What's the next step for a patient with prostate cancer (prostate ca) who was on active surveillance with a Gleason score of 3+3 and a rising Prostate-Specific Antigen (PSA) level from 9 to 10, and now has a rebiopsy showing a Gleason score of 3+4?

Management of Gleason 3+4 Prostate Cancer After Progression on Active Surveillance

This patient should discontinue active surveillance and proceed to definitive treatment with either radical prostatectomy or radiation therapy (with or without short-term androgen deprivation therapy for 4-6 months). 1

Why Active Surveillance Must End

Progression to Gleason score 3+4 (Grade Group 2) is a clear indication for intervention during active surveillance. 1 The established protocols explicitly state that progression to Gleason score 7 (4+3) or higher triggers treatment, and while your patient has 3+4 rather than 4+3, this still represents grade reclassification that warrants definitive therapy 1.

• The Canadian active surveillance protocol specifically lists "Progression to Gleason score of 7 (4+3) or higher" as an indication for intervention 1
• NCCN guidelines state that active surveillance is not recommended for patients with Gleason 3+4 who have high PSA density, and your patient's rising PSA from 9 to 10 suggests concerning kinetics 1
• The presence of any Gleason pattern 4 disease on repeat biopsy indicates cancer progression and should prompt treatment consideration 1

Risk Stratification: Now Intermediate-Risk Disease

Your patient has transitioned from low-risk to favorable intermediate-risk prostate cancer based on: 2

• Gleason score 3+4 (Grade Group 2)
• PSA of 10 ng/mL (at upper threshold)
• Presumably clinical stage T1c or T2a

This reclassification fundamentally changes management, as intermediate-risk disease requires definitive treatment rather than continued surveillance 1.

Definitive Treatment Options

Radical Prostatectomy with Pelvic Lymph Node Dissection

For patients with life expectancy >10 years, radical prostatectomy is a primary treatment option. 1

• Should include pelvic lymph node dissection if predicted probability of lymph node metastasis is ≥2% 1
• Outcomes after delayed surgery for progression on active surveillance show excellent results: 96% 5-year biochemical progression-free survival in the Johns Hopkins experience 1
• Critical caveat: Some data suggest that delayed intervention may result in slightly more complex surgery with potentially increased side effects, though this remains controversial 1

Radiation Therapy

External beam radiation therapy (EBRT) with or without 4-6 months of androgen deprivation therapy is equally effective. 1

• Doses of 75.6-81.0 Gy using highly conformal techniques (IMRT) are appropriate 1
• Short-term ADT (4-6 months) can be added for intermediate-risk disease 1
• Brachytherapy alone may be considered for patients with favorable factors (low volume disease) 1
• Combined EBRT plus brachytherapy is another option 1

Important Considerations Before Treatment

Confirm the Upgrade

• Ensure the rebiopsy was adequate (≥10 cores) and performed by an experienced pathologist 1
• Consider the percentage of cores positive and extent of Gleason pattern 4 involvement 3
• If there's diagnostic uncertainty, consider multiparametric MRI to better characterize disease extent 1

Assess PSA Kinetics

• Calculate PSA doubling time if sufficient data points are available (though this alone should not delay treatment) 1, 4
• PSA doubling time <3 years is associated with higher risk of progression and upgrading 1, 5
• Your patient's PSA rise from 9 to 10 over an unspecified timeframe warrants calculation of velocity and doubling time 4

Genomic Testing (Optional but Increasingly Utilized)

Consider genomic classifiers (Decipher, Oncotype DX, Prolaris) to better understand disease biology, though this should not delay definitive treatment 1:

• These tests can help predict risk of metastasis and cancer-specific mortality 1
• May inform treatment intensity decisions (e.g., whether to add ADT to radiation) 1

Common Pitfalls to Avoid

1. Do not continue active surveillance with Gleason 3+4 disease - This represents grade progression that mandates treatment 1

2. Do not rely solely on PSA kinetics - PSA doubling time has proven unreliable for detecting progression; biopsy findings are paramount 1

3. Do not delay treatment due to patient anxiety about side effects - While treatment-related erectile dysfunction and urinary issues are real concerns, cancer-specific survival must take priority 1

4. Do not assume the window for cure has closed - Data show excellent outcomes with delayed intervention for progression on active surveillance, with 96% biochemical control at 5 years 1

The Evidence on Delayed Treatment

Reassuringly, men who progress on active surveillance and receive delayed treatment have excellent outcomes: 1

• Johns Hopkins: 96% 5-year biochemical progression-free survival after radical prostatectomy for progression 1
• UCSF: 100% freedom from biochemical progression at median 37.5 months follow-up 1
• These outcomes are comparable to immediate treatment, suggesting the window for cure remains open 1

However, 71% of men with PSA doubling time 0-3 years continued on active surveillance despite recommendations for treatment, and these men had twice the risk of upgrading on subsequent biopsy 5. Your patient should not fall into this pattern of non-compliance.

Life Expectancy Considerations

Treatment intensity should be guided by life expectancy 1:

• If life expectancy >10 years: Definitive treatment with curative intent is appropriate 1
• If life expectancy <10 years: Consider observation or less aggressive approaches 1