1 A prospective study of quantitative SPECT/CT for evaluation of hepatopulmonary shunt fraction prior to SIRT of liver tumors Dittmann Helmut 1 , Kopp D 1 , Kupferschlaeger J 1 , Feil D 1 , Groezinger G 2 , Syha R 2 , Weissinger M 1 , la Fougère Christian 1 1 Department of Nuclear Medicine and Clinical Molecular Imaging, 2 Department of Diagnostic and Interventional Radiology; University of Tuebingen, Germany Corresponding Author: Helmut Dittmann, MD Email: [email protected]Otfried-Mueller –Str. 14 72076 Tuebingen Germany Tel ++49 7071-29 82164 FAX ++49 7071-29 5869 Word count 4979 Running Title SPECT/CT for lung shunt quantification Journal of Nuclear Medicine, published on January 25, 2018 as doi:10.2967/jnumed.117.205203
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1
A prospective study of quantitative SPECT/CT for evaluation of
hepatopulmonary shunt fraction prior to SIRT of liver tumors
The latter formula increases injected activity in order to compensate for loss due to lung
shunting rather than reducing the dose as in case of resin spheres.
The lung irradiation dose resulting from SIRT was then computed considering LSF, liver
target area and optionally the individual lung volume. Lung density measurements were not
available in this study, thus the lung density was assumed to be 0.3 g/cc (21).
Statistics
The Wilcoxon signed-rank test (two-tailed) was used to compare planar- and SPECT/CT-
based LSF employing Excel® software (Microsoft Cooperation, Redmond, WA, USA). An
alpha level of 0.05 was considered significant.
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RESULTS
Phantom study
Using SPECT/CT the calculated MAA-deposition in the lung inserts matched exactly with
the calibrated activity (Table 2). The total lung volume was overestimated by
approximately 10% by the segmentation algorithm. Liver activity concentration was
slightly overestimated while the organ volume was measured precisely. As a result, LSF
could be quantified with only marginal deviation from the true lung radioactivity by
SPECT/CT. In contrast, ROI analysis of planar scans resulted in an LSF overestimation of
approximately 40%.
Patient study
Mean MAA-uptake in the lung compartment was calculated as 1.4%ID by means of
SPECT/CT while liver uptake was computed as almost 78%ID (Table 3). Thus, both organs
together contained only about 80% of the decay-corrected radioactivity. The urinary
bladder showed prominent activity against background in 38/50 patients, equivalent to circa
1%ID. The kidneys pelvis did not contain noticeable radioactivity in the majority of
patients. Focal uptake due to shunts in gastrointestinal regions was observed in 3 patients
(small bowel n=2 [1.6 and 2.1%ID], large bowel n=1 [9.1%ID]). Apart from the latter
cases, no pronounced uptake was detected in organs other than liver and lung. Strikingly,
13%ID was present in the thoracic and abdominal body remainder. Consequently about
10% of radioactivity was missing in the SPECT/CT area most probably due to diffuse
distribution in the residual whole body.
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To analyze the congruence of CT and SPECT data we compared total lung volume as
measured on CT alone to the residual lung volume after subtraction of liver tissue
radioactivity within the lung VOI on the fused SPECT/CT images. In the majority of
patients, there was only a minor difference between volume estimates (mean total lung
volume 3.29 l vs. liver subtracted lung volume 3.21 l) indicating a good match of breath
hold during CT with flat breathing during SPECT (R2: 0.97); (Fig.1). Only in 6/50 patients,
total lung volume exceeded the liver activity-corrected measure by more than 5% (range:
5.1 to 21.1%).
Based on planar MAA scans, LSF was calculated at a median of 6.8% (mean 8.3; range 3.4
to 32.3%), while quantitation of SPECT/CTs yielded only 1.9% (mean 2.9; range 0.8 to
15.7%). Planar-derived estimation of LSF was significantly higher in all 50 individual
patients (p<0.0001), resulting in an average 3.6-times higher LSF when compared to
SPECT/CT-based LSF estimation (Fig. 2). Overall, there was a strong correlation (R2:
0.83) of LSF calculated with both approaches (Fig. 3). However the individual difference
between the two estimates was variable, especially in patients exhibiting low lung shunts.
Using planar imaging data, the LSF was calculated to be 10% or more in 10/50 cases
(Table 4; Fig. 2). In particular, two individuals showed a LSF in excess of 20% suggesting
contraindication against SIRT. In contrast, SPECT/CT quantitation resulted in substantial
shunting only in the latter two patients (15.7 and 13.5%; for imaging results see also Fig. 4)
while LSF remained below 10% in all other cases. As a consequence, dose reduction or
contraindication against radioembolization had to be considered in 20% of our patients as
based on planar imaging-derived LSF vs. less than 5% of cases as based on SPECT/CT.
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Lung dose calculation
(Table 4) displays various lung dose estimates in patients with LSF of 10% or more on
planar imaging. Evidently, the computed lung dose was influenced by the liver target
volume with lower doses in patients planned for lobar vs. whole liver treatment. Relatively
high lung doses were calculated in patients scheduled for glass microsphere treatment. In
particular, Pat-No. 18 would have to be expected to receive more than 50 Gy to the lungs or
at least 20 Gy as based on SPECT/CT. Notably, consideration of the CT-derived individual
lung volume resulted in a 20-45% increase in lung dose in 4 patients with comparatively
low lung volume.
SIRT
Based on the results of MAA-SPECT/CT dosimetry, SIRT was performed in 39/50 patients
within 2 weeks. Individual reasons for not performing SIRT were: non-correctable
gastrointestinal shunt (n= 4 patients, 3 detected at MAA-scan, 1 newly evolved at re-
angiography), insufficient tumor targeting on MAA-SPECT/CT (n=3), newly evolved
extrahepatic disease detected on CT (n= 2) or critically worsened liver function in the
interval between simulation and planned SIRT (n=2). No patient was excluded due to lung
shunting. In particular, both individuals with LSF exceeding 20% on planar scans (Pat-No
18 & 19 in Table 4) received SIRT. Pat-No 18 only had disease in the left liver and was
planned for lobar treatment with glass microspheres. In this case we chose to slightly
reduce the liver target dose to 100 Gy. The other individual received full-dose SIRT of the
entire liver using a two-step approach with 6 weeks interval between treatment of right and
left lobe. Mean follow up after SIRT for all patients was 7.2 months (range 3 – 18) without
any signs of pulmonary damage.
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DISCUSSION
The quantification algorithm used in the current study enabled reliable determination of
LSF from MAA-SPECT/CT while planar imaging led to a considerable overestimation.
Using an anthropomorphic torso phantom we demonstrated that liver and lung radioactivity
deposition could be accurately quantified by SPECT/CT.
Our clinical evaluation revealed lower LSF estimates based on SPECT/CT in all patients
included. Remarkably, the inconsistency between planar and SPECT/CT-derived LSF was
greatest in cases with low LSF. This might be explained by the higher relative contribution
of liver activity near to the basal lung area on planar imaging.
Overestimation of LSF was especially relevant for a subgroup of 10 patients for whom
planar scan analysis indicated dose reduction or even contraindication against SIRT
following current guidelines (4). As based on SPECT/CT, only two of these patients
showed a LSF for which dose modification had to be considered.
These results are in accordance with earlier studies (17,18,20) highlighting overestimation
of LSF due to lower attenuation of lung parenchyma on planar imaging. However, another
retrospective study (19) reported agreement with SPECT/CT-derived LSF in some cases.
Aiming to avoid spillover of liver radioactivity into the lung area, previous investigators
have either excluded the basal lung (19) or used only the left lung lobe (18) for
quantification. The resulting underestimation of lung radioactivity was then compensated
for by correcting for the total lung volume as measured by CT. The drawback of these
approaches is that they will depend on homogenous perfusion throughout the lung
parenchyma, a requirement that is not necessarily fulfilled (5) since the basal and central
lung areas are subject to comparatively higher-level perfusion (22). In our study, we chose
to delineate the liver area using its intensive MAA-uptake before definition of all lung
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parenchyma outside the liver area using CT HU-density. In addition, we aimed to acquire
the CT-images in a way that would allow for attenuation correction of the selective basal
lung/liver dome area asking patients to stop breathing at baseline level during CT and to
breathe flat during SPECT. These measures were communicated meticulously to patients
before SPECT/CT and usually well tolerated. Since comparison of lung volumes with or
without subtraction of liver activity showed no relevant misplacement of the liver into the
lung area in most patients, we conclude that this method allowed for an acceptable match of
SPECT and CT. However, we are aware of the fact that an exact definition of the liver area
from emission data would depend on respiratory gated SPECT acquisition.
In addition to LSF, the lung irradiation dose will be influenced by the individual lung mass.
Common methodology utilizes a standard lung mass of 1000 grams thus neglecting
individual variations of lung volume and density (4,5). Conversely, it is well recognized
that lung volume varies considerably between individuals while density is relatively
constant in healthy lungs (23). Similar results have been demonstrated by Kao and
coworkers (19) who used diagnostic CT to estimate lung volume and density for a
dedicated lung dosimetry. Thus sufficient assessment of the lung irradiation dose should
comprise LSF and individual lung volume, ideally completed by CT densitometry.
Currently, only about 80% of the expected radioactivity was located in liver and lungs
while a considerable amount was present in the body remainder. Possible reasons for this
finding are gastrointestinal shunts, right-to-left shunting or disintegration of the radiotracer.
Gastrointestinal uptake was in fact observed in 3 patients though only accounting for a
minor part of extrahepatopulmonary radioactivity. In case of circulation collateral to the
lungs, renal parenchyma uptake will be expected (24). Since no kidney uptake was seen in
any of our patients we conclude that activity in the body remainder was predominantly due
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to MAA disintegration. This finding emphasizes the need for perchlorate blockade to
prevent stomach uptake which might be misinterpreted as gastral shunting (25).
It has been shown that MAA is instable in vivo leading to an increase of LSF with longer
interval between injections and imaging (26). A recent study with planar imaging (27)
demonstrated that human serum albumin (HSA) instead of MAA represents a more stable
radiotracer for SIRT simulation. Our study confirmed significant radioactivity that is not
retained in the liver/lung compartment as early as 1 h from MAA injection. Naturally, an
even earlier imaging might have reduced the disintegrated MAA-fraction; however this was
not practicable due to transfer of patients from the angiography unit. Since planar
methodology involves ROI analysis of summed counts originating from the lungs and liver
as well as from overlaying tissue in the thoracic and abdominal wall, MAA fragments in
the background might have added to LSF.
Investigators have shown that LSF can be reduced by pretreatment with antiangiogenic
agents such as sorafenib (28) and bevacizumab (29) or by interventional techniques (30).
Above that, there is a growing body of evidence showing that LSF is an independent
prognostic factor for patients with liver tumors (31,32). Improved quantification by
SPECT/CT will be helpful in analyzing the effects of pretreatment and exploring the
prognostic potential of LSF in patients treated with SIRT.
Our clinical study has some limitations. There was no external gold standard to define LSF
independent of MAA distribution. A recent study (33) compared MAA to the novel
radioembolization agent Ho-166-microspheres showing considerable pulmonary uptake of
MAA but not Ho-166 in some patients. The authors concluded that MAA due to its
considerable content of small diameter particles (less than 20 µm) might be more prone to
arteriovenous shunting than the therapeutic microspheres, thus exaggerating LSF.
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Due to the low incidence of excessive lung shunting, only a small number of patients with
high LSF could be included into our study. There was no evidence of irradiation damage to
the lungs but the follow up interval was limited. Thus, late pulmonary toxicities could not
be excluded. Hence the safety of SIRT in patients with high LSF on MAA-SPECT/CT has
to be considered preliminary. The tolerable lung dose will have to be further evaluated.
CONCLUSIONS
SPECT/CT enables quantification of LSF from MAA scans in patients prior to SIRT. Since
SPECT/CT-based LSF is significantly lower than that derived from planar scans, the
resulting dose to the lung parenchyma may be less than conventionally assumed. However,
the safety of the SPECT/CT-based dose range will have to be evaluated. Our study
highlights considerable in vivo instability of MAA even if imaging is performed within 1 h
after injection.
FINANCIAL DISCLOSURE
This study was in part funded by a grant from GE Healthcare (SPECT/CT research grant
received by author CLF). No other potential conflict of interest relevant to this article was
reported.
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FIGURE 1: The relationship between total lung volume and lung volume after subtraction of
liver tissue activity spilling into the lung region during SPECT acquisition.
y = 0.917x + 0.19R² = 0.97
0
2
4
6
8
0 2 4 6 8
Tota
l lu
ng
vo
lum
e (L
)
Lung volume w/o liver spillover (L)
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FIGURE 2: A comparison of LSF as calculated from planar scans and SPECT/CT in 50 patients.
Data are presented in incremental order of planar scan derived LSF.
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FIGURE 3: The Correlation of LSF derived from SPECT/CT with that from planar scan.
y = 0.513x - 1.29R² = 0.83
0
5
10
15
20
0 10 20 30 40
LS
F (
%)
fro
m S
PE
CT
/CT
LSF (%) from planar scan
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FIGURE 4: A case with high LSF (Pat. No. 19, see table 4). LSF was estimated at 26.5% using
planar scans and at 15.7% in SPECT/CT, respectively.
Top: Planar MAA-Scans in anterior (A) and posterior (B) projections.
Low: Left image (C) shows a central coronal CT slice with delineated lung and liver areas.
Middle images represent transaxial CT (D) with liver and basal lung area and the corresponding
MAA-SPECT (E). The right figure (F) displays VOIs for lung and liver.
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all male female
Patients (n) 50 31 19
BMI (mean, range) 26 27, 20-64 24, 19-33
Age (mean, range) 66 65, 44-80 67, 39-81
Histology (n)
HCC 15 10 5
CRC 13 8 5
CCC 11 6 5
Ocular melanoma 4 3 1
Pankreatic cancer 3 2 1
Cervical Cancer 1 1
Squamous cell Carcinoma 1 1
NET midgut 1 1
Breast cancer 1 1
TABLE 1: Patient characteristics.
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compartment, parameter
dimension true value
measured value
deviation true volume
segmented volume
left lung MBq 8.7 8.7 ± 0.8 0% 900 ml 1010 ml
right lung MBq 11.1 10.9 ± 0.6 - 1.8% 1100 ml 1230 ml
liver kBq/ml 116 123 ± 31 + 6% 1160 ml 1120 ml
LSF (planar scan) % 11.5 15.9 + 38%
LSF (SPECT/CT) % 11.5 12.1 + 5%
TABLE 2: The results of SPECT/CT quantification using the antropomorphic phantom.
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compartment median %ID mean %ID SD
lung 2.5 1.4 3.0
liver 78 77.6 10.4
urinary bladder 1 0.9 0.9
body remainder 13.4 12.2 6.7
TABLE 3: The amount of radioactivity in lung, liver, urinary bladder and thoracic-abdominal
body remainder in patients as measured by MAA SPECT/CT.