Research ArticleClinical Investigation

18F-FDG PET/CT and 123I-Metaiodobenzylguanidine Imaging in High-Risk Neuroblastoma: Diagnostic Comparison and Survival Analysis

Nikolaos D. Papathanasiou, Mark N. Gaze, Kevin Sullivan, Matthew Aldridge, Wendy Waddington, Ahmad Almuhaideb and Jamshed B. Bomanji
Journal of Nuclear Medicine April 2011, 52 (4) 519-525; DOI: https://doi.org/10.2967/jnumed.110.083303

Abstract

The aim of our study was to evaluate prospectively the diagnostic performance and prognostic significance of 18F-FDG PET/CT in comparison with 123I-metaiodobenzylguanidine (123I-MIBG) imaging in patients with high-risk neuroblastoma. Methods: Twenty-eight patients with refractory or relapsed high-risk neuroblastoma (16 male and 12 female patients; age range, 2–45 y; median age, 7.5 y) were simultaneously evaluated with 18F-FDG PET/CT and 123I-MIBG imaging before treatment with high-dose 131I-MIBG. We compared the 2 methods in mapping tumor load, according to the extent of disease and intensity of positive lesions identified in each patient. Separate comparisons were performed for the soft-tissue and bone–bone marrow components of tumor burden. Survival analysis was performed to assess the prognostic significance of 18F-FDG and 123I-MIBG imaging parameters. Results: 18F-FDG PET/CT results were positive in 24 of 28 (86%) patients, whereas 123I-MIBG imaging results were positive in all patients. 18F-FDG was superior in mapping tumor load in 4 of 28 (14%) patients, whereas 123I-MIBG was better in 12 of 28 (43%) patients. In the remaining 12 (43%) patients, no major differences were noted between the 2 modalities. 18F-FDG PET/CT missed 5 cases of bone–bone marrow disease, 4 cases of soft-tissue disease, and 6 cases of skull involvement that were positive on 123I-MIBG scans. Cox regression and Kaplan–Meier survival curves showed that the group of patients (4/28) in whom 18F-FDG was superior to 123I-MIBG had a significantly lower survival rate than the others. Tumoral avidity for 18F-FDG (maximum standardized uptake value) and extent of 18F-FDG–avid bone–bone marrow disease were identified as adverse prognostic factors. Conclusion: 123I-MIBG imaging is superior to 18F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, 18F-FDG PET/CT has significant prognostic implications in these patients.

  • neuroblastoma
  • positron emission tomography
  • 18F-fluorodeoxyglucose (18F-FDG)
  • 123I-metaiodobenzylguanidine (123I-MIBG)

More than half of patients with neuroblastoma are defined as high risk according to unfavorable prognostic features such as age (≥18 mo at presentation), stage (distant metastases in lymph nodes, cortical bone, bone marrow, and liver), and molecular pathology (MYCN oncogene amplification) (1). These patients require multimodality treatment with intensified induction chemotherapy, surgery followed by high-dose chemotherapy consolidation with autologous hematopoietic stem cell support, external-beam radiotherapy, and treatment of minimal residual disease with retinoids. Such aggressive treatment has increased the response rate; nevertheless, a significant proportion of patients remains resistant to induction treatment. Of those patients whose disease responds fully, more than 50% will relapse after consolidation (2). Overall, the long-term cure rate is less than 25%–30% (3,4).

Several diagnostic modalities are applied to define disease status in these patients. CT or MRI is used to assess the extent of the primary tumor and to detect any vascular or other vital organ encasement and contiguous or distant nodal metastases. MRI is the preferred modality for assessment of spinal canal involvement (5,6). 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy is the nuclear imaging method of choice for neuroblastoma, being valuable for diagnosis, staging, and response assessment. 123I-MIBG scintigraphy has shown high diagnostic accuracy at initial staging, especially for the detection of osteomedullary lesions, and it subsequently provides an indispensable tool for the identification of residual, recurrent, or occult disease (5–8). The extent of 123I-MIBG–positive disease before, during, and after treatment has been shown to correlate with event-free and overall survival (9).

18F-FDG PET/CT is an established modality for many adult cancer types; however, its clinical role in pediatric malignancy is less well addressed (10,11). Lymphomas, primary brain neoplasms, and sarcomas have been most frequently studied, whereas few studies have investigated the use of 18F-FDG in neuroblastoma (12–15). Among these studies, initial reports showed tumor avidity for 18F-FDG (14), and it was later proposed that 18F-FDG PET could be implemented as the sole imaging modality to assess disease progression (12). However, the accuracy and clinical role of this technique have not been defined, especially for high-risk patients in whom determination of disease status is critical to gauge therapeutic management. Beyond disease detection, it is not known whether 18F-FDG PET is able to provide prognostic information or whether the imaging results correlate with survival; similarly, it is unclear whether, within this cohort of patients with high-risk, aggressive tumors, 18F-FDG PET can identify those who are likely to fail multimodality treatment.

The purpose of this study was to evaluate the diagnostic performance and prognostic significance of 18F-FDG PET/CT in comparison with 123I-MIBG imaging in patients with high-risk neuroblastoma.

MATERIALS AND METHODS

Study Population

Our prospective study considered 28 patients (Table 1; 16 male and 12 female patients; age range, 2–45 y; median age, 7.5 y) with high-risk, histologically proven neuroblastoma. Patients were referred to University College London Hospital, for combined high-dose 131I-MIBG and topotecan treatment (Metaiodobenzylguanidine And Topotecan In Neuroblastoma protocol (16)) because of disease refractory to induction treatment (43%) or disease relapse after consolidation (57%). All of the patients had stage IV neuroblastoma: 25 with bone–bone marrow disease, 2 with liver involvement, and 1 with distant nodal metastases. Each patient underwent a pair of 18F-FDG and 123I-MIBG scans, performed within 2 wk before treatment. Scans were acquired from November 2004 until October 2008. Detailed informed parental or, when appropriate, patient consent was obtained according to the Declaration of Helsinki.

View this table:
TABLE 1

Patients’ Demographic Data, Skeletal Scores, SUVmax of Most Intense Lesion per Patient, and Survival Data

Imaging Protocols

PET/CT studies were performed using a dedicated combined Discovery (GE Healthcare) PET/CT scanner; whole-body examinations were performed with the patient supine. Images were acquired 50–75 min after injection of 18F-FDG (5.5–7.7 MBq/kg), with a maximum dosage of 440 MBq. CT data were acquired using the four 3.75-mm detectors, a pitch of 1.5, and 5-mm collimation. The CT exposure factors were 120–140 kVp and 80 mA. While patient position was maintained, a whole-body PET emission scan was acquired in 2-dimensional mode (5 min per bed position) and covered an area identical to that covered by CT. PET images were reconstructed using CT data for attenuation correction. Transaxial PET emission images of 4.3 × 4.3 × 4.25 mm were reconstructed using ordered-subsets expectation maximization, with 2 iterations and 28 subsets.

123I-MIBG scans were obtained at 4 and 24 h after injection of 123I-MIBG (5.20 MBq/kg), with a maximum dose of 370 MBq. All patients received thyroid blockage with potassium perchlorate or potassium iodide before and for 2 d after 123I-MIBG administration. Anterior and posterior whole-body images were acquired. After initial review, planar whole-body images were supplemented with spot views or SPECT/CT of the chest and abdomen, if deemed necessary for anatomic localization of the lesion or clarification of equivocal findings. When necessary, sedation was used in accordance with guidelines before 18F-FDG PET/CT or 123I-MIBG imaging to ensure patient immobilization and adequate image quality.

Image Analysis

All studies were reviewed by 2 nuclear medicine physicians in consensus. For each single study (either 18F-FDG PET/CT or 123I-MIBG imaging), the presence or absence of disease was recorded separately for the soft-tissue compartment (primary mass, nodal, and liver metastases) and bone–bone marrow compartment. The number of involved soft-tissue regions (primary site, nodal sites, pleura–lung, and liver) detected by each modality was recorded.

For 18F-FDG PET/CT interpretation, any focal, superior-to-background 18F-FDG uptake in the primary mass, lymph nodes, liver, or skeleton was interpreted as positive or abnormal. Patchy inhomogeneous 18F-FDG uptake in the bone marrow, especially in the absence of recent chemotherapy or hematopoietic stimulating factors, was interpreted as positive for bone marrow infiltration. The maximum standardized uptake values (SUVmax) were recorded for the most intense soft-tissue and bone–bone marrow lesions per patient, after manual application of regions of interest in the transaxial attenuation-corrected PET slices, around the pixels demonstrating the greatest accumulation of 18F-FDG.

123I-MIBG and 18F-FDG PET/CT scans were assigned extent scores for bone–bone marrow lesions according to a previously applied semiquantitative method (17,18). The skeleton was divided into 10 segments: calvarium, skull base–face, cervical–thoracic spine, lumbar–sacral spine, sternum–ribs–scapula, pelvis, upper arms, forearms–hands, upper legs, and lower legs–feet. For each segment, disease was scored as 0, no lesion; 1, 1 positive lesion; 2, 2 or more positive lesions but involvement of less than 50% of segment; or 3, involvement of more than 50% of segment. A total score for each scan was calculated by adding all segmental scores (maximum score of 30).

At the end, each pair of scans was assigned a qualitative characterization: “18F-FDG better than 123I-MIBG” (Fig. 1), “18F-FDG equivalent to 123I-MIBG” (Fig. 2), or “18F-FDG inferior to 123I-MIBG” (Fig. 3). For this grouping, interpreters took into account 2 integrated factors: the extent of the disease identified—that is, the number and distribution of involved regions—and the intensity of positive lesions (qualitative estimation of tumor-to-background ratios) on each tracer imaging. The liver (14,18) or an area free of disease, if the liver was involved, was used as background to estimate the intensity of lesions.

FIGURE 1.
FIGURE 1.

18F-FDG PET/CT scan (maximum-intensity projection) in 4-y-old girl shows more extensive and pronounced bone–bone marrow disease in humeri, spine, pelvis, and femora than does 123I-MIBG scan (planar). Both modalities were negative for soft-tissue compartment and positive for the bone–bone marrow compartment. This pair of scans was characterized as showing better performance for 18F-FDG than for 123I-MIBG.

FIGURE 2.
FIGURE 2.

18F-FDG PET/CT (maximum-intensity projection) and 123I-MIBG (anterior planar) scans of 4-y-old boy with extensive stage IV neuroblastoma. There are multiple bone–bone marrow lesions in skull (right temporal bone, with soft-tissue component), ribs, pelvis, and extremities, which were avid on images obtained with both tracers (123I-MIBG and 18F-FDG skeletal scores of 13). There are soft-tissue masses in posterior mediastinum (blue arrow) and abdomen (black arrow), causing obstruction of left kidney (red arrow). This pair of scans was characterized as showing equivalence between 18F-FDG and 123I-MIBG.

FIGURE 3.
FIGURE 3.

18F-FDG PET/CT (maximum-intensity projection) and 123I-MIBG (anterior and posterior planar) scans of 3-y-old boy with stage IV neuroblastoma. There is extensive 123I-MIBG–avid disease in bone–bone marrow and 123I-MIBG–avid (black arrow) left adrenal mass (CT image; white arrowhead). 18F-FDG PET shows intense tracer uptake only in sternum (white arrow), in keeping with bone–bone marrow disease. This pair of scans was characterized as showing 18F-FDG to be inferior to 123I-MIBG.

Survival Analysis

Overall survival was calculated from time of imaging to death or last examination (cutoff date for analysis, August 1, 2009), according to the Kaplan–Meier method. Univariate Cox regression analysis was applied to check for the prognostic significance of the following factors: age, 123I-MIBG and 18F-FDG skeletal scores, 123I-MIBG and 18F-FDG–positive soft-tissue regions, SUVmax (of the most 18F-FDG–avid lesion in each patient), and 123I-MIBG–18F-FDG paired scan characterization (“18F-FDG better than 123I-MIBG” and “18F-FDG equivalent to 123I-MIBG” vs. “18F-FDG inferior to 123I-MIBG” as reference level). Analysis was performed using STATA software (version 10; StataCorp).

RESULTS

Image Analysis

123I-MIBG imaging was positive in all 28 patients, whereas 18F-FDG PET/CT was positive in 24 of 28, corresponding to an 86% per-patient sensitivity of 18F-FDG for neuroblastoma detection.18F-FDG missed 4 cases of disease in the soft tissue and 5 cases in the bone–bone marrow compartment, all of which were positive on 123I-MIBG, whereas only 1 case of soft-tissue compartment disease was positive on 18F-FDG and negative on 123I-MIBG. 123I-MIBG was superior to 18F-FDG in both soft-tissue and bone–bone marrow compartments; however, this difference was not statistically significant (McNemar test; P = 0.375 and 0.063, respectively; Tables 2 and 3).

View this table:
TABLE 2

123I-MIBG and 18F-FDG Imaging Results, per Patient, in Soft-Tissue Compartment

View this table:
TABLE 3

123I-MIBG and 18F-FDG Imaging Results, per Patient, in Bone–Bone Marrow Compartment

A total of 50 positive soft-tissue regions were identified in the whole study group, 32 (64%) of which were positive on both 18F-FDG and 123I-MIBG. Nonconcordant regions that were 123I-MIBG–positive/18F-FDG–negative (10/50 [20%]) were marginally more frequent than 123I-MIBG–negative/18F-FDG–positive regions (8/50 [16%]) (χ2 test, P = 0.8). Mean 123I-MIBG skeletal extent scores (6.9 ± 1.2 SE) in the whole study group were not significantly different from respective 18F-FDG scores (5.8 ± 1.3 SE) (paired t test, P = 0.22). Mean SUVmax was 5.6 ± 3.2 SD for the soft-tissue lesions and 5.1 ± 3.6 SD for the bone–bone marrow lesions. Patients’ skeletal scores and SUVmax are shown in Table 1.

Eight patients had skull lesions detected by 123I-MIBG imaging; in 2, the lesions had a large soft-tissue component and were visible on 18F-FDG PET/CT as well, whereas the other 6 lesions were missed by 18F-FDG. In 5 of these patients, these results had no implications for staging—18F-FDG was positive for the bone–bone marrow compartment anyway. In the other patient, 18F-FDG missed both skull involvement and bone–bone marrow disease detected by 123I-MIBG. The 2 cases of liver involvement were positive on 123I-MIBG scans, and 1 of them showed avidity for 18F-FDG as well.

Qualitative paired comparisons revealed 18F-FDG to be better than 123I-MIBG in mapping tumor load in 4 of 28 patients (14%; 95% confidence interval [CI], 6%–31%). These cases included 2 in which 18F-FDG detected more soft-tissue lesions and 2 in which 18F-FDG better delineated the bone–bone marrow component of the disease (Fig. 1). In 12 patients (43%; 95% CI, 27%–61%), 18F-FDG was inferior to 123I-MIBG. These cases comprised 3 in which 18F-FDG was worse in depicting disease in the soft-tissue compartment, 4 in which 18F-FDG was worse in depicting disease in the bone–bone marrow compartment, and 5 in which the performance of 18F-FDG was worse in both compartments (Fig. 3). In the remaining 12 patients (43%; 95% CI, 27%–61%), there was no significant discordance between the 2 modalities, and the paired scans were characterized as equivalent (Fig. 2).

Survival Analysis

Median observation time from imaging was 1.03 y (range, 0.27–3.5 y). Seventeen patients (61%) died during the observation period, and Kaplan–Meier median survival time was 1.32 y. The Kaplan–Meier estimate of the 3-y overall survival of the group was 17% (95% CI, 3%–41%). Cox regression analysis showed that compared with 123I-MIBG (paired 123I-MIBG–18F-FDG scan characterization) (Fig. 4), 18F-FDG uptake pattern, tumoral 18F-FDG uptake (SUVmax) (Fig. 5), and 18F-FDG skeletal extent score (Fig. 6) were significant factors associated with decreased survival (Table 4).

FIGURE 4.
FIGURE 4.

Kaplan–Meier survival curves of 3 groups of patients: “18F-FDG better than 123I-MIBG” (green line) and “18F-FDG equivalent to 123I-MIBG” (red line) vs. “18F-FDG inferior to 123I-MIBG” (blue line).

FIGURE 5.
FIGURE 5.

Kaplan–Meier survival curves of patients whose most intense lesion had a SUVmax > 5.3 (red line) vs. others with SUVmax < 5.3 (blue line). Mean SUVmax was selected as cutoff value.

FIGURE 6.
FIGURE 6.

Kaplan–Meier survival curves of patients with 18F-FDG skeletal score of >6 (red line) vs. skeletal score of ≤6 (blue line). Mean 18F-FDG skeletal score was selected as cutoff value.

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TABLE 4

Results of Univariate Cox Regression Analysis

DISCUSSION

Ours is one of the first prospective studies to directly compare the diagnostic performance of 18F-FDG PET/CT with 123I-MIBG imaging in high-risk neuroblastoma. The results show good per-patient sensitivity (86%) of 18F-FDG PET/CT for neuroblastoma detection; however, 123I-MIBG imaging was, overall, superior in mapping the extent of the disease. Most previous studies, though limited, are in accordance with our results. Initially, Shulkin et al. reported tumoral 18F-FDG avidity in 16 of 17 patients, yet in most cases MIBG was rated superior for tumor delineation (14). In a retrospective study of 85 paired scans in 40 stage IV patients, 123I-MIBG was superior to 18F-FDG PET (13). Similarly, 123I-MIBG was more sensitive overall and for bone lesions than 18F-FDG PET in patients of the New Approaches to Neuroblastoma Therapy (NANT) trial, assessed before 131I-MIBG therapy (15). Unlike these and our results, 1 study of 51 high-risk subjects showed 18F-FDG PET to be better than MIBG for detection of both extracranial osteomedullary and soft-tissue lesions (12).

The main advantage of 123I-MIBG over 18F-FDG was its superiority in depicting clearly the bone–bone marrow component of the disease (Table 3), because uptake of 123I-MIBG was not confounded by bone marrow activation due to previously applied therapies. Our finding is supported by results from previous studies (13,14). In contrast, 18F-FDG may exhibit physiologic accumulation in the bone marrow regardless of whether it is infiltrated, resulting in lower accuracy for detection of bone–bone marrow disease. 18F-FDG was inferior in detecting skull lesions, unless these demonstrated a considerable soft-tissue component, mainly because of the adjacent high physiologic 18F-FDG activity in the brain cortex. Although it has been hypothesized that 18F-FDG could be better in detecting liver lesions (5,19) because of physiologic 123I-MIBG distribution in the liver, this hypothesis was not confirmed by our results.

Beyond disease detection, 18F-FDG PET/CT had significant prognostic implications in high-risk neuroblastoma patients undergoing 131I-MIBG treatment. Tumoral metabolic activity (SUVmax) and extent of 18F-FDG–avid bone–bone marrow disease (18F-FDG skeletal scores) were identified as poor prognostic factors associated with decreased survival (Table 4; Figs. 5 and 6). A pattern of increased 18F-FDG activity, surpassing tumoral avidity for 123I-MIBG, corresponded to more aggressive disease and worse outcome (Table 4; Fig. 4). It is unknown whether this pattern mirrors neuroblastoma cell dedifferentiation. In a significant number of preclinical and clinical studies, 18F-FDG uptake was found to correlate with high proliferative activity, cellular dedifferentiation, and aggressive behavior of neuroendocrine tumors (20,21); however, preclinical models have failed to verify any association between 18F-FDG and neuroblastoma proliferation (22). MIBG is taken up by the neuroblastoma cells because of a specific noradrenaline transporter mechanism (23), but its uptake within tumors is highly variable and has not been found to correlate with neuroblastoma differentiation (24). There is a need for preclinical studies to clarify whether there is a pattern of unfavorable histology, with neuroblast cellular dedifferentiation correlating with increased 18F-FDG activity and lesser MIBG uptake.

Our results showed a nonsignificant association of 123I-MIBG imaging parameters (skeletal scoring systems and positive soft-tissue regions) with survival, probably reflecting our specific group selection of heavily pretreated patients with relapsed or refractory disease. In a similar group of 49 patients, Messina et al. reported that 123I-MIBG scores showed high reproducibility and correlated with therapeutic response but were not associated with survival outcome (18). In a different clinical setting, postinduction 123I-MIBG score was significantly associated with outcome: those with a score less than 3 had a 4-y event-free survival rate of 58% ± 11%, as compared with a survival rate of 0% in those with a score more than 3 (17). In a large study of 113 stage IV patients, the presence of 123I-MIBG–positive metastatic disease after 4 cycles of induction was related to decreased 3-y overall survival: 49.8% ± 6.1% vs. 65% ± 7.3% when 123I-MIBG was negative for metastatic disease (9). It seems that 123I-MIBG can predict outcome in initial treatment evaluation (after induction) but not later in patients with relapsed or refractory disease, who carry a dramatically poor prognosis.

The main limitation of this study is that we did not incorporate parameters (e.g., dosimetry, response evaluation) of subsequent 131I-MIBG treatment, or details of any other subsequent treatments, into the survival analysis. These factors could considerably affect total survival time, and to evaluate their effect we would require data from a larger cohort of patients to obtain adequate power and analyze with a multivariable model to exclude potential confounders. Such analysis was beyond the scope of the planned comparison of the 2 modalities and will be the subject of a subsequent study. Second, our imaging results were not validated against a standard reference method: obtaining tissue histology from all sites was not feasible or ethical and there is no imaging gold standard in the evaluation of neuroblastoma patients. Therefore, the effect of this inherent limitation on accuracies of imaging modalities cannot be correctly determined; the sensitivity of 18F-FDG PET/CT could have been overestimated because of false-positive lesions, especially in the bone–bone marrow compartment. Another limitation is the referral bias: we evaluated MIBG-avid neuroblastoma patients treated subsequently with 131I-MIBG; therefore, extending our conclusions to all high-risk neuroblastoma patients (MIBG-avid and -nonavid) should be done with caution. Finally, the use of 18F-FDG PET/CT in addition to 123I-MIBG scintigraphy at initial staging in all neuroblastoma patients (including those at high risk) requires prospective evaluation.

CONCLUSION

18F-FDG PET/CT cannot replace 123I-MIBG in high-risk neuroblastoma, mainly because of its limitation in identifying bone–bone marrow infiltration. 18F-FDG PET/CT could be useful in the evaluation of a small proportion (less than 10%) of neuroblastoma patients who do not accumulate 123I-MIBG or in cases in which it is suspected that the extent of disease exceeds that depicted with 123I-MIBG (13,14,19). Tumoral 18F-FDG avidity was associated with an earlier adverse outcome within this cohort of patients with a poor prognosis undergoing 131I-MIBG therapy. The practical incorporation of 18F-FDG PET/CT in treatment decision making would, however, require the development of novel effective treatments (25). In such a setting, 18F-FDG PET/CT could aid in identifying patients for whom a more aggressive treatment strategy would be required.

DISCLOSURE STATEMENT

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Acknowledgments

We thank Anastasios Boutsiadis and Xanthi Pedeli, biostatisticians, for statistical advice. This work was undertaken at the University College London Hospital, which receives a proportion of financial support from the U.K. Department of Health's NIHR Comprehensive Biomedical Research Centres funding scheme and from Cancer Research, United Kingdom.

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  • Received for publication September 13, 2010.
  • Accepted for publication January 7, 2011.