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Randomized Controlled Trial
. 2021 Aug 10;39(23):2552-2563.
doi: 10.1200/JCO.20.03144. Epub 2021 Jun 21.

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study

Alberto Garaventa  1 , Ulrike Poetschger  2 , Dominique Valteau-Couanet  3 , Roberto Luksch  4 , Victoria Castel  5 , Martin Elliott  6 , Shifra Ash  7 , Godfrey C F Chan  8 , Geneviève Laureys  9 , Maja Beck-Popovic  10 , Kim Vettenranta  11 , Walentyna Balwierz  12 , Henrik Schroeder  13 , Cormac Owens  14 , Maja Cesen  15 , Vassilios Papadakis  16 , Toby Trahair  17 , Gudrun Schleiermacher  18 , Peter Ambros  2 , Stefania Sorrentino  1 , Andrew D J Pearson  19 , Ruth Lydia Ladenstein  20
Affiliations
Randomized Controlled Trial

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study

Alberto Garaventa et al. J Clin Oncol. .

Abstract

Purpose: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]).

Patients and methods: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS.

Results: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 (P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 (P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 (P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) (P < .001); infection 35% versus 25% (P = .011); stomatitis 25% versus 3% (P < .001); nausea and vomiting 17% versus 7% (P < .001); and diarrhea 7% versus 3% (P = .011).

Conclusion: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

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Conflict of interest statement

Alberto GaraventaTravel, Accommodations, Expenses: Takeda Dominique Valteau-CouanetConsulting or Advisory Role: EUSA PharmaResearch Funding: Orphelia PharmaPatents, Royalties, Other Intellectual Property: Royalties from Apeiron to SIOPENTravel, Accommodations, Expenses: EUSA Pharma, Jazz Pharmaceuticals Martin ElliottConsulting or Advisory Role: Bayer Godfrey C. F. ChanLeadership: Xelllera, PengeniaConsulting or Advisory Role: Xellera, PengeniaSpeakers' Bureau: Xellera, PengeniaPatents, Royalties, Other Intellectual Property: Xellera, Pengenia Walentyna BalwierzHonoraria: Shire, Gilead Sciences, Novartis, AmgenConsulting or Advisory Role: Amgen, Novartis, Roche, TakedaTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Shire, Roche, Servier Cormac OwensEmployment: Ymabs Therapeutics Inc Vassilios PapadakisHonoraria: EUSA Pharma, NovartisConsulting or Advisory Role: SOBITravel, Accommodations, Expenses: Sanofi, Gilead Sciences, Novartis, Astellas Pharma Toby TrahairStock and Other Ownership Interests: CSL Limited, Osteopore Ltd, Medical Developments International, Cochlear Limited, Sonic Healthcare Limited, Medibank Private LimitedConsulting or Advisory Role: IPSOSExpert Testimony: EUSA Pharma, KMC HealthcareUncompensated Relationships: EUSA Pharma, KMC Healthcare Gudrun SchleiermacherHonoraria: BMSResearch Funding: Bristol Myers Squibb, Pfizer, MSDavenir, RocheTravel, Accommodations, Expenses: Roche Andrew D. J. PearsonConsulting or Advisory Role: Lilly, Takeda, Merck, CelgeneTravel, Accommodations, Expenses: Lilly, Takeda, Merck, Celgene Ruth Lydia LadensteinHonoraria: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaConsulting or Advisory Role: Apeiron Biologics, Boehringer Ingelheim, EUSA PharmaResearch Funding: Apeiron Biologics, EUSA PharmaPatents, Royalties, Other Intellectual Property: Apeiron Biologics, EUSA PharmaExpert Testimony: Apeiron Biologics, EUSA PharmaTravel, Accommodations, Expenses: Apeiron Biologics, EUSA PharmaNo other potential conflicts of interest were reported.

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