Superior lesion detection with ¹⁸F-AlF-NOTA-octreotide PET/CT compared to ¹²³I-MIBG SPECT/CT in neuroblastoma

Introduction

Neuroblastoma (NB) is one of the predominant extracranial solid tumors in pediatric populations. Despite accounting for only 8% of all pediatric cancers, its mortality rate is up to 15% (1,2). High-risk cases maintain a 5-year overall survival rate of 50% despite diverse therapeutic approaches (3). Additionally, metastatic disease presents in 50% of cases during initial presentation (4). Consequently, accurate imaging techniques play a crucial role in evaluating therapeutic response, facilitating follow-up surveillance, guiding treatment planning, and enhancing survival outcomes for patients with NB (3,5).

According to current National Comprehensive Cancer Network (NCCN) guidelines, NB evaluation relies on ¹²³I-meta-iodobenzylguanide (¹²³I-MIBG) single-photon emission computed tomography/computed tomography (SPECT/CT) as the primary imaging modality for detecting metastatic disease. However, it has limitations including suboptimal spatial resolution, time-consuming preparation and acquisition protocols, and quantification difficulties (4,6-9). In clinical settings, positron emission tomography/computed tomography (PET/CT) tracers have emerged as alternatives for assessing MIBG-negative or poorly avid lesions (10). The ⁶⁸Ga-Octreotide (⁶⁸Ga-OC) somatostatin receptor (SSTR)-targeted PET/CT has demonstrated superior detection capability over ¹²³I-MIBG SPECT/CT in identifying NB lesions. Nevertheless, ⁶⁸Ga-labeled tracers also have limitations including limited production capacity, rapid decay, and economic considerations (11-13). The ¹⁸F-AlF-NOTA-octreotide (¹⁸F-OC) has superior radiochemical properties, image resolution, and cost-efficiency, highlighting its viability as an alternative diagnostic tool (14-16). Additional research is needed to compare the diagnostic performances of ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT in NB lesion detection.

Our study aimed to evaluate and compare the values of ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT for therapeutic response assessment and recurrence surveillance of NB. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2456/rc).

Methods

Patients

A retrospective screening and data collection were performed for 832 patients with suspected recurrent NB between January 2021 and February 2024. To systematically evaluate and compare the lesion detection capabilities of two imaging methods in this patient population, further screening was conducted for those who had undergone ¹²³I-SPECT/CT examinations. The inclusion criteria were having undergone ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT imaging within one-month post-treatment with accessible imaging data. Patients who showed new disease progression or resolution of preexisting lesions between the two imaging sessions were excluded. Furthermore, patients who had received treatments that could influence the tracer distribution before the examinations were excluded. The patient enrollment process is detailed in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethics Committee of the Shandong Cancer Hospital and Institute (No. SDTHEC 2024008005) and individual consent for this retrospective analysis was waived.

Figure 1 Patients enrolled flowchart. NB, neuroblastoma; ¹⁸F-OC, ¹⁸F-AlF-NOTA-octreotide; ¹²³I-MIBG SPECT/CT, ¹²³I-meta-iodobenzylguanide single-photon emission computed tomography/computed tomography; PET/CT, positron emission tomography/computed tomography.

¹⁸F-OC PET/CT

Imaging was conducted on a Biograph PET/CT system (Siemens, Germany). All patients discontinued medications that interfered with ¹⁸F-OC uptake before the examination. Height and weight measurements were obtained before examination, with no specific requirements for glycemic control. ¹⁸F-OC was administered intravenously (3.70–4.44 MBq/kg) before scanning. Patients were instructed to rest quietly after the injection, with image acquisition commencing approximately 45–60 minutes later. They were subsequently asked to drink water to fill their stomachs 30 minutes before image acquisition and empty their bladders just before the examination to prevent urine contamination. The PET images were captured from the skull down to the feet, with each bed position scanned for 2.5–3 minutes. The acquisition matrix size was 256×256, and the total scanning time was 10–15 minutes. The CT images were acquired on a 64-slice CT system (120 keV, 50 mA, 5 mm collimation). Images were reconstructed using attenuation correction (AC) with time-of-flight ordered subset expectation maximization (OSEM) (24 iterations, 2 subsets). A supine inspiratory breath-holding spiral CT scan of thorax was subsequently obtained. After the acquisition was completed, the images were fused on the same device.

¹²³I-MIBG SPECT/CT

All imaging procedures were conducted with a SPECT/CT scanner (Siemens Symbia T16; Siemens, Munich, Germany). Prior to the examination, patients discontinued medications interfering with ¹²³I-MIBG uptake and were screened for iodine allergies. Thyroid blocking was performed using a saturated potassium iodide solution 24 h before administration of the imaging agent. Intravenous ¹²³I-MIBG (5.2 MBq/kg) was administered slowly. After the injection of the tracer, oral laxatives should be taken on the same day to clean the bowel. Image acquisition should perform at 24 h post-injection. Patients should empty their bladders just before the examination to prevent contamination. The Siemens scanner was calibrated according to the European Association of Nuclear Medicine (EANM) protocols for ¹²³I-MIBG imaging (17). Whole-body scintigraphy was acquired with a matrix size of 256×256, scanning speed of 6 cm/min, and time of 15–30 minutes. The image acquisition range is from the top of the skull to the sole of the foot. SPECT/CT imaging was performed in areas of suspicious or tumor uptake identified in the planar images, with a step-and-shoot mode, at 3° per step, collecting a total of 120 projections, 20–25 seconds per projection, with a matrix size of 128×128, and a total scanning time of 15–30 minutes. CT was performed at 100 keV and 50 mA with 5 mm collimation. The reconstruction utilized the OSEM algorithm (32 subsets and 6 iterations).

Image interpretation

Two senior nuclear specialists with 10 and 13 years of professional experience independently reviewed all imaging results of ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT under blinded conditions. Regarding the definition criteria for positive lesions, in addition to requiring that the uptake of the imaging agent exceeds the surrounding background and cannot be explained by physiological or clearly benign causes, the lesion must also be confirmed by pathological examination. For lesions without pathological specimens, we conducted systematic follow-up. Any lesion that cannot be confirmed as truly positive through systematic follow-up will be excluded from the research analysis. Any discrepancies in evaluations were resolved by a higher-ranking physician through consensus.

Statistical analysis

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS 26.0). Cohen’s kappa statistic and intraclass correlation coefficient were used to evaluate the inter-reader consistency for qualitative and quantitative data, respectively. McNemar’s test and paired t-test were used to assess the differences and consistency between the two imaging methods related to the number of patients or lesions detected. Wilson Score Confidence Intervals were calculated for lesion detection rates. P values <0.05 represented statistical significance.

Results

Patient cohort

This study included 74 NB patients. The cohort consisted of 48 males and 26 females with an average age of 4 years (range, 2–20 years). All enrolled patients had previously received treatment. The median interval between the two imaging procedures was 15 days (range, 3–29 days). According to the International Neuroblastoma Staging System (INSS) classification, four patients (5.4%) had stage III, 56 patients (75.7%) had stage IV, and 14 patients could not be staged due to incomplete data. Five patients underwent chemotherapy between the two imaging sessions, while the remaining patients were treatment-naïve during this period. The patient demographic data and clinical characteristics are shown in Table 1.

Patient-based comparison of the detection capabilities of the two imaging modalities

In general, the two imaging modalities provided consistent diagnostic results for 67 patients (90.5%), with 44 and 23 patients testing positive and negative, respectively, on both ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT. Among the seven patients with discordant results, five showed negative results on ¹²³I-MIBG SPECT/CT but positive results on ¹⁸F-OC PET/CT, while two showed positive results on ¹²³I-MIBG SPECT/CT but negative results on ¹⁸F-OC PET/CT (Figures 2,3). The difference in the detection capabilities between the two imaging modalities at the patient level was not statistically significant (McNemar, P>0.05) (Table 2). The diagnostic results of the two evaluators showed a very high inter-reader consistency (κ range of 0.97–1.0, P<0.001).

Figure 2 Comparative imaging in a 10-year-old girl with metastatic neuroblastoma. (A-D) ¹²³I-MIBG SPECT/CT showed no uptake of the radiotracer in the left pelvic obturator lymph nodes (red arrows). (E-H) Twenty-three days later, a ¹⁸F-OC PET/CT revealed radioactive distribution (red arrows). Subsequently, lymph node dissection was performed, and postoperative pathology confirmed lymph node metastasis of neuroblastoma. ¹²³I-MIBG SPECT/CT, ¹²³I-meta-iodobenzylguanide single-photon emission computed tomography/computed tomography; ¹⁸F-OC, ¹⁸F-AlF-NOTA-octreotide; PET/CT, positron emission tomography/computed tomography.

Figure 3 Comparative imaging in a 11-year-old boy with metastatic ganglioneuroblastoma. (A-D) ¹⁸F-OC PET/CT images showed no significant high-uptake uptake in cranial and periorbital lesions (red arrows). (E-H) ¹²³I-MIBG SPECT/CT performed 27 days later demonstrating abnormal radiotracer accumulation in the periorbital bone (red arrows), consistent with metastatic lesions previously identified on contrast-enhanced MRI. ¹⁸F-OC, ¹⁸F-AlF-NOTA-octreotide; ¹²³I-MIBG SPECT/CT, ¹²³I-meta-iodobenzylguanide single-photon emission computed tomography/computed tomography; MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography.

In the NB subgroup, both imaging modalities demonstrated concordance in diagnosing 35 patients (92.1%), with 20 patients testing positive and 15 testing negative for both modalities; only three patients showed discrepancies. For the ganglioneuroblastoma (GNB) subgroup, consistent diagnostic results were observed in 30 patients (90.9%), with 22 patients positive and eight negative for both modalities. There were slight differences in the diagnostic outcomes between the two imaging techniques across different pathological subtypes; however, these differences were not statistically significant at the patient level (McNemar, P>0.05).

Lesion-based comparison of detection capabilities of the two imaging modalities

Overall, ¹⁸F-OC PET/CT exhibited a significant advantage in lesion detection. Of the 1,009 positive lesions, ¹⁸F-OC PET/CT identified 965, whereas ¹²³I-MIBG SPECT/CT detected only 571. The overall lesion detection rate of ¹⁸F-OC PET/CT was significantly higher than that of ¹²³I-MIBG SPECT/CT (95.6% vs. 56.6%, P<0.01). Specifically, for bone metastases, ¹⁸F-OC PET/CT achieved a detection rate of 96.4%, significantly surpassing the 56.6% detection rate of ¹²³I-MIBG SPECT/CT (P<0.01). For other types of lesions, ¹⁸F-OC PET/CT also demonstrated a higher detection rate, albeit this was not significantly different from that of ¹²³I-MIBG SPECT/CT: primary lesions (85.7% vs. 71.4%, P>0.05), soft tissue metastases (76.5% vs. 64.7%, P>0.05), and lymph node metastases (89.8% vs. 52.5%, P>0.05) (Table 3). The consistency analysis indicated that the diagnostic results of the two evaluators exhibited very high inter-reader consistency (ICC range of 0.98–0.99, P<0.001).

In the NB and GNB subgroups, ¹⁸F-OC PET/CT demonstrated significantly higher overall detection and bone metastasis detection rates relative to ¹²³I-MIBG SPECT/CT (94.2% vs. 58.6% and 94.7% vs. 58.3%; 96.6% vs. 56.9% and 97.3% vs. 57.4%; P<0.05). However, the differences between ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT in detecting primary lesions, soft tissue metastases, and lymph node metastases were not statistically significant. The detailed data are presented in Table 3.

Discussion

Findings interpretation

Accurate evaluation of therapeutic outcomes and monitoring for recurrence are critical for improving the prognosis of patients with NB. In clinical practice, PET/CT is recommended as a complementary imaging method for patients who test negative for MIBG (10). A small-scale study has demonstrated that ⁶⁸Ga-OC PET/CT is more effective than ¹²³I-MIBG SPECT/CT in detecting NB lesions (11). However, the comparison of the lesion-detection capabilities of ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT for NB still needs further research. Therefore, this study compares the diagnostic performances of ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT in therapeutic response assessment and recurrence monitoring of NB. It was found that ¹⁸F-OC PET/CT has demonstrated superior capability in detecting bone metastasis lesions and is superior to the ¹²³I-MIBG SPECT/CT.

In our study, the two imaging modalities demonstrated a high level of consistency in detecting NB in patients. This suggests that both ¹⁸F-OC PET/CT and ¹²³I-MIBG SPECT/CT are effective in identifying positive cases of NB. Kroiss et al. (11) conducted a study involving five patients with NB to compare the accuracies of ⁶⁸Ga-DOTATOC PET/CT and ¹²³I-MIBG SPECT/CT in diagnosing and staging NB. They found that both methods had identical sensitivities in their patient-based analysis. Shahrokhi et al. (18) prospectively enrolled 15 patients with NB to assess and compare the diagnostic, staging, and follow-up capabilities of ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT/CT. Their findings revealed comparable sensitivities for the two imaging techniques at the patient-based level, further corroborating our findings.

Lesion-based analysis revealed that ¹⁸F-OC PET/CT detected more lesions overall, particularly with significant differences in identifying bone and bone marrow metastases. Previous studies with small sample sizes have reported that SSTR PET/CT outperforms ¹²³I-MIBG SPECT/CT in lesion detection for NB. In a lesion-based analysis, Kroiss et al. (11) determined that ⁶⁸Ga-DOTATOC PET/CT had a superior sensitivity to ¹²³I-MIBG SPECT/CT. Similarly, the prospective study by Shahrokhi et al. (18) showed that both imaging modalities had high sensitivity for detecting primary lesions (100%), with ⁶⁸Ga-DOTATATE PET/CT detecting more bone metastases relative to ¹²³I-MIBG SPECT/CT (15 vs. 5). The limited sensitivity of ¹²³I-MIBG SPECT/CT in detecting bone and bone marrow metastases is a major reason for false negatives. Previous lesion-based studies have shown that bone and bone marrow metastases decrease the overall sensitivity of ¹²³I-MIBG SPECT/CT to 60–70%, which is consistent with our findings (19-21). As NB is a highly aggressive cancer, with bone metastasis being one of the most common forms of spread, a higher detection rate enables earlier and more precise identification of disease progression or recurrence. This influences clinical decision-making. Moreover, a sensitive imaging modality is essential for assessing treatment effectiveness and refining therapeutic strategies.

The ¹⁸F-OC PET/CT identified more primary lesions, soft-tissue metastases, and nodal involvement, although the differences were insignificant. The diagnostic performances of the two imaging methods for the lesions and soft-tissue and lymph node metastases were comparable. Previous studies show that the sensitivity of ¹²³I-MIBG SPECT/CT for lesion detection varies between 67% and 100% (19,22-25). In this study, the sensitivity of ¹²³I-MIBG SPECT/CT for detecting primary lesions, soft tissue metastases, and lymph node metastases was relatively low. This may be due to the heterogeneity of NB, as some tumors show low norepinephrine receptor and high SSTR expressions (26). The patient cohort in this study consisted of patients with treated and/or recurrent NB. Most of the primary lesions had already been surgically removed, leading to an insufficient number of primary lesions, which reduced statistical power. Furthermore, the patients first underwent planar imaging during ¹²³I-MIBG SPECT/CT in this study, followed by tomographic imaging based on the suspicious or tumor-absorbing areas identified in the planar images. In contrast, tomographic images were acquired from the skull to the soles with image fusion for ¹⁸F-OC PET/CT. When lymph nodes are small and isolated, they are difficult to detect on planar images, which can lead to differences in soft-tissue metastasis detection between the two modalities. Finally, compared with SPECT/CT, PET/CT systems generally have better spatial resolution, and the difference in imaging resolution should also be considered as a factor influencing lesion detection (27).

In the context of evaluating therapeutic efficacy and monitoring recurrence in NB, ¹⁸F-OC PET/CT presents distinct advantages over conventional ¹²³I-MIBG SPECT/CT. PET/CT offers a significantly higher spatial resolution and superior image quality in comparison to SPECT/CT, leading to more accurate diagnostics. The longer half-life of ¹⁸F-labeled compounds enhances the flexibility of radiopharmaceutical preparation and transportation, thereby broadening the clinical utility of ¹⁸F-OC PET/CT. Furthermore, the shorter scan time of ¹⁸F-OC PET/CT improves patient comfort and minimizes the risk of motion artifacts, which is particularly beneficial for pediatric and adolescent patients with NB who may struggle to remain still for extended periods of time. Notably, our study demonstrated that ¹⁸F-OC PET/CT demonstrated greater sensitivity in detecting bone metastases and performed comparably well to the recommended imaging modalities for primary lesions, soft tissue metastases, and lymph node metastases. This capability may support earlier disease detection and timely optimization of treatment strategies. Among the 74 enrolled patients, 41 patients underwent ¹⁸F-OC PET/CT during the treatment cycle for efficacy evaluation, and the treatment plans of 26 patients were altered. Specifically, 3 patients received additional surgical treatment due to the discovery of metastatic lesions, 5 patients adjusted their radiotherapy plans due to the identification of additional bone metastases. The remaining 18 patients also had their medical treatment plans optimized with the support of PET/CT. In addition, 33 patients with clinically suspected recurrence underwent ¹⁸F-OC PET/CT examination, among which 3 patients had their treatment plans optimized due to ¹⁸F-OC PET/CT detected more disease recurrence. These results indicate that ¹⁸F-OC PET/CT not only enhances the sensitivity of disease detection but also provides crucial guidance for treatment decision-making.

In our study, one case of bone metastasis, one case of lymph node metastasis, and one case of soft tissue metastasis showed no radiotracer uptake on ¹⁸F-OC PET/CT, but were positive on ¹²³I-MIBG SPECT/CT. Subsequent follow-ups confirmed that these lesions were all tumor metastases. These findings indicate that while ¹⁸F-OC PET/CT demonstrates high diagnostic value overall, false-negative results may occur in certain cases. Therefore, in clinical practice, for patients with a high suspicion of recurrence but negative ¹⁸F-OC PET/CT results, it may be necessary to consider ¹²³I-MIBG SPECT/CT as a supplementary examination. The combined application of these two imaging modalities may provide more comprehensive diagnostic information, thereby facilitating more precise treatment decisions. Additionally, clinicians must consider the risk of false positives due to factors such as inflammation, infection, benign tumors, and physiological uptake (28,29).

There are some limitations in this study. First, being a retrospective study, it depended on previously collected clinical data, which may carry the risk of information bias and missing data. In this study, PET and SPECT scans were utilized for efficacy evaluation during treatment and for relapse monitoring post-treatment. However, this approach may introduce selection bias. Furthermore, the characteristics of a single-center study could further exacerbate the risk of selection bias, thereby negatively impacting the generalizability of the study results. Secondly, the main limitation of this study was the absence of histopathological validation of every detected lesions due to ethical and logistical constraints. As a result, we did not have a flawless reference standard to evaluate the diagnostic performance, leading to potential for false-positive lesions. To mitigate this, this study employed strict lesion confirmation criteria, requiring that all positive lesions must be validated through pathological examination. For lesions where tissue samples were difficult to obtain, confirmation was achieved through long-term systematic follow-up. Any lesions that cannot be confirmed as true positives using the above methods were excluded from the study analysis. These rigorous standards significantly enhanced the reliability and specificity of our results, effectively reducing the impact of false positive findings on the study conclusions. Therefore, we believe that the occurrence of false-positive lesions is rare. However, this approach may also present potential limitations, such as the overemphasis on specificity that could lead to the erroneous exclusion of certain true positive lesions, particularly those early lesions that were difficult to sample pathologically or temporarily stable during follow-up. For some slowly progressive lesions, even in our follow-up period, the absence of significant changes did not entirely rule out their potential malignant nature. Compared to studies that rely solely on imaging characteristics to confirm lesions, our method is more conservative and may underestimate the detection rate of certain specific types of lesions, but it significantly enhances the reliability of the lesions included in the analysis. Finally, the study was limited by a relatively small sample size; the majority of lesions were bone metastases, and fewer cases of primary lesions, soft tissue metastases, and lymph node lesions were included. Currently, a prospective single-center study is underway. Larger multicenter studies are needed to validate these findings.

Conclusions

¹⁸F-OC PET/CT has superior diagnostic efficacy over ¹²³I-MIBG SPECT/CT in assessing treatment response and detecting recurrence in pediatric NB, especially in identifying bone metastases. This indicates its potential as a reliable method for evaluating therapeutic efficacy and monitoring recurrence in NB, especially in assessing bone metastases, where it shows promise as a replacement for ¹²³I-MIBG SPECT/CT.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2456/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2456/dss

Funding: This work was supported by a grant from the National Natural Science Foundation of China (No. 82373424).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2456/coif). All authors report that the present study received funding from the National Natural Science Foundation of China (No. 82373424) and English language editing support from Editage (www.editage.cn). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethics Committee of the Shandong Cancer Hospital and Institute (No. SDTHEC 2024008005) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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