zinostatin and Carcinoma--Hepatocellular

A variety of treatments have recently been introduced to improve the prognosis of hepatocellular carcinoma (HCC). These anticancer therapies include the oily carcinostatic agent styrene maleic acid neocarzinostatin (SMANCS). SMANCS is a chemical conjugate of a synthetic copolymer of styrene maleic acid (SMA) and the proteinaceous anti-cancer agent neocarzinostatin (NCS), which dissolves in organic solvents such as pyridine and acetone, and particularly in Lipiodol. NCS is a simple protein capable of inhibiting DNA synthesis and inducing DNA degradation. Lipiodol is an ethyl ester of iodinated poppy seed oil in which most of the unsaturated double bonds in oleic, linoleic and linolenic acid are almost completely iodinated. When a homogeneous suspension of SMANCS with Lipiodol (SMANCS/Lipiodol) is administered intra-arterially, Lipiodol acts as a carrier of SMANCS. Many studies have demonstrated the clinical efficacy of SMANCS/Lipiodol in the treatment of HCC. We have shown that transcatheter arterial infusion (TAI) with SMANCS/Lipiodol has a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of HCC. However, recent clinical studies have indicated that SMANCS causes severe adverse reactions and complications. We have also reported a case of HCC in which multifocal hepatic infarction developed after TAI with SMANCS/Lipiodol. Arterial administration of SMANCS/Lipiodol, therefore, should be given as peripherally as possible via the tumor feeding arteries, to enhance the efficacy of the agent and to reduce the adverse effects.

Topics: Animals; Antineoplastic Agents; Capillary Permeability; Carcinoma, Hepatocellular; Humans; Maleic Anhydrides; Polystyrenes; Structure-Activity Relationship; Treatment Outcome; Zinostatin

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Catheters, Indwelling; Clinical Trials, Phase II as Topic; Drug Delivery Systems; Embolization, Therapeutic; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Treatment Outcome; Zinostatin

Topics: Antineoplastic Agents; Arterial Occlusive Diseases; Carcinoma, Hepatocellular; Hepatic Artery; Humans; Incidence; Injections, Intra-Arterial; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Risk Factors; Zinostatin

Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Epirubicin; Humans; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Zinostatin

Lipiodol, an oily contrast medium, is utilized to deliver the anticancer agent SMANCS to the target tumor in which the tumor selective delivery of 2,500 fold more than plasma was confirmed with prolonged retention in the tumor tissue. This unique tumor targeting is accomplished by the arterial injection of the oily formulation of the drug. The method utilizes unique vascular properties of tumor tissue. SMANCS is a derivative of neocarzinostatin conjugated with copolymer of styrene and maleic acid. It has much propronounced lipophilicity, stability against various harsh environments and exerts a potent cytotoxicity. Therapeutic effect of the drug to unresectable primary hepatoma is much better than the conventional method. For Child A category patients with intrahepatic metastasis in no more than three area, a 3 yr survival rate is more than 87%. When the Child's A and B are combined with no distant metastasis, 1-, 2- and 3-year survival rates are 87%, 50%, and 35%, respectively. The side effect of this treatment [SMANCS/Lipiodol, i.p.] is minimal; transitory low grade fever is the commonest one (40-50% of cases) which can be controlled by a routine protocol. No liver or marrow toxicity was observed. Procedural limitations for the lung cancer etc. are discussed.

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Evaluation; Fever; Furans; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

We have found that the lipid lymphographic agent, Lipiodol ultrafluid, remains selectively in hepatocellular carcinoma and other malignant solid tumors. Lipiodol administered arterially flows into the normal blood vessels of normal tissues and into the neovasculature of the tumor. Selective retention of Lipiodol in the tumor occurs due to early removal from the normal blood vessels and retention in the neovasculature and extravascular space in the tumor. Using this characteristic nature of Lipiodol, targeting cancer chemotherapy was achieved. It was shown that anticancer drugs had to be dissolved in Lipiodol and diffuse out gradually from the agent in order to achieve targeting cancer chemotherapy. Various kinds of oily anticancer agents which facilitate targeting cancer chemotherapy, such as SMANCS/Lipiodol, mitomycin/Lipiodol, adriamycin/Lipiodol and aclarubicin/Lipiodol were successfully developed. Clinically, these oily anticancer agents were administered to 260 patients with hepatocellular carcinoma. Selective long-lasting retention of Lipiodol in hepatocellular carcinoma was proved on the basis of CT and low-kVp X-ray examination, and persistent high biological activities of anticancer drugs in the tumor were also recognized. The serum AFP level and tumor size showed a decrease in 92% and 90% of cases, respectively. The survival period of these patients with unresectable tumor treated with this protocol was definitely longer than in the comparison group, i.e., the 50% survival period for the comparison group was 1.3 months, while that of the patients who received this protocol was 13 months. In patients administered a SMANCS dose of more than 0.25mg/cm2 of maximum cut-surface area, complete necrosis of the tumor was found, and importantly, non-cancerous liver tissue remained unaffected. Neither hematosuppression nor any severe side effects due to anticancer drugs were observed. Remarkable antitumor effects and reduced side effects could thus be achieved by targeting chemotherapy using Lipiodol as a carrier of anticancer drugs.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Carriers; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Zinostatin

Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival.. Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors.. Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646 days in the TACE group and 679days in the TAI group (p=0.383).. The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain.. The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4-8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m(2), and doses were increased in 1 mg/m(2) increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity.. Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m(2), and in two of six patients at 4 mg/m(2). The maximum-tolerated dose was judged to be 3 mg/m(2) with liver dysfunction and serum creatinine increase as the dose-limiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response.. Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m(2) may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

To evaluate the effect of styrene maleic neocarzinostatin-transcatheter arterial embolization (SMANCS-TAE), 40 patients with unresectable hepatocellular carcinoma (HCC) of hypervascular radiological feature, associated with liver cirrhosis (LC), 18 in clinical stage 2 and 20 in stage 3, were treated by SMANCS-TAE. SMANCS with Lipiodol and then gelatin sponge particles were injected into the artery branch supplying HCC using selective catheterization, and its effect was evaluated by computed tomography (CT) Grade. In patients with Grade III or less (Lipiodol accumulation < 99% in the entire tumor) after the first course of therapy, SMANCS-TAE or arterial injection of SMANCS-Lipiodol was performed once or twice more. Consequently, 32 of 40 patients (80%) obtained Grade IV (100% Lipiodol accumulation in the entire tumor) after from once to thrice (median, 1.6 courses). Grade IV was maintained in 26 of 32 patients, and non-recurrence was found 16 of 40 (40%) at the primary tumor to the time at last of follow up. Severe side effects were not noted except in 10 cases with narrowness of hepatic artery and cases of 2 biloma in patients undergoing therapy two or more times. The 1-, 2-, 3-, and 5-year survival rate was 85, 64, 35, and 26%, respectively. No significant difference was noted in the survival rate between clinical stage 2 and 3 liver cirrhosis (LC). But the survival rate of patients who continued to exhibit Grade IV at the primary tumor was significantly better than in those exhibiting Grade III or less (96, 68, 56, and 43% vs 64, 29, 0, and 0%, respectively; p < 0.01). In conclusion, the HCC patients, even those with decompensated LC, who obtained and maintained Grade IV after SMANCS-TAE could reduce the courses of treatment without severe side effects and survived longer. SMANCS-TAE might be useful for the good quality of life of HCC patients.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

Zinostatin stimalamer (SMANCS) is a lipophilic intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). In our previous study, transcatheter arterial infusion chemotherapy using SMANCS for HCC showed a response rate of 20%. In an effort to obtain a superior anti-tumor effect against HCC, we conducted a phase II study of transcatheter arterial embolization (TAE) using SMANCS and gelatin sponge in 50 chemotherapy-naive patients with HCC. Four milligrams SMANCS plus 4 ml lipiodol emulsion was injected into the hepatic artery, followed by an injection of gelatin sponge. The responses were evaluated by computed tomography (CT) 1 month after treatment and thereafter every 3-4 months. One patient (2%) showed complete response and 15 patients (30%) had partial response resulting in an overall response rate of 32% (16/50; 95% confidence interval 19-45%). In 33 patients (66%), the disease remained stable, and 1 patient (2%) showed progressive disease. In 35 patients (70%), the rate of necrotic area to whole tumor was more than 50% according to the evaluation method using lipiodol accumulation in CT. The 1-, 3- and 5-year survival rates were 90, 55 and 19%, respectively. Grade 3 hematological toxicity was observed as thrombocytopenia in 2 patients (4%). Grade 3 and 4 non-hematological toxicity (liver dysfunction) occurred in 17 (34%) and 7 patients (14%), respectively. TAE using SMANCS, which was well tolerated, may be an effective treatment for advanced HCC.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Humans; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Treatment Outcome; Zinostatin

We evaluated the focal therapeutic effect of oily carcinostatic agents administered by transcatheter arterial infusion (TAI) as the initial therapy in patients with hepatocellular carcinoma in a randomized controlled clinical trial. Group A (19 patients) received 4 mg of styrene maleic acid neocarzinostatin in 4 ml of Lipiodol, and group B (18 patients) received 100 mg of epirubicin in 4 ml of Lipiodol via the tumor feeding arteries as peripherally as possible. The grade of Lipiodol accumulation and the tumor regression rate were determined 2 weeks after TAI by computerized tomography. Adverse effects within 2 weeks after TAI were evaluated by subjective signs and symptoms such as fever (maximum body temperature) and the frequency of shaking chills and abdominal pain, and by biochemical parameters such as albumin, prothrombin time, and aspartate and alanine aminotransferases. Lipiodol accumulation in the tumor was significantly greater in group A (12/19; 63.2% showing grade IV Lipiodol accumulation) than in group B (3/18; 16.7% showing grade IV) (P<0.05). The tumor regression rate was also significantly greater in group A (8/17; 47.1% showing more than 25% tumor regression) than in group B (1/13; 7.7% showing more than 25% tumor regression) (P<0.05). Although clinically significant elevations of aminotransferases and reductions of cholinesterase, and shaking chills were observed more often in group A than in group B (P<0.0001), these factors had little influence on the clinical outcome. Our results suggest that styrene maleic acid neocarzinostatin in Lipiodol exerts a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of hepatocellular carcinoma.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Epirubicin; Female; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

A total of seventeen patients with hepatocellular carcinoma (HCC), nineteen HCCs, who underwent as an initial treatment transcatheter hepatic segmental or subsegmental arterial administration of SMANCS alone for hepatocellular carcinoma (HCC), were studied to evaluate the efficacy and complication of that treatment. The initial treatments provided CR in eight patients (47%), and repeat administrations of SMANCS achieved CR in an additional four patients (24%). The initial treatment provided a dense deposit of Lipiodol in the twelve tumors (63%), in five of which Lipiodol was thereafter washed out in some portions of the tumor. Complete necrosis was obtained in nine (75%) of fourteen hypervascular tumors, and in two (40%) of five intermediately vascular or hypovascular tumors. Segmental or subsegmental administration of SMANCS was well tolerated with self-controlled abdominal pain or fever well responding to medication. Ascites was seen in three cases, and atrophy of the segment infused occurred in five patients. Cholinesterase significantly reduced at one week and one month, then recovered to baseline two to three months after initial treatment. The cumulative survival rates were 77% at 1 year, 66% at 2 years, and 53% at 5 years in the whole patients. The survival rate was 100% at 5 years in the Child A group. In the patients who obtained CR using SMANCS alone, the survival rates were 89% at 1 year, 74% at 2 years and 56% at 5 years. Although this method may transiently deteriorate hepatic function, segmental or subsegmental administration of SMANCS may be an excellent therapeutic method for treatment of HCC and promising for use in properly selected patients.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

We report a Phase I/II clinical trial of poly-(styrene-co-maleyl-half-n-butylate)-neocarzinostatin (SMANCS) for intra-arterial treatment of hepatoma. Early patients received 4 or 8 mg SMANCS dissolved in Lipiodol; later patients were treated according to tumour size and degree of filling achieved. SMANCS/Lipiodol drained rapidly from normal liver but was retained within tumour interstitium. Tumour nodules filled with SMANCS/Lipiodol usually stabilised and often regressed. No UICC criteria-defined responses were achieved, partly due to difficulties of filling several lesions simultaneously. Signs of therapeutic activity suggest a more extensive clinical study is warranted.

Topics: Abdominal Pain; Adult; Aged; alpha-Fetoproteins; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Evaluation; Drug Hypersensitivity; Female; Fever; Humans; Hypotension; Injections, Intra-Arterial; Liver; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; Syncope; Treatment Outcome; Zinostatin

To assess the efficacy of the zinostatin derivative, the anti-tumor agent, styrene-maleic acid neocarzinostatin, in treating multiple small liver cancers, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intraarterial injections of this high molecular weight agent, mixed with Lipiodol. Computed tomography 3 months after the first therapy showed complete deposition of Lipiodol in the entire area of the original tumor in 8 patients (27.6%), 50%-99% deposition in 4 (13.8%), 10%-49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol deposition in the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol deposition depended on the angiographic vascularity of the tumor and on the images of the computed tomogram during arterial portography. Although complete deposition of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well demarcated round hypervascularity, only 1 (8.3%) of 12 patients with ill demarcated tumors showed complete deposition of Lipiodol in the tumors. Taking into account that hypervascularity on angiograms was closely correlated with the degree of Lipiodol accumulation on computed tomograms taken later, it appears that well demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy.

Topics: Adult; Aged; alpha-Fetoproteins; Antineoplastic Agents; Carcinoma, Hepatocellular; Contrast Media; Evaluation Studies as Topic; Female; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasms, Multiple Primary; Pilot Projects; Polystyrenes; Survival Rate; Time Factors; Tomography, X-Ray Computed; Zinostatin

In targeted chemotherapy, Lipiodol Ultrafluid was used as a carrier of anticancer drugs; these combinations were termed oily anticancer agents. Arterial injection therapy with these oily anticancer agents was performed in 330 patients with unresectable hepatocellular carcinoma (HCC) and 110 patients with unresectable metastatic liver cancer. The alpha-fetoprotein (AFP) level decreased in 178 of 186 AFP-positive patients with HCC. Tumor size was reduced in 256 of 269 evaluable patients with HCC. The treatment seemed to prolong survival and in 193 HCC patients who were good candidates for therapy (those without Child C liver cirrhosis, without tumor occupying all four segments of the liver, or without extrahepatic spread) the 1-, 2-, and 5-year survival rates were 85, 52, and 34% respectively. In the 110 patients with metastatic liver cancer, the carcinoembryonic antigen level and tumor size were reduced. The 1-, 2-, and 5-year survival rates of these 110 patients were 61, 32, and 22% respectively.

Topics: Aclarubicin; Adolescent; Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antineoplastic Agents; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Doxorubicin; Drug Delivery Systems; Female; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Mitomycin; Polystyrenes; Survival Analysis; Survival Rate; Treatment Outcome; Zinostatin

A phase II study of YM 881 (zinostatin stimalamer) to determine the response and safety was conducted in patients with hepatocellular carcinoma by injecting a suspension of the drug into the hepatic artery. Repeated doses of 4 to 6 mg of the drug were given every 4 weeks so that the tumor tissues were filled with the suspension. Of the 195 registered patients, 15 were ineligible for the study, 8 dropped out, and data were missing for 5. A total of 167 patients completed the study. Response was assessed in the 167 patients who completed the study. CR was found in one, PR in 59, MR in 25, NC in 67, and PD in 15, with a response rate of 35.9. The safety of the drug was assessed in 177, excluding ineligible patients and 3 who dropped out because of the concurrent use of other drugs. Adverse reactions were found in 93.2% of the patients, and abnormal values in clinical laboratory tests in 60.5%. Major unwanted symptoms included fever, nausea, vomiting, and anorexia. Major abnormal changes in laboratory tests were elevated total bilirubin and LDH and abnormal hepatic function. About half the patients had malaise and pain related to the intra-arterial infusion therapy. The one year survival rate was 56.9%, and the duration of survival of 50% of the patients was 407 days.

Topics: Adult; Aged; alpha-Fetoproteins; Anorexia; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Evaluation; Female; Fever; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Polystyrenes; Survival Rate; Zinostatin

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).

Topics: Aminoacridines; Amsacrine; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Clinical Trials as Topic; Doxorubicin; Humans; Leukopenia; Liver Neoplasms; Prospective Studies; Random Allocation; Thrombocytopenia; Zinostatin

The patient was a 61-year-old female with alcoholic liver cirrhosis, who was admitted to our hospital due to elevation of AFP.During the evaluation, both abdominal ultrasound and enhanced abdominal CT revealed a hepatocellular carcinoma measuring 4 cm in the S6-7 region, complicated with an arteriovenous shunt.Additionally, the lung CT examination showed 20 isolated bilateral lung tumors, all of which were less than 1.4 cm in diameter. Following the diagnosis, we performed a transcatheter arterial infusion chemotherapy of SMANCS at 3 mg through the right heptic artery. Thereafter, the AFP level returned to normal. Additionally, the tumors previously observed in both liver and lung, and exhibited by both lung CT and enhanced abdominal MRI, had disappeared.The patient has been in clinical remission more than 10 years to date.

Topics: Carcinoma, Hepatocellular; Disease-Free Survival; Female; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Maleic Anhydrides; Middle Aged; Polystyrenes; Time Factors; Tomography, X-Ray Computed; Zinostatin

Although iodized oil transarterial chemoembolization (TACE) has been found to have survival benefit in the care of patients with unresectable hepatocellular carcinoma, iodized oil infusion chemotherapy without embolization has not been clearly found inferior to or equal to TACE. The purpose of this study was to determine whether one of these therapies is superior to the other or the two are equal in survival benefit and whether embolization with gelatin sponge particles is indispensable to prolonging survival.. A prospective nonrandomized observational cohort study was conducted over 8 years. Among 11,030 patients with unresectable hepatocellular carcinoma, 8,507 underwent TACE, and 2,523 underwent transarterial infusion therapy with an emulsion of iodized oil and an anticancer agent as initial treatment. Patients with extrahepatic metastasis or any previous treatment were excluded. The primary end point was all-cause mortality. To minimize selection bias, propensity score analysis was used to compare the two groups.. During the follow-up period, 5,044 patients (46%) died. In the analysis of all patients, TACE was associated with a significantly higher survival rate than infusion therapy without embolization (hazard ratio, 0.60; 95% CI, 0.56-0.64; p = 0.0001). The propensity score analysis showed that the hazard ratio for death in the TACE group (n = 1,699 patients) compared with the group who underwent infusion therapy without embolization (n = 1,699) was 0.70 (95% CI, 0.63-0.76; p = 0.0001). The median survival time of the TACE group was 2.74 years, and the 1-, 3-, and 5-year survival rates were 81%, 46%, and 25%. The corresponding values for the group who underwent transarterial infusion therapy without embolization were 1.98 years and 71%, 33%, and 16%.. Propensity score analysis showed that in the treatment of patients with unresectable hepatocellular carcinoma, TACE was associated with significantly better overall survival rates than was transarterial infusion therapy without embolization. TACE can be recommended as initial treatment of these patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chi-Square Distribution; Cisplatin; Combined Modality Therapy; Diagnostic Imaging; Doxorubicin; Epirubicin; Female; Humans; Iodized Oil; Liver Neoplasms; Logistic Models; Male; Middle Aged; Mitomycin; Neoplasm Invasiveness; Neoplasm Staging; Proportional Hazards Models; Prospective Studies; Surveys and Questionnaires; Survival Rate; Treatment Outcome; Zinostatin

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a potent tool to trigger apoptosis in cancer therapy. However, since ∼60% of tumour cell lines and most primary cancers are resistant to TRAIL-induced apoptosis, several combined therapy approaches aimed to sensitize cells to TRAIL have been developed. One of the major targets of these approaches are cFLIP proteins as they interfere with the initiation of apoptosis induction by TRAIL, are over-expressed in many cancers and their down-regulation enhances TRAIL sensitivity. Although, DNA-damaging agents such as 5-fluorouracil (5-FU), etoposide and adriamycin have been successfully employed due to their ability to trigger cFLIP(L) and cFLIP(s) down-regulation the molecular mechanisms underneath their action have been only partially elucidated. We have recently identified ataxia telangiectasia mutated (ATM) as a modulator of cFLIP(L) and cFLIP(S) protein levels in the DNA damage response. Here, we provide genetic evidence that ATM kinase activity is required to trigger 5-FU- and neocarzinostatin-dependent cFLIP(L) and cFLIP(S) down-regulation, which in turn sensitize hepatocellular carcinoma (HCC) cell lines to TRAIL. ATM activity triggers cFLIP proteins down-regulation in HCC cells independently on p53 and enhances cFLIP(L) ubiquitination in response to DNA damage. Therefore, we propose that ATM kinase mediates the interplay between DNA damage and death receptor signalling and suggest that expression of catalytically competent ATM in tumour cells may play a key role for successful combinatorial use of TRAIL receptor agonists and DNA-damaging drugs in cancer therapy.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Carcinoma, Hepatocellular; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Cycle Proteins; DNA Damage; DNA-Binding Proteins; Down-Regulation; Fluorouracil; Humans; Immunoblotting; Immunoprecipitation; Liver Neoplasms; Protein Serine-Threonine Kinases; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitination; Zinostatin

A case of hepatocellular carcinoma, successfully treated with multimodal loco-regional treatments, is reported. An 80-year-old male presented with multiple pulmonary and peritoneal metastases 4 months after right heimihepatectomy for ruptured HCC. Bronchial artery infusion of mitomycin C induced pulmonary tumor regression and stabilization. Peritoneal tumor was treated by arterial infusion of SMANCS, followed by percutaneous injection of absolute ethanol, which ended in surgical removal in 28-postoperative month due to abscess formation. He had been well until right adrenal and left pulmonary metastases appeared. Resection of both metastases was carried out in 39-post hepatectomy month. Recurrent left pulmonary metastasis was treated with two sessions of bronchial artery infusion with no effect this time. Video-assisted partial resection of the left lung was performed in 54 post-hepatectomy month. But his AFP level kept rising. Eventually pulmonary metastasis recurred and tumor thrombus reached the left atrium 58 months after hepatectomy. He wanted no more treatment. He died of cerebral infarction caused by tumor thrombus. He enjoyed a good QOL for five years through multimodal loco-regional treatments.

Topics: Aged, 80 and over; Antineoplastic Agents; Bronchial Arteries; Carcinoma, Hepatocellular; Ethanol; Hepatectomy; Humans; Infusions, Intra-Arterial; Injections, Intralesional; Liver Neoplasms; Lung Neoplasms; Male; Maleic Anhydrides; Mitomycin; Peritoneal Neoplasms; Polystyrenes; Zinostatin

In 1993, a 55-year-old-man was diagnosed with chronic active hepatitis (HCV). In January 1999, a solitary hepatocellular carcinoma (HCC) was discovered in his liver S8, and a sub-segmental hepatectomy was performed. In July 1999, multiple recurrences in the liver were noticed, and on August 6, 1999, the first SMANCS-TAE was performed. After that, PEIT was added, and then on July 18, 2000 and November 9, 2000, a second and third SMANCS-TAE were carried out, respectively. This time multiple HCCs in the bilateral lobes were discovered, and the 4 th SMANCS-TAE was undergone on April 12, 2001. On a celiac angiogram, the right hepatic artery was shown to have been obliterated by the last TAE. In addition, accessory left gastric artery (accessory LGA) originating in the left hepatic artery (LHA) proximal to the umbilical point (UP) could be seen. So we advanced a microcatheter to the LHA distal to the accessory LGA and injected SMANCS (0.8 mg) into the left hepatic artery. On April 24, he was admitted to hospital by ambulance due to severe upper abdominal pain. The muscular defense was noticed, and an air pocket under the diaphragm was indicated on an X-ray. An emergency total gastrectomy and R-Y re-construction were performed under the diagnosis of gastric perforation. A hole of approximately 10 cm in diameter was found in the anterior wall between the cardia and the upper body, and the accessory left gastric artery (LGA) was obliterated. The principal known side effects of SMANCS are fever, nausea and vomiting. However, as far as this writer has investigated, gastric perforation has never been reported. SMANCS presumably can flow into the stomach wall through the accessory LGA, triggering necrosis of the gastric wall due to circulatory damage. Although arterial infusion of SMANCS is an effective treatment, it causes considerable vascular damage, so intensive follow-up treatment is necessary.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Hepatectomy; Hepatic Artery; Hepatitis C, Chronic; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; Rupture, Spontaneous; Stomach Diseases; Zinostatin

A 55-year-old female was admitted to our hospital for a third recurrence of hepatoma. She was treated with transcatheter arterial embolization (TAE) in April and November 1996. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed multiple tumors of S4/S8 and S7 in the liver. After the third TAE using SMANCS, Lipiodol and Spongel, abdominal CT revealed insufficient Lipiodol retention and the in efficacy of this treatment. A right lobectomy of the liver was performed for the TAE resistant multiple recurrence of HCC. After the surgery, the patient survived for over 5 years with no recurrence. It appears that this surgery may be a useful modality for TAE resistant multiple recurrence hepatoma in cases of good liver function and lesions limited to the hemi lobe.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatectomy; Humans; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Middle Aged; Neoplasm Recurrence, Local; Polystyrenes; Survivors; Zinostatin

Topics: Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Carcinoma, Hepatocellular; CD8 Antigens; Chemoembolization, Therapeutic; Granuloma; Humans; Immunohistochemistry; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

We report a patient with hepatocellular carcinoma who developed multiple hepatic infarction after transcatheter arterial infusion (TAI) with a suspension of styrene maleic acid neocarzinostatin (SMANCS) and Lipiodol (SMANCS/Lipiodol). The parameters of hepatic functional reserve were apparently decreased after the second TAI with SMANCS/Lipiodol, and the patient died of hepatic failure 103 days after the second TAI. The autopsy liver specimen revealed multiple hepatic infarctions associated with peripheral arterial stenosis or occlusion, and portal thrombosis. It is speculated that both the arterial occlusion and the portal thrombosis caused the hepatic infarction, based on a long-term insufficiency of blood supply to the hepatocytes arising from toxic arteritis caused by SMANCS/Lipiodol.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Catheterization; Contrast Media; Humans; Infarction; Infusions, Intra-Arterial; Iodized Oil; Liver; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

In February, 1996, a 73-year-old male with liver dysfunction was admitted to our hospital for further examination and treatment of liver tumor. The liver tumor was revealed by imaging examination, which was mainly in the S4-S8 of liver with a thrombus growing from the right anterior branch to the right branch of the portal vein, and from the right hepatic vein to the inferior vena cava and right atrium. The serum AFP and PIVKA-II levels were elevated to 3.610 ng/ml and 54 AU/ml, respectively. The patient was diagnosed as having hepatocellular carcinoma, and was treated by arterial administration of anticancer drugs (epirubicin hydrochloride, mitomycin C and carboplatin) and TAE. Though the main tumor (S4-S8 of liver) was reduced by TAE, the portal and atrial tumor thrombus did not respond. One month after TAE (20 May, 1996), the first arterial administration of Lipiodol-SMANCS was given, followed by 4 successive procedures with an interval of about 1.5 months (total dose 15 mg), resulting in remarkable tumor thrombus shrinkage and reduction of AFP levels to 80 ng/ml. This case shows that arterial administration of SMANCS may be one of the effective treatments for hepatocellular carcinoma, even with tumor thrombus of hepatic vein, IVC and right atrium.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Heart Atria; Hepatic Veins; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Polystyrenes; Vena Cava, Inferior; Zinostatin

To determine the incidence of nausea and vomiting and the antiemetic effect of ondansetron hydrochloride (OND) in patients with hepatocellular carcinoma treated with arterial chemo-embolization, we studied 59 patients with hepatocellular carcinoma who were treated with transcatheter arterial embolization (TAE) or lipiodolized transcatheter arterial infusion (L-TAI). We investigated the incidence of nausea and vomiting and the amount of food intake when TAE or L-TAI was performed. All patients who experienced nausea and vomiting received OND administered prophylactically at the time of the next TAE or L-TAI to evaluate the antiemetic effect of the drug. Cumulative rates of nausea and vomiting during the week following arterial chemo-embolization were 44.8% and 27.6%, respectively. There was a tendency for the incidence to be higher in patients treated with the anticancer agent zinostatin stimalamer (SMANCS) than in those treated with epirubicin hydrochloride (EPI). Regarding food intake, 53.1% of the patients stated that they ate "half or more than half" of the food provided on the day of arterial chemo-embolization. The rate improved as time went on. In 5 patients who experienced nausea and vomiting at the time of arterial chemo-embolization, nausea and vomiting were inhibited satisfactorily by OND. When arterial chemo-embolization was performed, antiemetic treatment for approximately 3 days was necessary to improve patients' quality of life (QOL) to an acceptable level, and OND was found to be effective for the purpose in our 5 patients who had experienced nausea and/or vomiting at the previous treatment.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antiemetics; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Contrast Media; Eating; Epirubicin; Female; Follow-Up Studies; Humans; Incidence; Infusions, Intra-Arterial; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Mitomycin; Nausea; Ondansetron; Polystyrenes; Quality of Life; Vomiting; Zinostatin

The first drug only for arterial injection, SMANCS/Lipiodol, which offers targeted chemotherapy for hepatocellular carcinoma (HCC), now commercially available. Based on our experience using SMANCS/Lipiodol for 424 patients with HCC, the golden standard of how to use SMANCS/Lipiodol for complete necrosis of tumor was described. The initial dose of SMANCS/Lipiodol was varied 2 to 6 mg per body, mainly depending on the size of the tumor. All feeding arteries of HCC have to be verified on angiogram, and the drug must be injected via an adequate artery. Sometimes, a tumor changes its feeding arteries. Additional administrations with an interval of one month were done till the entire tumor was filled with SMANCS/Lipiodol (grade 4). One or two months after achievement of grade 4, we must examine how much drug was removed from tumor on CT. If the entire tumor is not filled with the drug, further injections are recommended to maintain grade 4. Almost all tumors shrank in 3 to 4 months while maintaining grade 4. Frequent administration of low doses (1-3 mg per body) is recommended. Discontinvation of administration was done on the following findings; tumor size reduction of over 90% or complete disappearance of tumor stain. With arterial injection therapy of SMANCS/Lipiodol, survival of patients with unresectable HCC was prolonged, especially in 272 patients who were good candidates for therapy. (Those with Child C liver cirrhosis, with a tumor occupying all four segments of the liver, and/or with extrahepatic spread at initial arterial injection of the drug were excluded.) The 1, 2, 5, and 10 year survival rates were 83%, 58%, 34%, and 25%, respectively.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Survival Rate; Zinostatin

To assess the characteristics of a zinostatin derivative, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intra-arterial injection of the high molecular weight anti-tumor agent, styrene-maleic acid neocarzinostatin, mixed with Lipiodol. Computerized tomography 3 months after the first therapy showed complete accumulation of Lipiodol in 8 patients (27.6%), 50% to 99% accumulation in 4 (13.8%), 10 to 49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol accumulation of the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol accumulation depended on the angiographic vascularity of the tumor and on the images of computerized tomogram during arterial portography. Although complete accumulation of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well-demarcated round-shaped hypervascularity, only one (8.3%) of 12 patients with ill-demarcated tumors could achieve complete accumulation of the Lipiodol in the tumors. Taking into account the fact that hypervascularity on angiograms is closely correlated with the degree of Lipiodol accumulation on computerized tomograms obtained later, well-demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy among various stages of liver cancer.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Molecular Weight; Neoplasms, Multiple Primary; Polystyrenes; Zinostatin

Four patients with advanced hepatocellular carcinoma were treated by repeated arterial infusion of zinostatin stimalamer (SMANCS). Every 4 weeks, 4 mg of SMANCS and 4 ml of Lipiodol were administered via the proper hepatic artery using an implantable arterial port. Three patients with advanced liver cirrhosis (Child B or C) could no longer be treated after 2 or 3 courses of SMANCS infusion because of hepatic failure. In the remaining patient also with compensated liver cirrhosis (Child A), a partial response was observed after 5 courses of chemo-infusion, but we discontinued infusion of SMANCS because of hepatic failure. To assess the usefulness of SMANCS for repeated arterial chemo-infusion by the port, we evaluated 103 patients with advanced HCC treated by Lipiodol emulsion mixed with 70 mg of epirubicin (EPI) using a port. An average course was 11 arterial infusions, and the overall response rate was 40%. One-year survival rates were 62% in Child A, 59% in Child B, and 53% in Child C. Compared with Child A and B patients, both elevation of serum total bilirubin levels and decrease of serum albumin levels were observed after 9 months in Child C patients. In conclusion, SMANCS may have more severe hepatic toxicity in comparison with Lipiodol emulsion mixed with EPI.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Epirubicin; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Iodized Oil; Liver Cirrhosis; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Fifty-five patients with hepatocellular carcinoma were treated with oily anticancer agent SMANCS dissolved in Lipiodol (SMANCS-LPD). The local response rate after the first arterial infusion in all patients was 39%, against 63% in 27 patients with Lipiodol accumulation occupying more than two thirds of tumor areas. The infusion therapy with SMANCS-LPD is adapted for a vascular-rich hepatocellular carcinoma. An infusion of 4 mg of SMANCS was ineffective for patients with tumors distributing in bilateral lobes of liver. Thus, an increase of infusion dosage or repeated infusions were recommended for such cases.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasms, Multiple Primary; Polystyrenes; Zinostatin

Though SMANCS-Lipiodol suspension has advantages over tumor regression, its disadvantages should also be considered: (1) Anaphylactic reaction due to its high molecular weight. (2) Since it readily destroys the tissue, a smaller dose and repeated administration are required. (3) Due to its low viscosity, it easily enters the arterioles and causes damage even to the extrahepatic organs. When this drug is infused into the left hepatic artery in subsegmental fashion, it enters the neighboring gastric tissues through the communication of the left hepatic and left gastric arteries, and this ultimately causes intractable gastric ulcers. Considering the above facts, this drug should be used carefully.

Topics: Adult; Aged; Anaphylaxis; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Drug Administration Schedule; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Polystyrenes; Stomach Ulcer; Vomiting; Zinostatin

We investigated the possible side effects and efficacy of arterial infusion of SMANCS as compared to Lipiodol + epirubicin TAE for multiple recurrent tumors after hepatic resection. As a result, no significant difference in GOT, GPT, and total bilirubin was observed between the two groups. No significant difference was found in white blood cell count and platelet count, and there was no significant difference in clinical side effects between the two groups. Grade III response rates after arterial infusion of SMANCS were found in 4 patients (66.6%), and these results showed no significant difference as compared to Lipiodol + epirubicin TAE. Proper hepatic arterial infusion of SMANCS appeared to be useful in multiple recurrent tumors from the standpoints of safety and the rate of Lipiodol deposition.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Epirubicin; Female; Hepatectomy; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Neoplasm Recurrence, Local; Polystyrenes; Zinostatin

Twenty-four patients were treated with arterial infusion of SMANCS dissolved in Lipiodol. Twenty of these patients had HCC with the main trunks of portal vein occluded by tumor, and four patients had severe cirrhosis and multiple HCC. The actual dose of SMANCS administered each patient ranged from 4 to 6 mg. Side effects occurred in 50%. Severe side effects such as shock and shivering-chilliness were observed in 18%. The differences between the values of hepatic functional serum indexes obtained before and after treatment with SMANCS were small and transient. With regard to the therapeutic response of the arterial infusion of SMANCS, the mean survival time was approximately 2.8 months. It was suggested that the more effective administration of SMANCS was combination of the arterial infusion of SMANCS-Lipiodol with TAE at the level of the right hepatic artery of left hepatic artery for multiple HCC.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver; Liver Neoplasms; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Hepatocellular carcinoma (HCC) often recurs in the remnant liver after hepatectomy. Treatment is often ineffective in cases of multiple recurrence. We treated 18 cases of multiple recurrence with SMANCS/Lipiodol injection (SML). Four patients were treated with SML once, 11 patients were treated twice, and each patient was treated with three or four times with SML. The Effective rate of the 1st SML was 30%, but the effective rate of the 2nd SML was 60% in the plasma tumor marker levels. The effective rate between unilobular recurrence and bilateral recurrence was the same. A complete response was obtained in 2 cases, and partial response in 2 cases. The effective rate of SML was 4/18 (22.2%). These effective cases suffered a recurrence within a year. The cumulative survival rate at the end of the 24th month was 42.4%. Overall survival was significantly higher in the group with SML than in the group with TAE or TAI with the multiple recurrence. SML may be effective in early recurrence because these recurrent nodules are vascular-rich and there is much lipiodol accumulation. SMANCS/lipiodol injection therapy is expected to be an effective treatment in cases of early multiple recurrence after hepatectomy.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasm Recurrence, Local; Polystyrenes; Remission Induction; Zinostatin

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Zinostatin

Although intra-arterial infusion of SMANCS has been demonstrated to be highly effective for treatment of patients with hepatocellular carcinoma, it is reported to cause critical adverse reactions and complications. We examined the adverse reactions of SMANCS on the hepatic artery in 78 patients with hepatocellular carcinoma, who were infused with SMANCS from right, left or proper hepatic artery at our hospital. SMANCS caused right hepatic artery occlusion in 15 patients (19%) and the average amount of infused SMANCS was 6.8 mg. The tumor volume in the artery occluded patients was smaller than that in the artery non-occluded patients. Then, the mechanism by which SMANCS caused arterial occlusion was its induction of arterial injuries by excess infusion. When SMANCS was infused to whole liver, it induced decreased hepatic functional reserve and liver atrophy, followed by delayed liver failure. Other adverse reactions were no different from those in patients infused with epirubicin-lipiodol emulsion.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Atrophy; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Thrombosis; Zinostatin

We compared the effectiveness of treatments and the influence of side effects on liver function and clinical symptoms between segmental SMANCS/ Lip TAI and segmental SMANCS/Lip-TAE. The early tumor response rate of the group treated by TAI was 23.6%, and that of the group treated by TAE was 80.0%. In the group treated by TAE, the therapeutic effects were better in the nodular type than in the diffuse type of HCC, and we were also able to obtain a good tumor response rate on the multiple HCC and large HCC. However, there was no difference in the response period between the groups treated by TAI and TAE. In both groups, there were no significant differences in the appearance rate and degree of side effects. In conclusion, segmental SMANCS/Lip-TAE seemed to be an effective treatment for HCC without any serious complications.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Zinostatin

To evaluate the effects of SMANCS/TAE for hepatocellular carcinoma, AFP reduction rates, tumor reduction rates of SMANCS/TAE were compared with those of SMANCS/TAI. SMANCS is a stylene-maleic acid neocarzinostatin. TAE means transcatheter arterial embolization with gelatin sponge after SMANCS infusion and TAI means transcatheter arterial infusion of only SMANCS-iodized oil suspension. For evaluation of the AFP reduction rate, 13 SMANCS/TAEs were compared with 32 SMANCS/TAIs. In these cases, pretreatment serum AFP levels were higher or equal to 100 ng/ ml. The average dose of SMANCS/TAE was 4.2 +/- 1.8 (S. D) mg and that of SMANCS/TAI was 3.9 +/- 1.8 (S. D) mg (N. S: t-test, p = 0.59). Student's t-test revealed that the AFP reduction rate of SMANCS/TAE was not significantly superior to that of SMANCS/TAI (p = 0.78), and both AFP reduction rate of SMANCS/TAE and SMANCS/ TAI were not correlated with the dose of SMANCS. Tumor reduction rates of 12 SMANCS/TAEs and 14 SMANCS/TAIs on CT examination were calculated. The average dose of SMANCS/TAE was 4.5 +/- 1.9 (S. D) mg and that of SMANCS/TAI was 3.8 +/- 2.1 (S. D) mg (N. S: t-test, p = 0.29). The average tumor reduction rate of SMANCS/TAE was 25.3 +/- 30.1 (S. D)% and of SMANCS/TAI was 13.8 +/- 29.1%. Student's t-test revealed the tumor reduction rate of SMANCS/TAE was not significantly larger than that of SMANCS/TAI (p = 0.33). AFP reduction rate and tumor reduction rate of SMANCS/TAE were not significantly different from those of SMANCS/TAI. Although the number of cases was not enough, these results suggest SMANCS/TAI should be applied for treatment of hepatocellular carcinoma rather than SMANCS/ TAE.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

The therapeutic effectiveness of transcatheter arterial embolization (TAE) with intraarterial infusion of SMANCS/lipiodol mixture was retrospectively compared to TAE with intraarterial infusion of epirubicin/lipiodol mixture in initial treatment of 54 patients with unresected hepatocellular carcinoma. The therapeutic effects were evaluated by the rate of tumor necrosis after the initial procedure and the cumulative survival rate. Eighteen patients were treated with SMANCS, and 36 patients were treated with epirubicin. There was no significant difference in patient background between the two groups; the hepatic functional reserve was not seriously disturbed in most of the patients, and multiple hepatic lesions were seen in half the patients. Complete tumor necrosis assessed by the imaging of dynamic CT one month after TAE was seen in approximately 40% of the cases in each group. Local recurrence was seen in half the patients after assessment of complete tumor necrosis within one year in both groups. There was no significant difference in survival period. There was also no significant difference of the frequency and degree of the side effects. In conclusion, no distinct difference of outcome was found in the two groups in this comparative study. Further studies in many cases over a longer period will be needed to elucidate the effects of SMANCS in TAE.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Middle Aged; Polystyrenes; Treatment Outcome; Zinostatin

The arterial infusion of lipiodol (LPD) containing SMANCS (SMANCS/LPD) has been considered to be a tumor-targeting therapy for hepatocellular carcinoma (HCC). It is important to establish a role of this new therapy in systematic strategies for HCC. LPD has no embolic effect, and the lipophilic anti-cancer agent, SMANCS, suspended in LPD and delivered selectively in tumors, shows therapeutic effect. Accordingly, it is essential for therapeutic efficacy that HCC cells have a chemosensitivity to SMANCS. The maximum dose of SMANCS/LPD is 6 ml at one time, which is not sufficient for voluminous tumors. These are the disadvantages of SMANCS/LPD therapy. Furthermore, HCC tissues, in which lipiodol is retained, is limited to moderately differentiated, with large blood spaces. SMANCS/LPD is not effective for well- and poorly -differentiated HCCs, because blood spaces in these histological types are too small for SMANCS/LPD to be deposited. On the other hand, transcatheter arterial embolization therapy (TAE) is effective by occluding feeding artery with small pieces of gelatin sponge, and a much tumor necrosis is obtained by TAE at one time. However, HCC cells beneath and within the capsule, and invading outside the capsule, are viable, possibly due to backflow of blood via drainage vein. Tumor thrombi and tiny intrahepatic metastases also escape the TAE effect. Previously we reported the new therapy at the first time: the combination of arterial infusion of SMANCS/LPD and TAE (LpTAE). LpTAE has some therapeutic benefits of both therapies; SMANCS/LPD fills up a whole tumor, and part of the LPD flows out from the tumor, is trapped in the capsular invasion and microscopic metastatic foci with the necrotic change. LPD prevents regurgitation of blood flow in drainage vein, and promotes necrotic change. After LpTAE, Lipiodol CT shows 4 kinds of LPD-deposition pattern in HCC; the therapeutic effects of LpTAE are exactly evaluated by these patterns. For total necrosis, HCC nodule shows a complete type, in which the whole tumor shows a metallic density by lipiodol deposition. In other patterns, the LPD-deposited area in tumors generally shows necrosis, and non-LPD-deposited areas are viable. The second line of the therapies. PEIT or resection, can be selected by the LPD-deposition pattern. We consider that the intraarterial infusion of SMANCS/LPD reinforces TAE, and LpTAE is one of the most effective therapies.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Embolization, Therapeutic; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Zinostatin

To evaluate the efficacy and adverse reaction of SMANCS, we reviewed 10 cases treated by TAE with SMANCS among 896 cases treated by TAE for liver cancer during the past three years at our institute. Our criteria for using SMANCS were as follows: a) reduced effectiveness of past TAE with Lipiodol, hydrophilic drugs and gelatin sponge; b) sufficient caliber and blood flow in the hepatic artery; and c) good hepatic function. The 1- and 2-year survival rates after treatment with SMANCS were 50% and 25%, respectively. The 3- and 5-year survival rates after initial treatment (first TAE, etc.) were 40% and 20%, respectively. There were no significant complications in clinical course, however, subsequent hepatic arteriogram often showed arterial change that may interfere with further regional therapy for the liver.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Therapeutic effects of SMANCS and LpTAE were evaluated for hepatocellular carcinoma (HCC). Since June 1995, SMANCS has been used in 59 patients for their first treatment. LpTAE had been performed for HCC before introduction of SMANCS in our hospital, and 71 patients treated after 1992 were chosen for comparison with the therapeutic effect of SMANCS. Among the patients treated with SMANCS, complete and partial responses (CR and PR) were obtained in 24 cases (41%) and 17 cases (33%), respectively. SMANCS accompanied by TAE was more effective than SMANCS alone. The effects did not depend on the level of the hepatic arterial branch at which SMANCS was administered. In patients treated with LpTAE, CR and PR were obtained in 12 cases (17%) and 18 cases (25%), respectively. SMANCS was significantly more effective than LpTAE. Because of our short experience with SMANCS, we could only show a two year survival rate. The one- and two-year survival rates for SMANCS were 71% and 57%, respectively. They were not significantly different from those for LpTAE, at 80% and 60%. Despite good results of treatment for HCC, a better prognosis could not be expected by SMANCS in this study. These results may be explained as follows. The evaluating the cause of death within two years after first treatment, hepatic failure was more common in patients treated with SMANCS. After treatment by SMANCS, 11 patients (55%) died from hepatic failure. On the other hand, 4 patients (15%) died from hepatic failure after LpTAE. Although there is no significant difference of Child Pugh score, this may indicate that SMANCS has been used for patients with lesser hepatic reserve and this leads to early deaths in patients treated with SMANCS. However, because of the short experience in this study, further observation is necessary for precise evaluation of clinical efficacy of SMANCS.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

Segmental SMANCS Lipiodol TAE (Seg. SMANCS Lp-TAE) using SMANCS was used to treat HCC in 58 patients and was evaluated in comparison with Seg. Lp-TAE using Epirubicin performed in 50 patients with respect to the course of atrophy of the embolized area, recurrence rate and side effects. On serial CT (Lp-CT) performed after TAE, in cases with P type in which the tumor is present in the periphery of the embolized area and showing Type I homogeneous accumulation of Lp within the tumor, the incidence of atrophy in the embolized area including the tumor was high and the recurrence rate was low. Although no significant difference in the recurrence rate was noted between the groups in which SMANCS and EPI were used, there were more cases with marked atrophy and a lower recurrence rate in the former. No difference was found in post-procedural side effects such as fever between the two groups, while hypotension was rarely observed during the procedure in the group in which SMANCS was used and was easily managed with intravenous steroids. The present results suggest that Seg. SMANCS Lp-TAE is an effective local treatment for HCC limited to a subsegment or segment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Administration Schedule; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

We have attempted transcatheter arterial embolization (TAE) with SMANCS and epiADM for 40 patients with hepatocellular carcinoma and evaluated its therapeutic effects and side effects. There were 7 cases of stage I disease, 10 cases of stage II disease, 10 cases of stage III disease and 13 cases of stage IV disease. Patients underwent TAE superselectively following infusion of w/o emulsion of epiADM and SMANCS-lipiodol. No severe side effect was observed compared with conventional Lp-TAE except in one case with hepatic biloma after treatment. The overall response rate was 70%, and 54.5% in the patients with recurrent tumor after Lp-TAE. The serum AFP value decreased in 16 patients out of 20 patients. Hepatic resection was performed in 2 patients after treatment, and no viable tumor cell was recognized in the specimen. Our result suggested that TAE with SMANCS and epiADM will contribute to improved therapeutic efficacy for hepatocellular carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Administration Schedule; Embolization, Therapeutic; Epirubicin; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Patients with unresectable hepatocellular carcinoma (hepatoma) with hypervascularity were treated by SMANCS-TAE, which was performed by a superselective catheterization technique to inject gelatin sponge particles after administration of SMANCS. In 24 of 30 (80%) patients of first hepatoma treated by SMANCS-TAE, Grade 4 was obtained after about 1.5 (1-3) courses. The 2-year survival rate was 33%. SMANCS-TAE appears to have the same potential and safety as Lipiodol-TAE, treated selectively. Moreover, we can reduce the course of treatment and obtain good QOL of hepatoma patients except in advanced cases (vp 3 or T 4).

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Survival Rate; Zinostatin

From January 1996 to August 1997, 24 patients with advanced hepatocellular carcinoma (HCC) equal to or more than 2 cm (mean +/- SD; 4.1 +/- 3.0 cm) in main tumor diameter were treated by SMANCS-TAE (20 cases) or SMANCS-TAI (4 cases) combined with PEI. Six cases had solitary lesion, 16 cases had multiple lesions, and 2 cases had massive lesions. After this combination therapy, 21 of 24 cases had complete tumor necrosis. During 3 to 19 months follow up period, 12 cases had cancer-free survival (SMANCS-TAI; 3 cases), and 9 cases had tumor recurrences (3 cases were local recurrences and 6 cases involved new lesions). Two cases died of hepatic infarction and cancer death, however, the remaining 22 cases were surviving. SMANCS-TAE combined with PEI is useful treatment for advanced large or multiple HCC lesions in patients who are poor surgical risks.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Ethanol; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Injections, Intralesional; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Recently, subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein has been performed to treat hepatic infarction in subregion hepatocellular carcinoma (HCC). Here, we report subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein with styrene maleic acid neocarzinostatin lipiodol (SMANCS) (SMANCS-TAE under balloon occlusion of the corresponding hepatic vein). This study included 9 patients with HCC who underwent SMANCS-TAE under balloon occlusion of the corresponding hepatic vein. In all patients, the therapeutic effects (TE) were evaluated according to the criteria of direct response to liver cancer treatment on abdominal computed tomography (CT) 3 weeks after surgery. In 7 patients who could be followed for more than one year, there was no postoperative relapse at the site of treatment. Furthermore, this procedure facilitated the detection of accumulation of SMANCS not only in the tumor but also in the subregion of the tumor in patients with HCC involving immature arterial tumor neoplastic vessels. In patients with large HCC complicated by severe heart failure showing a poor general condition, this procedure allowed treatment to be completed without complication. SMANCS-TAE under balloon occlusion of the corresponding hepatic vein, which can also embolize the portal vein by applying targeting chemotherapy with SMANCS, may cause necrosis not only in the tumor but also in noncancerous liver tissues. This procedure may be an indication for a larger number of cases than standard TAE, facilitating more complete local treatment.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Catheterization; Embolization, Therapeutic; Female; Hepatic Artery; Hepatic Veins; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Zinostatin

Patients with unresectable hepatocellular carcinoma (hepatoma) with hypervascularity were treated by SMANCS-TAE. A superselective catheterization technique was used to inject gelatin sponge particles after administration of SMANCS. In 30 patients of first hepatoma treated by SMANCS-TAE. Grade 4 was obtained after 1.7(1-3) courses. The 2-year survival rate was 22%. Some of the 24 patients of second hepatoma treated by SMANCS-TAE have survived over 2 years. Sixteen patients with advanced hepatoma (Vp2-3 or T4) were treated only by SMANCS injection, but none survived over 1 year. SMANCS-TAE appears to have the same potential and safety as L-TAE, when used selectively. Moreover, we can reduce the course of treatment and obtain good QOL for hepatoma patients except in advanced cases.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Embolization, Therapeutic; Female; Gelatin; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

A 47-year-old male patient with chronic hepatitis had a high AFP level during the follow-up period. Abdominal CT revealed at S5, which led to a diagnosis of hepatocellular carcinoma. In August 1992, partial resection of S5 was performed, and ethanol was injected into the tumor at S2. In July 1993, recurrent tumors were observed at S5 and S3. PEIT was performed for each lesion. In December 1994, multiple recurrence was observed and 4 mg SMANCS was injected through the proper hepatic artery. In July 1995, another 4 mg of SMANCS was injected into the tumors. In June 1996, only a 20 mm lesion at S5 remained while the other lesions disappeared. Under general anesthesia, the patient underwent percutaneous microwave tumor coagulation. In December 1997, the AFP level was normal, and imaging revealed disappearance of the recurrent tumor. Selection of local therapy for hepatocellular carcinoma achieved long survival in our case considering the QOL and frequent therapy administration.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Electrocoagulation; Ethanol; Hepatectomy; Humans; Injections, Intralesional; Liver Neoplasms; Male; Maleic Anhydrides; Microwaves; Middle Aged; Polystyrenes; Zinostatin

Although intra-arterial infusion of SMANCS is effective for the treatment of hepatocellular carcinoma, injury of the hepatic artery is occasionally encountered. We analyzed 78 patients with hepatocellular carcinoma who received intraarterial infusion of SMANCS. Twenty-seven patients who were treated by epirubicin were used as a control. Complete occlusion of the right hepatic artery was induced in 15 patients who received SMANCS infusion. The average number of administrations was 1.9 in the occluded group, 1.5 in the non-occluded group, and 1.6 in the epirubicin group. There was no statistically significant difference in the dose of drugs in a single session between the three groups (3.5 +/- 1.5 ml in the occluded group, 3.6 +/- 1.5 ml in the non-occluded group and 4.2 +/- 1.2 ml in the epirubicin group), and there was no statistically significant difference in total dose between the three groups (6.8 +/- 2.6 ml in the occluded group, 5.5 +/- 3.6 ml in the non-occluded group and 6.8 +/- 4.3 ml in the epirubicin group). However, total dose per tumor volume was significantly larger in the occluded group (1.1 +/- 1.0 cm3) than in the non-occluded group (0.5 +/- 0.5 cm3) (p < 0.05). Excess infusion of SMANCS for small hepatocellular carcinomas appears to be an important factor in vascular injury.

Topics: Aged; Antineoplastic Agents; Arterial Occlusive Diseases; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

We report on two patients who developed hepatic infarction after undergoing percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma (HCC). In both cases, liver function parameters deteriorated immediately after the ethanol injection, and enhanced computed tomography images showed a wedge-shaped avascular low-density area due to hepatic infarction. In one patient, PEIT was performed for a nodule treated with transcatheter arterial infusion (TAI) using a suspension of styrene maleic acid neocarzinostatin (SMANCS) 4 weeks before. In the other patient, TAI with SMANCS had been carried out 14 months previously for a different nodule in the same segment where the nodule treated with PEIT was located. When PEIT is used for patients with HCC who have previously undergone TAI, especially with SMANCS, PEIT may induce hepatic infarction.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Catheterization, Peripheral; Ethanol; Humans; Infarction; Injections, Intralesional; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

We compared the segmental SMANCS/Lip-TAI and the segmental SMANCS/Lip-TAE and studied the effectiveness of both treatments and the influence and/or the side effects on liver function. In resected cases, we studied histopathologic examination. The response rate of the group treated by TAI was 28.6%, and that of the group treated by TAE was 76.5%. In the group treated by TAE, the therapeutic effects were good in nodular type HCC, using small doses of SMANCS. In both groups, the incidence and degree of side effects showed no significant difference. Hepatic insufficiency occurred in a few cases of the group treated by TAI. In resected cases, viable areas remained below the tumor capsule. In conclusion, segmental SMANCS/Lip-TAE seemed to be an effective treatment without any serious complications.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Retrospective Studies; Zinostatin

Combination therapy consisting of Lipiodol (Laboratoire Guerbet, Villepinte, France) containing styrene maleic acid neocarzinostatin and transcatheter arterial embolization (L-TAE) has been an important conservative therapy for hepatocellular carcinoma (HCC). We examined the clinical and pathologic characteristics of 14 HCC cases that achieved total tumor necrosis in response to L-TAE. The HCCs of all cases were resected 45 +/- 17 days after L-TAE and were confirmed to be totally necrotic. Ultrasonography showed a mean tumor size of 2.5 +/- 1.0 cm, often with a halo formation around the tumor. Angiographically, neovascularity and clear tumor stains were observed in all cases. Computed tomography portography showed nodular perfusion defects in all the cases examined. There were portal invasions in two cases. On Lipiodol-computed tomography, Lipiodol was densely and homogeneously retained within the whole tumor. The number of tumors was single in all diagnostic images. Macroscopic view of HCCs were single nodular type in nine cases and single nodular type with extra growth in four cases. Clear capsular formation was seen in each HCC nodule. Soft x-rays were taken to observe the exact distribution of Lipiodol in the operative specimens. Microscopic intrahepatic metastases were found histologically in four cases. Histologic examination showed the trabecular pattern with broad blood spaces in which Lipiodol was positive with Sudan III staining. Necrosis was seen not only in the main tumor, but also in the capsular invasions and microscopic metastases with Lipiodol deposition. The characteristics of the cases with total tumor necrosis were as follows. Deposition of Lipiodol throughout the tumor was essential, and clinically the cases showed a single HCC tumor with a diameter of more than 5 cm and arterial hypervascularity. The pathologic findings included expansive growth with capsular formation and trabecular-type HCC with abundant blood spaces. These findings are important for evaluating the radical efficacy of L-TAE.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Necrosis; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

Twenty patients with unresectable hepatocellular carcinoma were treated by zinostatin stimalamer-transcatheter arterial embolization (SMANCS-TAE). After administration of SMANCS, a superselective catheterization technique was used to inject gelatin sponge particles into the artery or artery branch supplying the cancer-bearing segment. We compared the results of SMANCS-TAE with Lipiodol (Yamanouchi, Tokyo, Japan)-TAE performed during the same period. In 18 of 20 patients (90%), a tumor necrosis rate of 100% (grade 4) was obtained after one or two courses of SMANCS-TAE. The SMANCS group was superior to the Lipiodol-TAE group in terms of the tumor reduction rate, alpha-fetoprotein reduction rate, and cumulative 1.5-year survival rate, but not significantly. No severe side effects were noted after SMANCS-TAE. SMANCS-TAE appears to have potential as a new treatment for hepatocellularcarcinoma, and patients treated with this technique will be monitored to elucidate the long-term effects.

Topics: Aged; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Epirubicin; Female; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Radiography; Survival Rate; Zinostatin

A 47-year-old man with hepatocellular carcinoma (HCC) at anterior and medical segment in the liver was treated with hepatic arterial infusion of Zinostatin Stimalamer-lipiodol suspension (SMANCS). After the 2nd infusion of SMANCS, the accumulation of lipiodol in the tumor was not good (Grade II), so additional administration was undertaken at five-weeks intervals. His systolic blood pressure immediately decreased from 120 to 60 mmHg, and he had numbness of hands, shaking chills, sweating, chest pain and numerous urticaria-like red exanthema. In spite of treatment by anti-shock agents such as steroid and catecholamines, these symptoms did not disappear, but antihistaminics greatly improved them without any serious side effects. Because of the remarkable effects of the antihistaminics and possibility of antibody production (IgE) after repeated infusions of high molecular SMANCS, this patient may have suffered anaphylactic shock caused by massive histamine release from mast cells.

Topics: Anaphylaxis; Carcinoma, Hepatocellular; Hepatic Artery; Histamine H1 Antagonists; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Cirrhosis; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Forty-four patients with hepatocellular carcinoma were treated with oily anticancer agent SMANCS dissolved in Lipiodol (SMANCS-LPD). The local response rate after the first arterial infusion in all patients was 39%, against 63% in 27 patients with Lipiodol accumulation occupying more than two third of tumor areas. Repeated arterial infusion of SMANCS-LPD did not enhance the therapeutic effect. An infusion of 4mg of SMANCS was ineffective for patients with tumors distributing in bilateral lobes of liver, and 6 mg was recommended for such cases.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Zinostatin

We performed arterial infusion of SMANCS/Lipiodol in nineteen cases with hepatocellular carcinoma (HCC). We report two of these cases who survived for more than five years after the initial treatment. In case 1, HCC responded very well to the initial subsegmental infusion of SMANCS/Lipiodol with a prominent decrease in AFP level. In case 2, a 63-year-old male, repeated subsegmental infusion of SMANCS/Lipiodol for the local recurrence controlled the tumor well. In both cases, an approximately three-year period of complete remission passed until the tumor recurred. Arterial infusion of SMANCS/Lipiodol is expected to be a potent treatment for HCC. Its administration should be subsegmental, if possible, and should be repeated for local recurrence with a careful follow-up study.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Prognosis; Zinostatin

As chemoembolotherapy (TAE) for relatively small hepatocellular carcinoma (HCC) including small HCC of less than 2 cm in diameter, which is restricted to a sub-subsegment, subsegment or segment of the liver, segmental Lp-TAE using Lipiodol (Lp) mixed with an anticancer agent, which includes subsegmental and sub-sub-segmental therapy, not restricted to the tumor-bearing segment, is expected to move to the forefront of HCC treatments and also causes fewer complications and less strain to the patient. Of the 15 cases that underwent surgery following segmental Lp-TAE, complete necrosis was found histopathologically in more than 80% of the main tumor, satellite nodules in the embolized region and areas of capsular invasion. Its therapeutic efficacy for 51 cases with tumors smaller than 3 cm was comparable to that of surgery.

Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Survival Rate; Zinostatin

A 62-year-old man was admitted to our hospital for treatment of HCC with a thrombus growing from the right branch to the trunk of the portal vein. His hepatic functional reserve was fairly good. Serum levels of AFP and PIVKA-II were elevated to 1,780 ng/ml and 27 AU-ml, respectively. The hepatic arteriogram showed a hypervascular tumor approximately 4 cm in diameter in the right anterior segment and many ill-defined small tumor stains around the main tumor. Portal phase of superior mesenteric arteriogram revealed filling defect in the portal trunk, and no visualization of the right branch of portal vein. SMANCS-Lipiodol was infused via right hepatic artery, and Spongel was infused via right anterior branch of hepatic artery. Three months after the first therapy, the tumor markers normalized. A computed tomography scan showed that the main tumor and the tumor thrombus were markedly decreased in size, whereas the hepatic angiogram revealed tumor stains around the main tumor. SMANCS-Lipiodol was again infused via proper hepatic artery. He has remained well for 16 months after the first treatment. The combination of the arterial infusion of SMANCS-Lipiodol with the selective TAE was very effective for this case, probably because his hepatic functional reserve was fairly good and the left branch of portal vein was patent. It was suggested that SMANCS-Lipiodol with the selective TAE could be one therapy to be considered for a patient like this case.

Topics: Carcinoma, Hepatocellular; Embolization, Therapeutic; Hepatic Artery; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplastic Cells, Circulating; Polystyrenes; Portal Vein; Thrombosis; Zinostatin

A-68-year-old man had hepatocellular carcinoma (HCC) in the area of S6 segment which was resected surgically. Three months after surgery, multiple recurrent lesions were found in both lobes of the liver. A transcatheter arterial embolization (TAE) with 5-FU and zinostatin stimalamer (SMANCS) was done. After TAE, the tumor mass disappeared in the right lobe and reduced to 10% in the left lobe. Although mass lesions remained unchanged for 3 months, the increased of AFP (143.9 ng/ml) was noticed after 4 months. Ten months after the second TAE with 5-FU and SMANCS, the disappearance of tumor masses was confirmed by diagnostic images.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fluorouracil; Humans; Liver Neoplasms; Male; Maleic Anhydrides; Neoplasm Recurrence, Local; Polystyrenes; Remission Induction; Zinostatin

Antitumor activities of zinostatin stimalamer (YM881) were examined in human hepatoma cell lines (SK-Hep1 and HuH2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 causing a 50% inhibition of growth of SK-Hep1 and HuH2 cells were 6.7 and 27 nM, respectively. In VX2 tumor-bearing rabbits, administration of YM881 suspended in Lipiodol, an iodinated fatty acid ethylester of poppyseed oil, (YM881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs. sham-operated and Lipiodol-treated groups) inhibitory effects on tumor growth and histopathological changes at 1 and 2 weeks after administration. In contrast, Lipiodol (0.2 ml/body) tended to inhibit the growth of VX2 tumor (p < 0.1, vs. sham-operated group) at 1 week after administration, but showed only moderate effects at 2 weeks after administration. Minimal necrosis was observed at 1 and 2 weeks after administration of Lipiodol, and histopathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM881/Lipiodol suspension showed antitumor activity in VX2 tumor-bearing rabbits presumably due to the inhibition of the growth of hepatoma cells by YM881 itself. Lipiodol, on the other hand, is considered to augment the antitumor activity of YM881 by maintaining high YM881 concentrations in tumor tissue.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Division; Disease Models, Animal; Drug Screening Assays, Antitumor; Humans; Iodized Oil; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Maleic Anhydrides; Neoplasm Transplantation; Polystyrenes; Rabbits; Suspensions; Tumor Cells, Cultured; Zinostatin

A 68-year-old male was referred to our hospital for the precise examination of a giant hepatic tumor detected in a mass survey. The lesion occupied most of the right hepatic lobe, further advancing to the medial segment of the left lobe. However, hepatic functions were well preserved (ICG K = 0.141). Considering the characteristic images of the lesion with positive anti-HCV and high titer of PIVKA II (0.860 AU/ml), the diagnosis was hepatocellular carcinoma. First arterial administration of SMANCS was performed on May in 1994, followed by 6 successive procedures with an interval of about 2 months (total dosage 36 mg), resulting in remarkable tumor shrinkage and tumor marker normalization. On January in 1995, a metastatic lesion to the right rib was controlled by 2 mg of SMANCS administered to the intercostal artery combined with radiation therapy (60 Gray). Frequent administrations of SMANCS caused no serious complications, and tumor feeders were well preserved. Therefore, arterial administration of SMANCS is thought to be one choice for the therapy of giant HCC with good functional reserve.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Combined Modality Therapy; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Polystyrenes; Radiotherapy; Zinostatin

For targeted chemotherapy using Lipiodol as a carrier, it was found that anticancer agents had to be dissolved in Lipiodol and diffused gradually from it. Dose forms having properties for targeted chemotherapy were named "oily anticancer agents". Oily anticancer agents are completely different from simple mixture of Lipiodol and anticancer agents by pumping methods in antitumor activities and adverse effects. Up to 1,601 arterial injections of oily anticancer agents were given to 400 patients with unresectable hepatocellular carcinoma. Decrease in serum AFP levels was observed in 209 (94%) of 222 AFP-positive patients, and reduction of tumor size was observed in 308 (96%) of 322 patients who had evaluable tumors. Reduction in size to less than 50% was observed in 50% of patients 5 to 6 months after initial administration, and all tumors reduced to less than 50% one year after. In 45 of 60 patients whose tumors shrank to less than 10% of initial size, follow-up 1 year or more after tumor shrinkage could be done (range 1-9 years, average 3 years). These tumors did not regrow, so they were considered to be cured. Survival was prolonged, especially in 251 patients who were good candidates for therapy (excluding those with Child C liver cirrhosis, tumor occupying all four segments of the liver, and/or extrahepatic spread at initial arterial injection of the drug), the 1-, 2-, and 5-year survival rates were 83, 58, and 34%, respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Carriers; Female; Humans; Iodized Oil; Liver Cirrhosis; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Topics: Antineoplastic Agents; Capillary Permeability; Carcinoma, Hepatocellular; Drug Carriers; Humans; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Neoplasms; Polystyrenes; Zinostatin

Anti-tumor activities of zinostatin stimalamer (YM 881) were examined using human hepatoma cell lines (SK-Hep1 and HuH 2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 against SK-Hep 1 and HuH 2 cells were 6.7 and 27 mM, respectively. In VX2 tumor-bearing rabbits, administration of YM 881 suspended in iodinated fatty acid ethylesters of poppyseed oil (YM 881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs sham-operated and Lipiodol-treated groups) inhibitory effects on the growth and pathological changes 1 and 2 weeks after administration. On the other hand, Lipiodol (0.2 ml/body) showed a tendency to inhibit the growth of VX2 tumor (p < 0.1, vs sham-operated group) 1 week after administration, but it showed only moderate effects on the VX2 tumor growth 2 weeks after administration. Minimal necrosis was observed 1 and 2 weeks after administration of Lipiodol, and these pathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM 881/Lipiodol suspension showed the anti-tumor activity against VX2 tumor-bearing rabbits, presumably due to the inhibition of the growth of hepatoma cell by YM 881 per se. On the other hand, Lipiodol is considered to augment the anti-tumor activity by maintaining high YM881 concentrations in tumor tissue.

Topics: Animals; Carcinoma, Hepatocellular; Cell Division; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Liver Neoplasms, Experimental; Rabbits; Tumor Cells, Cultured; Zinostatin

Combination therapy (LpTAE) consisting of arterial infusion of a lipophilic anticancer drug, SMANCS, dissolved in an oily lymphographic agent, lipiodol (LPD), and transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) was studied with special reference to the pathological findings. A total of 32 patients were subjected to surgical resection after LpTAE. The pattern of LPD deposition in the tumor was examined by CT scan (Lipiodol CT, LpCT) at 7 days and/or 1 month after LpTAE. The resected materials were examined radiographically with soft X-rays and histologically. LPD was deposited in tiny daughter nodules with a diameter of less than 5 mm and in tumor thrombi as well as in the main tumors, which showed necrotic change. Part of the LPD flowed out from the main tumor via the drainage vein and was deposited in the capsular invasion, resulting in necrosis. LPD accumulated almost exclusively within the blood spaces of trabecular-type HCC, creating a pattern corresponding to a cast of the tumor vessels, which showed prominent necrosis. On the other hand, LPD was not deposited in scirrhous, compact, or well-differentiated HCC, which showed little or no necrosis. It was demonstrated that LpCT images, which accurately depicted the existence and the extent of LPD deposition and necrosis in the tumor, were useful for precise evaluation of the therapeutic effect. Our findings indicate that LpTAE and LpCT are valuable for the diagnosis and treatment of HCC and should play a central role in systemic therapeutic approaches to this disease.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

A phase I study of YM-881 (zinostatin stimalamer), neocarzinostatin combined with butylesterified styrene maleate, suspended in iodized poppy oil ethyl ester, was conducted in patients with hepatocellular carcinoma by giving single intra-arterial infusions via catheters inserted by Seldinger's method. Four dose levels, 2, 4, 6, and 8 mg, were tested. Major adverse reactions were fever, anorexia, nausea, vomiting, and abnormal hepatic function. Both the incidence and severity of adverse reactions tended to increase with the 8 mg dose. Tumor regression of 50% or more occurred in one receiving 2 mg and one receiving 4 mg. The results of the study suggest that doses of 6 mg or less may be appropriate for the phase II studies.

Topics: Adult; Aged; Anorexia; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Evaluation; Female; Fever; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Nausea; Polystyrenes; Zinostatin

A suspension of zinostatin stimalamer (YM881), an antitumor protein antibiotic in iodized poppy oil-fatty acid ester, was injected into the hepatic artery of 2 patients who received surgical treatment of hepatic tumors. Single doses of 4 mg of zinostatin stimalamer were injected into the hepatic artery by Seldinger's method. Two and 4 weeks after the dose, tissue samples were collected from the tumor and non-tumor regions close to and distant (normal tissues) from the tumor, and zinostatin stimalamer concentrations in these tissues were assayed by RIA. In one of the two patients, plasma concentrations of the drug were also assayed. Concentrations of zinostatin stimalamer in the tumor tissues (381.8 ng/g) were about 55 times greater than those in the normal tissue (6.9 ng/g) in patient No. 1 (week 4), and about 17 times in patients No. 2 (13.9 ng/g in the normal tissue and 229.8 ng/g in the tumor tissues in week 2). Plasma concentrations were assayed in patient No. 2, and were 510.3 ng/ml after one hr., 385.3 ng/ml after 3 hrs., 184.4 ng/ml after 6 hrs., and 45.4 ng/ml after 24 hrs., with a half life of 7.1 hrs. These results indicate that zinostatin stimalamer suspended in iodized poppy oil fatty acid ester persisted in the hepatic tumor tissues at the high concentrations, when injected into the hepatic artery, but was eliminated fairly rapidly from the plasma.

Topics: Aged; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Injections, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

The oily anticancer agents dissolved in lipiodol used for arterial administration against various solid tumors in our department were found to be applicable to treat for pleural or peritoneal carcinomatosis experimentally and clinically. The pharmacokinetic study with rat model showed oily anticancer agents were retained in a high concentration in the peritoneal cavity compared to water-soluble anticancer agents. In our pilot clinical study all patients with pleural or peritoneal carcinomatosis showed improvement cytologically and physically.

Topics: Adult; Aged; Animals; Antibiotics, Antineoplastic; Ascitic Fluid; Carcinoma, Hepatocellular; Doxorubicin; Female; Furans; Humans; Infusions, Parenteral; Iodized Oil; Liver Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Pleural Effusion; Polystyrenes; Rats; Rats, Inbred Strains; Zinostatin

Transcatheter arterial chemotherapy (SMANCS/lipiodol) was applied to massive hepatoma, which had a high AFP 213,000 ng/ml, A-P shunt, tumor thrombosis and metastatic lung cancer. After 3 months, the AFP value reduced to 18 ng/ml, massive hepatoma and the A-P shunt disappeared, but AFP-negative nodular hepatoma recurred around initial hepatoma. Each time, we injected SMANCS/lipiodol to the recurring hepatoma. The therapy in the initial stage was not so effective. The portal vein was not observed in the initial stage, but appeared after the second dosage. Metastatic lung cancer was declining in the initial dosage and 23 months later disappeared after the third dosage. The massive hepatoma occupied entirely the rt. lobe of the liver. The patient lived for 4 years, had total admission periods of 190 days and could return to life in society. In this case, we considered that transcatheter arterial chemotherapy (SMANCS/lipiodol) had remarkable effects.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Follow-Up Studies; Furans; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Lung Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Prognosis; Remission Induction; Zinostatin

Oily anticancer agents such as SMANCS dissolved in Lipiodol fluid (Lipiodol) were administered to 18 patients with recurrence of hepatocellular carcinoma after hepatic resection and to 87 patients with metastatic liver cancer. The following results were obtained. i) It was proved and to that Lipiodol worked as a carrier of anticancer drugs and that targeting chemotherapy could be achieved. ii) The serum AFP level and tumor size showed a decrease in 91% and 87% of patients with recurrence of hepatoma, respectively. iii) This method could be applied to extrahepatic metastasis of hepatoma, and anticancer activity was also observed in these lesions. iv) The serum CEA level was decreased in 53 patients (83%) and reduction of tumor size was observed in 32 patients (46%) with metastatic liver cancer. v) In 5 out of 7 tumors resected after arterial injection of oily anticancer agents, necrosis was found histologically in over 95% of the tumor.

Topics: Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Combined Modality Therapy; Furans; Hepatectomy; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Mitomycin; Mitomycins; Polystyrenes; Postoperative Period; Zinostatin

Topics: Adult; Aged; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

The lipid lymphographic agent, Lipiodol ultrafluid has been found to remain selectively in hepatocellular carcinoma. Using this characteristic nature of Lipiodol, a new targeting anticancer chemotherapy was devised. In order to achieve targeting anticancer chemotherapy and useful anticancer effects, anticancer drugs must be dissolved or suspended in Lipiodol and diffuse out from the Lipiodol gradually. Oily anticancer agents such as SMANCS dissolved in Lipiodol (SMANCS/Lipiodol), Mitomycin C in Lipiodol (MMC/Lipiodol), Aclarubicin in Lipiodol (ACR/Lipiodol) and a mixture of these were administered by catheterizing the celiac or hepatic artery under X-ray monitoring in 216 patients with hepatocellular carcinoma. Remarkable anticancer effects of this targeting chemotherapy were achieved, the serum AFP level and tumor size both showing a decrease in 91% of cases. The survival period of patients with unresectable hepatoma treated with the present protocol was definitely longer than the comparison group.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Embolization, Therapeutic; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Mitomycin; Mitomycins; Naphthacenes; Polystyrenes; Zinostatin

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Contrast Media; Furans; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Radiography; Zinostatin

Combined treatment with intraarterial administration of oily anti-cancer agent (SMANCS-Lipiodol; copolymer of styrene maleic acid conjugate of Neocarcinostatin disolved in Ethiodol) and transcatheter arterial embolization (TAE) was employed in 2 patients with small hepatoma. At 3-4 weeks after treatment, hepatic resection was performed. Histopathological examination of the 2 resected specimens showed total cell necrosis; CT and Softex revealed the distribution of lipiodol in the tumor and adjacent regions. This combination treatment showed combined effects, i.e. embolization by TAE, the anti-cancer effect of SMANCS and the selective delivery of lipidol to the hepatoma, especially the area of capsula invasion, the daughter nodule and tumor thrombus.

Topics: Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Embolization, Therapeutic; Furans; Hepatic Artery; Humans; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Female; Furans; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Tomography, X-Ray Computed; Zinostatin

A lymphographic agent, Ethiodol, injected via the hepatic artery was found to remain selectively in the tumor vessels of hepatoma for a long time in our clinic. Taking advantage of this selective continuous peripheral embolization, a lipophilic high molecular anticancer agent, SMANCS (Copolymer of styrene maleic acid conjugated to Neocarzinostatin) dissolved in Ethiodol was administered via the celiac axis or the hepatic artery with Seldinger's method. Anticancer effect was examined by histological findings of specimens removed using hepatic resection (13 cases) and autopsy (1 case) in 14 patients receiving this treatment. Anticancer effect of this treatment became clear through histological findings. In the patients administered SMANCS more than 0.26 mg per 1 cm2 of maximum cut-surface area, complete or widespread necrosis of the tumor occurred, whereas non-cancerous liver tissue remained unaffected.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Drug Evaluation; Ethiodized Oil; Female; Humans; Injections, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Zinostatin

A clinical evaluation of arterial infusion of high-molecular-weight antitumor agent SMANCS dissolved in lipid lymphographic agent (thiodol) in 44 patients with mostly unresectable hepatoma is described. The treatment regimen demonstrated significant merits both therapeutically and diagnostically. Marked antitumor effects were shown in the decreased serum alpha-fetoprotein levels (86% of cases) and tumor size (95% of cases), and in survival period and histological findings. Furthermore, there was increased diagnostic sensitivity using CT scan, plain X-rays or ultrasound. The procedure of selective arterial administration of 3-4 mg of SMANCS in 3-4 ml of ethiodol per dose was simple to perform and was required only once every 3-4 weeks. Both ethiodol and the drug accumulated more selectively in tumor than in any other tissues and their activity remained for more than 3 weeks. Only minimal side-effects were associated with SMANCS and ethiodol during this study.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Drug Combinations; Ethiodized Oil; Female; Humans; Injections, Intra-Arterial; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Polystyrenes; Prognosis; Tomography, X-Ray Computed; Zinostatin

Two advantages of the present therapeutic approach were described. Firstly, a selective deposition of lipiodol in tumor tissue was verified, thus more precise and accurate diagnosis by X-rays was possible either by CT or plain X-ray film. Secondly, pronounced accumulation of smancs in tumor tissue was observed, which established highly effective chemotherapy of unresectable hepatoma of 22 cases and 12 other cases based on (a) decrease in alpha-fetoprotein (86%), (b) tumor size (95%) and histology. Drug was given via the hepatic artery mostly 3-4 mg in 3-4 ml of lipiodol once every 3 to 4 weeks. Most patients have experienced a total dose of 6-8 mg in two cycles, but drug activity lasted more than 3 weeks. Neither hematosuppression nor anaphylaxis was observed. Major side effect was transient fever (38-39 degrees C) in about 50% of the cases which lasted no more than one week. Other minor side effect was abdominal pain during or after arterial infusion which lasted for about 20 min. Liver function was affected very slightly if any. Mild leukocytosis was observed in 65% of the patients.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Molecular Weight; Polystyrenes; Zinostatin

The characteristic of a slow infusion technique of angiography provided a new method of selective intraarterial administration. We named this new method "high pressure one hot injection." When we tried to apply this method to patients with inoperable hepatoma, we considered that Neocarzinostatin (NCS) was a very applicable antitumor drug in terms of cell killing kinetics. Fifteen patients with inoperable hepatoma were treated with NCS by the selective intra-hepatic arterial infusion method. Administration of NCS was given by using a technique of high pressure one shot injection. The administration dose of NCS was 6000u. or 10000u., and 10 patients received once, and the others twice or three times. Results were as follows: 1) According to both Karnofsky's criteria and the criteria of direct response for solid cancer, an objective response was observed in 6 patients (40%). In proportion to the increase of the total dose and frequencies the individual efficacy increased. 2) The median survival was 5.5 months. 3) Decrease of serum AFP was seen, prominently within one month after injection. 4) The major side effects were fever (93%), liver dysfunctions (53%), leukopenia (46%), thrombocytopenia (33.3%), and their frequencies were related to the dose of one injection and that of the total. These results suggest that the high pressure one shot injection of NCS is very effective to inoperable hepatoma, but both dose and interval of injection remain to discussed.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Middle Aged; Zinostatin

Because of encouraging single-agent activity for both zinostatin and doxorubicin in hepatocellular cancer, a phase I tolerance study with these drugs in combination was undertaken. The dose of zinostatin given daily for 5 consecutive days and repeated every 6 weeks was fixed at 2250 units/M2. The starting dose of doxorubicin was 45 mg/m2 on days 1 and 22 of every 6-week cycle, but this was escalated or deescalated by increments of 33% as tolerated. The occurrence of unpredictable severe and prolonged cumulative myelosuppressive toxicity in most patients resulted in considerable management difficulties. In addition, three patients developed congestive heart failure at cumulative doxorubicin doses ranging from 195 to 270 mg/m2 and two patients developed possible drug-related nephrotoxicity. Until reasons for the pharmacogenetic variability observed with zinostatin are defined, combination studies employing this drug are not recommended.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Bone Marrow Diseases; Carcinoma, Hepatocellular; Doxorubicin; Drug Evaluation; Female; Humans; Liver Neoplasms; Male; Zinostatin

Thirty evaluable patients with histologically confirmed primary liver cancer (PLC) were treated with neocarzinostatin (NCS). All patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 2, or 3. NCS 2250 units/m2 was given daily for 5 days, repeated at 28-day intervals. Hemopoietic suppression was the major side effect. In 23 of 30 patients (13 with leukopenia and 19 with thrombocytopenia), this toxic effect was documented. Other toxic effects included nausea, vomiting, allergic-type reaction, and elevation of NPN. Partial response, with a median duration of 12.7 weeks (range 4--37 weeks) was observed in seven patients. In nine patients the response was classified as no change, and in 14 patients there was progressive disease. NCS has some therapeutic activity in patients with PLC.

Topics: Adult; Antibiotics, Antineoplastic; Carcinoma, Hepatocellular; Child, Preschool; Drug Evaluation; Female; Humans; Leukopenia; Liver Neoplasms; Male; Pilot Projects; Thrombocytopenia; Zinostatin

Neocarzinostatin is a protein antitumor antibiotic isolated from cultures of Streptomyces carzinostaticus var.F41. The drug has undergone extensive clinical trial in Japan, and has been reported active against a variety of human tumors. A phase I and preliminary phase II evaluation of the drug has been performed, using an iv bolus daily x 5 schedule. Ninety-six patients have been treated at doses from 500 to 2250 units/m2/day. Courses were repeated at 4-week intervals if allowed by bone marrow recovery. Dose-limiting toxicity was myelosupppression, which occurred late (median nadir, Day 27). Myelosuppression was more pronounced in patients who had received previous chemotherapy. In nine patients (9%) thrombocytopenia was prolonged (greater than or equal to 45 days) or irreversible. Acute administration of the drug was associated with rigors in approximately half the patients. Gastrointestinal side effects were mild. Three patients had a severe acute reaction resembling anaphylaxis. The maximally tolerated dose for this dose schedule is approximately 2250 units/m2/day. Antitumor activity has been seen in hepatoma and hematologic malignancies. Activity in lung and colorectal carcinoma appears limited with this dose schedule.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Bone Marrow; Carcinoma, Hepatocellular; Child; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver Neoplasms; Male; Middle Aged; Neoplasms; Remission, Spontaneous; Thrombocytopenia; Zinostatin

Change in beta-glucuronidase activity of six Yoshida ascites hepatomas was examined after treatment of host rats with one of 12 anticancer agents. The hepatomas, AH-66F, AH-130, AH-109A, AH-60C, and AH-44, in decreasing order showed more or less distinct increase in beta-glucuronidase activity after treatment of the rats with Nitromin, Endoxan, 864-T, Carbazilquinone, Mitomycin-C, Toyomycin, Daunomycin, Neocarzinostatin, vincristine sulfate, 5-fluorouracil, or cytosine arabinoside only when the cytological effect was positive. Moreover, degree of the increase was generally correlated with that of cytological effect. Bleomycin was ineffective either enzymically or cytologically. AH-66 was insensitive to any of the agents tested in increasing beta-glucuronidase activity and showed only a very slight cytological response to some of the agents. Acid deoxyribonuclease behaved like beta-glucuronidase but to a lesser extent. The above order of drug sensitivity of the hepatomas was not in parallel with that of normal beta-glucuronidase level, which also did not correlate with the life span of host rats.

Topics: Animals; Antineoplastic Agents; Bleomycin; Carbazilquinone; Carcinoma, Hepatocellular; Chromomycins; Cyclophosphamide; Cytarabine; Daunorubicin; Deoxyribonucleases; Fluorouracil; Glucuronidase; Liver Neoplasms; Male; Mesylates; Mitomycins; Neoplasms, Experimental; Nitro Compounds; Rats; Sarcoma, Yoshida; Tosyl Compounds; Vincristine; Zinostatin