Initial workup

• History & physical examination
  • Family history
  • Performance status
  • Urinary symptoms (AUA score/IPSS)
  • Sexual function (SHIM score)

• Laboratory studies
  • PSA, 4K score (upgraded PSA)
    • calculate PSA density to account for prostate volume >0.15-0.2 is abnormal
  • Consider testosterone level

IPSS Score

Mild (symptom score less than of equal to 7)

Moderate (symptom score range 8-19)

Severe (symptom score range 20-35)

SHIM Score

Biopsy

Biopsy

risk assessment tools

Partin tables:

• Predicts pathologic stage based on:
  • Clinical stage
  • PSA
  • Gleason score
• Helps estimate risk of:
  • Organ-confined disease
  • Extracapsular extension
  • Seminal vesicle involvement
  • Lymph node metastasis

Memorial Sloan Kettering nomogram:

• Predicts probability of:
  • PSA recurrence after surgery
  • Lymph node involvement
  • Seminal vesicle invasion
• Available online at nomograms.mskcc.org

The Roach formula

Mack Roach III

UCSF

1990s - derived from the Partin nomogram to predict lymph node involvement.

• Risk of lymph node involvement:
  • 2/3 PSA + (Gleason score - 6) × 10
  • Used historically to guide pelvic nodal radiation
• Risk of extracapsular extension:
  • 3/2 PSA + (Gleason score - 3) × 10
• Risk of seminal vesicle involvement:
  • PSA + (Gleason score - 6) × 10

Historical context:

• Developed before widespread use of modern imaging
• May overestimate risk compared to modern series
• Still used in some clinical trial eligibility criteria
• Being replaced by more accurate tools like PSMA PET

CApra-S

UCSF

Risk of recurrence post-prostatectomy

Predict Prostate was first validated using a dataset of another 3,000 prostate cancer patients from the Eastern England data

2,546 men from a separate independent dataset from Singapore and followed up for a median of 5.1 years.

69,206 men from prostate cancer data base Sweden in 2020 with 13.9 years of median follow-up

171 942 men of diverse ethnicities from the US SEER database ( Lee at al in 2021). Here Predict Prostate maintained a high discrimination index of 0.82.

Genomic classifiers: Evidence

Decipher:

• 22-gene expression classifier
• Predicts:
  • Risk of metastasis
  • Prostate cancer-specific mortality
  • PREDICT-RT (ongoing)
    • Trial to determine length of ADT for high risk patients

Oncotype DX GPS:

• 17-gene expression panel
• Predicts:
  • Adverse pathology
  • Biochemical recurrence
  • Metastasis

Others:

• Prolaris
• ProMark

Notes:

• Most validated in post-prostatectomy setting
• Emerging data in radiation therapy
• May help guide active surveillance decisions
• Consider in borderline cases where treatment intensification is being considered

How to use Decipher

Key factors in treatment selection

Patient factors:

• Age and life expectancy
• Comorbidities
• Urinary function (IPSS score)
• Sexual function priorities
• Ability to tolerate procedures
• Treatment preferences

Disease factors:

• Risk group classification
• Percent positive cores
• Prostate size
• MRI findings if available

Treatment considerations:

• Local expertise available
• Technical feasibility
  • Prostate size for brachytherapy (<60cc)
  • Image guidance capability
  • Treatment duration impact
• Quality metrics of treating physician

Monitoring schedule:

• Confirmatory testing in 6-12 months (if no prostate MRI performed prior to diagnosis)
  • prostate biopsy,
  • mpMRI with calculation of PSA density
  • molecular tumor analysis

Then

• PSA every 6 months
• Digital rectal exam every 12 months
• Increased PSA or DRE change
  • repeat mpMRI, no more often than every 12 months
  • repeat prostate biopsy, if indicated by MRI or PSA change:
    • No more than every 12 months
    • Subsequent biopsies every 2-5 years
• transitioned to observation when life expectancy is <10 years

Triggers for intervention:

• Grade group progression (Gleason ≥7)
• Significant increase in tumor volume
• Patient preference

Active surveillance: Protocol

Ideal candidates:

• Life expectancy >10 years
• Good performance status
• No major comorbidities
• Acceptable surgical risk
• Motivated to undergo surgery

Relative contraindications:

• Prior extensive pelvic surgery
• Morbid obesity
• Large prostate size (>100g)
• Prior pelvic radiation
• Significant medical comorbidities

Special considerations:

• Patient preferences regarding side effects
• Surgeon experience/volume
• Nerve-sparing feasibility

Surgical approach options:

• Open retropubic
• Robotic-assisted
• Laparoscopic
• Similar oncologic outcomes across approaches

Keys to successful surgery:

• Good surgical exposure
• Careful apex dissection
• Preservation of urethral sphincter
• Water-tight anastomosis
• Nerve-sparing when appropriate
•  

Quality metrics:

Pelvic lymph node dissection ?

Current evidence:

• No proven therapeutic benefit in low/favorable intermediate risk
• Risk of lymph node involvement <5%
• NCCN guidelines: Not recommended

Supporting data:

• German trial (Steiner 2008)
  • N=100 low/intermediate risk
  • No positive nodes found
• SEER analysis (Bhuller 2020)
  • No survival benefit
  • Increased complications

Potential complications:

• Lymphocele
• Deep vein thrombosis
• Increased operative time
• Lymphedema

Active surveillance: Key evidence

PROTECT Trial

Performed in the UK with the support the NHS

• 15-year outcomes comparing active monitoring vs. surgery vs. radiation
• No difference in prostate cancer mortality
• 15-year results:
  • PCM: 2.2% vs. 1.5% vs. 2.1%
  • Metastasis: 7.1% vs. 3.5% vs. 3.7%
  • Overall mortality: Similar (~15%)

Study Design: PROTECT

15-year outcomes:

• Prostate cancer mortality
  • Active monitoring: 2.2%
  • Surgery: 1.5%
  • Radiation: 2.1%
  • No significant differences
• Distant metastases
  • Active monitoring: 7.1%
  • Surgery: 3.5%
  • Radiation: 3.7%
  • p<0.05 for both vs monitoring
• Overall mortality
  • Similar across all arms (~15%)

Clinical progression at 10 years:

• Active monitoring: 20%
• Surgery: 5.9%
• Radiation: 6.6%

PROTECT trial: Quality of life outcomes

Urinary function:

• Surgery
  • Worst incontinence (20% pad use)
  • Persists long-term
• Radiation
  • More irritative symptoms
  • Peaks at 6 months
  • Improves over time

Sexual function:

• Surgery
  • 85% ED at 6 months
  • Worst long-term function
• Radiation
  • 74% ED at 6 months
  • Improves after ADT cessation
• Active monitoring
  • Natural age-related decline

Bowel function:

• Worse with radiation
• 6% bloody stools
• Minimal impact with surgery

Active surveillance: Additional evidence

Johns Hopkins Experience (Tosoian 2015)

• Very low risk cohort
• 15-year outcomes:
  • Overall survival: 69%
  • Cancer-specific survival: 99.9%
  • Metastasis-free survival: 99.4%
  • Grade reclassification: 31%

CHHiP trial: Study design

Patient population:

• 3216 patients
• T1b-T3aN0M0
• 15% low risk, 73% intermediate risk, 12% high risk
• PSA <30

Treatment arms:

• Conventional: 74 Gy/37 fx
• Hypofractionated: 60 Gy/20 fx
• Hypofractionated: 57 Gy/19 fx

Key aspects:

• Non-inferiority design
• Most patients received 3-6 months ADT
• Primary endpoint: biochemical/clinical failure
• Dose constraints:
  • Rectum V20<85%, V30<57%, V40<38%
  • Bladder V60<5%, V48.6<25%

CHHiP trial: Key results

Efficacy outcomes:

• 5-year biochemical control
  • 74 Gy: 88%
  • 60 Gy: 91% (non-inferior)
  • 57 Gy: 86% (not non-inferior)
• 10-year outcomes
  • BC: 76% vs 80% vs 73%
  • OS: ~80% all arms

Toxicity:

• Acute effects peaked earlier with hypofractionation
• Late GI Grade 2+: ~12% all arms
• Late GU Grade 2+: 6.6-11.7%

Conclusions:

• 60 Gy/20 fx non-inferior to conventional
• 57 Gy/19 fx not recommended
• Similar late toxicity profile

PROFIT trial: Study design

Patient population:

• 1206 intermediate risk patients
• T1-T2
• No ADT allowed

Treatment arms:

• Conventional: 78 Gy/39 fx
• Hypofractionated: 60 Gy/20 fx

Important features:

• Non-inferiority design
• Strict dose constraints used
• Rectal wall constraints (not whole organ):
  • D30% <46 Gy
  • D50% <37 Gy
• Treatment time: 8 weeks vs 4 weeks

Primary endpoint:

• Biochemical-clinical failure

PROFIT trial: Key results

Efficacy:

• 5-year biochemical failure: 15% both arms
• Met non-inferiority endpoint
• No difference in patterns of failure

Toxicity:

• Acute GI:
  • Worse with hypofractionation
  • Resolved by 6 months
• Late toxicity:
  • No difference in GI or GU
  • Grade ≥2 GI: ~14% both arms
  • Grade ≥2 GU: ~22% both arms

Key implications:

• Established 60 Gy/20 fx as standard option
• Important role of strict dose constraints
• Safe without ADT in intermediate risk

RTOG 0415: Study design

Patient population:

• 1092 low risk patients
• T1-2a
• PSA ≤10
• Gleason ≤6

Treatment arms:

• Conventional: 73.8 Gy/41 fx
• Hypofractionated: 70 Gy/28 fx

Protocol details:

• Non-inferiority design
• ~80% used IMRT
• Daily IGRT required
• No ADT allowed
• 5mm margins (3mm posterior)

Dose constraints:

• Rectum: V75<15%, V70<25%, V65<35%, V60<50%
• Bladder: V80<15%, V75<25%, V70<35%, V65<50%
• Femoral heads: V50<5%

RTOG 0415: Outcomes

Efficacy:

• 5-year disease-free survival
  • Conventional: 85%
  • Hypofractionated: 86%
  • Met non-inferiority endpoint
• 12-year outcomes
  • DFS: 56% vs 62%
  • BF: 83% vs 90%
  • No OS difference

Toxicity:

• Late grade ≥2 GI: 15.4% vs 23.8%
• Late grade ≥2 GU: 26.8% vs 33.4%
• Late grade ≥3 GI: 3.2% vs 4.4%
• Late grade ≥3 GU: 3.4% vs 4.4%

Patient-reported outcomes:

• No difference in:
  • EPIC GI/GU domains
  • Sexual function
  • Anxiety/depression

ASCENDE-RT Trial: Study Design

Inclusion Criteria:

• Population: Intermediate- or high-risk prostate cancer (NCCN-defined).
• Intermediate-risk: T2b-T2c, PSA 10-20 ng/mL, or Gleason Score = 7.
• High-risk: T3a+, PSA >20 ng/mL, or Gleason Score ≥8.
• Performance Status: ECOG 0-2.
• Eligible for Treatment: Whole-pelvis radiation therapy + ADT + either DE-EBRT or LDR-PB.
• Informed Consent: Signed before enrollment.

Exclusion Criteria:

• Disease Characteristics:
• T3b+ disease, PSA >40 ng/mL.
• Prior pelvic RT or surgery (e.g., TURP).
• Prostate volume >75 cm³ post-ADT.
• Health Factors: Ineligibility for anesthesia or contraindications to ADT/RT.
• Advanced Disease: Evidence of nodal or distant metastases on imaging.

ASCENDE-RT Trial: Results

Clinical Implications:

• Benefits: Significant improvement in biochemical control with LDR-PB.
• Challenges: Increased GU toxicity and no significant difference in OS, CSS, or DMFS.
• LDR-PB may be suitable for patients prioritizing biochemical control and delaying ADT.
• Alternative modalities, such as SBRT or HDR, offer reduced toxicity with similar survival outcomes.

ASCENDE-RT Trial: Results

Toxicity Findings:

• Genitourinary (GU): 5-year grade 3 GU toxicity: 18% (LDR-PB) vs. 5% (DE-EBRT), p < 0.001.
• Gastrointestinal (GI): 5-year grade 3 GI toxicity: 8% (LDR-PB) vs. 3% (DE-EBRT), p = 0.12.
• Erectile Function: Preservation at 5 years: 45% (LDR-PB) vs. 37% (DE-EBRT), p = 0.30.