Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children's Oncology Group (COG A3973) study

Abstract

9505 Background: Myeloablative consolidation improves outcome for HR-NB pts, especially for pts in CR prior to consolidation. We assessed the toxicity and CR+VGPR rate of a dose-intensive multi-agent chemotherapy induction based upon the N7 regimen (JCO 22:4888, 2004) prior to myeloablative consolidation and peripheral blood autologous stem cell transplant (ASCT). Methods: Between 2/2001 and 3/2006, 489 eligible newly diagnosed HR- NB pts received the following induction consisting of 6 cycles of chemotherapy q 21 days. Cycles 1, 2, 4 & 6: cyclophosphamide 4.2 g/m2, doxorubicin 75 mg/m2, and vincristine 2 mg/m2 and Cycles 3 &5: cisplatin 200 mg/m2 and etoposide 600 mg/m2. Surgical resection of primary occurred after cycle 5. Following induction pts received purged or unpurged ASCT (as randomized), radiation, and then 13-cis-retinoic acid (13-cis-RA). Response was assessed after cycles 2 & 6 using the International Neuroblastoma Response Criteria and analyzed as intent-to-treat. Results: Median age was 3.1 yrs, 44% of 392 tumors tested had MYCN amplification. Fourteen pts (3%) died during induction (5 infection, 4 bleed into tumor, 4 compromised organ function from tumor, 1 unrelated to tumor/therapy). Patients experienced the following grade 3 & 4 toxicities at least once during induction: neutropenia 70%, thrombocytopenia 71%, hearing loss 6%, cardiac function 2% and renal function 3%. Documented infection occurred in 24% of cycles (90% bacterial, 3% viral, 7% fungal). Responses among the 489 pts at end of induction were CR 24%, VGPR 28%, PR 26%, SD 7%, and PD15%, with morphologically detectable bone marrow (BM) disease cleared in 87% and no disease remaining by MIBG scan in 55% of pts MIBG positive at baseline. Conclusions: Despite increased dose intensity of this regimen, toxicity was not excessive compared to prior HR-NB regimens. In a multi-center setting, the A3973 induction chemotherapy achieved morphologic BM clearance in 87% of pts prior to consolidation. The CR/VGPR rate of 52% is similar to that of prior less intensive regimens. The impact of this induction response on survival within the context of ASCT and 13-cis-RA on COG A3973 will be determined with longer follow-up. No significant financial relationships to disclose.