Second leading cause of cancer death in US men - but only 10% die from the disease

• 95% adenocarcinoma
• Most commonly located in peripheral zone (BPH is more central -> more LUTS)
• Metastasizes to: pelvic lymph nodes, bone (osteoblastic), lung, liver

Grading: 

• Gleason score based on architectural pattern of prostate gland (two most common; graded 1-5)
  • e.g. 4+3=7 is worse than 3+4=7
• 
• **hide**3: single glands separated by stroma
• **hide**4: ragged poorly formed glands with fusing
• **hide**5: no gland formation - single cells/cords/sheets
• **hide**Histological hallmark is disruption of glandular architecture and loss of basal cell layer
• Other findings
  • HG PIN (prostatic intraepithelial neoplasia) - manage like elevated PSA; shared decision making for repeat MRI/biopsy
    • Early studies showed increased risk of cancer on repeat biopsies and recommended early repeat biopsy, but more recent studies show no difference (in single core or multifocal HGPIN)
  • ASAP (atypical small acinar proliferation) - suspicious for cancer but not large enough to make diagnosis - should rebiopsy (40-50% of re-biopsy will be positive)
  • IDC (intraductal carcinoma) - graded as Gleason 4 - should manage definitively
  • Large cribriform pattern - also unfavorable histology

Staging:

• *pT2 used to be stratified into T2a/b/c similar to cT2. However little prognostic info with this, so as of AJCC 8th edition (2017), only classifed as T2.

• Usually asymptomatic - prostate cancer is located more peripherally, compared to BPH which is more central and thus causes more LUTS
• Advanced cancer: bone pain, LUTS, hematuria, urinary retention

Screening

• 90% of detected cancers are organ-confined; may not cause morbidity/mortality
  • **hide**NNT is 1000 to prevent 1 prostate cancer death (ERSPC trial).
  • **hide**Current USPSTF recommendation D→C: offer based on patient circumstances (panel had no urologists/oncologists).
  • The goal of screening is to identify aggressive prostate cancer while it can be cured.
• Adjust screening age/frequency based on risk (high baseline PSA, family hx, increased age, African descent)
  • Start screening age 45-55
    • Screen closer to age 40-45 for AA man with +fhx
    • Starting age varies with guidelines (AUA recommends starting at age 55; NCCN recommends age 45)
  • Stop if life expectancy < 10 years (stop ~ age 70)
  • If > 70 and still being screened: consider raising biopsy threshold to PSA > 10, and stopping screening for men with PSA < 3 (AUA guideline)
• Screening: PSA + DRE q1-2 years
  • PSA only estimates RISK of prostate cancer
  • Generally PSA > 4 = abnormal
  • Age-adjusted thresholds (MSKCC age-adjusted screening guidelines):
    • 40-49: 2.5
    • 50-59: 3.5
    • 60-69: 4.5 
    • > 70: 6.5
  • Other factors - UTI, Foley catheter, will artificially elevate PSA (do not test during this)
    • Normal/gentle DRE should not affect PSA
  • Family medicine/PCP practice:
    • 
• PSA should not be interpreted in a vacuum - use risk calculators to guide biopsy decision, shared decision making
  • If PSA < 1.0 at age 60, likelihood of prostate cancer death < 0.3%
  • While if PSA > 2.0 at age 60, number needed to screen is 23 to prevent 1 death at 15 years
  • PSA sensitivity ~ 85% in general population, but specificity is much worse
  • **hide**CAP, ERSPC, PLCO trials studied PSA screening - most prostate cancers are low/intermediate risk
• Other screening tests to help decide if biopsy is warranted:
  • Multiparametric MRI
  • Biomarkers - see table below
  • % free PSA (see table below)

    • % free PSA	Probability of cancer
      0-10%	56%
      10-15%	28%
      15-20%	20%
      20-25%	16%
      > 25%	8%

  • PSA density > 0.10 ng/ml
  • Taking 5-ARI and PSA consistently rises by any amount, or does not decline ≥ 50% by 12 mo after starting 5-ARI
  • PSA velocity (may not be good predictor/adds no value to PSA alone; no longer recommended)
    • **hide**≥ 0.35 ng/mL/yr [tPSA < 4]
    • **hide**≥ 0.75 ng/mL/yr [tPSA 4-10]
• Post-diagnosis tests to help guide management: all based on RNA markers
  • Prolaris - predicts likelihood of metastasis, cancer-specific mortality
  • Decipher - predicts likelihood of metastasis, cancer-specific mortality
  • Oncotype genomic prostate score - 17-gene PCR assay, predicts upgrading (Gl 4+3, extracapsular extension) on radical prostatectomy
• Prostate biopsy and prostate MRI

* PSA-based tests may not be valid if have taken 5-ARI in past 6 mo (lowers PSA).

Metastatic work-up

• Bone scan if:
  • High/very high risk; unfavorable intermediate risk if T2 and PSA > 10
  • Bone pain, elevated alkphos
• Pelvic CT/MRI (nodal staging) if: lymph node metastasis nomogram ≥ 10%
• PSMA PET scans now FDA approved for initial staging (do not need to get CT/bone scan first)
• True Gleason 6 has almost no metastatic potential (but half are upstaged to Gleason 7+ on surgical pathology due to inadequate sampling)

Risk stratification systems

• D'amico (1998) - original risk stratification (5-year risk of biochemical recurrence); most systems (AUA, NCCN etc) are generally similar to this
• NCCN (2019) system (below) adds very low risk; favorable/unfavorable intermediate risk; very high risk
  • IRF = intermediate risk factor - PSA 10-20, Gleason 7, or T2b/T2c
  • **hide**Still huge overlaps in risk in between these groups
• Other systems: nomograms; CAPRA, MSKCC nomogram

• ISUP (pathology) grading system released in 2014: Grade Group differentiates Gleason 7 by 3+4 vs 4+3

Prevention

• 5α-reductase inhibitors reduce risk of low Gleason score but small increase in risk of high Gleason score = no change in survival

Watchful waiting/active surveillance

• **hide**In US 40% of men on AS, compared to 80-90% of men in Europe w low risk disease
• WW is less aggressive than AS; use for life expectancy < 5 years (watch and treat with hormonal therapy after they develop metastatic disease)
• Confirm 'low-risk' with re-staging biopsy 1 year after diagnosis.
• Protocols vary among institutions, but typically PSA + DRE q3-6 mo
  • PASS (AS) trial - re-biopsy at 1 year, biopsy q2 years during first 5 years; PSA/DRE q6 months
• 30-50% of patients on AS 'progress', e.g. grade increases, by 5 years
• Triggers for recommending definitive treatment: increase in Gleason grade, #/% positive cores, increasing PSA/fear of cancer or repeat biopsies
• **hide**MRI vs normal biopsy in active surveillance - no difference in upgrading score on biopsy

Localized disease - Definitive treatment

Comparison of quality of life after radiation vs prostatectomy

Radical prostatectomy (RP)

• Generally do not offer to patients > ~75 yo due to morbidity
• Side effects:
  • ED (~ 20% able to have erection at 3 months, 40% at 6 months, 60% at 1 year)
    • Similar long-term outcomes to radiation therapy
    • SHIM score 0-25 (higher = better erectile function)
    • Calculator based on patient-reported outcomes
  • Urinary incontinence (of 'severe' pad-changing incontinence: 25% at 3 months, ~5-10% at 1 year)
    • IPSS score 0-35 (higher = worse urinary sx)
    • Risk of SUI for salvage RALP after radiation - much higher, 50-100%
  • Can perform nerve sparing with RP (erectile dysfunction worse but then improves over 1-4 yrs), but not with radiation/cryotherapy (effects emerge over many years).
• High risk/locally advanced prostate cancer - consider adjuvant vs salvage RT; RADICALS-RT trial showed no difference in biochemical progresison free survival between adjuvant vs salvage

Radiation therapy (RT)

• Typical dose 70-72 Gy; dose-escalation should be used when EBRT is primary treatment
• External beam radiation (EBRT), IMRT (more precise targeting, less dose to neighboring organs), cyberknife.
  • Generally 5 fractions/week x 8 weeks (1.8-2.0 Gy/fraction)
  • Hypofractionation = fewer sessions (daily x 5.5 weeks) with higher dose/fraction (2.4-4.0 Gy/fraction). Side effects about the same). Can be offered to all risk groups
  • SBRT = stereotactic body radiotherapy = higher dose, twice a week x 2.5 weeks (6.7 - 8.0 Gy/fraction. Total 35-40Gy to minimize toxicity).
• Brachytherapy (small prostates only, < 50-60 cc) - monotherapy or in combination with EBRT
  • LDR (low dose rate) - single day procedure, permanent implant
  • HDR (high dose rate) - 1-4 temporary implant sessions
• Low risk - EBRT or brachytherapy monotherapy
• Intermediate risk - EBRT +/- short course ADT +/- brachytherapy boost
  • 4-6 mo ADT, starting 2 mo before EBRT - more benefit for unfavorable intermediate risk compared to favorable intermediate risk
  • Brachytherapy monotherapy can be considered for favorable intermediate-risk cancer
• High risk - EBRT + long-course ADT (18-36 mo) +/- brachytherapy boost. May offer XRT to pelvic nodes
• Adjuvant (T3 disease, positive margins) - radiation to prostatic fossa
• Salvage (detectable PSA >= 0.1 ng/ml and rising, without radiographic evidence of metastasis) - radiation to prostatic fossa and pelvic lymph nodes
• For high risk patients (EPE, SV invasion, positive margins) with undetectable post-op PSA - no differences in relapse between adjuvant and salvage RT, though adjuvant RT a/w more side effects (RADICALS, RAVES trial)
  • Waiting for salvage radiation can spare radiation therapy
• Side effects: ED (50% incidence at 5 years), incontinence (~10% at 1 year), voiding sx from bladder irritation, proctitis. Brachytherapy has greater exacerbation of obstructive urinary symptoms
• Some patients experience "PSA bounce" 1-3 years after radiation therapy (~20%, in younger patients, especially after brachytherapy)
  • Transient PSA elevation 0.2-1.2 ng/mL
  • Not clinically significant - goes back down

**hide**Prostate cancer treatment trials

• **hide**SPCG-4 trial - WW vs RP
  • **hide**1990s, 40% detected due to symptoms, 5% detected from screening (pre-PSA era)
  • **hide**No RP if node dissection positive
  • **hide**Local progression treated with TURP (WW) or orchiectomy/ADT (RP)
  • **hide**Greatest survival benefit with RP is low/intermediate risk; no survival benefit (at ~20 yrs) for high risk
• **hide**ERSPC - q2y PSA screening
• **hide**PLCO - q2y PSA screening
• **hide**PIVOT trial - WW vs RP (US)
  • **hide**mid 1990s, 75% detected from screening, 75% had low risk prostate cancer
  • **hide**Low grade disease and less than 12 y LE do not benefit from RP
  • **hide**Issues - VA population (more comorbidities
• **hide**PROTECT - AS vs RP vs RT (UK)
  • **hide**At 10 years no difference in death from screen-detected prostate cancer (< 1%) (affirms AS for low-risk prostate cancer)
  • **hide**20% progressed in 10 years in AS
• PIVOT, PLCO trials - no survival benefit from prostate cancer intervention
• ERSPC, SPCG-4 European trials - 20% survival benefit from intervention

Regional node-positive disease:

• Clinically node-positive on imaging: ADT +/- radiation therapy to the primary
  • Surgical management of cN1 patients should be restricted to clinical trials
• Node-positive after prostatectomy: long-term ADT

Biochemical recurrence:

• PSA rise after definitive treatment, defined as
  • Post-RT: PSA nadir + 2 ng/mL (Phoenix criteria)
  • Post-RP: PSA ≥ 0.2 x 2
  • Post-RP persistence: PSA does not fall to undetectable levels
    • Get post-op PSA 6-8 wks after
• 1/3 of men have BCR after definitive treatment (median time ~ 8 yrs)
  • Natural history of progression - 34% with BCR develop mets (median time to mets 8 years); median time to death after mets 5 years. 
• PSA doubling time (PSADT)
  • > 15 mo is low risk for prostate cancer death over 10 years - surveillance if life expectancy < 10 yrs.
  • < 10-12 mo a/w higher risk of developing metastatic disease
  • < 3 mo should be treated aggressively.
• May get PET scan to assess for metastatic disease/recurrence
  • Prostate ca is not FDG-avid; use tracers such as F-18 (FACBC) or C-11 choline, but now PSMA approved and more sensitive
  • **hide**Bone scans are not very sensitive/specific for bone mets - also may see "flare" in lesions due to treatment response - re-scan in 6 weeks 
• In absence of metastasis, should offer observation or clinical trial enrollment. ADT should not be routinely initiated, but can offer intermittent ADT in this population

Advanced disease

Includes

• Biochemical recurrence only
• Metastatic castration-sensitive prostate cancer 
• Metastatic castrate-resistant prostate cancer (mCRPC)
• Non-metastatic castrate-resistant prostate cancer (nmCRPC) 

Androgen deprivation therapy (ADT)

• Indications: in conjunction with RT for localized disease; for metastatic disease
• Castration - surgical/orchiectomy or medical/LH suppressor are equally effective, but medical castration is reversible. 
  • Testosterone should be < 20-50 ng/dl after castration
• Inhibition of androgen signaling occurs through:
  • Suppression of hypothalamic-pituitary-gonadal axis (GnRH agonists/antagonists)
  • Inhibition of androgen biosynthesis (abiraterone)
  • Inhibition of androgen receptors (-amides)
    • (DHT binding activates translocation and transcription of androgen response genes)
• Typical regimen - Casodex/bicalutamide x 2 weeks before starting GnRH agonist (Lupron/Zoladex) injections
  • Bicalutamide (Casodex) 50 mg PO qd = nonsteroidal antiandrogen (receptor-based)
    • Blocks initial testosterone flare from GnRH agonist (~ 7 days)
    • Continue usually for 45 days at least
      • Not recommended except to treat testosterone flare, because newer generation (enzalutamide, apalutamide) much more effective
    • Fewer GI side effects than flutamide
  • Lupron/leuprolide, Zoladex/goserelin = GnRH agonists
    • Initial tesosterone flare - prevent clinical worsening of cancer symptoms by starting Casodex 2 weeks before
    • Reaches castrate level in 30 days
  • Degarelix/Firmagon = GnRH antagonist
    • Rapid castration and testosterone decline (within 3 days, compared to 3-4 weeks with GnRH agonist); ideal for symptomatic metastatic disease (prevent testosterone surge/symptomatic flare). (Ketaconazole can also achieve rapid castration)
• Side effects: Metabolic (body habitus, HLD, diabetes, CV disease), hot flashes, osteoporosis, gynecomastia
  • Perform baseline/periodic DEXA scans for ADT
• Stop ADT when:
  • PSA < 4 and no clinical progression after 6-9 mo of ADT.
  • Resume if PSA > 10-20 or clinical progression.

Metastatic castration-sensitive prostate cancer

• Overall survival rates at 2-3 years around 70-80%
• ADT PLUS... (not studied as monotherapies)

*high-volume = ≥ 4 bone mets with at least 1 outside of axial skeleton, and/or presence of visceral metastases. Low-volume = not high.

Castration-resistant prostate cancer

• PSA rises (or new metastatic lesions occur) despite testosterone < 50 ng/dl (generally after 2-3 years of castration)
  • Continue ADT (some cells still responsive)
  • Metastatic work-up for bone scan and pelvic imaging

Non-metastatic (nmCRPC)

• Goal is to delay metastasis
• PSA doubling time < 10 mo a/w disease progression
• ADT + androgen receptor inhibitor: enzalutamide, apalutamide, or darolutamide
• Median overall survivals 67-73 mo, compared to 56-60 for ADT alone
• 2024 retrospective cohort study (no head-to-head RCTs available) - darolutamide better tolerability (HR 0.6-0.7 risk of discontinuation), less disease progression to mCRPC (HR 0.6-0.65)

Metastatic (mCRPC)

• Evidence for: abiraterone, enzalutamide, docetaxel, cabazitaxel (used after docetaxel resistance)
  • Consider docetaxel more if high disease burden with visceral mets, rapidly progressive disease, or after at least one androgen inhibitor pathway drug has been used (e.g. abiraterone does not work well if already failed enzalutamide)
  • Enzalutamide slightly superior to abiraterone (1-2 mo benefit in OS (2024))
• As well as:
  • Provenge (sipuleucel-T) - autologous cellular immunotherapy. A/w mortality improvement, but not improvement in PSA or radiographic response, so use for asymptomatic or minimally symptomatic.
  • Xofigo (IV radium-223) - indicated for use with symptomatic bone metastases (radium has affinity for bone mets)
  • Pluvicto (Lu 177 vipivotide tetraxetan) - indicated for mCRPC 2nd line after ADT and chemotherapy (FDA approved 2022 (VISION trial - OS 15.3 vs 11.3 mo, HR death 0.6, PFS 8.7 vs 3.4 mo)).
• Perform germline/tumor testing (DNA repair genes including BRCA1/BRCA2)
  • PARP inhibitors Olaparib, rucaparib can be used to treat mCRPC with BRCA1/2. 
    • 10% discontinuation (nausea, fatigue, anemia), very small risk (< 1-2%) of AML/myelodysplastic syndrome
  • Pembrolizumab (PD-L1) can be used if deficient mismatch repair, or high microsatellite instability
• Median overall survivals 18-35 mo, compared to 16-30 mo (overall few mo survival advantage)
  • DNA repair gene mutations a/w lower survival ~ 10 mo

Bone mets

• Bone mets appear osteoblastic radiographically, but still have osteoclastic activity -> pathologic fractures, etc
• Bone-protective agents/osteoclastic inhibitors indicated for bone mets in castration-resistant prostate cancer (whether symptomatic or not) to reduce rate of skeletal-related events
  • Bisphosphonates (zoledronic acid)
  • Denosumab (human mAb against RANK ligant/osteoclast activity) 
  • Recent (2023) analysis of STAMPEDE patients shows benefit of bisphosphonates for metastatic castrate-sensitive patients also

Other treatments for localized cancer

Cryotherapy

• Indicated for low-risk disease; small glands (< 50 mL)
• A/w more impotence than other treatment modalities
• TRUS guidance of transperineal probe placement
• Tissue necrosis at -40°C once x 3 min or -20°C twice
  • Place a urethral warming catheter and place probes > 8 mm from urethra to protect the urethra from damage
  • Work anterior → posterior, as ice obscures detail anterior to it
• Follow-up/complications
  • Risk of urinary retention: Foley x 1-2 weeks
  • Oral abx until Foley removed
• Outcomes
  • Cancer control: 75.7% biochemically disease free at 3 years
  • Functional: 1.6% urinary incontinence, 42% ED, 0.1% rectourethral fistula

HIFU

• need to add info