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Purpose: Embolization microsphere loaded with irinotecan improve patient survival vs systemic FOLFIRI in liver metastases (Aliberti CIRSE 2011). In a model of VX2 liver metastases, we verified that the efficacy was due to irinotecan and not to the embolic and that two types of microspheres with different elution kinetics show different antitumor effects. Materials and Methods: VX2 cell suspension was injected in portal vein of 21 rabbits. After 14-21 days, multiple tumor nodules had developed in all liver lobes and embolization of common hepatic artery was performed with a fixed suspension volume of 1) bland Hepasphere 2) 100mg irinotecan-loaded HepaSphere 30/60µm, 3) 100mg irinotecan-loaded DC Bead 70-150µm. Five non-treated animals served as Control. Histology was performed at D3. Results: Liver tumor burden was significantly reduced in IRI treated group (5% total liver surface in HS-IRI, 17% in DC-IRI) compared to Control (32%, p=0.011). The reduction was not statistically significant for Bland HS (17%, p=0.175). Tumor necrosis was significantly increased for both HS-IRI (70% total tumor surface, p=0.006) and DC-IRI (50%, p=0.047) vs Control (24%), while it did not increased significantly with Bland (22%, p=0.465). HS-IRI were more frequently located outside tumor nodules (89%) than Bland HS (69%) and DC-IRI (52%). Necrosis of normal liver parenchyma was very limited (1% liver surface), NS between the four groups (p=0.760). Conclusion: Irinotecan-loaded microspheres reduced tumor burden and caused significant necrosis of tumor nodules. This outcome was only due to irinotecan local delivery. The higher efficacy of HS-IRI vs DC-IRI may result from different elution kinetics or bead repartition in tumor/liver. [Copyright &y& Elsevier]

Purpose: Hepasphere and DC Bead loaded with Doxorubicin differ in terms of size ranges, mechanical properties, drug/bead interactions, but were never compared in vivo. The present study has compared the safety and efficacy of the two microspheres in the model of rabbit liver VX2 tumor. Materials and Methods: VX2 tumors were grown in the liver of 20 rabbits for 11-12D then randomized to embolization with DC-DOX 100-300µm, HS-DOX 30/60µm, Bland-HS 30/60µm or non-treated (n=5/group). HS and DC were loaded with the same dose of drug (17mg/mL). DOX plasma concentration was assessed at 5/20/60/180min/24h/72h. Plasma biochemistry was assessed daily. Tumor and liver parenchyma necrosis were quantified on digitized histology sections at D3. Results: For the two DOX microspheres, drug plasma concentration was not significantly different at any time point with a peak at 5 min and not detectable after 3h. ALAT levels were highly elevated after embolization with a stronger increase in DOX vs Bland (p=0.0338), NS between HS-DOX and DC-DOX. Necrosis of peri-tumoral liver was increased for both HS-DOX and DC-DOX (23% and 34% liver surface respectively, p=0.465) compared to Bland-HS (5%) and non-treated (<1%). Tumor growth after embolization was <6% in the two DOX groups (p=0.361), not significantly different from Bland-HS (5%) but lower than non-treated (+148%, p=0.030). Tumor necrosis reached >99% tumor surface in the two DOX groups (p=0.523), significantly higher than in Bland-HS (80%) and non-treated group (32%) Conclusion: Hepasphere and DC Bead loaded with Doxorubicin demonstrated equivalent safety and efficacy in the present tumor model and higher efficacy compared to bland embolization. [Copyright &y& Elsevier]

Purpose: Small sizes of doxorubicin microspheres could act differently on tumors from large microspheres: 1) they could distribute differently inside/around the tumor 2) they may elute their drug load faster. We compared bead repartition, drug tissue distribution and antitumor effects for two sizes of doxorubicin-loaded microspheres in liver VX2 tumor model. Materials and Methods: Chemoembolization was randomly performed on VX2 liver tumors (age 12D, size 2.3±0.6cm) with a fixed volume of 50µL sediment HS-DOX 30/60µm or HS-DOX 50/100µm (n=5/group) loaded at same dose. Non-treated tumors (n=5) served as Control. DOX concentrations in bead, DOX tissue concentration profiles, bead distribution and tumor necrosis were assessed at D3. Results: HS-DOX 30/60 occluded vessels of smaller caliber than HS-DOX 50/100 (158µm vs 254µm, p=0.001). The majority of microspheres were located outside tumor for both sizes of HS-DOX (88% for small and 86% for large, p=0.835) though small HS-DOX were closer to tumor boundary than large HS-DOX (819µm vs 2800µm, p=0.059). The quantity of drug released by the microsphere at D3 was 55% of initial load for HS-DOX 30/60 and 70% for HS-DOX 50/100, not significantly different (p=0.331). For both sizes, DOX was detected in the tissue up to a radius of 800µm from the bead and above the drug IC50 in VX2 at a radius of 100µm. Tumor necrosis was >98% tumor surface for the two HS-DOX groups (p=0.784), significantly higher than for non-treated tumors (34%, p=0.004). Conclusion: The two sizes of HS-DOX were very similar in terms of repartition in embolized territory, elution properties and strong antitumor efficacy. [Copyright &y& Elsevier]