Clinical Application Study of [123I]Metaiodobenzylguanidine and Somatostatin Receptor-Targeted Imaging in the Diagnosis and Staging of Neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid tumor in children. More than 50 % of cases occur before the age of two, while diagnoses after 10 years old are rare. NB accounts for approximately 6 - 10 % of pediatric malignancies. Its biological behavior is highly heterogeneous, with diverse molecular features, a high risk of metastasis, and often occult primary sites, making early detection and definitive diagnosis difficult [1-3]. Rapid disease progression further complicates treatment.

In recent years, driven by large international multicenter collaborations, the diagnosis and management of pediatric NB have entered an era of molecular imaging and targeted theranostics. Especially overseas, rapid advances in screening, diagnosis, treatment research, and clinical translation have yielded well-established guidelines and consensus statements, markedly improving the 5-year survival rate [4]. In contrast, research and clinical translation in China lag behind, and understanding of NB biology varies across regions, leading to uneven diagnostic and therapeutic levels without unified protocols. As a result, an increasing number of Chinese patients seek molecular imaging and targeted therapy abroad. Accelerating domestic translation of new NB technologies is thus critical to improving outcomes.

Nuclear medicine imaging (molecular imaging) employs radionuclide-labeled tracers for early lesion detection. For NB, modalities include classic radioiodinated metaiodobenzylguanidine (MIBG) imaging (¹³¹I/¹²³I/¹²⁴I-MIBG, ¹⁸F-MFBG), ¹⁸F-FDG metabolic imaging, somatostatin-receptor (SSTR)-targeted imaging (⁶⁸Ga-DOTA-TATE/TOC/NOC peptides), and ¹⁸F-DOPA imaging. With continual upgrades of SPECT/CT, quantitative SPECT/CT, and PET/CT-MRI, comparative studies on diagnostic accuracy, staging, early detection of relapse/metastasis, radiation safety, and therapy response assessment have flourished. International indications for NB radionuclide imaging include [5-7]: confirmation of suspected NB/pheochromocytoma/ganglioneuroma, disease staging, treatment planning and response evaluation, post-therapy follow-up, and selection for radionuclide therapy.

NB cells overexpress the norepinephrine transporter; hence norepinephrine analogs such as MIBG are ideal imaging (and therapeutic) ligands. Radioiodinated MIBG accumulates in neural-crest-derived tissues and tumors, exhibiting high sensitivity (88-92 %) and specificity (83-92 %) [8]. It distinguishes residual tumor from non-specific findings on anatomic imaging and more accurately evaluates bone marrow metastases than MRI [10, 11]. ¹³¹I-MIBG is widely used therapeutically, and post-therapy ¹³¹I-MIBG scans assess tracer uptake, disease status, and predict response, forming part of theranostic guidelines [8, 9, 12-14]. However, ¹³¹I emits high-energy γ-photons (364 keV) and has a long half-life, resulting in poorer SPECT image quality and lower sensitivity than ¹²³I (159 keV, much shorter half-life). The shorter half-life of ¹²³I permits higher administered activity within the same radiation dose, yielding superior images [15]. Consequently, ¹²³I-MIBG is expected to become the optimal screening tool for selecting patients for ¹³¹I-MIBG therapy. In high-risk NB, ¹²³I-MIBG detects recurrent bone metastases in 94 % of cases versus 43 % for ¹⁸F-FDG PET/CT [9, 10]. MIBG imaging remains the standard for staging and treatment assessment [16-18].

About 10 % of NBs show low or absent MIBG uptake, risking false-negative results. Combining modalities helps overcome this limitation. Somatostatin, a hypothalamic peptide that inhibits pituitary growth hormone and gastrointestinal hormones [19-21], binds receptors found on pancreatic, neuroendocrine, meningeal, and breast tumors [21-24]. High-affinity SSTRs are expressed in 77-89 % of NB cells [25-28]. Numerous ⁶⁸Ga-DOTA peptides target SSTRs, such as ⁶⁸Ga-DOTA-TATE (highest affinity for SSTR2), ⁶⁸Ga-DOTA-TOC (SSTR5), and ⁶⁸Ga-DOTA-NOC (SSTR3 and SSTR5) [29]. Compared with ¹²³/¹³¹I-MIBG, SSTR-PET/CT offers advantages: faster plasma clearance (2 h vs 2 days), same-day injection and imaging, shorter ⁶⁸Ga half-life (68 min vs 13.1 h/8 days), rapid acquisition (20-40 min vs ~1 h), and minimal preparation (no Lugol's solution). One study showed ⁶⁸Ga-DOTA-TOC PET/CT sensitivity of 94.4 %, significantly higher than ¹²³I-MIBG (76.9 %).

Systematic data on MIBG and SSTR imaging in Chinese NB are scarce. Peptide receptor radionuclide therapy (PRRT) with agents like ¹⁷⁷Lu-DOTA-TATE-proven feasible and safe abroad [30, 31]-is attractive, offering outpatient treatment without thyroid blockade, simplifying care for children and families. Small studies have applied PRRT to relapsed pediatric NB [32-35].

Given tumor heterogeneity, different molecular probes deliver complementary diagnostic and therapeutic information. Although combination imaging is well studied internationally, domestic data are lacking. Ethnic and regional factors warrant investigation. This study will employ ¹²³I-MIBG SPECT/CT fusion and SSTR PET/CT or(and) MRI for NB diagnosis, staging, and follow-up, aiming to provide valuable insights for early definitive diagnosis, precise staging, radionuclide-targeted therapy, and response evaluation in Chinese patients. In heterogeneous tumors, multimodal imaging is expected to offer clear advantages for staging, phenotype characterization, prognostication, and treatment planning.

Inclusion criteria

• Ages 0-18 years, any sex
• Histologically confirmed or clinically highly suspected neuroblastoma with planned imaging assessment
• At least one measurable lesion on conventional imaging such as CT or MRI
• ECOG performance status 0-2 and an expected survival of ≥3 months
• Hematologic, hepatic, and renal function meeting the following criteria: Hb ≥ 90 g/L, ANC ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L, ALT/AST ≤ 2.5 × ULN, Cr ≤ 1.5 × ULN
• Informed consent signed by the subject or legal guardian

Exclusion criteria

• Known history of severe allergy to the radioactive isotope or molecular probe components to be used;
• Pregnancy or lactation;
• Receipt of high-dose chemotherapy/radiotherapy, radionuclide therapy, or participation in other interventional clinical trials within the past 4 weeks;
• Severe or uncontrolled cardiac, pulmonary, hepatic, or renal insufficiency, or active severe infection;
• Bone marrow suppression not yet recovered (Hb < 90 g/L, ANC < 1.5 × 10⁹/L, platelets < 100 × 10⁹/L);
• Inability to complete imaging examinations such as PET/CT (e.g., severe claustrophobia, inability to lie supine for ≥ 30 min);
• Any other situation deemed inappropriate for enrollment by the investigator.