What is the recommended management approach for a patient with locally advanced prostate cancer and a Gleason score of 4+3?

Management of Gleason 4+3 (Grade Group 3) Locally Advanced Prostate Cancer

For Gleason 4+3 locally advanced prostate cancer, the standard treatment is external beam radiation therapy (minimum 75.6-78 Gy) combined with long-term androgen deprivation therapy for 2-3 years, which provides superior survival outcomes compared to radiation alone or short-term hormonal therapy. 1, 2

Risk Classification and Prognosis

Gleason 4+3 disease represents unfavorable intermediate-risk to high-risk prostate cancer depending on additional factors 3, 4:

• Grade Group 3 (Gleason 4+3=7) has predominantly poorly formed/fused/cribriform glands with a lesser component of well-formed glands 3
• 5-year biochemical recurrence-free survival after radical prostatectomy is only 63% 3
• This is significantly worse than Gleason 3+4 disease and approaches high-risk disease outcomes 3, 5

The critical distinction is that Gleason 4+3 behaves more aggressively than Gleason 3+4 because the dominant pattern is poorly differentiated, requiring more intensive treatment 3, 5.

Definitive Treatment Algorithm

Primary Treatment: Radiation Therapy Plus Long-Term ADT (Preferred)

External beam radiation therapy (75.6-78 Gy) combined with 2-3 years of ADT is the Category 1 recommendation for locally advanced disease with Gleason 8-10 or T3 disease 1:

• Dose escalation to at least 75.6-78 Gy using 3D-CRT or IMRT with daily image guidance 1, 4
• Pelvic lymph node radiation (45 Gy) for locally advanced disease 1, 6
• Long-term ADT (24-36 months) significantly improves all outcomes compared to short-term ADT (4-6 months) 2:
  • 10-year disease-specific survival: 88.7% vs 83.9% (p=0.0042) 2
  • 10-year distant metastasis: 14.8% vs 22.8% (p<0.0001) 2
  • 10-year biochemical failure: 51.9% vs 68.1% (p<0.0001) 2

For Gleason 8-10 disease specifically, long-term ADT provides a significant overall survival advantage (45.1% vs 31.9% at 10 years, p=0.0061) 2

Alternative: Radical Prostatectomy with Pelvic Lymph Node Dissection

Radical prostatectomy is an option only in highly selected patients with no fixation to adjacent organs 1:

• Must include pelvic lymph node dissection (ilio-obturator regions) 1, 4
• Reserved for patients with life expectancy >10 years 1
• 36% progression-free survival reported for Gleason 8 or greater after radical prostatectomy alone 1
• Consider adjuvant radiation therapy for positive margins or extracapsular extension 1

ADT Regimen Specifications

Standard ADT consists of GnRH agonist monotherapy 7, 8:

• Goserelin acetate implant or leuprolide acetate depot 7, 9
• Duration: 24-36 months for locally advanced disease 1, 2
• Combined androgen blockade (adding antiandrogen like bicalutamide) should not be used routinely 1

Critical timing: ADT should be initiated 2-4 months before radiation therapy (neoadjuvant), continued during radiation (concurrent), and extended for 24-36 months total (adjuvant) 1

Special Consideration for Gleason 4+3 vs 3+4

Gleason 4+3 disease requires more aggressive treatment than Gleason 3+4 5:

• Patients with Gleason 4+3 or T2c disease showed significant benefit from adding ADT to dose-escalated RT (74% vs 94% freedom from failure, p=0.005) 5
• Hazard ratio for recurrence is 4.6 for unfavorable intermediate-risk (including Gleason 4+3) compared to favorable intermediate-risk 5
• Short-term ADT (4-6 months) is insufficient for Gleason 4+3 disease; long-term ADT (24-36 months) is required 8, 2

Required Staging Before Treatment

Complete staging evaluation must include 4:

• Cross-sectional imaging (CT or MRI of abdomen and pelvis) for lymph node assessment 4
• Bone scan if PSA >10 ng/mL or symptomatic 4
• Calculate predicted probability of lymph node involvement using nomograms 4

Post-Treatment Surveillance

After radiation therapy plus ADT 1, 4:

• PSA measurement every 6 months for first 5 years, then annually 4
• Digital rectal examination every 6 months 1
• Biochemical recurrence defined as PSA rise ≥2 ng/mL above nadir 1, 4

Common Pitfalls to Avoid

Do not use short-term ADT (4-6 months) for Gleason 4+3 locally advanced disease - this is inadequate and associated with significantly worse outcomes compared to long-term ADT 2, 5

Do not perform radical prostatectomy without pelvic lymph node dissection - the predicted probability of lymph node involvement is >2% in this population 1, 4

Do not use brachytherapy monotherapy - this is contraindicated for Gleason pattern 4 or 5 disease 1

Do not delay ADT initiation - combined modality treatment with radiation therapy plus ADT improves overall survival (74% vs 66% at 7 years, HR 0.77, p=0.033) compared to ADT alone 6