- Email: [email protected]
Scientific Session 25 Oncologic Interventions: Trans-arterial Therapies for Hepatic Malignancy
RESULTS: One to ninety-seven months postoperatively (mean 19±2l months), there was a slight but significant (p<.05) increase in creatinine for both TFX (J .34±.52 to 1.49±.79) and IFX (J.26±.69 to J.43±.85) groups. The mea n postoperative creatinine cIearances for both groups decreased slightly but significantly (p<.05) (TFX: 52.6±17.7 to 48.7±16.3;IFX: 56.9±21.8 to 53.5±24.5). There were4(6.0%) new smali renal infarcts detected by CT in the TFX gro up compared to I (J .6%) in the IFX group. There were no new renal artery occIusions (CT) in either group. Two patients in each group required dialysis (3.0% of TFX, 3.3% of IFX). There were no significant differences between the two grou ps in the increase in creatinine (p=0.19), decrease in creatinine cIearance (p=0.68), or number of renat infarcts (p=0.37). CONCLUSION: Though there is an increase in creatinine and decrease in creatinine cIearance after aortic endografting, these changes were comparable in patients with TFX and IFX. TFX may produce more smali renal infarcts, but these do not impair rena] function. Thus, TFX can be perforrned safely with no greater change in renal function than that observed after IFX.
Scientific Session 25 Oncologic Interventions: Trans-arterial Therapies for Hepatic Malignancy Monday, March, 31, 2003 1:30 PM - 3:30 PM Moderator(s): Chamaree Chuapetcharasopon, MD Chieh-Min Fan, MD
1:30PM
AbstractNo.194
Plasmid DNA Delivery to the Isolated Rabbit Liver: A Novel Use of Interventional Radiology for Gene Therapy. K.M. Baskin, Children:S Hospital ojPhiladelphia, Philadelphia, PA, USA. S.J. Eastman • R.K. Scheule • BL Hodges • Q. Chu • R.B. Towbin PURPOSE: Gene delivery using viral vectors is relatively efficient, but limits the size of the gene that can be delivered, and carries the potential for hallnful immune-mediated and toxlc effects on the host, especially on readministration. In theory, delivery of "nak.ed" plasmid DNA (pDNA) avoids these problems, but in practice has been either so inefficient that satisfactory levels of expression cannot be achieved, or has required such invasive methods of delivery as to not be clinically practicable. This prospective study was designed to evaluate the efficacy and safety of a new method of pDNA delivery, using minimally-invasive transcatheter hydrodynarnic delivery targeted to the liver as a depot organ through the mechanically isolated Iiver vasculature in arabbit model. MATERIALS AND METHODS: These IACUC-approved studies were performed in male New Zealand White rabbits (3-4 kg). A whole organ technique (n = 28) was employed with pDNA solution injected hydrodynarnically via the vena cava between balloons used to block hepatic venous outflow. Using a lobar technique (n = 8), pDNA was hydrodynamically delivered to a single hepatic lobe using an IVC baJJoon catheter to occIude hepatic veoous outflow.
hepatic parenchymal distribution of CAT expression. Despite a smaller bolus, lobar delivery resulted in significant levels of transgene product in the serum (mean SEAP = 26 mcg/mL, SD= 16) and demonstrated the highest levels of CAT expression in the injected lobe.
CONCLUSION: These preliminary studies suggest that catheter-mediated hydrodynarnic delivery of pDNA to the isolated liver may provide a method for human gene therapy that is both therapeutically significant and clinically practicable. These studies also highlight the potential for use of fundamental techniques in interventional radiology in novel combinations to solve essential problems in emergiog areas of investigation such as molecular and gene therapy and organ-specific delivery.
1:41 PM
Abstract No. 195
Effects of the Type of Embolization Particles on Carboplatinum Concentration in the VX2 Liver Cancer Model. i.H. Geschwind, iohns Hopkins University School oj Medicine, Baltil7wre, MD, USA. H. Kobeiter • S. Baker • M. Alaa • M.S. Torbenson • K. Kim PURPOSE: To assess the effects of Embospheres on intratumoraI concentration of chemotherapy during chemoembolization of liver tumors (rabbit model of liver cancer) and compare them to those of PVA. MATERJALS AND METHODS: The VX2 tumors were grown in the liverof 18 rabbits. Animals were divided into 3 groups (n = 6): group l: chemoembolization/Embospheres (150m3ODm), group 2: chemoembolizationIPVA (J50m-250m), group 3: saline injection lA (controI). Animals were sacrificed 48 hours after treatment their liver explanted and submitted for histopathologic analysis. Carboplatin (5 mglkg) was selected because of its known potency against the VX2 tumor. To measure the concentration of carboplatin, blood and tumor tissue sampIes were collected from the peripheral zone and necrotic center ofthe tumors as well as from the non-tumorous liver. Carboplatin concentration was then measured by atomic absorption spectroscopy. RESULTS: In the PVA group (group 2), the mean carboplatin concentration was 55.5 mg/g within the necrotic center of the tumor and 11.35 mg/g at the rim. The plasma concentration was less than 0.079 mg/mJ. No carboplatin was detected in non-tumorous liver tissue. In the Embospheres group (group l), the mean carboplatin concentration was 104.25 mg/g within the necrotic center ofthe tumor and 12.32 mg/g at the rim. The plasma concentration was less than 0.053 mg/mI. No carboplatin was detected in non-tumorous liver tissue. CONCLUSlON: Carboplatin concentration was significantly greater (2 to 8 fold) within the necrotic center than at the periphery of the tumor in both treated groups. Carboplatin concentration within the necrotic center of the tumor was significantly greater in Embosphere than in PVA group, but was only slightly greater within the peripheral rim of the tumor. Embospheres may therefore be advantageous when administered during TACE sioce the concentration of carboplatin within the tumor is greater than that obtained with PVA.
RESULTS: Whole organ coadministration of plasmids encoding both a secreted alkaline phosphatase reporter gene (pCFl-SEAP) and a non-secreted transgene, chloramphenicol acetyltransferase (pGZB-sCAT), yielded an average circulating level of SEAP at 24 hr of 76 mcg/mL (SD=93) and a broad
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1:52PM
Abstract No. 196
Safety and Initial Results of Hepatic Arterial Radioembolization Malignancies of the Liver. D.M. Coldwell, Fax Chase Cancer Center, Philadelphia, PA, USA - A.S. Kennedy - R. Murthy - C.D. Nutting - K.A. Morton - D.A. VanEcho, et al. PURPOSE: Unreseetable solid tumors in the liver have a historical survival of 12-14 months even with the best of therapy. Residual islands of tumor have limited the effeetiveness of liver -direeted therapy. New radioaetive embolie particles should reduee the amount of residual tumor present after embolization. This study was performed to elueidate the safety, eomplieations, and immediate results of this treatment. MATERIALS AND METHODS: Patients with solid tumors in the liver with normal CBC, ereatinine, bilirubin < 2.0, and predominately liver disease were enrolled in this IRB approved study. Pre-treatment sereening included hepatie arteriogram and Te99m labeled MAA sean to identify a disqualifying shunt to the lungs or Gl traet. A target dose of 150 Gy of aetivity was planned in a sequential unilobar embolization. Ali patients were treated with proton pump inhibitors for three months after therapy. Routine antibioties were not utilized except in cases where upper abdominal surgery had oceurred. RESULTS: 150 patients (100 men, 50 women) were included who received treatment at three sites under identical protocols. The mean age ofthe patients was 59 (range 31-89). A median total dose of 142 Gy was achieved per lobe. Atotal of 234 treatments were performed. Tumors treated incłuded hepatoeellular carcinoma (39), metastatic eolo-rectal eancer (62), neuroendocrine tumor (20), other metastases (29). There were no complieations during administration of the radioactive microspheres but 20 patients were admitted overnight. No patient experienced liver failure or fatal veno-occlusive disease. 34 patients had pain in the epigastrium during infusion of the left hepatie artery; 14 ofthese patients developed ulcers. One patient developed a hepatie abscess but recovered after drainage. Technieal success rate was 99% for administration. Only a single misadministration occurred with less than 80% of the target dose administered. CONCLUSION: For patients with unresectable hepatie tumors, this treatment promises a safe option but the longer term efficacy has yet to be proven. There were few complication and none fataJ.
Abstract No. 197
2:03PM
Intra-Arterial 166 Holmium·Chitosan Complex Injection for the Treatment of Hepatocellular Carcinoma. J. y. Won, Yonsei University Hospital, Seoul, Seoul, Korea HJ. Moon -D.Y. Lee -K.H Han
-N.c.
Yoo -J.T. Lee
PURPOSE: To evaluate the clinical efficiency and safety of intra-arterial injection of 166 Holmium-Chitosan eomplex in patients with hepatoceł1ular carcinoma (HCC).
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MATERIALS AND METHODS: Between January 1999 and July 2001,118 patients (100 male, 18 female, mean age=56.7yrs) with HCCs were enrolled in this study. The inclusion criteria of HCCs were; nodular type, single or two HCCs with same feeding artery, diameter less than lOcm, no arterio-portal or arterio-venous shunt on angiography. 92 patients were Child-Pugh class A and 22 patients were class B. 4 patients were class C. We injected 166 Holmium-Chitosan eomplex, 20mCi/em of tumor diameter through 3F mierocatheter. After finishing the injeetion, garnrna camera
imaging was obtained to depict the radioactivity within the tumor. Blood sarnpling and beta radioactivity counting were also performed to evaluate the systemic leakage ofRolmium. Follow up CT scans and angiography were taken I, 6 and 12 months after the procedure and clinical status of each patient was also evaluated. We caleulated the cumulative survival rates ofthe patients using the Kaplan-Meier method with the 95% confidenee intervaI. RESULTS: Total injection dose ofholmiumranged from 30 to 200 mCi (mean=105). Immediately after the procedure, 22 patients (18.6%) showed transient leukopenia and thrombocytopenia, and 3 patients (2.5%) showed liver abseess. Follow up CT seans and angiography showed complete tumor necrosis in 72 patients (63.2%), >50% necrosis in 18 (15.8%), <50% necrosis in 8 (6.8%), no response in 16 (14.0%). Other 4 patients were lost during the follow up period. Six patients (5.3%) expired due to the procedure related complications; 4 from hepatic failure after the procedure, 1 from paneytopenia, 1 with systemie leakage of 166 HolmiumChitosan eomplex. Overał11-year survival rate was 92.8%; 95.3% with Child-Pugh class A and 79.7% with B. CONCLUSION: Intra-arterial administration of 166 Holmium-Chitosan eomplex was effeetive and safe for the treatment of HCC and eould be a new treatment modality to controI inoperable HCC.
2:14PM
Abstract No. 198
Outcome ofHepatic Artery Chemoembolization (RACE) in the Treatment of Metastatic Carcinoid of the Liver. R.R.P. Warner, Mount Sinai School ofMedicine, New York, NY, USA - Ps. Nowakowski - HA. Mitty - J. Guller - A. Falk - M. Sung, et al. PURPOSE: To retrospeetively evaluate response of metastatie eareinoid of the liver to HACE treatrnent. MATERIALS AND METHODS: Analysis of 156 HACE procedures in 75 patients with evaluable neuroendocrine tumor (NET) between 1986 and 2002 was performed. Ali patients had multiple metastases in the liver. 62 had carcinoid syndrome (CS); 5 were non-funetioning carcinoids. The remainder were non-carcinoid NETs. Ali were treated with multiple modalities before and/or after RACE incłuding surgieal debulking, ehemotherapy, octreotide, and alpha interferon. HACE was performed via femoral artery catheterization, subselection of the desired hepatic artery, and infusion of embolization material (gelfoam, polyvinyl alcohol, or mierospheres) and Cisplatin (50-80 mg), Adria:myein (15-30 mg), and Mitomycin C (10-20 mg). AlI reeeived pre- and post-procedure antibioties, hydroeortisone, and IV hydratioo. Ali eareinoid patients recieved oetreotide and were maintained on antibiotics. Ali were foł1owed with periodic deterrnination of the subjeetive responses to pain, flushing and diarrhea and the objeetive responses of changes in funetional capacity, biochemieal tumor markers, and imaging~ This study was approved by the MSSM IRB. RESULTS: Ali patients with endoerine-related symptoms treated by RACE had subjeetive and/or objective improvement of varying duration after this treatment. The one proeedurerelated death was due to liver failure two weeks following HACE. Kaplan-Meier survival analysis for the 62 carcinoid syndrome patients shows that median survival time after first RACE is 5.6 years with 95% eonfidenee interval (CI) (2.9, 6.7), and mean survival time is 5.7 years with 95% CI (4.4, 6.9). Mediao survival time from ooset of symptoms is 12.3 years with 95% CI (9.3, 17 .0), and mean survival time from onset of symptoms of 12.6 years with 95% CI (10.7,14.4).
The mean survival times are significantly longer than the survival time previously reported for untreated historical control CS patients (3.2 years). CONCLUSION: HACE produces subjective and objective improvement and prolonged survival in CS patients who are treated sequentially with additional modalities.
2:25PM
Abstract No. 199
Hepatic Arterial Infusion Chemotherapy in Patients with Advanced HepatocelluJar Carcinoma;Prognostic Factors. A. Hamada, Mie University School ojMedicine, Edobashi, Tsu, Mie, Japan • K. Yamakado • A. Nakatsuka • N. Tanaka fi J. Uraki • K. Takeda PURPOSE: This study was retrospectively undertaken to identify factors affecting prognosis in patients with advanced hepatocel1ularcarcinoma who received hepatic arterial infusion chemotherapy. MATERIAlS AND METHODS: Seventy-eight patients with advanced hepatocellular carcinoma underweot repeat hepatic arterial infusion chemotherapy using an implanted port every 1-4weeks. Patients received arterial infusion chemotherapy due to tumor progression following chemoembolization, percutaneous ethanol injection therapy, and/or surgery in 63 patients, and portal venous invasion in the other 15 patients. The cumulative survival rate was estimated using the KaplanMeier method. Twenty-two variabies representing patients' and tumors' characteristics, previous treatments, and liver profiles were analyzed with univariate and multivariate analysis. RESULTS: The cumulative survival rate was 56%, 36%, 25%, and 6% at 1-,2-, 3-, and 4-years, respectively, with a mean survival period of 19.6 months. Okuda staging is the onły significant factor having significant impact on prognosis in both univariate and multivariate analyses. CONCLUSION: Repeat hepatic arteria] infusion chemotherapy can be a usefu-l treatment when first-line treatment fai led to control tumors or portal venous invasion was present in patients with advanced hepatocellular carcinoma. Okuda staging appears to be a reliable predictor of these patients' prognosis.
2:36PM
Abstract No. 200
Repeat Hepatic Intra-Arterial InCusion Chemotherapy Using 2.7Fr Coaxial Implantable Microcatheter-Port System. A. Nakatsuka, Dep. ojRadiology, Mie Univ. SchooloJ Medicine, Tsu, Mie PreJecture, Japan • K. Yamakado • A. Hamada. N. Tanaka • N. Terada. K. Takeda PURPOSE: Repeat hepatic arterial infusion chemotherapy using a 5F implantabie catheter-port system (reservoir) is an effective palliative treatment forunresectable liverneoplasms. However, it is not easy to place a 5F catheter if the hepatic artery shows occlusion, severe stricture, or tortuosity. We have developed a 2.7F cOaJdal implantabie microcatheter-port system to implant reservoir system easily. This study was undertaken to evaluate feasibility and safety to implant this coaxial reservoir system. MATERIALS AND METHODS: Fifty-six patients with unresectable liver tumors underwent implantation of coaxial implantable microcatheter-port system to perform arterial infusion chemotherapy. Occlusion, severe stenosis and/or tortuosity was found in the hepatic artery in these patients.
A 2.7Fr microcatheter with a side hole was inserted in the peripheral hepatic artery or in the gastroduodenal artery using a coaxial method and the catheter tip was embolized with coils to prevent catheter dislocation. In 4 patients with hepatic arterial occlusion, a 2.7F catheter was placed in the pancreatic arcade perfusing the liver. RESULTS: A coaxial reservoir system was successfully implanted without any complication in all patients. Repeat arteria! infusion chemotherapy was perfonned with no troubles with a mean period of 4.6+/-1 months (range, 1-14 months) in 50 patients (89%). Catheter dislocation was found in 2 patients and arteria! occlusion was found in the replaced hepatic artery (n=2) and the pancreatic arcade (n=2) in 4 patients. A coaxial reservoir system was successfully re-implanted in 4 out of these 6 patients. Therefore, repeat arterial infusion chemotherapy was successfully performed using a coaxial reservoir system in all but 2 patients (96%) after reimplantation. CONCLUSION: Although sequellae should be evaluated over a long-tenn period, implantation of the 2.7F coaxial reservoir system described here appears to be asafe, feasible, and useful method to perform arterial infusion chemotherapy in patients with unresectable hepatic neoplasm and hepatic arterial occlusion, stenosis, and tortuosity.
2:47PM
Abstract No. 201
A Phase IlU Trial oC Hepatic Delivery oC Doxorubicin Adsorbed to Magnetic Targeted Carriers in Patients with HCC. R. Kerlan, UCSF, San Francisco, CA, USA. M. Wilson. E.D. Walser • JE Koda. A. Venook • S. Goodwin PURPOSE: To test the safety, maximum tołerated dose (MTD), pharmacokinetic profile, and tumor response following a single selective arterial infusion of doxorubicin adsorbed to Magnetic Targeted Carriers (MTC-OOX) under magnetic guidance in patients with HCC. MATERlAlS AND METHODS: A phase I/ll dose escalation study was undertaken in 33 patients. MTC-DOX was delivered to the tumor via super-selective arterial catheterization. An external magnet (field strength of 5 KG) was positioned over the tumor to both guide the materiał into the proper location and to extravasate the material into the tumor parenchyma. Tumor localization of MTC-DOX was confinned by MRI post administration. A range of tumor sizes was treated (cross-sectional areas of 4 to 222 cm 2 ). Hepatic CT imaging was obtained prior to and 28 days following therapy and analyzed for tumor response (NCI criteria). Some patients (n=13) received additionaJ CT imaging 60 to 90 days following therapy. Patients were folIowed for survivaJ. RESULTS: Localization of MTC-DOX to the tumor was achieved in 31/33 patients. The MTD was detennined to be 60 mg DOX adsorbed to 600 mg MTC (total dose). The dose is limited by diminished arterial flow post MTC-DOX administration. Measurements of DOX in plasma were undetectable or low (under 10 ng/mL in five patients, and under 30 ng/mL in one patient). The most common adverse event was transient abdominal pain (66%) primarily observed on day of treatment. Best response data for 37 lesions (n=32 evaluable) treated with MTC-DOX was l complete response, 2 partial response, 9 minor response, 18 stable disease, and 7 progressive disease. Median survival (censored 8/24/02) for all patients is 7.5 months, and survival for patients treated with a minimally effective dose of 0.1 mg DOX! cm2 tumor area is 11.5 months.
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CONCLUSION: In tra-arterial administration of MTC-DOX has no clinically significant toxicities, and demonstrates possible activity against HCC. The lesion control rate is 83% and median survival exceeds that reported for historical controls. A randomized clinical trial is in progress to confinn these initial safety and efficacy results for MTC-DOX. 2:58PM
Abstract No. 202
Magnetic Targeted Delivery of 90y to VX2 Rabbit Liver Thmors. l.H Geschwind, lohns Hopkins Universtiy, Baltimore, MD, USA - H Kobeiter - e. Peterson - T. Leakakos
PURPOSE: To investigate magnetic targeted delivery of the radionuclide,90y, in liver-implanted rabbit tumors as a means of localized radiotherapy. MATERJALS AND METHODS: CT scans and angiography were used to confinn VX2 tumor development. Rabbits were anesthetized and the left hepatic artery was selectively catheterized to within 2 cm of the tumor for a single intraarterial injection of either 90Y labeled Magnetic Targeted Carriers (90Y-MTC) or MTCs alone. Three control animals received a single 5 ml infusion containing 25 mg MTCs. In the low dose group with intended delivered activity of 50 Gy, 4 animals received an infusion containing 142 ~mCi 90y irreversibly bound to 25 mg MTCs. In the high dose group with intended delivered activity of 100 Gy, 2 animals received 284 ~mCi 90Y bound to 25 mg MTCs. An external magnetic field was focused on the tumor throughout the infusion and for 15 min foliowing treatmenŁ. Radioactivity was measured in blood collected 30 min and l hr after dosing. Biodistribution of90y in the liver,lung, spleen, and bone was evaluated in one rabbit 24 hr after treatment. Remaining animals were recovered and kept for 7 days. Prior to necropsy and subsequent rustopathological examination, arumals were evaluated by CT to measure tumor size and MRI for particle localization. RESULTS: No embolization or adverse clinical signs were associated with magnetic targeted delivery of 90Y-MTCs. Blood levels of radioactivity were < 1% of 90y administered and decreased between 30 min and 1 hr. Radioactivity measured in organs 24 hr post-dosing showed the majority of the 90y was localized in the liver. MRI performed 7 days after treatrnent showed the presence of the iron component of the MTC particles primarily in the liver tumors. CT scans at 6 days posl-dosing showed no treatment-related effects on the progression of tumor growth compared to untreated controls. Microscopic examination of tissue showed the presence of particles confined to the liver. Liver necrosis was greater in treated animals (> 70% necrosis) as compared to controls (50% necrosis). CONCLUSION: Feasibility of intratumoraI radiotherapy using magnetic targeting was demonstrated and warrants further investigation. 3:09PM
Abstract No. 203
Transmicrocatheter Embolization with Liquid Embolizers for Treatment of Hepatocellular Carcinoma with A-P Shunts. HE. Shi, Nanjing Medical University Hospital, Nanjing, liangsu Province, China - S. Liu - L.S. Li
PURPOSE: To evaluate the feasibility and effect of embolization using liquid embolic agents for occlusion of arterioportal shunts in patients with hepatoceliular carcinomas.
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MATERlALS AND METHODS: The arterioportal shunts were embolized through microcatheter in 19 patients with hepatocellular carcinomas, which was folIowed by Lipiodol chemoembolization. Absolute ethanol was injected in 23 hepatic arterial branches, N-Butyl-2-Cyanoacrylate (NBCA) mixed with Lipiodol (l: 1.5-2.5) in 4 branches. The degree of occlusion was observed via immediate angiography in all cases and follow-up angiography 1 to 8 months after embolization in 16. RESULTS: The occlusion of arterio-portal shunt was total in 15 patients and nearly total (over 90%) in other 4 immediately after procedure, which did not affect the following chemoembolization. Among 16 patients with repeat intraarterial procedures, the shunt was not found in II, remained with less than half degree of original shunt in the other 5. There were no symptomatic complications associated with embolization. CONCLUSION: The transmicrocatheter embolization of arterioportal shunts with injection of liquid embolic agents, incJuding absolute ethanol and NBCA, is safe and effective in patients with hepatocellular carcinomas.
Scientific Session 26 Percutaneous Management of Carotid Occlusive Disease Monday, March, 31, 2003 1:30 PM - 3:30 PM Moderator(s): l.J. "Buddy" Connors, lll, MD 1:30PM
Abstract No. 204
FEATUREO A8STRACT
Commentator: Robert Fl'rguson, MO Carotid Endarterectomy Is Safe in High Risk Surgical Patients. T.N. Boules, University ojMichigan Medical Center, Ann Arbor, MI, USA - M. e. Proctor - A. Arej - G.R. Upchurch, lr. -J.e. Stanley -PK. Henke
PURPOSE: Carotid endarterectomy (CEA) has clearly been shown to be effective in reducing the risk of stroke in selected symptomatic and asymptomatic patients with extracranial carotid stenosis. Recently, carotid angioplasty with stenting (CAS)has been suggested as an alternative treatment in high risk surgical patients. Trus study tested the hypothesis that high-risk patients can undergo CEA without associated increased incidence of stroke, TIA or death. MATERlALS AND METHODS: Medical records for consecutive patients who underwent CEA from 1996-2001 were reviewed for demographics, past medical history, and hospital course. High-risk patients were definedas those with MI or CHF within 4 weeks; unstable angina; steroiddependent COPD; prior ipsilateral CEA, neck dissection or irradiation; high carotid bifurcation;and those with combined cardiac-carotidprocedures. Poor postoperative outcome was defined as stroke, TIA or death witrun 30 days. Univariate, multivariate, and Kaplan-Meier analysis was used as appropriate. RESULTS: Four hundred twenty-nine patients underwent 499 CEAs, of which 84 (17%) were considered high-risk. A total of 11 postoperative strokes (2.2%), 7 TIAs (1.4%), and 3 deaths (0.6%) occurred within 30 days after surgery. There was no difference in 30 day poor outcome between high- and low-risk patients (4.8% vs. 4.1 %, p =0.77). When these risk
Scientific Session 25 Oncologic Interventions: Trans-arterial Therapies for Hepatic Malignancy Monday, March, 31, 2003 1:30 PM - 3:30 PM Moderator(s): Chamaree Chuapetcharasopon, MD Chieh-Min Fan, MD
1:30PM
AbstractNo.194
Plasmid DNA Delivery to the Isolated Rabbit Liver: A Novel Use of Interventional Radiology for Gene Therapy. K.M. Baskin, Children:S Hospital ojPhiladelphia, Philadelphia, PA, USA. S.J. Eastman • R.K. Scheule • BL Hodges • Q. Chu • R.B. Towbin PURPOSE: Gene delivery using viral vectors is relatively efficient, but limits the size of the gene that can be delivered, and carries the potential for hallnful immune-mediated and toxlc effects on the host, especially on readministration. In theory, delivery of "nak.ed" plasmid DNA (pDNA) avoids these problems, but in practice has been either so inefficient that satisfactory levels of expression cannot be achieved, or has required such invasive methods of delivery as to not be clinically practicable. This prospective study was designed to evaluate the efficacy and safety of a new method of pDNA delivery, using minimally-invasive transcatheter hydrodynarnic delivery targeted to the liver as a depot organ through the mechanically isolated Iiver vasculature in arabbit model. MATERIALS AND METHODS: These IACUC-approved studies were performed in male New Zealand White rabbits (3-4 kg). A whole organ technique (n = 28) was employed with pDNA solution injected hydrodynarnically via the vena cava between balloons used to block hepatic venous outflow. Using a lobar technique (n = 8), pDNA was hydrodynamically delivered to a single hepatic lobe using an IVC baJJoon catheter to occIude hepatic veoous outflow.
hepatic parenchymal distribution of CAT expression. Despite a smaller bolus, lobar delivery resulted in significant levels of transgene product in the serum (mean SEAP = 26 mcg/mL, SD= 16) and demonstrated the highest levels of CAT expression in the injected lobe.
CONCLUSION: These preliminary studies suggest that catheter-mediated hydrodynarnic delivery of pDNA to the isolated liver may provide a method for human gene therapy that is both therapeutically significant and clinically practicable. These studies also highlight the potential for use of fundamental techniques in interventional radiology in novel combinations to solve essential problems in emergiog areas of investigation such as molecular and gene therapy and organ-specific delivery.
1:41 PM
Abstract No. 195
Effects of the Type of Embolization Particles on Carboplatinum Concentration in the VX2 Liver Cancer Model. i.H. Geschwind, iohns Hopkins University School oj Medicine, Baltil7wre, MD, USA. H. Kobeiter • S. Baker • M. Alaa • M.S. Torbenson • K. Kim PURPOSE: To assess the effects of Embospheres on intratumoraI concentration of chemotherapy during chemoembolization of liver tumors (rabbit model of liver cancer) and compare them to those of PVA. MATERJALS AND METHODS: The VX2 tumors were grown in the liverof 18 rabbits. Animals were divided into 3 groups (n = 6): group l: chemoembolization/Embospheres (150m3ODm), group 2: chemoembolizationIPVA (J50m-250m), group 3: saline injection lA (controI). Animals were sacrificed 48 hours after treatment their liver explanted and submitted for histopathologic analysis. Carboplatin (5 mglkg) was selected because of its known potency against the VX2 tumor. To measure the concentration of carboplatin, blood and tumor tissue sampIes were collected from the peripheral zone and necrotic center ofthe tumors as well as from the non-tumorous liver. Carboplatin concentration was then measured by atomic absorption spectroscopy. RESULTS: In the PVA group (group 2), the mean carboplatin concentration was 55.5 mg/g within the necrotic center of the tumor and 11.35 mg/g at the rim. The plasma concentration was less than 0.079 mg/mJ. No carboplatin was detected in non-tumorous liver tissue. In the Embospheres group (group l), the mean carboplatin concentration was 104.25 mg/g within the necrotic center ofthe tumor and 12.32 mg/g at the rim. The plasma concentration was less than 0.053 mg/mI. No carboplatin was detected in non-tumorous liver tissue. CONCLUSlON: Carboplatin concentration was significantly greater (2 to 8 fold) within the necrotic center than at the periphery of the tumor in both treated groups. Carboplatin concentration within the necrotic center of the tumor was significantly greater in Embosphere than in PVA group, but was only slightly greater within the peripheral rim of the tumor. Embospheres may therefore be advantageous when administered during TACE sioce the concentration of carboplatin within the tumor is greater than that obtained with PVA.
RESULTS: Whole organ coadministration of plasmids encoding both a secreted alkaline phosphatase reporter gene (pCFl-SEAP) and a non-secreted transgene, chloramphenicol acetyltransferase (pGZB-sCAT), yielded an average circulating level of SEAP at 24 hr of 76 mcg/mL (SD=93) and a broad
567
1:52PM
Abstract No. 196
Safety and Initial Results of Hepatic Arterial Radioembolization Malignancies of the Liver. D.M. Coldwell, Fax Chase Cancer Center, Philadelphia, PA, USA - A.S. Kennedy - R. Murthy - C.D. Nutting - K.A. Morton - D.A. VanEcho, et al. PURPOSE: Unreseetable solid tumors in the liver have a historical survival of 12-14 months even with the best of therapy. Residual islands of tumor have limited the effeetiveness of liver -direeted therapy. New radioaetive embolie particles should reduee the amount of residual tumor present after embolization. This study was performed to elueidate the safety, eomplieations, and immediate results of this treatment. MATERIALS AND METHODS: Patients with solid tumors in the liver with normal CBC, ereatinine, bilirubin < 2.0, and predominately liver disease were enrolled in this IRB approved study. Pre-treatment sereening included hepatie arteriogram and Te99m labeled MAA sean to identify a disqualifying shunt to the lungs or Gl traet. A target dose of 150 Gy of aetivity was planned in a sequential unilobar embolization. Ali patients were treated with proton pump inhibitors for three months after therapy. Routine antibioties were not utilized except in cases where upper abdominal surgery had oceurred. RESULTS: 150 patients (100 men, 50 women) were included who received treatment at three sites under identical protocols. The mean age ofthe patients was 59 (range 31-89). A median total dose of 142 Gy was achieved per lobe. Atotal of 234 treatments were performed. Tumors treated incłuded hepatoeellular carcinoma (39), metastatic eolo-rectal eancer (62), neuroendocrine tumor (20), other metastases (29). There were no complieations during administration of the radioactive microspheres but 20 patients were admitted overnight. No patient experienced liver failure or fatal veno-occlusive disease. 34 patients had pain in the epigastrium during infusion of the left hepatie artery; 14 ofthese patients developed ulcers. One patient developed a hepatie abscess but recovered after drainage. Technieal success rate was 99% for administration. Only a single misadministration occurred with less than 80% of the target dose administered. CONCLUSION: For patients with unresectable hepatie tumors, this treatment promises a safe option but the longer term efficacy has yet to be proven. There were few complication and none fataJ.
Abstract No. 197
2:03PM
Intra-Arterial 166 Holmium·Chitosan Complex Injection for the Treatment of Hepatocellular Carcinoma. J. y. Won, Yonsei University Hospital, Seoul, Seoul, Korea HJ. Moon -D.Y. Lee -K.H Han
-N.c.
Yoo -J.T. Lee
PURPOSE: To evaluate the clinical efficiency and safety of intra-arterial injection of 166 Holmium-Chitosan eomplex in patients with hepatoceł1ular carcinoma (HCC).
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MATERIALS AND METHODS: Between January 1999 and July 2001,118 patients (100 male, 18 female, mean age=56.7yrs) with HCCs were enrolled in this study. The inclusion criteria of HCCs were; nodular type, single or two HCCs with same feeding artery, diameter less than lOcm, no arterio-portal or arterio-venous shunt on angiography. 92 patients were Child-Pugh class A and 22 patients were class B. 4 patients were class C. We injected 166 Holmium-Chitosan eomplex, 20mCi/em of tumor diameter through 3F mierocatheter. After finishing the injeetion, garnrna camera
imaging was obtained to depict the radioactivity within the tumor. Blood sarnpling and beta radioactivity counting were also performed to evaluate the systemic leakage ofRolmium. Follow up CT scans and angiography were taken I, 6 and 12 months after the procedure and clinical status of each patient was also evaluated. We caleulated the cumulative survival rates ofthe patients using the Kaplan-Meier method with the 95% confidenee intervaI. RESULTS: Total injection dose ofholmiumranged from 30 to 200 mCi (mean=105). Immediately after the procedure, 22 patients (18.6%) showed transient leukopenia and thrombocytopenia, and 3 patients (2.5%) showed liver abseess. Follow up CT seans and angiography showed complete tumor necrosis in 72 patients (63.2%), >50% necrosis in 18 (15.8%), <50% necrosis in 8 (6.8%), no response in 16 (14.0%). Other 4 patients were lost during the follow up period. Six patients (5.3%) expired due to the procedure related complications; 4 from hepatic failure after the procedure, 1 from paneytopenia, 1 with systemie leakage of 166 HolmiumChitosan eomplex. Overał11-year survival rate was 92.8%; 95.3% with Child-Pugh class A and 79.7% with B. CONCLUSION: Intra-arterial administration of 166 Holmium-Chitosan eomplex was effeetive and safe for the treatment of HCC and eould be a new treatment modality to controI inoperable HCC.
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Abstract No. 198
Outcome ofHepatic Artery Chemoembolization (RACE) in the Treatment of Metastatic Carcinoid of the Liver. R.R.P. Warner, Mount Sinai School ofMedicine, New York, NY, USA - Ps. Nowakowski - HA. Mitty - J. Guller - A. Falk - M. Sung, et al. PURPOSE: To retrospeetively evaluate response of metastatie eareinoid of the liver to HACE treatrnent. MATERIALS AND METHODS: Analysis of 156 HACE procedures in 75 patients with evaluable neuroendocrine tumor (NET) between 1986 and 2002 was performed. Ali patients had multiple metastases in the liver. 62 had carcinoid syndrome (CS); 5 were non-funetioning carcinoids. The remainder were non-carcinoid NETs. Ali were treated with multiple modalities before and/or after RACE incłuding surgieal debulking, ehemotherapy, octreotide, and alpha interferon. HACE was performed via femoral artery catheterization, subselection of the desired hepatic artery, and infusion of embolization material (gelfoam, polyvinyl alcohol, or mierospheres) and Cisplatin (50-80 mg), Adria:myein (15-30 mg), and Mitomycin C (10-20 mg). AlI reeeived pre- and post-procedure antibioties, hydroeortisone, and IV hydratioo. Ali eareinoid patients recieved oetreotide and were maintained on antibiotics. Ali were foł1owed with periodic deterrnination of the subjeetive responses to pain, flushing and diarrhea and the objeetive responses of changes in funetional capacity, biochemieal tumor markers, and imaging~ This study was approved by the MSSM IRB. RESULTS: Ali patients with endoerine-related symptoms treated by RACE had subjeetive and/or objective improvement of varying duration after this treatment. The one proeedurerelated death was due to liver failure two weeks following HACE. Kaplan-Meier survival analysis for the 62 carcinoid syndrome patients shows that median survival time after first RACE is 5.6 years with 95% eonfidenee interval (CI) (2.9, 6.7), and mean survival time is 5.7 years with 95% CI (4.4, 6.9). Mediao survival time from ooset of symptoms is 12.3 years with 95% CI (9.3, 17 .0), and mean survival time from onset of symptoms of 12.6 years with 95% CI (10.7,14.4).
The mean survival times are significantly longer than the survival time previously reported for untreated historical control CS patients (3.2 years). CONCLUSION: HACE produces subjective and objective improvement and prolonged survival in CS patients who are treated sequentially with additional modalities.
2:25PM
Abstract No. 199
Hepatic Arterial Infusion Chemotherapy in Patients with Advanced HepatocelluJar Carcinoma;Prognostic Factors. A. Hamada, Mie University School ojMedicine, Edobashi, Tsu, Mie, Japan • K. Yamakado • A. Nakatsuka • N. Tanaka fi J. Uraki • K. Takeda PURPOSE: This study was retrospectively undertaken to identify factors affecting prognosis in patients with advanced hepatocel1ularcarcinoma who received hepatic arterial infusion chemotherapy. MATERIAlS AND METHODS: Seventy-eight patients with advanced hepatocellular carcinoma underweot repeat hepatic arterial infusion chemotherapy using an implanted port every 1-4weeks. Patients received arterial infusion chemotherapy due to tumor progression following chemoembolization, percutaneous ethanol injection therapy, and/or surgery in 63 patients, and portal venous invasion in the other 15 patients. The cumulative survival rate was estimated using the KaplanMeier method. Twenty-two variabies representing patients' and tumors' characteristics, previous treatments, and liver profiles were analyzed with univariate and multivariate analysis. RESULTS: The cumulative survival rate was 56%, 36%, 25%, and 6% at 1-,2-, 3-, and 4-years, respectively, with a mean survival period of 19.6 months. Okuda staging is the onły significant factor having significant impact on prognosis in both univariate and multivariate analyses. CONCLUSION: Repeat hepatic arteria] infusion chemotherapy can be a usefu-l treatment when first-line treatment fai led to control tumors or portal venous invasion was present in patients with advanced hepatocellular carcinoma. Okuda staging appears to be a reliable predictor of these patients' prognosis.
2:36PM
Abstract No. 200
Repeat Hepatic Intra-Arterial InCusion Chemotherapy Using 2.7Fr Coaxial Implantable Microcatheter-Port System. A. Nakatsuka, Dep. ojRadiology, Mie Univ. SchooloJ Medicine, Tsu, Mie PreJecture, Japan • K. Yamakado • A. Hamada. N. Tanaka • N. Terada. K. Takeda PURPOSE: Repeat hepatic arterial infusion chemotherapy using a 5F implantabie catheter-port system (reservoir) is an effective palliative treatment forunresectable liverneoplasms. However, it is not easy to place a 5F catheter if the hepatic artery shows occlusion, severe stricture, or tortuosity. We have developed a 2.7F cOaJdal implantabie microcatheter-port system to implant reservoir system easily. This study was undertaken to evaluate feasibility and safety to implant this coaxial reservoir system. MATERIALS AND METHODS: Fifty-six patients with unresectable liver tumors underwent implantation of coaxial implantable microcatheter-port system to perform arterial infusion chemotherapy. Occlusion, severe stenosis and/or tortuosity was found in the hepatic artery in these patients.
A 2.7Fr microcatheter with a side hole was inserted in the peripheral hepatic artery or in the gastroduodenal artery using a coaxial method and the catheter tip was embolized with coils to prevent catheter dislocation. In 4 patients with hepatic arterial occlusion, a 2.7F catheter was placed in the pancreatic arcade perfusing the liver. RESULTS: A coaxial reservoir system was successfully implanted without any complication in all patients. Repeat arteria! infusion chemotherapy was perfonned with no troubles with a mean period of 4.6+/-1 months (range, 1-14 months) in 50 patients (89%). Catheter dislocation was found in 2 patients and arteria! occlusion was found in the replaced hepatic artery (n=2) and the pancreatic arcade (n=2) in 4 patients. A coaxial reservoir system was successfully re-implanted in 4 out of these 6 patients. Therefore, repeat arterial infusion chemotherapy was successfully performed using a coaxial reservoir system in all but 2 patients (96%) after reimplantation. CONCLUSION: Although sequellae should be evaluated over a long-tenn period, implantation of the 2.7F coaxial reservoir system described here appears to be asafe, feasible, and useful method to perform arterial infusion chemotherapy in patients with unresectable hepatic neoplasm and hepatic arterial occlusion, stenosis, and tortuosity.
2:47PM
Abstract No. 201
A Phase IlU Trial oC Hepatic Delivery oC Doxorubicin Adsorbed to Magnetic Targeted Carriers in Patients with HCC. R. Kerlan, UCSF, San Francisco, CA, USA. M. Wilson. E.D. Walser • JE Koda. A. Venook • S. Goodwin PURPOSE: To test the safety, maximum tołerated dose (MTD), pharmacokinetic profile, and tumor response following a single selective arterial infusion of doxorubicin adsorbed to Magnetic Targeted Carriers (MTC-OOX) under magnetic guidance in patients with HCC. MATERlAlS AND METHODS: A phase I/ll dose escalation study was undertaken in 33 patients. MTC-DOX was delivered to the tumor via super-selective arterial catheterization. An external magnet (field strength of 5 KG) was positioned over the tumor to both guide the materiał into the proper location and to extravasate the material into the tumor parenchyma. Tumor localization of MTC-DOX was confinned by MRI post administration. A range of tumor sizes was treated (cross-sectional areas of 4 to 222 cm 2 ). Hepatic CT imaging was obtained prior to and 28 days following therapy and analyzed for tumor response (NCI criteria). Some patients (n=13) received additionaJ CT imaging 60 to 90 days following therapy. Patients were folIowed for survivaJ. RESULTS: Localization of MTC-DOX to the tumor was achieved in 31/33 patients. The MTD was detennined to be 60 mg DOX adsorbed to 600 mg MTC (total dose). The dose is limited by diminished arterial flow post MTC-DOX administration. Measurements of DOX in plasma were undetectable or low (under 10 ng/mL in five patients, and under 30 ng/mL in one patient). The most common adverse event was transient abdominal pain (66%) primarily observed on day of treatment. Best response data for 37 lesions (n=32 evaluable) treated with MTC-DOX was l complete response, 2 partial response, 9 minor response, 18 stable disease, and 7 progressive disease. Median survival (censored 8/24/02) for all patients is 7.5 months, and survival for patients treated with a minimally effective dose of 0.1 mg DOX! cm2 tumor area is 11.5 months.
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CONCLUSION: In tra-arterial administration of MTC-DOX has no clinically significant toxicities, and demonstrates possible activity against HCC. The lesion control rate is 83% and median survival exceeds that reported for historical controls. A randomized clinical trial is in progress to confinn these initial safety and efficacy results for MTC-DOX. 2:58PM
Abstract No. 202
Magnetic Targeted Delivery of 90y to VX2 Rabbit Liver Thmors. l.H Geschwind, lohns Hopkins Universtiy, Baltimore, MD, USA - H Kobeiter - e. Peterson - T. Leakakos
PURPOSE: To investigate magnetic targeted delivery of the radionuclide,90y, in liver-implanted rabbit tumors as a means of localized radiotherapy. MATERJALS AND METHODS: CT scans and angiography were used to confinn VX2 tumor development. Rabbits were anesthetized and the left hepatic artery was selectively catheterized to within 2 cm of the tumor for a single intraarterial injection of either 90Y labeled Magnetic Targeted Carriers (90Y-MTC) or MTCs alone. Three control animals received a single 5 ml infusion containing 25 mg MTCs. In the low dose group with intended delivered activity of 50 Gy, 4 animals received an infusion containing 142 ~mCi 90y irreversibly bound to 25 mg MTCs. In the high dose group with intended delivered activity of 100 Gy, 2 animals received 284 ~mCi 90Y bound to 25 mg MTCs. An external magnetic field was focused on the tumor throughout the infusion and for 15 min foliowing treatmenŁ. Radioactivity was measured in blood collected 30 min and l hr after dosing. Biodistribution of90y in the liver,lung, spleen, and bone was evaluated in one rabbit 24 hr after treatment. Remaining animals were recovered and kept for 7 days. Prior to necropsy and subsequent rustopathological examination, arumals were evaluated by CT to measure tumor size and MRI for particle localization. RESULTS: No embolization or adverse clinical signs were associated with magnetic targeted delivery of 90Y-MTCs. Blood levels of radioactivity were < 1% of 90y administered and decreased between 30 min and 1 hr. Radioactivity measured in organs 24 hr post-dosing showed the majority of the 90y was localized in the liver. MRI performed 7 days after treatrnent showed the presence of the iron component of the MTC particles primarily in the liver tumors. CT scans at 6 days posl-dosing showed no treatment-related effects on the progression of tumor growth compared to untreated controls. Microscopic examination of tissue showed the presence of particles confined to the liver. Liver necrosis was greater in treated animals (> 70% necrosis) as compared to controls (50% necrosis). CONCLUSION: Feasibility of intratumoraI radiotherapy using magnetic targeting was demonstrated and warrants further investigation. 3:09PM
Abstract No. 203
Transmicrocatheter Embolization with Liquid Embolizers for Treatment of Hepatocellular Carcinoma with A-P Shunts. HE. Shi, Nanjing Medical University Hospital, Nanjing, liangsu Province, China - S. Liu - L.S. Li
PURPOSE: To evaluate the feasibility and effect of embolization using liquid embolic agents for occlusion of arterioportal shunts in patients with hepatoceliular carcinomas.
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MATERlALS AND METHODS: The arterioportal shunts were embolized through microcatheter in 19 patients with hepatocellular carcinomas, which was folIowed by Lipiodol chemoembolization. Absolute ethanol was injected in 23 hepatic arterial branches, N-Butyl-2-Cyanoacrylate (NBCA) mixed with Lipiodol (l: 1.5-2.5) in 4 branches. The degree of occlusion was observed via immediate angiography in all cases and follow-up angiography 1 to 8 months after embolization in 16. RESULTS: The occlusion of arterio-portal shunt was total in 15 patients and nearly total (over 90%) in other 4 immediately after procedure, which did not affect the following chemoembolization. Among 16 patients with repeat intraarterial procedures, the shunt was not found in II, remained with less than half degree of original shunt in the other 5. There were no symptomatic complications associated with embolization. CONCLUSION: The transmicrocatheter embolization of arterioportal shunts with injection of liquid embolic agents, incJuding absolute ethanol and NBCA, is safe and effective in patients with hepatocellular carcinomas.
Scientific Session 26 Percutaneous Management of Carotid Occlusive Disease Monday, March, 31, 2003 1:30 PM - 3:30 PM Moderator(s): l.J. "Buddy" Connors, lll, MD 1:30PM
Abstract No. 204
FEATUREO A8STRACT
Commentator: Robert Fl'rguson, MO Carotid Endarterectomy Is Safe in High Risk Surgical Patients. T.N. Boules, University ojMichigan Medical Center, Ann Arbor, MI, USA - M. e. Proctor - A. Arej - G.R. Upchurch, lr. -J.e. Stanley -PK. Henke
PURPOSE: Carotid endarterectomy (CEA) has clearly been shown to be effective in reducing the risk of stroke in selected symptomatic and asymptomatic patients with extracranial carotid stenosis. Recently, carotid angioplasty with stenting (CAS)has been suggested as an alternative treatment in high risk surgical patients. Trus study tested the hypothesis that high-risk patients can undergo CEA without associated increased incidence of stroke, TIA or death. MATERlALS AND METHODS: Medical records for consecutive patients who underwent CEA from 1996-2001 were reviewed for demographics, past medical history, and hospital course. High-risk patients were definedas those with MI or CHF within 4 weeks; unstable angina; steroiddependent COPD; prior ipsilateral CEA, neck dissection or irradiation; high carotid bifurcation;and those with combined cardiac-carotidprocedures. Poor postoperative outcome was defined as stroke, TIA or death witrun 30 days. Univariate, multivariate, and Kaplan-Meier analysis was used as appropriate. RESULTS: Four hundred twenty-nine patients underwent 499 CEAs, of which 84 (17%) were considered high-risk. A total of 11 postoperative strokes (2.2%), 7 TIAs (1.4%), and 3 deaths (0.6%) occurred within 30 days after surgery. There was no difference in 30 day poor outcome between high- and low-risk patients (4.8% vs. 4.1 %, p =0.77). When these risk