Role of radiotherapy in neuroblastoma

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neuroblastoma radiotherapy treatment

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Role of Radiotherapy in Neuroblastoma

Neuroblastoma is the most common extracranial solid malignancy in children, arising from neural crest cells of the sympathetic nervous system. Its treatment is multimodal - surgery, chemotherapy, immunotherapy, and radiotherapy - with the role of radiation stratified by risk group.

1. General Principles

Radiotherapy is effective for local control in neuroblastoma. The risk of local relapse correlates with biologic markers (MYCN amplification, unfavorable histology, diploidy). Irradiation has not provided benefit in low-stage disease, but has increased local control in:

Stage IV (metastatic) advanced disease
Bulky stage III disease

A randomized trial directly comparing radiotherapy alone vs. surgery for local control has not been performed.

Campbell Walsh Wein Urology, p. 1549

2. Role by Risk Group

Low-Risk Neuroblastoma

Observation alone (after surgery or even without surgery for infants with favorable biology)
Radiotherapy: Not indicated

Intermediate-Risk Neuroblastoma

Surgery + chemotherapy (cisplatin, cyclophosphamide, doxorubicin, etoposide)
Radiotherapy: Generally not part of standard treatment
The COG trial A3961 established that survival is excellent with biologically based, reduced-intensity chemotherapy

High-Risk Neuroblastoma

Radiotherapy is a standard, integral component of the multimodal treatment sequence:
1. Induction chemotherapy (cisplatin, cyclophosphamide, vincristine, doxorubicin, etoposide)
2. Surgical resection (aggressive debulking, >90% resection goal)
3. External beam radiotherapy (EBRT) to the primary tumor site - for local control
4. Myeloablative consolidation + autologous stem cell transplant (ASCT)
5. Immunotherapy (dinutuximab / anti-GD2) + isotretinoin

The landmark COG trials CCG-3891 and ANBL0532 established this sequence. The treatment table from Mulholland's surgery text explicitly lists "External beam radiation therapy" under the high-risk standard treatment plan alongside chemotherapy and ASCT.

Mulholland and Greenfield's Surgery, Table 103.6

3. External Beam Radiotherapy (EBRT)

Doses used: 15-30 Gy to the primary tumor bed, depending on:
- Patient's age
- Tumor location
- Extent of residual disease after surgery
Target volume: Primary tumor site/bed (post-surgical)
Patients with incomplete resection (residual tumor) benefit from higher-dose radiation
Local relapse risk is directly tied to biologic risk markers, justifying routine RT in high-risk disease
Campbell Walsh Wein Urology, p. 1549-1551

4. Intraoperative Radiation Therapy (IORT)

Used in patients with unresectable disease
Delivers a higher dose directly to the operative field while sparing adjacent normal tissues
Theoretical advantage: precise targeting
However, IORT has not been convincingly shown to improve control compared to EBRT in available studies (Haas-Kogan et al., 2000)
Campbell Walsh Wein Urology, p. 1551

5. Spinal Cord Compression - Where Radiotherapy Is Avoided

Up to 5% of neuroblastoma patients present with spinal cord compression; up to 13% have radiographic intraspinal extension
Historically managed with laminectomy, RT, or chemotherapy - neurologic outcomes were similar across all modalities
Current recommendation: Chemotherapy first; reserve laminectomy for progressive neurologic deterioration
Radiotherapy is now generally avoided in spinal cord compression due to its adverse effect on vertebral growth and risk of scoliosis
Similarly, RT is contraindicated for intraspinal tumors due to vertebral damage, growth arrest, and scoliosis
Campbell Walsh Wein Urology, p. 1556; Sabiston Textbook of Surgery, p. 2699

6. Radioisotope Therapy: ¹³¹I-MIBG

Metaiodobenzylguanidine (MIBG) is an analogue of norepinephrine concentrated selectively in sympathetic tissue (including neuroblastoma). Both diagnostic and therapeutic applications exist:

Diagnostic: ¹³¹I-MIBG scan for staging and treatment response monitoring
Therapeutic (targeted radionuclide therapy):
- Objective tumor responses occur even in previously heavily treated patients
- Causes significant myelosuppression with dose escalation - stem cell support required
- Primarily used in relapsed/refractory disease
- Being investigated as frontline "up-front" therapy
- A 2025 systematic review (PMID 39732302) confirms ¹³¹I-MIBG remains a key tool in relapsed/refractory neuroblastoma
Campbell Walsh Wein Urology, p. 1544; Mulholland's Surgery, p. 3806

7. Total Body Irradiation (TBI) in Myeloablative Consolidation

Some myeloablative conditioning regimens for ASCT incorporate TBI as part of the preparative regimen. This is used in the consolidation phase for high-risk patients. However, high-dose chemotherapy (cisplatin, etoposide, cyclophosphamide) regimens without TBI have become the predominant approach, given concerns about late effects in growing children.

8. Palliation

Radiotherapy is used for palliative control of:

Painful bone metastases
Orbital/periorbital metastases
Symptomatic soft tissue deposits

9. Optimal Utilization Rate - Recent Evidence

A 2024 systematic review and meta-analysis (Fukushima et al., Radiotherapy and Oncology) estimated the optimal radiotherapy utilization rate (oRUR) for childhood neuroblastoma:

Setting	oRUR
Global	64% (95% CI: 58%-71%)
High-income countries	50%
Low- and middle-income countries	68%

The higher rate in LMICs reflects more advanced stage at diagnosis due to limited healthcare access. The variation in RT indications between major international protocols (COG vs. SIOPEN) was negligible in its impact on the oRUR.

PMID 38806114

Summary Table

Indication	Role of Radiotherapy	Notes
Low-risk disease	Not indicated	Observation ± surgery
Intermediate-risk disease	Not standard	Surgery + moderate chemotherapy
High-risk disease (primary tumor bed)	Standard - EBRT 15-30 Gy	After induction chemo + surgery
Unresectable disease	IORT considered	Not proven superior to EBRT
Spinal cord compression	Avoided	Risk of scoliosis, growth arrest
Intraspinal tumors	Contraindicated	Vertebral damage, scoliosis
Relapsed/refractory disease	¹³¹I-MIBG therapy	Requires stem cell support
Palliation	Used	Bone mets, orbital disease

Late Effects - Important Consideration

Because neuroblastoma predominantly affects young children, radiation-related late effects are a major concern:

Musculoskeletal: Scoliosis, vertebral growth arrest, asymmetric growth
Endocrine: Hypothyroidism (neck/mediastinal RT), adrenal insufficiency
Renal: Nephrotoxicity (abdominal fields)
Second malignancies: Long-term risk in survivors
Cardiac and pulmonary: With thoracic fields

These concerns drive the trend toward RT dose reduction and field minimization in protocols, and explain why RT is withheld in low/intermediate risk groups where chemotherapy alone gives excellent disease control.

Who are low risk cases

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Low-Risk Neuroblastoma: Who Qualifies?

Risk stratification in neuroblastoma is based on four key parameters: INRG/INSS stage, age at diagnosis, tumor histology/differentiation, and molecular biology (primarily MYCN status and chromosomal aberrations).

The Two Main Classification Systems

1. INSS (International Neuroblastoma Staging System) - Surgical/Postsurgical

Older system, based on surgical findings.

INSS Stage	Description
1	Localized, completely resected; ipsilateral lymph nodes negative
2A	Localized, incomplete resection; ipsilateral nodes negative
2B	Localized ± incomplete resection; ipsilateral nodes positive
3	Unresectable crossing midline, or bilateral extension
4	Distant metastases (bone, BM, liver, lymph nodes, other)
4S	Special: infant <12 months, localized primary + spread limited to liver, skin, minimal BM

2. INRG (International Neuroblastoma Risk Group) - Pretreatment (Imaging-Based)

Newer system. Stages L1, L2, M, MS based on image-defined risk factors (IDRFs).

INRG Stage	Meaning
L1	Localized, no IDRFs
L2	Localized, with IDRFs
M	Distant metastatic disease
MS	Metastatic ("special") in child <18 months - liver, skin, BM only

INRG Pretreatment Low-Risk Categories

From Table 103.5 (Mulholland and Greenfield's Surgery):

INRG Stage	Age	Histology	MYCN	11q Aberration	Ploidy	Risk Group
L1 or L2	Any	GN maturing or GNB intermixed	-	-	-	A - Very Low
L1	Any	Any (except GN/GNB intermixed)	Not amplified	-	-	B - Very Low
L2	<18 months	Any (except GN/GNB intermixed)	Not amplified	No	-	D - Low
L2	>18 months	GNB nodular; neuroblastoma - Differentiating	Not amplified	No	-	E - Low
MS	<18 months	-	Not amplified	-	Hyperploid	F - Low

Simplified Risk Table (COG-Based, Clinical Use)

From Tietz Laboratory Medicine, Table 63.6:

Feature	Low Risk
MYCN amplification	No
Stage at diagnosis	Stage 4S (infant) or locoregional
Age at diagnosis	<12 months (for 4S) or ≤21 years (locoregional)
5-year survival	>95%
Treatment	Supportive care or Surgery ± Chemotherapy

Key Defining Features of Low-Risk Neuroblastoma

1. Stage

INSS Stage 1, 2A, 2B - localized tumors (the COG P9641 trial established surgery alone gives ≥95% 3-year OS in these stages)
INSS Stage 4S - the "special" infant metastatic pattern (see below)

2. Age

Infants <18 months generally have more favorable biology
Stage 4S only applies to infants <12 months (INSS) or <18 months (INRG)

3. Molecular/Biologic Markers

MYCN: Not amplified (essential criterion - MYCN amplification immediately moves a patient to high risk regardless of stage)
No 11q chromosomal aberration
Favorable DNA ploidy (hyperdiploidy is favorable; diploidy is unfavorable)
Favorable histology: well-differentiated, low mitosis-karyorrhexis index (MKI), presence of Schwann cells (Shimada classification)

Special Case: Stage 4S / Stage MS

This is the most clinically distinctive low-risk group:

Infant <12-18 months
Localized primary tumor
Metastases limited to: liver, skin, and/or bone marrow (<10% involvement)
No MYCN amplification
Most tumors spontaneously regress - observation alone is appropriate
Surgery not recommended given the high rate of spontaneous differentiation/regression
Biopsy of primary or metastatic site for biology studies is required

Exception: Massive hepatomegaly causing abdominal compartment syndrome may require:

Low-dose chemotherapy
Radiotherapy (to reduce liver size/organ dysfunction)
Decompressive laparotomy + ventilator support
Mulholland and Greenfield's Surgery, p. 3751

Treatment for Low-Risk Disease

Primary treatment: Surgery alone (maximally safe resection preserving organs/vessels)
Goal: complete resection + lymph node sampling + tissue for biologic studies
Chemotherapy reserved for:
- Relapse or treatment failure
- <50% resection achieved
- Disease compromising organ function or life-threatening
- Risk of spinal cord compression
- If used: carboplatin, cyclophosphamide, doxorubicin, etoposide for 6-24 weeks
Radiotherapy: Seldom given; reserved only for life-threatening symptoms (e.g., massive hepatomegaly in MS disease)

Summary

Low-risk neuroblastoma = localized disease (L1/L2 without IDRFs, or INSS 1/2) with MYCN non-amplification and favorable histology, OR Stage 4S/MS in infants without MYCN amplification. These patients have >95% 5-year survival with surgery alone or observation.

The single most important rule: any MYCN amplification = immediately high risk, regardless of stage.

Mulholland and Greenfield's Surgery, p. 3743-3751
Tietz Textbook of Laboratory Medicine, Table 63.6
Sabiston Textbook of Surgery, Table 117.2

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