Intrahepatic Arterial Injection Research Articles

Influence of Early Versus Delayed Hepatic Artery Perfusion Scan on 90Y Selective Internal Radiation Therapy Planning.

Purpose: The aim of this study was to evaluate the effect of an increase in the time interval between hepatic intra-arterial injection of 99mTc-macroaggregated albumin (MAA) and hepatic artery perfusion scintigraphy (HAPS) on the lung shunt fraction (LSF) and perfused volume (PV) calculations in the treatment planning of selective internal radiation therapy (SIRT). Methods: The authors enrolled 51 HAPS sessions from 40 patients diagnosed with primary or metastatic liver malignancy. All patients underwent scan at the first and fourth hour after hepatic arterial injection of 99mTc-MAA. Based on single-photon emission computed tomography images, LSF values were measured from each patient's first and fourth hour images. PV1 and PV4 were also calculated based on three-dimensional images using 5% and 10% cutoff threshold values and compared with each other. Results: The authors found that the median of LSF4 was statistically significantly higher than LSF1 (3.05 vs. 4.14, p ≤ 0.01). There was no statistically significant difference between PV1 and PV4 on the 10% (p = 0.72) thresholds. Conclusions: LSF values can be overestimated in case of delayed HAPS, potentially leading to treatment cancellation due to incorrectly high results in patients who could benefit from SIRT. Threshold-based PV values do not significantly change over time; nevertheless, keeping the short interval time would be safer.

Clinical and Dosimetric Implications of Calculating Lung Shunt Fraction for Hepatic 90Y Radioembolization Using SPECT/CT Versus Planar Scintigraphy.

BACKGROUND. Accurate assessment of hepatopulmonary shunting, typically performed by planar scintigraphy, is critical in planning 90Y radioembolization. High lung shunt fractions (LSFs) may alter treatment. OBJECTIVE. The purpose of this study is to compare LSFs calculated from planar scintigraphy versus SPECT/CT in patients with high planar LSFs (> 15%) and to describe the potential clinical and dosimetric implications of SPECT/CT LSF calculations. METHODS. This retrospective study included 36 patients (29 men and seven women; mean age, 62.4 ± 9.8 [SD] years) who underwent 99mTc-macroaggregated albumin (MAA) planar scintigraphy for planning hepatic radioembolization, had a planar LSF greater than 15%, and underwent concurrent SPECT/CT. Clinically reported planar LSFs were recorded. SPECT/CT LSFs were retrospectively calculated using automatically generated volumetric ROIs around the lungs and liver with subsequent manual adjustments. Total lung and perfused liver doses were calculated using a medical internal radiation dose model. Values derived from planar and SPECT/CT data were compared using Mann-Whitney U tests. Multivariable regression analysis was performed of factors associated with the discrepancy in LSF between the techniques. RESULTS. Mean planar LSF was 25.1% ± 11.6%, and mean SPECT/CT LSF was 16.0% ± 9.3% (p < .001). Mean lung dose was 18.8 ± 8.0 Gy for planar LSF versus 12.3 ± 7.2 Gy for SPECT/CT LSF (p < .001). Mean perfused liver dose was 92.9 ± 36.1 Gy using planar LSF versus 102.7 ± 39.1 Gy using SPECT/CT LSF (p < .001). In multivariable analysis, a larger discrepancy in LSF between planar scintigraphy and SPECT/CT was associated with a body mass index (weight in kilograms divided by the square of height in meters) of 26 or higher (p = .02), maximum tumor size of less than 9 cm (p = .05), and left hepatic intraarterial injection (p = .02). Fourteen of 36 patients did not undergo upfront radioembolization due to a planar LSF greater than 20% and instead underwent shunt-reducing embolization with subsequent radioembolization (n = 7), transarterial chemoembolization (n = 5), or no treatment (n = 2). Five of these 14 patients had a SPECT/CT LSF of less than 20% and would have been eligible for upfront radioembolization based on SPECT/CT LSF. Seven of 29 patients treated with radioembolization underwent prescribed dose reductions based on planar LSF; six of these patients would have qualified for standard radioembolization without dose reduction using SPECT/CT LSF. CONCLUSION. Planar scintigraphy yields greater LSFs compared with SPECT/CT, possibly leading to unnecessary shunt-reducing procedures and prescribed dose reductions. CLINICAL IMPACT. SPECT/CT should be considered for clinical LSF calculations before radioembolization in patients with high LSFs.

MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-co-glycolic Acid)/Poly(styrene-alt-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer.

In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly(styrene-alt-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 ± 3 μm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (∼25% at pH 5.4 and ∼8% at pH 7.4) and accumulated significantly in an MT1-MMP-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC.

Intraportal mesenchymal stem cell transplantation prevents acute liver failure through promoting cell proliferation and inhibiting apoptosis

Transplantation of mesenchymal stem cells (MSCs) has been regarded as a potential treatment for acute liver failure (ALF), but the optimal route was unknown. The present study aimed to explore the most effective MSCs transplantation route in a swine ALF model. The swine ALF model induced by intravenous injection of D-Gal was treated by the transplantation of swine MSCs through four routes including intraportal injection (InP group), hepatic intra-arterial injection (AH group), peripheral intravenous injection (PV group) and intrahepatic injection (IH group). The living conditions and survival time were recorded. Blood samples before and after MSCs transplantation were collected for the analysis of hepatic function. The histology of liver injury was interpreted and scored in terminal samples. Hepatic apoptosis was detected by TUNEL assay. Apoptosis and proliferation related protein expressions including cleaved caspase-3, survivin, AKT, phospho-AKT (Ser473), ERK and phospho-ERK (Tyr204) were analyzed by Western blotting. The average survival time of each group was 10.7+/-1.6 days (InP), 6.0+/-0.9 days (AH), 4.7+/-1.4 days (PV), 4.3+/-0.8 days (IH), respectively, when compared with the average survival time of 3.8+/-0.8 days in the D-Gal group. The survival rates between the InP group and D-Gal group revealed a statistically significant difference (P<0.01). Pathological and biochemical analysis showed that liver damage was the worst in the D-Gal group, while less injury in the InP group. Histopathological scores revealed a significant decrease in the InP group (3.17+/-1.04, P<0.01) and AH group (8.17+/-0.76, P<0.05) as compared with that in the D-Gal group (11.50+/-1.32). The apoptosis rate in the InP group (25.0%+/-3.4%, P<0.01) and AH group (40.5%+/-1.0%, P<0.05) was lower than that in the D-Gal group (70.6%+/-8.5%). The expression of active caspase-3 was inhibited, while the expression of survivin, AKT, phospho-AKT (Ser473), ERK and phospho-ERK (Tyr204) was elevated in the InP group. Intraportal injection was superior to other pathways for MSC transplantation. Intraportal MSC transplantation could improve liver function, inhibit apoptosis and prolong the survival time of swine with ALF. The transplanted MSCs may participate in liver regeneration via promoting cell proliferation and suppressing apoptosis during the initial stage of ALF.

Superselective intra-arterial hepatic injection of indocyanine green (ICG) for fluorescence image-guided segmental positive staining: experimental proof of the concept.

Intraoperative liver segmentation can be obtained by means of percutaneous intra-portal injection of a fluorophore and illumination with a near-infrared light source. However, the percutaneous approach is challenging in the minimally invasive setting. We aimed to evaluate the feasibility of fluorescence liver segmentation by superselective intra-hepatic arterial injection of indocyanine green (ICG). Eight pigs (mean weight: 26.01±5.21kg) were involved. Procedures were performed in a hybrid experimental operative suite equipped with the Artis Zeego®, multiaxis robotic angiography system. A pneumoperitoneum was established and four laparoscopic ports were introduced. The celiac trunk was catheterized, and a microcatheter was advanced into different segmental hepatic artery branches. A near-infrared laparoscope (D-Light P, Karl Storz) was used to detect the fluorescent signal. To assess the correspondence between arterial-based fluorescence demarcation and liver volume, metallic markers were placed along the fluorescent border, followed by a 3D CT-scanning, after injecting intra-arterial radiological contrast (n=3). To assess the correspondence between arterial and portal supplies, percutaneous intra-portal angiography and intra-arterial angiography were performed simultaneously (n=1). Bright fluorescence signal enhancing the demarcation of target segments was obtained from 0.1mg/mL, in matter of seconds. Correspondence between the volume of hepatic segments and arterial territories was confirmed by CT angiography. Higher background fluorescence noise was found after positive staining by intra-portal ICG injection, due to parenchymal accumulation and porto-systemic shunting. Intra-hepatic arterial ICG injection, rapidly highlights hepatic target segment borders, with a better signal-to-background ratio as compared to portal vein injection, in the experimental setting.

Abstract 4204: Intraarterial delivery of doxorubicin-loaded hollow gold nanospheres for photothermal ablation chemotherapy of hepatocellular carcinoma in the liver of rats

Abstract Purpose: We sought to use combretastatin A-4 phosphate disodium (CA4P) to enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS; Dox@PEG-HAuNS) for improved photothermal ablation (PTA)-chemotherapy of hepatocellular carcinoma (HCC) in rats under image guidance. Materials and Methods: Two groups of 10 HCC-bearing rats each received intrahepatic arterial (IA) injection of either PEG-HAuNS/Lipiodol alone or CA4P followed by PEG-HAuNS/Lipiodol 5 min later. Each group was subdivided, and the Au content of tumors and tissues excised at 1 h or at 24 h was quantified using neutron activation analysis (n = 5/time point). Five rats received CA4P plus PEG-[64Cu]-HAuNS/Lipiodol and underwent μPET/CT. Therapeutic effects were compared among 3 groups of 6 rats each that received IA injection of saline (control group), CA4P plus Dox@PEG-HAuNS/Lipiodol (chemotherapy group), or CA4P plus Dox@PEG-HAuNS/Lipiodol plus near-infrared irradiation (PTA-chemotherapy group). Findings were verified with postmortem histopathology and/or autoradiography. Results: PEG-HAuNS uptake in CA4P-pretreated tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 h (P&amp;lt;0.05) and 24 h (P&amp;lt;0.01). The tumor-to-liver PEG-HAuNS uptake ratios at 1 h and 24 h were 5.63±3.09 and 1.68±0.77, respectively, in the CA4P-treated group and 1.29±2.40 and 0.14±0.11, respectively, in the non-CA4P-treated group. μPET/CT clearly delineated the tumors, enabling quantitative imaging guidance. Tumor volumes 10 d after therapy were 1.68±1.01, 3.96±1.75, and 6.13±2.27 cm3 in the PTA-chemotherapy, chemotherapy, and control groups, respectively, with significant differences between the PTA-chemotherapy group and other groups (P&amp;lt;0.05). Conclusion: CA4P pretreatment causes a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the anti-HCC efficacy of μPET/CT-guided PTA-chemotherapy in rats. (Supported in part by the John S. Dunn Foundation) Citation Format: Junjie Li, Min Zhou, Chiyi Xiong, Wanqin Wang, Qizhen Cao, Xiaoxia Wen, Xin Ji, Andrew Wang, Sanjay Gupta, Chun Li. Intraarterial delivery of doxorubicin-loaded hollow gold nanospheres for photothermal ablation chemotherapy of hepatocellular carcinoma in the liver of rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4204.

Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation-Chemoembolization Therapy in Rats.

Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm3 ± 1.01, 3.96 cm3 ± 1.75, and 6.13 cm3 ± 2.27 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P < .05). Conclusion CA4P pretreatment caused a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the efficacy of anti-HCC treatment with PTA-CET in rats. © RSNA, 2016 Online supplemental material is available for this article.

Local Retention and Combination Effects of Biocompatible Doxorubicin-Loaded and Radioiodine-Labeled Microhydrogels in Cancer Therapy.

I-131-labeled chitosan microhydrogels (I-131-CMH) that are retained at an injection site without leaking free I-131 into normal tissue can provide opportunities to improve cancer therapy. This study focuses on the development of doxorubicin-loaded I-131-CMH (Dox-I-131-CMH) for use in radiochemotherapy against cancer. The radiolabeling of I-131-CMH was found to be stable over a period of 2 weeks with no disassociation of free I-131, and Dox showed a sustained release from the CMH. When I-131-CMH were injected into the thigh muscle or tumor tissue, in vivo gamma imaging showed a retention at the injection site with no significant leakage of I-131 into other areas of normal tissue, and after an intrahepatic arterial injection, I-131-CMH were selectively retained in the liver. Dox-I-131-CMH had significant synergistic therapeutic effects of radiation and chemotherapy on mouse breast cancer models. In this regard, Dox-I-131-CMH may be a new alternative agent for cancer therapy.

Gene therapy for rhesus monkeys heterozygous for LDL receptor deficiency by balloon catheter hepatic delivery of helper-dependent adenoviral vector.

Autosomal dominant familial hypercholesterolemia (FH) is a monogenic life-threatening disease. We tested the efficacy of low-density lipoprotein receptor (LDLR) gene therapy using helper-dependent adenoviral vector (HDAd) in a nonhuman primate model of FH, comparing intravenous injection versus intrahepatic arterial injection in the presence of balloon catheter-based hepatic venous occlusion. Rhesus monkeys heterozygous for mutant LDLR gene (LDLR+/−) developed hypercholesterolemia while on a high cholesterol diet. We treated them with HDAd-LDLR either by intravenous delivery, or by catheter-based intra-hepatic artery injection. Intravenous injection of ≤1.1×1012 viral particles (vp)/kg failed to have any effect on plasma cholesterol. Increasing the dose to 5×1012 vp/kg led to a 59% lowering of the plasma cholesterol that lasted for 30 days before it returned to pretreatment levels by day 40. A further increase in dose to 8.4×1012 vp/kg resulted in severe lethal toxicity. In contrast, direct hepatic artery injection following catheter-based hepatic venous occlusion enabled the use of a reduced HDAd-LDLR dose of 1×1012 vp/kg that lowered plasma cholesterol within a week, and reached a nadir of 59% pretreatment level on days 20 to 48 after injection. Serum alanine aminotransaminase (ALT) remained normal until day 48 when it went up slightly and stayed mildly elevated on day 72 before it returned to normal on day 90. In this monkey, the HDAd-LDLR-induced trough of hypocholesterolemia started trending upwards on day 72 and returned to pretreatment levels on day 120. We measured the LDL apolipoprotein B turnover rate at 10 days before, and again 79 days after, HDAd-LDLR treatment in two monkeys that exhibited a cholesterol lowering response. HDAd-LDLR therapy increased the LDL fractional catabolic rate by 78% and 50%, respectively, in the two monkeys, coincident with an increase in hepatic LDLR mRNA expression. In conclusion, HDAd-mediated LDLR gene delivery to the liver using a balloon catheter occlusion procedure is effective in reversing hypercholesterolemia in a nonhuman primate FH model; however, the unsustainability of the hypocholesterolemic response during 3–4 months of follow up and heterogeneous response to the treatment remains a challenge.

Therapeutic efficacy of 188Re-MN-16ET lipiodol in an animal model of hepatocellular carcinoma

In our recent study, we developed a new radiopharmaceutical (Re-188 MN-16ET lipiodol) with encouraging results for the treatment of liver malignancy. In this study, we further evaluated the therapeutic efficacy of this radiopharmaceutical by measuring tumor response and survival times in rats with liver tumors after intra-hepatic arterial injection of Re-188 MN-16ET lipiodol. Twelve male rats bearing hepatic tumors were divided into three groups. Group 1 received an intra-hepatic arterial injection of 18.5 MBq Re-188 MN-16ET lipiodol; Group 2 received lipiodol and Group 3 received normal saline. Tumor size was measured by liver sonography before injection, at 2, 4, and 8 weeks after injection. Survival time and response rate were calculated. All rats showed good response and survived over 60 days in Group 1 while all rats showed poor response in Group 2 and Group 3 with only 25 % of rats in Group 2 and none (0 %) in Group 3 survived over 60 days. The p value was 0.0067 between Group 1 and Group 3; 0.04 between Group 1 and Group 2; and 0.034 between Group 2 and Group 3. Re-188 MN-16ET lipiodol has good potential for the treatment of hepatoma.

A comparison of Re-188-MN-16ET-lipiodol and transcatheter arterial chemoembolization in the treatment of hepatoma: An animal study

In patients with unresectable HCC, transcatheter arterial chemoembolization (TACE) is a widely used treatment. Recently, as an alternative treatment modality for HCC, transcatheter arterial embolization with radioisotopes has been investigated. In this study, we compared the therapeutic efficacy of an intra-hepatic arterial injection of Re-188-MN-16ET-lipiodol and the TACE method in rats with liver tumors. Twelve male rats bearing hepatic tumors were divided into three groups to evaluate the efficacy of treatment (four in each group). Group 1 received an intra-hepatic arterial injection of 0.2mCi of Re-188-MN-16ET-lipiodol; group 2 received epirubicin (0.5mg/kg) and 0.1ml of lipiodol emulsion; group 3 received 0.1ml of normal saline and served as the control group. Tumor size was measured by liver sonography before injection, at two weeks, four weeks and eight weeks after injection. Survival time was calculated from the day of treatment to 56days after treatment by the life-table method. The response to treatment and the survival time in each group were evaluated and compared. All rats treated with Re-188 MN-16ET-lipiodol showed good response to the therapy. Their tumor size decreased and all rats survived over eight weeks. All rats treated with epirubicin plus lipiodol survived over 8weeks; however, two rats (50%) showed increased tumor size in the 8th week. As for the control group (rats treated with normal saline), all rats survived less than 37days with continuous tumor growth. Results showed that Re-188-MN-16ET-lipiodol can be a potential therapeutic pharmaceutical for the treatment of liver tumors.

Hepatic Arterial Infusion of Doxorubicin-Loaded Microsphere for Treatment of Hepatocellular Cancer: A Multi-Institutional Registry

Hepatic intra-arterial therapy for unresectable hepatocellular cancer (HCC) has been shown to improve overall survival, but can have significant toxicity. A recent prospective randomized controlled trial demonstrated superior response rates and significantly less morbidity and doxorubicin-related adverse events with drug-eluting beads with doxorubicin (DEBDOX) compared with conventional chemoembolization. The aim of this study was to confirm the efficacy of DEBDOX for the treatment of unresectable HCC. This open-label, multicenter, multinational single-arm study included 118 intermediate-staged HCC patients who were not candidates for transplantation or resection. Patients received DEBDOX at each treatment. Complications and response rates to treatment were analyzed. There were 118 patients who received a total of 186 DEBDOX treatments with a median total treatment dose of 75 mg (range 38 to 150 mg), and median overall total hepatic exposure of 150 mg (range 150 to 600 mg). Five lesions were targeted, with a median size of 5.3 cm (range 1.0 to 16.9 cm). Severe adverse events related to liver dysfunction were seen after 4% of treatments. Overall survival was a median of 14.2 months (range 5 to 30 months), with progression-free survival of 13 months and hepatic-specific progression-free survival of 16 months. Okuda class less than 1 at time of treatment, reduction of alpha-fetoprotein of 1,000 ng/mL at the first post-treatment evaluation, delivery of more than 200 mg doxorubicin, and less than 25% liver involvement were all predictors of favorable overall survival assessed by multivariable analyses. Hepatic intra-arterial injection of DEBDOX is safe and effective in the treatment of HCC, as demonstrated by a minimal complication rate and robust and durable tumor response.

Pharmacokinetics of miriplatin in experimental dog models of hepatic or renal impairment

Miriplatin is an anticancer platinum complex for treatment of hepatocellular carcinomas by intra-hepatic arterial injection suspended in an iodinated ethyl ester of fatty acids from poppy seed oil as a carrier. Effects of liver and kidney function on( 14)C-miriplatin pharmacokinetics were assessed using dog models of hepatic and renal impairment introduced by thioacetamide exposure and 7/8 nephrectomy, respectively. Miriplatin was selectively delivered to the liver; platinum and radioactive component were gradually released into systemic circulation and excreted into urine. Microautoradiographic analysis of liver specimens showed( 14)C-miriplatin to be localized in blood vessels and/or macrophage-like cells. These features of miriplatin disposition were not affected by hepatic impairment. Thus, in clinical settings, hepatic impairment would not be expected to affect the intra-hepatic distribution and systemic pharmacokinetics of miriplatin. In dogs with renal impairment, although inconclusive, plasma concentrations of ultrafilterable platinum and radioactivity increased due to reduction in renal clearance.

Treatment Planning and Daily Image-guidance Optimization for Liver Radiotherapy with Intrahepatic Arterial Injection of Ethiodol Prior to Simulation

Treatment Planning and Daily Image-guidance Optimization for Liver Radiotherapy with Intrahepatic Arterial Injection of Ethiodol Prior to Simulation

Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy

Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the beta-emitting isotope yttrium-90 ((90)Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues. We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80). Radioembolization with (90)Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.

Prospective randomized study comparing hepatic intra-arterial injection of Yttrium-90 resin-microspheres (HAI-Y90) with protracted IV 5FU (5FU CI) versus 5FU CI alone for patients with liver-limited metastatic colorectal cancer (LMCRC) refractory to standard chemotherapy (CT)

4096 Background: Chemorefractory LMCRC has a poor prognosis. We hypothesized a significant improvement of the patient's outcome after internal radiotherapy of the hepatic metastases with HAI-Y90 given along with 5FU CI over 5FU CI alone. Methods: This prospective, multicentric, randomized trial compared arm A: 5FU CI (300 mg/m2 D1–14 q3weeks) with arm B: HAI-Y90 and 5FU CI (225 mg/m2 D1–14 followed by 300 mg/m2 D1–14 q3weeks) until disease progression. Eligibility criteria were: chemo-refractory (5FU, oxaliplatin, irinotecan) LMCRC, PS max 2, normal direct bilirubin, and no lung shunting. Primary endpoint was time to liver progression (TTLP). Secondary endpoints were time to progression (TTP), overall survival (OS) and safety. Cross-over (HAI-Y90 monotherapy) was permitted in arm A after disease progression. Analysis was by intention to treat. To detect an increase in median TTLP from 6 to 18 weeks, 35 local progressions were needed (alpha 5%, power 90%). Distribution of time to events variables was modelled through Cox regression (likelihood ratio tests). Results: Trial randomized 46 patients (pts) of whom 44 were eligible for analysis (23 in arm A and 21 in arm B). Pts’ characteristics in the 2 arms were well balanced. Local progression was documented in 41 pts. Median length of follow-up was 108 weeks. Results are summarized in the table . Treatment was well tolerated with few side effects reported, essentially grade 3 asthenia (5 pts; 22%) in arm A. Most pts (25/44) received further treatment after local progression, including 10 pts with cross-over to HAI-Y90 in arm A, which may explain to some degree the lack of difference in OS. Conclusions: HAI-Y90 with 5FU CI significantly improves TTLP and TTP over 5FU CI alone and is a valid salvage therapeutic option for chemo-refractory LMCRC. [Table: see text] No significant financial relationships to disclose.

Effect of Acute Hepatic Failure on Epirubicin Pharmacokinetics after Intrahepatic Arterial Injection in Rats

In the case of cancer chemotherapy for hepatocellular carcinoma, anthracycline anticancer agents such as epirubicin are widely used, and have typically been given by intrahepatic arterial (i.a.) infusion to increase treatment efficacy and to reduce systemic toxicity. The anthracyclines are eliminated primarily by the liver, and the use of these drugs in patients with hepatic failure can be difficult. In this study, we investigated the effect of acute hepatic failure on the pharmacokinetics of epirubicin after i.a. injection in rats. Experimental acute hepatic failure was induced by carbon tetrachloride-treatment. Epirubicin was injected into the hepatic artery or the saphenous vein of the rats at a dose of 2 mg/kg. After both intravenous (i.v.) and i.a. injection, the serum concentration and the AUC 0-24 of epirubicin in hepatic failure rats were significantly higher than the values in control rats. The AUC 0-24 ratio of hepatic failure (i.a.) to control (i.a.) was higher than the ratio of hepatic failure (i.v.) to control (i.v.). These results suggest that the influence of hepatic failure on serum epirubicin concentration is larger with the i.a. route than with the i.v. route. The liver concentration of epirubicin after i.a. administration in hepatic failure rats was significantly lower than that in control rats. This result suggests that the effect of the liver-selective drug targeting after i.a. injection in hepatic failure rats is lower than in normal rats. Therefore, we should be careful when administering epirubicin by the i.a. route in patients with acute hepatic failure.

Hepatic intra-arterial injection of 3-bromopyruvate in rabbit vx2 tumor

To evaluate the antitumoral effects of an intra-arterial injection of 3-bromopyruvate (3-BrPA) on liver VX2 tumor in rabbits. Twenty rabbits with surgically implanted liver VX2 tumors were used. The rabbits were divided into three groups: a control, a saline, and a 3-BrPA group. Four rabbits were not treated at all, and they served as the control group. The saline group (n = 6) received only intra-arterial saline injection. The 3-BrPA group (n = 10) received an intra-arterial injection of 3-bromopyruvate through the hepatic artery. The delivered amounts of 3-bromopyruvate were as follows: 25 ml of 0.5 mM in six rabbits, 25 ml of 1.0 mM in two rabbits, and 25 ml of 2.0 mM in two rabbits. Four days after intra-arterial injection, the rabbits were sacrificed and histopathologic analysis of the explanted livers was performed with comparison of the tumor necrosis ratio (a percentage of the necrotic area versus the entire tumorous area) in each group. The mean tumor necrosis ratio was 12.5+/-4.2%, 44.8+/-24.7%, and 49.4+/-14.3% in the control, saline, and 3-BrPA groups, respectively. Between the control and the saline group, and between the control and the 3-BrPA group the mean tumor necrosis ratio appeared to be significantly different (P<0.05). However, there was no statistical difference in the mean tumor necrosis ratio between the saline and the 3-BrPA group (P = 0.416). A single session of intra-arterial injection of 3-BrPA showed no better results in terms of tumor necrosis than that of saline injection in a rabbit VX2 tumor model.

Cytotoxic-loaded albumin microspheres: a novel approach to regional chemotherapy.

Adriamycin-loaded albumin microspheres (15-40 micron diameter) incorporating 1 per cent by weight of Adriamycin were prepared by cross linking albumin with glutaraldehyde. After systemic administration in rats, the microspheres were trapped in the pulmonary capillary bed, biodegradation occurring over 48 h. After selective intrarenal arterial injection of 99mTc-labelled albumin microspheres in rabbits, 97 per cent of the injected microspheres were trapped within the kidney; less than 1 per cent were found in the contralateral kidney, lungs and liver. Similar results were obtained after selective intrahepatic arterial injection. The selective injection of cytotoxic-loaded microspheres may provide a reliable method of administering high concentrations of cytotoxic drug to a target organ without producing high serum levels; this technique may have a role in the management of solid tumours.

Large-Volume Liver Metastases from Neuroendocrine Tumors: Hepatic Intraarterial90Y-DOTA-Lanreotide as Effective Palliative Therapy

To prospectively evaluate the safety and effectiveness of hepatic intraarterial injection of yttrium 90 ((90)Y) tetraazacyclododecane tetraacetic acid (DOTA) lanreotide as a treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors. The study was local ethics committee approved, and all patients gave informed consent. Twenty-three patients (13 men, 10 women; age range, 21-69 years; median age, 57 years) with histologically proved large-volume liver metastases from neuroendocrine cancers were treated. All patients had radiologic evidence of liver disease progression and high uptake of indium 111 ((111)In) pentetreotide at scintigraphy. Selective hepatic intraarterial injection of (90)Y-DOTA-lanreotide (total of 36 treatments; median activity per dose, 1 GBq) was administered with or without embolization. Treatment cycles were performed in 8-week intervals. Clinical, biologic, and radiologic tumor responses were assessed 8-12 weeks after each treatment cycle. Objective tumor response was classified according to World Health Organization response criteria as complete regression, partial response, stable disease, or disease progression. Kaplan-Meier survival curves were used to calculate 1-year survivals. Partial response to treatment was achieved in three (16%) of 19 patients, and stable disease was achieved in 12 (63%). Four (21%) of 19 patients had continued disease progression. Clinical improvement was reported by 14 (61%) of the 23 patients, and a reduction in biologic marker levels was observed in nine (60%) of 15 patients. Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade > 2) occurred in three patients. The 1-year survival rate was 63% (median survival time, 15 months). Hepatic intraarterial injection of (90)Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors.