Extended induction chemotherapy with topotecan, cyclophosphamide, and etoposide does not improve event-free survival (EFS) and overall survival (OS) in patients with high-risk neuroblastoma, and it increases the number of toxic side effects, according to findings published in the Annals of Oncology.

The open-label, prospective, randomized controlled phase 3 NB2004-HR trial (ClinicalTrials.gov Identifier: NCT03042429) included patients aged 1 to 21 years with stage IV neuroblastoma and those aged 6 months to 21 years with MYCN-amplified tumors. The study was conducted at 58 sites in Germany and Switzerland and enrolled patients from October 12, 2004 to December 31, 2016. EFS was the primary endpoint, and OS was a key secondary endpoint.

Participants were randomly assigned to standard induction therapy with 6 chemotherapy courses or to experimental induction chemotherapy beginning with 2 additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (8 total courses). The patients then received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Participants who had active tumors at the end of induction chemotherapy received radiotherapy.

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A total of 422 patients were randomly assigned between the treatment arms: 211 to the standard arm (median age 3.2 years at diagnosis) and 211 to the experimental arm (median age 3.0 years at diagnosis). Participants in both arms were similar regarding disease stage, genomic MYCN status, lactate dehydrogenase (LDH) levels, sex, primary or metastatic sites, and tumor markers.

The median follow-up time was 3.32 years (interquartile range, 1.65-5.92). A total of 140 patients in the experimental arm and 146 in the standard arm had an event. The 3-year EFS was similar in the 2 treatment groups (log-rank P =.258); EFS was 34% (95% CI, 28-40) in the experimental arm and 32% (95% CI, 26-38) in the standard arm.

OS results were also similar between the 2 treatment groups (P =.558), with a 3-year OS of 54% (95% CI, 46-62) in the experimental arm and 48% (95% CI, 40-56) in the standard arm.

An analysis of major clinical subgroups that were defined by the stratifying risk factors LDH, MYCN amplification, stage, age, or response to induction chemotherapy, also demonstrated no difference in EFS and OS between the 2 treatment arms. Univariable analyses showed an unfavorable prognostic effect on EFS for elevated LDH levels at diagnosis, liver metastasis, lung or pleural metastasis, and poor response to induction chemotherapy.

Nonfatal grade 3 and 4 toxicities occurred more frequently in the experimental arm with the 2 additional courses of chemotherapy (P <.001, as-treated per protocol cohorts), although the median number of toxicities per chemotherapy course was similar. Grade 3 and 4 thrombocytopenia occurred more frequently in the experimental group, and oral mucositis occurred less frequently although statistical significance was not achieved (P =.07). In the experimental arm, 7 patients had a second neoplasm compared with none in the standard therapy arm.

The trial had several limitations, as it was powered to detect differences between the treatment arms but not among subgroups, and so the subgroup analyses should be regarded as descriptive only, according to the investigators. Also, of the 536 patients who were eligible for randomization, 21% were not randomized.

The study’s results “…strongly suggest that extended induction chemotherapy with topotecan, cyclophosphamide, and etoposide cannot be recommended for high-risk neuroblastoma patients,” the researchers concluded.


Berthold F, Faldum A, Ernst A, et al. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol. 2020;31(3):422-429. doi:10.1016/j.annonc.2019.11.011