Y90 Radioembolization Dosimetry Using a Simple Semi-Quantitative Method in Intrahepatic Cholangiocarcinoma: Glass versus Resin Microspheres
Abbreviated title: Glass versus Resin Y90 Microspheres Dosimetry
Keywords: Intrahepatic cholangiocarcinoma, Y90, radioembolization, dosimetry, glass, resin.
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 hours from Y90-RE, Bremsstrahlung SPECT/CT was obtained. Regions of interest (ROI’s) 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 of administered Tc-99m MAA between the Glass and Resin groups (5.1 vs. 4.9 mci, p=0.71). There was no difference in mean Tc-99m MAA tumor uptake between the Glass and Resin groups (31.3% vs. 32.6%, p=0.63). Mean administered activity of Y90 in the Glass group was higher than the Resin group (67.3 vs. 43.7 mci, p<0.001). The tumor Y90 uptake was significantly higher in the Glass group compared to the Resin group (41.3% vs. 33.5%, p<0.001), corresponding to the mean tumor dose of 205.6 vs.128.9 Gy, respectively (p<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
Both Y90 glass and resin-based microsphere yttrium-90 radioembolization are feasible and safe in patients with intrahepatic cholangiocarcinoma, while Y90 glass microsphere delivers higher dose of Y90 to the targeted tumors.
Implications for patient Care
Both ofY90 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.
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic cancer . Although ICC is relatively uncommon, its growing incidence currently accounts for up to 15% of primary liver cancers with an age-adjusted rate of about 2.1/100,000 people per year in western countries .
Despite the new advances in chemotherapy and radiation therapy, surgical resection still remains the only potential curative treatment. However, up to 40% of ICC patients are not candidate for surgical resection by the time of diagnosis . Untreated patients with unresectable ICCs have a median survival of less than 8 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.
Given the relative radiation sensitivity of ICC , 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, and preliminary results from a few studies have 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].
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 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.
Methods and Materials
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 underwent radioembolization with glass or resin were included in this study.
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, whereas the patients treated with Y90 resin microsphere were a part of another clinical trial and had chemorefractory ICC[15-17].
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.
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 glass-based Y90 was calculated using the following formula:
Activity desired GBq=Target dose (Gy) x lobe liver mass (kg)50
Alternatively, the activity for Resin-based Y90 was calculated in the following fashion:
Administered ActivityGBq= (BSA – 0.2) + (% Tumor Involvement100)
% Tumor Involvement=volume of tumour x 100volume 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 1.03g/cm3 of liver tissue. Based on recommended guidelines, 120 Gy was used as a target dose to the treated liver lobe. The radiation dose to the lungs was estimated using the following formula:
Lung radiation dose Gy= Activity GBq × LSF × 50 Mass of lungs (kg)
With total lung mass assumed to be 1 kg. Maximum per treatment lung dose was set at 30 Gy with maximum cumulative lung dose of 50 Gy for patients with prior Y90 therapy. Administered activity was reduced in patients with predicted lung dose of ≥ 30 Gy based on initial assumptions during above-described planning.
Y90 radioembolization procedure
Y90 microspheres was administered based on previously described guidelines. On an outpatient basis, using sterile femoral arterial 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. 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 hours 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.
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.
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 Tc-99m MAA.
Within less than 2 hours 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 seconds 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 semi-quantitative, to produce a more uniform distribution of activity[26, 27].
Analysis of intrahepatic biodistribution of Y90
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 (Figure 1A).
Using the same method described previously, baseline CT abdomen imaging with tumor and entire liver ROI was fused with Y90 Bremsstrahlung SPECT/CT (Figure 1B). Proportional Y90 activity delivered to the tumor was calculated using the following formula:
Y90 tumor to liver ratio= 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 GBq=Y90 tumor dose Gy × Tumor mass (kg) 50
Y90 livr activity GBq= Tumor dose (Gy) × Tumor Mass (kg) 50
Y90 dose to the targeted tumor(s) and liver were calculated using the following formulas:
Y90 tumor dose Gy= Y90 tumor activity GBq × 50Tumor mass kg×1.03 (g/cm3)
Liver dose Gy=Y90 liver activity GBq × 50Liver 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 unit activity (MBq/cm3) = Y90 tumor activity (MBq)Tumor volume (cm3)
All developed contours and subsequent calculations were reviewed and agreed on by nuclear medicine and interventional radiologists with at least 10 years of experience. Figure 1 A and B demonstrates how we calculated Y90 tumor dose in a patient with central ICC. ROI’s formed around the tumor and the liver on baseline CT Abdomen Liver mass protocol exam and using our proposed method. We, then, fused the CT images with post Y90 Bremsstrahlung study.
All statistical analysis and data management were performed using SPSS statistical software package for windows version 23.0 (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 Independent sample t-test were used to compare Glass and Resin groups. A p value of less than 0.05 was considered significant.
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.
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 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<0.001).
Y90 distribution in tumor and normal liver parenchyma
Intratumoral Y90 activity
A larger proportion of Y90 was taken up by tumors in the Glass group compared to the Resin group, 41.3% vs. 33.5% respectively (Figure 2.A, p<0.001).
Tumor Y90 dose
The mean Y90 dose within the targeted tumors in the Glass group was higher than the Resin group (205.6 versus128.9 Gy, p<0.001;Figure 2.B).
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 vs. 53.6 Gy (Figure 2.C, <0.001).
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 vs. 2.4 respectably (Figure 2.D, p<0.001).
The Table 4 demonstrates the toxicity of Y90-RE in both groups. No mortality or side effects was happened within 30 days after Y90-RE. There was no Y90–related complications, including gastrointestinal ulceration or pneumonitis, in either of groups. No radiation induced renal toxicity was observed. The most common treatment-related complication was transient fatigue, experienced by one patient 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.
Our findings showed that Y90 glass microsphere delivers significantly higher estimated Y90 tumor to normal liver paranchyma dose in the ICC patients. Overall, it is validated that local radiotherapies normally deliver a total radiation dose between 20 to 60 Gy up to 1 cm from the source. 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 greater than 80.5 Gy. 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 (>200 Gy) resulted in survival rate similar to surgical resection in patients with focal hepatocellular carcinoma but ineligible for surgical resection. Overall, glass microspheres deliver higher radiation doses, compared to resin microsphere, which is mostly due to the higher Y90 dose 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.
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 . 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.
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-know 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. PRS is the most common complications reported as high as 70 to 80% in literatures. 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[36-38], and partially coiled aberrant esophageal artery has been reported as the underlying cause of this morbidity. No case of portal vein thrombosis is seen in any of groups as well. Early after radioembolization, induction 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. 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. 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.
In conclusion, Y90-RE using both glass and resin based microspheres is feasible and safe, with theglass microsphere radioembolization delivering higher estimated dose of Y90 to targeted tumors in ICC patients.
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Figure 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. Quantitiave data were as following: Tumor volume = 377.6 cm3, Liver volume = 1879.1 cm3, Tumor-count = 310384, Liver -count= 668228, Intratumoral Y90 ratio = 46.5%, Y90 administered activity= 45.2 mCi, Y90 tumor activity = 0.465 x 43.3 = 20.1 mCi, Y90 tumor dose = (50×20.1×37.6)/(337.6×1.03) = 108.7 Gy.
Figure 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<0.001).
|Table 1. Study inclusion and exclusion criteria.|
|Inclusion criteria||Exclusion criteria|
||1. Uncorrectable gastrointestinal flow on diagnostic angiogram.|
||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 >2.0 mg/dl, serum albumin < 2.5 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 > 75% of entire liver|
|6. Any serious ongoing extra-hepatic disease such as infections|
|Table 2. Baseline studied patients’ characteristics.|
|Age at diagnosis||Median (years)||61.8||62.7||0.43|
|Caucasians||3 (60%)||3 (60%)||1|
|Other||2 (40%)||2 (40 %)|
|Number of tumors||≤ 5||3 (60%)||4(80%)||0.49|
|> 5||2 (40%)||1(20 %)|
|Tumor size (cm)||Mean||7.4||6.8||0.37|
|CA-19.9||Increased||3 (60%)||3 (60%)||1|
|Normal||2 (40%)||2 (40%)|
|Child-Pugh||A||4 (80%)||3 (60 %)||0.49|
|B or above||1 (20%)||2 (40%)|
|ECOG||0||2 (40%)||2 (40 %)||1|
|≥1||3 (60%)||3 (60 %)|
|ECOG: Eastern Cooperative Oncology Group, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase.|
|Table 3. 99mTc-MAA, HPSF and administered Y90 activity in Resin and Glass microsphere groups.|
|Tc-99m MAA||Administered dose (mCi)||5.1||4.9||0.71|
|Tumor uptake (%)||72.3||68.6||0.63|
|Administered Y90 activity||mCi||73.2||44.5||<0.001|
|Tc-99m MAA: technetium-99m-labeled macroaggregated albumin, HPSF: Heptopulmonary shunt fraction.|
|Table 4. Post Y90 radioembolization associated toxicities.|
|Cumulative Toxicology Analysis||Glass||Resin||p value|
|Clinical toxicities||Treatment-related mortality||0 (0%)||0%||1|
|Non-specific, mild abdominal pain||1 (20%)||1 (20%)||1|
|Fatigue||5 (100%)||5 (100%)||1|
|Laboratory toxicities||Bilirubin||Total||4 (80%)||5 (100%)||0.52|
|Grade 1||2 (40%)||2 (40%)|
|Grade 2||2 (40%)||2 (40%)|
|Grade 3||0||1 (20%)|
|Grade ≥4||0||0 %|
|Transaminases (AST/ALT)||Total||5 (100%)||4 (80)||0.38|
|Grade 1||4 (80%)||3(60%)|
|Grade 2||1 (20%)||1 (20%)|
|Grade ≥3||0||0 %|
|Alkaline phosphatase||Total||2 (40%)||3 (60%) %||0.28|
|Grade 1||1 (20%)||2 (20%) %|
|Grade ≥2||0||0 %|
(RBC, WBC, platelets)
|Grade 1||1 (20%)||1 (20%) %||1|
|Renal toxicity||Any Grade||0||0 %||1|
|AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, RBC: Red blood cell, WBC: White blood cell.|
|Table 5. Comparison of Y90 glass and resin microspheres.|
|Size||20 – 30 μm||20 – 60 μm|
|Isotope||Y90 in glass matrix||Y90 on resin surface|
|Dose activity||Partition Model||Body Surface Model|
|Manufacture||Reactor (neutron flux)||Generator (Sr-90)|
|Specific Gravity||3.6 g/dL||1.6 g/dL|
|Activity/Sphere||150-2200 Bq||65-140 Bq|
|Right Liver Dose||4.75 GBq||1.5 GBq|
|Endpoint||Target Dose||Target Dose or Stasis|
|Number of microspheres||2.5 – 30 Millions||15 – 19 Millions|
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