Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study

doi:10.1016/S0360-3016(02)04506-6

International Journal of Radiation OncologyBiologyPhysics

Volume 56, Issue 1, 1 May 2003, Pages 28-39

https://doi.org/10.1016/S0360-3016(02)04506-6 Get rights and content

Abstract

Purpose

To assess the effect of local radiation administered to primary disease sites in children with high-risk neuroblastoma.

Methods and materials

A total of 539 eligible patients were entered on protocol CCG-3891, consisting of chemotherapy, primary surgery, and 10 Gy of external beam radiation therapy (EBRT) to gross residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). ABMT patients received total body irradiation (TBI).

Results

Estimated event-free survival and overall survival at 5 years were 25% ± 2% and 35% ± 2%, respectively. Estimated 5-year locoregional recurrence rates were 51% ± 5% and 33% ± 7% for CC and ABMT patients (p = 0.004). For patients who received 10 Gy of EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with CC (22% ± 12% and 52% ± 8%, p = 0.022). EBRT did not increase acute toxicity, except for increased total parenteral nutrition administration.

Conclusions

In combination with EBRT to the primary tumor site, the addition of 10 Gy of TBI as a component of high-dose chemotherapy with ABMT improved local control compared with CC without TBI. Results suggest a dose–response relationship for local EBRT. Short-term toxicity of local EBRT is limited.

Introduction

Neuroblastoma, the most common extracranial solid tumor of childhood, is a neoplasm that arises from sympathetic ganglion cells. Approximately 650 children are diagnosed with it in the United States each year, half of them presenting with Stage IV metastatic disease (1). Despite concerted clinical and scientific efforts, prognoses of patients with high-risk neuroblastoma remain poor. Less than 30% of patients with high-risk disease who are older than 1 year survive more than 5 years (2).

The risk of relapse at the primary disease site presents a significant challenge. Patients with Stage IV neuroblastoma usually present with large, invasive primary tumors that are rarely eradicated by chemotherapy alone and pose complex hurdles to surgery (2). As a result, local recurrences occur in 17%–74% of patients 3, 4, 5, 6, 7, 8. Although no randomized trials have addressed the role of radiation in children with Stage IV disease, some recent studies reported apparently improved local control rates by adding radiation therapy or increasing radiation doses to primary sites of disease 7, 8, 9, 10, 11. Current multimodality protocols for high-risk neuroblastoma patients have incorporated radiation to the primary disease site (12). However, optimal application of radiation to high-risk patients, specifically dosage, timing, and use with macroscopic and microscopic disease, remains elusive.

The recently reported randomized Children’s Cancer Group study (CCG-3891) showed superior clinical outcomes for patients with high-risk neuroblastoma who were treated with myeloablative chemotherapy and total body irradiation (TBI) with transplantation of purged autologous bone marrow, followed by treatment with 13-cis-retinoic acid (12). External beam radiation therapy (EBRT) was prescribed for all patients with gross residual disease after induction chemotherapy and surgery. Patients randomly assigned to the transplantation arm received additional TBI as a component of the ablative regimen. The purpose of the study described here was to analyze efficacy of radiation administered to residual primary disease sites in children with high-risk neuroblastoma treated on CCG protocol 3891.

Section snippets

Patients

The CCG-3891 protocol was a randomized study that compared conventional-dosage treatment with ablative chemoradiotherapy supported by purged autologous bone marrow transplantation (ABMT) for patients with high-risk neuroblastoma. Enrollment began in January 1991 and ended in April 1996. Eligible patients had newly diagnosed high-risk neuroblastoma and were 1 to 18 years old. Table 1 delineates patient characteristics. Four hundred fifty-three patients had Evans Stage IV disease. Seventy-two had

Results

For all 539 eligible patients entered, the median follow-up was 66 months (range: 2–114 months), and the estimated EFS and OS rates at 5 years were 25% ± 2% and 35% ± 2%, respectively. In CCG-3891, EBRT was prescribed to the primary disease site for patients who underwent grossly incomplete (partial) resections or had postoperative radiologic evidence of gross residual disease. Radiation therapy is delivered to improve local disease control, so analyses focused on local control at the primary

Discussion

Radiation, like surgery, is therapy to control local, not systemic, disease. As systemic therapy for high-risk neuroblastoma becomes more aggressive, response rates improve, and survival increases, local control becomes a formidable problem (5). This is shown by the high local relapse rates of 51% ± 5% and 33% ± 7% at 5 years for patients in the present report that received continuation chemotherapy and transplantation, respectively. For Stage III and IV neuroblastoma, local relapse is a major

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Impaired Aortic Growth in Neuroblastoma Patients After Intensive Treatment
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This study evaluated the abdominal aortic diameter in high-risk neuroblastoma (NB) patients and the risk of aortic narrowing following intensive treatment.
We measured the aortic diameter at four specific levels of the abdominal aorta (diaphragmatic crus, celiac axis, and the root of the superior (SMA) and inferior (IMA) mesenteric arteries) on contrast CT scans. The control group consisted of 56 children with non-oncologic disorders, while the NB group included 35 patients with high-risk abdominal NB. We used regression analysis of age and aortic diameter to determine the regression formula for each level in each group and performed intergroup comparisons using t-test.
We evaluated a total of 160 contrast-enhanced CTs performed in the 35 eligible cases. The aortic diameter of pretreated NB patients was not significantly different from the controls. After receiving any treatment, the aortic diameter was significantly smaller in the NB group (p < 0.01 each). Patients who underwent radical surgery, particularly gross total resection (n = 26), had smaller aortic diameters at all levels compared to controls (p < 0.01 each). Patients treated with radiotherapy (RT) had smaller aortic diameters than controls. External beam radiotherapy (EBRT) patients (n = 24) had smaller aortic diameters at all levels except the celiac axis (crus, SMA, IMA; p < 0.01 each), and intraoperative radiotherapy (IORT) ± EBRT patients (n = 5) had smaller aortic diameters at all levels (p < 0.01 each).
Patients with NB may experience impaired development of the abdominal aorta after multimodal therapy, particularly after RT. Close observation and long-term follow-up is essential to monitor for catastrophic vascular complications.
LEVEL III.
Enhancing the sensitization of neuroblastoma to radiotherapy by the construction of a dual-channel parallel free radicals nanoamplifier
2023, Materials Today Bio
Radiation therapy (RT) has emerged as one of the most promising anti-tumor strategies for neuroblastoma. Nevertheless, the special tumor microenvironment (TME), including hypoxic and GSH-overexpressed TME, often greatly restricts the RT outcome. In this study, we demonstrated a dual-channel parallel radicals nanoamplifier (ATO@PAE-PEG-AS1411/Fe³⁺). The nanoamplifier was shaped into a bilayer shell-core structure, in which atovaquone-loaded poly (β-amino esters)-poly (ethylene glycol) (ATO@PAE-PEG) served as the core while Fe³⁺-absorbed AS1411 aptamer (AS1411/Fe³⁺) served as the shell. Taking advantage of the targeting ability of AS1411, ATO@PAE-PEG-AS1411/Fe³⁺ specifically accumulated in tumor cells, and then released ATO as well as Fe³⁺ in response to the acidic TME. The released ATO dramatically inhibited the mitochondrial respiration of tumor cells, thus sparing vast amounts of oxygen for the generation of free radicals during RT process, which was the first free radicals-amplifying pathway Meanwhile, the released Fe³⁺ could consume the tumor-overexpressed GSH through the redox reaction, thus effectively preserving the generated free radicals in RT process, which was the second free radicals-amplifying pathway. Taken together, our study demonstrates a dual-channel parallel free radicals-amplifying RT strategy, and it is expected this work will promote the clinical application prospects of RT treatment against neuroblastoma.
Neuroblastoma: Essential genetic pathways and current therapeutic options
2022, European Journal of Pharmacology
Neuroblastoma is a very diverse pediatric tumor that starts from the neural crest, and it is responsible over more than 15% of all juvenile cancer deaths. Clinical signs and symptoms are highly dependent on tumor origin and spread. Bone, lymph nodes, liver, intracranial and orbital tissues, lungs, and the central nervous system are frequently involved in metastatic neuroblastoma. Neuroblastoma enhances with contrast in Computed Tomography (CT) scans as a solid heterogeneous mass which might invade to adjacent ipsilateral or contralateral lymph nodes, tissues, and vessels. Whereas the Magnetic Resonance Imaging (MRI) acquires an acceptable diagnostic accuracy for detection of spinal cord and musculoskeletal metastases. Lorlatinib, a novel ALK inhibitor designed to overcome this resistance, is currently being tested in the New Approaches to Neuroblastoma Therapy (NANT) consortium. Aurora kinase inhibitors have been reported to disrupt MYCN, which is particularly attractive considering the lack of direct inhibitors targeting this driver in neuroblastoma. Sorafenib, a RAF kinase inhibitor, and newer PI3K inhibitors are being tested in children with neuroblastoma in an attempt to block the RAS pathway. Despite various therapies including chemotherapy, radiotherapy, immunotherapy and autologous stem cell transplantation in different neuroblastoma risk groups, most patients undergo surgical removal of the tumoral mass. This review is aimed to summarize the updated knowledge about the neuroblastoma, pathogenesis, it's essential genetic pathways and the current available therapeutic options for neuroblastoma.
Role and toxicity of radiation therapy in neuroblastoma patients: A literature review
2020, Critical Reviews in Oncology/Hematology
Neuroblastoma is the most common extracranial solid tumor, arising from primitive sympathetic ganglion cells, in pediatric patients. The unique features of neuroblastoma include variable clinical behaviors, such as rapid progression to death and maturation to benign ganglioneuroma, followed by regression. Radiation therapy (RT) is usually administered to both the primary tumor bed and persistent metastatic sites after induction chemotherapy for high-risk neuroblastoma. RT to the tumor bed after surgical resection contributes significantly to local disease control and prevention of local relapse, confirming the role of RT. Palliative radiotherapy for metastatic neuroblastoma is also effective and safe and mainly provides symptomatic relief. The late side effects of RT in neuroblastoma patients include growth and developmental failure, hypothyroidism, gastrointestinal dysfunction, neurocognitive defects, pulmonary and cardiac abnormalities, infertility, and secondary cancers. In this article, we reviewed the role and toxicity of RT in neuroblastoma patients.
Pediatric Cancer
2020, Hematology/Oncology Clinics of North America
Impact of extent of resection on survival in high-risk neuroblastoma: A systematic review and meta-analysis
2019, Journal of Pediatric Surgery
Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor. Many studies designed to elaborate the association between the extent of resection (EOR) and outcome have reported conflicting results. We performed a meta-analysis to assess whether greater EOR is associated with improved overall survival (OS) and event-free survival (EFS) in patients with high-risk neuroblastoma.
Embase, PubMed, Cochrane library, and conference proceedings were searched between March 10 and October 1, 2017. Studies of pediatric patients with newly diagnosed high-risk neuroblastoma comparing various EOR and presenting objective overall or event-free survival data were included. Primary outcomes were relative risk (RR) for mortality at 3 and 5 years. Secondary outcomes were 3-year and 5-year EFS rates.
19 retrospective studies including a total of 2358 cases were identified. Compared with subtotal resection (STR), patients who underwent gross total resection (GTR) had significantly decreased mortality at 3 years (RR, 0.69; 95% CI, 0.58–0.82; P < 0.001; I² = 27%) and 5 years (RR, 0.70; 95% CI, 0.60–0.82; P < 0.001; I² = 38%). A similar decrease was revealed in the 3-year risk for mortality for STR compared with biopsy (RR, 0.71; 95% CI, 0.53–0.95; P = 0.02; I² = 0%). When comparing any resection with biopsy, resection group also showed a decreased risk for mortality at 3 years (RR, 0.66; 95% CI, 0.53–0.83; P < 0.001; I² = 8%) and 5 years (RR, 0.67; 95% CI, 0.50–0.91; P = 0.009; I² = 61%). With respect to the risk ratio for EFS, there were no significant differences in any comparisons.
This literature highlights the importance of “extent of resection” in treating high-risk neuroblastoma, and when feasible, the currently available evidences in favor of the use of GTR for high-risk neuroblastoma for reducing 3- and 5-year mortality.
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^☆: Supported in part by ASCO Career Development Award (DAH-K) and Pfizer Scholar Grant for New Faculty (DAH-K), Kasle and Tcalcevik Neuroblastoma Research Fund (KKM), and Children’s Cancer Group (CA13539), from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Contributing Children’s Cancer Group investigators, institutions, and grant numbers are given in the appendix.

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Clinical investigation: pediatricsImpact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study☆

Abstract

Purpose

Methods and materials

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

J Pediatr Surg

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Sympathetic nervous system tumors, cancer incidence and survival among children and adolescentsUnited States SEER program 1975–1995

NeuroblastomaBiology and therapy

Oncology

Long-term results of therapy for stage C neuroblastoma

J Surg Oncol

NeuroblastomaThe Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital experience

J Clin Oncol

Patterns of relapse after autologous purged bone marrow transplantation for neuroblastomaA Children’s Cancer Group pilot study

J Clin Oncol

High-dose consolidation with local radiation and bone marrow rescue in patients with advanced neuroblastoma

Med Pediatr Oncol

Phase I trial of carboplatin, etoposide, melphalan, and local irradiation (CEM-L1) with purged autologous bone marrow transplantation (ABMT) for high risk neuroblastoma

Med Pediatr Oncol

Hyperfractionated low-dose radiotherapy for high-risk neuroblastoma after intensive chemotherapy and surgery

J Clin Oncol

Clinical investigation: pediatrics
Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study☆