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Understanding the distribution and embolization effects of ultrasmall doxorubicin eluting beads in a rodent model of hepatocellular carcinoma
S158
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Wednesday
Scientific Session
when the balloon microcatheter was inflated rather than deflated in all 20 paired embolic deliveries (by 2.4-fold, on average, p ¼ 0.0002), despite delivery of an equivalent number of total microspheres. Conclusions: Balloon occlusion significantly reduces blood pressure in the downstream vascular compartment, resulting in proportionally increased delivery of emboli to a targeted intrahepatic arterial collection catheter relative to other portions of the embolized vascular compartment, likely due to blood flowing into this compartment from neighboring hepatic and extrahepatic arteries.
3:27 PM
Abstract No. 365
Drug dose mapping using radiopaque, drugeluting embolic beads following DEBTACE in rabbit VX2 using MDCT and micro CT
WEDNESDAY: Scientific Sessions
A. Mikhail1, E. Levy2, V. Krishnasamy2, A. Negussie1, W. Pritchard1, D. Woods1, J. Thompson2, D. Amchin2, I. Bakhutashvili1, J. Esparza-Trujillo1, F. Banovac3, J. Karanian1, Y. Tang4, C. Macfarlane5, S. Willis4, A. Lewis6, B. Wood7; 1National Institutes of Health, Bethesda, MD; 2NIH, Bethesda, MD; 3N/A, Mc Lean, VA; 4 BTG Biocompatibles, Camberley, Surrey; 5 Biocompatibles Uk Ltd, Farnham, Surrey, United Kingdom; 6Biocompatibles, Inc., Oxford, CT; 7 National Institutes of Health, North Bethesda, MD Purpose: To estimate and model drug levels in the liver postDEBTACE based on x-ray attenuation of drug-loaded, intrinsically radiopaque embolic microspheres (LC Bead LUMI) in a preclinical model. Materials: Rabbits bearing VX2 liver tumors underwent TACE using doxorubicin-loaded radiopaque embolic beads (70-150 mm, LC Bead LUMI) until flow stasis under fluoroscopic guidance. The rabbits were euthanized 1h after DEBTACE and the livers resected, frozen and imaged with a 16-slice multidetector CT (MDCT). The frozen livers were inserted into patient-specific 3D printed molds and precisely sectioned into 5 mm thick tissue samples. Bead volume and attenuation were measured on MDCT of tissue samples that were co-localized with whole liver MDCT. DOX was extracted from the samples and correlated with bead attenuation. MicroCT (mCT) of liver specimens was also performed. Drug microdistribution relative to beads was evaluated using fluorescence microscopy of frozen sections of liver. MDCT of a range of bead concentrations suspended in 1% agar solution (wt/v) was also performed to assess linearity of x-ray absorption in vitro. Results: Radiopaque beads in ex vivo liver samples were highly conspicuous on MDCT and mCT. Evaluation of drug microdistribution in liver sections demonstrated colocalization of beads and drug (drug penetration o 400 mm, radially). A linear correlation was found between beadassociated attenuation and bead volume in both in vitro phantoms and ex-vivo liver on MDCT (r2 ¼ 0.999 and r2 ¼ 0.971). Moreover, a linear correlation was found between DOX levels and bead attenuation in both in vitro phantoms and ex-vivo liver (r2 ¼ 0.998 and r2 ¼ 0.834, respectively). Conclusions: The volume and drug content of LC Bead LUMI loaded with DOX were linearly correlated with
’
JVIR
bead-associated attenuation in rabbit livers following TACE. This relationship potentially estimates drug dose and drug distribution on post-embolization imaging, enabling real-time identification of potentially under-dosed regions of tumor. The immediate availability of such drug map estimates during LC Bead LUMI DEBTACE on CBCT could inform reproducibility, standardization, and optimization.
3:36 PM
Abstract No. 366
Understanding the distribution and embolization effects of ultrasmall doxorubicin eluting beads in a rodent model of hepatocellular carcinoma H. Nishiofuku1, A. Cortes2, A. Minhaj3, K. Maldonado2, K. Dixon2, N. Muñoz4, C. Kingsley2, A. Mcwatters5, K. Kichikawa6, M. Hicks2, R. Avritscher7; 1Nara Medical University, Kashihara, Nara, Japan; 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3 UT MD Anderson Cancer Center, Houston, TX; 4University of Texas MD Anderson Cancer Center, Houston, TX; 5The University of Texas M.D. Anderson Cancer Cente, Houston, TX; 6Nara Medical University, Kashihara, Nara, Japan; 7MD Anderson Cancer Center, Houston, TX Purpose: To evaluate the distribution and embolization effect of ultrasmall 40-60 mm doxorubicin eluting beads (DEBs) versus small 70-150 mm DEBs after intra-arterial administration in the N1S1 rat model of hepatocellular carcinoma (HCC). Materials: All studies were approved by our institutional animal care and use committee and were performed in accordance with institutional guidelines. Twenty adult male Sprague-Dawley rats underwent hepatic arterial chemoembolization using a left transcarotid approach and were randomly assigned to receive a fixed dose of 4x10*4 of ultrasmall or small DEBs. The embolization endpoint was the injection of the entire dose. After 3 or 7 days, five animals per group were euthanized. Each tumor was sectioned in three equidistant regions along axial planes (cranial, middle and caudal). Bead number, spatial distribution, and percentage of tumor necrosis were measured on histology section. Mann-Whitney and Wilcoxon test were used to evaluate differences between groups. Results: The overall percentage of necrosis was 33% and 56% for the ultrasmall DEBs at 3 and 7 days, and 10% and 28% for the small group, respectively (Po0.001). The effect of the treatment with ultrasmall DEBs was similar across different areas of the same tumor (p40.05). Small DEBs showed necrosis predominantly in the cranial (34%) and central (25%) regions at day 7 (p ¼ 0.004). No significant differences in the total number of beads were observed between the groups at any of the time points (p40.05). Significant differences in bead distribution were observed in the ultrasmall size group, at both time points, by comparing tumor versus normal parenchyma regions (po0.05). Small beads aggregate more frequently within the tumor, whereas the ultrasmall beads were equally distributed across normal liver and tumor. Conclusions: Higher rates of tumor necrosis were observed after ultrasmall DEB chemoembolization using equivalent bead dose. Small beads demonstrated a more heterogeneous tumor necrosis pattern with certain tumor regions consistently spared after embolization. Ultrasmall beads tend to be evenly
JVIR
’
Scientific Session
Wednesday
distributed across both normal liver and tumor, whereas small beads distribute preferentially within tumor.
3:45 PM
Abstract No. 367
Phase1 study of immune-enhanced locoregional therapy: hepatic artery embolization combined with intra-tumoral and systemic poly-ICLC to treat liver cancer A. Jon1, P. Kisza2, S. Contractor3, A. De la Torre4; 1 Rutgers-New Jersey Medical School, Newark, NJ; 2 Rutgers, The State University of New Jersey/New Jersey Medical School, South Orange, NJ; 3New Jersey Medical School, Newark, NJ; 4Rutgers New Jersey Medical SchoolUniversity Hospital, Newark NJ, Newark, NJ
3:54 PM
Abstract No. 368
Irinotecan-eluting LC Bead-M1 (DEBIRI-M1) for patients with liver metastases from colorectal cancer: a phase II single-center study A. Fereydooni1, B. Letzen1, S. Huber1, P. Hu2, M. Rudek2, T. Schlachter1, J. Chapiro1, J. Geschwind1, C. Georgiades2; 1Yale University School of Medicine, New Haven, CT; 2Johns Hopkins University, Baltimore, MD
S159
Purpose: The primary endpoint of this prospective trial was to determine the feasibility and safety of transarterial chemoembolization (TACE) with drug-eluting LC Bead M1 loaded with irinotecan (DEBIRI-M1) for the treatment of patients with hepatic metastases from colorectal cancer (CRC). Secondary endpoints were efficacy and survival, and the exploratory objectives included studying the pharmacokinetics of irinotecan, and the association between serum Vascular Endothelial Growth Factor (VEGF) levels and treatment outcomes. Materials: 14 patients, with a diagnosis of CRC with hepatic metastases who had failed or are intolerant to at least one line of systemic chemotherapy, were treated with DEBIRI-M1TACE. Patients were allowed to receive up to 4 TACEs in the first 4 cycles (6 months) as needed. Any technical complications and adverse events (according to CTCAE v4.03) were recorded. Radiologic response was assessed according to World Health Org. (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Survival was estimated using Kaplan Meier analysis. Levels of irinotecan, SN-38 (active metabolite), circulating VEGF and soluble VEGF Receptor were measured at baseline and multiple time points post-DEBIRI-M1 administration. Results: A total of 32 TACEs were successfully performed in all 14 patients (mean 2.29 procedures, range 1-4) without procedural complications. Grade 1-4 toxicities, one month after the first TACE, were abdominal pain (50%), elevated ALP (14.29%), anemia (14.29%), hypoalbuminemia (7.14%), nausea (7.14%) and leukopenia (7.14%). The only frequently encountered grade 3-4 toxicity was abdominal pain (28.57%). The RECIST and WHO objective response rates were 14.29% and 28.57% respectively. The 1-year survival percentage from first treatment was 35.71%. Average Cmax of irinotecan and the SN-38 were 1299 ⫾ 2276 ng/mL and 41.5 ⫾ 26.1 ng/mL, respectively, with average t½ of 5.7 ⫾ 1.2 h and 8.6 ⫾ 2.6 h following the first TACE. The treatment caused significant decreases of VEGFR1 at 24h rather than VEGF or VEGFR2. Conclusions: DEBIRI-M1-TACE is a well-tolerated and technically feasible treatment option that can be used safely in the palliative treatment of hepatic metastases from CRC.
4:03 PM
Abstract No. 369
Clinical toxicity of irinotecan-eluting microsphere TACE for colorectal cancer hepatic metastases: oncozene versus LC bead G. Laidlaw, D. Wang, D. Sze, G. Hwang, J. Louie; Stanford University School of Medicine, Stanford, CA Purpose: Transarterial chemoembolization (TACE) using irinotecan-eluting microspheres (DEBIRI) is associated with greater patient pain than TACE with doxorubicin-eluting microspheres, a difference attributed to rapid irinotecan elution. We compared clinical toxicity of irinotecan TACE using microspheres with different drug elution characteristics in treatment of colorectal cancer hepatic metastases (hmCRC). Materials: From March 2010 to May 2016, 40 hmCRC patients underwent 71 irinotecan TACE procedures at a single institution. 49 procedures in 28 patients (69.0% of procedures) and 22 procedures in 12 patients (31.0% of
WEDNESDAY: Scientific Sessions
Purpose: To determine if combining transarterial embolization (TAE) or transarterial chemoembolization (TACE) with immune modulators within the hepatic and tumor microenvironment may be a potential way to shift the balance away from immune tolerance towards cytotoxic tumor immune responsiveness to combat liver cancers. Materials: This phase I trial investigates the safety of combining several steps to: 1) increase tumor antigen visibility with focal nonlethal radiation, 2) induce an immunologic “danger” response in the tumor microenvironment using transarterial hepatic artery embolization (TAE) or chemoembolization (TACE) and intra/ peri-tumoral injection of the Toll-Like-Receptor (TLR) 3 agonist, (IT) poly-ICLC and systemically boost the response with intramuscular (IM) poly-ICLC. Several patients were also pretreated with metronomic cyclophosphamide (Cyp) to reduce toleragenic T-regulatory cells. Primary endpoints were safety of the protocol agents; secondary endpoints were radiological response and overall survival at 6 months, 1 and 2 years. Results: Eighteen patients with hepatocellular cancer (HCC) who were not eligible for surgery or liver transplant were enrolled. Aside from one embolization-related severe adverse event (SAE), all events were r grade II. Overall two-year survival was 39%. In patients o 60 years old, 2 years survival was 62.5% 60 vs. 11.1% in patients age 4 60 (Po 0.05). Several patients with unusually prolonged progression free and overall survival were observed. Conclusions: Combining TAE or TACE with intra-tumoral injection of the TLR3 agonist poly ICLC in patients with liver cancer is well tolerated and can be safely combined with local non-lethal radiation and hepatic artery embolization. Further work is in progress to characterize changes in immunity and evaluate if this approach can reliably improve survival.
’
’
Wednesday
Scientific Session
when the balloon microcatheter was inflated rather than deflated in all 20 paired embolic deliveries (by 2.4-fold, on average, p ¼ 0.0002), despite delivery of an equivalent number of total microspheres. Conclusions: Balloon occlusion significantly reduces blood pressure in the downstream vascular compartment, resulting in proportionally increased delivery of emboli to a targeted intrahepatic arterial collection catheter relative to other portions of the embolized vascular compartment, likely due to blood flowing into this compartment from neighboring hepatic and extrahepatic arteries.
3:27 PM
Abstract No. 365
Drug dose mapping using radiopaque, drugeluting embolic beads following DEBTACE in rabbit VX2 using MDCT and micro CT
WEDNESDAY: Scientific Sessions
A. Mikhail1, E. Levy2, V. Krishnasamy2, A. Negussie1, W. Pritchard1, D. Woods1, J. Thompson2, D. Amchin2, I. Bakhutashvili1, J. Esparza-Trujillo1, F. Banovac3, J. Karanian1, Y. Tang4, C. Macfarlane5, S. Willis4, A. Lewis6, B. Wood7; 1National Institutes of Health, Bethesda, MD; 2NIH, Bethesda, MD; 3N/A, Mc Lean, VA; 4 BTG Biocompatibles, Camberley, Surrey; 5 Biocompatibles Uk Ltd, Farnham, Surrey, United Kingdom; 6Biocompatibles, Inc., Oxford, CT; 7 National Institutes of Health, North Bethesda, MD Purpose: To estimate and model drug levels in the liver postDEBTACE based on x-ray attenuation of drug-loaded, intrinsically radiopaque embolic microspheres (LC Bead LUMI) in a preclinical model. Materials: Rabbits bearing VX2 liver tumors underwent TACE using doxorubicin-loaded radiopaque embolic beads (70-150 mm, LC Bead LUMI) until flow stasis under fluoroscopic guidance. The rabbits were euthanized 1h after DEBTACE and the livers resected, frozen and imaged with a 16-slice multidetector CT (MDCT). The frozen livers were inserted into patient-specific 3D printed molds and precisely sectioned into 5 mm thick tissue samples. Bead volume and attenuation were measured on MDCT of tissue samples that were co-localized with whole liver MDCT. DOX was extracted from the samples and correlated with bead attenuation. MicroCT (mCT) of liver specimens was also performed. Drug microdistribution relative to beads was evaluated using fluorescence microscopy of frozen sections of liver. MDCT of a range of bead concentrations suspended in 1% agar solution (wt/v) was also performed to assess linearity of x-ray absorption in vitro. Results: Radiopaque beads in ex vivo liver samples were highly conspicuous on MDCT and mCT. Evaluation of drug microdistribution in liver sections demonstrated colocalization of beads and drug (drug penetration o 400 mm, radially). A linear correlation was found between beadassociated attenuation and bead volume in both in vitro phantoms and ex-vivo liver on MDCT (r2 ¼ 0.999 and r2 ¼ 0.971). Moreover, a linear correlation was found between DOX levels and bead attenuation in both in vitro phantoms and ex-vivo liver (r2 ¼ 0.998 and r2 ¼ 0.834, respectively). Conclusions: The volume and drug content of LC Bead LUMI loaded with DOX were linearly correlated with
’
JVIR
bead-associated attenuation in rabbit livers following TACE. This relationship potentially estimates drug dose and drug distribution on post-embolization imaging, enabling real-time identification of potentially under-dosed regions of tumor. The immediate availability of such drug map estimates during LC Bead LUMI DEBTACE on CBCT could inform reproducibility, standardization, and optimization.
3:36 PM
Abstract No. 366
Understanding the distribution and embolization effects of ultrasmall doxorubicin eluting beads in a rodent model of hepatocellular carcinoma H. Nishiofuku1, A. Cortes2, A. Minhaj3, K. Maldonado2, K. Dixon2, N. Muñoz4, C. Kingsley2, A. Mcwatters5, K. Kichikawa6, M. Hicks2, R. Avritscher7; 1Nara Medical University, Kashihara, Nara, Japan; 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3 UT MD Anderson Cancer Center, Houston, TX; 4University of Texas MD Anderson Cancer Center, Houston, TX; 5The University of Texas M.D. Anderson Cancer Cente, Houston, TX; 6Nara Medical University, Kashihara, Nara, Japan; 7MD Anderson Cancer Center, Houston, TX Purpose: To evaluate the distribution and embolization effect of ultrasmall 40-60 mm doxorubicin eluting beads (DEBs) versus small 70-150 mm DEBs after intra-arterial administration in the N1S1 rat model of hepatocellular carcinoma (HCC). Materials: All studies were approved by our institutional animal care and use committee and were performed in accordance with institutional guidelines. Twenty adult male Sprague-Dawley rats underwent hepatic arterial chemoembolization using a left transcarotid approach and were randomly assigned to receive a fixed dose of 4x10*4 of ultrasmall or small DEBs. The embolization endpoint was the injection of the entire dose. After 3 or 7 days, five animals per group were euthanized. Each tumor was sectioned in three equidistant regions along axial planes (cranial, middle and caudal). Bead number, spatial distribution, and percentage of tumor necrosis were measured on histology section. Mann-Whitney and Wilcoxon test were used to evaluate differences between groups. Results: The overall percentage of necrosis was 33% and 56% for the ultrasmall DEBs at 3 and 7 days, and 10% and 28% for the small group, respectively (Po0.001). The effect of the treatment with ultrasmall DEBs was similar across different areas of the same tumor (p40.05). Small DEBs showed necrosis predominantly in the cranial (34%) and central (25%) regions at day 7 (p ¼ 0.004). No significant differences in the total number of beads were observed between the groups at any of the time points (p40.05). Significant differences in bead distribution were observed in the ultrasmall size group, at both time points, by comparing tumor versus normal parenchyma regions (po0.05). Small beads aggregate more frequently within the tumor, whereas the ultrasmall beads were equally distributed across normal liver and tumor. Conclusions: Higher rates of tumor necrosis were observed after ultrasmall DEB chemoembolization using equivalent bead dose. Small beads demonstrated a more heterogeneous tumor necrosis pattern with certain tumor regions consistently spared after embolization. Ultrasmall beads tend to be evenly
JVIR
’
Scientific Session
Wednesday
distributed across both normal liver and tumor, whereas small beads distribute preferentially within tumor.
3:45 PM
Abstract No. 367
Phase1 study of immune-enhanced locoregional therapy: hepatic artery embolization combined with intra-tumoral and systemic poly-ICLC to treat liver cancer A. Jon1, P. Kisza2, S. Contractor3, A. De la Torre4; 1 Rutgers-New Jersey Medical School, Newark, NJ; 2 Rutgers, The State University of New Jersey/New Jersey Medical School, South Orange, NJ; 3New Jersey Medical School, Newark, NJ; 4Rutgers New Jersey Medical SchoolUniversity Hospital, Newark NJ, Newark, NJ
3:54 PM
Abstract No. 368
Irinotecan-eluting LC Bead-M1 (DEBIRI-M1) for patients with liver metastases from colorectal cancer: a phase II single-center study A. Fereydooni1, B. Letzen1, S. Huber1, P. Hu2, M. Rudek2, T. Schlachter1, J. Chapiro1, J. Geschwind1, C. Georgiades2; 1Yale University School of Medicine, New Haven, CT; 2Johns Hopkins University, Baltimore, MD
S159
Purpose: The primary endpoint of this prospective trial was to determine the feasibility and safety of transarterial chemoembolization (TACE) with drug-eluting LC Bead M1 loaded with irinotecan (DEBIRI-M1) for the treatment of patients with hepatic metastases from colorectal cancer (CRC). Secondary endpoints were efficacy and survival, and the exploratory objectives included studying the pharmacokinetics of irinotecan, and the association between serum Vascular Endothelial Growth Factor (VEGF) levels and treatment outcomes. Materials: 14 patients, with a diagnosis of CRC with hepatic metastases who had failed or are intolerant to at least one line of systemic chemotherapy, were treated with DEBIRI-M1TACE. Patients were allowed to receive up to 4 TACEs in the first 4 cycles (6 months) as needed. Any technical complications and adverse events (according to CTCAE v4.03) were recorded. Radiologic response was assessed according to World Health Org. (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Survival was estimated using Kaplan Meier analysis. Levels of irinotecan, SN-38 (active metabolite), circulating VEGF and soluble VEGF Receptor were measured at baseline and multiple time points post-DEBIRI-M1 administration. Results: A total of 32 TACEs were successfully performed in all 14 patients (mean 2.29 procedures, range 1-4) without procedural complications. Grade 1-4 toxicities, one month after the first TACE, were abdominal pain (50%), elevated ALP (14.29%), anemia (14.29%), hypoalbuminemia (7.14%), nausea (7.14%) and leukopenia (7.14%). The only frequently encountered grade 3-4 toxicity was abdominal pain (28.57%). The RECIST and WHO objective response rates were 14.29% and 28.57% respectively. The 1-year survival percentage from first treatment was 35.71%. Average Cmax of irinotecan and the SN-38 were 1299 ⫾ 2276 ng/mL and 41.5 ⫾ 26.1 ng/mL, respectively, with average t½ of 5.7 ⫾ 1.2 h and 8.6 ⫾ 2.6 h following the first TACE. The treatment caused significant decreases of VEGFR1 at 24h rather than VEGF or VEGFR2. Conclusions: DEBIRI-M1-TACE is a well-tolerated and technically feasible treatment option that can be used safely in the palliative treatment of hepatic metastases from CRC.
4:03 PM
Abstract No. 369
Clinical toxicity of irinotecan-eluting microsphere TACE for colorectal cancer hepatic metastases: oncozene versus LC bead G. Laidlaw, D. Wang, D. Sze, G. Hwang, J. Louie; Stanford University School of Medicine, Stanford, CA Purpose: Transarterial chemoembolization (TACE) using irinotecan-eluting microspheres (DEBIRI) is associated with greater patient pain than TACE with doxorubicin-eluting microspheres, a difference attributed to rapid irinotecan elution. We compared clinical toxicity of irinotecan TACE using microspheres with different drug elution characteristics in treatment of colorectal cancer hepatic metastases (hmCRC). Materials: From March 2010 to May 2016, 40 hmCRC patients underwent 71 irinotecan TACE procedures at a single institution. 49 procedures in 28 patients (69.0% of procedures) and 22 procedures in 12 patients (31.0% of
WEDNESDAY: Scientific Sessions
Purpose: To determine if combining transarterial embolization (TAE) or transarterial chemoembolization (TACE) with immune modulators within the hepatic and tumor microenvironment may be a potential way to shift the balance away from immune tolerance towards cytotoxic tumor immune responsiveness to combat liver cancers. Materials: This phase I trial investigates the safety of combining several steps to: 1) increase tumor antigen visibility with focal nonlethal radiation, 2) induce an immunologic “danger” response in the tumor microenvironment using transarterial hepatic artery embolization (TAE) or chemoembolization (TACE) and intra/ peri-tumoral injection of the Toll-Like-Receptor (TLR) 3 agonist, (IT) poly-ICLC and systemically boost the response with intramuscular (IM) poly-ICLC. Several patients were also pretreated with metronomic cyclophosphamide (Cyp) to reduce toleragenic T-regulatory cells. Primary endpoints were safety of the protocol agents; secondary endpoints were radiological response and overall survival at 6 months, 1 and 2 years. Results: Eighteen patients with hepatocellular cancer (HCC) who were not eligible for surgery or liver transplant were enrolled. Aside from one embolization-related severe adverse event (SAE), all events were r grade II. Overall two-year survival was 39%. In patients o 60 years old, 2 years survival was 62.5% 60 vs. 11.1% in patients age 4 60 (Po 0.05). Several patients with unusually prolonged progression free and overall survival were observed. Conclusions: Combining TAE or TACE with intra-tumoral injection of the TLR3 agonist poly ICLC in patients with liver cancer is well tolerated and can be safely combined with local non-lethal radiation and hepatic artery embolization. Further work is in progress to characterize changes in immunity and evaluate if this approach can reliably improve survival.
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