, their degree of relatedness and their age at diagnosis

Chromosomal and germline detail

• Chromosome 8 — typically loss of the p arm and gain of the q arm; the most common chromosomal abnormality in advanced prostate cancer
  • The best-established prostate cancer locus: 8q24 is a germline GWAS susceptibility locus (with 17q21)
  • 8q is home to MYC and frequently undergoes somatic whole-arm gain
  • High-risk 8q24 alleles are more common in Black men — paralleling their highest incidence (172.6 per 100,000 in the US) and roughly double the cancer-specific mortality of White men
• > 100 germline GWAS SNPs influence prostate cancer risk — multi-SNP panels can identify very low- and very high-risk men, but none correlate with aggressiveness
• Chromosomes 10 and 7 are also altered; others — 13q, 16q, 17p, 18q
• PTEN is more frequently altered in advanced disease
• BRCA2 is the most common germline mutation in metastatic prostate cancer, and is associated with lethal disease
• BRCA2 and Lynch syndrome each raise the risk of developing prostate cancer 2–6 fold
• BRCA1, BRCA2 and ATM are inherited DNA damage-repair genes that increase the risk of aggressive disease

Germline vs Somatic Testing

• Most mutations in prostate cancer are somatic

Indications for germline testing

• High-risk prostate cancer
• N1 or M1 disease
• Significant family history — first-degree, younger age at diagnosis (< 65), number of members affected
  • Exam answer: a strong family history is a brother or father diagnosed < 60, dying of prostate cancer or with metastatic disease
    • → screen from age 40 and test for BRCA1/2, Lynch syndrome, ATM and CHEK2
• Ductal, intraductal or cribriform patterns

---

PSA Biology & Interpretation

• Half-life: 2–3 days; a glycoprotein, molecular weight 33 kD, 7% carbohydrate
• Organ-preferential, not organ-exclusive — elevated PSA is most characteristic of prostate and breast malignancies
  • 30–70% of breast carcinomas express PSA, driven by steroid receptors
  • In breast cancer, PSA positivity correlates with ER/PR-positive disease and a more favorable prognosis — the opposite of its meaning in prostate cancer
• Why serum PSA rises in cancer: basal cell loss disrupts the basement membrane and lumen architecture — even though each cancer cell makes less PSA than normal prostate tissue
• Bound to: α1-antichymotrypsin, α1-protease inhibitor
  • 70–80% bound — mainly to α1-antichymotrypsin (ACT), lesser to α1-protease inhibitor and α2-macroglobulin; the remaining 20–30% circulates free
  • The PSA–ACT complex is the major form of PSA in serum — found at higher concentrations in cancer than in benign disease
• ↑ by: BPH, prostatitis, UTI, biopsy (↑6–8 ng/mL, normalizes 2–3 wk), TURP, cycling
• Minimal effect: DRE, catheterization, TRUS without biopsy
• 5-ARIs halve PSA at 12 mo → double observed value
  • PSA reaches its nadir by 6–12 months
• 25–40% of newly elevated PSAs normalize → repeat before biopsy

Other Markers

Before diagnosis — after a previously negative biopsy

• PCA3 — best predicts the need for repeat biopsy after a negative biopsy with a rising PSA: FDA-approved in this setting and independent of prostate size
  • A prostate-specific long non-coding RNA, measured in the first 20–30 mL of urine after an attentive DRE
  • Score = PCA3 mRNA ÷ PSA mRNA × 1000
• Urinary diversion + prior negative biopsy → ConfirmMDx on the prior biopsy tissue — the urine contains no prostate mRNA, so urine-based tests are inappropriate

After diagnosis — biopsy-based genomic tests

• These three predict adverse pathology, metastasis or cancer-specific mortality — and are NOT indicated prior to a diagnosis of prostate cancer
  • Oncotype DX (mRNA of 17 genes) → the test in low-risk disease that predicts adverse pathology: Gleason 4+3=7 or extracapsular extension at prostatectomy
  • Decipher and Prolaris → predict metastasis or cancer-specific mortality

---

Screening

• PSA elevation occurs 6–13 years before prostate cancer causes symptoms
• An abnormal PSA should be repeated in the same lab after 4–6 weeks
  • PSA 3–10 ng/mL with a nonsuspicious DRE → repeat PSA after 4 weeks before deciding on biopsy — because of analytical and biological variability
  • Use the same assay too; avoid recent ejaculation, manipulation and urinary infection
  • If it normalizes → next PSA in 1 year
• Start screening at 50; if high risk, start at 40 — family history, African ancestry, germline mutations
• Men aged 40–49 have a median PSA of 0.7 ng/mL — a man in this age group above the median is at higher risk of developing prostate cancer with an aggressive subtype
• Annual screening is advised for: African ancestry, family history, or a PSA above the median for the age group

Age 70–75 — the decision point

Screening intervals

DRE

• Prostate cancer is found in 30% of suspicious DREs
  • With PSA ≤ 4 ng/mL, a suspicious DRE has a PPV of 5–30%
  • An abnormal DRE also predicts a higher ISUP grade group and advanced disease
• DRE raises PSA by only 0.26 ng/mL — not a reason to defer testing

PSA density

• PSAD = PSA ÷ prostate volume; suspect cancer if PSAD > 0.15

Free PSA — the higher the free PSA%, the lower the risk

• Do not use free PSA in ESRD patients on hemodialysis
  • Severe CKD raises absolute free PSA and percent free PSA (free/total); total PSA and other isoforms such as proPSA are not associated with renal dysfunction
  • Free PSA is a component of PHI and the 4Kscore → in severe CKD these give an artificially lower estimated cancer risk
• Cystoscopy raises free PSA

---

MRI & PI-RADS

• PI-RADS 5 with negative biopsy → repeat MRI then biopsy
• Hypoechoic lesion on TRUS → ~57% cancer
  • Hypoechoic lesions should be biopsied, but are not pathognomonic for cancer and do not correlate with Gleason score (aggressiveness)
  • 39% of cancers are isoechoic and 1% hyperechoic; an irradiated prostate is diffusely hypoechoic
• Corpora amylacea — echogenic calcifications along the surgical capsule, highlighting the plane between the transition and peripheral zones; a normal landmark, not a pathologic finding
• Small, multiple diffuse calcifications on TRUS → a normal incidental result of age; larger symptomatic calculi may reflect infection or inflammation → need further evaluation
• Post-biopsy: wait 6–8 weeks before MRI

---

Factors Suggesting Need for Biopsy

• Abnormal DRE
  • A nodule is an independent indication regardless of PSA — even at PSA 1.0 ng/mL; ~18% of cancers are detected by suspect DRE alone
• Abnormal PSA, PSAV, or PSAD (single abnormal PSA alone should not trigger biopsy → repeat first)
• Abnormal MRI (PI-RADS ≥3)
• PSA fails to decline on 5-ARI
  • A rise from nadir while still on the 5-ARI is suspicious for malignancy regardless of the absolute value → biopsy
• After TRUS biopsy: ~75% negative | False-negative rate 20–30%
• Most common complications post-biopsy: hematospermia and hematuria
  • Bleeding is the commonest complication even with normal coagulation: hematuria 23–63%, hematospermia 9.8–50.4% → both usually self-limited
  • Hematospermia can persist up to 4–6 weeks → no clinical consequence, but counsel patients about its likelihood
  • Serious complications needing hospitalization < 2% · clot retention ~0.7% · intervention for hematuria < 1%

PSA velocity thresholds

• > 0.35 ng/mL/yr when PSA < 4
• > 0.75 ng/mL/yr when PSA 4–10

Technique

• Minimum 12 cores [AUA]
• Ciprofloxacin is the pre-procedure antibiotic of choice
• A second biopsy must target the midline peripheral zone, the anterior apical peripheral zone, and the anterior transition zone —
  • These are where cancer hides when the first biopsy was falsely negative

Contraindications

• Absolute: significant coagulopathy, severe immunosuppression, acute UTI / prostatitis
• Relative: painful anorectal conditions or anal stenosis → avoid office TRUS biopsy under local anesthesia; biopsy under general or regional anesthesia, or use a transperineal route

Seminal Vesicle Biopsy — Indications

• Suspected SV invasion
• Planning salvage cryotherapy after radiation
• PSA > 15, or a large tumor at the base of the prostate

Prognostic Factors on TRUS Biopsy

• Gleason score / Grade Group — the most important prognostic factor
  • Presence of Gleason pattern 5 most strongly determines metastatic risk → SV invasion, extraprostatic extension and nodal disease are downstream markers of spread
• Number & % of positive cores
• SV involvement
• Periprostatic invasion
• Perineural invasion
• Cribriform / intraductal patterns

---

TNM Staging (AJCC 8th)

T

• Tissue resected in T1a/T1b = e.g., TURP chips

N

• N1: regional LN
• The side on which the lymph nodes are involved does not affect the N stage

M

• M1a: non-regional LN | M1b: bone | M1c: other (liver, lung, brain)
• When more than one site of metastasis is present, the most advanced category is used

Pathologic Stage

• There is no pathologic T1 classification
• A positive surgical margin is indicated by an R1 descriptor — residual microscopic disease

Assigning the Gleason Grade

On prostatectomy

• Primary grade = the most predominant pattern
• Secondary grade = the second most predominant pattern
• If there are 3 different grades, a tertiary pattern is reported if it is higher than the secondary grade
  • A small tertiary (third, usually more aggressive) pattern is recorded as a note alongside the grade group → associated with increased biochemical recurrence risk

On biopsy

• Primary grade = the most predominant pattern
• Secondary grade = the highest non-predominant pattern — the most dangerous one, not the second most common
  • Counted however small the focus, because biopsy underestimates high-grade tumor → predominant 4 + focal 5 = 4+5 = 9 (GG5)

Worked examples

• Gleason score is difficult to characterize accurately in a patient who has received ADT
• Gleason scores 2–5 are no longer assigned — the lowest is 3+3 = 6 (GG1) → a biopsy reported as 5 (e.g., 3+2) needs slide review before staging or treatment
  • Same after TURP: a Gleason sum of 3 cannot be placed on the current risk scale → re-evaluate and re-biopsy, with MRI first, before choosing management

Gleason → ISUP Grade Group

---

Risk Stratification

• GG1 means Gleason ≤ 6 with no pattern 4 or 5
• When a lesion is biopsied with MRI-, TRUS- or DRE-guided targeting, all positive cores from that lesion count as a single positive core. For systematic biopsies this assumes ≥ 10 cores were taken
• NCCN additionally requires cancer in < 50% of biopsy cores as a mandatory criterion for favorable intermediate disease
• EAU (exam answer): Gleason 3+4 (GG2) + PSA < 10 + cT1–2 = favorable intermediate (cT2c alone is EAU high risk — see High Risk); GG2 + PSA 10–20 = unfavorable intermediate
• EAU risk groups derive from the D'Amico classification → they group patients with similar risk of biochemical recurrence after RP or EBRT

Very Low (Epstein)

• PSA <10, GG1, ≤3 cores, ≤50% involvement, PSAD <0.15, T1c
  • PSAD < 0.15 ng/mL/cc is the NCCN cut separating very low from low → PSA 9 in a 45-mL gland = 0.2 → Gleason 3+3 disease is low risk

Low

• PSA <10 AND GG1 AND ≤T2a
  • → AS first choice | alternatives: RP, EBRT, brachy
    • AS stays preferred (normal DRE, PSA < 10, Gleason 3+3 = 6) even with an isolated family history but no known germline mutation
  • → No imaging indicated

Intermediate — Favorable

• GG1 + PSA <20 OR GG2 + PSA <10
  • → LE >10 yr: AS, RP ± PLND (if nomogram >2%), OR EBRT ± brachy
  • → LE <10 yr: Observation (preferred) OR EBRT ± brachy
  • → Imaging: bone scan optional; cross-sectional imaging only if a nomogram indicates > 10% risk of regional node metastasis (see Imaging Indications)

Intermediate — Unfavorable

• GG2 + PSA 10–20 OR GG3 + PSA <20
  • → LE >10 yr: RP + PLND (first choice) OR EBRT + short-term ADT
  • → LE <10 yr: Observation OR EBRT + short-term ADT
  • → Imaging: A/P + bone

High Risk

• PSA >20 OR GG4–5 OR ≥T3
  • EAU (exam answer): high risk with any one of ISUP 4–5, PSA > 20 or cT2c → cT2c alone qualifies
  • → LE >5 yr: RP + PLND OR EBRT + long-term ADT (preferred)
  • → LE <5 yr: Observation OR ADT OR EBRT
  • → Imaging: A/P + bone

---

Treatment Options in Order, by Risk

• AS for favorable intermediate is acceptable when the tumor is T2a or less, PSA < 10, < 10% Gleason pattern 4, and < 33% of cores positive
• AUA (exam answer): HIFU and other ablation should not be used in low-risk disease (AS preferred) or, outside a clinical trial, in high-risk disease
  • In intermediate risk they are not preferred → high-quality comparative data are lacking
• ProtecT: RP and EBRT give equivalent oncological outcomes → 15-yr cancer-specific survival 97.8% vs 97.1%, metastatic progression 4.7% vs 5.0%
• Intermediate risk + closed-angle glaucoma → EBRT + short-term (4–6 months) ADT → robotic/laparoscopic RP needs prolonged steep-Trendelenburg pneumoperitoneum, which raises intraocular pressure

Cryotherapy

• For very low, low and intermediate risk, with no history of TURP, prostate size < 40 cc, and able to undergo transrectal ultrasound
• An alternative to RP in the obese patient, or after previous pelvic surgery or pelvic radiation
• Side effects — AUR, genital swelling, penile paresthesia, ED, urinary incontinence, fistula, rectal pain, urethral sloughing
  • AUA: counsel that ED is an expected outcome of whole-gland cryosurgery; in a young man with aggressive histology it likely undertreats the disease
• Local recurrence after cryotherapy tends to occur at the apex
• Temperature: below −40°C destroys prostate cells completely in a single freeze cycle; complete cell death is unlikely above −20°C
• After the lowest temperature, the number of freeze/thaw cycles is the most clinically important parameter → a repeated cycle causes more extensive tissue damage than a single cycle

HIFU

• Delivered transrectally → previous abdominoperineal resection is an absolute contraindication
• Age, PSA level and Gleason score are not contraindications
• Median lobe = relative contraindication → some centers perform TURP before HIFU to lower the likelihood of urinary retention

---

Imaging Indications

Initial imaging to assess for metastasis in men without cancer-related symptoms

* Bone scan is optional per AUA, not recommended per NCCN or EAU.

Cross-sectional imaging is optional per AUA, not recommended per EAU; NCCN recommends CT or MRI if a nomogram indicates > 10% risk of regional node metastasis.

mpMRI may detect nodal metastasis better than CT. NCCN prefers mpMRI over CT for pelvic nodes; AUA and EAU express no preference.

• Obtain a bone scan regardless if there is bone pain or a high ALP
• EAU:
  • No staging imaging for low- or favorable intermediate-risk localized disease
  • PSMA PET/CT if available, or at least abdominopelvic cross-sectional imaging + bone scan, for unfavorable intermediate (weak) and high risk (strong)
• AUA (exam answer):
  • No staging in asymptomatic low- or intermediate-risk disease — consider it if unfavorable intermediate
  • High risk → bone scan + CT or mpMRI, and PSMA PET may be added if these are negative
• NCCN (exam answer):
  • Tc-99m bone scan + CT or MRI in high risk
  • In intermediate risk only when a nomogram predicts > 10% probability of pelvic lymph node involvement

Bone Scan

• Unfavorable or high risk
  • AUA high risk = PSA ≥ 20 ng/mL, Grade Group 4–5 or cT3 — any single feature is enough, so PSA 25 with Gleason 6 still warrants a staging bone scan
• Bone pain
• Elevated ALP
• Vertebral uptake with a negative plain x-ray in a man likely to have metastases → spine MRI before any definitive local therapy
  • FDG-PET is not useful in prostate cancer

PSMA-PET

• Biochemical recurrence after local therapy
• High-risk disease (initial staging)
  • e.g. Gleason 8 (GG4) → PSMA PET/CT can substitute for CT + bone scan — more sensitive for lymph node and bone metastases
• ~27% higher accuracy than conventional imaging (proPSMA)

---

Management Overview

Localized → risk-stratified (see above)

Locally advanced (T3 or N1)

• Neoadjuvant ADT + EBRT + Adjuvant ADT (preferred)
  • Applies to high risk too — RTOG and EORTC trials show better outcomes with longer ADT alongside EBRT
  • Fit men, cN0 M0 → IMRT/VMAT + IGRT + long-term ADT ≥ 2 years (Strong)
  • cN0 M0 with ≥ 2 high-risk factors (cT3–4, Gleason ≥ 8, PSA ≥ 40 ng/mL) → add 2 years of abiraterone
• RP + PLND ± XRT ± ADT
  • Multimodal RP is only Weak — RCTs in locally advanced disease exist only for EBRT

Metastatic → systemic therapy (see below)

• M1 disease is not curable — the patient will never be labeled disease-free

Watchful waiting

• The intent is to give palliative therapy if the cancer progresses to the point where cancer-related symptoms are imminent or present
  • Preserves quality of life by avoiding upfront local treatment and ADT
  • vs active surveillance, which monitors men who are candidates for cure so the window of curability isn't missed
• Typically used in men with non-metastatic (M0) prostate cancer whose life expectancy is under 5–10 years
  • Advised when life expectancy is ≤ 5 years; definitive therapy needs 8–10 years of life expectancy to reduce prostate cancer death
  • e.g. incidental Gleason 3+3 in ≤ 5% of TURP tissue (cT1a) in a comorbid 80-year-old → watchful waiting
  • Asymptomatic localized disease, even Gleason 8, with life expectancy < 5 years (e.g. dialysis-dependent ESRD, EF 25% heart failure) → observation
    • In this limited-life-expectancy setting, ADT alone is for men with local symptoms

When to start ADT on watchful waiting

• PSA > 50
• PSADT < 12 months
  • PSADT is the single most predictive factor for prostate cancer mortality
• High PVR or ureteric obstruction
  • Bilateral ureteral obstruction from untreated disease (incl. progression on watchful waiting) → ADT + nephrostomy — drainage relieves the kidneys now
    • ADT shrinks the hormone-naive tumor, so the tubes can often be removed
  • Percutaneous nephrostomy beats retrograde stents for extrinsic compression — stents work poorly and must cross the tumor-invaded trigone; nephrostomy lets each kidney's output be measured

Clinical N0M0 → pathologic N1 (prostatectomy already done)

• ADT — lifelong (the best established evidence to date)
• ADT ± XRT
• Observation

Clinical N1

• Life expectancy < 5 years → watchful waiting
• Life expectancy > 5 years → 1st: RP + long-term ADT + XRT · 2nd: XRT + long-term ADT
  • Gleason 9 with bladder invasion (cT4) + enlarged pelvic node (cN1), CT and bone scan negative (exam answer) → XRT + long-term ADT; docetaxel + ADT is for metastatic disease

---

Active Surveillance Protocol

• PSA every 6 months; DRE annually
• Confirmatory biopsy at 1 year
  • Diagnosed on systematic biopsy without MRI → MRI first, then confirmatory biopsy within 1–2 years of diagnosis — grade misattribution (25–30%) far exceeds true progression (1–2.3% per year)
• Then biopsy or MRI every 2–5 years after the confirmatory biopsy
• mpMRI to augment (does NOT replace biopsy)
• Surveillance biopsy must include the anterior apical peripheral zone and the anterior transition zone

AS is mainly for low and very low risk.

• If the patient has > 20 years life expectancy, is of African ancestry, or has high volume (> 2 cores), the risk of progression is higher — therapeutic options are better
• PSA density is one of the strongest predictors of upgrading in men with very low grade disease considering AS
• Low-risk disease (Gleason 3+3, PSA ~5) on AS → 5-year cancer-specific survival effectively 100% — low-risk disease almost never kills in the short to medium term
• ProtecT (median 15-year follow-up):
  • No difference in cancer-specific or overall survival between active monitoring, surgery and radiotherapy (CSS ~99% at 10 years, ~97% at 15) — but monitoring increased metastasis

Triggers for Intervention

• Grade reclassification (GG≥2)
• Volume reclassification
• Rapidly rising PSA — a rise > 0.7/yr is the point to worry
  • Exam answer: a rising or fluctuating PSA alone should not prompt immediate definitive treatment → search for higher-grade disease with MRI or surveillance biopsy
• Patient preference

Contraindications to Active Surveillance

• Intraductal carcinoma
  • Aggressive → definitive treatment; to preserve sexual function, nerve-sparing RP is optimal and radiotherapy acceptable — adding ADT increases early/intermediate sexual dysfunction
• Cribriform histology
• Small cell / neuroendocrine variant — treatment is upfront chemotherapy, as it is resistant to ADT
• Germline BRCA2 (more than BRCA1 or ATM) — 80% of carriers on AS are upgraded by 10 years → consider definitive therapy even for low-grade disease

---

Radical Prostatectomy

• Ideal candidates for nerve-sparing — T2 or less, low risk, good baseline erection
• Bladder neck preservation does not improve the degree of incontinence, but may allow continence to return sooner
• Surgery is deferred 6–8 weeks after prostate biopsy and 12 weeks after TURP

Operative pearls

• Opening the endopelvic fascia: the small vessels crossing from the prostate to the pelvic sidewall are tributaries of the pudendal artery and veins, perforating the pelvic musculature
• Puboprostatic ligaments — divide only superficially, enough to expose the apex–dorsal vein complex junction
  • Keep the pubourethral component intact to preserve anterior fixation of the striated sphincter to the pubis
• Dividing the dorsal vein complex anteriorly → the striated urethral sphincter is the major structure at risk → incontinence
• Troublesome DVC bleeding → divide the complex completely over the urethra and oversew the end — partial division + traction on the prostate opens the cut veins and worsens bleeding
• Vesicourethral anastomosis — tension-free when tied (anterior suture first); if there is tension, release the bladder from its peritoneal attachments

Complications

• After RP, incontinence is usually secondary to intrinsic sphincter deficiency
• Risk factors for SUI — surgeon experience, baseline continence, OAB, diabetes, cancer extension, prior radiotherapy, previous TURP
  • Age is the strongest preoperative predictor of continence — older men have a thinner, more collagen-rich striated sphincter
  • Also: larger prostate size, shorter membranous urethral length, no bilateral NVB preservation
• Nerve-sparing speeds the return of continence but does not improve final continence
• A patient needing acute transfusion for hypotension after RP should be explored to evacuate the pelvic hematoma — this reduces the likelihood of bladder neck contracture and incontinence

Prognostic Factors from RP Pathology

• Positive margins — 50% of patients with positive margins do not recur
• Capsular penetration
• SV involvement
• Gleason 8 or higher
• Lymph nodes (pathologic or gross)
• These factors are what drive the choice of salvage vs adjuvant radiotherapy

Risk factors for positive margins

• Gleason 8 or higher
• T2b–T4
• Higher number of positive cores
• PSA > 10

Positive margin site

• The most common site for a positive margin is the apex, followed by posterior, then posterolateral
  • Arises while dividing the striated sphincter–dorsal vein complex — the anterior apical surface of the prostate is hard to identify

Recovery of Erectile Function

Three factors matter:

• Age — younger than 65
• Status of potency preoperatively
• Ability to preserve both neurovascular bundles intraoperatively

On-demand dosing of PDE5 inhibitors appears to be the most effective method to aid recovery of sexual function

---

The Neurovascular Bundle

• The NVB carries the cavernous nerves and lies outside the prostate, between the layers of lateral pelvic fascia — the levator fascia and the prostatic fascia
  • Runs posterolateral to the prostate, within the lateral prostatic fascia (levator = endopelvic fascia) — not in Denonvilliers fascia
• It is formed by a sympathetic component via the hypogastric nerve (T12–L1), joining the parasympathetic component (S2–S4) just below the base of the prostate
  • Capsular branches of the inferior vesical artery and veins run with the pelvic plexus branches — the NVB is the macroscopic landmark for the microscopic cavernosal nerves
• There is a 3–5 mm separation between the NVB and the prostatic capsule — which is why most men with localized disease can be offered nerve-sparing surgery

Dissection planes

Deciding when to excise the NVB

• No definite decision is made preoperatively — the call is made at surgery
• When the endopelvic fascia is opened:
  • If induration is palpable in the lateral pelvic fascia, the NVB on that side is widely excised.
  • If there is no induration but the NVB appears fixed to the prostate as it is released, it is also excised

High anterior release of the NVB at the apex

• Associated with significantly earlier recovery and return to baseline sexual function, and speeds recovery of continence
• Do NOT do a high anterior release if 2 or more of these are present:
  • PSA > 10
  • Gleason 6 or higher
  • Biopsy core involvement on that side > 20%
  • Cores with tumor on that side > 33%
  • Abnormal DRE
• Because recovery at 12 months after unilateral high release equaled bilateral, it is now routinely done on one side only — the side with the more favorable pathology

Urine Leak After RP

• Contrast extravasation is usually posterior, along the weakest point of the anastomosis
• Diagnosis: fluid creatinine, cystogram or CT cystogram; CT urogram if ureteric injury is a concern

Management, in order

1. Ensure the urethral catheter is patent — adequate bladder drainage is the most important step. Side-fenestrated catheters drain better and should replace other types
2. Check on CT whether the drain is lying on the anastomosis — if so, adjust it; drain any collections
3. Keep the drain off suction
4. If those fail, put the Foley on suction — low intermittent wall suction, or an underwater pleural suction system. Avoid continuous suction, which may suck in bladder mucosa instead
5. Divert the urine — bilateral nephrostomy, or bilateral open-ended ureteric catheters with the distal ends exteriorized alongside the urethral catheter, rendering the anastomosis dry
6. If all fail — reconstruction

Rectal Injury

• Minor lacerations in a preoperatively prepped rectum can be repaired primarily with multilayered, non-overlapped sutures
• Moderate to extensive injuries — especially after salvage prostatectomy following radiation — are best managed with primary repair + diverting colostomy
  • e.g. a 3 cm tear after pelvic radiation → layered primary repair + diverting colostomy
• Gross fecal spillage during robotic salvage RP → convert to open, colostomy, and delayed repair
• Risk of a later recto-anastomotic fistula ↑ with the extent of the laceration, prior radiation and intraoperative signs of rectal infiltration
• Postoperatively: low-residue diet and broad-spectrum antibiotics for 3–7 days

Rectourethral fistula

• Follows 1–2% of radical retropubic prostatectomies, usually at the vesicourethral anastomosis; risk ↑ after prior pelvic XRT, rectal surgery or TURP
• Large (3 cm) fistula in an irradiated pelvis → catheter drainage + fecal diversion + staged repair — catheter drainage alone rarely succeeds

PLND

• All high-risk patients
• For intermediate risk, the nomogram threshold differs by body:

• Complications — VTE, obturator nerve injury, lymphocele
• The internal iliac lymph nodes are the primary landing zone for nodal metastasis
  • Internal iliac (hypogastric) nodes carry the highest independent risk in high-risk disease; external iliac, obturator, common iliac and presacral nodes are involved less often
• Pure Gleason 3+3 (GG1) at RP does not metastasize to pelvic nodes — nodal metastasis 0% GG1 · 0.6% GG2 · 4.3% GG3

---

Radiation Therapy

• Definitive dose 76–82 Gy
• Intermediate risk → ADT for 6 months
• High risk → ADT for 2–3 years
  • Delivered as IMRT/VMAT + IGRT to 76–78 Gy (or moderate hypofractionation) with long-term ADT — not the 4–6 months used for intermediate risk
• Post-RP radiotherapy must be at least 64–65 Gy
  • Adjuvant RT dose (exam answer): > 60 Gy (possible threshold 61.2 or 64 Gy) — whereas primary prostate RT improves with ≥ 78 Gy

PSA bounce

• May last 6–18 months after radiotherapy (some sources report up to 5 years)
• Occurs at a mean of 9 months from therapy
• Seen in about 20% of men (12–38% reported), usually within 2 years
• Rising PSA within 30 months → monitor; bounce persisting > 30 months → biopsy

XRT field and ADT duration by risk

ADT here means castration with or without a first-generation antiandrogen, typically starting 2 months before XRT.

* If classified favorable intermediate on PSA/DRE/grade but molecular tests suggest more aggressive cancer, treat as unfavorable intermediate.

Nomograms predicting SV and regional node involvement help decide whether those areas are radiated.

Brachytherapy

• Unfavorable intermediate risk (Gleason 4+3, Grade Group 3) treated with seeds → trimodality therapy: short-term ADT (4–6 months) + brachytherapy + EBRT
  • LDR brachytherapy alone is reserved for favorable intermediate risk
• Brachytherapy + EBRT combined → the implant usually goes first, so EBRT can be stopped if toxicity develops
  • Trimodality therapy improves biochemical control but raises long-term urinary morbidity
• Severe obstructive LUTS → prefer EBRT over brachytherapy; keep TURP for obstruction that persists (brachytherapy causes more GU toxicity, especially with prostatic hyperplasia)
• Acute urinary retention after brachytherapy: 12–35%
  • Risk factors — prostate volume > 35 g, post-treatment volume > 55 g, > 33 needle punctures, AUA Symptom Score > 12
• TURP after brachytherapy → incontinence correlates with an interval of ≥ 2 years since implantation and obstructive symptoms at TURP
  • Not with ADT, prostate size, pretreatment IPSS, brachytherapy dose or PSA

Rectourethral fistula after radiation

• UTIs after EBRT + brachytherapy; VCUG shows an irregular prostatic urethra with immediate rectal filling and a normal bladder → urethrorectal fistula
• First step → urinary and fecal diversion, with deferred repair
  • Obliterative endarteritis leaves irradiated tissue unable to heal an early repair; diversion controls sepsis
• Staged repair is indicated for large fistulae, radiation-related fistulae, uncontrolled local or systemic infection, immunocompromise, or inadequate bowel preparation at definitive repair

---

Post-Prostatectomy Management

Indications for Adjuvant / Salvage RT

• Positive surgical margin (most common site = apex)
• Extracapsular extension
• SV invasion (T3)
• Detectable PSA

Indication for ADT after RP

• Positive lymph nodes (pN1)
  • Adjuvant ADT is reserved for pN1 — positive margins or PSA kinetics do not select for it; pN0 → no adjuvant ADT
  • pN1 after extended node dissection [EAU] → adjuvant ADT, ADT + RT, or observation (observation only with ≤ 2 positive nodes and an undetectable PSA)
  • Adjuvant ADT + RT to the prostatic fossa and pelvic nodes improves survival over ADT alone or observation — most in higher-risk pathology (grade group 4, pT3, more positive nodes)

Salvage RT

• Start at PSA ≤0.5 for best outcomes
  • A negative PSMA PET with rising PSA does not exclude microscopic fossa disease (it may miss low-PSA pelvic disease)
    • → still give early salvage RT to the prostate bed, before PSA reaches 0.5, rather than continuing surveillance
• Minimum dose: 64 Gy to prostatic bed
  • EAU: image-guided IMRT or VMAT, offered after two consecutive PSA rises without waiting for a PSA threshold
• Add ADT if PSA >0.6 (RTOG 96-01)
  • Add at least 4–6 months of ADT (extendable to 18–24 months) for high-risk recurrence — Gleason 8, positive margins, short time to recurrence, or short PSA doubling time
  • ADT + abiraterone is not recommended for non-metastatic biochemical recurrence

Adjuvant vs Salvage Radiotherapy

• Ideal salvage candidates — PSA < 1, long PSADT, recurrence > 1–2 years after RP, life expectancy > 10 years
• The data show no difference between them, so salvage is the better default.
  • The RADICALS and RAVES trials found no difference in overall survival, but the adjuvant group had more urinary tract and GI toxicity
• Adjuvant RT vs observation
  • EORTC 22911 — better biochemical and clinical progression-free survival (5-year biochemical PFS 74% vs 53%), the biochemical benefit seen mainly in positive-margin patients
    • No overall survival benefit
  • SWOG 8794 — improved median metastasis-free survival (14.7 vs 12.9 years) and overall survival (15.2 vs 13.3 years; NNT 9.1)

Selection for salvage radical prostatectomy — the patient must have:

• Biopsy-proven radio-recurrent prostate cancer
• At least 10 years of life expectancy
• No identifiable metastasis on imaging
• PSA < 10 ng/mL

---

Recurrence

PSA Persistence (> 0.1 ng/mL)

• 5–20% of men have PSA persistence at 4–8 weeks post-operatively
  • RP is successful only if PSA becomes undetectable — persistence (PSA ≥ 0.1 ng/mL) independently predicts metastasis and cancer-specific death
  • 15-year metastasis-free survival 53% with persistent PSA vs 93% with undetectable PSA (metastasis HR 3.59)
• Persistent PSA after RP is associated with more advanced disease —
  • Positive surgical margins
  • Pathologic stage > T3a
  • Positive nodal status
  • ISUP grade ≥ 3
• Repeat PSA after 8 weeks. If still persistent → PSMA. If local → XRT + ADT
  • Measure the first PSA at about 8 weeks (2 months) — PSA half-life 2–3 days needs time to clear before an undetectable level can be confirmed
  • PSA checked within 3 weeks is > 0.1 ng/mL in 77%, yet only 21% stay detectable → early values mislead, especially if preoperative PSA ≥ 20 ng/mL

Distinguish this from biochemical recurrence, where the PSA became undetectable first and rose later.

After RP

• PSA ≥0.2 with confirmatory rise
  • Confirmatory value > 0.2 ng/mL — a sensitive cutoff that sets the timing of salvage therapy, not its site
  • A single PSA of 0.15 ng/mL is not yet recurrence (needs 0.2 on two sequential tests) → repeat the PSA before MRI, PSMA PET, ADT or salvage RT
• Imaging if mets suspected: CT, bone scan, or PSMA-PET
• Risk assessment → Salvage RT ± ADT
• If local → salvage XRT + ADT — 6 months if PSA < 1, 2 years if PSA > 1
• If mets → treat as M1 disease

After RT

• PSA ≥nadir + 2
  • Phoenix definition — a rise that stays below it (e.g. nadir 0.6 → 1.8) is observed, not biopsied or treated
  • Biochemical failure with a PSA doubling time not explained by testosterone recovery → local salvage unlikely; define the recurrence site with mpMRI staging first, then salvage only with caution
• Imaging if mets suspected: CT, bone scan, or PSMA-PET
• Biopsy the prostate and seminal vesicles
  • Interpretable only 30 months after RT is completed
  • Salvage candidate with Phoenix failure, negative PSMA PET and a suspicious MRI lesion → MRI-fusion targeted biopsy (systematic alone is insufficient) to prove viable cancer before salvage
  • If localized → Salvage RP, cryotherapy, brachy ± ADT
  • If negative biopsy → ADT alone
• mpMRI after RT — atrophy and fibrosis lower the T2 signal across the whole gland, so T2 is less reliable; a focal T2-hypointense lesion with restricted diffusion suggests local recurrence

Contraindications OF Radiotherapy (ST-LIAR)

After HIFU or Cryotherapy

• No end-points have been validated against clinical progression for these modalities
• Do PSMA and a prostate biopsy plus SV biopsy
  • After focal therapy, success is judged by targeted biopsy of the treated area + systematic biopsy of the untreated zone — not by PSA, DRE or mpMRI alone
  • 2013 ICUD follow-up — mpMRI with a mandatory 4–6-core targeted biopsy at 3–6 months, then mpMRI + systematic biopsy at 1–2 and 5 years to catch recurrence outside the treated zone
• If mets → treat as M1 disease
• If local → salvage radical prostatectomy or salvage cryoablation

---

Biochemical Recurrence

• It usually takes about 8 years from the onset of biochemical recurrence until radiological metastases appear
  • Then a further 5 years from metastasis to death → recurrence to death > 13 years (untreated BCR after RP; median times)
• EAU risk groups (BCR after RP)
  • Low risk — PSA-DT > 1 year and Gleason < 8 (grade group < 4)
  • High risk — PSA-DT ≤ 1 year or Gleason 8–10 (grade group 4–5)

Workup

• PSMA-PET — recommended as the initial imaging in biochemical recurrence [EAU]
  • After RP (PSA > 0.2 ng/mL with two consecutive rises) → PSMA PET/CT is the next step if it will change treatment — separates fossa-confined from distant recurrence before salvage RT
  • PSMA hybrid imaging is the most sensitive modality at PSA < 0.5 ng/mL; the PSA threshold that best predicts further metastases after RP is > 0.4 ng/mL and rising
• Conventional CT/bone scan: low yield
  • After RP, limited value below PSA 10 ng/mL; after RT, CT is not useful for local recurrence at PSA < 20 ng/mL
• mpMRI performs better than PET/CT for identifying local recurrence, especially at low levels of biochemical failure
  • After RP, reliably detects local recurrence at PSA 0.4–1.4 ng/mL
  • After RT, MRI (contrast-enhanced, spectroscopy, diffusion-weighted) is the most sensitive test for local recurrence —
    • Diffusion-weighted MRI showed 100% sensitivity and specificity against a 22-core biopsy
    • TRUS is no better than DRE
• Pelvic CT mass at the urethrovesical anastomosis, anterior to the rectum (slowly rising PSA after RP) → prostatectomy-bed recurrence, not a lymph node or seminal vesicle

Management

• Local failure → Salvage (see above)
• Distant failure → Treat as mHSPC (see below)

---

Androgen Deprivation Therapy (ADT)

Goal

• Testosterone <50 ng/dL (or <1.7 nmol/L)

General Principles

• Intermittent ADT reduces ADT-related side effects compared with continuous ADT without compromising cancer control or survival
• Prostate cancer responds to castration for an average of 2–3 years before CRPC develops — though the range runs from months to > 10 years
• In men with CRPC, some cancer cells still respond to androgen suppression — so castration must be CONTINUED while other therapies are given
• ADT side effects: hot flushes, low libido, lethargy, ED, gynecomastia
  • Anemia on long-term LHRH agonists — normochromic normocytic, from androgen loss (not marrow metastases); appears within 6 months and takes up to a year to reverse after ADT stops
  • ADT-induced anemia is symptomatic in only about 13%; pre-ADT anemia (Hb < 12 g/dL) is associated with shorter survival
• Megestrol acetate 20 mg twice daily significantly reduces the frequency of hot flushes
  • Megestrol is a progestational steroidal antiandrogen; hot flashes affect 44–80% of men on ADT and usually start about 3 months into therapy
  • Progestational agents beat antidepressants — hot-flash score cut by 94.5% with cyproterone acetate and 83.7% with medroxyprogesterone, vs 47.2% with venlafaxine
• Patients on an LHRH agonist need an annual bone density scan plus regular calcium and vitamin D

Time to castrate testosterone

---

Mechanisms

Androgen biosynthesis inhibition

Ketoconazole

• A competitive inhibitor of several cytochrome P450 enzymes, including 11β-hydroxylase and CYP17
• Inhibiting CYP17 reduces androgen synthesis in the adrenal glands and testicles
• Inhibiting 11β-hydroxylase reduces aldosterone and glucocorticoid synthesis — so mineralocorticoids and steroids are necessary

Abiraterone (Zytiga) — take on an empty stomach

• A selective, irreversible inhibitor of CYP17
  • Inactivating CYP17 blocks androgen synthesis in both testes and adrenals
• In the adrenal glands, inhibiting CYP17 reduces androgens and glucocorticoids but increases mineralocorticoids

Abiraterone side effects

• Hyperaldosteronism / mineralocorticoid excess — fluid retention or edema 27%, hypokalemia 28%, hypertension 9%, alkalosis
• Fatigue, musculoskeletal pain, nausea, vomiting, hot flushes, diarrhea, cough, headache
• High LFTs are the most common toxicity — requires dose reduction or stopping the drug
• If the patient develops fatigue soon after starting, increase the prednisone dose
  • Fatigue, nausea and anorexia on prednisone 5 mg twice daily, despite responding bone metastases = ACTH excess → temporarily double the prednisone rather than switching to enzalutamide

Steroids are mandatory with abiraterone

• mCSPC → prednisone 5 mg once daily
• mCRPC → prednisone 5 mg twice daily
• Why low-dose prednisone — complete CYP17 blockade removes pituitary feedback → mineralocorticoid excess; if hypertension, edema or hypokalemia appear → add or increase prednisone

Monitoring on abiraterone: blood pressure, potassium, phosphate, LFTs, fluid retention, and signs of adrenocortical insufficiency — every 2 weeks for the first 3 months, then monthly

• Abiraterone is approved for mCRPC before and after chemotherapy, but not for non-metastatic CRPC

1st-gen anti-androgens

Nonsteroidal antiandrogens are FDA-approved with castration, but not approved for monotherapy.

• Mastodynia on hormonal therapy (from flutamide, nilutamide or bicalutamide) → stop the drug if possible, or give tamoxifen, or breast XRT 15 Gy, or breast reduction surgery
• Nonsteroidal antiandrogens vs castration — they block testosterone at the AR rather than lowering it → circulating testosterone rises ~1.5-fold, without hypogonadism
  • Unlike steroidal cyproterone acetate, they block central ARs and remove testosterone feedback → LH, testosterone and estrogen all rise → gynecomastia and mastodynia
• Nilutamide — delayed adaptation to darkness after bright light in about a quarter of men; highest interstitial pneumonitis rate (1–2%), a class effect of nonsteroidal antiandrogens
• Bicalutamide 150 mg — no PFS benefit in localized disease (overall survival trended worse, HR 1.15); improved PFS in locally advanced disease (HR 0.67), without overall survival gain

2nd-gen anti-androgens

• These inhibit multiple steps in the AR signaling pathway; all are metabolized by hepatic cytochrome P450
• Shared side effects: fatigue, hot flushes, nausea, diarrhea, hypertension, asthenia, falls, bone fracture, musculoskeletal pain, seizure, mental impairment, ischemic heart disease

FDA-approved indications

LHRH Agonists

• Agents — leuprolide (Lupron), goserelin (Zoladex) 10.8 mg q3-monthly, triptorelin
• Causes testosterone flare → cover with 1st-gen anti-androgen(Bicalutamide)
• Flare is prevented by starting the antiandrogen either at the time the LHRH agonist starts, or up to 7 days before, and continuing it for 4 weeks
• Nafarelin (LHRH agonist) → largest prostate shrinkage (~30–40%) — castration removes both testosterone and DHT; cyproterone, finasteride and flutamide shrink it progressively less

GnRH Antagonists

• Degarelix (Firmagon): 280 mg induction → 80 mg q28 days
• No flare | castration in ~3 days
• Relugolix (Orgovyx) — an oral GnRH antagonist; castration in ~15 days
  • Do not use relugolix with abiraterone, enzalutamide, darolutamide or apalutamide — potential drug interactions
    • It has not been adequately studied in combination with chemotherapy or any of those agents

Hormonal Interventions — Overview

---

Metastatic Prostate Cancer

• 55% of patients with no metastases on bone scan or CT actually have metastases on PSMA-PET

Prognostic factors

• Number of bone metastases
• Location of bone metastases
• Visceral metastases
• ISUP grade
• Initial PSA
• Performance status
• PSA level after 7 months of ADT

mCSPC

Do these in every metastatic patient

• Genetic counseling and germline testing
• Assess disease burden and symptoms
• Start calcium and vitamin D
• Start denosumab or zoledronic acid if bone metastases are present
• Add steroids if giving abiraterone or docetaxel

High volume (visceral mets OR ≥4 bone mets with ≥1 outside vertebrae/pelvis)

• ADT + docetaxel OR 2nd-gen AR agent (Apalutamide,Enzalutamide,Darolutamide)
  • CHAARTED: ADT + docetaxel benefit only in high-volume disease (OS +14 mo)

Low volume — absence of visceral metastasis, any number of nodal metastases, and any of: no bone metastasis · 1–4 bone metastases in any distribution · > 4 bone metastases all confined to the vertebral bodies and pelvis

• ADT + 2nd-gen AR agent (Apalutamide,Enzalutamide,Darolutamide)
• ± prostate radiation (STAMPEDE) — men on lifelong ADT (± upfront docetaxel) randomized to prostate radiation or none
  • Low volume: improved failure-free survival AND overall survival (+8% OS at 3 years)
  • High volume: improved failure-free survival, but NOT overall survival

---

mCRPC

Definition of CRPC: castrate serum testosterone < 50 ng/dL (< 1.73 nmol/L) plus either:

• Biochemical progression — three consecutive rises in PSA, at least one week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL OR
• Radiological progression — new lesions: either two or more new bone lesions on bone scan, or a soft tissue lesion

Symptomatic progression alone is NOT sufficient to diagnose CRPC

No prior docetaxel

Prior docetaxel

Radium-223 — the full criteria

• Indicated for men with ALL of: symptomatic bone metastases, no visceral metastases, and malignant lymphadenopathy ≤ 3 cm
• Treats bone metastases in CRPC — not a treatment for locally advanced or nodal disease itself (e.g. cT4 cN1 → XRT + long-term ADT)
• Do NOT combine radium-223 with chemotherapy — cumulative myelosuppression
• Do NOT combine radium-223 with abiraterone — increased fractures and mortality

Sipuleucel-T — not recommended in men with any of:

• Using opioids to control cancer-related pain
• Visceral metastasis
• Rapidly progressive disease
• Life expectancy < 6 months
• Large tumor burden
• ECOG performance status ≥ 2
• Small cell or neuroendocrine prostate cancer

Antihistamines must be given with sipuleucel-T

PARP inhibitors (Olaparib/Rucaparib)

• Target tumors with DNA repair defects
• Durable responses in mCRPC with germline BRCA2 mutations, or somatic DNA-repair gene mutations — BRCA1/2, ATM, Fanconi anemia genes, CHEK2 (detected by next-generation sequencing)

Chemotherapy

Docetaxel — a mitotic inhibitor that prevents cell division. Give with prednisone 5 mg BID. For high-volume metastatic disease.

• Side effects — bone marrow suppression, fatigue, neutropenia, anemia, nausea, vomiting, diarrhea, sensory neuropathy, alopecia, nail dystrophy, dysgeusia, stomatitis, dyspnea, peripheral edema

Cabazitaxel — same mechanism. Approved for mCRPC previously treated with a docetaxel-containing regimen.

• Side effects similar to docetaxel, but additionally low platelets, neutropenia (including febrile neutropenia) and diarrhea — but generally NOT neuropathy
• Cabazitaxel is not susceptible to MDR1, which is why it retains efficacy in docetaxel-resistant cancers

Platinum agents

• Indicated in small cell prostate cancer, and perhaps in other mCRPC subsets — combined TP53 and PTEN inactivation, or DNA repair deficiency mutations
• Neuroendocrine tumors are invariably unresponsive to hormonal manipulation, but are transiently sensitive to radiotherapy and chemotherapy — platinum-etoposide or platinum-taxane combinations

AR-V7 — a blood-based biomarker used to help choose therapy in mCRPC

• AR-V7 positive → may benefit more from taxane chemotherapy
• AR-V7 negative → may benefit similarly from either AR-directed therapy or chemotherapy

nmCSPC

Not curable, and local therapy has failed.

• Asymptomatic → surveillance or ADT
• Symptomatic → ADT

nmCRPC

• nmCRPC = rising PSA + castrate testosterone + negative CT and bone scan
• PSADT >10 months → observe
• PSADT <10 months + LE >5 yr → ADT + AR-targeted therapy (Apalutamide / Enzalutamide / Darolutamide)
  • Pivotal trials (SPARTAN, PROSPER, ARAMIS) enrolled PSADT ≤ 10 months → agent added to ongoing ADT → metastasis-free survival AND overall survival benefit

---

Bone Health in CRPC with Mets

• Denosumab 120 mg SC q4wk OR Zoledronate 4 mg IV q4wk + Ca + vitamin D
  • Calcium and vitamin D given daily with both agents
• Denosumab vs zoledronate: superior time-to-first SRE; no OS difference
• Zoledronate contraindicated if CrCl <30; denosumab no renal adjustment
  • Serum creatinine elevation is the zoledronate toxicity that governs dosing → check renal function before each dose; dose-adjust for lesser renal impairment
  • Denosumab → no renal monitoring needed either
• Denosumab is not eliminated by the kidney; zoledronic acid is — denosumab SC, zoledronic acid IV
• Both cause osteonecrosis of the jaw
  • ONJ = exposed maxillofacial bone that fails to heal within 8 weeks in a patient on or previously on bisphosphonates, without prior craniofacial radiotherapy
  • Zoledronic acid → ONJ in 21% after the third year → dental examination before starting therapy
• Other bisphosphonate side effects: pyrexia · hypocalcemia (plus renal impairment and ONJ, above)

How zoledronic acid works

• A nitrogen-containing bisphosphonate — concentrates in bone at sites of active resorption
• Inside the osteoclast it inhibits farnesyl pyrophosphate synthase → blocks prenylation of small GTPases (Ras, Rho, Rac) → osteoclast apoptosis

How denosumab works

• When cancer metastasizes to bone it increases RANK ligand, which activates more RANK receptor, driving osteoclast activity
• Denosumab is a monoclonal antibody that binds RANK ligand, preventing it from binding the RANK receptor — breaking the link that causes bone resorption

NOT approved for SRE prevention in mHSPC

Spinal Cord Compression

• Emergency — MRI is diagnostic
• → Dexamethasone (10 mg load, 4 mg q6h) + RT ± surgical decompression
  • Start high-dose corticosteroids on mere suspicion — don't wait for imaging
  • Dose range (exam answer): dexamethasone 4–10 mg load, then 4–24 mg q6h (the regimen above sits within this range)
  • RT and/or surgical decompression follow imaging
• Surgery first if: unknown tissue dx, prior RT to area, pathological fracture with instability

Palliative RT for Bone Pain

• Single fraction 800 cGy = preferred for uncomplicated non-spinal bone mets