Phase III Trial Compares Induction Regimens in High-Risk Neuroblastoma

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As reported in the Journal of Clinical Oncology by Garaventa et al, the phase III International Society of Pediatric Oncology European Neuroblastoma Group (SIOPEN) HR-NBL1.5 trial showed no significant differences in metastatic complete response rate or event-free survival with the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen vs rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, cyclophosphamide) induction therapy in high-risk neuroblastoma.

Study Details


  • No difference in metastatic complete response or 3-year event-free survival was observed between the rCOJEC and MSKCC-N5 groups.
  • rCOJEC was associated with a lower incidence of grade 3-4 nonhematologic toxicity.

In the open-label trial, 630 patients from SIOPEN centers in 23 European countries, Israel, Australia, and Hong Kong were randomly assigned between October 2011 and June 2017 to receive induction with rapid COJEC (n = 313) or MSKCC-N5 (n = 317). Patients were between the ages of 1 and 20 and had previously untreated stage IV disease or were younger than age 1 and had stage IV or IVS disease with MYCN amplification.

Rapid COJEC consisted of eight cycles within 70 days alternating vincristine and carboplatin (course A); vincristine and cisplatin (course B); and vincristine, etoposide, and cyclophosphamide (course C) in the sequence ABCBABCB, with the interval between courses being 10 days irrespective of hematologic recovery. MSKCC-N5 consisted of high-dose cyclophosphamide, doxorubicin with vincristine (CAV) alternating with high-dose cisplatin and etoposide (PE) for a total of five courses (CAV, PE, CAV, PE, and CAV) within 110 days. Following induction, treatment consisted of primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with dinutuximab beta antibody with or without interleukin-2 immunotherapy.

The primary endpoints were rate of metastatic complete response (no skeletal uptake on 123iodine–metaiodobenzylguanidine [mIBG] scintigraphy in mIBG-avid primary tumors or complete response in bone marrow and other metastatic sites) and 3-year event-free survival.

Treatment Outcomes

Metastatic complete response was observed in 86 of 272 evaluable patients (32%) in the rapid COJEC group vs 99 of 281 evaluable patients (35%) in the MSKCC-N5 group (P = .368). Partial response or better was observed in 197 of 280 evaluable patients (70%) in the rapid COJEC group vs 213 of 286 evaluable patients (74%) in the MSKCC-N5 group (P = .273).

Median follow-up was 3.6 years (interquartile range = 2.1–4.7 years). Event-free survival at 3 years was 44% in the rapid COJEC group vs 47% in the MSKCC-N5 group (unadjusted P = .527; hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.77–1.22, P = .787, after adjustment for metastatic sites and national group). Overall survival at 5 years was 60% vs 65% (P = .379; adjusted HR = 0.88, 95% CI = 0.68–1.15, P = .355). The 3-year cumulative incidence of relapse was 52% vs 48% (P = .376). The 3-year cumulative incidence of nonrelapse mortality was 4% vs 5% (P = .571).


Grade 3 or 4 hematologic toxicity occurred in more than 90% of patients during induction in both groups. Grade 3 or 4 nonhematologic toxicity during induction occurred in 48% of the rapid COJEC group vs 68% of the MSKCC-N5 group (P < .001), with significant differences observed for infection (25% vs 35%, P = .011), stomatitis (3% vs 25%, P < .001), nausea and vomiting (7% vs 17%, P < .001), and diarrhea (3% vs 7%, P = .011). A total of seven patients died of toxicity: among three in the rapid COJEC group, two died of infection (one after switching to MSKCC-N5 after early disease progression) and one of endothelial toxicity; all four deaths in the MSKCC-N5 group were due to infection.

The investigators concluded: “No difference in outcome was observed between rapid COJEC and MSKCC-N5; however, acute toxicity was less with rapid COJEC, and therefore rapid COJEC is the preferred induction regimen for the International Society of Pediatric Oncology European Neuroblastoma Group.”

Ruth Lydia Ladenstein, MD, PhD, of the Children’s Cancer Research Institute, Vienna, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by a European Commission Fifth Frame Work grant, Italian Ministry of Health, and others. For full disclosures of the study authors, visit

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