Yttrium-90 Radioembolization in the VX2 Rabbit Model: Radiation Safety and Factors Influencing Delivery Efficiency.

The purpose of this study was to define the optimal infusion parameters and operator radiation exposure for yttrium-90 (90Y) radioembolization in the VX2 rabbit model of liver cancer. Forty-one rabbits with VX2 were treated with glass microspheres with vial sizes of 1, 3, and 5 GBq. The mean administered activity was 51.5 MBq (95% CI, 39.1-63.9). Delivery efficiency improved with 1 GBq versus with 3 GBq (residual 11.0% vs 46.4%, respectively; P = .0013) and improved with 1 GBq versus with 5 GBq (residual 11.0% vs 33.8%, respectively; P = .0060). The mean operator extremity exposure was 41.7 µSv/infusion. The optimal minimum infusion volume and rate was 49 mL and 21 mL/min, respectively. Fecal elimination occurred with microsphere uptake in the gallbladder at 1 and 2 weeks. 90Y radioembolization can be safely and efficiently performed in the VX2 rabbit model. Methodological considerations as a "how-to" for the setup of a preclinical 90Y laboratory are included to support future translational research.

Yttrium-90 Radioembolization to the Prostate Gland: Proof of Concept in a Canine Model and Clinical Translation.

PURPOSE: To investigate the feasibility, safety, and absorbed-dose distribution of prostatic artery radioembolization (RE) in a canine model. MATERIALS AND METHODS: Fourteen male castrated beagles received dihydroandrosterone/estradiol to induce prostatic hyperplasia for the duration of the study. Each dog underwent fluoroscopic prostatic artery catheterization. Yttrium-90 (90Y) microspheres (TheraSphere; Boston Scientific, Marlborough, Massachusetts) were delivered to 1 prostatic hemigland (dose escalation from 60 to 200 Gy), with the contralateral side serving as a control. Assessments for adverse events were performed throughout the follow-up (Common Terminology Criteria for Adverse Events v5.0). Positron emission tomography/magnetic resonance (MR) imaging provided a confirmation after the delivery of absorbed-dose distribution. MR imaging was performed before and 3, 20, and 40 days after RE. Tissue harvest of the prostate, rectum, bladder, urethra, penis, and neurovascular bundles was performed 60 days after RE. RESULTS: All the animals successfully underwent RE. Positron emission tomography/MR imaging demonstrated localization to and good coverage of only the treated hemigland. No adverse events occurred. The MR imaging showed a significant dose-dependent decrease in the treated hemigland size at 40 days (25%-60%, P < .001). No extraprostatic radiographic changes were observed. Necropsy demonstrated no gross rectal, urethral, penile, or bladder changes. Histology revealed RE-induced changes in the treated prostatic tissues of the highest dose group, with gland atrophy and focal necrosis. No extraprostatic RE-related histologic findings were observed. CONCLUSIONS: Prostate 90Y RE is safe and feasible in a canine model and leads to focal dose-dependent changes in the gland without inducing unwanted extraprostatic effects. These results suggest that an investigation of nonoperative prostate cancer is warranted.

Yttrium-90 Radioembolization and Tumor Hypoxia: Gas-challenge BOLD Imaging in the VX2 Rabbit Model of Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: To use a rapid gas-challenge blood oxygen-level dependent magnetic resonance imaging exam to evaluate changes in tumor hypoxia after 90Y radioembolization (Y90) in the VX2 rabbit model. MATERIALS AND METHODS: White New Zealand rabbits (n = 11) provided a Y90 group (n = 6 rabbits) and untreated control group (n = 5 rabbits). R2* maps were generated with gas-challenges (O2/room air) at baseline, 1 week, and 2 weeks post-Y90. Laboratory toxicity was evaluated at baseline, 24 hours, 72 hours, 1 hours, and 2 weeks. Histology was used to evaluate tumor necrosis on hematoxylin and eosin and immunofluorescence imaging was used to assess microvessel density (CD31) and proliferative index (Ki67). RESULTS: At baseline, median tumor volumes and time to imaging were similar between groups (p = 1.000 and p = 0.4512, respectively). The median administered dose was 50.4 Gy (95% confidence interval:44.8-55.9). At week 2, mean tumor volumes were 5769.8 versus 643.7 mm3 for control versus Y90 rabbits, respectively (p = 0.0246). At two weeks, ΔR2* increased for control tumors to 12.37 ± 12.36sec-1 and decreased to 4.48 ± 9.00sec-1 after Y90. The Pearson correlation coefficient for ΔR2* at baseline and percent increase in tumor size by two weeks was 0.798 for the Y90 group (p = 0.002). There was no difference in mean microvessel density for control versus Y90 treated tumors (p = 0.6682). The mean proliferative index was reduced in Y90 treated tumors at 30.5% versus 47.5% for controls (p = 0.0071). CONCLUSION: The baseline ΔR2* of tumors prior to Y90 may be a predictive imaging biomarker of tumor response and treatment of these tumors with Y90 may influence tumor oxygenation over time.

Correlation and Agreement of Yttrium-90 Positron Emission Tomography/Computed Tomography with Ex Vivo Radioembolization Microsphere Deposition in the Rabbit VX2 Liver Tumor Model.

PURPOSE: To demonstrate a stronger correlation and agreement of yttrium-90 (90Y) positron emission tomography (PET)/computed tomography (CT) measurements with explant liver tumor dosing compared with the standard model (SM) for radioembolization. MATERIALS AND METHODS: Hepatic VX2 tumors were implanted into New Zealand white rabbits, with growth confirmed by 7 T magnetic resonance imaging. Seventeen VX2 rabbits provided 33 analyzed tumors. Treatment volumes were calculated from manually drawn volumes of interest (VOI) with three-dimensional surface renderings. Radioembolization was performed with glass 90Y microspheres. PET/CT imaging was completed with scatter and attenuation correction. Three-dimensional ellipsoid VOI were drawn to encompass tumors on fused images. Tumors and livers were then explanted for inductively coupled plasma (ICP)-optical emission spectroscopy (OES) analysis of microsphere content. 90Y PET/CT and SM measurements were compared with reference standard ICP-OES measurements of tumor dosing with Pearson correlation and Bland-Altman analyses for agreement testing with and without adjustment for tumor necrosis. RESULTS: The median infused activity was 33.3 MBq (range, 5.9-152.9). Tumor dose was significantly correlated with 90Y PET/CT measurements (r = 0.903, P < .001) and SM estimates (r = 0.607, P < .001). Bland-Altman analyses showed that the SM tended to underestimate the tumor dosing by a mean of -8.5 Gy (CI, -26.3-9.3), and the degree of underestimation increased to a mean of -18.3 Gy (CI, -38.5-1.9) after the adjustment for tumor necrosis. CONCLUSIONS: 90Y PET/CT estimates were strongly correlated and had better agreement with reference measurements of tumor dosing than SM estimates.

Yttrium-90 Portal Vein Radioembolization in Sprague-Dawley Rats: Dose-Dependent Imaging and Pathological Changes in Normal Liver.

PURPOSE: Portal vein embolization (PVE) is an established neoadjuvant method to induce future liver remnant hypertrophy prior to surgical resection of hepatic tumors. The purpose of our study was to examine the feasibility of PVE with glass 90Y microspheres (Y90 PVE) in Sprague-Dawley rats. We tested the hypothesis that increased doses of Y90 PVE would increase target lobe fibrosis and atrophy. METHODS: Twenty-two rats were assigned to four groups for Y90 PVE to the right median lobe: very high- (273.8 MBq; n = 2), high- (99.9 MBq; n = 10), medium- (48.1 MBq; n = 5), and low-dose (14.8 MBq; n = 5). An untreated control group included seven rats. 90Y PET/CT of 90Y distributions confirmed lobar targeting. MRI volumes were measured at baseline, 2-, 4-, 8- and 12-weeks. Explanted hepatic lobes were weighed, sectioned, and stained for H&E and immunohistochemistry. Digitized slides allowed quantitative measurements of fibrosis (20 foci/slide). RESULTS: Ex vivo measurements confirmed 91-97% activity was localized to the target lobe (n = 4). The percent growth of the target lobe relative to baseline was - 5.0% (95% CI - 17.0-6.9%) for high-, medium dose rats compared to + 18.6% (95% CI + 7.6-29.7%) in the low-dose group at 12-weeks (p = 0.0043). Radiation fibrosis increased in a dose-dependent fashion. Fibrotic area/microsphere was 22,893.5, 14,946.2 ± 2253.3, 15,304.5 ± 4716.6, and 5268.8 ± 2297.2 µm2 for very high- (n = 1), high- (n = 4), medium- (n = 3), and low-dose groups (n = 5), respectively. CONCLUSION: Y90 PVE was feasible in the rat model, resulted in target lobe atrophy, and dose-dependent increases in hepatic fibrosis at 12 weeks. The onset of imaging-based volumetric changes was 8-12 weeks.

Feasibility of Combination Intra-arterial Yttrium-90 and Irinotecan Microspheres in the VX2 Rabbit Model.

PURPOSE: To evaluate the combination of 90Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model. MATERIALS AND METHODS: An initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology. RESULTS: Infused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology. CONCLUSION: Intra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

Streamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation.

BACKGROUND & AIMS: Pre-treatment Tc-99m macroaggregated albumin (MAA) scans are routinely performed prior to transarterial radioembolization (TARE) to estimate lung shunt fraction (LSF) and lung dose. In this study, we investigate LSF observed in early hepatocellular carcinoma (HCC) and provide the scientific rationale for eliminating this step from routine practice. METHODS: Patients with HCC who underwent Y90 from 2004 to 2018 were reviewed. Inclusion criteria were early stage HCC (UNOS T1/T2/Milan criteria: solitary ≤5 cm, 3 nodules ≤3 cm). LSF was determined using MAA in all patients. Associations between LSF and baseline characteristics were investigated. A "no-MAA" paradigm was then proposed based on a homogenous group that expressed very low LSF. RESULTS: Of 1,175 patients with HCC treated with TARE, 448 patients met inclusion criteria. Mean age was 65.6 years and 303 (68%) were males. A total of 352 (79%) had solitary lesions and 406 (91%) unilobar disease. Two-hundred and forty-three (54%), 178 (40%) and 27 (6%) patients were Child-Pugh class A, B and C, respectively. Median LSF was 3.9% (IQR 2.4-6%). Median administered activity was 0.9 GBq (IQR 0.6-1.4), for a median segmental volume of 170 cm3 (range: 60-530). Median lung dose was 1.9 Gy (IQR: 1.0-3.3). The presence of a transjugular intrahepatic portosystemic shunt (TIPS; n = 38) was associated with LSF >10% (odds ratio 12.2; 95% CI 5.2-28.6; p <0.001). Median LSF was 3.8% (IQR: 2.4-5.7%) and 6% (IQR: 3.8-15.3%) in no-TIPS vs. TIPS patients (p <0.001). CONCLUSION: LSF is clinically negligible in patients with UNOS T1/T2 HCC without TIPS. When segmental injections are planned, this step can be eliminated, thereby reducing time-to-treatment, number of procedures, and improving convenience for patients traveling from faraway. LAY SUMMARY: Transarterial radioembolization is a microembolic transarterial treatment for hepatocellular carcinoma. In our study, we found that early stage patients, where segmental injections are planned, exhibited low lung shunting, effectively eliminating the risk of radiation pneumonitis. We propose that the lung shunt study be eliminated in this subgroup, thus leading to fewer procedures, a cost reduction and improved convenience for patients.

Long-Term Hepatotoxicity of Yttrium-90 Radioembolization as Treatment of Metastatic Neuroendocrine Tumor to the Liver.

PURPOSE: To determine long-term hepatotoxicity of yttrium-90 (90Y) radioembolization in patients treated for metastatic neuroendocrine tumor (mNET) and evaluate if imaging and laboratory findings of cirrhosis-like morphology are associated with clinical symptoms. MATERIALS AND METHODS: Retrospective review from 2003 to 2016 was performed for patients with mNET treated with 90Y glass microspheres. Fifty-four patients with > 2 year follow-up were stratified into unilobar (n = 15) vs whole-liver (n = 39) treatment. The most common primary mNET sites were small bowel (19 of 54), pancreas (19 of 54), and unknown (8 of 54). Preradioembolization imaging and laboratory findings were compared with most recent follow-up for indications of worsening portal hypertension and decline in hepatic function. RESULTS: Among patients who underwent unilobar radioembolization, imaging follow-up at a mean of 4.1 years (range, 2.0-15.2 y) revealed cirrhosis-like morphology in 26.7% (4 of 15), ascites in 13.3% (2 of 15), varices in 6.7% (1 of 15), and a 21.9% increase in splenic volume. The respective incidences in patients treated with whole-liver 90Y radioembolization were 56.4% (22 of 39), 41.0% (16 of 39), and 15.4% (6 of 39), with a 64.7% increase in splenic volume. Patients treated with whole-liver radioembolization exhibited significantly decreased platelet counts (P = .023) and lower albumin levels (P = .0002). Eight patients (20.5%) treated with whole-liver radioembolization who exhibited cirrhosis-like morphology showed clinical signs of hepatic decompensation; only 2 of 39 patients (5.1%) had no other causes of hepatotoxicity. CONCLUSIONS: Whole-liver 90Y radioembolization for patients with mNET results in long-term imaging findings of cirrhosis-like morphology and portal hypertension in > 50% of treated patients, but the majority remain clinically asymptomatic. Long-term hepatotoxicity solely attributable to 90Y develops in a small percentage of patients.

Indicators of Lung Shunt Fraction Determined by Technetium-99 m Macroaggregated Albumin in Patients with Hepatocellular Carcinoma.

PURPOSE: To determine the correlation of pre-procedural and imaging characteristics with lung shunt fraction (LSF) measured by technetium-99 m macroaggregated albumin (99mTc-MAA) scan in patients with hepatocellular carcinoma. METHODS: A retrospective study was conducted of 428 subjects with hepatocellular carcinoma from 2004 to 2011 assessed for lung shunting by 99mTc-MAA scan. Baseline characteristics included age, gender, ethnicity, tumor burden, maximum dimension, number of lesions, presence of extrahepatic metastases, macrovascular (hepatic and portal vein) invasion, ascites on imaging, laboratory values, and alpha-fetoprotein (AFP). Univariate and multivariate logistic regression analysis was performed. Receiver operating characteristic curves were used to obtain sensitivity (SN), specificity (SP), and positive likelihood ratios (LR+) of characteristics for low LSF (LSF <10%) and high LSF (LSF >20%). RESULTS: Statistically significant (p < 0.05) independent indicators of low LSF included bilirubin <1.45 mg/dL (SN = 49.5%, SP = 69.1%, LR+ = 1.60), maximum tumor size <7.15 cm (SN = 66.0%, SP = 75.9%, LR+ = 2.74), AFP ≤200 ng/mL (SN = 64.6%, SP = 65.0%, LR+ = 1.85), and absent macrovascular invasion (SN = 73.9%, SP = 64.9%, LR+ = 2.11). Independent indicators of high LSF included albumin <2.65 g/dL (SN = 64.3%, SP = 64.1%, LR+ = 1.79) and macrovascular invasion (SN = 74.4%, SP = 67.4%, LR+ = 2.28). A combined risk factor model was constructed. If there is no macrovascular invasion: [Formula: see text]. With macrovascular invasion, [Formula: see text] (R 2 = 0.257). Since these factors all have LR+ between 2 and 5, they only reflect slight increase in LSF predictivity. CONCLUSION: Serum AFP, albumin, bilirubin, and portal/hepatic vein invasion on cross-sectional imaging are statistically significant but weak clinical indicators of LSF, as shown by low SN, SP, and LR+ for clinically relevant cutoff LSF values. Thus, these factors cannot be relied upon in clinical practice.

Same-day 90Y radioembolization: implementing a new treatment paradigm.

PURPOSE: To assess the feasibility of conducting pretreatment mesenteric angiography, coil embolization, 99mTc macroaggregated albumin (99mTc-MAA) scintigraphy, and 90Y radioembolization treatment in a single, same-day, combined outpatient encounter. METHODS: This was a retrospective study of 78 patients treated during the period 2008 - 2015 who were managed in a single outpatient encounter under the guidance of the Interventional Radiology Department and The Nuclear Medicine Department. Pretreatment planning was performed by reviewing baseline imaging and estimated perfused liver volume bearing the tumor. The region of interest was estimated using 3-D software; this value was used for dosimetry planning. Maximum lung shunting fractions of 10 % for hepatocellular carcinoma and 5 % for liver metastases were assumed. Subsequently, hepatic angiography and 99mTc-MAA scintigraphy were performed followed by 90Y treatment in one outpatient encounter. Total in-room procedure time was recorded. RESULTS: All patients underwent same-day angiography, 99mTc-MAA scintigraphy and 90Y radioembolization. Of the 78 patients, 16 received multiple segmental treatments to both lobes, 44 received treatment to the right lobe, and 18 received treatment to the left lobe. The median dose was 106 Gy. The median number of 90Y vials needed was two (range one to six). The median in-room time was 160 min (75 - 250 min). The residential status of the patients was as follows, 18 % (14/78) were local residents, 55 % (43/78) traveled from outside the city limits, 18 % (14/78) were from out-of-state, and 9 % (7/78) were resident abroad. Of the 78 patients, 61 (77 %) had hepatocellular carcinoma, and 17 (22 %) had liver metastases. The median lung dose was 3.5 Gy. CONCLUSION: This study demonstrated the feasibility of same-day 90Y evaluation and treatment while maintaining the principles of safe and effective 90Y infusion including tumoricidal dosimetry (lobar, segmentectomy), minimization of nontarget flow, and minimization of lung dose. This paradigm translates into expeditious cancer care and significant cost savings.

Independent Analysis of Albumin-Bilirubin Grade in a 765-Patient Cohort Treated with Transarterial Locoregional Therapy for Hepatocellular Carcinoma.

PURPOSE: To assess validity of albumin-bilirubin (ALBI) grade as a predictor of survival in patients undergoing transarterial embolization for hepatocellular carcinoma. MATERIALS AND METHODS: Baseline albumin and bilirubin values of 765 consecutive patients treated with conventional transarterial chemoembolization or yttrium-90 ((90)Y) radioembolization at a single institution were used to determine liver function according to ALBI grade. Survival outcomes were stratified by ALBI grade using Kaplan-Meier and stratified by Child-Pugh (C-P) class and Barcelona Clinic Liver Cancer (BCLC) stage. Discriminatory ability was assessed by C-index. RESULTS: For 428 patients receiving (90)Y radioembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade revealed different survival outcomes for C-P B (P = .001), BCLC A (P < .001), BCLC B (P = .001), and BCLC C (P < .001). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.792, 0.763, respectively). For 337 patients receiving transarterial chemoembolization, ALBI grade yielded distinct survival curves (P < .001). When stratified by C-P class and BCLC stage, ALBI grade provided distinct survival curves for C-P B (P = .02), BCLC B (P = .001), and BCLC C (P = .02). When substratified by BCLC stage, ALBI grade was a better discriminator of survival than C-P class (C-index 0.739, 0.735, respectively). CONCLUSIONS: ALBI grade outperforms C-P class at discriminating survival in patients receiving transarterial chemoembolization or (90)Y radioembolization. ALBI grade is also valuable in patients with moderate liver dysfunction and BCLC B disease.

90Y Radioembolization of Colorectal Hepatic Metastases Using Glass Microspheres: Safety and Survival Outcomes from a 531-Patient Multicenter Study.

UNLABELLED: Hepatic metastases of colorectal carcinoma are a leading cause of cancer-related mortality. Most colorectal liver metastases become refractory to chemotherapy and biologic agents, at which point the median overall survival declines to 4-5 mo. Radioembolization with (90)Y has been used in the salvage setting with favorable outcomes. This study reports the survival and safety outcomes of 531 patients treated with glass-based (90)Y microspheres at 8 institutions, making it the largest (90)Y study for patients with colorectal liver metastases. METHODS: Data were retrospectively compiled from 8 institutions for all (90)Y glass microsphere treatments for colorectal liver metastases. Exposure to chemotherapeutic or biologic agents, prior liver therapies, biochemical parameters before and after treatment, radiation dosimetry, and complications were recorded. Uni- and multivariate analyses for predictors of survival were performed. Survival outcomes and clinical or biochemical adverse events were recorded. RESULTS: In total, 531 patients received (90)Y radioembolization for colorectal liver metastases. The most common clinical adverse events were fatigue (55%), abdominal pain (34%), and nausea (19%). Grade 3 or 4 hyperbilirubinemia occurred in 13% of patients at any time. The median overall survival from the first (90)Y treatment was 10.6 mo (95% confidence interval, 8.8-12.4). Performance status, no more than 25% tumor burden, no extrahepatic metastases, albumin greater than 3 g/dL, and receipt of no more than 2 chemotherapeutic agents independently predicted better survival outcomes. CONCLUSION: This multiinstitutional review of a large cohort of patients with colorectal liver metastases treated with (90)Y radioembolization using glass microspheres has demonstrated promising survival outcomes with low toxicity and low side effects. The outcomes were reproducible and consistent with prior reports of radioembolization.

Gastric injury from (90)Y to left hepatic lobe tumors adjacent to the stomach: fact or fiction?

PURPOSE: Radioembolization with (90)Y microspheres is a locoregional radiation therapy for unresectable hepatic neoplasm. Non-target delivery of (90)Y microspheres resulting in gastrointestinal (GI) symptoms is a recognized complication; there is minimal knowledge regarding the radiation effect to the gastric wall from left hepatic lobe (90)Y treatments. Our aim was to study the incidence of GI complications when the target tissue (hepatic parenchyma ± tumor) is in close proximity to the gastric wall. We hypothesized that liver (tumor) to stomach proximity does not correlate with increased toxicity. METHODS: Between November 2011 and September 2013, we studied all patients who underwent left lobe radioembolization with (90)Y glass microspheres. With Institutional Review Board (IRB) approval, we retrospectively reviewed MRI/CT images of these patients, identifying a subset of patients with the left hepatic lobe <1 cm from the gastric wall. Patients were seen in clinic 1 month posttreatment and subsequently at 3-month intervals. Short- and long-term gastric adverse events were tabulated. RESULTS: Ninety-seven patients successfully underwent left hepatic lobe (90)Y microsphere radioembolization in which the average distance from the liver to the stomach wall was 1.0 ± 2.8 mm. The average dose for patients who received radioembolization to the left hepatic lobe was 109 ± 57 Gy. Fifty patients had tumor within 1 cm of the gastric wall. The average dose for patients who received radioembolization to the left hepatic lobe with tumor within 1 cm of the gastric wall was 121 ± 41 Gy. There were no reportable or recordable medical events. Of the patients, 34% reported abdominal pain that was grade 1-2; 65% of the patients reported no abdominal pain. None of the 97 patients developed a clinically evident GI ulcer. CONCLUSION: Patients with left lobe tumors adjacent to or abutting the stomach do not exhibit acute or chronic radiation effects following radioembolization with glass microspheres.

Intraarterial Hepatic SPECT/CT Imaging Using 99mTc-Macroaggregated Albumin in Preparation for Radioembolization.

UNLABELLED: Current standard practice for radioembolization treatment planning makes use of nuclear medicine imaging (NMI) of (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) arterial distributions for the assessment of lung shunting and extrahepatic uptake. Our aim was to retrospectively compare NMI with mapping angiography in the detection and localization of extrahepatic (99m)Tc-MAA and to evaluate the typical and atypical findings of NMI in association with catheter placement. METHODS: One hundred seventy-four patients underwent diagnostic angiography in preparation for radioembolization. (99m)Tc-MAA was administered to the liver via a microcatheter positioned in the desired hepatic artery. Planar scintigraphy imaging followed by SPECT/CT imaging was obtained within 2 h. All images were reviewed for hepatic and extrahepatic (99m)Tc-MAA deposition and compared with the mapping angiogram. RESULTS: Intrahepatic lobe shunting was present on NMI in only 2.9% of the cases but was present in 62.5% of the patients with portal vein thrombosis. Extrahepatic distributions included lungs (100%), the gallbladder (49%) if present, and locations involving hepaticoenteric arterial anatomy recognized on angiograms (16%). Free pertechnetate was identified on 38% of the nuclear medicine images. Three percent of nuclear medicine images showed alternative findings such as a thyroid nodule or metallic artifact. CONCLUSION: Patients being considered for radioembolization should undergo both angiography and scintigraphy for the assessment of hepaticoenteric arterial anatomy, hepatopulmonary shunting, and appropriate dosimetry considerations. Knowledge of the expected distribution of (99m)Tc-MAA with normal variants and potential nontarget delivery to adjacent structures is critical in improving clinical outcomes.

Yttrium-90 radioembolization stops progression of targeted breast cancer liver metastases after failed chemotherapy.

PURPOSE: To determine, in an open-label, retrospective report, the safety and effectiveness of locoregional therapy with yttrium-90 ((90)Y) radioembolization for patients with progressing breast cancer liver metastases (BCLMs) despite multi-agent chemotherapy. MATERIALS AND METHODS: Seventy-five patients with progressing BCLMs and stable extrahepatic disease were treated with radioembolization at a single institution. Retrospective review of a prospectively collected database was performed to evaluate clinical and biochemical toxicities, tumor response, overall survival (OS), and time to progression. Radiologic response assessments included Response Evaluation Criteria In Solid Tumors in primary index lesions and metabolic activity on positron emission tomography (PET). Univariate and multivariate analyses were performed. RESULTS: The mortality rate at 30 days was 4% (n = 3). Clinical toxicity and hyperbilirubinemia of grade 3 or worse occurred in 7.6% (n = 5) and 5.9% of patients (n = 4), respectively. Partial response (PR) was seen in 35.3% of patients (n = 24), stable disease (SD) in 63.2% (n = 43), and progressive disease in 1.5% (n = 1). PET imaging was available in 25 patients, and 21 (84%) had a complete response, PR, or SD. The median OS was 6.6 months (95% confidence interval [CI], 5.0-9.2 mo). The hazard ratio (HR) for OS on multivariate analysis was 0.39 (95% CI, 0.23-0.66) for tumor burden less than 25% compared with greater burden. Elevated bilirubin levels were shown to reduce OS. The HR for hepatic progression was 0.22 (95% CI, 0.05-0.98) for solitary versus multifocal disease. CONCLUSIONS: Locoregional therapy with (90)Y radioembolization is safe and stops or delays the progression of targeted chemorefractory BCLMs. Adverse prognosticators were identified.

Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy.

PURPOSE: The aim of this study was to analyze the safety, treatment characteristics and survival outcomes of Yttrium-90 (Y90) radioembolization for unresectable colorectal carcinoma (CRC) liver metastases refractory to standard of care therapy. METHODS: A total of 214 patients with CRC metastases were treated with Y90 radioembolization over 12 years. Toxicity was assessed using National Cancer Institute common terminology criteria. Overall survival was analyzed from date of diagnosis of primary cancer, hepatic metastases and from the first Y90. Uni/multivariate analyses were performed. Substratification by era of chemotherapeutics was performed. RESULTS: Most patients were male (60 %) and <65 years old (61 %). Of them, 98 % had been exposed to chemotherapy. Grade 3 lymphocyte, bilirubin, albumin, ALP and AST toxicities were observed in 39 %, 11 %, 10 %, 8 % and 4 % of patients, respectively. Grade 4 lymphocyte and ALP toxicities were observed in 5 % and 3 % of patients, respectively. Median overall survival was 43.0, 34.6, and 10.6 months from date of diagnosis of primary cancer, hepatic metastases and first Y90, respectively. Survival was significantly longer in patients: (1) who received ≤2 cytotoxic drugs (n = 104) than those who received 3 (n = 110) (15.2 vs. 7.5 months, p = 0.0001); and (2) who received no biologic agents (n = 52) compared with those that did (n = 162) (18.6 vs. 9.4 months, p = 0.0001). Multivariate analyses identified ≤2 cytotoxic agents, no exposure to biologics, ECOG 0, tumor burden <25 %, lack of extrahepatic disease and albumin >3 g/dL as independent predictors of survival. CONCLUSION: In this largest metastatic CRC series published to date, Y90 radioembolization was found to be safe; survival varied by prior therapy. Further studies are required to further refine the role of Y90 in metastatic CRC.

Comparative study of staging systems for hepatocellular carcinoma in 428 patients treated with radioembolization.

PURPOSE: To compare the utility of different staging systems and analyze independent predictors of survival in patients with hepatocellular carcinoma (HCC) treated with yttrium-90 ((90)Y) radioembolization. MATERIALS AND METHODS: During the period 2004-2011, 428 patients with HCC were treated with (90)Y radioembolization. All patients were staged prospectively by the following staging systems: Child-Turcotte-Pugh (CTP), United Network for Organ Sharing, Barcelona Clinic Liver Cancer (BCLC), Okuda classification, Cancer of the Liver Italian Program (CLIP), Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire, Chinese University Prognostic Index, and Japan Integrated Staging. The ability of the staging systems to predict survival was assessed. The staging systems were compared using Cox proportional hazards regression model, linear regression, Akaike information criterion (AIC), and concordance index (C-index). Univariate and multivariate analyses were employed to assess independent predictors of survival. RESULTS: When tested independently, all staging systems exhibited significant ability to discriminate early (long survival) from advanced (worse survival) disease. CLIP provided the most accurate information in predicting survival outcomes (AIC = 2,993, C-index = 0.8503); CTP was least informative (AIC = 3,074, C-index = 0.6445). Independent predictors of survival included Eastern Cooperative Oncology Group performance status grade 0 (hazard ration [HR], 0.56; confidence interval [CI], 0.34-0.93), noninfiltrative tumors (HR, 0.62; CI, 0.44-0.89), absence of portal venous thrombosis (HR, 0.60; CI, 0.40-0.89), absence of ascites (HR, 0.56; CI, 0.40-0.76), albumin ≥ 2.8 g/dL (HR, 0.72; CI, 0.55-0.94), alkaline phosphatase ≤ 200 U/L (HR, 0.68; CI, 0.50-0.92), and α-fetoprotein ≤ 200 ng/mL (HR, 0.67; CI, 0.51-0.86). CONCLUSIONS: CLIP was most accurate in predicting survival in patients with HCC. Given that not all patients receive the recommended BCLC treatment strategy, this information is relevant for clinical trial design and predicting long-term outcomes after (90)Y radioembolization.

Chemoradiation of hepatic malignancies: prospective, phase 1 study of full-dose capecitabine with escalating doses of yttrium-90 radioembolization.

PURPOSE: Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ((90)Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of (90)Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. METHODS AND MATERIALS: Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the second cycle, whole-liver (90)Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after (90)Y infusion. If a DLT was not observed, the (90)Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of (90)Y with full-dose capecitabine. RESULTS: Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing (90)Y MTD were not met, indicating an MTD of >170 Gy. CONCLUSION: The MTD of (90)Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest (90)Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.