Prostate Cancer — PSA Screening, Active Surveillance, and ADT

Prostate cancer is the most common noncutaneous malignancy and second leading cause of cancer death among men in the United States. It arises from epithelial cells within the peripheral zone of the prostate gland in 70% of cases.

Epidemiology

• Incidence: ~250,000 new cases annually in the US
• Age: Median age at diagnosis is 66 years; rare before age 50
• Risk factors: Advanced age, African American ethnicity, family history, germline mutations (BRCA2, HOXB13)
• Geographic variation: Higher incidence in developed countries, partly due to PSA screening

[HIGH_YIELD] The Gleason scoring system remains the most important prognostic factor, ranging from 6 (3+3) to 10 (5+5), with Grade Groups 1-5 corresponding to Gleason scores 6, 7(3+4), 7(4+3), 8, and 9-10 respectively.

Pathophysiology

Prostate cancer development involves:

• Androgen dependence: Testosterone and dihydrotestosterone (DHT) drive growth via androgen receptor (AR) signaling
• Genomic alterations: Common mutations include TMPRSS2-ERG fusion (50%), PTEN loss, TP53 mutations
• Progression: From localized disease to biochemical recurrence to castration-resistant prostate cancer (CRPC)

[KEY_CONCEPT] Castration-resistant prostate cancer (CRPC) develops through multiple mechanisms including AR amplification, AR mutations, intratumoral androgen synthesis, and AR-independent pathways.

PSA Screening Guidelines

[HIGH_YIELD] Current screening recommendations vary by organization:

Clinical Presentation

Early-stage disease is typically asymptomatic, discovered through elevated PSA or abnormal digital rectal examination (DRE).

Advanced local disease may present with:

• Lower urinary tract symptoms: Frequency, urgency, nocturia, weak stream
• Hematuria or hematospermia
• Erectile dysfunction

Metastatic disease symptoms:

• Bone pain: Most common site of metastasis (axial skeleton)
• Pathologic fractures
• Spinal cord compression (oncologic emergency)
• Constitutional symptoms: Weight loss, fatigue

[CLINICAL_PEARL] PSA velocity (rate of change >0.75 ng/mL/year) and PSA density (PSA/prostate volume >0.15) can help distinguish cancer from benign prostatic hyperplasia.

PSA Interpretation

• Normal: <4.0 ng/mL (age-adjusted ranges available)
• Gray zone: 4-10 ng/mL (requires further evaluation)
• Highly suspicious: >10 ng/mL
• Castrate level: <0.5 ng/mL (on ADT)

Diagnostic Algorithm

Elevated PSA or Abnormal DRE | Repeat PSA in 6-8 weeks | Persistently elevated? | Yes | Consider multiparametric MRI | MRI-guided or systematic biopsy | Histologic confirmation | Risk stratification

Biopsy Techniques

• Transrectal ultrasound (TRUS)-guided biopsy: Traditional 12-core systematic sampling
• MRI-guided biopsy: Targeted approach for PI-RADS 3-5 lesions
• Transperineal biopsy: Reduced infection risk, better anterior/apical sampling

Risk Stratification

[HIGH_YIELD] NCCN Risk Groups:

Staging Studies

• Localized disease: Bone scan and CT/MRI if intermediate/high risk
• Advanced disease:
  • Conventional imaging: CT chest/abdomen/pelvis, bone scan
  • Advanced imaging: PSMA PET/CT (FDA-approved for biochemical recurrence)

[CLINICAL_PEARL] Genomic tests (Oncotype DX, Prolaris, Decipher) can help refine prognosis and treatment decisions in select patients.

Treatment Approach by Risk Category

Very Low/Low Risk

Active Surveillance is preferred:

• Criteria: NCCN very low or favorable low-risk disease
• Monitoring protocol:
  • PSA every 6 months for 2 years, then annually
  • DRE every 12 months
  • Repeat biopsy at 1 year, then every 2-5 years
• Progression triggers: Grade reclassification, volume progression, patient preference

[HIGH_YIELD] Active surveillance is appropriate for >50% of newly diagnosed prostate cancer patients and avoids overtreatment of indolent disease.

Intermediate/High Risk

Definitive Treatment Options:

Radical Prostatectomy

• Indications: Life expectancy >10 years, localized disease
• Approaches: Open, laparoscopic, robotic-assisted
• Advantages: Provides staging, eliminates primary tumor
• Complications: Incontinence (5-20%), erectile dysfunction (20-70%)

Radiation Therapy

External Beam Radiation (EBRT):

• Conventional: 70-80 Gy in 35-40 fractions
• Hypofractionated: 60-70 Gy in 20-28 fractions
• Stereotactic: Ultra-hypofractionated (5 fractions)

Brachytherapy:

• Low-dose rate (LDR): Permanent seed implants
• High-dose rate (HDR): Temporary catheter-based

Androgen Deprivation Therapy (ADT)

[KEY_CONCEPT] ADT indications:

• Neoadjuvant/adjuvant with radiation (intermediate/high risk)
• Biochemical recurrence (select cases)
• Metastatic disease (primary treatment)
• Castration-resistant disease (with novel agents)

ADT Agents

[CLINICAL_PEARL] GnRH antagonists avoid testosterone flare and achieve faster castration compared to agonists, important for symptomatic metastatic disease.

Castration-Resistant Prostate Cancer (CRPC)

First-Line mCRPC Treatment

Novel hormonal agents have improved survival:

Abiraterone + Prednisone

• Mechanism: CYP17A1 inhibitor blocking androgen synthesis
• Survival benefit: 4.6-month improvement in overall survival
• Monitoring: Hypertension, hypokalemia, fluid retention, hepatotoxicity

Enzalutamide

• Mechanism: AR antagonist with reduced nuclear translocation
• Survival benefit: 4.8-month improvement in overall survival
• Side effects: Fatigue, seizure risk (0.6%), cognitive impairment

Chemotherapy

Docetaxel remains standard for chemotherapy-eligible patients:

• Regimen: 75 mg/m² every 21 days + prednisone
• Survival benefit: 2.4-month improvement
• Subsequent therapy: Cabazitaxel for docetaxel-resistant disease

Bone-Targeted Therapy

• Denosumab: RANKL inhibitor, preferred over zoledronic acid
• Radium-223: For bone-predominant metastases, improves survival
• Indications: Skeletal-related event prevention, bone pain palliation

Immunotherapy & Targeted Therapy

Sipuleucel-T

• Mechanism: Autologous cellular immunotherapy
• Indication: Asymptomatic/minimally symptomatic mCRPC
• Survival benefit: 4.1-month improvement

Pembrolizumab

[HIGH_YIELD] FDA-approved for mCRPC with:

• MSI-H/dMMR tumors (tissue-agnostic approval)
• TMB-H (≥10 mutations/megabase)
• KEYNOTE-199 trial: 5% response rate in unselected mCRPC

PARP Inhibitors

Olaparib and Rucaparib approved for mCRPC with:

• Germline/somatic BRCA1/2 mutations
• Other homologous recombination repair gene alterations
• Companion diagnostics: Foundation Medicine, Myriad myChoice CDx

[CLINICAL_PEARL] Genetic counseling is recommended for all men with high-risk, very high-risk, regional, or metastatic prostate cancer due to potential hereditary cancer syndromes.

Post-Treatment Surveillance

After Radical Prostatectomy

• PSA monitoring: Every 3-6 months for 5 years, then annually
• Biochemical recurrence: PSA ≥0.2 ng/mL on two occasions
• DRE: If PSA rises or clinically indicated

After Radiation Therapy

• PSA monitoring: Every 6 months for 5 years, then annually
• Biochemical recurrence: PSA nadir + 2 ng/mL (Phoenix criteria)
• Late toxicity assessment: Urinary and bowel function

ADT Side Effect Management

[HIGH_YIELD] ADT complications require proactive management:

Quality of Life Measures

Patient-reported outcome measures (PROMs):

• EPIC-26: Expanded Prostate Cancer Index Composite
• FACT-P: Functional Assessment of Cancer Therapy-Prostate
• AUA Symptom Score: Lower urinary tract symptoms

Survivorship Care

• Annual comprehensive history and physical
• Age-appropriate screening: Colonoscopy, mammography (gynecomastia screening on ADT)
• Lifestyle modifications: Diet, exercise, smoking cessation
• Psychosocial support: Support groups, counseling resources

[CLINICAL_PEARL] Intermittent ADT can be considered in select patients to minimize side effects while maintaining disease control, particularly in biochemical recurrence with long PSA doubling times.

Prognosis

• 5-year survival rates: Localized (100%), Regional (100%), Distant (31%)
• 10-year prostate cancer-specific mortality: Very low risk (1%), Low risk (3%), Intermediate risk (11%), High risk (20%)
• Factors affecting prognosis: Gleason score, PSA, stage, age, comorbidities, treatment response