Management of Prostate Cancer

Epidemiology & Risk Factors

• Textbook of Family Medicine 9e, p. 1204

Diagnosis & Screening

PSA Testing

• PSA is a glycoprotein produced by prostatic epithelial cells; levels rise with adenocarcinoma, BPH, prostatitis, procedures, and ejaculation
• Conventional upper limit of normal: 4.0 ng/mL, though cancer exists across all PSA levels (15% of men with PSA <4.0 ng/mL have cancer; 15% of those are high-grade)
• Screening guidelines are contested: USPSTF recommends against routine PSA screening; ACS recommends informed decision-making for men ≥50 (high-risk men from age 40–45); AUA recommends individual risk-benefit discussion for men aged 55–69

Digital Rectal Examination (DRE)

• A firm nodule may indicate tumor; however, only 18–28% of abnormal DREs predict cancer, and up to 25% of biopsy-detected cancers occur on the contralateral side
• Textbook of Family Medicine 9e, p. 1204–1205

Biopsy & Grading

• Gleason score grades the two most prevalent cellular differentiation patterns on biopsy (range 2–10)
  • Gleason 2–4: low risk, low probability of death from prostate cancer
  • Gleason 5–7: intermediate (treatment is controversial)
  • Gleason 8–10: high risk; high probability of cancer-specific death within 10 years

Staging

• Local disease: transrectal ultrasound (TRUS) and MRI
• Metastatic workup: bone scan (⁹⁹ᵐTc-MDP) + CT scan
• PET tracers approved for staging/recurrence: ¹¹C-choline, ¹⁸F-fluciclovine, ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL (PSMA-targeted agents have superior sensitivity for small-volume disease)

• Goldman-Cecil Medicine, p. 1008–1010

Treatment by Disease Stage

TABLE: Treatment of Prostate Cancer (Goldman-Cecil Medicine)

Localized Disease

1. Watchful Waiting & Active Surveillance

• Watchful waiting: Appropriate for men with competing causes of death (life expectancy <10 years); no intent to treat unless symptomatic progression
• Active surveillance: For low-risk, clinically insignificant cancer in men who are fit for treatment
  • PSA every 6 months; DRE annually; repeat biopsy every ~12 months; consider MRI spectroscopy
  • Ki-67 (proliferation marker) and PTEN loss may identify patients requiring escalation
• The PIVOT trial found no improvement in all-cause or prostate-cancer-specific mortality at 12 years from prostatectomy vs. observation for localized tumors
• Goldman-Cecil Medicine, p. 1023–1025

2. Radical Prostatectomy (RP)

• Positive surgical margin rates: ~10–16% overall; pT2 disease ~4–13%; pT3 ~34–35%
• 5-year biochemical recurrence-free survival comparable to open RP
• Blood loss lower than open approaches

• Campbell Walsh Wein Urology, p. 4762; Smith & Tanagho's General Urology, p. 183

3. Radiation Therapy

• External-beam radiation therapy (EBRT): Definitive treatment for localized/locally advanced disease; combined with ADT for high-risk disease significantly improves outcomes vs. monotherapy
• Brachytherapy: Radioactive seed implants (low-dose rate) for low- to intermediate-risk disease
• High-risk and locally advanced disease: Combined modality (RT + ADT) is preferred over surgery alone

4. Other Local Therapies

• Cryotherapy: Freezing of prostate tissue; also used as salvage therapy after radiation failure
• High-intensity focused ultrasound (HIFU): Thermal ablation; used in select centers
• Salvage options after RT failure: Salvage RP, salvage cryotherapy, salvage HIFU

Locally Advanced & Biochemical Recurrence

• Post-prostatectomy PSA rise: If PSA doubling time (PSADT) ≤10 months or Gleason ≥8 → higher risk of metastatic progression
  • Gleason ≥8 with recurrence: 71% probability of metastatic disease at 7 years
  • Salvage RT to the prostate bed is the standard option
• Post-radiation PSA rise (biochemical failure): Salvage local therapy considered if biopsy-proven local recurrence and no evidence of distant disease
• New molecular imaging (PSMA-PET) is reshaping the detection and management of recurrence

Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

• Goldman-Cecil Medicine, p. 1081–1084; Harrison's Principles of Internal Medicine 22e

• GnRH agonists (leuprolide, goserelin): Chemical castration; initial testosterone flare possible — relatively contraindicated in obstructive symptoms, cancer pain, or spinal cord compression
• GnRH antagonists (degarelix, relugolix): No testosterone flare; preferred in cardiovascular risk patients
• AR antagonists (bicalutamide, flutamide): Block testosterone-receptor binding; combined with GnRH agonists to prevent flare
• Surgical orchiectomy: Irreversible; least acceptable to patients

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Chemotherapy

• Docetaxel (75 mg/m² q3 weeks + prednisone): First-line cytotoxic; if progression occurred >12 months after prior use, retreatment is reasonable
• Cabazitaxel: Second-line taxane post-docetaxel progression

Next-Generation Hormonal Agents

• Abiraterone acetate + prednisone: CYP17 inhibitor; blocks androgen synthesis in testes, adrenals, and tumor; FDA approved pre- and post-chemotherapy
• Enzalutamide: Second-generation AR antagonist; no glucocorticoid needed
• Darolutamide: AR antagonist; FDA-approved in mCRPC
• Note: If a patient progresses on one AR-targeted agent, do NOT switch to another; use a different drug class (e.g., docetaxel)

Targeted/Precision Therapy

Immunotherapy

• Sipuleucel-T: Autologous cellular immunotherapy targeting prostatic acid phosphatase; indicated for asymptomatic or minimally symptomatic mCRPC; toxicities include infusion reactions (fatigue, fever, chills, nausea)

Bone-Targeting Therapy

• Radium-223 (Ra-223): Alpha-emitting radiopharmaceutical; targets bone metastases; improves OS in symptomatic bony mCRPC without visceral metastases; also reduces skeletal-related events
• ¹⁷⁷Lu-PSMA-617 (Lutetium vipivotide tetraxetan): PSMA-directed radionuclide therapy; extends survival in patients with PSMA-expressing tumors who have exhausted prior therapies (VISION trial)
• Denosumab / Zoledronic acid: Bone-protective agents for skeletal-related events

Neuroendocrine/Small Cell Transformation

• Aggressive phenotype, AR-independent; treat with cisplatin/carboplatin + etoposide

Side Effects of Key Treatments

Key Recent Evidence (2024–2025)

• Advances in targeted therapy for mCRPC (Grewal et al., 2025, PMID 40299225): Reviews novel agents including PARP inhibitors, PSMA-targeted therapies, and combination regimens
• Biochemical recurrence management (Shore et al., 2024, PMID 37679602): Risk-stratified approach to rising PSA post-definitive therapy
• Metastatic CRPC: advances in treatment and symptom management (Kulasegaran & Oliveira, 2024, PMID 38913213): Updated sequencing strategies for mCRPC

Summary: Management Algorithm

Localized (low-risk)
 └── Active surveillance OR EBRT/brachytherapy OR radical prostatectomy

Localized (intermediate/high-risk)
 └── Radical prostatectomy ± adjuvant RT/ADT
 └── EBRT + ADT (2–3 years for high-risk)

Locally advanced (T3/T4)
 └── EBRT + ADT (preferred)
 └── Radical prostatectomy + adjuvant therapy

Metastatic hormone-sensitive
 └── ADT + docetaxel OR abiraterone OR enzalutamide OR apalutamide OR darolutamide

Castration-resistant (mCRPC)
 └── Next-gen hormonal (abiraterone/enzalutamide/darolutamide)
 └── Docetaxel → Cabazitaxel
 └── Molecular testing → PARP inhibitors (BRCA/HRR) / pembrolizumab (MSI-H)
 └── Sipuleucel-T, Radium-223, ¹⁷⁷Lu-PSMA-617