- Email: [email protected]
P-513 Repeated arterial infusion chemotherapy using implantable drug delivery system in 100 patients with hepatocellular carcinoma
Posters / International Hepatology Communications 3 Suppl. (1995) $37-$169
P-512
EVALUATION OF ADMINISTRATION ROUTES ON HEPATIC EXTRACTION RATIO OF ADRIAMYCIN USING HEPATIC VENOUS ISOLATION AND CHARCOAL HEMOPERFUSION M. Tominaga, Y. Ku, M. Shiotani, T. Kitagawa, 1. Maeda. S. Kusunoki, S. Muramastu, Y, Kuroda and Y. Saitoh 1st Dept, of Surgery. Kobe University School of Medicine. Kobe, Japan
P-513 REPEATED ARTERIAL INFUSION C H E M O ~ Y USING IMPLANTABLE DRUG DELIVERY SYSTEM IN 100 PATIENTS WITH HEPATOCELLULAR CARCINOMA T.Ihaya,* S.Sawada,**E.Nisinmuki,Y.Horie.HKawasaki Dept. of Radiology,Tottori Red Cross Hosp.,Tottori,Japan
We evaluated the first pass hepatic extraction ratio of adriamycin after hepatic arterial infuion and portal venous infusion using a novel system consisting of hepatic venous isolation and charcoal hemoperfusion (HVICHP). HVI'CHP was used to accurately measure the drug amount leaking in the hepatic effluent and to eliminate hepatic re-entry of the drug. Beagles received adriamycin (lmo~kg) through either the hepatic artery (Group I, n=5) or the portal vein (Group II. a=5/. During aud after 10 rain drug infusion in both groups, bepatic effluent was isolated and directed to a charcoal filter. The filtered hepatic effluant was returned to the body through the left jugular vein. During 20-rain HVI. CHP, plasma adriamycin levels were serially measured in prefilter (hepatic vein blood), postfilter and systemic serum. Based on flow rates and adriamycin levels in the hepatic effluent, hepatic extraction ratio (HER) of adriamyein was calculated. Irrespective of administration routes, hepatic re-entry of adriamycin through the hepatic artery and the portal vein after the first pass became negligible. Systemic adriamycin levels were similar throughout HVI" CHP in both groups. However, prefilter adriamyciu levels were significantly lower in group I than those in group II during HVI' CHP (p<0.01). Thus, the area under tbe time concantration curve of prefilter levels in group l (6.1 ± 1.6 min'mg]ml) was significantIy lower than that in group lI (16.9-t-5.0 min'mg/ml, p<0.01). HER (c/c) in group [ (81 234.7) was significantly higher than that in group II (47.2--+9 9, p<0.01 ). HV1. CHP is an useful system for measurement of hepatic tissue extraction ratios of the drugs sbowing good charcoal affinity. Adriamyciu was more effectively extracted by the liver when administered via the hepatic artery compared with the portal vein. These results indicate that hepatic arterial infusion of adriamycin is superior to portal venous infusion in terms of local drug delivery to the liver.
* *2rid Dept. of Internal Medicine,Tottori Univ. Hosp.,Yonagojapan
P-514
TRANSCATHETER ARTERIAL EMBOLIZATION THERAPY FOR THE PATIENT WITH HEPATOCELLULAR C A R C I N O M A U S I N G T H E L E F T B R A C H I A L ARTERY APPROACH S . W a t a n a b e , Y.Miyauchi, M.Shirai, K . A r i m a . M . N i s h i o k a . Third Department o f Internal Medicine, K a g a w a Medical S c h o o l , Japan We e v a l u a t e d the u s e f u l n e s s o f T r a n s c a t h e t e r arterial e m b o l i z a t i o n (TAE) f o r H C C u s i n g the left b r a c h i a l artery a p p r o a c h a n d w h e t h e r this a p p r o a c h is a safe alternative to the femoral artery a p p r o a c h f r o m the viewpoint of complications. Materials and m e t h o d s : A total o f 4 6 patients (38 m e n a n d 8 w o m e n ) w h o u n d e r w e n t TAE using a 4 - F r e n c h catheter were entered in this study. The m e a n age w a s 59.5 years. A total o f 61 arteries w e r e injected on these 4 6 patients b e t w e e n July, 1989 and March, 1994. The Lipiodol-TAE treatment consisted o f ethiodized oil (Lipiodol) mixed with doxorubicin hydrochloride(25 patients) or epirubicin hydrochloride(18 patients) or Mitomycin C (2 patients). F o l l o w i n g this p r o c e d u r e , the feeding arteries were embolized with gelatin s p o n g e cubes ( G e l f o a m , 1-to 2 - r a m pieces). Results: The technical success rate o f the procedure w a s 9 5 . 3 % . T h e m e a n s e r u m c~-fetoprolein levels in 4 6 patients with H C C b e f o r e Lipiodol-TAE ( 2 0 8 6 - 4 - 8 0 1 7 n g / m l ) w a s significantly h i g h e r than that one m o n t h after the therapy ( 1078 ± 4681 ng/ml )(p<0.01 ). No severe c o m p l i c a t i o n s w e r e o b s e r v e d , but m i n o r c o m p l i c a t i o n s o c c u r r e d in 18%. C o m p l i c a t i o n rates o f the brachial artery p u n c t u r e w e r e 8 . 2 % per artery injected. The a s s o c i a t e d c o m p l i c a t i o n s w e r e statistically the s a m e as the p r o c e d u r e f r o m the t r a n s - f e m o r a l a p p r o a c h , w h i c h w a s later p e r f o n n e d in 24 patients. Conclusion: TAE u s i n g the left brachial a p p r o a c h is a safe a n d effective alternative to the trans-femoral a p p r o a c h .
S165
Dept. of Radio~ogy,Tottori Univ. Hosp.,Youago,Japan
We performed clinical evaluation of repeated arterial infusion chemotherapy using an implantable drug delivery system for the patients with inoperable hepatocellular carcinoma0tCC). 100 patients with inoperable HCC have been treated with the implantable drug delivery system. Most of our patients could not receive transcatheter arterial embolization(TAE) because of extreme tumor extension and/or accompanying advanced cirrhosis. In most patients we implanted a 5Fr catheter non-surgically and connected it to an implanted rejection port. The treatment consisted of weekly or biweekly intrahepatic one shot administration of anticancer drugs. The response rate(CR+PR) of the cases was 22.0% The median survival period was 436.0 days. The 6-month,l-year, and 2-year survival rates were 76.0% ,46.4% and 18.4% respectively There was no severe side effect or complication except arterial occulusions that precluded further infusion chemotherapy Tumor regression showed a close correlation with the duration of survival and the reserve liver function was also the significant prognostic factor in this treatment. Distant metastases were found during the therapy in 16 Cases out of 88 cases. These results suggest that the repeated artenal infusion chemotherapy is useful but distant metastasis during the therapy is the serious problem and must be resolved for the improvement of the prognosis of the patients with advanced HCC.
1FI t " t ~, I-'DI~ POTENTIATION BY AMILOR1DE OF DOXORUBICIN EFFECT ON NORMAL AND TUMOR LIVER CELLS "IN VITRO".
J. Ptrez de Diego, C. Trilla and R. Garcia Cafiero. Bioqulmiea Experimental, Cllniea Puerta de Hierro, Madrid, Spain. Aim. Combination chemotherapy has been used during the resection ofhuman liver tumor mass. However, antineoplasti¢ agents could have un-dcsired side effects on regenerating normal liver cells induced to growth because of tumor resection ."In vitro" liver cell models could he helpful in the study of combination therapies that minimize these side effects. This work deals with pH~ homeostasis differences between normal and cancer cells in culture, comparing the effect produced by the intracellular acidifier anliloride and the antineoplastic doxorubiein on a rat normal liver cell line (Clone 9) and a rat hepatoma cell line (HTC). Methods. Clone-9 (CL9) was cultured in Ham's F12K/10% FCS; HTC cells were cultured in DMEM/10% FCS. p ~ was determined after loading cells with BCECF-AM. Fluorescence was determined at 490/450 nm excitation and 530 nm emission or using a FLUOSTAR (SLT) fluorescence reader (485 nm excitation and 538 nm emission ). Cytotoxieity was measured by nnentral red accumulation, as well as doxorubicin uptake, using the plate reader at 544 nm excitation/590 ran emission. DNA synthesis, cell counts and cellular protein were measured by standard methods, Results. CL9 cells have a minor saturation density, less sensitivity to Genistein ,.,I , .~,~, ~,i,li~,rq t 'E,,," 1Two c~ o~.n c~, x'¢r~. "r "~2+(1{~4.n-t, } Amiloride promotes mtracellular acldaication in HfC cell~ and inhibits more DNA synthesis in a concentration range in which CL9 remains unaltered. Nonsisr6ficam cytotoxieitywas detected in both cell lines. Doxorubicin ( 0 - 10 ~M) markedly inhibits DNA synthesis, cell growth and induces cytotoxieity in HTC cells, without affecting CL9 cells. Low amiloride concentrations in combination with Doxombicin greatly increase the above effects on HTC which are not due to Increased doxorubiein uptake in HTC cells in presence of amiloride. Conclusions. Our results seem to indicate thet the combination of intraeelinlar acidifiers with anticaneer agents potentiates the effect on tumor cells, diminishing the eytotoxicity associated with its use in normal liver tissue.
P-512
EVALUATION OF ADMINISTRATION ROUTES ON HEPATIC EXTRACTION RATIO OF ADRIAMYCIN USING HEPATIC VENOUS ISOLATION AND CHARCOAL HEMOPERFUSION M. Tominaga, Y. Ku, M. Shiotani, T. Kitagawa, 1. Maeda. S. Kusunoki, S. Muramastu, Y, Kuroda and Y. Saitoh 1st Dept, of Surgery. Kobe University School of Medicine. Kobe, Japan
P-513 REPEATED ARTERIAL INFUSION C H E M O ~ Y USING IMPLANTABLE DRUG DELIVERY SYSTEM IN 100 PATIENTS WITH HEPATOCELLULAR CARCINOMA T.Ihaya,* S.Sawada,**E.Nisinmuki,Y.Horie.HKawasaki Dept. of Radiology,Tottori Red Cross Hosp.,Tottori,Japan
We evaluated the first pass hepatic extraction ratio of adriamycin after hepatic arterial infuion and portal venous infusion using a novel system consisting of hepatic venous isolation and charcoal hemoperfusion (HVICHP). HVI'CHP was used to accurately measure the drug amount leaking in the hepatic effluent and to eliminate hepatic re-entry of the drug. Beagles received adriamycin (lmo~kg) through either the hepatic artery (Group I, n=5) or the portal vein (Group II. a=5/. During aud after 10 rain drug infusion in both groups, bepatic effluent was isolated and directed to a charcoal filter. The filtered hepatic effluant was returned to the body through the left jugular vein. During 20-rain HVI. CHP, plasma adriamycin levels were serially measured in prefilter (hepatic vein blood), postfilter and systemic serum. Based on flow rates and adriamycin levels in the hepatic effluent, hepatic extraction ratio (HER) of adriamyein was calculated. Irrespective of administration routes, hepatic re-entry of adriamycin through the hepatic artery and the portal vein after the first pass became negligible. Systemic adriamycin levels were similar throughout HVI" CHP in both groups. However, prefilter adriamyciu levels were significantly lower in group I than those in group II during HVI' CHP (p<0.01). Thus, the area under tbe time concantration curve of prefilter levels in group l (6.1 ± 1.6 min'mg]ml) was significantIy lower than that in group lI (16.9-t-5.0 min'mg/ml, p<0.01). HER (c/c) in group [ (81 234.7) was significantly higher than that in group II (47.2--+9 9, p<0.01 ). HV1. CHP is an useful system for measurement of hepatic tissue extraction ratios of the drugs sbowing good charcoal affinity. Adriamyciu was more effectively extracted by the liver when administered via the hepatic artery compared with the portal vein. These results indicate that hepatic arterial infusion of adriamycin is superior to portal venous infusion in terms of local drug delivery to the liver.
* *2rid Dept. of Internal Medicine,Tottori Univ. Hosp.,Yonagojapan
P-514
TRANSCATHETER ARTERIAL EMBOLIZATION THERAPY FOR THE PATIENT WITH HEPATOCELLULAR C A R C I N O M A U S I N G T H E L E F T B R A C H I A L ARTERY APPROACH S . W a t a n a b e , Y.Miyauchi, M.Shirai, K . A r i m a . M . N i s h i o k a . Third Department o f Internal Medicine, K a g a w a Medical S c h o o l , Japan We e v a l u a t e d the u s e f u l n e s s o f T r a n s c a t h e t e r arterial e m b o l i z a t i o n (TAE) f o r H C C u s i n g the left b r a c h i a l artery a p p r o a c h a n d w h e t h e r this a p p r o a c h is a safe alternative to the femoral artery a p p r o a c h f r o m the viewpoint of complications. Materials and m e t h o d s : A total o f 4 6 patients (38 m e n a n d 8 w o m e n ) w h o u n d e r w e n t TAE using a 4 - F r e n c h catheter were entered in this study. The m e a n age w a s 59.5 years. A total o f 61 arteries w e r e injected on these 4 6 patients b e t w e e n July, 1989 and March, 1994. The Lipiodol-TAE treatment consisted o f ethiodized oil (Lipiodol) mixed with doxorubicin hydrochloride(25 patients) or epirubicin hydrochloride(18 patients) or Mitomycin C (2 patients). F o l l o w i n g this p r o c e d u r e , the feeding arteries were embolized with gelatin s p o n g e cubes ( G e l f o a m , 1-to 2 - r a m pieces). Results: The technical success rate o f the procedure w a s 9 5 . 3 % . T h e m e a n s e r u m c~-fetoprolein levels in 4 6 patients with H C C b e f o r e Lipiodol-TAE ( 2 0 8 6 - 4 - 8 0 1 7 n g / m l ) w a s significantly h i g h e r than that one m o n t h after the therapy ( 1078 ± 4681 ng/ml )(p<0.01 ). No severe c o m p l i c a t i o n s w e r e o b s e r v e d , but m i n o r c o m p l i c a t i o n s o c c u r r e d in 18%. C o m p l i c a t i o n rates o f the brachial artery p u n c t u r e w e r e 8 . 2 % per artery injected. The a s s o c i a t e d c o m p l i c a t i o n s w e r e statistically the s a m e as the p r o c e d u r e f r o m the t r a n s - f e m o r a l a p p r o a c h , w h i c h w a s later p e r f o n n e d in 24 patients. Conclusion: TAE u s i n g the left brachial a p p r o a c h is a safe a n d effective alternative to the trans-femoral a p p r o a c h .
S165
Dept. of Radio~ogy,Tottori Univ. Hosp.,Youago,Japan
We performed clinical evaluation of repeated arterial infusion chemotherapy using an implantable drug delivery system for the patients with inoperable hepatocellular carcinoma0tCC). 100 patients with inoperable HCC have been treated with the implantable drug delivery system. Most of our patients could not receive transcatheter arterial embolization(TAE) because of extreme tumor extension and/or accompanying advanced cirrhosis. In most patients we implanted a 5Fr catheter non-surgically and connected it to an implanted rejection port. The treatment consisted of weekly or biweekly intrahepatic one shot administration of anticancer drugs. The response rate(CR+PR) of the cases was 22.0% The median survival period was 436.0 days. The 6-month,l-year, and 2-year survival rates were 76.0% ,46.4% and 18.4% respectively There was no severe side effect or complication except arterial occulusions that precluded further infusion chemotherapy Tumor regression showed a close correlation with the duration of survival and the reserve liver function was also the significant prognostic factor in this treatment. Distant metastases were found during the therapy in 16 Cases out of 88 cases. These results suggest that the repeated artenal infusion chemotherapy is useful but distant metastasis during the therapy is the serious problem and must be resolved for the improvement of the prognosis of the patients with advanced HCC.
1FI t " t ~, I-'DI~ POTENTIATION BY AMILOR1DE OF DOXORUBICIN EFFECT ON NORMAL AND TUMOR LIVER CELLS "IN VITRO".
J. Ptrez de Diego, C. Trilla and R. Garcia Cafiero. Bioqulmiea Experimental, Cllniea Puerta de Hierro, Madrid, Spain. Aim. Combination chemotherapy has been used during the resection ofhuman liver tumor mass. However, antineoplasti¢ agents could have un-dcsired side effects on regenerating normal liver cells induced to growth because of tumor resection ."In vitro" liver cell models could he helpful in the study of combination therapies that minimize these side effects. This work deals with pH~ homeostasis differences between normal and cancer cells in culture, comparing the effect produced by the intracellular acidifier anliloride and the antineoplastic doxorubiein on a rat normal liver cell line (Clone 9) and a rat hepatoma cell line (HTC). Methods. Clone-9 (CL9) was cultured in Ham's F12K/10% FCS; HTC cells were cultured in DMEM/10% FCS. p ~ was determined after loading cells with BCECF-AM. Fluorescence was determined at 490/450 nm excitation and 530 nm emission or using a FLUOSTAR (SLT) fluorescence reader (485 nm excitation and 538 nm emission ). Cytotoxieity was measured by nnentral red accumulation, as well as doxorubicin uptake, using the plate reader at 544 nm excitation/590 ran emission. DNA synthesis, cell counts and cellular protein were measured by standard methods, Results. CL9 cells have a minor saturation density, less sensitivity to Genistein ,.,I , .~,~, ~,i,li~,rq t 'E,,," 1Two c~ o~.n c~, x'¢r~. "r "~2+(1{~4.n-t, } Amiloride promotes mtracellular acldaication in HfC cell~ and inhibits more DNA synthesis in a concentration range in which CL9 remains unaltered. Nonsisr6ficam cytotoxieitywas detected in both cell lines. Doxorubicin ( 0 - 10 ~M) markedly inhibits DNA synthesis, cell growth and induces cytotoxieity in HTC cells, without affecting CL9 cells. Low amiloride concentrations in combination with Doxombicin greatly increase the above effects on HTC which are not due to Increased doxorubiein uptake in HTC cells in presence of amiloride. Conclusions. Our results seem to indicate thet the combination of intraeelinlar acidifiers with anticaneer agents potentiates the effect on tumor cells, diminishing the eytotoxicity associated with its use in normal liver tissue.