Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

Ladenstein, Ruth; Pötschger, Ulrike; Pearson, Andrew D.J.; Brock, Pénélope; Luksch, Roberto; Castel, Victoria; Yaniv, Isaac; Papadakis, Vassilios; Laureys, Geneviève; Malis, J; Balwierz, Walentyna; Ruud, Ellen; Kogner, Per; Schrøeder, Henrik; Lacerda, Ana Forjaz de; Beck‐Popovic, Maja; Bician, P.; Garami, Miklós; Trahair, Toby N.; Cañete, Adela; Ambros, Peter F.; Holmes, Keith; Gaze, Mark; Schreier, Günter; Garaventa, Alberto; Vassal, Gilles; Michon, Jean; Valteau‐Couanet, Dominique

doi:10.1016/s1470-2045(17)30070-0

Cited by 278 publications

(321 citation statements)

References 29 publications

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“…However, it is the cut-off score of >3 post-induction that clearly discriminates an actionable decision point for altered innovative strategies in a very poor prognosis group. The higher rate of complete skeletal disease remission in the COG A3973 trial suggests that the COG A3973 induction regimen is more effective in clearing skeletal disease than the SIOPEN induction regimen, either due to the inclusion of anthracyclines in COG A3973 or related to the longer duration of induction therapy [6, 11, 12, 14, 29]. SIOPEN currently is addressing the induction question by randomising Rapid COJEC [11] against the modified N7 [29] regimen, but results are not yet complete.…”

Section: Discussionmentioning

confidence: 99%

“…Both trial designs are summarised in Fig. 2 and are fully described elsewhere [11, 12, 14, 15]. I-131-mIBG therapy was not part of treatment in either of the two protocols.…”

Section: Methodsmentioning

confidence: 99%

“…Third, an analysis was performed, using tertiles of the total SIOPEN score. Fourth, the prognostic value of the threshold score of 3 [12] was tested. Fifth, a grid search to identify an optimal cut point was conducted aligned with the Youden-Index approach previously used by the COG group [23, 24].…”

Section: Methodsmentioning

confidence: 99%

“…The International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) is a network of 183 paediatric oncology treatment centres in 22 countries [11, 12]. The SIOPEN semi-quantitative mIBG skeletal scoring system has previously been shown to have excellent inter- and intra-observer reproducibility and to provide a reliable prognostic indicator in neuroblastoma [13].…”

Section: Introductionmentioning

confidence: 99%

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Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

Ladenstein

Lambert

Pötschger

et al. 2017

Eur J Nucl Med Mol Imaging

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Background Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations. Results The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0–6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response. Conclusions Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

“…Both trial designs are summarised in Fig. 2 and are fully described elsewhere [11, 12, 14, 15]. I-131-mIBG therapy was not part of treatment in either of the two protocols.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

Ladenstein

Lambert

Pötschger

et al. 2017

Eur J Nucl Med Mol Imaging

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show abstract

“…Prior to AHCT, patients underwent induction therapy with rapid COJEC (8 courses in total), and if inadequate metastatic disease response at that time, went on to receive 2 courses of topotecan, vincristine and doxorubicin prior to proceeding to AHCT. The Bu/Mel regimen consisted of either oral or IV busulfan, at doses that ranged from 0.8–1.2 mg/kg per dose for 16 doses (dose based on patient weight), followed by a single 140 mg/m 2 dose of Melphalan IV 31 . For the 267 patients that received the Bu/Mel regimen, there was a median ANC recovery of 12 days, and a median platelet > 20 × 10 3 /mm 3 recovery of 20 days 34 .…”

Section: Discussionmentioning

confidence: 99%