Residency · Residency · Radiation Oncology
Neuroblastoma: Radiation in High-Risk Disease
Introduction
Neuroblastoma is the most common extracranial solid tumor in children, originating from neural crest cells of the sympathetic nervous system. It represents about 8% of pediatric cancers and displays significant clinical variability, ranging from spontaneous regression in infants to aggressive, treatment-resistant forms. Radiation therapy plays a crucial role in managing high-risk neuroblastoma, focusing on the primary tumor bed and selected metastatic sites to improve local control and overall outcomes.
Risk Stratification
Neuroblastoma is stratified into low-, intermediate-, and high-risk categories based on clinical and biological factors. Low-risk disease typically involves Stage L1 tumors, which are localized without image-defined risk factors and have favorable biology. These cases often require only surgery, with observation being appropriate for some infants, and radiation therapy is generally not indicated. Intermediate-risk neuroblastoma includes Stage L2 or MS disease, the latter being a special metastatic pattern seen in infants under 18 months. Treatment usually consists of chemotherapy and surgery, with radiation rarely necessary. These tumors are characterized by non-amplified MYCN and favorable histology. High-risk neuroblastoma is defined by MYCN amplification regardless of stage, age over 18 months with Stage M metastatic disease, or unfavorable histology in older children. Management involves multimodal therapy, including induction chemotherapy, surgery, high-dose chemotherapy with autologous stem cell transplant (ASCT), radiation, and immunotherapy. Despite aggressive treatment, the 5-year event-free survival remains around 50%.
Role of Radiation in High-Risk Neuroblastoma
Radiation therapy is integral to high-risk neuroblastoma treatment, particularly after high-dose chemotherapy and ASCT. Radiation targets the post-surgical tumor bed to reduce the risk of local recurrence, which occurs in 30-50% of cases without radiation but decreases to 10-20% with its use. This approach is a standard component of the Children's Oncology Group (COG) high-risk protocol. Additionally, radiation may be applied to metastatic sites that remain MIBG-avid after induction therapy, as investigated in the COG ANBL1232 trial. However, doses to metastatic sites are limited by normal tissue tolerances, and whole-body irradiation is not standard practice.
Radiation Dose and Technique
The standard radiation dose to the primary tumor site is 21.6 Gy delivered in 12 fractions of 1.8 Gy each, as per COG protocols. For areas with gross residual disease, a boost of 14.4 Gy is added, bringing the total dose to 36 Gy. Radiation typically begins about 2 to 4 weeks after hematologic recovery following ASCT. Target volume delineation involves defining the clinical target volume (CTV) based on the pre-operative tumor volume, using imaging obtained before chemotherapy and surgery, then adapting it to post-operative anatomy. The CTV includes the surgical bed and any residual tumor, with a margin of 1 to 1.5 cm added to create the planning target volume (PTV). It is important to include the vertebral body symmetrically within the radiation field to prevent scoliosis. Treatment planning may utilize 3D-conformal radiation therapy, intensity-modulated radiation therapy (IMRT), or proton therapy. Proton therapy offers advantages in sparing critical organs such as the kidneys, liver, and bowel. Organ constraints are particularly important for the remaining kidney (especially if nephrectomy has been performed), liver, and spinal cord. For tumors located in the abdomen or thorax, four-dimensional CT imaging may be necessary to account for respiratory motion.
MIBG Therapy
Meta-iodobenzylguanidine (MIBG) is selectively taken up by neuroblastoma cells, allowing targeted radiotherapy using therapeutic 131I-MIBG. This approach delivers radiation directly to MIBG-avid disease sites, with response rates of 30-40% in relapsed or refractory neuroblastoma. The COG ANBL1232 trial incorporated 131I-MIBG into upfront therapy for high-risk patients. This radionuclide therapy can be combined with external beam radiation to the primary tumor site. High-activity MIBG therapy, typically administered at 18 mCi/kg, requires stem cell rescue due to hematologic toxicity, which is dose-limiting. Thyroid blockade with potassium iodide is mandatory to protect the thyroid gland. Whole-body dosimetry is used to guide treatment planning and optimize safety.
Special Anatomic Considerations
The most common primary site for neuroblastoma is the adrenal gland. Radiation target volumes for adrenal primaries include the adrenal bed, any residual tumor, and involved retroperitoneal lymph nodes. The ipsilateral kidney is often displaced or removed, making dose constraints for the liver and contralateral kidney critical. Posterior mediastinal tumors, which may extend through neural foramina forming dumbbell-shaped masses, require careful attention to spinal cord dose constraints, with a maximum cumulative dose below 36 Gy, including any prior exposure. Heart and lung doses should be minimized using IMRT or proton therapy. Pelvic primaries, such as presacral tumors, necessitate minimizing radiation exposure to the bladder, rectum, and pelvic growth centers, with consideration of potential impacts on gonadal function and future fertility.
Late Effects Considerations
Radiation to the vertebral bodies can cause asymmetric growth leading to scoliosis and growth retardation. To prevent this, the entire vertebral body width should be included symmetrically in the radiation field. Patients require monitoring of height velocity during follow-up. Renal function is another critical consideration; the remaining kidney must be kept below tolerance doses, generally less than 12-14 Gy in pediatric patients. Baseline and serial assessments of renal function are essential, especially since prior exposure to nephrotoxic agents like cisplatin increases the risk of renal impairment. Radiation also carries a risk of secondary malignancies, including sarcomas and carcinomas within the radiation field. This risk increases with higher radiation doses and younger age at treatment, necessitating lifelong cancer surveillance.
Key Clinical Pearls
Radiation therapy to the primary tumor bed is a standard component of high-risk neuroblastoma treatment following ASCT, significantly reducing local recurrence rates from approximately 40% to 15%. The standard radiation dose is 21.6 Gy delivered in 12 fractions, with a boost to 36 Gy for gross residual disease. Proton therapy should be considered when available to minimize radiation exposure to critical organs such as the kidneys, liver, and developing tissues. The use of 131I-MIBG therapy is an emerging systemic radionuclide treatment option for patients with MIBG-avid disease. Ensuring symmetric inclusion of the vertebral bodies within the radiation field is essential to prevent scoliosis in growing children.
References
- Haas-Kogan DA, Swift PS, Selch M, et al. Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys. 2003;56(1):28-39.
- Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a Children's Oncology Group study. J Clin Oncol. 2009;27(7):1007-1013.
- Wilson JS, Gains JE, Moroz V, et al. A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma. Eur J Cancer. 2014;50(4):801-815.
- Casey DL, Kushner BH, Cheung NKV, et al. Local control with 21-Gy radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2016;96(2):393-400.