What chemotherapy regimen can be used for a child with advanced or refractory neuroblastoma when topotecan is unavailable?

Alternative Chemotherapy Regimens for Advanced/Refractory Neuroblastoma When Topotecan is Unavailable

The most effective alternative to topotecan-based regimens for children with advanced or refractory neuroblastoma is irinotecan combined with temozolomide, which has demonstrated objective response rates of 15-24% and excellent tolerability in heavily pretreated patients. 1, 2, 3

Primary Recommendation: Irinotecan-Temozolomide

Use irinotecan-temozolomide as your first-line alternative regimen, as this combination has the strongest evidence base in relapsed/refractory neuroblastoma and can be administered entirely orally for convenience. 1, 3

Standard Dosing Protocol

• Temozolomide: 100-150 mg/m² orally daily for 5 consecutive days 2, 3
• Irinotecan: 50 mg/m² IV daily for 5 days (or 10 mg/m²/dose orally 5 days/week for 2 weeks) 1, 3
• Cycle length: Every 21-28 days 2, 3
• Oral cefixime prophylaxis: Administer daily to reduce irinotecan-associated diarrhea 1

Expected Outcomes

• Objective response rate: 15-24% across multiple phase II trials 2, 3
• Disease stabilization: 50-68% of patients achieve stable disease or better 2, 3
• Median response duration: 8.5 months in responders 2
• 12-month progression-free survival: 42% 4

Toxicity Profile

The regimen is notably well-tolerated compared to other salvage options:

• Grade 3/4 neutropenia occurs in 62-89% of patients but febrile neutropenia is uncommon (<10%) 2, 3
• Grade 3/4 thrombocytopenia in 47-71% of patients 2
• Grade 3 diarrhea in less than 6% of patients when cefixime prophylaxis is used 1, 3

Enhanced Regimen for MYCN-Amplified Disease

If the patient has MYCN-amplified neuroblastoma, strongly consider adding dasatinib and rapamycin to irinotecan-temozolomide (RIST regimen), as this specifically targets MYCN-driven disease with superior outcomes. 4

RIST Protocol Dosing

• Rapamycin: Loading dose 3 mg/m² on day 1, then 1 mg/m² on days 2-4 orally 4
• Dasatinib: 2 mg/kg/day orally for 4 days, then 3 days off 4
• Irinotecan: 50 mg/m²/day IV for 5 days, then 2 days off 4
• Temozolomide: 150 mg/m²/day orally for 5 days, then 2 days off 4

RIST Efficacy in MYCN-Amplified Disease

• Median progression-free survival: 6 months versus 2 months with irinotecan-temozolomide alone (HR 0.45, p=0.012) 4
• Overall median progression-free survival: 11 months versus 5 months (HR 0.62, p=0.019) 4
• Critical caveat: This benefit is exclusive to MYCN-amplified tumors; patients without MYCN amplification showed no significant benefit 4

Alternative Regimen: Irinotecan-Temozolomide-Dinutuximab

For patients with available anti-GD2 antibody therapy, irinotecan-temozolomide-dinutuximab demonstrates the highest objective response rate (53%) among all tested combinations. 5

Dosing Schedule

• Temozolomide: 100 mg/m² orally on days 1-5 5
• Irinotecan: 50 mg/m² IV on days 1-5 5
• Dinutuximab: 17.5-25 mg/m²/day IV on days 2-5 5
• GM-CSF: 250 μg/m² subcutaneously on days 6-12 5
• Cycle length: 21 days 5

Response Rates

• Objective response rate: 53% (including 5 complete responses and 4 partial responses in 17 patients) 5
• This represents the highest response rate among all tested combinations for relapsed/refractory neuroblastoma 5

Toxicity Considerations

• Grade 3/4 pain in 44% of patients (protocol-defined and manageable) 5
• Grade 3/4 hypokalaemia in 38% requiring supplementation 5
• Grade 3/4 hypoxia in 25% of patients 5
• Important: One patient experienced grade 4 hypoxia meeting criteria for unacceptable toxicity 5

Additional Salvage Options from Sarcoma Guidelines

While the evidence is primarily from Ewing's sarcoma, these regimens have activity in refractory solid tumors and can be considered when neuroblastoma-specific options fail:

• Cyclophosphamide with irinotecan: 44% response rate in refractory sarcomas 6
• Ifosfamide and etoposide: Active in relapsed/refractory disease 6
• Ifosfamide, carboplatin, and etoposide: Triple-drug combination for aggressive disease 6

Clinical Decision Algorithm

1. First, determine MYCN status (if not already known from initial diagnosis)

   • If MYCN-amplified → Consider RIST regimen (irinotecan-temozolomide-dasatinib-rapamycin) 4
   • If MYCN non-amplified → Standard irinotecan-temozolomide 1, 2, 3

2. Assess anti-GD2 antibody availability and patient tolerance

   • If dinutuximab available and patient can tolerate pain/hypoxia risk → Irinotecan-temozolomide-dinutuximab 5
   • If not available or prior anti-GD2 exposure → Standard irinotecan-temozolomide 3

3. Consider disease burden and prior treatments

   • Measurable soft tissue disease → Any of the above regimens 3, 5
   • MIBG-avid or bone marrow disease only → Irinotecan-temozolomide shows 19% response rate in this subset 3

Critical Pitfalls to Avoid

• Do not omit cefixime prophylaxis when using irinotecan, as diarrhea rates increase significantly without it 1
• Do not use RIST regimen in MYCN non-amplified patients, as no benefit was demonstrated and toxicity is increased 4
• Do not delay GM-CSF when using dinutuximab, as it is essential for antibody-dependent cellular cytotoxicity 5
• Monitor for hypoxia closely with dinutuximab, particularly in patients with lung metastases 5
• Assess response after 2-3 cycles (6-9 weeks) rather than waiting longer, as non-responders should be switched to alternative therapy 2, 3