This study examined the feasibility of quantification in [123I]mIBG SPECT/CT data in phantom measurements and NB patients as a basis for potential application of quantitative image parameters for predictive or prognostic purposes.
Numerous factors influence quantitative accuracy in SPECT/CT. While attenuation is routinely addressed with CT-based attenuation correction, correction for scatter, e.g. within the patient, is not necessarily an integral part of iodine-123 SPECT/CT reconstruction in clinical routine (i.e., for visual interpretation). As highlighted by the current data, the scatter proportion estimated by the DEW method for iodine-123 in an IEC phantom geometry can account for up to half (NaI; LEHR collimator) (23) or even > 70% of the acquired counts (CZT; WEHR45 collimator). This implicates that in [123I]mIBG imaging for children, which is in principle characterized by low count statistics and unfavorable noise properties, the additionally available counts in non-SC data could be beneficial for image quality and resulting confidence for visual reading in clinical care.
However, if quantitative accuracy is intended, high trueness (i.e., low systematic deviations from the true value) and precision (i.e., high reproducibility of measurements) are required. In phantom measurements, trueness of non-SC data in recovering the background activity concentration in the IEC phantom based on volume sensitivity of the smaller, homogenously filled phantom was poor (average relative error > 70%). In contrast, SC data showed high trueness (low average relative error < 5%) and high precision (low variability between serial scans) suggesting that the DEW method with a low-energy scatter window could be sufficient for SC in iodine-123 SPECT/CT if only the accurate depiction of homogenous activity concentrations in a sufficiently large volume is required. However, SC data considerably overestimated CR of the larger sphere inserts. This is, among other effects, due to the inability of the DEW method to account for the spatial distribution of scattered photons that originate from the sphere inward but are detected in the background and therefore systematically increase sphere-to-background ratios (24). This overestimation increases with an increase of the weighting factor k for the scatter window (k = 1.0 in the current study for both cameras) (25). In contrast, without SC, CRpeak underestimated the AC of larger sphere inserts by about 30% (NaI) or 40% (CZT) which is in accordance with Lagerburg et al. (25). The consistent results for CRmax and CRpeak show that this observation is not merely due to the chosen delineation method (CRpeak) or statistical outliers (CRmax). The general observation that CRpeak better represents sphere AC in larger spheres compared CRmax, which usually overestimates it, has been previously demonstrated for positron emission tomography (PET) (26).
In patient data, trueness usually cannot be determined unless the standard of truth is known from activity concentrations determined in vivo (e.g., in the urine (27)). However, one should aim at achieving comparability between camera systems. Similarity in average normal organ SUV between both cameras served as a surrogate assuming that normal organ SUV should be similar on average – even in different patient samples. Under this premise, SUV in non-SC data were similar between both cameras for all normal organs. Intuitively, the similarity of estimated scatter proportions between the homogenous phantom and organs such as liver and myocardium as well as between the IEC phantom and organs such as MBPS and spine would suggest that the DEW method could overall account for varying scatter geometries in different organs. Consequently, normal organ SUV in SC data should also be similar between both cameras – irrespective of the examined organ and its estimated scatter proportion. In contrast, in specific organ geometries with high estimated scatter proportions (spleen, MBPS, spine, gluteal muscles), SUV in SC data were different between CZT and NaI patients. It must be hypothesized that the use of a unique k value for both systems accentuates these effects of SC. Furthermore, SC could not reduce the imprecision in patient data when the variation of normal organ SUVmean (CV) between different examinations was used as a surrogate.
In summary, surrogates for both trueness and precision in the current patient data imply that SC based on the DEW method with a low-energy scatter window is insufficient for quantitative accuracy in clinical iodine-123 SPECT/CT with both CZT (WEHR45) and NaI cameras (LEHR collimator). In both detectors, the DEW method is limited by the inability to account for spatial distribution of scattered photons (see above). Moreover, it relies on calibration of the k factor which is then applied indiscriminately to the acquired dataset, and DEW cannot account for downscatter from the 529 keV iodine-123 peak (28, 29); both adaptations would require a third energy window above the photopeak window. In CZT detectors, overestimation of scatter using the DEW method will result from the detector-specific low-energy tail which is caused by contamination from photons that are unscattered but detected with lower energy (28, 30).
Considering these spatially variant and invariant sources of error in SC for iodine-123 with the simplified DEW method, Monte Carlo based SC in combination with CDR modelling may be superior in achieving accurate quantitative data in the complex and variable geometry of the patient body (13, 31); however, these algorithms are resource consuming and not commonly integrated in clinical SPECT/CT systems. Brady et al. recently investigated SUV in [123I]mIBG SPECT/CT acquired with two NaI cameras (LEHR and ME collimator) in 43 patients with NB. Using Monte Carlo based SC and volume sensitivity from a homogenously filled cylindrical phantom, normal organ SUV (salivary glands, heart, liver, adrenal glands, urinary bladder) were – on average – similar between both cameras. However, considerable variation in SUV of all organs remained between examinations. IQR of liver SUV was 1 to 2 and therefore comparable to CZT examinations in the current study but lower than in NaI examinations in the present analysis (IQR, 1 to 3). It may be noted that even with optimal image acquisition and processing, physiological variability of normal organ SUV will occur, which will itself vary between organs (e.g., due to varying sympathetic innervation of the left ventricular myocardium (32)). If normal organ SUV variation remains high, it could ultimately limit the potential of normal organ SUV in [123I]mIBG imaging to serve as physiological intraindividual reference as has been commonly proposed for the liver or MBPS SUV in [18F]fluorodeoxyglucose (FDG) PET (33, 34).
Independent of the SC method used for quantifying patient data, an appropriate calibration procedure (e.g., scan protocol, phantom geometry) must be chosen to estimate volume sensitivity for SPECT data. If the employed SC method is accurate, it would be sufficient to obtain volume sensitivity from a homogenously filled cylindrical phantom (20). Appropriateness of the volume sensitivity could be examined under varying scatter properties using a body phantom. However, the current results suggest that further steps will be required to ensure that the SC method is appropriate for normal organ and lesion quantification in patients. This may ultimately require in vivo measurements of activity concentrations, e.g. in the urine (27).
Further influencing factors were examined in the current study (detector radius, acquisition time reduction with the CZT). Differences in volume sensitivity for the homogenous phantom between acquisition with body contour or fixed 27 cm detector radius were < 5% in SC data. This is facilitated by resolution recovery as part of image reconstruction which aims at compensation for CDR including its variation at different detector radii along the angular range (35, 36). Although relative differences were small, volume sensitivity with the CZT at 27 cm radius was significantly lower than with body contouring. This may be due to higher dependency of effective spatial resolution from source-to-collimator distance compared to NaI detectors (37–39). Consequently, variation in detector distance among patients could add system-specific variance in quantitative accuracy. However, the currently chosen differences in detector radii were comparably large, especially considering the context of a pediatric population, with the aim of identifying the consequential deviations under extreme conditions – while (considerably) smaller deviations can usually be expected in clinical routine. Furthermore, volume sensitivity for both phantoms as well as CRmax and CRpeak of the sphere inserts did not differ relevantly between 100% or 50% acquisition time (CZT).
This underlines that the appropriateness of SC remains the most relevant factor in determining the accuracy in quantification of [123I]mIBG SPECT/CT data and that SC optimization should be prioritized. The current approach and results could serve as a blueprint for a convenient clinical workflow towards quantitative [123I]mIBG SPECT/CT data. Volume sensitivity for the in-house acquisition protocol can be obtained with a homogenously filled cylindrical phantom. Body contour acquisition is recommended for optimized CDR.
In the light of these results, MTV*SUVmax of NB lesions in patients with serial examinations were examined as a measure of lesional metabolic tumor load. It was hypothesized that this could be a surrogate for response to therapy, and correlation of changes in MRI volume with MTV*SUVmax changes was moderate for non-SC and SC data. The prognostic value of [123I]mIBG scintigraphy in NB beyond definition of the tumor stage is currently limited to visual scores of whole-body lesion counts in planar scintigraphy (Curie score and SIOPEN score) which have shown prognostic value at initial staging and after chemotherapy (40, 41). A quantifiable parameter of lesional metabolic activity could serve as a supplementary prognostic or predictive measure. However, the current explorative analysis on MTV*SUVmax in patient data is only exemplifying. Systematic investigation of the reproducibility and clinical implications of quantitative parameters in NB in a multicenter setting with international cooperative group trials is needed.