Optimizarea managementului nutrițional în neuroblastomul pediatric: revizuire narativă a strategiilor și intervențiilor disponibile

Introduction

Neuroblastoma (NB) is a rare and highly aggressive pediatric malignancy, and represents the most common extracranial solid tumor in infancy. The disease is predominantly diagnosed in children younger than 5 years of age, with incidence rates declining significantly with increasing age. Despite extensive research efforts, the etiology and risk factors associated with neuroblastoma remain incompletely understood, largely due to its marked biological heterogeneity and relatively low overall incidence^(1-3). 

Primary tumors most frequently originate in the adrenal medulla or along the sympathetic chain within the abdomen. Less common primary sites include the mediastinum, pelvis and cervical region. A major clinical challenge in the management of neuroblastoma is its frequent presentation at an advanced stage, often accompanied by widespread metastatic disease. Consequently, therapeutic strategies commonly require intensive, multimodal treatment approaches, particularly in patients with high-risk disease.

Neuroblastoma is characterized by substantial genetic and molecular heterogeneity, which plays an important role in tumor behavior, risk stratification and clinical outcomes. In contrast to many adult malignancies, neuroblastoma exhibits a relatively low somatic mutational burden; however, recurrent chromosomal alterations and structural genomic abnormalities are frequently observed^(1,2). Amplification of the MYCN oncogene represents one of the most clinically relevant genetic aberrations in neuroblastoma, occurring in approximately 20-25% of cases and being strongly associated with aggressive tumor growth, rapid disease progression and poor prognosis^(3,4). Additional recurrent genomic alterations include segmental chromosomal aberrations, such as gain of chromosome arm 17q and deletions of chromosomal regions 1p36 and 11q, which have been independently associated with unfavorable clinical outcomes^(5,6); furthermore, activating mutations in the ALK (anaplastic lymphoma kinase) gene constitute the most common somatic mutations observed in sporadic neuroblastoma and are also involved in familial cases⁽⁷⁾. Other genes involved in neuroblastoma pathogenesis include PHOX2B, a key regulator of neural crest development, and ATRX, whose mutations are more frequently observed in older children and adolescents, and are associated with a more indolent yet therapy-resistant disease course^(8,9).

Recent advances in high-throughput sequencing technologies have further underscored the contribution of epigenetic dysregulation – including aberrant DNA methylation patterns, chromatin remodeling and altered non-coding RNA expression – to neuroblastoma tumorigenesis and disease progression⁽¹⁰⁾. In this context, accurate disease staging is fundamental for effective risk stratification and therapeutic planning. The currently preferred staging framework is the International Neuroblastoma Risk Group Staging System (INRGSS), which is based on pretreatment imaging characteristics rather than surgical findings⁽¹¹⁾. The INRGSS categorizes neuroblastoma into four stages (L1, L2, M and MS), facilitating standardized international comparisons and supporting biologically driven treatment approaches⁽¹²⁾.

The clinical course of neuroblastoma is highly variable, ranging from spontaneous regression to highly aggressive, treatment-refractory disease. Prognosis is determined through an integrated risk stratification system that incorporates multiple clinical and biological factors, including age at diagnosis, disease stage, histopathological features and molecular characteristics⁽¹³⁾. Favorable prognostic factors include younger age at diagnosis – particularly in patients younger than 18 months old – localized disease, hyperdiploid tumor DNA content and absence of MYCN amplification⁽¹⁴⁾. In contrast, adverse prognostic indicators include MYCN amplification, segmental chromosomal aberrations (such as deletions of 1p and 11q), metastatic disease (stage M) and unfavorable histology as defined by the International Neuroblastoma Pathology Classification (INPC)⁽¹⁵⁾. Based on these parameters, patients are stratified into low-, intermediate- and high-risk groups, which directly guide treatment intensity. While long-term survival rates exceed 90% in patients with low-risk neuroblastoma, outcomes for high-risk disease remain poor, with five-year overall survival rates of approximately 40-50% despite aggressive multimodal therapeutic regimens^(16,17).

Given the aggressive nature of the disease and the intensity of treatment protocols, children with neuroblastoma are particularly vulnerable to nutritional challenges. Pediatric oncology patients experience nutritional deficiencies that can profoundly impact treatment outcomes, overall prognosis, and quality of life. Malnutrition is a pervasive issue, often exacerbated by the disease itself (e.g., anorexia, pain, malabsorption) and the arduous treatment regimens (e.g., chemother­apy-induced nausea, mucositis, surgical complications). Effective nutritional management is crucial for supporting growth, maintaining immune function, mitigating treatment-related toxicities, and ultimately improving survival rates in these vulnerable patients⁽¹⁸⁾.

This review aims to comprehensively analyze the specific dietary recommendations and scientific evidence pertaining to nutritional management in neuroblastoma. We explore the latest findings on metabolic alterations, the role of specific diets (e.g., ketogenic diet) and the potential of various nutraceutical interventions. The goal is to synthesize the current knowledge in order to provide a robust overview for clinicians and researchers, highlighting established practices and areas requiring further investigation.

Methodology

This review synthesizes current scientific literature concerning the dietary implications and nutritional management strategies in pediatric neuroblastoma. This review follows best-practice recommendations for narrative reviews in clinical research, aiming for a structured, rigorous approach.

Search strategy. A comprehensive search was conducted across several electronic databases, including PubMed, Scopus and Web of Science. The primary search terms and their combinations included: “neuroblastoma” and “pediatric oncology”, “nutrition”, “malnutrition”, “resting energy expenditure”, “macronutrients”, “physical activity”, “ketogenic diet”, “nutraceuticals”, “curcumin”, “allicin”, “resveratrol”, “vitamin D”, “dietary intervention” and “nutritional assessment”. No date restrictions were initially applied to capture a broad overview, but a focus was placed on more recent publications (last 10-15 years) where available, to ensure up-to-date information. Specific older seminal works were included to provide foundational context.

Inclusion and exclusion criteria. Studies were included if they focused on pediatric patients with neuroblastoma, addressed nutritional status, metabolic parameters, specific dietary interventions (e.g., ketogenic diet), or the role of nutraceuticals. Both preclinical (in vitro and animal models) and clinical studies (observational, interventional, and review) were considered. Editorials, letters to the editor and non-peer-reviewed articles were generally excluded.

Data extraction and synthesis. Relevant data regarding study design, patient populations, interventions, outcomes and conclusions were extracted from the selected articles. The information was then thematically synthesized to identify key trends, consistent findings, and areas of controversy or knowledge gaps. The collected evidence was critically appraised to inform the discussion and future directions.

Results

Nutritional status in neuroblastoma

Nutritional status is a critical determinant of prognosis in pediatric oncology, including neuroblastoma (NB). A study involving 24 pediatric NB patients highlighted the importance of nutritional status, both prior to and during oncologic treatment, for improving survival rates. Anemia was observed in 62.5% of the subjects, correlating with a higher risk of complications, with 75% of deceased patients being anemic. Similarly, patients experiencing hypoproteinemia exhibited an inadequate response to treatment⁽¹⁹⁾. Although this specific study did not demonstrate a statistically significant association between malnutrition and survival, a larger cohort study involving 1787 oncology patients, including 30 with neuroblastoma, reported reduced survival rates among malnourished individuals⁽²⁰⁾. Conversely, a study on 455 children with cancer (13 with NB) indicated that in advanced stages, survival rates were reduced irrespective of the patients’ nutritional status⁽²⁰⁾. Yet, according to Pedretti et al., malnutrition is prevalent in approximately 50% of newly diagnosed neuroblastoma patients and in 20-50% of cases undergoing treatment. This significantly impacts treatment response, complications and mortality risk. After the initiation of oncologic treatment, the risk of malnutrition is heightened, often necessitating nasogastric tube feeding. The benefits of tube feeding versus oral feeding are still under investigation, often guided by clinical assessment of feeding tolerance and nutritional adequacy^(22,23).

Literature consistently indicates a decreased survival rate in children with growth restriction, attributed to compromised immunity and an elevated risk of infections. Furthermore, alterations in the lean mass-to-fat mass ratio can influence the metabolism of chemotherapeutic agents, leading to an increased frequency and/or intensity of adverse effects such as nausea, vomiting, appetite loss or altered bowel transit. Malnutrition is also associated with increased mortality, morbidity and risk of relapse⁽²¹⁾.

 Metabolism and energy requirements

Metabolic alterations are frequently observed in pediatric NB patients, and they can substantially influence prognosis. Specifically, rapidly proliferating neuroblastoma cells demand efficient energy metabolism, often relying on glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect⁽²⁴⁾.

A central aspect of metabolic evaluation is the resting energy expenditure (REE). A study investigated REE in a cohort of NB subjects, hypothesizing that the common malnutrition at diagnosis or during treatment might stem from an increased metabolic rate. However, this hypothesis was not confirmed; instead, undernutrition was likely attributed to anorexia induced by the disease itself and associated symptomatology, rather than an elevated REE⁽²⁵⁾. This observation is corroborated by studies analyzing dietary patterns in pediatric oncological patients, which reveal that NB patients often exhibit restrictive eating habits, frequently consuming low-calorie snacks, which account for weight loss in the context of a normal REE. Evidence also suggests that patients with brain tumors may exhibit a lower REE per kg body weight. Therefore, when individual total energy expenditure cannot be precisely determined, it is recommended to estimate energy requirements similarly to healthy subjects, taking into account potential increases during periods of rapid growth or recovery⁽²⁶⁾.

Specific macronutrient needs – particularly proteins – are crucial for supporting growth, tissue repair and immune function. Protein requirements are estimated to exceed 1 g/kg body weight, but can vary depending on the patient’s age at diagnosis, individual metabolic status and the intensity of treatment. Sufficient caloric intake from carbohydrates and fats is also essential to spare protein for its vital functions^(27,28).

 Physical activity

Maintaining physical activity within tolerated limits is recommended for pediatric neuroblastoma patients to preserve muscle mass, reduce anxiety, enhance quality of life and optimize metabolic profiles. Moderate activity, defined as sports activities performed three times a week for 10-60 minutes per session at 50-75% of maximum aerobic capacity, is suggested, always under medical guidance and tailored to the child’s condition and treatment phase. Early implementation of physical activity programs can mitigate sarcopenia and improve functional capacity⁽²⁹⁾.

Dietary interventions: ketogenic diet (KD)

The ketogenic diet, initially employed in the 1920s for drug-resistant epilepsy, has since demonstrated therapeutic potential across various pathologies⁽³⁰⁾. While its efficacy as an adjuvant antitumor therapy remains a subject of ongoing debate, particularly concerning neuroblastoma, preclinical research has yielded promising results.

An extensive study in animal models evaluated the benefits of several dietary regimens in treating this oncological pathology: standard caloric restriction, ketogenic diet based on long-chain fatty acids without caloric restriction, and calorically restricted ketogenic diet. The results at day 19 indicated slower tumor volume growth in mice across all three intervention groups compared to mice fed with a standard diet. By day 33, tumor mass was significantly smaller in mice undergoing caloric restriction, irrespective of fat intake modulation. However, growth inhibition was not significant at this assessment for mice on a ketogenic diet without caloric restriction⁽³¹⁾. In mice with SH-SY5Y tumors, the survival rate at day 22 of the study was significantly improved: 100% of mice fed with a calorically restricted ketogenic diet survived, whereas only 50% of those on a ketogenic diet without caloric restriction remained alive. An improved survival rate was observed across all three analyzed regimens compared to standard diets. Similar results were obtained for SK-N-BE tumors. Regarding metabolic adaptation, a reduction in glycemia was recorded in calorically restricted mice, without significant changes in subjects on a ketogenic diet. Weight changes were significant in SH-SY5Y subjects on a hypocaloric standard diet or a calorically restricted ketogenic diet, while for SK-N-BE tumors, only the calorically restricted ketogenic diet induced significant weight changes⁽³¹⁾.

The proposed mechanisms for the antitumoral effects of the ketogenic diet include reducing glucose availability for tumor cells, forcing them to utilize less efficient fatty acids and modulating tumor signaling pathways. KD may also amplify the effect of certain chemotherapeutic agents, such as cyclophosphamide, and improve survival rates in MYCN-amplified NB xenograft models by intensifying beta-oxidation and inducing autophagy. This can also reduce angiogenesis through negative regulation of HIF-1α and vascular endothelial growth factor⁽³²⁾.

Despite potential benefits as an adjuvant therapy, the ketogenic diet is considered contraindicated in certain situations. Patients with BRAF V600E mutations represent one such contraindication, although this type of mutation is rare in neuroblastoma. Additionally, for patients with hypoglycemia secondary to underlying pathology complications, the ketogenic diet is either not recommended or indicated solely under strict medical supervision due to the risk of severe hypoglycemic episodes. Known adverse reactions, termed “keto flu” (headache, nausea, lethargy), can exacerbate symptoms specific to the oncological pathology and its treatment, necessitating careful monitoring. Implementing KD in children requires rigorous evaluation, considering the risk of malnutrition, growth impairment, and endocrine dysfunction^(33,34).

Nutraceuticals

The use of nutraceuticals as adjuvant therapy in oncological treatment aims to inhibit tumor cell invasion and reduce the risk of metastasis without adversely affecting healthy tissues. Although they offer potential benefits, most nutraceuticals are not yet integrated into standard medical treatment protocols, and their effects in the pediatric population remain underevaluated due to a lack of large-scale clinical trials^(35,36).

Curcumin, primarily derived from turmeric, is being investigated for anticancer therapies due to its ability to induce apoptosis and reduce tumor growth by regulating the activity of p53, PTEN and HSP60. Furthermore, curcumin supplementation has been associated with reduced tumor cell migration via TIMP1 activation, and has shown synergistic effects with conventional chemotherapeutics such as doxorubicin^(37-39).

Allicin and other compounds extracted from garlic have demonstrated induction of cellular apoptosis and inhibition of cell proliferation. These effects are mediated through alterations in mitochondrial permeability, regulation of ornithine decarboxylase 1 activity, cell cycle arrest at G2/M phase, and activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)^(40-43).

Resveratrol, predominantly found in grapes, influences disease risk by inducing cellular apoptosis and inhibiting cell proliferation via p53 activation and modulation of sirtuin 1 pathways^(44-46). Other constituents with the potential to influence disease risk include diallyl disulfide, all-trans retinoic acid, 9-cis-retinoic acid, epigallocatechin-3-gallate, bergamot essential oil, bergamottin, caffeine and berberine. Dietary sources for these compounds vary, encompassing garlic, coffee, green tea, vitamin A metabolites from animal or plant products, and various medicinal plants. Their mechanisms of action involve anti-apoptotic effects, reduction of tumor growth in vivo, reduced phosphorylation of p38, induction of apoptosis through increased caspase-3 and p53 activity, and reduction of Bcl-2/Bcl-XL expression. For instance, epigallocatechin-3-gallate, found in green tea, and 6-OH-11-O-hydroxyphenanthrene have been shown to limit BE-C neuroblastoma cell growth and neurosphere formation in vitro. Didymin, a citrus flavonoid, also shows promise effect on targeting neuroblastoma^(47-54).

Vitamin D

While previous assumptions suggested that vitamin D supplementation might be beneficial for neuroblastoma patients, an extensive research project found no significant association between serum 25-hydroxyvitamin D levels and neuroblastoma risk. This finding contrasts with the significant reduction in disease risk observed for other oncological pathologies, such as lung cancer. Recent studies, however, show that vitamin D deficiency is a concern in pediatric cancer patients, and some research indicates a relationship between NB and vitamin D signaling pathways, given vitamin D’s antiproliferative and anti-invasive properties, particularly in high-risk NB. Despite this, large-scale supplementation for NB prevention or general treatment is not broadly supported by current evidence. Research projects suggest that widespread screening for circulating vitamin D and broad supplementation are not warranted for patients at risk of neuroblastoma, although individualized assessment for deficiency and targeted supplementation may be considered in cases of documented deficiency^(55,56).

Dietary monitoring and intervention

Current studies indicate that dietary assessment in pediatric oncological patients is more feasible and accurate with 24-hour dietary recalls (24H-R) than with food diaries, given the challenges of adherence and recall bias in a pediatric population undergoing demanding treatments. Furthermore, research demonstrates that a controlled dietary intervention implemented over a year benefits all pediatric patients after the oncological diagnosis, underscoring the importance of early intervention. This needs a comprehensive nutritional assessment, including anthropometry, biochemical evaluation and clinical nutritional examination, at diagnosis and throughout treatment⁽⁵⁷⁾.

Discussion

The synthesis of current literature highlights the complex interplay between nutrition and neuroblastoma prognosis. Malnutrition is a prevalent issue in pediatric NB patients, significantly impacting treatment tolerance, complication rates and overall survival. While previous assumptions linked this to an elevated resting energy expenditure, recent findings suggest that disease- and treatment-induced anorexia, along with altered nutrient metabolism, are primary drivers of undernutrition, rather than a hypermetabolic state. This reevaluates the approach to energy requirement estimation, advocating for calculations similar to those of healthy individuals unless specific needs are identified⁽⁵⁸⁾.

The emphasis on adequate macronutrient intake – particularly protein – underscores its crucial role in supporting growth, tissue repair and immune function in these vulnerable patients. Furthermore, maintaining moderate physical activity is critical not only for muscle preservation but also for psychological well-being and metabolic optimization, thereby improving quality of life^(25-30).

The ketogenic diet emerges as a promising adjuvant therapy, primarily from preclinical studies. Its proposed mechanisms – including glucose deprivation for tumor cells, modulation of tumor signaling pathways and enhancement of chemotherapeutic effects – offer a compelling rationale for further investigation. However, the limited number of large-scale clinical trials and the potential for adverse effects such as “keto flu” and specific contraindications (e.g., BRAF V600E mutations, severe hypoglycemia) require careful patient selection and stringent medical supervision. Implementing KD in a growing child population poses unique challenges due to the risks of malnutrition and endocrine dysregulation, requiring a multidisciplinary approach involving dietitians, oncologists and endocrinologists^(31-35).

Nutraceuticals, including curcumin, allicin and resveratrol, represent an intriguing area of research due to their diverse anticancer mechanisms, including induction of apoptosis, inhibition of proliferation and modulation of gene expression. These compounds hold potential for complementary therapies, offering avenues to target cancer cells with potentially fewer systemic toxicities than conventional treatments. However, the transition from promising in vitro and animal model results to established clinical protocols requires extensive human trials to ascertain efficacy, optimal dosing, bioavailability and safety in pediatric populations. Standardized extraction methods and formulations are also critical for reliable clinical application^(38-55).

Regarding micronutrients, the role of vitamin D in neuroblastoma remains less clear. While its anti-proliferative and anti-invasive properties are recognized in cancer biology generally, direct evidence linking 25-hydroxyvitamin D levels to neuroblastoma risk or prognosis is inconsistent across studies. Therefore, universal vitamin D supplementation for NB prevention or treatment is not currently supported by robust evidence, though individualized assessment for deficiency and targeted supplementation may be warranted^(56,57).

Effective nutritional management hinges on early and accurate assessment. The preference for 24-hour dietary recalls over food diaries indicates a shift towards more practical and reliable assessment methods in this population. The overarching recommendation for sustained dietary intervention post-diagnosis for at least one year highlights the chronic nature of nutritional support required for pediatric oncology patients. A comprehensive nutritional assessment, integrating anthropometric, biochemical and clinical evaluations, is paramount for guiding individualized interventions and improving patient outcomes^(59-63). 

Despite advances in understanding the role of nutrition in neuroblastoma, significant gaps in the literature remain to be explored. Rigorous clinical trials – particularly randomized controlled trials – are imperative for evaluating the safety and efficacy of specific dietary interventions, such as the ketogenic diet, in pediatric neuroblastoma patients. Standardization of nutritional assessment methods and interventions is crucial to facilitate study comparability and the formulation of evidence-based guidelines.

Future research should also focus on:

Identifying specific nutritional biomarkers that indicate malnutrition risk or predict response to dietary interventions, potentially leveraging metabolomics and proteomics.

Elucidating the molecular mechanisms by which nutraceuticals exert their antitumoral effects in neuroblastoma and their potential integration into multimodality treatment protocols. This includes studies on optimal dosing, bioavailability and potential drug-nutrient interactions.

Developing individualized nutritional strategies tailored to the unique metabolic and clinical needs of each patient, accounting for the genetic and phenotypic heterogeneity of neuroblastoma and variable treatment responses.

Long-term evaluation of the impact of dietary interventions on quality of life, growth and neurocognitive development in neuroblastoma survivors, acknowledging that nutritional support extends beyond active treatment.

Integrated, multidisciplinary approaches, combining nutrition with standard oncological therapies, are essential for improving the prognosis and quality of life for children with neuroblastoma. Collaborative efforts across institutions will be vital to generate the robust evidence required to translate promising preclinical findings into effective clinical practice.

Conclusions

Current research underscores a significant risk of malnutrition in neuroblastoma patients, often characterized by imbalanced dietary intake but without substantial alterations in resting energy expenditure. Nutritional strategies emphasize early, specialized intervention and meticulous monitoring for at least one-year post-diagnosis. The ketogenic diet, with or without caloric restriction, shows therapeutic promise in preclinical neuroblastoma models, yet its broader clinical application requires confirmation through larger, longer-term studies in pediatric cohorts. While widespread vitamin D supplementation lacks sufficient evidence for general recommendation in neuroblastoma, nutraceuticals such as curcumin, allicin and resveratrol have promising mechanisms of action that warrant further clinical investigation as potential adjuvant therapies.

Autor corespondent:  Roxana‑Maria Martin-Hadmaș E-mail: roxana.hadmas@umfst.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.