Quantitative 166Ho-microspheres SPECT derived from a dual-isotope acquisition with 99mTc-colloid is clinically feasible

doi:10.21203/rs.3.rs-20717/v2

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Original research

Quantitative ¹⁶⁶Ho-microspheres SPECT derived from a dual-isotope acquisition with ^99mTc-colloid is clinically feasible

https://doi.org/10.21203/rs.3.rs-20717/v2

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Journal Publication

published 14 Jul, 2020

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Purpose: Accurate dosimetry is essential in radioembolization. To this purpose, an automatic protocol for healthy liver dosimetry based on dual isotope (DI) SPECT imaging, combining holmium-166 (¹⁶⁶Ho)-microspheres and technetium-99m (^99mTc)-colloid, was developed: ¹⁶⁶Ho-microspheres used as scout and therapeutic particles and ^99mTc-colloid to identify the healthy liver. DI SPECT allows for an automatic and accurate estimation of absorbed doses, introducing true personalized dosimetry. However, photon crosstalk between isotopes can compromise image quality. This study investigates the effect of ^99mTc downscatter on ¹⁶⁶Ho dosimetry, by comparing ¹⁶⁶Ho-SPECT reconstructions of patient scans acquired before (¹⁶⁶Ho-only) and after additional administration of ^99mTc-colloid (¹⁶⁶Ho-DI).

Methods: The ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI scans were performed in short succession by injecting ^99mTc-colloid on the scanner table. To compensate for ^99mTc downscatter, its influence was accounted for in the DI image reconstruction using energy window-based scatter correction methods. The qualitative assessment was performed by independent blinded comparison by two nuclear medicine physicians assessing 65 pairs of SPECT/CT. Inter-observer agreement was tested by Cohen's kappa coefficient. For the quantitative analysis, two volumes of interest within the liver, VOI_TUMOR and VOI_HEALTHY, were manually delineated on the ¹⁶⁶Ho-only reconstruction and transferred to the co-registered ¹⁶⁶Ho-DI reconstruction. Absorbed dose within the resulting VOIs, and in the lungs (VOI_LUNGS), was calculated based on the administered therapeutic activity.

Results: The qualitative assessment showed no distinct clinical preference for either ¹⁶⁶Ho-only or ¹⁶⁶Ho-DI SPECT (kappa=0.093). Quantitative analysis indicated that the mean absorbed dose difference between ¹⁶⁶Ho-DI and ¹⁶⁶Ho-only was -2.00±2.84 Gy (median 27 Gy; p-value<0.00001), -5.27±8.99 Gy (median 116 Gy; p-value =0.00035) and 0.80±1.08 Gy (median 3 Gy; p-value<0.00001) for VOI_HEALTHY,VOI_TUMORand VOI_LUNGSrespectively. The corresponding Pearson’s correlation coefficient between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI for absorbed dose was 0.97, 0.99 and 0.82, respectively.

Biophysics

Radioembolization – Holmium-166 – SPECT/CT – Dual Isotope – Technetium – Scatter Correction

Over the past decade, the number of radioembolization procedures in the treatment of liver-only or liver-dominant hepatic malignancy has rapidly increased [1]. Radioembolization is a catheter-based therapy that delivers internal radiation to tumors. Currently, three devices are commercially available: SIR-Spheres® (SIRTeX Medical Ltd.) and TheraSphere® (BTG Ltd. / Boston Scientific), both loaded with yttrium-90 (⁹⁰Y), and QuiremSpheres® (Quirem Medical B.V.), loaded with holmium-166 (¹⁶⁶Ho). Radioembolization requires a comprehensive initial safety evaluation (identifying potential non-target tissue irradiation) and assessment of intrahepatic microsphere distribution for dosimetric evaluation. Pre-treatment image-based dosimetry enables radioembolization optimization, because it allows assessment of the biodistribution of microspheres in the liver, which is often heterogeneous and clustered. Because absorbed dose and treatment outcome (toxicity and efficacy) are correlated, dosimetry should ultimately lead to improved patient selection and individualized treatment planning [2]. For this reason, prior to treatment, either ^99mTc-MAA or a ¹⁶⁶Ho-scout dose (QuiremScout®, Quirem Medical B.V.) is administered to simulate the actual treatment. ¹⁶⁶Ho-microspheres may be preferred as simulation particles (i.e. scout dose), because they are identical to the treatment particles, which makes them superior in the prediction of the treatment dose distribution [3], [4]. Additionally, ¹⁶⁶Ho allows for quantitative SPECT analysis and consequently dosimetric assessment [5].

For personalized treatment planning, several dosimetric thresholds need to be determined: 1) the minimum required tumor radiation absorbed dose to obtain an adequate tumor response, 2) an acceptable healthy liver tissue absorbed dose to limit post-treatment toxicities and 3) the maximum tolerable lung shunt dose to prevent radiation pneumonitis. Obtaining these dosimetric values requires delineation of the liver, tumors and lungs using anatomical images such MRI and CT. Accurate tumor and healthy liver delineation (segmentation) and image co-registration are challenging. Segmentation is usually done manually, which is time-consuming and user dependent. Registration between anatomical images (MRI or contrast-enhanced CT), acquired hours to weeks prior to the treatment, and the functional image (SPECT) following the scout procedure is challenging due to interval deformations of the liver. Therefore, a dual-isotope SPECT/CT protocol was developed to improve dosimetry [6], having the potential to allow for the automatic delineation of tumor and healthy liver, and obviating the need for co-registration. To this end, a ¹⁶⁶Ho-scout dose for treatment simulation is followed by intravenously injected colloid (^99mTc-stanneous phytate, PHYTACIS^® by Curium Pharma, Petten, The Netherlands). The colloid accumulates in Kupffer cells, present in healthy liver tissue and absent in tumorous tissue [7]. It allows for automatic normal liver tissue segmentation by thresholding the ^99mTc image. This dual-isotope protocol enables the automatic estimation of the healthy tissue absorbed dose, which is considered to be the major dose-limiting factor. It facilitates performing dosimetry in every patient, which may lead to an improved and more personalized prescribed activity, avoiding over-dosing or, even more frequently, under-dosing the target, sacrificing efficacy for safety [8]. Dual isotope (DI) SPECT however comes with the technical challenge of correcting for the cross-talk between the two isotopes: scatter from ^99mTc contaminating the main ¹⁶⁶Ho energy window and vice versa.

In previous work, van Rooij et al. [9]demonstrated the technical feasibility of quantitative ¹⁶⁶Ho SPECT reconstructions in the presence of ^99mTc in a phantom study. These reconstructions were obtained using in-house developed Monte Carlo SPECT reconstruction software (UMCS). However, a systematic comparison between ¹⁶⁶Ho-DI SPECT and ¹⁶⁶Ho-only SPECT using patient data reconstructed using a commercially available software is required to consider this DI concept for clinical practice. For this reason, a qualitative and quantitative comparison between ¹⁶⁶Ho-only acquisitions and ¹⁶⁶Ho acquisitions in presence of ^99mTc was investigated.

Study population

For all SPECT/CT acquisitions used in this study, informed consent was obtained as part of the HEPAR PLuS study [10]. Thirty-one patients with liver metastases of neuroendocrine tumors were analyzed, 29 scout (pre-treatment) procedures (average administered activity 208 ± 52 MBq) and 36 therapeutic treatments (average administered activity 5757 ± 2716 MBq). Baseline characteristics of these patients are presented in Tab.1. Two subjects were excluded because of the impossibility of segmenting the minimum desired volumes of interest (25 ml) in compliance with the defined resolution requirements for a proper absorbed dose estimate using SPECT. This constrain was introduced in order to limit the errors related to registration and dosimetry quantification accuracy, affected by small volume definition. According to the mentioned study protocol, for each of the 65 procedures considered, two SPECT/CT images were acquired after the activity injection, a ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI SPECT. According to the image acquisition protocol, all scans were performed when the total activity at the scanning time was approximately 250 MBq, enabling a comparison between pre and post-treatment images.

Image acquisition

All patients were scanned on a Symbia T16 dual head SPECT/CT scanner (Siemens, Erlangen, Germany), using a medium-energy low-penetration collimator, on a 128 × 128 matrix (pixel spacing, 4.8 × 4.8 mm), with 120 angles (15 s per projection) over a non-circular 360° orbit. An energy window centered at the 81 keV photopeak with a width of 15% was used for both ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI acquisitions (see Fig.1). An additional energy window centered at 118 keV (12% width) was used to correct the ¹⁶⁶Ho photopeak data for downscatter using a window-based scatter correction [11]. ^99mTc was imaged using a 140 keV, 15% wide, energy window, with an upper scatter window at 170 keV (12% width) to correct for ¹⁶⁶Ho downscatter. The first SPECT/CT was acquired after the intra-arterial injection of ¹⁶⁶Ho-microspheres (¹⁶⁶Ho-only SPECT), while the second SPECT/CT was acquired 10 minutes after additional 50 MBq ^99mTc-stannous phytate injection (¹⁶⁶Ho-DI SPECT). To minimize patient motion, ^99mTc-stannous phytate was administered while the patient remained on the SPECT/CT table in supine position. The optimal ¹⁶⁶Ho - ^99mTc ratio, yielding a high accuracy in DI reconstruction, was previously empirically determined by van Rooij et al. [9] in our institution, based on phantom data, and the resulting 5:1 ¹⁶⁶Ho - ^99mTc activity ratio was adopted for this study.

SPECT reconstruction

SPECT images were reconstructed using a 3D OSEM algorithm (Flash 3D; Siemens) with 10 iterations, 8 subsets, incorporating attenuation correction. To correct for scatter during the reconstruction of the ¹⁶⁶Ho activity distribution, downscatter in the 81 keV photopeak window due to higher energy emissions of both ¹⁶⁶Ho and ^99mTc was estimated from the 118 keV energy window by applying a single combined k-factor of 1.15 (see Supplemental material for details). Photopeak scatter, i.e., scattered photons originating from the 81 keV primary photopeak, was not accounted for.

Qualitative Analysis

For the qualitative assessment, 65 pairs of SPECT/CT reconstructions (¹⁶⁶Ho-only and DI) were considered, divided into 29 scout dose SPECTs and 36 post-treatment SPECTs, a Gaussian filter with σ = 4.2 mm was applied to reduce the noise. Two nuclear medicine physicians (M.L. and A.B., >5 years’ experience) were randomly and blindly presented each pair of acquisitions (an example is depicted in Fig.2). Then they were independently asked to express clinical preference for either ¹⁶⁶Ho-only or DI and whether both acquisitions could be considered clinically acceptable for diagnostic purpose or not.

Quantitative Analysis

To allow for a comparison between pre- and post-treatment data, all SPECT images were scaled to units of Bq/ml, in such a way that for each image the total activity matched the administered treatment activity, based on the assumption that the entire activity was present in the reconstructed field-of-view. Under the general assumption that microspheres remain lodged long enough for their entire activity to decay, the absorbed radiation dose in a VOI can be calculated as:

See formula 1 in the supplementary files.

where 15.87 mJ/MBq represents the deposited energy due to the β decay of 1 MBq initial ¹⁶⁶Ho activity. For the liver, a soft tissue density of 1.06 g/cm³was applied [12], while the lung density value was set to 0.3 g/cm³[13], assuming, for both organs, a homogenous organ density value, constant among patients. Since the mean penetration of the β emission of ¹⁶⁶Ho (2.5 mm) is small compared to the voxel size (4.8 mm), all energy was assumed to be absorbed within the considered voxel [4]. The β radiation accounts for 96% of the emitted energy (=15.87 mJ/MBq), the other 4% of the energy is for the most part emitted through γ radiation. Because of the relatively large penetration distance of these γ and the inverse square law, the absorbed radiation dose due to γ emissions was ignored in this study.

For the assessment of the mean absorbed dose in the liver, all of the ¹⁶⁶Ho-DI SPECT/CT images were co-registered with the corresponding ¹⁶⁶Ho-only SPECT/CT images to compensate for possible patient movement during the time lag between the two acquisitions (10 minutes to account for ^99mTc-stannous phytate injection and distribution). Since the patient remained on the table, a rigid registration was performed. The registration was carried out with Elastix [14], based on the SPECT related LDCT (primarily used to compute the attenuation correction map), using an adaptive stochastic gradient descendent approach as optimizer and a mutual information metric. Subsequently, two volumes of interest (VOIs) for each pair of acquisitions were manually defined on the ¹⁶⁶Ho-only SPECT/CT: VOI_HEALTHY(3D ellipsoidal shape within the healthy liver), and VOI_TUMOR(one manually segmented tumor among the multiple tumors present), as depicted in Fig.3 (b). For both VOI_HEALTHY and VOI_TUMOR, it has been decided to constrain the minimum volume to 25 ml, to ensure a reliable activity recovery. These VOIs were applied to the co-registered ¹⁶⁶Ho-DI SPECT to compute the mean absorbed dose within these VOIs for comparison.

To estimate the mean lung shunt dose, the lungs were semi-automatically delineated on both the corresponding ¹⁶⁶Ho-only CT and ¹⁶⁶Ho-DI CT images with Q-suite^™ software (Quirem Medical B.V.). Before the lung masks were applied to the SPECT reconstructions for the absorbed dose computation, the delineations were shrunk by 2 cm to avoid any partial volume effect close to the edges and to minimize the influence of scatter from activity in the liver.

The mean absorbed dose, expressed in gray [Gy], was chosen as the metric for comparison since it was deemed the most clinically relevant parameter. The dose difference between ¹⁶⁶Ho-DI and ¹⁶⁶Ho-only was reported, since it was considered more relevant from a clinical point of view than a relative measurement (e.g. percentage difference).

Statistical analyses

In each comparative analysis, the ¹⁶⁶Ho-only SPECT/CT images were considered as reference standard. Inter-observers’ agreement was measured by means of Cohen's kappa statistic () [15], for the qualitative assessment. For this analysis it was assumed that ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI SPECT/CT data were paired, as both scans were acquired within a short time interval (<10 minutes), with patient and bed table in the same position. Pre and post-treatment results were also independently reported for completeness of the data presented. To compare the absorbed dose in the VOIs between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI, after a visual assessment for data normality, Bland Altman analyses were performed. For each plot, the mean absorbed dose difference between ¹⁶⁶Ho-DI and ¹⁶⁶Ho-only, expressed in Gy, and limits of agreements (LoA), [Gy], were reported. LoA are computed as mean ± coefficient of reproducibility (CRP), equal to 1.96*standard deviation. The linear correlation between absorbed dose in ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI was expressed in terms of the Pearson correlation coefficient . In addition, two-sided paired T-test (at α = 0.05) was performed to check the statistical difference between mean absorbed dose based on ¹⁶⁶Ho-only and on ¹⁶⁶Ho-DI SPECT (null hypothesis is no difference between mean absorbed dose values computed on ¹⁶⁶Ho-only and on ¹⁶⁶Ho-DI SPECT).

Qualitative Analysis

According to the qualitative assessment carried out by two expert nuclear medicine physicians, all ¹⁶⁶Ho-SPECT reconstructions were considered reliable for a diagnostic purpose. Based on their preference for either ¹⁶⁶Ho-only or ¹⁶⁶Ho-DI, their inter observer agreement (Cohen’s kappa coefficient) was equal to 0.09 (= -0.63 and = 0.14 for pre-treatment and post-treatment data respectively). The Cohen’s value, close to 0, shows the lack of agreement on a favorite imaging option (¹⁶⁶Ho-only or ¹⁶⁶Ho-DI). Moreover, both were considered suitable for diagnostic use. Therefore, no distinct preference for either one of the reconstructions for use in clinical practice could be concluded.

Quantitative analysis

The constraint in volume for the VOIs (≥ 25 ml), led to the exclusion of 21 procedures for the VOI_TUMOR, and of 7 procedures for the VOI_HEALTHY, since they did not satisfy this requirement. The lower limit for the VOI volume was introduced to ensure an adequate dose recovery. The included dataset is reported in Tab.2.

The results, for each of the three VOIs, for both the dataset considered entirely and split among pre- and post-treatment data, are reported in Tab.3

Bland Altman plots for VOI_HEALTHY, VOI_TUMORand VOI_LUNGS are shown in Fig.4 (a), (b) and (c), respectively.
The mean absorbed dose difference between ¹⁶⁶Ho-DI and ¹⁶⁶Ho-only was negative for the VOIs within the liver, while it was slightly positive for VOI_LUNGS. CRP was equal to 5.56 Gy for VOI_HEALTHY, 17.62 Gy for VOI_TUMOR and 2.12 Gy for VOI_LUNGS.

The linear correlation between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DIHo-DI, assessed using Pearson’s correlation coefficient (depicted in Fig.4 (d-e-f), was equal to 0.99 for VOI_TUMOR(for both pre- and post-treatment data)_, 0.97 for VOI_HEALTHY (r=0.96 for pre- and r=0.98 for post-treatment data) and 0.82 for VOI_LUNGS (r=0.72 for pre- and r=0.89 for post-treatment data).

T-test p-values results are <0.00001, 0.00035 and <0.00001 for VOI_HEALTHY, VOI_TUMOR and VOI_LUNGSrespectively.

In this study, the qualitative and quantitative accuracy of a ¹⁶⁶Ho reconstruction derived from a DI acquisition was investigated. The inter-observer agreement (κ = 0.093) indicated no specific preference for either the ¹⁶⁶Ho-only or DI acquisition in the qualitative analysis. The quantitative analysis demonstrated a good correlation between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI with a Pearson’s correlation coefficient > 0.95 for both VOI_HEALTHY and VOI_TUMOR and 0.82 for VOI_LUNGS. The difference between mean absorbed dose between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI SPECT was statistically significant for all VOIs (p-value < 0.0005), however the mean difference was considered clinically not relevant. The limits of agreement for the difference between ¹⁶⁶Ho-DI and ¹⁶⁶Ho-only were deemed acceptable by experienced nuclear medicine physicians. Because assessments of dose to the tumor, healthy liver and lungs serve a different purpose clinically, physicians defined different acceptable limits of agreement for each category prior to this study. A mean difference of 2 Gy with a limit of agreement of ±5 Gy was considered adequate for healthy liver assessment (median absorbed dose for ¹⁶⁶Ho-only VOI_HEALTHY: 27 ± 7.08 Gy), being the dose-limiting factor for radioembolization treatments. A less restrictive value may be applied for the absorbed dose in the tumor because the clinical range for efficacy is variable and not well defined (median absorbed dose for ¹⁶⁶Ho-only VOI_TUMOR: 116 ± 44.91 Gy). With respect to the lungs, according to ¹⁶⁶Ho-miscrospheres instructions for use [16], a predicted average lung absorbed dose > 30 Gy is a contraindication for the radioembolization treatment. In this study, the clinical acceptable deviation from the difference between ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI was defined at approximately 3 Gy. This overestimation prevents underestimation of the lung absorbed dose (median absorbed dose for ¹⁶⁶Ho-only VOI_LUNGS: 3 ± 0.99 Gy). For all VOIs, 95% of the data was well within the corresponding clinically acceptable limits of agreement

Even though rarely encountered (<1%) [17], radiation pneumonitis is a serious complication that can occur when microspheres inadvertently shunt to the lung parenchyma. So far, lung shunt fraction (LSF) has been the most used metric in clinical routine to determine the activity that shunts to the lungs. Counts in liver and lungs are determined on planar scintigraphy. Despite that the inadequacy of this approach has been demonstrated in multiple studies [18], it is still used in clinical practice. Within the scope of this study, to estimate the difference in the mean absorbed dose between ¹⁶⁶Ho-DI and on ¹⁶⁶Ho-only in the VOI_LUNGS, the lungs were delineated on the corresponding attenuation correction LDCT. However, the lungs were not always entirely visible within the field of view of the SPECT. This drawback is negligible in case the lung perfusion is homogeneous, but this assumption is not always correct [19][20]. In addition, the very low values of mean absorbed dose in VOI_LUNGS, were more affected by this drawback. This explains the lower Pearson correlation coefficient (0.82) and the higher number of outliers.

The use of the proposed DI protocol has potential benefits, amongst which the possibility to (semi) automatically identify and delineate tumor and healthy tissue within a single SPECT/CT acquisition. Additionally, simultaneous acquisition of both isotopes avoids the registration difficulties, both being time consuming and prone to additional errors in dosimetry.

SPECT images showing either ^99mTc distribution or ¹⁶⁶Ho accumulationHo accumulation H can be processed to obtain an automatic delineation of the regions of interest. Healthy liver might be delineated on the ^99mTc reconstruction while tumor lesions presenting focused ¹⁶⁶Ho uptake can be delineated on the ¹⁶⁶Ho image.HH The definition of these two compartments is a requirement for the use of the partition model [21]. This method allows the determination of a selective prescribed activity aiming at maximization of the absorbed dose to the tumor tissue, while restricting radiation absorbed dose to the healthy tissue.

Some limitations apply to this study. All images were acquired with the same SPECT/CT scanner, which restricts the used k-factor to this imaging setup. Nonetheless, it is possible to extend this study to other scanners (see Supplemental material). Further more, the liver VOIs were manually segmented to ensure an adequate volume definition, similar among all datasets (as can be seen in Tab.2), and to avoid the introduction of errors due to thresholding of the ^99mTc images. Because of the need to apply the same VOIs to both ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI for tumor and healthy liver, a co-registration process was involved. This can lead to small misalignments, which may have impacted on the mean absorbed dose difference. In addition, tumors with a volume smaller than the 25 ml considered for this study could be more affected by registration related error and partial volume effect which will further hamper the tumor dosimetry quantification.

To cope with the mentioned limitations, some future steps can be taken. A phantom experiment could help to determine the accuracy with which it is possible to recover the absorbed dose at different activity concentration, both with and without the presence of ^99mTc-colloid. To compensate for the lungs region just partially covered by the SPECT field of view, it could be possible to implement a two-bed position protocol to cover both the liver and the abdominal region. An assessment of ^99mTc crosstalk impact on ¹⁶⁶Ho acquisitions stratified by volume of interest dimensions, could provide a better insight in the possibility to perform 166Ho-DI acquisition without being hampered by an increase effect of partial volume effect due to the presence of an additional isotope.

The possibility to skip the ¹⁶⁶Ho-only SPECT/CT acquisition has a beneficial effect on patients, decreasing the discomfort related to an imaging procedure that takes half an hour. Further analysis is required to implement a clinical workflow to automatically process information derived from the DI protocol and obtain personalized planning for radioembolization.

Based on a qualitative, as well as a quantitative analysis on patient data, a ¹⁶⁶Ho-DI SPECT can be safely used instead of a ¹⁶⁶Ho-only acquisition. The differences between the ¹⁶⁶Ho-only and ¹⁶⁶Ho-DI protocol reconstructions were considered to be clinically acceptable and thus the dual isotope protocol can be adopted in clinical practice.

Funding

This research project received funding by the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek), under grant R4873.

Conflicts of interest/Competing interests

MGEHL has acted as a consultant for BTG and Terumo. AJATB has acted as speaker for BTG, Sirtex Medical and Terumo. The University Medical Center Utrecht (UMC Utrecht) receives royalties from Quirem Medical, producer of ¹⁶⁶Ho-microspheres, and receives research support from BTG, Terumo and Quirem Medical.

MS, RvR, and HWAMdJ declare no relationships with any companies whose products or services may be related to the subject matter of the article.

Ethics approval

The HEPAR PLuS study was approved by the Medical Ethics Committee of the University Medical Center Utrecht in 2014.

Consent to participate

Patients consent the use of their personal data for research purposes.

Consent for publication

Informed consent from the presented patient was obtained, as part of the HEPAR PLuS study

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The code used and during the current study is available from the corresponding author on reasonable request.

Authors' contribution

RvR and AJATB contributed to the design of the study. AJATB and MGEHL collected the data. MS, RvR and AJATB analyzed the data and wrote the manuscript draft. HWAMJ and MGEHL were major contributors to the manuscript. All authors read, critically reviewed, and approved the final manuscript.

¹⁶⁶Ho: Holmium-166;
^99mTc: Technetium-99m;
CRP: coefficient of reproducibility;
DI: dual-isotope;
HEPAR PLuS: Holmium Embolization Particles for Arterial Radiotherapy Plus ¹⁷⁷Lu-DOTATATE in Salvage NET patients;
LDCT: low dose computed tomography
LoA: limits of agreement;
SPECT: Single photon emission computed tomography;
VOI: Volume of interest

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Tab. 1

Characteristics	N or median
N patient	29
Pre-Treatment Post-Treatment	26 32^‡
Sex
Male Female	21 8
Age (years)^*	63 ± 8
Treatment Type	Pre-Treatment	Post-Treatment
Whole liver Partial liver	21^† 5	15^† 17
^*at first treatment, ^†after right side hemi hepatectomy, ‡ multiple radioembolization treatment based on the same scout procedure

Tab. 2

a)	Pre-Treatment		Post-Treatment


VOI	Number	Volume	Number	Volume
Healthy	26	27.57 ml	32	27.57 ml
Tumor	21	27.50 ml ± 3.91	23	26.27 ml ± 2.23
Lungs	26	2399.30 ml ± 971.77 (¹⁶⁶Ho-Only) 2182.47 ml ± 794.58 (¹⁶⁶Ho-DI)	31	2578.09 ml ± 1026.67 (¹⁶⁶Ho-Only) 2263.47 ml ± 841.22 (¹⁶⁶Ho-DI)

b)	¹⁶⁶Ho-only		¹⁶⁶Ho-DI


VOI	Median	Quartile Deviation (IQR/2)	Median	Quartile Deviation (IQR/2)
Healthy	27.12 Gy	7.08 Gy	26.22 Gy	8.00 Gy
Tumor	116.27 Gy	44.91 Gy	108.96 Gy	46.00 Gy
Lungs	2.99 Gy	0.99 Gy	3.88 Gy	1.07 Gy

Tab. 3

		*VOI _HEALTHY*	*VOI _TUMOR*	*VOI _LUNGS*
All Data	Average ± SD [Gy]	- 2.00 ± 2.84	- 5.27 ± 8.99	0.80 ± 1.08
All Data	Limits of Agreement [Gy]	- 7.56 + 3.56	- 22.89 +12.35	- 1.32 +2.92

Pre-Treatment Data	Average ± SD [Gy]	- 2.69 ± 3.23	- 4.51 ± 8.69	0.86 ± 1.24
Pre-Treatment Data	Limits of Agreement [Gy]	- 9.02 + 3.64	- 21.54 + 12.52	- 1.57 + 3.29

Post-Treatment Data	Average ± SD [Gy]	- 1.44 ± 2.27	- 5.96 ± 9.01	0.74 ± 0.92
Post-Treatment Data	Limits of Agreement [Gy]	- 5.89 + 3.01	- 23.62 + 11.70	- 1.06 + 2.54

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Journal Publication

published 14 Jul, 2020

Read the published version in EJNMMI Physics →

Editorial decision: Accept
02 Jul, 2020
Review #2 received at journal
30 Jun, 2020
Reviewer #2 agreed at journal
25 Jun, 2020
Review #1 received at journal
21 Jun, 2020
Editor assigned by journal
10 Jun, 2020
Reviewers invited by journal
10 Jun, 2020
Reviewer #1 agreed at journal
10 Jun, 2020
Submission checks completed at journal
09 Jun, 2020
Editor invited by journal
09 Jun, 2020

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Quantitative ¹⁶⁶Ho-microspheres SPECT derived from a dual-isotope acquisition with ^99mTc-colloid is clinically feasible

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