European Journal of Radiology 84 (2015) 201–207
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Hepatopulmonary shunting in patients with primary and secondary liver tumors scheduled for radioembolization Maciej Janusz Powerski a,∗ , Christoph Erxleben b,1 , Christian Scheurig-Münkler b,1 , Dominik Geisel b,1 , Uwe Heimann b,1 , Bernd Hamm b,1 , Bernhard Gebauer b,1 a b
Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany Department of Radiology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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Article history: Received 2 August 2014 Received in revised form 23 September 2014 Accepted 6 November 2014 Keywords: Radioembolization Liver tumor Hepatopulmonary shunt
a b s t r a c t Purpose: In patients undergoing transarterial radioembolization (RE) of malignant liver tumors, hepatopulmonary shunts (HPS) can lead to nontarget irradiation of the lungs. This study aims at analyzing the HPS fraction in relation to liver volume, tumor volume, tumor-to-liver volume ratio, tumor vascularity, type of tumor, and portal vein occlusion. Materials and methods: In the presented retrospective study the percentage HPS fraction was calculated from SPECT/CT after infusion of Tc-99m macroaggregated albumin (Tc-99m MAA) into the proper hepatic artery of 233 patients evaluated for RE. Results: HPS fractions correlate very weakly with liver volume (r = 0.303), tumor volume (r = 0.345), and tumor-to-liver volume ratio (r = 0.340). Tumors with strong contrast enhancement (HPSmedian(range) = 11.7%(46.3%); n = 73) have significantly larger shunt fractions than tumors with little enhancement (HPS = 8.3%(16.4%); n = 61; p < 0.001). Colorectal cancer metastases (HPS = 10.6%(28.6%); n = 68) and hepatocellular cancers (HPS = 11.7%(39.4%); n = 63) have significantly larger HPS fractions than metastases from breast cancer (HPS = 7.4%(16.7%); n = 40; p = 0.012 and p = 0.001). Patients with compression (HPS = 13.9%(43.7%); n = 33) or tumor thrombosis (HPS = 15.8% (31.2%); n = 33) of a major portal vein branch have significantly higher degrees of shunting than patients with normal portal vein perfusion (HPS = 8.1% (47.0%); n = 167; both p < 0.001). The shunt fraction is largest in patients with HCC and thrombosis or occlusion of a major portal vein branch (HPS = 16.6% (31.0%); n = 32). Conclusion: The degree of hepatopulmonary shunting depends on the type of liver tumor, tumor vascularity, and portal vein perfusion. There is little to no correlation of HPS with liver volume, tumor volume, or tumor-to-liver volume ratio. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Radioembolization (RE) of liver tumors is performed using yttrium-90-loaded microspheres semiselectively injected through a catheter placed in a hepatic artery. A few weeks to a few days before the radioactive microspheres are injected, a patient scheduled for this procedure needs to have an angiographic evaluation with coil and/or plug embolization of any hepatoenteral and
∗ Corresponding author. Tel.: +49 391 6713030; fax: +49 391 6713029. E-mail addresses: [email protected] (M.J. Powerski), [email protected] (C. Erxleben), [email protected] (C. Scheurig-Münkler), [email protected] (D. Geisel), [email protected] (U. Heimann), [email protected] (B. Hamm), [email protected] (B. Gebauer). 1 Tel.: +49 30 450557002; fax: +49 30 450557901. http://dx.doi.org/10.1016/j.ejrad.2014.11.004 0720-048X/© 2014 Elsevier Ireland Ltd. All rights reserved.
hepatopancreatic branches and determination of the hepatopulmonary shunt (HPS) fraction [1]. Branches not supplying the liver need to be occluded before RE to prevent microsphere migration and complications such as radiation ulcer [2]. The HPS fraction is estimated from a scintigram obtained after administration of technetium-99m macroaggregated albumin (Tc-99m MAA) into hepatic arteries. It is calculated as the pulmonary proportion of the total Tc-99m MAA signals from the lungs and liver. Both manufacturers currently offering RE microspheres – Sirtex Medical (Lane Cove, Australia) and BTG (London, United Kingdom) – consider the HPS fraction calculated from Tc-99m MAA scintigrams to accurately predict pulmonary shunting of their microspheres [3,4]. A higher HPS fraction results in more excessive nontarget irradiation of the lung after RE and increases the risk of inducing radiation pneumonitis, pulmonary fibrosis, and pulmonary hypertension [5,6]. Sirtex Medical considers RE to be contraindicated when pulmonary
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shunting exceeds 20% and recommends to reduce total activity by administering a smaller amount of microspheres in patients with a HPS of 11–20% [3]. When microspheres from BTG are used, the pulmonary fraction is incorporated in the equation for calculating the activity to be applied in a patient. BTG considers RE to be contraindicated when pulmonary shunting results in a calculated lung activity of 610 MBq (approx. 30 Gy single lung dose) [4]. An elevated pulmonary shunt fraction leads to exclusion of approx. 5–14% of patients evaluated for RE [7,8]. The aim of the present study was to investigate various parameters including liver volume, tumor volume, tumor vascularity, tumor entity, and portal vein occlusion (PVO) by compression or thrombosis determined by computed tomography (CT) in terms of their predictive value for pulmonary shunting in 233 patients scheduled for RE. 2. Materials and methods 2.1. Patients The study included all patients who were evaluated for RE and underwent whole-liver angiography in our department between 2009 and 2013. Patients with a history of hemihepatectomy of any kind and Patients with hepatic arterial supply other than Michels’ type I, IX or X were excluded [9]. A total of 233 patients were analyzed. Approval for this retrospective analysis was obtained from the local ethics committee (ref No. EA1-273-12). 2.2. Computed tomography, volumetry, arterial-phase contrast enhancement, and portal vein occlusion All patients underwent three-phase computed tomography (CT) of the liver a few days before angiographic evaluation. Liver CT examinations were performed on a GE VCT 64 scanner (General Electric, Fairfield, Connecticut, USA) after IV injection of 120 ml of contrast medium (Xenetix 350, Guerbet, Villepinte, France). The arterial-phase scan was triggered with a 5 s delay after a threshold of 250 HU was observed at the level of the upper abdominal aorta. The portal venous and venous phases were triggered with delays of 35 s and 75 s, respectively. CT was performed with the following parameters: 0.9 pitch factor, 0.5 s rotation time, 0.6 mm slice thickness, 120 pKV tube voltage, and tube current according to Care dose. Liver and tumor volumes were calculated from venousphase CT scans (5 mm slice thickness) using the BrachyVisionTM , version 10.0, software tool (Varian Medical Systems, Palo Alto, CA, USA). Volumetry was performed by three interventional radiologists with more than 5 years of experience in RE. Classification of liver tumors according to arterial-phase enhancement was done using arterial-phase CT images. All patients were assigned to one of three categories (no or little enhancement, moderate enhancement, and strong enhancement). Two fully trained radiologists with several years of experience in abdominal CT imaging working in consensus assessed enhancement using Visage 7.1 (Visage Imaging GmbH, Berlin, Germany) as PACS system. Portal vein occlusion (PVO) was identified and classified by underlying cause (external compression of major portal vein branch by tumor or intraluminal presence of tumor or thrombus in major branch) using arterial, portal-venous-, and venous-phase CT images. Major portal vein branches were the first-order branches of the portal vein. Two fully trained radiologists with several years of experience in abdominal CT imaging working in consensus performed the assessment using Visage 7.1 as PACS system. 2.3. Angiographic evaluation and SPECT/CT Two to four weeks before radioembolization treatment, candidates were evaluated by angiography, performed on a flat-panel
Table 1 Patient characteristics.
Total Female Male
n [%]
Median [age]
Range [years]
233/100% 110/47.2% 123/52.8%
64 59 66
60 50 60
Volume Liver Tumor
Median [ml] 1943 277
Range [ml] 5761 3650
Ratio
Median
Range
Vtumor /Vliver
0.144
0.733
Tumorentity
n
%
mCRC HCC mBC CCC mPCA mNET mSCA Other Total
68 63 40 15 11 10 5 ≤2 233
29.2 27.0 17.2 6.4 4.7 4.3 2.1 9.1 100
V: volume; mCRC: metastatic colorectal cancer; HCC: hepatic cell carcinoma; mBC: metastatic breast cancer; CCC: cholangio cell carcinoma; mPCA: metastatic pancreatic cancer; mNET: metastatic neuroendocrine tumor; mSCA: metastatic stomach cancer.
angiography system (Allura XPER FD20, Philips, Best, Netherlands), using a transfemoral access. This angiography included coil and/or plug embolization of gastric (e.g., right hepatic artery) and gastroenteral (e.g., gastroduodenal artery) anastomoses and subsequent catheter-based administration of Tc-99m MAA (Draximage® MAA, Jubilant Draximage Inc., Kirkland, Canada) with an activity of 150–175 MBq into the proper hepatic artery. Thereafter, a whole-body SPECT/CT examination (Symbia T6, Siemens, Munich, Germany) was performed. Regions of interest (ROI) were placed in the lungs and the liver, and the HPS fraction was calculated dividing the total lung counts by the sum of the lung and liver counts. 2.4. Statistical analysis Results are presented either descriptively, providing absolute numbers (n) and percentages of the total population (%) or, when nonnormal distribution was assumed, providing parameters of nonparametric statistics (median and range) (Table 1). Correlations presented in Fig. 1 and Table 2 were calculated according to Pearson (r = Pearson product–moment correlation coefficient; r2 = coefficient of determination). The boxplots present medians and first/third quartiles, with the whiskers indicating the minimum and maximum within 1.5-fold interquartile ranges and the circles representing outliers (Tukey boxplot). The null hypotheses (Figs. 3, 4 and 7) were assessed with the Kruskal–Wallis test. When the null hypothesis was rejected (p ≤ 0.05), this was followed by pairwise testing with the Mann–Whitney U-test. The groups in Fig. 3 were additionally analyzed for a trend of increase going from low to high arterial enhancement using the Jonckheere-Terpstra test. In Figs. 5 and 8, the Mann–Whitney U-test was applied directly. Statistically significant differences were assumed for p ≤ 0.05. All data analyses were performed using SPSS 22 (IBM Corporation, NY, USA). 3. Results The patient characteristics are summarized in Table 1. There was wide scatter of liver sizes, tumor volumes, and tumor-to-liver volume ratios. The three most common liver tumors treated in our patient population were (in decreasing order): colorectal cancer
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Table 2 Correlation of arteriovenous hepatic shunting to liver volume, tumor volume and ratio of tumor to liver volume according to tumor entity, tumor vascularity and PVO. n
Liver volume (LV) r
Tumor volume (TV) r
TV/LV r
All tumors +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
49 66 52 12 33 21
0.065 0.152 0.161 0.312 0.369 0.266
0.416 0.221 0.195 0.308 0.301 0.242
0.422 0.267 0.195 0.335 0.197 0.192
mBC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
17 12 2 2 6 1
0.178 0.265 (1) (1) 0.201 –
0.473 0.323 (1) (1) 0.377 –
0.543 0.443 (1) (1) 0.449 –
mCRC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
12 32 9 2 8 5
0.140 0.324 0.507 (1) 0.358 0.084
0.380 0.479 0.443 (1) 0.433 0.199
0.466 0.426 0.522 (1) 0.374 0.457
HCC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
3 6 22 6 15 11
0.267 0.025 0.014 0.290 0.340 0.061
0.994 0.303 0.056 0.044 0.206 0.018
0.873 0.400 0.079 0.035 0.008 0.054
n: number of patients; mCRC: metastatic colorectal cancer; HCC: hepatic cell carcinoma; mBC: metastatic breast cancer; V: volume; r: Pearson product–moment correlation coefficient
Fig. 1. Scatter diagrams of the HPS fraction plotted against liver volume (A), tumor volume (B), and tumor-to-liver volume ratio (C) in the total study population (n = 233).
with metastatic spread to the liver (mCRC), hepatocellular carcinoma (HCC), and liver metastases from metastatic breast cancer (mBC). Fig. 1 presents scatter diagrams of HPS fractions plotted against liver volume (A), tumor volume (B), and tumor-to-liver volume ratio (C). For these three analyses, correlation coefficients r ranged from 0.303 to 0.345.
Fig. 2 shows representative examples of abdominal CT scans depicting liver tumors with strong (A), moderate (B), and little (C) enhancement during the arterial phase. All patients were assigned to one of these three groups, and the enhancement groups were plotted against HPS fractions (Fig. 3). The HPS fraction was smallest in patients with liver tumors showing little contrast medium uptake (HPSmedian(range) = 8.3%(16.5%)), followed by patients with tumors displaying moderate (HPS = 9.4%(40.0%)) and strong enhancement (HPS = 11.7% (46.3%)). The trend of HPS increase going from low to high arterial enhancement was statistically significant (p = 0.001). Comparison of the degree of pulmonary shunting among the three most common hepatic tumors in our patient population showed the smallest HPS fractions for mBC (HPS = 7.4% (16.7%)) and significantly higher fractions for mCRC (HPS = 10.6%(28.6.%); p = 0.012) and HCC (HPS = 11.7%(39.4%); p = 0.001) (Fig. 4). Two of the three strongly enhancing mBC had HPS fractions of 10.8% and 19.0%, which was above the median of mBC with little enhancement (HPS = 6.7%(12.5%); the third strongly enhancing mBC had an HPS fraction of 5.5% (Fig. 5). In the group of mCRC, HPS fractions of strongly enhancing tumors were significantly higher than those of patients with tumors showing little enhancement (HPSstrong = 16.1%(20.0%) vs. HPSlittle = 9.3%(13.6%); p = 0.039) (Fig. 5). The HPS fraction of strongly enhancing HCC (HPS = 12.0%(34%) was not significantly larger than that of HCC with little enhancement (HPS = 9.5%(13.2%) (Fig. 5). Fig. 6 presents representative examples of portal vein occlusion (PVO) caused by tumor compression (A) or tumor thrombosis (B) of a major portal vein branch. Patients with PVO had higher degrees of pulmonary shunting (HPSportal vein compression = 13.8%(43.7%); HPSportal vein tumor thrombosis = 15.8%(31.2%)) compared to patients without hemodynamically compromised portal vein
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Fig. 3. HPS fractions in patients with primary and secondary liver tumors showing strong (high), moderate (medium), and little (low) contrast enhancement.
Fig. 2. Representative examples of abdominal CT scans of primary and secondary liver tumors showing strong (A), moderate (B), and little (C) contrast enhancement during the arterial phase.
Fig. 4. HPS fractions for the three most common liver tumor entities evaluated for radioembolization.
perfusion (HPS = 8.1%(47.0%); p < 0.001 for each portal compression and portal tumor thrombosis) (Fig. 7). All three tumor entities – mBC, mCRC, and HCC – showed significantly higher degrees of shunting when PVO was present (HPSmBC without PVO = 6.7%(16.0%) vs. HPSmBC with PVO = 12.5%(13.3%); p = 0.021; HPSmCRC without PVO = 8.8%(28.6%) vs. HPSmCRC with PVO = p = 0.001; HPSHCC without PVO = 9.3%(39.3%) vs. 15.6%(22.4%); HPSHCC with PVO = 15.8%(30.1%); p < 0.001) (Fig. 8). Table 2 presents data on the correlation of HPS fractions with liver volume, tumor volume, and tumor-to-liver volume ratio in relation to tumor entity, tumor vascularity, and presence of PVO. Correlation coefficient r ranged from 0.008 to 0.543 for groups with n > 3. 4. Discussion Estimating the HPS fraction in patients considered for radioembolization treatment of malignant hepatic tumors is a major component of the angiographic evaluation performed before RE
Fig. 5. HPS fractions for the three most common tumor entities with little (low) versus strong (high) enhancement during arterial-phase abdominal CT.
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Fig. 6. Representative examples of PVO due to tumor compression (A) and tumor thrombosis of a major portal vein branch (B). Arrows indicate the cause of obstruction.
besides embolization of extrahepatic gastroenteral or pancreatic branches [10,11]. A planar scintigraphy, SPECT, or SPECT-CT following catheter-based injection of Tc-99m MAA into the hepatic arteries can predict the expected distribution of radioactive microspheres in the liver and the tumor as well as migration (HPS) of radioactive material into the lungs [12,13]. An HPS fraction of over 20% determined with use of Tc-99m MAA (typical average size 20–40 m [14]) or a calculated hypothetical single lung dose during RE of over 30 Gy (maximum total dose exposure of 50 Gy) is
Fig. 7. Comparison of HPS fractions between patients with normal portal vein perfusion and patients with compression or thrombosis/infiltration of a major portal vein branch.
considered a contraindication to liver tumor treatment with radioactive microspheres [3,4]. Very early studies report HPS fractions of 5–10% for healthy livers [15]. The higher degree of pulmonary shunting seen in some patients with liver malignancies is primarily attributed to the pathologic vasculature in the tumor [16] but could also be induced due to paraneoplastic effects in the residual liver tissue. Addressing these two aspects – tumor shunt or liver shunt – there are several possible predictors of an increased HPS fraction that can be easily determined from preinterventional cross-sectional
Fig. 8. Comparison of HPS of the three most common tumor entities between patients with normal portal vein perfusion and patients with PVO.
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imaging examinations. These include total liver volume, tumor volume, and relative tumor volume (of total liver volume). Nevertheless, systematic studies are rare [7,17]. Older studies using planar scintigraphy showed no or low correlation of HPS with tumor volume [17] and did not correlate HPS with total liver size or tumor-to-liver volume ratio. In this study, r was 0.086 for 125 patients with HCC. In comparison, correlation for tumor volume tended to be higher in our study (r = 0.345) but is still rather poor (Fig. 1B). The same holds true for the correlation of the HPS fraction with total liver volume (Fig. 1A) or of HPS with tumor-to-liver volume (Fig. 1C), for which we found values of r = 0.303 and r = 0.340, respectively. The poor correlation of these volume parameters with the HPS fraction suggests that the degree of pulmonary shunting depends on other factors. To show strong enhancement on arterial-phase CT scans, tumors must have a high blood perfusion rate. High perfusion can result from increased capillary density [18] or the presence of arteriovenous shunts, which are commonly associated with tumors [19]. As shown in Fig. 3, tumors with early arterial enhancement indeed have significantly higher HPS fractions compared with tumors showing no or little arterial enhancement. Interestingly, not one case with no or little arterial enhancement reaches the threshold HPS fraction of 20%, [3], above which SIRTEX discourages RE. A comparison of HPS fractions among the three most common liver tumor entities treated in our patient population shows that mBC have a significantly lower HPS fraction than mCRC and HCC (p = 0.012 and p = 0.001, respectively) and that none of our cases of mBC reaches the critical 20% threshold. The median HPS fractions of all three tumor entities are increased for those with strong arterial enhancement, but the difference is significant only for mCRC. The lack of significance for mBC and HCC must be interpreted in light of the low number of cases (mBChigh = 3; HCClow = 9), even more so as there are data from other studies suggesting that hypervascularity in HCC is associated with significantly larger HPS fractions [7,17]. What may also alter hepatic perfusion and hence contribute to shunt formation in patients with liver tumors is impaired blood flow in the portal vein due to external compression of the vein, thrombus formation, or tumor invasion of the portal vein. As shown in Fig. 7, the HPS fraction is significantly increased in patients with both compression of intrahepatic portal vein branches and thrombosis or tumor infiltration of the portal vein. An association between PVO and significantly increased hepatopulmonary shunting is also confirmed by the results obtained for each of the three most common tumor entities (Fig. 8). Although evidence for such an association had already been provided for HCC in the study of Gaba et al. [7], the precise mechanism leading to increased hepatopulmonary shunting when blood flow in the portal vein is compromised is still unclear. A possible mechanism is as follows: under normal conditions, the hepatic arteries supply bile duct structures and connective tissue of the portal field and, at the border of the hepatic acini, end as normal capillaries in the hepatic sinusoids, which receive their main blood supply from the portal vein [20]. When the portal vein is occluded, the liver receives only arterial blood, which is always clearly seen by an increase in caliber of the affected hepatic artery on ultrasound or CT angiography [21,22]. If the same mechanism also occurred at the microscopic level, this should induce an increase in diameter of the tiny arterioles/capillaries (6–10 m [23]) to approach the diameter of the hepatic sinusoids (20–30 m [23]). If this occurred, a larger proportion of transarterially infused Tc-99m MAA tracers (which have typical average size of 20–40 m) could pass the enlarged arterioles/capillaries and reach the lungs. Especially the results presented in Fig. 7 suggest that an increased HPS fraction is poststenotic in origin since the increase is seen in association both with portal vein compression and with portal vein thrombosis or tumor invasion.
When we correlated total liver volume, tumor volume, or the tumor-to-liver volume ratio with tumor entity, arterial-phase contrast enhancement, or PVO, we saw no relevant increase in correlation coefficients for groups with statistically analyzable case numbers of n > 3 compared with the results for the total study population as presented in Fig. 1 (Table 2). In the final analysis, we must concede that the correlation of HPS with total liver volume or tumor volume and with the derived tumor-to-liver volume ratio is flawed by the fact that it assumes homogeneous behavior of tumors in terms of perfusion. However, Fig. 2 already proves this assumption to be wrong. In fact, early arterial contrast enhancement of many tumors is confined to the periphery, and the width of the enhancing margin varies with the tumor entity and the size of central necrosis, which tends to be avascular [24]. Moreover, this assumption also ignores the histologic makeup and maturation of blood vessels, which may vary considerably depending on the type of tumor, the histologic grade, and prior chemotherapy [25]–especially when patients have received antiangiogenic drugs. 5. Conclusions The aim of this study was to evaluate the predictive value of liver volume, tumor volume, tumor vascularity, tumor entity, and portal vein occlusion for the HPS fraction. In summary, our results in 233 patients allow the following conclusions to be drawn: all mBC in our study (n = 40) and tumors with little or no contrast enhancement in arterial-phase CT (n = 61) have an HPS fraction below 20%, making relevant lung exposure during RE unlikely. The median HPS fractions of mBC, mCRC and HCC are increased for tumors with strong arterial enhancement, however, the difference is significant only for mCRC. Reduced perfusion of a major portal vein branch – regardless of whether it is due to thrombosis, tumor invasion, or tumor-related external compression, results in a significant increase in HPS. This means that physicians must carefully pay attention to HPS in patients with PVO in order to prevent iatrogenic pulmonary damage due to irradiation. Finally, our results suggest that liver volume, tumor volume, or tumor-to-liver volume ratio have no relevant positive correlation with the degree of hepatopulmonary shunting. This means that the tumor burden in pretherapeutic cross-sectional imaging provides no orientation for the degree of HPS to be expected in a patient considered for radioembolization treatment. Conflict of interest Dr. Gebauer is Proctor for Sirtex Medical and received funding for congress and scientific meetings. The other authors declare no conflict of interest. References [1] Powerski MJ, Scheurig-Munkler C, Banzer J, Schnapauff D, Hamm B, Gebauer B. Clinical practice in radioembolization of hepatic malignancies: a survey among interventional centers in Europe. Eur J Radiol 2012;81:804–11. [2] Powerski MJ, Erxleben C, Scheurig-Münkler C, Geisel D, Hamm B, Gebauer B. Anatomic variants of arteries often coil-occluded prior to hepatic radioembolization. Acta Radiol 2014;(January), pii: 0284185114522148 [epub ahead of print]. [3] http://www.radmed.com.tr/usr img/sir spheres/pdf/package insert sirtex.pdf [last time visited 02.08.14]. [4] http://www.therasphere.com/physicians-package-insert/package-insert-euge.pdf [last time visited 02.08.14]. [5] Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, Metreweli C, Johnson PJ, Li AK. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys 1995;33:919–24. [6] Wright CL, Werner JD, Tran JM, Gates VL, Rikabi AA, Shah MH, Salem R. Radiation pneumonitis following yttrium-90 radioembolization: case report and literature review. J Vasc Interv Radiol 2012;23:669–74.
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Hepatopulmonary shunting in patients with primary and secondary liver tumors scheduled for radioembolization Maciej Janusz Powerski a,∗ , Christoph Erxleben b,1 , Christian Scheurig-Münkler b,1 , Dominik Geisel b,1 , Uwe Heimann b,1 , Bernd Hamm b,1 , Bernhard Gebauer b,1 a b
Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany Department of Radiology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
a r t i c l e
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Article history: Received 2 August 2014 Received in revised form 23 September 2014 Accepted 6 November 2014 Keywords: Radioembolization Liver tumor Hepatopulmonary shunt
a b s t r a c t Purpose: In patients undergoing transarterial radioembolization (RE) of malignant liver tumors, hepatopulmonary shunts (HPS) can lead to nontarget irradiation of the lungs. This study aims at analyzing the HPS fraction in relation to liver volume, tumor volume, tumor-to-liver volume ratio, tumor vascularity, type of tumor, and portal vein occlusion. Materials and methods: In the presented retrospective study the percentage HPS fraction was calculated from SPECT/CT after infusion of Tc-99m macroaggregated albumin (Tc-99m MAA) into the proper hepatic artery of 233 patients evaluated for RE. Results: HPS fractions correlate very weakly with liver volume (r = 0.303), tumor volume (r = 0.345), and tumor-to-liver volume ratio (r = 0.340). Tumors with strong contrast enhancement (HPSmedian(range) = 11.7%(46.3%); n = 73) have significantly larger shunt fractions than tumors with little enhancement (HPS = 8.3%(16.4%); n = 61; p < 0.001). Colorectal cancer metastases (HPS = 10.6%(28.6%); n = 68) and hepatocellular cancers (HPS = 11.7%(39.4%); n = 63) have significantly larger HPS fractions than metastases from breast cancer (HPS = 7.4%(16.7%); n = 40; p = 0.012 and p = 0.001). Patients with compression (HPS = 13.9%(43.7%); n = 33) or tumor thrombosis (HPS = 15.8% (31.2%); n = 33) of a major portal vein branch have significantly higher degrees of shunting than patients with normal portal vein perfusion (HPS = 8.1% (47.0%); n = 167; both p < 0.001). The shunt fraction is largest in patients with HCC and thrombosis or occlusion of a major portal vein branch (HPS = 16.6% (31.0%); n = 32). Conclusion: The degree of hepatopulmonary shunting depends on the type of liver tumor, tumor vascularity, and portal vein perfusion. There is little to no correlation of HPS with liver volume, tumor volume, or tumor-to-liver volume ratio. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Radioembolization (RE) of liver tumors is performed using yttrium-90-loaded microspheres semiselectively injected through a catheter placed in a hepatic artery. A few weeks to a few days before the radioactive microspheres are injected, a patient scheduled for this procedure needs to have an angiographic evaluation with coil and/or plug embolization of any hepatoenteral and
∗ Corresponding author. Tel.: +49 391 6713030; fax: +49 391 6713029. E-mail addresses: [email protected] (M.J. Powerski), [email protected] (C. Erxleben), [email protected] (C. Scheurig-Münkler), [email protected] (D. Geisel), [email protected] (U. Heimann), [email protected] (B. Hamm), [email protected] (B. Gebauer). 1 Tel.: +49 30 450557002; fax: +49 30 450557901. http://dx.doi.org/10.1016/j.ejrad.2014.11.004 0720-048X/© 2014 Elsevier Ireland Ltd. All rights reserved.
hepatopancreatic branches and determination of the hepatopulmonary shunt (HPS) fraction [1]. Branches not supplying the liver need to be occluded before RE to prevent microsphere migration and complications such as radiation ulcer [2]. The HPS fraction is estimated from a scintigram obtained after administration of technetium-99m macroaggregated albumin (Tc-99m MAA) into hepatic arteries. It is calculated as the pulmonary proportion of the total Tc-99m MAA signals from the lungs and liver. Both manufacturers currently offering RE microspheres – Sirtex Medical (Lane Cove, Australia) and BTG (London, United Kingdom) – consider the HPS fraction calculated from Tc-99m MAA scintigrams to accurately predict pulmonary shunting of their microspheres [3,4]. A higher HPS fraction results in more excessive nontarget irradiation of the lung after RE and increases the risk of inducing radiation pneumonitis, pulmonary fibrosis, and pulmonary hypertension [5,6]. Sirtex Medical considers RE to be contraindicated when pulmonary
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shunting exceeds 20% and recommends to reduce total activity by administering a smaller amount of microspheres in patients with a HPS of 11–20% [3]. When microspheres from BTG are used, the pulmonary fraction is incorporated in the equation for calculating the activity to be applied in a patient. BTG considers RE to be contraindicated when pulmonary shunting results in a calculated lung activity of 610 MBq (approx. 30 Gy single lung dose) [4]. An elevated pulmonary shunt fraction leads to exclusion of approx. 5–14% of patients evaluated for RE [7,8]. The aim of the present study was to investigate various parameters including liver volume, tumor volume, tumor vascularity, tumor entity, and portal vein occlusion (PVO) by compression or thrombosis determined by computed tomography (CT) in terms of their predictive value for pulmonary shunting in 233 patients scheduled for RE. 2. Materials and methods 2.1. Patients The study included all patients who were evaluated for RE and underwent whole-liver angiography in our department between 2009 and 2013. Patients with a history of hemihepatectomy of any kind and Patients with hepatic arterial supply other than Michels’ type I, IX or X were excluded [9]. A total of 233 patients were analyzed. Approval for this retrospective analysis was obtained from the local ethics committee (ref No. EA1-273-12). 2.2. Computed tomography, volumetry, arterial-phase contrast enhancement, and portal vein occlusion All patients underwent three-phase computed tomography (CT) of the liver a few days before angiographic evaluation. Liver CT examinations were performed on a GE VCT 64 scanner (General Electric, Fairfield, Connecticut, USA) after IV injection of 120 ml of contrast medium (Xenetix 350, Guerbet, Villepinte, France). The arterial-phase scan was triggered with a 5 s delay after a threshold of 250 HU was observed at the level of the upper abdominal aorta. The portal venous and venous phases were triggered with delays of 35 s and 75 s, respectively. CT was performed with the following parameters: 0.9 pitch factor, 0.5 s rotation time, 0.6 mm slice thickness, 120 pKV tube voltage, and tube current according to Care dose. Liver and tumor volumes were calculated from venousphase CT scans (5 mm slice thickness) using the BrachyVisionTM , version 10.0, software tool (Varian Medical Systems, Palo Alto, CA, USA). Volumetry was performed by three interventional radiologists with more than 5 years of experience in RE. Classification of liver tumors according to arterial-phase enhancement was done using arterial-phase CT images. All patients were assigned to one of three categories (no or little enhancement, moderate enhancement, and strong enhancement). Two fully trained radiologists with several years of experience in abdominal CT imaging working in consensus assessed enhancement using Visage 7.1 (Visage Imaging GmbH, Berlin, Germany) as PACS system. Portal vein occlusion (PVO) was identified and classified by underlying cause (external compression of major portal vein branch by tumor or intraluminal presence of tumor or thrombus in major branch) using arterial, portal-venous-, and venous-phase CT images. Major portal vein branches were the first-order branches of the portal vein. Two fully trained radiologists with several years of experience in abdominal CT imaging working in consensus performed the assessment using Visage 7.1 as PACS system. 2.3. Angiographic evaluation and SPECT/CT Two to four weeks before radioembolization treatment, candidates were evaluated by angiography, performed on a flat-panel
Table 1 Patient characteristics.
Total Female Male
n [%]
Median [age]
Range [years]
233/100% 110/47.2% 123/52.8%
64 59 66
60 50 60
Volume Liver Tumor
Median [ml] 1943 277
Range [ml] 5761 3650
Ratio
Median
Range
Vtumor /Vliver
0.144
0.733
Tumorentity
n
%
mCRC HCC mBC CCC mPCA mNET mSCA Other Total
68 63 40 15 11 10 5 ≤2 233
29.2 27.0 17.2 6.4 4.7 4.3 2.1 9.1 100
V: volume; mCRC: metastatic colorectal cancer; HCC: hepatic cell carcinoma; mBC: metastatic breast cancer; CCC: cholangio cell carcinoma; mPCA: metastatic pancreatic cancer; mNET: metastatic neuroendocrine tumor; mSCA: metastatic stomach cancer.
angiography system (Allura XPER FD20, Philips, Best, Netherlands), using a transfemoral access. This angiography included coil and/or plug embolization of gastric (e.g., right hepatic artery) and gastroenteral (e.g., gastroduodenal artery) anastomoses and subsequent catheter-based administration of Tc-99m MAA (Draximage® MAA, Jubilant Draximage Inc., Kirkland, Canada) with an activity of 150–175 MBq into the proper hepatic artery. Thereafter, a whole-body SPECT/CT examination (Symbia T6, Siemens, Munich, Germany) was performed. Regions of interest (ROI) were placed in the lungs and the liver, and the HPS fraction was calculated dividing the total lung counts by the sum of the lung and liver counts. 2.4. Statistical analysis Results are presented either descriptively, providing absolute numbers (n) and percentages of the total population (%) or, when nonnormal distribution was assumed, providing parameters of nonparametric statistics (median and range) (Table 1). Correlations presented in Fig. 1 and Table 2 were calculated according to Pearson (r = Pearson product–moment correlation coefficient; r2 = coefficient of determination). The boxplots present medians and first/third quartiles, with the whiskers indicating the minimum and maximum within 1.5-fold interquartile ranges and the circles representing outliers (Tukey boxplot). The null hypotheses (Figs. 3, 4 and 7) were assessed with the Kruskal–Wallis test. When the null hypothesis was rejected (p ≤ 0.05), this was followed by pairwise testing with the Mann–Whitney U-test. The groups in Fig. 3 were additionally analyzed for a trend of increase going from low to high arterial enhancement using the Jonckheere-Terpstra test. In Figs. 5 and 8, the Mann–Whitney U-test was applied directly. Statistically significant differences were assumed for p ≤ 0.05. All data analyses were performed using SPSS 22 (IBM Corporation, NY, USA). 3. Results The patient characteristics are summarized in Table 1. There was wide scatter of liver sizes, tumor volumes, and tumor-to-liver volume ratios. The three most common liver tumors treated in our patient population were (in decreasing order): colorectal cancer
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Table 2 Correlation of arteriovenous hepatic shunting to liver volume, tumor volume and ratio of tumor to liver volume according to tumor entity, tumor vascularity and PVO. n
Liver volume (LV) r
Tumor volume (TV) r
TV/LV r
All tumors +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
49 66 52 12 33 21
0.065 0.152 0.161 0.312 0.369 0.266
0.416 0.221 0.195 0.308 0.301 0.242
0.422 0.267 0.195 0.335 0.197 0.192
mBC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
17 12 2 2 6 1
0.178 0.265 (1) (1) 0.201 –
0.473 0.323 (1) (1) 0.377 –
0.543 0.443 (1) (1) 0.449 –
mCRC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
12 32 9 2 8 5
0.140 0.324 0.507 (1) 0.358 0.084
0.380 0.479 0.443 (1) 0.433 0.199
0.466 0.426 0.522 (1) 0.374 0.457
HCC +/PVO− ++/PVO− +++/PVO− +/PVO+ ++/PVO+ +++/PVO+
3 6 22 6 15 11
0.267 0.025 0.014 0.290 0.340 0.061
0.994 0.303 0.056 0.044 0.206 0.018
0.873 0.400 0.079 0.035 0.008 0.054
n: number of patients; mCRC: metastatic colorectal cancer; HCC: hepatic cell carcinoma; mBC: metastatic breast cancer; V: volume; r: Pearson product–moment correlation coefficient
Fig. 1. Scatter diagrams of the HPS fraction plotted against liver volume (A), tumor volume (B), and tumor-to-liver volume ratio (C) in the total study population (n = 233).
with metastatic spread to the liver (mCRC), hepatocellular carcinoma (HCC), and liver metastases from metastatic breast cancer (mBC). Fig. 1 presents scatter diagrams of HPS fractions plotted against liver volume (A), tumor volume (B), and tumor-to-liver volume ratio (C). For these three analyses, correlation coefficients r ranged from 0.303 to 0.345.
Fig. 2 shows representative examples of abdominal CT scans depicting liver tumors with strong (A), moderate (B), and little (C) enhancement during the arterial phase. All patients were assigned to one of these three groups, and the enhancement groups were plotted against HPS fractions (Fig. 3). The HPS fraction was smallest in patients with liver tumors showing little contrast medium uptake (HPSmedian(range) = 8.3%(16.5%)), followed by patients with tumors displaying moderate (HPS = 9.4%(40.0%)) and strong enhancement (HPS = 11.7% (46.3%)). The trend of HPS increase going from low to high arterial enhancement was statistically significant (p = 0.001). Comparison of the degree of pulmonary shunting among the three most common hepatic tumors in our patient population showed the smallest HPS fractions for mBC (HPS = 7.4% (16.7%)) and significantly higher fractions for mCRC (HPS = 10.6%(28.6.%); p = 0.012) and HCC (HPS = 11.7%(39.4%); p = 0.001) (Fig. 4). Two of the three strongly enhancing mBC had HPS fractions of 10.8% and 19.0%, which was above the median of mBC with little enhancement (HPS = 6.7%(12.5%); the third strongly enhancing mBC had an HPS fraction of 5.5% (Fig. 5). In the group of mCRC, HPS fractions of strongly enhancing tumors were significantly higher than those of patients with tumors showing little enhancement (HPSstrong = 16.1%(20.0%) vs. HPSlittle = 9.3%(13.6%); p = 0.039) (Fig. 5). The HPS fraction of strongly enhancing HCC (HPS = 12.0%(34%) was not significantly larger than that of HCC with little enhancement (HPS = 9.5%(13.2%) (Fig. 5). Fig. 6 presents representative examples of portal vein occlusion (PVO) caused by tumor compression (A) or tumor thrombosis (B) of a major portal vein branch. Patients with PVO had higher degrees of pulmonary shunting (HPSportal vein compression = 13.8%(43.7%); HPSportal vein tumor thrombosis = 15.8%(31.2%)) compared to patients without hemodynamically compromised portal vein
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Fig. 3. HPS fractions in patients with primary and secondary liver tumors showing strong (high), moderate (medium), and little (low) contrast enhancement.
Fig. 2. Representative examples of abdominal CT scans of primary and secondary liver tumors showing strong (A), moderate (B), and little (C) contrast enhancement during the arterial phase.
Fig. 4. HPS fractions for the three most common liver tumor entities evaluated for radioembolization.
perfusion (HPS = 8.1%(47.0%); p < 0.001 for each portal compression and portal tumor thrombosis) (Fig. 7). All three tumor entities – mBC, mCRC, and HCC – showed significantly higher degrees of shunting when PVO was present (HPSmBC without PVO = 6.7%(16.0%) vs. HPSmBC with PVO = 12.5%(13.3%); p = 0.021; HPSmCRC without PVO = 8.8%(28.6%) vs. HPSmCRC with PVO = p = 0.001; HPSHCC without PVO = 9.3%(39.3%) vs. 15.6%(22.4%); HPSHCC with PVO = 15.8%(30.1%); p < 0.001) (Fig. 8). Table 2 presents data on the correlation of HPS fractions with liver volume, tumor volume, and tumor-to-liver volume ratio in relation to tumor entity, tumor vascularity, and presence of PVO. Correlation coefficient r ranged from 0.008 to 0.543 for groups with n > 3. 4. Discussion Estimating the HPS fraction in patients considered for radioembolization treatment of malignant hepatic tumors is a major component of the angiographic evaluation performed before RE
Fig. 5. HPS fractions for the three most common tumor entities with little (low) versus strong (high) enhancement during arterial-phase abdominal CT.
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Fig. 6. Representative examples of PVO due to tumor compression (A) and tumor thrombosis of a major portal vein branch (B). Arrows indicate the cause of obstruction.
besides embolization of extrahepatic gastroenteral or pancreatic branches [10,11]. A planar scintigraphy, SPECT, or SPECT-CT following catheter-based injection of Tc-99m MAA into the hepatic arteries can predict the expected distribution of radioactive microspheres in the liver and the tumor as well as migration (HPS) of radioactive material into the lungs [12,13]. An HPS fraction of over 20% determined with use of Tc-99m MAA (typical average size 20–40 m [14]) or a calculated hypothetical single lung dose during RE of over 30 Gy (maximum total dose exposure of 50 Gy) is
Fig. 7. Comparison of HPS fractions between patients with normal portal vein perfusion and patients with compression or thrombosis/infiltration of a major portal vein branch.
considered a contraindication to liver tumor treatment with radioactive microspheres [3,4]. Very early studies report HPS fractions of 5–10% for healthy livers [15]. The higher degree of pulmonary shunting seen in some patients with liver malignancies is primarily attributed to the pathologic vasculature in the tumor [16] but could also be induced due to paraneoplastic effects in the residual liver tissue. Addressing these two aspects – tumor shunt or liver shunt – there are several possible predictors of an increased HPS fraction that can be easily determined from preinterventional cross-sectional
Fig. 8. Comparison of HPS of the three most common tumor entities between patients with normal portal vein perfusion and patients with PVO.
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imaging examinations. These include total liver volume, tumor volume, and relative tumor volume (of total liver volume). Nevertheless, systematic studies are rare [7,17]. Older studies using planar scintigraphy showed no or low correlation of HPS with tumor volume [17] and did not correlate HPS with total liver size or tumor-to-liver volume ratio. In this study, r was 0.086 for 125 patients with HCC. In comparison, correlation for tumor volume tended to be higher in our study (r = 0.345) but is still rather poor (Fig. 1B). The same holds true for the correlation of the HPS fraction with total liver volume (Fig. 1A) or of HPS with tumor-to-liver volume (Fig. 1C), for which we found values of r = 0.303 and r = 0.340, respectively. The poor correlation of these volume parameters with the HPS fraction suggests that the degree of pulmonary shunting depends on other factors. To show strong enhancement on arterial-phase CT scans, tumors must have a high blood perfusion rate. High perfusion can result from increased capillary density [18] or the presence of arteriovenous shunts, which are commonly associated with tumors [19]. As shown in Fig. 3, tumors with early arterial enhancement indeed have significantly higher HPS fractions compared with tumors showing no or little arterial enhancement. Interestingly, not one case with no or little arterial enhancement reaches the threshold HPS fraction of 20%, [3], above which SIRTEX discourages RE. A comparison of HPS fractions among the three most common liver tumor entities treated in our patient population shows that mBC have a significantly lower HPS fraction than mCRC and HCC (p = 0.012 and p = 0.001, respectively) and that none of our cases of mBC reaches the critical 20% threshold. The median HPS fractions of all three tumor entities are increased for those with strong arterial enhancement, but the difference is significant only for mCRC. The lack of significance for mBC and HCC must be interpreted in light of the low number of cases (mBChigh = 3; HCClow = 9), even more so as there are data from other studies suggesting that hypervascularity in HCC is associated with significantly larger HPS fractions [7,17]. What may also alter hepatic perfusion and hence contribute to shunt formation in patients with liver tumors is impaired blood flow in the portal vein due to external compression of the vein, thrombus formation, or tumor invasion of the portal vein. As shown in Fig. 7, the HPS fraction is significantly increased in patients with both compression of intrahepatic portal vein branches and thrombosis or tumor infiltration of the portal vein. An association between PVO and significantly increased hepatopulmonary shunting is also confirmed by the results obtained for each of the three most common tumor entities (Fig. 8). Although evidence for such an association had already been provided for HCC in the study of Gaba et al. [7], the precise mechanism leading to increased hepatopulmonary shunting when blood flow in the portal vein is compromised is still unclear. A possible mechanism is as follows: under normal conditions, the hepatic arteries supply bile duct structures and connective tissue of the portal field and, at the border of the hepatic acini, end as normal capillaries in the hepatic sinusoids, which receive their main blood supply from the portal vein [20]. When the portal vein is occluded, the liver receives only arterial blood, which is always clearly seen by an increase in caliber of the affected hepatic artery on ultrasound or CT angiography [21,22]. If the same mechanism also occurred at the microscopic level, this should induce an increase in diameter of the tiny arterioles/capillaries (6–10 m [23]) to approach the diameter of the hepatic sinusoids (20–30 m [23]). If this occurred, a larger proportion of transarterially infused Tc-99m MAA tracers (which have typical average size of 20–40 m) could pass the enlarged arterioles/capillaries and reach the lungs. Especially the results presented in Fig. 7 suggest that an increased HPS fraction is poststenotic in origin since the increase is seen in association both with portal vein compression and with portal vein thrombosis or tumor invasion.
When we correlated total liver volume, tumor volume, or the tumor-to-liver volume ratio with tumor entity, arterial-phase contrast enhancement, or PVO, we saw no relevant increase in correlation coefficients for groups with statistically analyzable case numbers of n > 3 compared with the results for the total study population as presented in Fig. 1 (Table 2). In the final analysis, we must concede that the correlation of HPS with total liver volume or tumor volume and with the derived tumor-to-liver volume ratio is flawed by the fact that it assumes homogeneous behavior of tumors in terms of perfusion. However, Fig. 2 already proves this assumption to be wrong. In fact, early arterial contrast enhancement of many tumors is confined to the periphery, and the width of the enhancing margin varies with the tumor entity and the size of central necrosis, which tends to be avascular [24]. Moreover, this assumption also ignores the histologic makeup and maturation of blood vessels, which may vary considerably depending on the type of tumor, the histologic grade, and prior chemotherapy [25]–especially when patients have received antiangiogenic drugs. 5. Conclusions The aim of this study was to evaluate the predictive value of liver volume, tumor volume, tumor vascularity, tumor entity, and portal vein occlusion for the HPS fraction. In summary, our results in 233 patients allow the following conclusions to be drawn: all mBC in our study (n = 40) and tumors with little or no contrast enhancement in arterial-phase CT (n = 61) have an HPS fraction below 20%, making relevant lung exposure during RE unlikely. The median HPS fractions of mBC, mCRC and HCC are increased for tumors with strong arterial enhancement, however, the difference is significant only for mCRC. Reduced perfusion of a major portal vein branch – regardless of whether it is due to thrombosis, tumor invasion, or tumor-related external compression, results in a significant increase in HPS. This means that physicians must carefully pay attention to HPS in patients with PVO in order to prevent iatrogenic pulmonary damage due to irradiation. Finally, our results suggest that liver volume, tumor volume, or tumor-to-liver volume ratio have no relevant positive correlation with the degree of hepatopulmonary shunting. This means that the tumor burden in pretherapeutic cross-sectional imaging provides no orientation for the degree of HPS to be expected in a patient considered for radioembolization treatment. Conflict of interest Dr. Gebauer is Proctor for Sirtex Medical and received funding for congress and scientific meetings. The other authors declare no conflict of interest. References [1] Powerski MJ, Scheurig-Munkler C, Banzer J, Schnapauff D, Hamm B, Gebauer B. Clinical practice in radioembolization of hepatic malignancies: a survey among interventional centers in Europe. Eur J Radiol 2012;81:804–11. [2] Powerski MJ, Erxleben C, Scheurig-Münkler C, Geisel D, Hamm B, Gebauer B. Anatomic variants of arteries often coil-occluded prior to hepatic radioembolization. Acta Radiol 2014;(January), pii: 0284185114522148 [epub ahead of print]. [3] http://www.radmed.com.tr/usr img/sir spheres/pdf/package insert sirtex.pdf [last time visited 02.08.14]. [4] http://www.therasphere.com/physicians-package-insert/package-insert-euge.pdf [last time visited 02.08.14]. [5] Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, Metreweli C, Johnson PJ, Li AK. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys 1995;33:919–24. [6] Wright CL, Werner JD, Tran JM, Gates VL, Rikabi AA, Shah MH, Salem R. Radiation pneumonitis following yttrium-90 radioembolization: case report and literature review. J Vasc Interv Radiol 2012;23:669–74.
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