What is the next step in management for a 64-year-old man with a rising Prostate-Specific Antigen (PSA) level, normal Digital Rectal Examination (DRE), and a previous negative 12-core biopsy, who has undergone a multiparametric Magnetic Resonance Imaging (MRI) showing no target lesions?

Management of Rising PSA with Negative MRI After Previous Negative Biopsy

For a 64-year-old man with rising PSA (from 5 to 6.2 ng/mL), normal DRE, previous negative 12-core biopsy, large prostate (95g), and negative multiparametric MRI, the next step should be systematic plus targeted biopsy of the right peripheral zone (option D).

Rationale for Recommendation

Clinical Scenario Analysis

• Patient has risk factors for clinically significant prostate cancer:
  • Age 64 years
  • Rising PSA (5 to 6.2 ng/mL over 6 months)
  • Large prostate (95g) increasing risk of sampling error
  • Previous negative biopsy

Evidence-Based Approach

1. Negative MRI Does Not Rule Out Cancer

   • PI-RADS v2 fails to detect all cancers but detects the majority of tumors capable of causing patient harm 1
   • A negative MRI has limitations, particularly in large prostates where sampling error is more likely 2

2. Combined Biopsy Approach is Superior

   • The combination of systematic and targeted biopsy detects more clinically significant cancers than either method alone 2
   • The American College of Radiology and NCCN recommend combining systematic and targeted biopsy approaches for men with prior negative biopsies and rising PSA 2

3. Large Prostate Considerations

   • Patients with large prostates (>80g) are at higher risk of sampling error with standard systematic biopsy alone 2
   • The patient's prostate volume (95g) significantly increases risk of sampling error from previous biopsy

Specific Biopsy Strategy

Right Peripheral Zone Focus

• Despite no visible MRI lesions, the right peripheral zone should be targeted based on:
  • Most prostate cancers originate in the peripheral zone
  • Systematic sampling alone may miss clinically significant disease, especially in large prostates
  • Combined approach (systematic plus targeted) maximizes detection while minimizing missed clinically significant disease 2

Biopsy Technique Recommendations

• Transperineal approach preferred over transrectal to reduce infection risk
• Systematic 12-core biopsy plus targeted sampling of the right peripheral zone
• Consider saturation biopsy (>20 cores) given the large prostate size and previous negative biopsy 2

Expected Outcomes

• MRI-targeted biopsy has cancer detection rates of 34-51% in men with previous negative biopsies 2
• In studies of patients with rising PSA after negative biopsy, systematic plus targeted biopsy detected clinically significant prostate cancer in 15.5% of cases 3
• Combined systematic and targeted biopsies have demonstrated superior detection rates compared to either approach alone 4

Alternative Approaches Considered

1. PSA in three to six months (Option A)

   • Inadequate given the already rising PSA trend and large prostate
   • Delays diagnosis of potentially significant disease

2. Decipher genomic test (Option B)

   • Not indicated at this stage without tissue diagnosis
   • More appropriate after cancer diagnosis for risk stratification

3. Targeted biopsy only (Option C)

   • Insufficient given negative MRI findings
   • Would miss cancers not visible on imaging

4. Left peripheral zone biopsy (Option E)

   • No specific indication for left-sided focus without MRI findings

Conclusion

The evidence strongly supports performing a combined systematic plus targeted biopsy of the right peripheral zone to maximize detection of clinically significant prostate cancer while minimizing the risk of missing important disease, especially given the patient's rising PSA, prior negative biopsy, large prostate, and negative MRI.