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Analysis of the incidence, characteristics, and risk factors of complications during induction chemotherapy in children with high-risk neuroblastoma

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Abstract

Patients with high-risk neuroblastoma (HR-NB) exhibit suboptimal 5-year survival rates, leading to a widespread international preference for high-intensity chemotherapeutic regimens in these children. We analyzed the incidence and risk factors for complications during induction chemotherapy in children with HR-NB and tried to assist clinicians in predicting such complications and optimizing therapeutic strategy. The clinical data of children with HR-NB admitted to our hospital from January 2007 to December 2019 were retrospectively analyzed. The incidence, characteristics, and risk factors of complications (infection, hemorrhage, and chemotherapy-related adverse reactions (CRAR)) requiring hospitalization during induction chemotherapy in these children were explored. (1) A total of 108 patients with HR-NB were included in the final analysis. The overall infection rate was 92.6% (100/108), with the highest incidence of 71.3% observed during the first cycle. FN, bacterial infection, as well as fungal infection were common infectious complications in children with HR-NB during induction chemotherapy. (2) The overall hemorrhage rate was 24.1% (26/108), with the highest incidence of 14.8% also observed in the first cycle. Among the children with hemorrhage, there were 72% with bone marrow involved, while 65.0% of them had a high vanillylmandelic acid (VMA) value. And children with hemorrhage also exhibited neuron-specific enolase (NSE) ≥ 200 µg/L in 88.5% of cases and lactic dehydrogenase (LDH) ≥ 1000U/L in 73.1% of cases. (3) The incidence of CRAR rate was 100%, and 99.1% (107/108) patients experienced myelosuppression. The incidence of myelosuppression peaked in the third cycle, reaching up to 85.2%. Most children suffered severe myelosuppression existed with bone marrow metastases (76.3%), abnormal VMA (67.5%), and LDH ≥ 1000 U/L (60%). (4) Non-myelosuppressive adverse effects were observed in 75.9% children (82/108), with the highest incidence occurring in the third cycle at 42.6%. (5) Patients who experienced three types of complications had a lower median survival time (MST) of 54.4 months, a 3-year event-free survival (EFS) rate of (44.2 ± 10.7)%, and a 3-year overall survival (OS) rate of (75.8 ± 8.6)%, in comparison to those with only one or two complications, who had a higher MST of 59.5 months, a 3-year EFS rate of (73.5 ± 5.2)% (X2 = 10.457, P = 0.001), and a 3-year OS rate of (84.8 ± 4.1)% (X2 = 10.511, P = 0.001).

Conclusion: The presence of bone marrow involved and increased VMA were high-risk factors for infection, while NSE ≥ 200 µg/L and LDH ≥ 1000 U/L were high-risk factors for hemorrhage. For those children who had experienced severe myelosuppression, the presence of bone marrow metastases, increased VMA, and LDH ≥ 1000 U/L were their risk factors. The presence of bone involvement was a high-risk factor for children to have non-myelosuppressive adverse effects. Complications that arise during induction chemotherapy could negatively impact the children’s prognosis and overall quality of life.

What is Known:

• The high-risk neuroblastoma (HR-NB) had a worse prognosis; there was a general international preference for high-intensity chemotherapeutic regimens in the induction phase to these children.

What is New:

• We analyzed the incidence and risk factors of complications during induction chemotherapy in children with HR-NB and tried to help clinicians predict such complications and adopt optimized therapeutic strategy.

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Data availability

The data associated with our research are available upon request from the corresponding author. We are more than willing to provide the necessary data to interested researchers upon reasonable request.

Abbreviations

CCCG:

Chinese Children’s Cancer Group

CDDP:

Cisplatin

COG:

Children’s Oncology Group

CRAR:

Chemotherapy-related adverse reactions

CTCAE:

Common Terminology Criteria for Adverse Events

CTX:

Cyclophosphamide

DOXO:

Doxorubicin

FN:

Febrile neutropenia

G-CSF:

Granulocyte colony-stimulating factors

HR-NB:

High-risk neuroblastoma

INPC:

The International Neuroblastoma Pathology Classification

INSS:

International Neuroblastoma Staging System

LDH:

Lactic dehydrogenase

MST:

Median survival time

NB:

Neuroblastoma

NSE:

Neuron-specific enolase

EFS:

Event-free survival

OS:

Overall Survival

PBSC:

Peripheral blood stem cell

PICU:

Pediatric Intensive Care Unit

sAML:

Secondary acute myeloid leukemia (sAML)

TLS:

Tumor lysis

TOPO:

Topotecan

VCR:

Vincristine

VIPN:

Peripheral neurotoxicity

VP-16:

Etoposide

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Acknowledgements

The authors wish to thank the patients, their parents, and all staff in the Department of Pediatric Hematology/Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.

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  1. Department of Pediatric Hematology/Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiaxi Du & Xiaojun Yuan

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Contributions

All authors contributed to the conception and design of the study. Data collection and analysis were performed by Jiaxi Du, who also wrote the initial draft of the manuscript. Xiaojun Yuan commented on previous versions of the manuscript and made revisions.

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Correspondence to Xiaojun Yuan.

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The ethics approval was granted by the ethics committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine with approval number XHEC-D-2023-008. This study was conducted in accordance with the principles of the Declaration of Helsinki.

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The authors declare no competing interests.

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Du, J., Yuan, X. Analysis of the incidence, characteristics, and risk factors of complications during induction chemotherapy in children with high-risk neuroblastoma. Eur J Pediatr 183, 185–202 (2024). https://doi.org/10.1007/s00431-023-05273-w

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