Why continue Lutetium-177 (Lu-177) infusions for prostate cancer after two infusions?

Continuing Lu-177 Infusions Beyond Two Cycles for Prostate Cancer

Lu-177 therapy for prostate cancer should be continued for a total of four to six cycles, not stopped after just two infusions, to achieve optimal therapeutic benefit and improve survival outcomes.

Standard Treatment Protocol for Lu-177 in Prostate Cancer

• The NCCN Prostate Cancer Guidelines recommend Lu-177-PSMA-617 as a category 1 treatment option for patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been previously treated with androgen receptor-directed therapy and taxane-based chemotherapy 1
• The standard protocol for Lu-177-PSMA-617 involves administering 7.4 GBq (200 mCi) every 6 weeks for up to 4-6 cycles 1, 2
• In the pivotal VISION trial that led to FDA approval, patients received up to four cycles of Lu-177-PSMA-617 at six-weekly intervals, with a maximum cumulative dose of 29.6 GBq (800 mCi) 2
• Stopping after only two cycles would deliver suboptimal cumulative radiation dose to tumor tissue, potentially compromising therapeutic efficacy 3

Evidence Supporting Continuation Beyond Two Cycles

• The phase III VISION trial demonstrated significant improvement in overall survival (15.3 vs 11.3 months) and progression-free survival (8.7 vs 3.4 months) when patients completed the full treatment course of Lu-177-PSMA-617 1, 4
• Health-related quality of life and pain outcomes were significantly better in patients who received the complete course of Lu-177-PSMA-617 compared to standard of care alone 4
• The number of treatment cycles is an independent prognostic indicator for overall survival, with more cycles correlating with better outcomes 5
• In clinical practice, patients typically undergo a median of three cycles of Lu-177 therapy, with some receiving the full four cycles, demonstrating the real-world implementation of multiple cycles 6

Response Assessment and Monitoring

• PSA response rates of ≥50% decline are observed in 44.9-51.8% of patients receiving multiple cycles of Lu-177 therapy 6, 5
• Patients achieving PSA response have longer median overall survival (15.0 vs 9.5 months) and PSA progression-free survival (6.5 vs 2.9 months) 5
• Pain score improvement is seen in a significant proportion of patients who complete the full treatment course 5, 4
• Post-therapeutic Lu-177 scans after each cycle provide valuable information on uptake intensity and tracer localization, helping assess response to prior cycles and guide decisions about subsequent cycles 3

Safety Considerations for Multiple Cycles

• The most common adverse effects of Lu-177-PSMA therapy are generally mild and include dry mouth, transient nausea, and fatigue 7
• Grade 3 or 4 hematological adverse events include decreased hemoglobin (15%), lymphocyte concentrations (51%), and platelet counts (9%) 4
• Complete blood count should be performed every 2-4 weeks between cycles to monitor for hematological toxicity 3
• If blood values fall below acceptable limits, options include administering a lower activity in subsequent cycles, extending the interval between cycles, or interrupting therapy 3

Clinical Decision Algorithm for Continuing Lu-177 Therapy

1. After two cycles, assess:

   • Clinical response (pain reduction, performance status) 4
   • Biochemical response (PSA decline) 5
   • Hematological parameters (CBC, platelets) 3, 4
   • Renal function (creatinine clearance) 3

2. Continue with cycles 3 and 4 if:

   • No prohibitive toxicity (grade 3-4 hematological toxicity) 4
   • Adequate organ function (especially renal and bone marrow) 3
   • Evidence of clinical benefit or disease stabilization 5, 4

3. Consider additional cycles 5-6 in selected patients with:

   • Good response to initial 4 cycles 1
   • Minimal cumulative toxicity 3
   • High tumor burden requiring additional treatment 5

Conclusion Points

• Premature discontinuation after only two cycles may result in suboptimal outcomes in terms of survival, disease control, and quality of life 3, 4
• The full recommended course of 4-6 cycles of Lu-177-PSMA-617 maximizes therapeutic benefit while maintaining an acceptable safety profile 1, 4
• Regular monitoring between cycles allows for dose adjustments or treatment modifications to optimize the risk-benefit ratio for individual patients 3