What is the recommended chemo-immunotherapy (chemotherapy + immunotherapy) regimen for neuroblastoma using irinotecan (a topoisomerase I inhibitor)?

Chemo-Immunotherapy with Irinotecan in Neuroblastoma

For relapsed or refractory neuroblastoma, irinotecan combined with temozolomide is the preferred chemotherapy regimen, administered at 10 mg/m²/dose for 5 consecutive days per week for 2 weeks, with temozolomide 100 mg/m²/dose for 5 days, repeated every 3 weeks. 1

Standard Chemo-Immunotherapy Approach

For Newly Diagnosed High-Risk Disease

The standard post-consolidation immunotherapy regimen does not routinely incorporate irinotecan. Instead, the NCCN Category 1 recommendation consists of: 2

• Anti-GD2 monoclonal antibody (dinutuximab) combined with:
  • Sargramostim (GM-CSF) in cycles 1,3, and 5
  • Isotretinoin (13-cis-retinoic acid)
  • Interleukin-2 is no longer recommended due to increased toxicity without improved outcomes 2

This regimen achieved 2-year event-free survival of 66% compared to 46% with isotretinoin alone in the landmark ANBL0032 trial. 2

For Relapsed or Refractory Disease

When disease progresses or relapses, irinotecan-based chemotherapy becomes the backbone of salvage therapy, though it is typically used as chemotherapy alone rather than in formal combination with immunotherapy. 1

Irinotecan-Temozolomide Regimen Details

Dosing Schedule

• Irinotecan: 10 mg/m²/dose intravenously daily for 5 consecutive days per week for 2 weeks 1
• Temozolomide: 100 mg/m²/dose orally for 5 days 1
• Cycle frequency: Every 3 weeks 1
• G-CSF support: Administer when absolute neutrophil count <1,000/μL 3

Response Rates and Clinical Benefit

• Objective response rate: 15-19% overall, with higher responses (19%) in patients with disease detectable by MIBG or bone marrow analysis (stratum 2) 1
• Stable disease: Achieved in 50-56% of patients, indicating clinical benefit even without objective responses 1
• Complete responses: Documented in both refractory and progressive disease settings 3

Toxicity Profile and Management

The irinotecan-temozolomide combination is notably well-tolerated: 1

• Gastrointestinal toxicity: <6% experienced grade ≥3 diarrhea 1
• Myelosuppression: Manageable with G-CSF support; <10% developed infection while neutropenic 1
• No cumulative toxicity: Multiple courses can be administered without organ damage 3
• Organ-sparing: Feasible in patients with poor bone marrow reserve or prior cardiac/renal complications 3
• Limited immunosuppression: Lymphocyte function normalizes even after high-dose alkylator therapy 3

Alternative Irinotecan Schedules

An earlier phase I/II study used a different schedule with higher individual doses: 3

• Irinotecan: 50 mg/m² (1-hour infusion) for 5 days
• Temozolomide: 150 mg/m² orally for 5 days
• Cycle frequency: Every 3-4 weeks
• Platelet requirement: >30,000/μL before treatment

This regimen achieved objective responses in 47% of refractory patients and 18% of progressive disease patients, but the COG study using lower irinotecan doses (10 mg/m²) became the standard due to better tolerability. 3, 1

Integration with Immunotherapy

Current Practice

Irinotecan-based chemotherapy is not formally combined with anti-GD2 immunotherapy in standard protocols. The typical sequence is: 2

1. Induction chemotherapy (topotecan, cyclophosphamide, cisplatin, etoposide, doxorubicin)
2. Consolidation (high-dose chemotherapy with stem cell rescue)
3. Post-consolidation immunotherapy (anti-GD2 + sargramostim + isotretinoin)
4. Continuation therapy (eflornithine, FDA-approved December 2023)

For Progressive Disease During Treatment

If disease progresses during induction or consolidation, the NCCN recommends switching to alternative chemotherapy regimens such as: 4

• High-dose cyclophosphamide-based combinations
• Topotecan-containing regimens (topotecan is structurally related to irinotecan as a topoisomerase I inhibitor)
• Irinotecan-temozolomide (by extension, though not explicitly listed)

Critical Clinical Considerations

When to Use Irinotecan-Based Therapy

Use irinotecan-temozolomide for: 1

• Relapsed neuroblastoma after completion of frontline therapy
• Refractory disease not responding to standard induction
• Patients requiring organ-sparing therapy due to prior toxicities
• Disease detectable primarily by MIBG or bone marrow (higher response rates)

Schedule-Dependent Efficacy

Preclinical data demonstrates that protracted low-dose schedules are superior to intensive high-dose courses. 5 The [(dx5)2]3 schedule (5 days × 2 weeks, repeated for 3 cycles) achieved 100% complete responses in neuroblastoma xenografts at doses as low as 5 mg/kg, whereas single intensive cycles had high relapse rates despite initial responses. 5

Monitoring Requirements

• Response assessment: After 3 and 6 courses using International Neuroblastoma Response Criteria 1
• Hematologic monitoring: Frequent CBC with differential
• Infection surveillance: Despite neutropenia, infection rates remain low with appropriate G-CSF support 1

Common Pitfalls to Avoid

1. Do not use single intensive cycles: Protracted schedules with multiple courses are essential for durable responses 5
2. Do not withhold therapy for poor bone marrow reserve: This regimen is specifically feasible in patients with compromised hematologic function 3
3. Do not expect high objective response rates in bulky disease: Patients with CT/MRI-measurable disease have lower response rates (15%) compared to MIBG/marrow-positive disease (19%), but stable disease still provides clinical benefit 1
4. Do not combine with interleukin-2: IL-2 increases toxicity without improving outcomes and is no longer recommended 2