Role and practical guidelines for the use of radiotherapy in neuroblastoma — a narrative review of literature and clinical trial protocols

Abstract

Neuroblastoma is the most common extracranial solid tumor in children, requiring multidisciplinary treatment, including radiotherapy, which is primarily applied in the high-risk group to prevent disease progression.

The review highlights indications for radiotherapy, its role in multimodal treatment, and addresses aspects of radiotherapy planning, including target volume definition, prescribed radiation doses, optimal timing for radiotherapy implementation, and potential side effects.

Particular attention is drawn to the lack of consensus regarding the necessity of an additional radiation dose for persistent residual disease in the primary tumor and the irradiation of metastatic sites remaining after induction therapy.

To conclude, monitoring quality assurance in radiotherapy planning and delivering processes based on unified standards appears to be crucial.

Introduction

Neuroblastoma is the second most common solid tumor in children, following tumors of the central nervous system (CNS), making it the most frequent extracranial solid tumor. This malignant neoplasm arises from primitive cells of sympathetic ganglia and often requires multidisciplinary treatment, including surgery, systemic therapies, and radiation. Radiotherapy is primarily employed in cases with a high risk of disease progression and should be administered in specialized centers.

This paper reviews the literature on the role of radiotherapy in treating neuroblastoma. It also examines clinical trial protocols that guide multidisciplinary treatment for pediatric neuroblastoma patients in Poland.

Epidemiology

Neuroblastoma accounts for 5–10% of all childhood cancers [1–3]. According to data from the Surveillance, Epidemiology, and End Results (SEER) database in the United States, incidence rates since 1975 have been estimated at 0.23 per 100,000 people per year [4]. Globally, around 14,000 cases are diagnosed annually [5]. The National Cancer Registry data from Poland reported 49 cases of adrenal tumors in 2020 and 31 in 2021 [International Statistical Classification of Diseases and Related Health Problems 10^th Revision (ICD-10) — C74] [6].

Diagnosis, clinical staging, and risk groups

The diagnostic algorithm for suspected neuroblastoma includes histopathological examination of tumor tissue, complemented by immunohistochemistry, molecular profiling of the tumor, ploidy assessment of cancer cells, MYCN oncogene amplification status, and structural and numerical chromosomal aberrations. Biochemical analyses of catecholamines and their metabolites in urine, lactate dehydrogenase (LDH) activity, and levels of neuron-specific enolase (NSE) are also conducted. Stratification of the patients based on the identified risk-factors is used for radiotherapy qualification and planning. The molecular and genetic alterations commonly found in neuroblastoma include [3, 7]:

• MYCN amplification is present in approximately 20% of cases, and is associated with poorer event free survival (EFS) and overall survival (OS);

• ALK gene mutations — around 10% incidence, with amplification in an additional 3–4%, linked to unfavorable outcomes in EFS and OS;

• TrkB receptor abnormalities — associated with worse treatment outcomes;

• telomerase activity abnormalities — generally elevated, correlating with reduced EFS and OS;

• TERT gene mutations;

• loss of 1p and/or 11q or gain of 17q;

• chromothripsis.

Standard assessments currently evaluate MYCN gene copy number, ALK gene status, ploidy, 1p36 deletion, and 17q gain.

The currently accepted histopathological classification by the International Neuroblastoma Pathology Committee (INPC) categorizes neuroblastoma into favorable and unfavorable subtypes [8, 9].

Staging of neuroblastic tumors is based on imaging studies and histopathological identification of metastatic lesions. Among the required diagnostic procedures are:

• computed tomography (CT) and/or magnetic resonance imaging (MRI) of the tumor region, determined by the tumor’s location, with MRI recommended for lesions near the spinal cord;

• bone marrow trephine biopsy to assess marrow involvement;

• meta-iodobenzylguanidine (MIBG) scintigraphy using ¹²³I-MIBG; for MIBG-negative patients, positron emission tomography (PET)-CT with fluorodeoxyglucose (FDG) should be ordered [10].

To assess the primary lesion, both CT and MRI should be considered [11].

For staging and detection of distant metastases, CT of the chest, abdomen, and pelvis is recommended [11]. Some experts also advise brain imaging (CT or MRI) in cases of distant metastases [11] or high-risk or recurrent disease [12].

Staging classification and risk groups

In 1971, the Evans Staging System was introduced to assess neuroblastoma stages. Current staging systems incorporate surgical and objective risk factors derived from imaging studies. Before initiating treatment, it is necessary to stage the disease using the International Neuroblastoma Risk Group Staging System (INRGSS) classification, based on image-defined risk factors (IDRFs) identified in diagnostic imaging — assigning to L1 (localized tumor without IDRF), L2 (localized tumor with IDRF), M (distant metastatic disease), and MS (distant metastatic disease, age < 18 months) stage [13].

Defining the patient’s risk group is essential and includes disease stage, patient age, tumor histology, tumor differentiation, MYCN status, 11q aberration status, and tumor cell ploidy. This pre-therapeutic risk classification places patients into one of four groups:

• very low-risk — L1 or L2 stage with histopathological ganglioneuroma maturing or ganglioneuroblastoma intermixed structure, or L1 without MYCN amplification;

• low-risk — age ≤ 18 months at L2 stage or age ≤ 12 months with MS stage, without MYCN amplification;

• intermediate-risk — age > 18 months at L2 stage, without MYCN amplification, histopathology showing neuroblastoma or nodular ganglioneuroblastoma; also, children at L1 stage with MYCN amplification independent of age, or age < 12 months at M stage without MYCN amplification;

• high-risk — age > 365 days at diagnosis with M stage (metastases) or any age with L2, M, or MS stage with MYCN amplification.

Postoperatively, a reassessment of the disease stage is necessary using the International Neuroblastoma Staging System (INSS) with stages 1, 2a, 2b, 3, 4, and 4S [13].

The most frequent tumor site is the abdomen (60–80%), followed by the chest (15%), neck (2–5%), and pelvis (2–5%) [2].

Around 40–50% of cases are diagnosed with distant metastases [11, 14]. Common metastatic sites include the bone marrow and the skeletal system, while liver, lymph nodes, and skin metastases are less common [11, 14].

Clinical trial protocols, recommendations and guidelines

In Europe, key clinical trials and treatment recommendations for pediatric patients with neuroblastoma are developed by the International Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN).

Significant European clinical trial protocols for neuroblastoma include:

• LINES Study — European Low and Intermediate Risk Neuroblastoma Protocol: A SIOPEN Study (latest protocol version: 30 May 2011). This multicenter, randomized Phase III clinical trial aimed to evaluate the therapy in the low- and intermediate-risk patients;

• high-risk neuroblastoma 1 (HR-NBL1) — ClinicalTrials. gov Identifier: NCT01704716, HRNBL1.7 (latest protocol version: 4 April 2014);

• high-risk neuroblastoma 2 (HR-NBL2) — ClinicalTrials. gov Identifier: NCT04221035 (latest protocol version: 19 July 2019). This multicenter, randomized Phase III trial’s primary endpoints include comparisons of two induction chemotherapy regimens (GPOH vs. RAPID COJEC), single high-dose chemotherapy using busulfan and melphalan versus tandem high-dose chemotherapy using thiotepa, and radiotherapy of 21.6 Gy to the preoperative tumor area versus 21.6 Gy with a sequential boost to 36 Gy for patients with residual macroscopic tumor. Recruitment is ongoing.

These protocols have led the European Society for Pediatric Oncology (SIOPE) to establish specific recommendations for low- and high-risk groups under the European Reference Network (ERN) for rare cancers [15, 16].

In addition to European standard clinical practice recommendations, Germany has its own recommendations for radiotherapy indications in intermediate- and high-risk group, which differ from SIOPEN’s [17]. According to them, in Germany radiotherapy is indicated for unresectable residual lesions that remain after induction systemic treatment and surgery [17].

Current American clinical trial protocols include:

• ANBL0532 — ClinicalTrials.gov Identifier: NCT00567567 (latest protocol version: 16 August 2011). This multicenter, randomized Phase III trial aimed to intensify systemic consolidation treatment, introduce new induction regimens, and analyze the role of high-dose radiotherapy in newly diagnosed high-risk patients who could not undergo optimal surgery;

• ANBL1531 — ClinicalTrials.gov Identifier: NCT03126916 (latest protocol version: 14 January 2022). This multicenter, randomized Phase III trial focuses on adding ¹³¹I-MIBG or lorlatinib to induction therapy in newly diagnosed high-risk patients. The second version of the National Comprehensive Cancer Network^® (NCCN) guidelines is now available, with radiotherapy being conducted according to the clinical trial protocol Children’s Oncology Group (COG) ANBL1531 [18].

Multidisciplinary treatment

The treatment of neuroblastoma depends on the patient’s risk group. General overview on treatment of neuroblastoma according to European recommendations and stratification into risk groups is given in Table 1.

Table 1.

Overview on the risk group and the treatment methods in neuroblastoma

Risk group	Group	INRG stage	Age (mos)	MYCN amplification	Genetics	LTS	Histology	Chemotherapy	Surgery	Auto-SCT	RTx	Retinoids	Anti-GD2 therapy
Low risk	1	L2	≤ 18	−	NCA	−	Any	No therapy OR CO × 2–4	±	−	−	-	-
								± VP/Carbo × 2)
	2	L2	≤ 18	−	NCA	+		VP/Carbo × 2	±		−	-
								± CADO × 2
	3	L2	≤ 18	−	SCA	±		VP/Carbo × 2–4	±		−	-
								± CADO × 2
	4	Ms	≤ 12	−	NCA	−		−	−		−	-
	5	Ms	≤ 12	−	NCA	+		VP/Carbo × 2	−		−	-
								± CADO × 2
	6	Ms	≤ 12	−	SCA	±		VP/Carbo × 2–4	±		−	-
								± CADO × 2
Intermediate risk	7	L2	> 18	−	Any		Differentiating	VP/Carbo × 2	±		−	−
								+ CADO × 2 OR VP/Carbo × 2
	8	L2	> 18	−			Poorly differentiated/undifferentiated	VP/Carbo × 2, CADO × 2,	±		+	+
								VP/Carbo × 1 + CADO × 1 OR CADO × 2
	9	INSS1	Any	+	Any			VP/Carbo × 2, CADO × 2,	+		+	+
								VP/Carbo × 1, CADO x1
	10	M	≤ 12	−				VP/Carbo × 2–4	±		−	−
								± CADO × 2–4
High risk	M		> 12	±				COJEC OR N7	+	+	+	+	+
	M		≤ 12	+
	L2 (INSS 2,3)		> 12	+
Other	Ganglioneuroma OR							−	±	−	−	−	−
	Ganglioneuroblastoma intermixed
		L1	Any	−	Any			−	±	−	−	−	−

Risk group — pretreatment risk group; INRG — The International Neuroblastoma Risk Group; MOS — months; LTS — life threatening symptoms; auto-SCT — autologous stem cell transplantation; RTx — radiotherapy; SCA — segmental chromosome alterations; NCA — numerical chromosomal abnormalities; INSS — International Neuroblastoma Staging System; CO — cyclophosphamide + vincristine; VP/Carbo — vincristine + etoposide phosphate + carboplatin; CADO — cyclophosphamide + doxorubicin + vincristine; COJEC — cyclophosphamide + oncovin (vincristine) + carboplatin + etoposide + cisplatin; N7 — sequential cyclophosphamide/doxorubicin/vincristine and cisplatin/etoposide

Patients in the very low-risk group often do not require active treatment due to the high likelihood of spontaneous regression or transformation into a benign form [3].

For patients in the low-risk group, the treatment typically involves surgical resection alone. Adjuvant radiotherapy or chemotherapy is only indicated in cases of residual disease progression after incomplete resection or in cases of disease recurrence [3].

Treatment of patients in the intermediate-risk group includes surgery and multidrug chemotherapy, with treatment sequence adjusted based on tumor resectability [3]. Radiotherapy may be used in some patients with poorly differentiated or undifferentiated tumors, as well as in cases with MYCN amplification.

Patients in the high-risk group require a multimodal approach. Treatment includes multidrug chemotherapy, surgical resection, high-dose therapy with autologous stem cell transplantation, radiotherapy, and maintenance therapy based on immunotherapy anti-GD2 antibodies and 13-cis-retinoic acid.

In Poland, children diagnosed with neuroblastoma are currently treated according to the SIOPEN recommendations, based on clinical trial protocols.

Optimizing the use of radiotherapy is an important quality measure in neuroblastoma treatment. In a 2024 international publication, authors identified an optimal radiotherapy utilization rate (oRUR) of 64% for newly diagnosed neuroblastoma cases globally, with rates of 50% in high-income countries and 68% in low-income countries. These differences reflect variations in disease stage distribution and healthcare access [19].

Indications for primary tumor radiotherapy

According to the current European LINES protocol for the intermediate-risk group, the indications for radiotherapy include:

• L1 stage with MYCN amplification;

• L2 stage in patients older than 18 months without MYCN amplification, with poorly differentiated or undifferentiated tumor histology.

There are no indications for radiotherapy in the low-risk group or intermediate-risk patients with distant metastasis.

In contrast, in the European HR-NBL1 and HR-NBL2 protocols for high-risk groups, primary tumor radiotherapy is indicated in all cases as part of consolidation treatment, regardless of the extent of surgical resection.

Additionally, European recommendations derived from these protocols include specific criteria for initiating radiotherapy:

• absence of disease progression following high-dose chemotherapy and autologous stem cell transplantation;

• interval of 60 to 90 days between the last transplant and radiotherapy;

• performance status of ≥ 50%;

• blood parameters: absolute neutrophil count (ANC) > 0.5 × 10⁹/L, platelet count > 20 × 10⁹/L;

• acceptable liver function test results if the liver is included in the radiation field: alanine transaminase (ALT) < 3.0 × upper limit of normal (ULN), blood bilirubin < 1.5 × ULN (toxicity < grade 2) [16].

The American ANBL1531 protocol recommends primary tumor radiotherapy following induction systemic treatment under the following circumstances:

• low-risk group — emergencies such as spinal cord compression or hepatomegaly with respiratory distress and vision loss;

• intermediate-risk group — tumor progression during chemotherapy or persistent disease after the full course of treatment;

• high-risk group — radiotherapy is indicated in every case [11].

Role of radiotherapy in primary tumor treatment

Neuroblastoma is a highly radiosensitive tumor. The primary objective of radiotherapy in neuroblastoma treatment is to improve local control [20–23]. However, distant metastases remain a major challenge in successful outcomes. Evidence suggests that improved local control is predictive of better OS [21].

In the 1990s, a randomized clinical trial demonstrated the benefit of radiotherapy in the high-risk group [22]. This study compared patients who received radiotherapy to those who did not. Patients who had undergone postoperative irradiation of the tumor bed or residual tumor and regional lymph nodes showed better outcomes, with EFS at 73% vs. 59% (p = 0.009) and OS at 41% vs. 32% (p = 0.008) [22]. It should be noted, however, that retrospective analysis of these patients classified them as intermediate-risk.

A 2018 systematic review examined evidence of the efficacy of radiotherapy in neuroblastoma. Overall, the strength of evidence for radiotherapy’s effectiveness (targeting the tumor bed or residual tumor) was graded as moderate, with a low strength of evidence for specific subgroups according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system [23].

In 2010, a retrospective analysis (n = 44) found that local-regional control positively influenced OS (p = 0.06), with five-year OS rates of 48.3% in patients without local-regional relapses and 21.8% in those with relapses [21].

Role of radiotherapy in local tumor recurrence treatment

There is no established consensus on the treatment of local recurrence in neuroblastoma.

Treatment typically requires a multidisciplinary approach, which includes systemic therapy (often high-dose chemotherapy with stem cell transplantation), surgical intervention, re-irradiation through external beam radiotherapy or intraoperative radiotherapy [24–26]. Additionally, no specific guidelines exist regarding re-irradiation in the same area; however, authors consider re-irradiation a viable component in the treatment of recurrent disease [27].

Indications for radiotherapy in cases of distant metastasis

Metastatic disease is the primary cause of mortality in high-risk neuroblastoma patients.

European clinical trial protocols do not currently recommend routine irradiation of metastatic lesions that persist after induction chemotherapy (HR-NBL1 and HR-NBL2) as part of radical treatment for newly diagnosed patients. In contrast, the routine irradiation of metastatic lesions is included in the American COG protocols.

Role of radiotherapy in the treatment of metastatic lesions

There are three clinical scenarios regarding radiotherapy for metastatic lesions:

• systematic consolidation irradiation of oligoresidual metastatic lesions after induction chemotherapy as part of radical treatment for newly diagnosed patients;

• radical irradiation of metastatic lesions in cases of recurrence at the metastatic site (known as oligoprogression);

• palliative irradiation of metastatic lesions.

Some retrospective studies have demonstrated that radiotherapy of metastatic sites improves local control at the irradiated location [28–33]. In the previously mentioned 2018 systematic review, the strength of the evidence supporting radiotherapy for metastatic lesions in neuroblastoma was classified as low according to the GRADE system [23]. Additionally, a 2023 report by the European Society for Pediatric Oncology Radiotherapy Working Group systematically reviewed the literature and found no high-quality evidence supporting radiotherapy for residual metastatic lesions after induction chemotherapy in high-risk primary treatment cases [34]. The authors recommended considering randomized trials to evaluate the benefits of such an approach and proposed appropriate designs for clinical trials [34]. Specific recommendations are lacking for the other two clinical scenarios.

Metastatic lesions in the central nervous system

A 2022 analysis by the Polish Solid Tumor Group reported a 4.5% incidence (13 out of 286 patients) of isolated CNS recurrences in high-risk neuroblastoma patients treated between 2001 and 2019 across eight pediatric oncology centers in Poland [12]. No European protocols provide specific recommendations for managing CNS recurrences. However, the American protocol ANBL1531 suggests irradiation of the craniospinal axis at a dose of 21.6 Gy in 12 fractions for CNS involvement.

In a 2010 study, Croog and colleagues analyzed patients who had undergone craniospinal irradiation and found that it enabled prolonged remissions and improved survival compared to localized irradiation [35]. Additionally, a 2020 study by Luo et al. showed comparable results in patients who received either 18 Gy or 21 Gy to the craniospinal axis, establishing this approach as a standard practice [36].

Radiotherapy treatment planning

According to the HR-NBL2 protocol, radiotherapy planning includes the following:

• supine position with arms raised above the head;

• use of individualized immobilization devices;

• CT scans with transverse slices ≤ 3 mm;

• intravenous contrast is recommended (note: an additional non-contrast CT may be necessary for accurate dose distribution analysis);

• 4D computed tomography (4D-CT).

4D-CT integrating respiratory movements is particularly recommended for tumors located near the diaphragm or in areas with high respiratory mobility [11].

The American ANBL1531 protocol provides additional technical recommendations:

• simulation marks: Two axial planes should be marked, even when cone beam computed tomography (CBCT) verification is used, ideally on the anterior superior iliac spine and xiphoid process;

• adrenal region tumors: legs should be raised under the knees to flatten the lower spine relative to the treatment table, improving immobilization;

• head and neck region tumors: preoperative diagnostic CT should be performed in the treatment position.

• paraspinal tumors: MRI should be performed in the treatment position;

• to account for the respiratory motion: eg. with 4D-CT, even when using intensity-modulated radiation therapy (IMRT).

For radiotherapy planning under the HR-NBL2 protocol, the following imaging and surgical reports are required:

• preoperative contrast-enhanced CT and/or MRI images and descriptions;

• postoperative CT or MRI and MIBG scan results following high-dose chemotherapy;

• surgical report and postoperative histopathology report;

No protocol includes MRI sequences as a reference for radiotherapy planning.

Radiotherapy timing

For the intermediate-risk group (according to the European LINES protocol), radiotherapy should be administered after completing chemotherapy and surgical resection, between 21 and 42 days following the previous treatment stage.

For the high-risk group (according to the European HR-NBL protocol), radiotherapy should be performed after completing chemotherapy and surgery, but before retinoid therapy, with an interval of at least 60 days and no more than 90 days following autologous stem cell transplantation.

In the American protocols, radiotherapy should be initiated no sooner than 42 days and no later than 80 days after stem cell transplantation.

Longer intervals are permissible only in cases of severe transplant-related complications, including:

• hematological complications: neutrophil count < 500/μL and/or thrombocytopenia < 40,000/μL;

• active veno-occlusive disease;

• acute respiratory distress syndrome (ARDS) with laryngeal edema ≥ grade 2;

• diarrhea Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2;

• significant renal dysfunction;

• uncontrolled hematuria.

Radiotherapy target volumes for primary and metastatic tumors

For postoperative patients receiving radiotherapy to the primary tumor area, the following target volumes (TVs) are defined:

• gross target volume (GTV) — visible tumor area on imaging;

• clinical target volume (CTV) — Includes the GTV along with potential microscopic spread;

• planned target volume (PTV) — accounts for organ motion and potential patient positioning errors.

A summary of target volume delineation guidelines for primary tumor radiotherapy, based on current clinical trial protocols, is presented in Table 2.

Table 2.

Guidelines for target volume delineation for primary tumor radiotherapy based on clinical trial protocols

SIOPEN LINES — Intermediate-Risk Group	SIOPEN HR-NBL1/HR-NBL2 — High-Risk Group	COG ANBL1531
GTV — primary tumor visible on imaging after chemotherapy and before surgery; should include the tumor and affected regional lymph nodes	GTV — primary tumor visible on imaging (CT, MRI) after chemotherapy and before surgery; should include the tumor and persistent, enlarged regional lymph nodes	GTV_PreSurgery — primary tumor visible on preoperative imaging GTV should encompass GTV_PreSurgery in the superior and inferior extents GTV should include the tumor and lymph nodes identified during surgery. It should not include the prechemotherapy tumor area or uninvolved lymph nodes (no indication for elective lymph node irradiation) If a large portion of the tumor was removed at diagnosis, GTV should be defined based on the preoperative tumor In cases of inconclusive imaging, irradiate a larger volume If the tumor extended into adjacent structures (e.g., lung or liver), only a narrow margin (< 3 mm) should be included in GTV
	HR-NBL2 only — boost = GTVb = CTVb; includes macroscopic residual tumor post-surgery
CTV = GTV + 10 mm In the abdominal area, modify CTV to exclude the kidney, liver, or small intestine if they were compressed or displaced but not invaded Extend CTV to include adjacent vertebrae to ensure homogeneous dosing and reduce scoliosis risk	CTV = GTV + 5 mm Ensure CTV includes areas specified in surgical and pathology reports	CTV = GTV1 + 1 cm For abdominal tumors, modify CTV to exclude the kidney, liver, and vertebral bodies; for head and neck, thoracic, and pelvic tumors, exclude uninvolved bones Superior and inferior CTV limits should encompass the tumor’s preoperative area (GTV_PreSurgery)
	HR-NBL2 only — boost area (additional dose) = CTVb = GTVb
PTV = CTV + ≥ 5 mm	PTV = CTV + 5–10 mm	PTV = CTV + 0.3–0.8 cm (subdiaphragmatic area + 0.5–0.8 cm)

HR-NBL — high-risk neuroblastoma; GTV — gross target volume; CT — computed tomography; MRI — magnetic resonance imaging; CTV — clinical target volume; PTV — planned target volume

The Quality and Excellence in Radiotherapy and Imaging for Children and Adolescents with Cancer in Clinical Trials (QUARTET initiative), a project by SIOPE, enables centralized quality control of radiotherapy. The HR-NBL protocols incorporate quality assurance measures for consistent target and organs at risk delineation across participating centers.

In the American COG protocol, irradiation of metastatic lesions persisting after induction therapy is recommended before high-dose chemotherapy and stem cell transplantation.

Guidelines for delineating metastatic target volumes in the ANBL1531 protocol include:

• metastatic GTV — area of metastatic lesions with residual mass > 1 cm³ or MIBG/FDG activity before consolidation; CTV = GTV + 1 cm; PTV = CTV + 0.5 – 0.8 cm;

• if the radiotherapy area involves more than 50% of the bone marrow volume, verification by the study coordinator is required;

• for > 5 lesions detected on MIBG/PET, repeat imaging 28 days after autologous stem cell transplantation and irradiate only areas with active disease;

• special recommendations apply to radiotherapy of the calvarium, skull base, extremities, spine, and ribs.

Elective nodal irradiation

Studies have not shown a benefit from elective nodal irradiation [37].

Emergencies in radiotherapy for neuroblastoma

According to American protocols, in cases of stage MS disease, radiotherapy may sometimes be necessary to halt rapid tumor progression, particularly for tumors located near the liver where there is a risk of cardiopulmonary failure, impending spinal cord compression, or incomplete response to chemotherapy. In these emergencies, a low dose of 4.5 Gy in three fractions is typically used [3].

Dose, role of boost, and fractionation schedules

The recommended radiotherapy doses according to current clinical trial protocols are summarized in Table 3.

Table 3.

Fractionation schedules based on clinical trial protocols

SIOPEN LINES — Intermediate-Risk Group	SIOPEN HR-NBL1 — High-Risk Group	SIOPEN HR-NBL2 — High-Risk Group	COG ANBL1531
PTV = 21 Gy/14 fractions over 18–20 days If optimal doses cannot be achieved in organs at risk, two-phase treatment may be necessary: Phase 1 with 15 Gy in 10 fractions, followed by Phase 2 with 6 Gy in 4 fractions to a smaller area	PTV = 21 Gy/14 fractions over a maximum of 21 days If optimal doses cannot be achieved in critical organs, two-phase treatment may be necessary. No indications for a dose boost in cases of residual disease	PTV = 21.6 Gy/12 fractions over a maximum of 17 days (if an unscheduled break occurs, weekend irradiation or twice-daily radiotherapy with a 6-hour interval is recommended) This applies to patients without macroscopic residual disease who meet the following three conditions: No residual disease on MRI (or CT if MRI is unavailable). No residual disease on MIBG scintigraphy. The surgical report documents complete resection. If optimal doses cannot be achieved in organs at risk, two-phase treatment may be necessary Randomization studies (regarding the use of a boost) should be conducted after high-dose chemotherapy or 2–3 weeks post-surgery	PTV 1 = 21.6 Gy/12 fractions PTV for metastatic lesions = 21.6 Gy/12 fractions Irradiation of the primary tumor area and metastatic lesions should be performed simultaneously Hepatomegaly: 4.5 Gy/3 fractions Craniospinal axis: 21.6 Gy/1.8 Gy
		PTV = 21.6 Gy/12 fractions PTV Boost = 14.4 Gy/8 fractions to the residual lesion (total dose 36 Gy/20 fractions) For macroscopic residual disease
		If parents decline randomization, the patient receives 21.6 Gy

HR-NBL — high-risk neuroblastoma; PTV — planned target volume; MRI — magnetic resonance imaging; CT — computed tomography; MIBG — meta-iodobenzylguanidine

In previous American guidelines and ANBL0532 protocol, an additional boost to the residual primary tumor was recommended following induction chemotherapy. However, analysis of ANBL0532 data showed that boosting did not reduce the five-year cumulative local recurrence risk [38]. Meanwhile, the European SIOPEN — HR-NBL2 protocol includes randomization by a multidisciplinary team with the use of a boost dose in residual disease. Studies on dose-response relationships in neuroblastoma are inconclusive [39–42], and a systematic review classified the evidence strength for dose escalation efficacy as low according to GRADE [23]. All protocols above use conventional fractionation, with daily doses of 1.5–1.8 Gy.

Some studies have reported on hyperfractionated radiotherapy, delivering 1.5 Gy twice daily up to a total dose of 21 Gy [43].

Image-guided radiotherapy

To verify patient positioning accuracy, imaging must be performed before each radiotherapy fraction. Standard methods for this verification include 2D kilovoltage (kV) images or CBCT.

In the American protocol ANBL1531, recommended PTV margins vary depending on the location and type of imaging used (CBCT vs. non-CBCT). If non-CBCT imaging is used, a PTV margin of 5 mm is recommended across all sites, with the possibility of increasing this margin to 8 mm in the abdominal region. When CBCT is used, a margin of 3–5 mm is advised, with 3 mm for head and neck regions and 5 mm for thoracic regions.

Type of radiotherapy (proton vs. photon)

Both European and American protocols and recommendations allow for the use of either photon or proton radiation.

Radiotherapy technique

The LINES protocol (2011) allows only for 3D conformal radiotherapy. In contrast, the HR-NBL and ANBL protocols permit the use of both 3D conformal radiotherapy and IMRT techniques. IMRT can reduce doses to the kidneys in patients with centrally located tumors, although it may increase doses to other organs, such as the spleen, liver, and stomach, in cases of laterally located tumors [44]. Dynamic techniques, including IMRT and volumetric-modulated arc therapy (VMAT), are increasingly used in clinical practice, with usage rates rising significantly in recent years (Tab. 4) [45–47].

Table 4.

Radiotherapy techniques in primary tumor irradiation for high-risk neuroblastoma

First author’s name and publication year	Study period	Analysis type	Number of patients	Radiotherapy technique
Gatcombe 2009 [42]	2001–2007	Retrospective	34	AP/PA 82% IMRT 18%
Casey 2016 [43]	2000–2014	Retrospective	246	AP/PA + 3D-CRT 65% IMRT 35%
Ferris 2017 [20]	2003–2014	Retrospective	67	AP/PA 58,2% 3D-CRT 9% IMRT 4,5% VMAT 28,4%
Chen 2019 [45]	2009–2015	Retrospective	24	IMRT/HT 100%
Selles 2023 [52]	2004–2020	Retrospective	42	3D-CRT 7% IMRT/VMAT 93%

AP/PA — anterior-posterior/posterior-anterior fields; 3D-CRT — 3D conformal radiotherapy; IMRT — intensity-modulated radiation therapy; VMAT — volumetric-modulated arc therapy

Intraoperative radiotherapy

There are no specific guidelines for the use of intraoperative radiotherapy (IORT) in the treatment of neuroblastoma, nor is this technique mentioned in current clinical trial protocols for this cancer. The largest single-center analysis (n = 92), from the United States, reports on 27 years of experience using IORT for recurrent neuroblastoma [25]. This study concluded that IORT is both effective and safe.

Organs at risk and dose limitations

Dose limitations for organs at risk, as outlined in various clinical trial protocols, are summarized in Table 5.

Table 5.

Dose limitations for organs at risk according to LINES, HR-NBL, and ANBL protocols

Organ at risk	Dose limitations according to protocol
	LINES	HR-NBL1.7	HR-NBL2	COG ANBL1531
Contralateral kidney	–	Tolerance dose for functioning kidneys: 15 Gy, considering potential kidney damage from prior treatment; 21 Gy allowed on one kidney if the other functions normally.	Tolerance dose for functioning kidneys: 15 Gy, considering potential kidney damage from prior treatments; ≥ 21.6 Gy allowed on one kidney if the other functions normally.	V18 Gy < 25%
Ipsilateral kidney	V12 Gy < 80%			V18 Gy < 75% V14.4 Gy < 100% Mean dose ≤ 18 Gy
Liver	V100 ≤ 15 Gy	V100 ≤ 19 Gy V50 ≤ 21Gy	V100 ≤ 19 Gy V50 ≤ 21Gy	Mean dose < 15 Gy
Vertebral body	The whole vertebra should be irradiated	Homogeneous coverage recommended	Homogeneous dose up to ~21.6 Gy	Minimum of 18 Gy to include vertebral body, pedicles, transverse, and spinous processes; vertebrae should not be included in PTV, only design additional pseudotarget
Spinal cord	–	–	21.6 Gy and 36 Gy are acceptable regardless of segment length; caution after busulfan treatment	–
Lungs	V15 < 20%	V12 Gy ≤ 50% V15 Gy ≤ 25%	V12 Gy ≤ 50% V15 Gy ≤ 25%	V20 Gy < 30%
Ipsilateral lung	–	–	–	V20 Gy < 30%
Contralateral lung	–	–	–	V20 Gy < 10%

PTV — planned target volume

In 2019, the SIOPE Working Group published guidelines on vertebral contouring, emphasizing consistent dose homogeneity and gradient limits for pediatric patients [48]. A 2023 publication based on clinical trials, including HR-NBL2, highlighted substantial variations in vertebral contouring, affecting dosimetry, and included an atlas for two cases [49]. The authors recommend the following contouring guidelines:

• adjacent vertebral body and arch but excludes processes, spinal canal, and intervertebral discs (VBs_Adj);

• non-adjacent vertebrae structures for superior and inferior vertebrae (VB_Nadj_S and VB_Nadj_L).

• Dose guidelines include:

• for VBs_Adj: homogeneous dose; allowable gradient of < 3 Gy for children under 2 years and < 5 Gy for older children;

• for VB_Nadj_S and VB_Nadj_L: D5% ≤ 10 Gy for children under 2 years and D5% ≤ 15 Gy for older children.

Another organ at risk, previously considered incidental in radiotherapy, is the pancreas. It appears that reporting the radiotherapy dose to specific parts of the pancreas may help identify patients at increased risk of developing diabetes [50, 51].

Adverse effects of radiotherapy

Radiotherapy-related complications depend on the irradiated area and the administered dose.

Acute radiation reactions include gastrointestinal symptoms from small intestine irradiation such as nausea and vomiting, diarrhea, abdominal pain, and hematologic toxicity [3]. Hematologic toxicity mainly manifests as leukopenia, with data suggesting that a leukocyte count reduction of > 50% from baseline is associated with poorer OS (p = 0.031) [52].

Potential late effects of radiotherapy in neuroblastoma treatment include [3, 53–55]:

• musculoskeletal disorders, such as spinal deformities (scoliosis, lordosis, kyphosis), bone or muscle hypoplasia, and related growth disturbances;

• endocrine disorders including hypothyroidism, hypogonadism, and growth hormone deficiencies;

• pulmonary and cardiovascular disorders;

• nephrological complications;

• second cancers.

The most common late complications after radiotherapy are musculoskeletal abnormalities, occurring in 31% of cases approximately six years post-irradiation, as reported in French clinical studies [53–55]. A threshold dose for these complications has been established at > 31 Gy [54]. Additionally, the risk of scoliosis 15 years after treatment is estimated to be around 25% [56]. Studies indicate that survivors of neuroblastoma treatment are at elevated risk of metabolic syndrome and diabetes [57, 58]. Renal abnormalities often manifest as imaging-detected atrophy or physiological changes without symptomatic acute or chronic dysfunction [59]. Second cancers primarily include thyroid cancers and soft tissue or bone sarcomas [54, 55].

Treatment outcomes in high-risk neuroblastoma

Tables 6 and 7 summarize treatment outcomes in high-risk neuroblastoma patients based on single-center analyses and prospective studies.

Table 6.

Treatment outcomes in high-risk neuroblastoma patients based on single-center analyses

First author’s name and publication year	Analysis type	Study period and place	N	Radiotherapy dose (mean in Gy)	Follow up time (mean in months)	Local control (%)			LRF (%)	DFS (%)	OS (%)
						2-year	3-year	5-year
Gatcombe 2009 [42]	Retrospective	2001–2007 USA	34	22	33.6	–	94	–	5.8	66 (3-year)	86 (3-year)
Pai panandiker 2010 [21]	Retrospective	2000–2006 USA	44	23.4	34	–	–	–	25	–	48.3 (without LRF) 21.8 (with LRF)
Mazloom 2014 [30]	Retrospective	2006–2011 USA	30	24	33	–	–	84	–	–	59%
Casey 2016 [43]	Retrospective	2000–2014 USA	246	21	55.2	–	–	90.2	8.9	40 (5-year)	64.6 (5-year)
Ferris 2017 [20]	Retrospective	2003–2014 USA	67	21.6	54	95.5	–	94	7.5	–	–
Chen 2019 [45]	Retrospective	2009–2015 Taiwan	24	21.6	43.5	–	78.9	–	21.1 (3-year)	45.8 (3-year)	62.9 (3-year)
Wei 2022 [46]	Retrospective	2011–2019 China	69	36	30.5	–	96.9	–	–	56.3 (3-year)	74.6 (3-year)
Jang 2024 [47]	Retrospective	2001–2021 Korea	37	21	69	–	88.7	88.7	10.8	59.1	37

LRF — locoregional failures; DFS — disease-free survival; OS — overall survival

Table 7.

Treatment outcomes in high-risk neuroblastoma patients based on prospective studies

Study/first author’s name and publication year	Analysis type	Treatment period and place	N	Dose [Gy]	LRF (%)	DFS (%)	OS (%)
HR-NBL1.7 Pasqualini 2020 [16]	Prospective multicenter phase III trial	Europe 2002–2016	1297	21	23% (with residual tumor) 15% (no residual tumor)	38% (with residual tumor) 49% (no residual tumor)	–
ANBL0532 Liu 2020 [38]	Prospective multicenter phase III trial	USA 2007–2012	323	1.6–36	16.3% (CLIP)	50.9%	68.1%

LRF — locoregional failures; DFS — disease-free survival; OS — overall survival

Post-treatment follow-up

According to the European HR-NBL2 protocol, oncological follow-up should be conducted every 3 months during the first year post-treatment, every 4 months during the second year post-treatment, and every 6 months during the third year post-treatment, and following this, patients should enter a long-term surveillance program. The American ANBL1531 protocol provides follow-up guidelines on a dedicated website containing detailed information on childhood cancer surveillance [60].

For high-risk patients, the surveillance plan includes:

• laboratory tests of blood and urine, including catecholamine levels;

• ultrasound of the primary tumor region at each visit; for tumors located in the chest, MRI (preferred) or CT is recommended.

For patients with metastatic disease, routine MIBG scintigraphy or PET and bone marrow trephine biopsy are not required; however, these may be considered annually.

Summary

Radiotherapy plays an essential role as a component of multidisciplinary treatment for neuroblastoma. It is primarily used in high-risk group following surgery, targeting the primary tumor area post-chemotherapy. There is no consensus on the use of additional dose (boost) for residual disease at the primary tumor site; however, the European HR-NBL2 study plans randomization, whereas the American protocol has excluded this option. Additionally, there is no consensus on the irradiation of residual metastatic lesions following induction treatment, though this is routinely included in American protocols. Guidelines diverge on the irradiation of metastatic sites in cases of disease recurrence. Nonetheless, radiotherapy remains an effective palliative treatment, especially for metastases in the skeletal system.

It is worth noting that a standardized methodology, including terminology for recurrence reporting in neuroblastoma, is needed. In 2009, Pai Panandiker et al. [21] proposed the following terms:

• in-field recurrence: within the PTV;

• marginal recurrence: outside the PTV, where a dose between 5% and 95% of the prescribed dose was delivered;

• adjacent recurrence: in lymph nodes or tissues adjacent to the primary tumor and outside the PTV, where less than 5% of the prescribed dose was delivered;

• distant recurrence: in locations non-adjacent to the primary tumor;

• locoregional recurrence: combination of in-field and adjacent recurrences.

In contrast, Dove et al. used two categories: local recurrence, defined as the primary tumor site or adjacent lymph nodes, and regional recurrence, defined as recurrence in lymph nodes within the regional lymphatic drainage, but not connected to the primary site [26].

All protocols discussed include quality control guidelines for radiotherapy planning and delivering. The primary initiative for quality assurance is QUARTET, which enables centralized verification of target areas and radiotherapy plans. Both HR-NBL protocols are associated with QUARTET for quality control — retrospective quality control for HR-NBL1 and prospective for HR-NBL2. From a radiation oncologist’s perspective, clinical trial protocols should contain detailed information on current contouring standards for target areas, ideally with delineation examples, as seen in the ANBL1531 protocol. Equally important are guidelines for organs at risk contouring and subsequent evaluation of complications.

A multidisciplinary approach to treatment decisions is recommended, and parents should be fully informed of the planned radiotherapy, with the opportunity to consult with a radiation oncologist. An objective evaluation of radiotherapy frequency is also necessary, based on simple indicators such as the optimal radiotherapy utilization rate (oRUR). Authors of a 2024 study emphasized that understanding the oRUR is crucial for assessing current practices, identifying gaps in access, and planning future radiotherapy protocols [19].