What are the next steps for a patient with elevated free Prostate-Specific Antigen (PSA) levels?

Management of Elevated Free PSA

For patients with elevated free PSA, proceed with multiparametric MRI (mpMRI) followed by targeted biopsy if suspicious lesions are found, as this approach leads to lower rates of unnecessary biopsies and better detection of clinically significant prostate cancer. 1

Initial Risk Assessment

• Evaluate PSA level, digital rectal examination (DRE), life expectancy, family history, and ethnicity as part of the initial risk assessment 1
• Any nodule, asymmetry, or areas of increased firmness on DRE warrant immediate referral regardless of PSA level 2
• Patients with PSA values above 4.0 ng/ml should be referred to urology due to increased risk of prostate cancer 2
• Significant PSA velocity changes (≥1.0 ng/ml/year) should prompt referral, even if absolute PSA is within normal range 2

Diagnostic Algorithm

• Confirm elevated PSA with a repeat test under standardized conditions (no ejaculation, manipulations, or urinary tract infections) in the same laboratory before considering further testing 1
• Calculate PSA density (PSA-D; serum PSA divided by prostate volume) as it is one of the strongest predictors for clinically significant prostate cancer (csPCa), especially with a cut-off of 0.15 ng/ml/cc 1
• Order multiparametric MRI (mpMRI) as it has high sensitivity (91% for ISUP grade 2 cancers) and can reduce unnecessary biopsies 1
• Use the risk-adapted matrix table linking PI-RADS score (1-2,3, and 4-5) to PSA-D categories to guide biopsy decisions 1

Biopsy Decision-Making

• For patients with PI-RADS 4-5 lesions and PSA-D >0.20 ng/ml, proceed with targeted biopsy plus perilesional sampling 1
• Consider percent free PSA as an additional tool to improve specificity - a cutoff of 25% free PSA detects 95% of cancers while avoiding 20% of unnecessary biopsies 3
• Lower percentage of free PSA is associated with higher risk of cancer (range 8%-56%), with percent free PSA ≤10% indicating higher risk of clinically significant and potentially fatal prostate cancer 3, 4
• In men with elevated PSA and two previous negative biopsies, an endorectal MRI can help rule out prostate cancer when negative, avoiding subsequent biopsies with low yield 5

Special Considerations

• High-risk patients (family history, African American race) should be considered for referral if their PSA is in the "gray zone" (2.6-4.0 ng/ml) 2
• For patients on testosterone replacement therapy, refer if PSA rises above 4.0 ng/ml or increases by >1.0 ng/ml in the first 6 months of treatment 2
• Men who have <15 years of life expectancy are unlikely to benefit from early diagnosis 1
• Breaking the compulsory link between diagnosis and active treatment is the only way to decrease overtreatment risk while maintaining potential benefit of early diagnosis 1

Treatment Options if Cancer is Diagnosed

• Treatment depends on Gleason score, clinical stage, patient's age, overall health, and preferences 6
• Options include radical prostatectomy (for localized disease), radiation therapy, active surveillance (for low-risk cancers), and androgen deprivation therapy (for advanced disease) 6
• After radical prostatectomy, PSA should become undetectable (<0.1 ng/ml) within one month 6

Follow-up Recommendations

• For men aged 50-70 years with PSA <3.0 ng/ml and normal DRE, repeat testing at 1-2 year intervals is appropriate 7
• Regular PSA monitoring is essential after definitive treatment 6
• After radical prostatectomy, biochemical recurrence is defined as PSA ≥0.2 ng/ml with a confirmatory value 6