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90Y radioembolization dosimetry using a simple semi-quantitative method in intrahepatic cholangiocarcinoma: Glass versus resin microspheres
Nuclear Medicine and Biology 59 (2018) 22–28
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Nuclear Medicine and Biology journal homepage: www.elsevier.com/locate/nucmedbio
Y90 radioembolization dosimetry using a simple semi-quantitative method in intrahepatic cholangiocarcinoma: Glass versus resin microspheres Nariman Nezami a, Nima Kokabi a, Juan C. Camacho b, David M. Schuster c, Minzhi Xing a, Hyun S. Kim a,d,⁎ a
Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA Department of Radiology, Medical University of South Caroline, Charleston, SC, USA c Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, USA d Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA b
a r t i c l e
i n f o
Article history: Received 18 September 2017 Received in revised form 26 December 2017 Accepted 10 January 2018 Available online xxxx Keywords: Intrahepatic cholangiocarcinoma Y90 Radioembolization Dosimetry Glass Resin
a b s t r a c t Introduction: There are two different types of Y90 Microspheres, glass and resin, in the market for Y90 radioembolization (Y90-RE). This study aimed to investigate the dose of radiation delivered through glass vs. resin-based Y90-RE to intrahepatic cholangiocarcinoma (ICC). Methods: In this retrospective study, 10 patients with ICC underwent Y90-RE, five underwent glass (Glass group) and other 5 resin (Resin group) microspheres. Technetium-99m macro-aggregated albumin (Tc-99m MAA) shunt study was performed two weeks before Y90-RE. Within 2 h from Y90-RE, Bremsstrahlung SPECT/CT was obtained. Regions of interest (ROIs) were segmented around the targeted tumor and the liver. Tumor and liver volumes, corresponding radioactive counts, and tumor to liver count ratio were calculated using MIM software and compared between Glass and Resin groups. Results: Mean hepatopulmonary shunt fraction was 7.1 vs. 6.2% for the Glass and Resin groups (p = 0.83), with no extrahepatic activity. There was no difference in the activity and tumor uptake of administered Tc-99m MAA between both groups (p = 0.71 and p = 0.63). Mean administered activity of Y90 in the Glass group was higher than the Resin group (73.2 ± 24.3 vs. 44.5 ± 18.2 mCi, p b 0.001). The tumor Y90 uptake was significantly higher in the Glass group compared to the Resin group (41.3% vs. 33.5%, p b 0.001), corresponding to the mean tumor dose of 205.7 ± 19.7 vs. 128.9 ± 10.6 Gy, respectively (p b 0.001). The tumor to normal liver parenchyma Y90 dose ratio was significantly higher in the Glass group compared to the Resin group, 4.9 ± 0.7 versus 2.4 ± 0.3 respectably (p b 0.001). Conclusions: Both Y90 glass and resin-based microsphere Y90-RE are feasible and safe in patients with ICC, while Y90 glass microsphere delivers higher dose of Y90 to the targeted tumors. Advances in knowledge: While both Y90 glass and resin-based microsphere yttrium-90 radioembolization are feasible and safe treatment options for in patients with intrahepatic cholangiocarcinoma, Y90 glass microsphere delivers higher dose of Y90 to the targeted tumors. Implications for patient care: Both of Y90 glass and resin-based microsphere can be safely and feasibly used for treatment of intrahepatic cholangiocarcinoma, difference in dose of Y90 delivered to the targeted tumors should be clinically considered while choosing the microsphere type. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic cancer [1]. Although ICC is relatively uncommon, its growing incidence currently accounts for up to 15% of primary liver
⁎ Corresponding author at: Yale University School of Medicine, Yale Cancer Center, 330 Cedar Street, TE 2-224, New Haven, CT 06510, USA. E-mail address: [email protected] (H.S. Kim). https://doi.org/10.1016/j.nucmedbio.2018.01.001 0969-8051/© 2018 Elsevier Inc. All rights reserved.
cancers with an age-adjusted rate of about 2.1/100,000 people per year in western countries [2]. Despite the new advances in chemotherapy and radiation therapy, surgical resection still remains the only potential curative treatment [3]. However, up to 40% of ICC patients are not candidate for surgical resection by the time of diagnosis [4]. Untreated patients with unresectable ICCs have a median survival of b8 month, which can be increased up to approximately 12 months with systemic therapies [2,5,6]. Locoregional therapies, including embolotherapies and ablative procedures have shown benefits, improving survival [7].
N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28
Given the relative radiation sensitivity of ICC [8], yttrium-90 radioembolization (Y90-RE) has been introduced as a source for internal radiation, and shown as a safe and efficient locoregional treatment [2,7]. The goal of Y90-RE is to deliver lethal doses of radiation to tumors but sublethal doses to normal parenchyma [9], and preliminary results from a few studies have suggested that higher Y90 tumor dose predicts objective (complete or partial) imaging response according to European Association of Study of Liver criteria assessing the degree tumor necrosis [10,11]. Currently, two different types of Y90 Microspheres, glass and resin, with distinct futures are available in the market for Y90-RE [2,12]. In this study, we used our previously validated simple semi-quantitative method [13] to estimate the biodistribution of Y90 delivered to the targeted liver lobe and ICC tumor(s), as well as intratumoral dose of Y90 based on glass and resin microspheres. 2. Methods and materials 2.1. Study design and objectives In this retrospective, single-center, institutional review board approved study, patients with hepatic dominant ICC were enrolled for Y90-RE. Ten consecutive patients with ICC who had radioembolization with glass or resin were included in this study. 2.2. Study population and eligibility criteria All patients were evaluated by a multidisciplinary cancer tumor board, composed of interventional radiologist, medical oncologist, gastroenterologist, and pharmacist, and were found to meet the criteria for Y90-RE. Information on demographics, baseline disease characteristics, and previous therapies was recorded at the patients' first visit. Subsequent follow-up visits were done to concomitant treatments, adverse events, and outcomes were collected. Patients 18 years or older with histopathologic diagnosis of ICC were screened for the following inclusion and exclusion criteria (Table 1). The patients who met all the inclusion and exclusion criteria were enrolled into the study. The patients treated with Y90 glass microsphere had a naïve ICC tumor and were part of a prospective trial with concurrent treatment of Y90-RE and gemcitabine [14], whereas the patients treated with
Table 1 Study inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
1. Predominant unresectable intrahepatic cholangiocarcinoma or hepatic tumor of liver from pancreatic adenocarcinoma 2. Native intrahepatic cholangiocarcinoma in Glass group and chemorefractory in Resin group 3. Limited extra hepatic metastasis as i) Six or less nodules with no nodule N1.5 cm in lungs, ii) abdominal lymph nodes, iii) pancreatic primary as long as the size is b4 cm in size, iv) bone metastasis.
1. Uncorrectable gastrointestinal flow on diagnostic angiogram.
4. Measurable target tumors using standard imaging techniques 5. Eastern Cooperative Oncology Group (ECOG) performance score 0–1 6. b20% lung shunting fraction (LSF) and estimated lung dose N30 Gy.
2. Contraindication to angiography
Inadequate hepatic function by Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ratio of more than five times higher than normal limit, bilirubin N2.0 mg/dl, serum albumin b2.5 g/dL or history of hepatic encephalopathy. 3. Prior external beam radiotherapy to the upper abdomen 4. Clinical evidence of peritoneal metastasis or ascites 5. Tumor burden of N75% of entire liver 6. Any serious ongoing extra-hepatic disease such as infections
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Y90 resin microsphere were a part of another clinical trial and had chemorefractory ICC [15–17]. 2.3. Hepatic vascular mapping and hepatopulmonary shunt evaluation All enrolled patients underwent hepatopulmonary shunt study and diagnostic angiography of the celiac and superior mesenteric arteries. Based on the baseline imaging studies, a selective lobar hepatic artery angiogram was obtained to identify hypervascular lesions. If required, embolization of the gastroduodenal, right gastric, or left gastric branch artery or combination of arteries was performed using coils to prevent non-targeted embolization of stomach or duodenum. No other nearby artery required embolization in this study. In addition, the enrolled patients had hepatopulmonary shunt study, to exam any possible extrahepatic shunt. Approximately 148 MBq (4 mCi) of technetium-99m macro-aggregated albumin (Tc-99m MAA) was administered using a 3-Fmicrocatheter placed at the origin of the common hepatic artery. Planar and SPECT/CT images were then obtained and lung shunt fraction (LSF) were calculated using planar images, and the presence of extrahepatopulmonary activity was evaluated on both planar and SPECT images. 2.4. Y90 therapy planning Treatment planning was performed according to the manufacturer's recommendation and published guidelines [18,19]. Based on the volume of the liver lobe to be treated, the amount of desirable activity for Y90 was calculated using the following formula: Activity desired ðGBqÞ ¼
Target dose ðGyÞ Lobe liver mass ðkgÞ 50
Alternatively, the activity for Resin-based Y90 was calculated in the following fashion: Administered activity ðGBqÞ ¼ ðBSA–0:2Þ þ
%Tumor involvement 100
where, %Tumor Involvement ¼
Volume of tumor 100 Volume of liver
The mass of the liver lobe to be treated was estimated by determining the volume of the lobe using a medical image processing software, MIM v 5.6.1 (MIM Software Inc., Cleveland, Ohio); region of interest (ROI) was Created using a combination of edge enhancement with manual adjustment surrounding the liver lobe on sequential axial images of baseline MR imaging. The volume was calculated by the software, and liver mass was determined assuming density of 1.03 g/cm 3 of liver tissue. Based on recommended guidelines, 120 Gy was used as a target dose to the treated liver lobe [20]. The radiation dose to the lungs was estimated using the following formula [21]: Lung radiation dose ðGyÞ ¼
Activity ðGBqÞ LSF 50 Mass of lungs ðkgÞ
With total lung mass assumed to be 1 kg [22]. Maximum per treatment lung dose was set at 30 Gy with maximum cumulative lung dose of 50 Gy. Administered activity was reduced in patients with predicted lung dose of ≥30 Gy based on initial assumptions during abovedescribed planning. 2.5. Y90 radioembolization procedure Y90 microspheres were administered based on previously described guidelines [20]. On an outpatient basis, using sterile femoral arterial
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approach, a 3-F microcatheter was placed at the origin of the corresponding lobar artery supplying the targeted tumor. The preplanned Y90 activity was administered at low pressure (20–40 psi). A circumferential clip-based vascular closure device was used to achieve hemostasis at the femoral artery access site [23]. The patients were then transferred to the nuclear medicine department for Y90 Bremsstrahlung SPECT/CT. Once, the scan was done, the patients were observed for 3 h in the post procedural recovery area and then discharged home if stable. Patients were followed up in the Interventional Oncology Clinic at 1 week, 1 month, and 3 months after Y90 therapy and every 3 months thereafter. During each clinical follow-up examination, a complete blood chemistry panel was obtained to evaluate for organ-specific toxicity using Common Terminology Criteria for Adverse Events version 4.03 [24].
2.8. Bremsstrahlung SPECT/CT Within b2 h from Y90-RE, the patient was transferred to the nuclear medicine department, and Y90 Bremsstrahlung SPECT/CT was carried out to ensure delivery of the radiopharmaceutical to the targeted lesion. Bremsstrahlung SPECT/CT was performed on the same scanner used for hepatopulmonary shunt study using the following setting 75 keV, 54% energy window, 30 stops at 40 s per stop for 60 projections. SPECT reconstruction was done using the manufacturer's ordered subset expectation maximization–based software (2 subsets, 30 iterations) with attenuation correction. CT-based attenuation correction used an attenuation coefficient for the center of the energy window. In the liver, attenuation correction or Bremsstrahlung could be performed semiquantitative, to produce a more uniform distribution of activity [26,27]. 2.9. Analysis of intrahepatic biodistribution of Y90
2.6. Y90 glass microsphere Five patients underwent Y90 Glass microsphere radioembolization (TheraSphere ®, BTG Interventional Medicine Inc., London, UK) after detailed treatment planning according to the manufacturer's recommendation and published guidelines [2,19]. The recommended method for activity calculation is based on the Medical Internal Radiation Dose (MIRD) model of single compartment. It is recommended to calculate the activity using the MIRD model in order to deliver an absorbed dose to the treated volume of 80–150 mGy, based on patient specific characteristics (target tumor size and lung shunt). Although the radiation is not distributed uniformly, the MIRD formalism is effective in guiding users in the selection of the proper activity of the glass microspheres for destroying the tumor and avoiding radiation-induced liver damage [22].
2.7. Y90 resin microsphere Y90 Resin microsphere (SIR-Spheres ®, Sirtex Medical Inc., Lane Cove, NSW, Australia) was used for radioembolization of other five patients. The partition model method based on the MIRD formalism and three compartments: lung, tumor and normal liver. The partition model is well described in the User's Manual and Package Insert provided by the manufacturer [2,25]. The partition model method, that is the only true dosimetric approach at the treatment, should always be used when the tumor can be localized as a discrete volume and clearly identified as an area of interest on single-photon emission CT imaging, acquired after the intrahepatic administration of Tc99m MAA.
The MIM image processing software was again used to delineate a three dimensional ROI around the targeted tumor using a combination of automated edge enhancement option and manual correction. A second ROI was drawn along the entire liver. Tumor and Liver volumes were calculated (Fig. 1A). Using the same method described previously, baseline CT abdomen imaging with tumor and entire liver ROI was fused with Y90 Bremsstrahlung SPECT/CT (Fig. 1B). Proportional Y90 activity delivered to the tumor was calculated using the following formula: Y90 tumor to liver ratio ¼
Tumor Y90 count Liver Y90 count
Based on the administered activity (total activity) during the radioembolization procedure and LSF, Y90 activity delivered to the tumor(s) and liver were estimated using the following formulas: Y90 tumor activity ðGBqÞ ¼
Y90 livr activity ðGBqÞ ¼
Y90 tumor dose ðGyÞ Tumor mass ðkgÞ 50
Tumor dose ðGyÞ Tumor Mass ðkgÞ 50
Y90 dose to the targeted tumor(s) and liver were calculated using the following formulas: Y90 tumor dose ðGyÞ ¼
Y90 tumor activity ðGBqÞ 50 Tumor mass ðkgÞ 1:03 g=cm3
Fig. 1. A. Determining liver and tumor volumes by drawing ROI around the liver (blue contour) and the tumor (purple contour) on sequential axial images of the arterial phase at baseline. B. Sequential baseline MR images co-registered with 90Y bremsstrahlung SPECT images with ROI surrounding the entire liver and the treated tumor. Quantitative data were as following: Tumor volume = 377.6 cm3, liver volume = 1879.1 cm3, tumor-count = 310,384, liver-count = 668,228, intratumoral Y90 ratio = 46.5%, Y90 administered activity = 45.2 mCi, Y90 tumor activity = 0.465 × 43.3 = 20.1 mCi, Y90 tumor dose = (50 × 20.1 × 37.6) / (337.6 × 1.03) = 108.7 Gy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28 Table 2 Baseline studied patients' characteristics. Variable Age at diagnosis Gender Race Number of tumors Tumor size (cm) CA-19.9 Child-Pugh ECOG Bilirubin (mg/dL) AST (U/mL) ALT (U/mL)
Median (years) Female/male Caucasians Other ≤5 N5 Mean Range Increased Normal A B or above 0 ≥1 Mean Mean Mean
Glass (n = 5)
Resin (n = 5)
p value
61.8 3/2 3 (60%) 2 (40%) 3 (60%) 2 (40%) 7.4 2.8–11.4 3 (60%) 2 (40%) 4 (80%) 1 (20%) 2 (40%) 3 (60%) 1.7 41 57
62.7 2/3 3 (60%) 2 (40%) 4 (80%) 1 (20%) 6.8 1.6–12.3 3 (60%) 2 (40%) 3 (60%) 2 (40%) 2 (40%) 3 (60%) 1.2 48 41
0.43 0.53 1 0.49 0.37 1 0.49 1 0.28 0.68 0.41
ECOG: Eastern Cooperative Oncology Group, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase.
Liver dose ðGyÞ ¼
Y90 liver activity ðGBqÞ 50 Liver volume cm3 1:03 g=cm3
Unit activity delivered to tumor (Y90 tumor unit activity) was defined as radioactivity delivered to each cubic centimeter of treated tumor using the following equation: Y90 tumor activity ðMBqÞ 3 Y90 tumor unit activity MBq=cm ¼ Tumor volume cm3 All segmentations and calculations were confirmed by nuclear medicine and interventional radiologists with at least 10 years of experience. Fig. 1A and B demonstrates how Y90 tumor dose is calculated in a patient with central ICC. ROIs were drawn around the tumor and the liver on baseline CT Abdomen Liver mass protocol exam using the proposed method. Then, the CT images were fused with post Y90 Bremsstrahlung exam.
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levels of Tc-99m MAA uptake (Table 3, p = 0.63). Similarly, there was no significant difference in HPFS of two groups (p = 0.83). However, the administered Y90 activity of the Glass group was higher than the Resin group (Table 3, p b 0.001). 3.3. Y90 distribution in tumor and normal liver parenchyma 3.3.1. Intratumoral Y90 uptake A larger proportion of Y90 was taken up by tumors in the Glass group compared to the Resin group, 41.3% versus 33.5% respectively (Fig. 2A, p b 0.001). 3.3.2. Tumor Y90 dose The mean Y90 dose within the targeted tumors in the Glass group was higher than the Resin group (205.7 ± 19.7 versus128.9 ± 10.6 Gy, p b 0.001; Fig. 2B). 3.3.3. Normal liver parenchyma Y90 dose In addition, Y90 dose in normal liver parenchyma was lower in the Glass group when compared to the Resin group, respectively 42.4 ± 4.5 versus 53.6 ± 4.3 Gy (Fig. 2C, b0.001). 3.3.4. Tumor to normal liver parenchyma Y90 dose ratio Furthermore, there was a significantly higher ratio of Y90 dose delivered to the tumor vs. normal liver in the Glass group compared to the Resin group, 4.9 ± 0.7 versus 2.4 ± 0.3 respectably (Fig. 2D, p b 0.001). 3.3.5. Y90-RE toxicity The Table 4 demonstrates the toxicity of Y90-RE in both groups. No mortality or serious side effects was happened within 30 days after Y90-RE. There were no Y90–related complications, including gastrointestinal ulceration or pneumonitis, in either of groups. No radiation induced renal toxicity was observed. The most common treatmentrelated complication was transient fatigue, experienced by all patients in each group; these symptoms were resolved within the first post therapy week without requiring hospitalization. Overall, all patients developed some degree of transient liver toxicity after Y90-RE in both Glass and Resin groups. None of the patients required hospitalization for hepatobiliary toxicity and no sequel of hepatobiliary toxicity happened within 6 months from treatment.
2.10. Statistical analysis 4. Discussion All statistical analysis and data management were performed using SPSS statistical software package for windows version 24.0 (IBM Inc., Armonk, New York). All quantitative data are presented as mean ± standard deviation (SD), while qualitative data are shown as numbers and percentage. Fisher exact test and Mann-Whitney U test were used to compare Glass and Resin groups. A p value of b0.05 was considered significant. 3. Results 3.1. Baseline characteristics Overall, 10 patients were included in this study, five each group. The baseline characteristics of both groups are summarized in Table 2. There was no significant difference in baseline demographic and clinical characteristics of two groups. 3.2. Tc-99m MAA dose and tumor uptake, HPSF and administered Y90 activity No extrahepatic activity was observed during this study. Similar dose of Tc-99m MAA was administered in both groups at origin of proper hepatic artery (p = 0.71). Both groups demonstrated similar
Our findings showed that Y90 glass microsphere delivers significantly higher estimated Y90 tumor to normal liver paranchyma dose in the ICC patients, which is at least in part due to higher activity administered. Overall, it is validated that local radiotherapies normally deliver a total radiation dose between 20 and 60 Gy up to 1 cm from the source [28]. Though study on three-dimensional conformal radiation therapy (3D-CRT) in inoperable ICC recommended that higher total radiation doses delivered per fraction should be considered for ICC patients to achieve biologic equivalent dose N80.5 Gy [29]. All external beam radiation studies, particularly stereotactic body radiation therapy (SBRT), suggest a dose response relationship, to the point that radiation segmentectomy using Y90 glass microspheres providing an ablating radiation dose (N200 Gy) resulted in survival rate similar to surgical resection in patients with focal hepatocellular carcinoma but ineligible for surgical resection [30]. Overall, glass microspheres deliver higher radiation doses, compared to resin microsphere, which is mostly due to the higher Y90 activity administered based on the manufacture instruction [19,25]. Higher dose of radiation delivered by Y90 glass microspheres potentially induces more effective DNA breaks and catastrophic cellular injury failing maintenance of genetic integrity and leading to cell death via a variety of mechanisms such as apoptosis, autophagy, necrosis, and mitotic catastrophe [31].
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Table 3 99mTc-MAA, HPSF and administered Y90 activity in Resin and Glass microsphere groups.
Tc-99m MAA
Administered Y90 activity
Administered dose
mCi MBq
Tumor uptake (%) HPSF (%) mCi GBq
Glass
Resin
p value
5.1 ± 0.4 188.7 ± 14.8 72.3 7.1 73.2 ± 24.3 2.75 ± 0.90
4.9 ± 0.3 181.3 ± 11.1 68.6 6.2 44.5 ± 18.2 1.67 ± 0.67
0.71 0.63 0.83 b0.001
Tc-99m MAA: technetium-99m-labeled macroaggregated albumin, HPSF: Heptopulmonary shunt fraction.
The ideal radiation therapy is to deliver as high as possible lethal doses of radiation to tumors while exposing the normal liver parenchyma to as less as possible radiation doses [9]. This desired pattern was also better fulfilled by glass microspheres, presumably due to the microspheres features (Table 5). Y90 glass microspheres radioembolization permits radiation dose escalation without significant increment in normal tissue toxicity, thereby increasing the effective radiation dose [32]. The higher doses of radiation delivered through different methods of external radiation therapies to inoperable ICC, mere millimeters from luminal organs, were well tolerated, and improved local tumor control which translated into a major survival benefit comparable to those reported after surgical resection [29,33]. Preliminary studies of primary hepatic tumors have also suggested that higher Y90 tumor dose predicts objective imaging response according to European Association of Study of Liver criteria assessing the degree tumor necrosis [10,11].
No mortality happened during 30 days post treatment as well as side effects during the current study, which has been validated in prior reports [34,35]. The well-known post-treatment side effects are categorized into post-radioembolization syndrome (PRS), gastrointestinal ulceration, hepatic dysfunction, biliary squeal, portal hypertension, radiation pneumonitis, vascular injury, lymphopenia and a miscellaneous category [36]. PRS is the most common complications reported as high as 70 to 80% in literatures [2]. All patients in both groups developed post treatment PRS in this study. No extrahepatic deposition of activity including radiation induced gastroesophageal junction ulcer or pneumonitis was seen in any of groups. Only two such case reports of gastroesophageal junction ulcer have been reported till today [36–39], and partially coiled aberrant esophageal artery has been reported as the underlying cause of this morbidity [37]. No case of portal vein thrombosis is seen in any of groups as well. Early after radioembolization, induction
Fig. 2. A. Intratumoral Y90 activity. B. Tumor Y90 dose. C. Normal liver parenchyma Y90 dose. D. Tumor to normal liver parenchyma Y90 dose ratio. All Intratumoral Y90 activity, tumor Y90 dose, and tumor to normal liver parenchyma Y90 dose ratio were higher in Glass group, while normal liver parenchyma Y90 dose was higher in Resin group (p b 0.001).
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Table 4 Post Y90 radioembolization associated toxicities. Cumulative toxicology analysis Clinical toxicities
Laboratory toxicities
Treatment-related mortality Non-specific, mild abdominal pain Fatigue Bilirubin
Transaminases (AST/ALT)
Alkaline phosphatase
Hematological toxicity (RBC, WBC, platelets) Renal toxicity
Total Grade 1 Grade 2 Grade 3 Grade ≥ 4 Total Grade 1 Grade 2 Grade ≥ 3 Total Grade 1 Grade ≥ 2 Grade 1 Any Grade
Glass
Resin
p value
0 (0%) 1 (20%) 5 (100%) 4 (80%) 2 (40%) 2 (40%) 0 0 5 (100%) 4 (80%) 1 (20%) 0 2 (40%) 1 (20%) 0 1 (20%) 0
0% 1 (20%) 5 (100%) 5 (100%) 2 (40%) 2 (40%) 1 (20%) 0% 4 (80) 3(60%) 1 (20%) 0% 3 (60%) % 2 (20%) % 0% 1 (20%) % 0%
1 1 1 0.52
0.38
0.28
1 1
AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, RBC: Red blood cell, WBC: White blood cell.
of oxidative stress and simultaneously proinflammatory pathways may result in endothelial injury with activation of the coagulation cascade, particularly with higher doses. Our study was limited to a small studied population (n = 10). It must be reiterated that this study used a semi- quantitative method to estimate intratumoral Y90 dose, which was examined before [13]. A true quantitative dosimetry is more complex than the simple methodology using Bremsstrahlung imaging. Although most energy is deposited locally owing to the short mean path of beta particles from Y90, the apparent activity recorded from the low-energy polychromatic nature of the Bremsstrahlung photons may lead to indefinable errors in accuracy. Nevertheless, same methodology was used for both groups, which decreased the risk of error. Though, this methodology needs to be validated using quantitative techniques such as positron emission tomography [40]. Another possible source of bias could be the difference in location of Y90 microcatheters in different patients during administration. In this study, Y90 microcatheters were placed at the origin of the proper hepatic artery in both groups to avoid any discrepancy. In this study, none of patients had a bilobar, central or infiltrative tumor that was supplied by bilateral/variant hepatic arterial systems, which could be a potential general source of bias. Furthermore, studied groups population was different in baseline characteristics; the patients treated with Y90 glass microspheres concurrently received gemcitabine, while the patients underwent Y90 resin microspheres had chemorefractory ICC. The ideal dose calculation and Y90 biodistribution may be more accurate on treatment-naïve ICC and different between previously treated and treatment naïve ICC. As another limitation, the current study did not investigate potential effect of these microspheres on overall survival, progress free disease or long-term toxicity, which could be addressed by future studies.
Table 5 Comparison of Y90 glass and resin microspheres [12]. Parameter
Glass (TheraSphere)
Resin (SIR-Spheres)
Size Isotope Dose Manufacture Specific gravity Activity/sphere Right liver dose Status Endpoint Number of microspheres
20–30 μm Y90 in glass matrix Partition model Reactor (neutron flux) 3.6 g/dL 150–2200 Bq 4.75 GBq HDE Target dose 2.5–30 million
20–60 μm Y90 on resin surface Body surface model Generator (Sr-90) 1.6 g/dL 65–140 Bq 1.5 GBq PMA Target dose or stasis 15–19 million
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N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28 Liver criteria using delayed-phase imaging at an early time point predict survival in patients with unresectable intrahepatic cholangiocarcinoma following yttrium-90 radioembolization. J Vasc Interv Radiol 2014;25:256–65. Gallio E, Richetta E, Finessi M, Stasi M, Pellerito RE, Bisi G, et al. Calculation of tumour and normal tissue biological effective dose in 90Y liver radioembolization with different dosimetric methods. Phys Med 2016;32:1738–44. Salem R, Thurston KG, Carr BI, Goin JE, Geschwind JF. Yttrium-90 microspheres: radiation therapy for unresectable liver cancer. J Vasc Interv Radiol 2002;13:S223–9. Salem R, Lewandowski RJ, Gates VL, Nutting CW, Murthy R, Rose SC, et al. Research reporting standards for radioembolization of hepatic malignancies. J Vasc Interv Radiol 2011;22:265–78. Berger MJ. Distribution of absorbed dose around point sources of electrons and beta particles in water and other media. J Nucl Med 1971(Suppl. 5):5–23. Bolch WBE, Eckerman KF, Sgouros G, Thomas SR. In: SoN medicine, editor. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetry—standardization of nomenclature. New York: Society of Nuclear Medicine; 2009. Prajapati HJ, Rafi S, Edalat F, Kooby DA, Kim HS. Safety and efficacy of a circumferential clip-based vascular closure device in cirrhotic and coagulopathic patients with hepatocellular carcinoma after doxorubicin drug-eluting beads transarterial chemoembolization. Cardiovasc Intervent Radiol 2014;37:664–70. Services UDoHaH. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; 2009. Limited SM. SIR-spheres package insert; 2004. Ljungberg M, Sjogreen-Gleisner K. The accuracy of absorbed dose estimates in tumours determined by quantitative SPECT: a Monte Carlo study. Acta Oncol 2011; 50:981–9. Minarik D, Ljungberg M, Segars P, Gleisner KS. Evaluation of quantitative planar 90Y bremsstrahlung whole-body imaging. Phys Med Biol 2009;54:5873–83. Nakeeb A, Pitt HA. Radiation therapy, chemotherapy and chemoradiation in hilar cholangiocarcinoma. HPB (Oxford) 2005;7:278–82. Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT, et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol 2016;34:219–26.
[30] Braat AJ, Smits ML, Braat MN, van den Hoven AF, Prince JF, de Jong HW, et al. (9)(0)Y hepatic radioembolization: an update on current practice and recent developments. J Nucl Med 2015;56:1079–87. [31] Chaudhry MA. Biomarkers for human radiation exposure. J Biomed Sci 2008;15: 557–63. [32] Czito BG, Anscher MS, Willett CG. Radiation therapy in the treatment of cholangiocarcinoma. Oncology (Williston Park) 2006;20:873–84 [discussion 86–8, 93–5]. [33] Sulpice L, Rayar M, Boucher E, Pracht M, Meunier B, Boudjema K. Treatment of recurrent intrahepatic cholangiocarcinoma. Br J Surg 2012;99:1711–7. [34] Michl M, Haug AR, Jakobs TF, Paprottka P, Hoffmann RT, Bartenstein P, et al. Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: efficacy, safety and prognostic factors. Oncology 2014;86:24–32. [35] Ludwig JM, Ambinder EM, Ghodadra A, Xing M, Prajapati HJ, Kim HS. Lung shunt fraction prior to Yttrium-90 radioembolization predicts survival in patients with neuroendocrine liver metastases: single-center prospective analysis. Cardiovasc Intervent Radiol 2016;39:1007–14. [36] Riaz A, Lewandowski RJ, Kulik LM, Mulcahy MF, Sato KT, Ryu RK, et al. Complications following radioembolization with yttrium-90 microspheres: a comprehensive literature review. J Vasc Interv Radiol 2009;20:1121–30 [quiz 31]. [37] Jia Z, Paz-Fumagalli R, Frey G, Sella DM, McKinney JM, Wang W. Resin-based Yttrium-90 microspheres for unresectable and failed first-line chemotherapy intrahepatic cholangiocarcinoma: preliminary results. J Cancer Res Clin Oncol 2017;143:481–9. [38] Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-ofthe-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol 2006;17: 1251–78. [39] Ghorashi S, Maghzi AH, Nezami S, Maghzi H, Ghodratnejad N, Mojtehedi M, et al. Introducing two new devises for blood warming. J Res Med Sci 2012;17: S281–5. [40] Srinivas SM, Natarajan N, Kuroiwa J, Gallagher S, Nasr E, Shah SN, et al. Determination of radiation absorbed dose to primary liver tumors and normal liver tissue using post-radioembolization (90)Y PET. Front Oncol 2014;4:255.
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Nuclear Medicine and Biology journal homepage: www.elsevier.com/locate/nucmedbio
Y90 radioembolization dosimetry using a simple semi-quantitative method in intrahepatic cholangiocarcinoma: Glass versus resin microspheres Nariman Nezami a, Nima Kokabi a, Juan C. Camacho b, David M. Schuster c, Minzhi Xing a, Hyun S. Kim a,d,⁎ a
Division of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, USA Department of Radiology, Medical University of South Caroline, Charleston, SC, USA c Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA, USA d Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA b
a r t i c l e
i n f o
Article history: Received 18 September 2017 Received in revised form 26 December 2017 Accepted 10 January 2018 Available online xxxx Keywords: Intrahepatic cholangiocarcinoma Y90 Radioembolization Dosimetry Glass Resin
a b s t r a c t Introduction: There are two different types of Y90 Microspheres, glass and resin, in the market for Y90 radioembolization (Y90-RE). This study aimed to investigate the dose of radiation delivered through glass vs. resin-based Y90-RE to intrahepatic cholangiocarcinoma (ICC). Methods: In this retrospective study, 10 patients with ICC underwent Y90-RE, five underwent glass (Glass group) and other 5 resin (Resin group) microspheres. Technetium-99m macro-aggregated albumin (Tc-99m MAA) shunt study was performed two weeks before Y90-RE. Within 2 h from Y90-RE, Bremsstrahlung SPECT/CT was obtained. Regions of interest (ROIs) were segmented around the targeted tumor and the liver. Tumor and liver volumes, corresponding radioactive counts, and tumor to liver count ratio were calculated using MIM software and compared between Glass and Resin groups. Results: Mean hepatopulmonary shunt fraction was 7.1 vs. 6.2% for the Glass and Resin groups (p = 0.83), with no extrahepatic activity. There was no difference in the activity and tumor uptake of administered Tc-99m MAA between both groups (p = 0.71 and p = 0.63). Mean administered activity of Y90 in the Glass group was higher than the Resin group (73.2 ± 24.3 vs. 44.5 ± 18.2 mCi, p b 0.001). The tumor Y90 uptake was significantly higher in the Glass group compared to the Resin group (41.3% vs. 33.5%, p b 0.001), corresponding to the mean tumor dose of 205.7 ± 19.7 vs. 128.9 ± 10.6 Gy, respectively (p b 0.001). The tumor to normal liver parenchyma Y90 dose ratio was significantly higher in the Glass group compared to the Resin group, 4.9 ± 0.7 versus 2.4 ± 0.3 respectably (p b 0.001). Conclusions: Both Y90 glass and resin-based microsphere Y90-RE are feasible and safe in patients with ICC, while Y90 glass microsphere delivers higher dose of Y90 to the targeted tumors. Advances in knowledge: While both Y90 glass and resin-based microsphere yttrium-90 radioembolization are feasible and safe treatment options for in patients with intrahepatic cholangiocarcinoma, Y90 glass microsphere delivers higher dose of Y90 to the targeted tumors. Implications for patient care: Both of Y90 glass and resin-based microsphere can be safely and feasibly used for treatment of intrahepatic cholangiocarcinoma, difference in dose of Y90 delivered to the targeted tumors should be clinically considered while choosing the microsphere type. © 2018 Elsevier Inc. All rights reserved.
1. Introduction Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic cancer [1]. Although ICC is relatively uncommon, its growing incidence currently accounts for up to 15% of primary liver
⁎ Corresponding author at: Yale University School of Medicine, Yale Cancer Center, 330 Cedar Street, TE 2-224, New Haven, CT 06510, USA. E-mail address: [email protected] (H.S. Kim). https://doi.org/10.1016/j.nucmedbio.2018.01.001 0969-8051/© 2018 Elsevier Inc. All rights reserved.
cancers with an age-adjusted rate of about 2.1/100,000 people per year in western countries [2]. Despite the new advances in chemotherapy and radiation therapy, surgical resection still remains the only potential curative treatment [3]. However, up to 40% of ICC patients are not candidate for surgical resection by the time of diagnosis [4]. Untreated patients with unresectable ICCs have a median survival of b8 month, which can be increased up to approximately 12 months with systemic therapies [2,5,6]. Locoregional therapies, including embolotherapies and ablative procedures have shown benefits, improving survival [7].
N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28
Given the relative radiation sensitivity of ICC [8], yttrium-90 radioembolization (Y90-RE) has been introduced as a source for internal radiation, and shown as a safe and efficient locoregional treatment [2,7]. The goal of Y90-RE is to deliver lethal doses of radiation to tumors but sublethal doses to normal parenchyma [9], and preliminary results from a few studies have suggested that higher Y90 tumor dose predicts objective (complete or partial) imaging response according to European Association of Study of Liver criteria assessing the degree tumor necrosis [10,11]. Currently, two different types of Y90 Microspheres, glass and resin, with distinct futures are available in the market for Y90-RE [2,12]. In this study, we used our previously validated simple semi-quantitative method [13] to estimate the biodistribution of Y90 delivered to the targeted liver lobe and ICC tumor(s), as well as intratumoral dose of Y90 based on glass and resin microspheres. 2. Methods and materials 2.1. Study design and objectives In this retrospective, single-center, institutional review board approved study, patients with hepatic dominant ICC were enrolled for Y90-RE. Ten consecutive patients with ICC who had radioembolization with glass or resin were included in this study. 2.2. Study population and eligibility criteria All patients were evaluated by a multidisciplinary cancer tumor board, composed of interventional radiologist, medical oncologist, gastroenterologist, and pharmacist, and were found to meet the criteria for Y90-RE. Information on demographics, baseline disease characteristics, and previous therapies was recorded at the patients' first visit. Subsequent follow-up visits were done to concomitant treatments, adverse events, and outcomes were collected. Patients 18 years or older with histopathologic diagnosis of ICC were screened for the following inclusion and exclusion criteria (Table 1). The patients who met all the inclusion and exclusion criteria were enrolled into the study. The patients treated with Y90 glass microsphere had a naïve ICC tumor and were part of a prospective trial with concurrent treatment of Y90-RE and gemcitabine [14], whereas the patients treated with
Table 1 Study inclusion and exclusion criteria. Inclusion criteria
Exclusion criteria
1. Predominant unresectable intrahepatic cholangiocarcinoma or hepatic tumor of liver from pancreatic adenocarcinoma 2. Native intrahepatic cholangiocarcinoma in Glass group and chemorefractory in Resin group 3. Limited extra hepatic metastasis as i) Six or less nodules with no nodule N1.5 cm in lungs, ii) abdominal lymph nodes, iii) pancreatic primary as long as the size is b4 cm in size, iv) bone metastasis.
1. Uncorrectable gastrointestinal flow on diagnostic angiogram.
4. Measurable target tumors using standard imaging techniques 5. Eastern Cooperative Oncology Group (ECOG) performance score 0–1 6. b20% lung shunting fraction (LSF) and estimated lung dose N30 Gy.
2. Contraindication to angiography
Inadequate hepatic function by Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ratio of more than five times higher than normal limit, bilirubin N2.0 mg/dl, serum albumin b2.5 g/dL or history of hepatic encephalopathy. 3. Prior external beam radiotherapy to the upper abdomen 4. Clinical evidence of peritoneal metastasis or ascites 5. Tumor burden of N75% of entire liver 6. Any serious ongoing extra-hepatic disease such as infections
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Y90 resin microsphere were a part of another clinical trial and had chemorefractory ICC [15–17]. 2.3. Hepatic vascular mapping and hepatopulmonary shunt evaluation All enrolled patients underwent hepatopulmonary shunt study and diagnostic angiography of the celiac and superior mesenteric arteries. Based on the baseline imaging studies, a selective lobar hepatic artery angiogram was obtained to identify hypervascular lesions. If required, embolization of the gastroduodenal, right gastric, or left gastric branch artery or combination of arteries was performed using coils to prevent non-targeted embolization of stomach or duodenum. No other nearby artery required embolization in this study. In addition, the enrolled patients had hepatopulmonary shunt study, to exam any possible extrahepatic shunt. Approximately 148 MBq (4 mCi) of technetium-99m macro-aggregated albumin (Tc-99m MAA) was administered using a 3-Fmicrocatheter placed at the origin of the common hepatic artery. Planar and SPECT/CT images were then obtained and lung shunt fraction (LSF) were calculated using planar images, and the presence of extrahepatopulmonary activity was evaluated on both planar and SPECT images. 2.4. Y90 therapy planning Treatment planning was performed according to the manufacturer's recommendation and published guidelines [18,19]. Based on the volume of the liver lobe to be treated, the amount of desirable activity for Y90 was calculated using the following formula: Activity desired ðGBqÞ ¼
Target dose ðGyÞ Lobe liver mass ðkgÞ 50
Alternatively, the activity for Resin-based Y90 was calculated in the following fashion: Administered activity ðGBqÞ ¼ ðBSA–0:2Þ þ
%Tumor involvement 100
where, %Tumor Involvement ¼
Volume of tumor 100 Volume of liver
The mass of the liver lobe to be treated was estimated by determining the volume of the lobe using a medical image processing software, MIM v 5.6.1 (MIM Software Inc., Cleveland, Ohio); region of interest (ROI) was Created using a combination of edge enhancement with manual adjustment surrounding the liver lobe on sequential axial images of baseline MR imaging. The volume was calculated by the software, and liver mass was determined assuming density of 1.03 g/cm 3 of liver tissue. Based on recommended guidelines, 120 Gy was used as a target dose to the treated liver lobe [20]. The radiation dose to the lungs was estimated using the following formula [21]: Lung radiation dose ðGyÞ ¼
Activity ðGBqÞ LSF 50 Mass of lungs ðkgÞ
With total lung mass assumed to be 1 kg [22]. Maximum per treatment lung dose was set at 30 Gy with maximum cumulative lung dose of 50 Gy. Administered activity was reduced in patients with predicted lung dose of ≥30 Gy based on initial assumptions during abovedescribed planning. 2.5. Y90 radioembolization procedure Y90 microspheres were administered based on previously described guidelines [20]. On an outpatient basis, using sterile femoral arterial
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N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28
approach, a 3-F microcatheter was placed at the origin of the corresponding lobar artery supplying the targeted tumor. The preplanned Y90 activity was administered at low pressure (20–40 psi). A circumferential clip-based vascular closure device was used to achieve hemostasis at the femoral artery access site [23]. The patients were then transferred to the nuclear medicine department for Y90 Bremsstrahlung SPECT/CT. Once, the scan was done, the patients were observed for 3 h in the post procedural recovery area and then discharged home if stable. Patients were followed up in the Interventional Oncology Clinic at 1 week, 1 month, and 3 months after Y90 therapy and every 3 months thereafter. During each clinical follow-up examination, a complete blood chemistry panel was obtained to evaluate for organ-specific toxicity using Common Terminology Criteria for Adverse Events version 4.03 [24].
2.8. Bremsstrahlung SPECT/CT Within b2 h from Y90-RE, the patient was transferred to the nuclear medicine department, and Y90 Bremsstrahlung SPECT/CT was carried out to ensure delivery of the radiopharmaceutical to the targeted lesion. Bremsstrahlung SPECT/CT was performed on the same scanner used for hepatopulmonary shunt study using the following setting 75 keV, 54% energy window, 30 stops at 40 s per stop for 60 projections. SPECT reconstruction was done using the manufacturer's ordered subset expectation maximization–based software (2 subsets, 30 iterations) with attenuation correction. CT-based attenuation correction used an attenuation coefficient for the center of the energy window. In the liver, attenuation correction or Bremsstrahlung could be performed semiquantitative, to produce a more uniform distribution of activity [26,27]. 2.9. Analysis of intrahepatic biodistribution of Y90
2.6. Y90 glass microsphere Five patients underwent Y90 Glass microsphere radioembolization (TheraSphere ®, BTG Interventional Medicine Inc., London, UK) after detailed treatment planning according to the manufacturer's recommendation and published guidelines [2,19]. The recommended method for activity calculation is based on the Medical Internal Radiation Dose (MIRD) model of single compartment. It is recommended to calculate the activity using the MIRD model in order to deliver an absorbed dose to the treated volume of 80–150 mGy, based on patient specific characteristics (target tumor size and lung shunt). Although the radiation is not distributed uniformly, the MIRD formalism is effective in guiding users in the selection of the proper activity of the glass microspheres for destroying the tumor and avoiding radiation-induced liver damage [22].
2.7. Y90 resin microsphere Y90 Resin microsphere (SIR-Spheres ®, Sirtex Medical Inc., Lane Cove, NSW, Australia) was used for radioembolization of other five patients. The partition model method based on the MIRD formalism and three compartments: lung, tumor and normal liver. The partition model is well described in the User's Manual and Package Insert provided by the manufacturer [2,25]. The partition model method, that is the only true dosimetric approach at the treatment, should always be used when the tumor can be localized as a discrete volume and clearly identified as an area of interest on single-photon emission CT imaging, acquired after the intrahepatic administration of Tc99m MAA.
The MIM image processing software was again used to delineate a three dimensional ROI around the targeted tumor using a combination of automated edge enhancement option and manual correction. A second ROI was drawn along the entire liver. Tumor and Liver volumes were calculated (Fig. 1A). Using the same method described previously, baseline CT abdomen imaging with tumor and entire liver ROI was fused with Y90 Bremsstrahlung SPECT/CT (Fig. 1B). Proportional Y90 activity delivered to the tumor was calculated using the following formula: Y90 tumor to liver ratio ¼
Tumor Y90 count Liver Y90 count
Based on the administered activity (total activity) during the radioembolization procedure and LSF, Y90 activity delivered to the tumor(s) and liver were estimated using the following formulas: Y90 tumor activity ðGBqÞ ¼
Y90 livr activity ðGBqÞ ¼
Y90 tumor dose ðGyÞ Tumor mass ðkgÞ 50
Tumor dose ðGyÞ Tumor Mass ðkgÞ 50
Y90 dose to the targeted tumor(s) and liver were calculated using the following formulas: Y90 tumor dose ðGyÞ ¼
Y90 tumor activity ðGBqÞ 50 Tumor mass ðkgÞ 1:03 g=cm3
Fig. 1. A. Determining liver and tumor volumes by drawing ROI around the liver (blue contour) and the tumor (purple contour) on sequential axial images of the arterial phase at baseline. B. Sequential baseline MR images co-registered with 90Y bremsstrahlung SPECT images with ROI surrounding the entire liver and the treated tumor. Quantitative data were as following: Tumor volume = 377.6 cm3, liver volume = 1879.1 cm3, tumor-count = 310,384, liver-count = 668,228, intratumoral Y90 ratio = 46.5%, Y90 administered activity = 45.2 mCi, Y90 tumor activity = 0.465 × 43.3 = 20.1 mCi, Y90 tumor dose = (50 × 20.1 × 37.6) / (337.6 × 1.03) = 108.7 Gy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28 Table 2 Baseline studied patients' characteristics. Variable Age at diagnosis Gender Race Number of tumors Tumor size (cm) CA-19.9 Child-Pugh ECOG Bilirubin (mg/dL) AST (U/mL) ALT (U/mL)
Median (years) Female/male Caucasians Other ≤5 N5 Mean Range Increased Normal A B or above 0 ≥1 Mean Mean Mean
Glass (n = 5)
Resin (n = 5)
p value
61.8 3/2 3 (60%) 2 (40%) 3 (60%) 2 (40%) 7.4 2.8–11.4 3 (60%) 2 (40%) 4 (80%) 1 (20%) 2 (40%) 3 (60%) 1.7 41 57
62.7 2/3 3 (60%) 2 (40%) 4 (80%) 1 (20%) 6.8 1.6–12.3 3 (60%) 2 (40%) 3 (60%) 2 (40%) 2 (40%) 3 (60%) 1.2 48 41
0.43 0.53 1 0.49 0.37 1 0.49 1 0.28 0.68 0.41
ECOG: Eastern Cooperative Oncology Group, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase.
Liver dose ðGyÞ ¼
Y90 liver activity ðGBqÞ 50 Liver volume cm3 1:03 g=cm3
Unit activity delivered to tumor (Y90 tumor unit activity) was defined as radioactivity delivered to each cubic centimeter of treated tumor using the following equation: Y90 tumor activity ðMBqÞ 3 Y90 tumor unit activity MBq=cm ¼ Tumor volume cm3 All segmentations and calculations were confirmed by nuclear medicine and interventional radiologists with at least 10 years of experience. Fig. 1A and B demonstrates how Y90 tumor dose is calculated in a patient with central ICC. ROIs were drawn around the tumor and the liver on baseline CT Abdomen Liver mass protocol exam using the proposed method. Then, the CT images were fused with post Y90 Bremsstrahlung exam.
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levels of Tc-99m MAA uptake (Table 3, p = 0.63). Similarly, there was no significant difference in HPFS of two groups (p = 0.83). However, the administered Y90 activity of the Glass group was higher than the Resin group (Table 3, p b 0.001). 3.3. Y90 distribution in tumor and normal liver parenchyma 3.3.1. Intratumoral Y90 uptake A larger proportion of Y90 was taken up by tumors in the Glass group compared to the Resin group, 41.3% versus 33.5% respectively (Fig. 2A, p b 0.001). 3.3.2. Tumor Y90 dose The mean Y90 dose within the targeted tumors in the Glass group was higher than the Resin group (205.7 ± 19.7 versus128.9 ± 10.6 Gy, p b 0.001; Fig. 2B). 3.3.3. Normal liver parenchyma Y90 dose In addition, Y90 dose in normal liver parenchyma was lower in the Glass group when compared to the Resin group, respectively 42.4 ± 4.5 versus 53.6 ± 4.3 Gy (Fig. 2C, b0.001). 3.3.4. Tumor to normal liver parenchyma Y90 dose ratio Furthermore, there was a significantly higher ratio of Y90 dose delivered to the tumor vs. normal liver in the Glass group compared to the Resin group, 4.9 ± 0.7 versus 2.4 ± 0.3 respectably (Fig. 2D, p b 0.001). 3.3.5. Y90-RE toxicity The Table 4 demonstrates the toxicity of Y90-RE in both groups. No mortality or serious side effects was happened within 30 days after Y90-RE. There were no Y90–related complications, including gastrointestinal ulceration or pneumonitis, in either of groups. No radiation induced renal toxicity was observed. The most common treatmentrelated complication was transient fatigue, experienced by all patients in each group; these symptoms were resolved within the first post therapy week without requiring hospitalization. Overall, all patients developed some degree of transient liver toxicity after Y90-RE in both Glass and Resin groups. None of the patients required hospitalization for hepatobiliary toxicity and no sequel of hepatobiliary toxicity happened within 6 months from treatment.
2.10. Statistical analysis 4. Discussion All statistical analysis and data management were performed using SPSS statistical software package for windows version 24.0 (IBM Inc., Armonk, New York). All quantitative data are presented as mean ± standard deviation (SD), while qualitative data are shown as numbers and percentage. Fisher exact test and Mann-Whitney U test were used to compare Glass and Resin groups. A p value of b0.05 was considered significant. 3. Results 3.1. Baseline characteristics Overall, 10 patients were included in this study, five each group. The baseline characteristics of both groups are summarized in Table 2. There was no significant difference in baseline demographic and clinical characteristics of two groups. 3.2. Tc-99m MAA dose and tumor uptake, HPSF and administered Y90 activity No extrahepatic activity was observed during this study. Similar dose of Tc-99m MAA was administered in both groups at origin of proper hepatic artery (p = 0.71). Both groups demonstrated similar
Our findings showed that Y90 glass microsphere delivers significantly higher estimated Y90 tumor to normal liver paranchyma dose in the ICC patients, which is at least in part due to higher activity administered. Overall, it is validated that local radiotherapies normally deliver a total radiation dose between 20 and 60 Gy up to 1 cm from the source [28]. Though study on three-dimensional conformal radiation therapy (3D-CRT) in inoperable ICC recommended that higher total radiation doses delivered per fraction should be considered for ICC patients to achieve biologic equivalent dose N80.5 Gy [29]. All external beam radiation studies, particularly stereotactic body radiation therapy (SBRT), suggest a dose response relationship, to the point that radiation segmentectomy using Y90 glass microspheres providing an ablating radiation dose (N200 Gy) resulted in survival rate similar to surgical resection in patients with focal hepatocellular carcinoma but ineligible for surgical resection [30]. Overall, glass microspheres deliver higher radiation doses, compared to resin microsphere, which is mostly due to the higher Y90 activity administered based on the manufacture instruction [19,25]. Higher dose of radiation delivered by Y90 glass microspheres potentially induces more effective DNA breaks and catastrophic cellular injury failing maintenance of genetic integrity and leading to cell death via a variety of mechanisms such as apoptosis, autophagy, necrosis, and mitotic catastrophe [31].
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N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28
Table 3 99mTc-MAA, HPSF and administered Y90 activity in Resin and Glass microsphere groups.
Tc-99m MAA
Administered Y90 activity
Administered dose
mCi MBq
Tumor uptake (%) HPSF (%) mCi GBq
Glass
Resin
p value
5.1 ± 0.4 188.7 ± 14.8 72.3 7.1 73.2 ± 24.3 2.75 ± 0.90
4.9 ± 0.3 181.3 ± 11.1 68.6 6.2 44.5 ± 18.2 1.67 ± 0.67
0.71 0.63 0.83 b0.001
Tc-99m MAA: technetium-99m-labeled macroaggregated albumin, HPSF: Heptopulmonary shunt fraction.
The ideal radiation therapy is to deliver as high as possible lethal doses of radiation to tumors while exposing the normal liver parenchyma to as less as possible radiation doses [9]. This desired pattern was also better fulfilled by glass microspheres, presumably due to the microspheres features (Table 5). Y90 glass microspheres radioembolization permits radiation dose escalation without significant increment in normal tissue toxicity, thereby increasing the effective radiation dose [32]. The higher doses of radiation delivered through different methods of external radiation therapies to inoperable ICC, mere millimeters from luminal organs, were well tolerated, and improved local tumor control which translated into a major survival benefit comparable to those reported after surgical resection [29,33]. Preliminary studies of primary hepatic tumors have also suggested that higher Y90 tumor dose predicts objective imaging response according to European Association of Study of Liver criteria assessing the degree tumor necrosis [10,11].
No mortality happened during 30 days post treatment as well as side effects during the current study, which has been validated in prior reports [34,35]. The well-known post-treatment side effects are categorized into post-radioembolization syndrome (PRS), gastrointestinal ulceration, hepatic dysfunction, biliary squeal, portal hypertension, radiation pneumonitis, vascular injury, lymphopenia and a miscellaneous category [36]. PRS is the most common complications reported as high as 70 to 80% in literatures [2]. All patients in both groups developed post treatment PRS in this study. No extrahepatic deposition of activity including radiation induced gastroesophageal junction ulcer or pneumonitis was seen in any of groups. Only two such case reports of gastroesophageal junction ulcer have been reported till today [36–39], and partially coiled aberrant esophageal artery has been reported as the underlying cause of this morbidity [37]. No case of portal vein thrombosis is seen in any of groups as well. Early after radioembolization, induction
Fig. 2. A. Intratumoral Y90 activity. B. Tumor Y90 dose. C. Normal liver parenchyma Y90 dose. D. Tumor to normal liver parenchyma Y90 dose ratio. All Intratumoral Y90 activity, tumor Y90 dose, and tumor to normal liver parenchyma Y90 dose ratio were higher in Glass group, while normal liver parenchyma Y90 dose was higher in Resin group (p b 0.001).
N. Nezami et al. / Nuclear Medicine and Biology 59 (2018) 22–28
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Table 4 Post Y90 radioembolization associated toxicities. Cumulative toxicology analysis Clinical toxicities
Laboratory toxicities
Treatment-related mortality Non-specific, mild abdominal pain Fatigue Bilirubin
Transaminases (AST/ALT)
Alkaline phosphatase
Hematological toxicity (RBC, WBC, platelets) Renal toxicity
Total Grade 1 Grade 2 Grade 3 Grade ≥ 4 Total Grade 1 Grade 2 Grade ≥ 3 Total Grade 1 Grade ≥ 2 Grade 1 Any Grade
Glass
Resin
p value
0 (0%) 1 (20%) 5 (100%) 4 (80%) 2 (40%) 2 (40%) 0 0 5 (100%) 4 (80%) 1 (20%) 0 2 (40%) 1 (20%) 0 1 (20%) 0
0% 1 (20%) 5 (100%) 5 (100%) 2 (40%) 2 (40%) 1 (20%) 0% 4 (80) 3(60%) 1 (20%) 0% 3 (60%) % 2 (20%) % 0% 1 (20%) % 0%
1 1 1 0.52
0.38
0.28
1 1
AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, RBC: Red blood cell, WBC: White blood cell.
of oxidative stress and simultaneously proinflammatory pathways may result in endothelial injury with activation of the coagulation cascade, particularly with higher doses. Our study was limited to a small studied population (n = 10). It must be reiterated that this study used a semi- quantitative method to estimate intratumoral Y90 dose, which was examined before [13]. A true quantitative dosimetry is more complex than the simple methodology using Bremsstrahlung imaging. Although most energy is deposited locally owing to the short mean path of beta particles from Y90, the apparent activity recorded from the low-energy polychromatic nature of the Bremsstrahlung photons may lead to indefinable errors in accuracy. Nevertheless, same methodology was used for both groups, which decreased the risk of error. Though, this methodology needs to be validated using quantitative techniques such as positron emission tomography [40]. Another possible source of bias could be the difference in location of Y90 microcatheters in different patients during administration. In this study, Y90 microcatheters were placed at the origin of the proper hepatic artery in both groups to avoid any discrepancy. In this study, none of patients had a bilobar, central or infiltrative tumor that was supplied by bilateral/variant hepatic arterial systems, which could be a potential general source of bias. Furthermore, studied groups population was different in baseline characteristics; the patients treated with Y90 glass microspheres concurrently received gemcitabine, while the patients underwent Y90 resin microspheres had chemorefractory ICC. The ideal dose calculation and Y90 biodistribution may be more accurate on treatment-naïve ICC and different between previously treated and treatment naïve ICC. As another limitation, the current study did not investigate potential effect of these microspheres on overall survival, progress free disease or long-term toxicity, which could be addressed by future studies.
Table 5 Comparison of Y90 glass and resin microspheres [12]. Parameter
Glass (TheraSphere)
Resin (SIR-Spheres)
Size Isotope Dose Manufacture Specific gravity Activity/sphere Right liver dose Status Endpoint Number of microspheres
20–30 μm Y90 in glass matrix Partition model Reactor (neutron flux) 3.6 g/dL 150–2200 Bq 4.75 GBq HDE Target dose 2.5–30 million
20–60 μm Y90 on resin surface Body surface model Generator (Sr-90) 1.6 g/dL 65–140 Bq 1.5 GBq PMA Target dose or stasis 15–19 million
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