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Transcatheter Arterial Chemoembolization Therapy for Hepatocellular Carcinoma Using Polylactic Acid Microspheres Containing Acla

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Transcatheter Arterial Chemoembolization Therapy for Hepatocellular Carcinoma Using Polylactic Acid Microspheres Containing Acla [CANCER RESEARCH 49. 4357-4362, August 1. 1989] Transcatheter Arterial Chemoembolization Therapy for Hepatocellular Carcinoma Using Polylactic Acid Microspheres Containing Aclarubicin Hydrochloride 1omonimi Ichihara,1 Kiyoshi Sakamoto, Katsutaka Mori, and Masanobu Akagi Department of Surgery II, Kumamoto University Medical School, Kumamoto 860, Japan 4BSTRACT MATERIALS AND METHODS Transcatheter arterial Chemoembolization therapy using polylactic Preparation of PLA-ACRms acid microspheres containing aclarubicin hydrochloride (ACR) was per PLA-ACRms were prepared in the pharmacy of the Kumamoto formed in 62 patients with primary hepatocellular carcinoma. These microspheres were about 200 ¡anin diameter and contained 10% (w/w) University Hospital. Briefly, aclarubicin hydrochloride and isopropyl aclarubicin. A single dose of polylactic acid microspheres containing ACR myristate, a medium-chain fatty acid ester, were dissolved in 7.5% (50-100 mg of ACR) was administered 1 to 8 times with a mean of 2.2 polylactic acid-methylene chloride. The resultant solution was dispersed in 1% gelatin solution and sterilized in an autoclave for 20 min at doses (a total of 160 treatments) in 62 patients. Antitumor effects were 120°C;thismixture was then stirred with a magnetic stirrer at 500 rpm observed from the decrease in serum a-fetoprotein levels (82.1% of the patients) and in two dimensional size of tumor on computed tomography for 1 h. The resultant microspheres were collected by filtration through (93.6%). The cumulative survival rate was 54.3% at 1 year, 24.6% at 2 a membrane filter (3 //m pore diameter), rinsed 2 to 3 times (in 1 liter years, and 19.2% at 3 years, respectively, among 59 patients with of distilled water), and dried under reduced pressure for 5 days. These unresectable tumors. In 3 resected liver specimens, there was a significant steps were carried out aseptically in a clean bench. Polylactic acid, the accumulation of ACR in the tumor, and severe necroses of the tumors base for microspheres, is biodegradable, can be molded into a solid were observed histologically. Systemic toxicity was mild and all patients form, and is metabolized into H:O and CO2 in vivo. ACR is a new tolerated this treatment. These results suggest that transcatheter arterial derivative of doxorubicin, developed in 1975. Unlike doxorubicin, the Chemoembolization with the use of polylactic acid microspheres contain cytocidal action of ACR is time dependent in low concentrations, with ing ACR is a useful tumor-targeting chemotherapy and is effective in the inhibition of RNA synthesis (18-20). ACR was provided by Sanraku treatment of hepatocellular carcinoma. Ocean Co. (Tokyo, Japan), and PLA was supplied by Mitui Toatsu Co. (Ohmuta, Japan). PLA was an L form with a molecular weight of about 35,000. The PLA-ACRms were about 200 Mm in mean diameter and contained ACR at about 10% and isopropyl myristate at about 25% INTRODUCTION concentration. Surgical therapy is the only radical treatment for HCC,2 and In Vivo Studies on Release of ACR from PLA-ACRms the survival rate among patients in whom tumors were detected The amount of ACR released into circulating venous blood following and resected early has been high. However, this cancer is often injection of PLA-ACRms into the hepatic artery was determined in associated with liver cirrhosis in Japan, and therefore the rate comparison with an aqueous solution of ACR. Determination of ACR of resection has not increased significantly (1, 2). Moreover, in blood was carried out by high performance liquid chromatography despite the recent progress in diagnostic imaging, approxi (21) at the Central Laboratories of Sanraku Ocean Co. mately 70% of the detected cancers are unresectable (3-5). Determination of Plasma ACR Levels in Dogs. The abdomens of adult These inoperable HCCs used to be treated by ligation of the mongrel dogs weighing 5-9 kg were opened under anesthesia with hepatic artery or with anticancer drugs given by continuous pentobarbital, and a 5 French vascular catheter was introduced through the gastroduodenal artery, with the tip placed into the proper hepatic intraarterial infusion, by one shot intraarterial injection, or by artery. PLA-ACRms or the aqueous solution of ACR were administered systemic i.v. administration. However, none of these methods in doses of 1.5 mg/kg of ACR through this catheter. Subsequently, 3- produced satisfactory results. In 1968, Doppman et al. (6) first ml blood samples were serially collected from the carotid vein through used transcatheter arterial embolization with gelatin sponge the catheter retained in the inferior vena cava. These specimens were fragments for arteriovenous malformation of the spinal cord. placed in heparinized test tubes and immediately centrifuged for 10 In 1976, Goldstein et al. (7) applied this procedure to the min at 3000 rpm. Plasma was separated and frozen at -20°C until treatment of abdominal tumors including HCC. This mode of determination. therapy has subsequently been shown to have epoch-making Determination of Plasma ACR Levels in Humans. Blood samples antitumoral effects. In 1979, Yamada et al. (8) treated 19 were serially collected from the antecubital vein in patients who received PLA-ACRms or the aqueous solution of ACR (1 mg/kg of ACR) patients with unresectable HCC by TACE with gelatin sponge through the catheter introduced into the hepatic artery via the femoral fragments containing anticancer drugs and obtained a good artery by the technique of Seldinger (22). The specimens were similarly survival rate in patients with unresectable HCC in Japan. These treated and frozen at -20°Cuntil determination. achievements have established TACE as a procedure not only for inoperable patients but also for a preoperative use. We Clinical Study developed biodegradable polylactic acid microspheres (9-13) Sixty-two patients (TACE-micropheres group) with advanced HCC containing aclarubicin-HCl (14-16), an anthracycline antican- were treated with PLA-ACRms at our department and affiliated hos cer antibiotic for TACE, after preliminary studies in animals pitals between April 1984 and March 1988. All patients gave consent (17). to the treatment protocol. Diagnoses were made primarily by imaging (angiography, ultrasonography, computed tomography), serum exami Received 12/30/88; accepted 4/20/89. nations including AFP, and histological examination in some of the The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in patients. accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The age of the patients ranged from 43 to 76, with a mean of 60.9 1To whom requests for reprints should be addressed. years, and the male to female ratio was 6:1. Twenty-five (40.3%) of 62 2The abbreviations used are: HCC, hepatocellular carcinoma; TACE, patients were in stage I, 18 (29.0%) in stage II, and 19 (30.7%) in stage transcatheter arterial Chemoembolization; PLA-ACRms, polylactic acid micro- III, respectively, according to Okuda's stage classification (3), and were spheres containing aclarubicin hydrochloride; AFP, a-fetoprotein; CT, computed tomography. judged to be unresectable on admission (Table 1). A total of 160 4357 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1989 American Association for Cancer Research. INTRAARTERIAL INFUSION OF PLA-ACR M1CROSPHERE Table 1 Summary of patients with hepatocellular carcinoma Mean age (years), 60.9; sex (male: Iemali-), 6:1; N, number of cases. Stage"(%)I A/ o o PLA-ACR mt (n=S) (40.3) a .ACR solution (n=5) IIIIITotal25 18(29.0) 19(30.7) 62(100) " According to Okuda's classification (3). treatment courses were given to the 62 patients. A single dose of PLA- ACRms (50-100 mg of ACR) was administered 1 to 8 times, with a 0.101 mean of 2.2 doses. These 62 patients were treated with PLA-ACRms alone (38 cases) and additional anticancer drugs (24 cases). In the latter 24 group, Adriamycin was given in combination to 2 patients, t/.v-platinum Hours after injection to 6, mitomycin C to 1, and Adriamycin plus cis-platinum to 10 (Table Fig. 2. Plasma levels of aclarubicin following administration of aclarubicin 2). Three patients who underwent resection following the TACE ther hydrochloride (1.5 mg/kg) in saline solution or microspheres into the hepatic apy were not included in the calculation of survival rate. PLA-ACRms artery in the dog. were administered as follows. A 6.5 French vascular catheter was introduced through the femoral artery under local anesthesia according to Seldinger's technique. First, portography was carried out through cumulative survival rate. Tumors resected following treatment with the superior mesenteric artery with the aid of 20 ¿tgofprostaglandin PLA-ACRms were submitted to histopathological examination. Ei as a vasodilator to determine the presence or absence of occlusion of the portal trunk. Then, a catheter was selectively introduced through the celiac artery into the hepatic artery, and PLA-ACRms (50-100 mg RESULTS of ACR) suspended in a mixture of about 10 ml of contrast medium Behavior of Drugs in Circulating Blood and physiological saline were gently infused while monitoring by fluo- roscopy to avoid reflux. The serial treatment consisted of 2-3 doses of Determination of Plasma ACR Levels in Dogs. Fig. 2 shows PLA-ACRms per course given at intervals of 2-4 weeks. Patients under the plasma concentrations of ACR in blood following injection long-term follow-up received the treatment at intervals of 6-12 months. of PLA-ACRms or the aqueous solution of ACR into the Fig. 1 shows angiograms taken before and after treatment with PLA- hepatic artery of dogs. The drug given in the aqueous solution ACRms in one patient. Embolization occurred at the level of the 3rd resulted in a biphasic disappearance curve; the plasma concen to 4th order intrahepatic arterial branches.
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