Systematic Review Compares [18F]-mFBG and [123I]-MIBG Imaging for Neuroblastoma

Neuroblastoma, a rare but often aggressive childhood cancer of the sympathetic nervous system, may be easier to detect with a newer molecular imaging technique than with the scan currently regarded as the clinical standard. A systematic review and meta-analysis comparing two radiotracers found that positron emission tomography/computed tomography (PET/CT) using meta-[18F]fluorobenzylguanidine, or [18F]-mFBG, identified substantially more neuroblastoma disease than conventional [123I]-metaiodobenzylguanidine ([123I]-MIBG) scintigraphy combined with single-photon emission computed tomography/CT. The analysis, which brought together five head-to-head studies involving 115 patients and 1,644 lesions, found that [18F]-mFBG PET/CT had a pooled sensitivity of 97 percent on a patient-by-patient basis, compared with 82 percent for [123I]-MIBG SPECT/CT. Both methods had an identical pooled specificity of 82 percent. The results suggest that a scan completed with a PET tracer could eventually offer clinicians a faster and more sensitive way to map neuroblastoma before treatment and to assess whether tumors have responded afterward. But the researchers emphasize that the evidence remains preliminary and that better detection does not automatically prove that the new scan improves survival or changes medical decisions.

Neuroblastoma develops from immature cells of the sympathetic nervous system, the network involved in the body’s “fight-or-flight” responses. It is the most common solid tumor outside the brain in children and can occur anywhere along the sympathetic chain, although it frequently begins in the abdomen near the adrenal glands. The disease is biologically diverse: some tumors regress spontaneously, while others spread rapidly to bones, bone marrow, lymph nodes, liver or other organs. In high-risk cases, metastases are already present when the cancer is diagnosed, and long-term survival remains only about 40 to 50 percent. Treatment typically involves several intensive stages, including chemotherapy, surgery, high-dose chemotherapy supported by stem cells, radiotherapy and targeted treatments such as anti-GD2 immunotherapy. Because treatment is complex and carries significant risks, physicians need accurate information about where cancer is located and how much remains after therapy. Imaging is therefore not simply a way to produce pictures; it is a central part of risk classification, treatment planning and response assessment.

The established imaging approach, [123I]-MIBG scintigraphy, exploits the biology of neuroblastoma cells. MIBG is a radiolabeled chemical analogue of norepinephrine, a neurotransmitter released by sympathetic nerve cells. Neuroblastoma cells often possess transport systems that take up norepinephrine and related molecules, allowing MIBG to accumulate inside tumor tissue. Iodine-123 emits gamma radiation that can be detected by a gamma camera, producing whole-body images. Additional SPECT/CT acquisitions provide three-dimensional information and anatomical localization. MIBG imaging can reveal both the primary tumor and distant metastases, and its results can be converted into validated scores with prognostic significance. Yet the method has practical and technical drawbacks. Imaging commonly involves a delayed acquisition around 24 hours after injection and may require a multi-day protocol. Patients must also receive thyroid blockade to reduce uptake of radioactive iodine by the thyroid gland. Compared with PET, SPECT has lower spatial resolution, making small or closely spaced lesions more difficult to separate. MIBG can also produce false-negative findings in roughly one in ten patients.

The newer tracer, [18F]-mFBG, targets the same broad catecholaminergic biology but is labeled with fluorine-18, a positron-emitting isotope used widely in PET. After injection, the tracer is transported into adrenergic tumor cells. Fluorine-18 decays by emitting a positron, which quickly encounters an electron. Their annihilation produces two gamma photons traveling in nearly opposite directions. PET scanners detect these paired photons and use their timing and trajectories to reconstruct a three-dimensional map of tracer distribution. This physical process gives PET higher sensitivity and spatial resolution than conventional planar scintigraphy and allows clinicians to quantify uptake using measures such as the maximum standardized uptake value, or SUVmax. SUVmax estimates the highest concentration of tracer in a lesion after accounting for injected activity and patient body characteristics. In the studies included in the review, [18F]-mFBG PET/CT images were generally acquired about 60 minutes after injection, while MIBG images were obtained at 24 hours. That difference could make the PET examination more convenient as well as more sensitive, although direct comparisons of scan timing and clinical workflow require further study.

To evaluate the evidence, two nuclear medicine physicians independently searched the Cochrane Library, Embase and PubMed/MEDLINE through November 30, 2025. They looked specifically for studies that compared [18F]-mFBG PET/CT directly with [123I]-MIBG imaging in at least five people with neuroblastoma. Reviews, preclinical experiments, phantom studies, individual case reports, very small case series and studies with overlapping patient data were excluded. The search initially produced 16 records, but only five prospective studies met the inclusion criteria. These studies were conducted in the United States, the Netherlands, Denmark and China, and included patients ranging in age from less than one month to 45 years. The investigators extracted patient characteristics, radiotracer doses, imaging intervals, image-analysis methods and diagnostic outcomes. They then combined the results using a bivariate random-effects model, which is designed to account for the relationship between sensitivity and specificity across diagnostic studies. The analysis also assessed heterogeneity, or the extent to which study results differed beyond what would be expected from chance alone.

The patient-level results favored [18F]-mFBG strongly. Across the five studies, the pooled sensitivity of PET/CT was 97 percent, with a 95 percent confidence interval of 91 to 99 percent. The corresponding sensitivity for MIBG SPECT/CT was 82 percent, with a 95 percent confidence interval of 67 to 91 percent. Sensitivity measures the proportion of patients with disease who are correctly identified, so the difference indicates that [18F]-mFBG could miss fewer affected patients. The advantage was even larger when the researchers analyzed individual lesions rather than patients. On this lesion-based analysis, [18F]-mFBG PET/CT reached a pooled sensitivity of 99 percent, whereas [123I]-MIBG SPECT/CT reached 51.5 percent. This means the PET method appeared particularly capable of detecting separate tumor deposits, a feature that could be important in metastatic disease and in evaluating the distribution of residual cancer. Specificity, which measures how often a test correctly identifies patients or lesions without disease, was 82 percent for both tracers in the patient-based analysis. A highly sensitive scan can still produce findings that require confirmation, so PET-positive areas would remain part of a broader diagnostic assessment rather than acting as an automatic diagnosis.

The apparent advantage of [18F]-mFBG is biologically and technically plausible, but the comparison is not free from limitations. The five studies together included only 115 patients, and individual studies enrolled between five and 40 participants. Although no study crossed the investigators’ threshold for an unacceptable overall risk of bias, the quality assessment identified uncertainty about whether the imaging tests had been interpreted blindly and how the final diagnosis had been established. None of the studies used histopathological confirmation for every lesion. Instead, the reference standard combined CT or magnetic resonance imaging, laboratory data, clinical follow-up and radiological follow-up. In some cases, [123I]-MIBG itself contributed to that composite reference standard. This creates a potential incorporation bias: the comparator test becomes part of the definition of whether disease is truly present. Such a design can influence estimates of diagnostic accuracy and may favor the test embedded in the reference process. The researchers also noted methodological differences among studies, including variations in injected activity, acquisition protocols and the interval between examinations.

For patients and families, the most important unanswered question is not simply which scan detects more lesions, but whether the extra information changes what doctors do and improves outcomes. A more sensitive examination could identify metastatic disease earlier, refine radiation fields, reveal previously unsuspected residual tumor or prevent clinicians from underestimating the extent of cancer. It might also shorten the imaging pathway because PET/CT is typically performed during a single visit, rather than relying on delayed imaging over one or more days. However, detecting additional abnormalities can also complicate care if some findings are biologically insignificant or cannot be confirmed easily. The current analysis did not establish that [18F]-mFBG PET/CT changes treatment decisions, reduces toxicity, improves response rates or extends survival. It also does not show that MIBG should be abandoned, particularly because MIBG remains deeply integrated into neuroblastoma risk assessment, treatment planning and clinical practice. The researchers argue that future prospective studies should test whether PET findings alter management and should follow patients long enough to measure clinical outcomes, ideally using standardized imaging protocols and independent reference standards.

The findings position [18F]-mFBG PET/CT as one of the most promising alternatives to MIBG for molecular imaging of neuroblastoma, but not yet as a universally established replacement. Its combination of catecholaminergic targeting, the sensitivity of fluorine-18 PET and detailed CT anatomy could provide a sharper view of disease than conventional scintigraphy. The result that it detected 97 percent of affected patients and nearly 99 percent of lesions in the pooled analysis is likely to attract attention because neuroblastoma can spread through the body in patterns that are difficult to capture with lower-resolution imaging. Still, the evidence comes from a small number of studies and includes a reference-standard weakness that limits how confidently the percentages can be interpreted. Larger multicenter trials will need to determine how [18F]-mFBG performs across different ages, tumor subtypes and treatment stages, and whether its availability, radiation exposure and cost are practical in routine pediatric care. For now, the meta-analysis offers a compelling signal: a next-generation PET tracer may make one of childhood cancer’s most consequential imaging tasks faster and more precise, while the ultimate test will be whether that sharper picture leads to better decisions and healthier children.