Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.

BACKGROUND/AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Allergic contact dermatitis to copolymers in cosmetics--case report and review of the literature.

Copolymers or heteropolymers are large molecules with high molecular weights (>1000 D). They have been underestimated for a long time as to their sensitizing capacities. Allergic contact dermatitis to 6 copolymers in cosmetics and 1 in a medical dressing has been described; however, the nature of the hapten is still unknown. We report a case of allergic contact dermatitis to polyvinylpyrrolidone (PVP)/hexadecene copolymer in a purple-colored lipstick and review the literature on allergic contact dermatitis to 7 copolymers: PVP/hexadecene, PVP/eicosene, PVP/1-triacontene, methoxy polyethyleneglycol (PEG)-22/dodecyl glycols, methoxy PEG-17/dodecyl glycols, phthalic anhydride/trimellitic anhydride/glycols, and polyvinyl methyl/maleic acid anhydride.

[Case of gastric perforation after TAI (trancatheter arterial infusion) of SMANCS with special reference to accessory left gastric artery].

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.

Transcatheter arterial embolization with zinostatin stimalamer for hepatocellular carcinoma.

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.

Multiple hepatic infarction after transcatheter arterial infusion with SMANCS.

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.

SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy.

This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy, in particular the development and use of SMANCS, a conjugate of neocarzinostatin and poly(styrene-comaleic acid). The various topics covered include a brief description of the chemistry and polymer conjugation, the binding of the conjugate to albumin and the biological behaviour in vitro and in vivo after arterial injection in animals, including plasma half-life, and the lipid solubility of SMANCS in medium chain triglycerides and Lipiodol, a lipid contrast medium suitable for use in X-ray-computed tomography. The biological response-modifying effects and the tumor-targeting mechanism of SMANCS and other macromolecular drugs are also discussed. The latter mechanism is accounted for in terms of a tumor 'enhanced permeability and retention' (or EPR) effect. A principal advantage in the use of SMANCS or other macromolecular drugs is the potential for a reduction or elimination of toxicity. Macromolecular drugs such as a pyran copolymer-NCS conjugate show a marked reduction in bone marrow toxicity normally associated with the use of NCS. This is believed to be due to a hypothetical blood-bone marrow 'barrier' which, relative to NCS, restricts or limits access of the macromolecular drug to the bone marrow. In addition, the clinical possibilities for SMANCS are discussed, including the suggestion that angiotensin II-induced hypertension has clinical potential in improving the selective delivery of macromolecular drugs (i.e. SMANCS) to tumors. Aqueous SMANCS formulations have been tested in pilot studies in patients with solid tumors of the ovary, esophagus, lung, stomach, adrenal gland and in the brain. Formulations based on SMANCS/Lipiodol have been shown to be effective both as a diagnostic tool and for therapeutic use in solid tumors where the formulations are given arterially via a catheter. In a pilot study in primary unresectable hepatoma, an objective reduction in tumor size was observed for about 90% of cases when an adequate amount of the macromolecular drug was administered. A patient receiving such treatment with no active liver cirrhosis and tumor nodules/lesion confined within one liver segment might expect to have a 90% chance of survival after treatment for at least 5 years.

Tumor-targeted chemotherapy with SMANCS in lipiodol for renal cell carcinoma: longer survival with larger size tumors.

OBJECTIVES: To evaluate the anticancer effects of a lipophilic macromolecular anticancer agent, poly(styrene-co-maleic acid)-conjugated neocarzinostatin (SMANCS), dissolved in a lipid contrast medium (Lipiodol) given via the renal artery to patients with renal cell carcinoma. METHODS: Among 467 patients with renal cell carcinoma treated between April 1984 and March 1993, 191 were treated with SMANCS dissolved in a lipid contrast medium (a 3:2 mixture of Lipiodol F and Lipiodol Ultrafluid; Lpd). Selective arterial infusion of SMANCS/Lpd was performed at a dose of 1.0 or 1. 5 mg/mL. The infusion was repeated at intervals of about 2 weeks or longer, but the doses and the total number of infusions varied among patients, according to results of computed tomography analysis. RESULTS: Statistical analysis was performed for 415 patients who met the criteria of this study. Twenty-six surgical patients with metastases who underwent infusion therapy of SMANCS/Lpd for primary lesions showed 3 and 5-year survival rates of 23.0% and 12.8%, respectively; the rates were 19.3% and 9.7% in 31 patients who did not receive SMANCS infusion therapy. In 125 surgical patients without metastases who underwent SMANCS/Lpd infusion, the 5 and 10-year survival rates were 83.0% and 75.2%, respectively, whereas rates of 84.6% and 78.9% were observed in 199 surgical patients whose median tumor size was significantly smaller, however, than the SMANCS/Lpd infusion group. The maximal tumor diameter at the beginning of treatment was significantly larger (mean diameter 70.8 mm) in the SMANCS/Lpd infusion group than in the noninfusion group (59.1 mm). The survival rate was statistically better for patients with tumors of 100 mm diameter or larger in the SMANCS/Lpd infusion group (P <0.05): 5 and 10-year survival rates were 70.4% and 61.6%, respectively, for the infusion group and 64.6% and 50.9% for the group receiving no drug. In patients with larger tumor (greater than 110 mm), the survival rate at 13 years was 75% in the SMANCS/Lpd infusion group and 0% in the surgery group. CONCLUSIONS: Arterial infusion therapy with SMANCS/Lpd appears to be effective for large renal cell carcinoma without metastases in conjunction with surgery.

Nausea and vomiting induced by arterial chemo-embolization in patients with hepatocellular carcinoma and the antiemetic effect of ondansetron hydrochloride.

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.

[Evaluation of hepatic artery occlusion after intra-arterial infusion of SMANCS in patients with hepatocellular carcinoma].

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.

Transarterial chemotherapy with zinostatin stimalamer for hepatocellular carcinoma.

Zinostatin stimalamer (SMANCS) is a lipophilic intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Thirty HCC patients underwent transcatheter arterial injection of 4 mg SMANCS-lipiodol emulsion. Their responses were evaluated by computed tomography 1 month after treatment. Complete response (CR) was defined as disappearance or 100% necrosis of all tumors. Partial response (PR) was defined as > or = 50% reduction and/or > or = 50% necrosis. We regarded the lipiodol accumulation in tumors as being necrotic. CR and PR were observed in 8 patients (27%) and 4 patients (13%), respectively, and the overall response rate (CR + PR/all patients) was 40% (12/30). Of 12 patients whose serum alpha-fetoprotein levels had been more than 200 ng/ml before treatment, 5 patients (42%) showed more than 50% reduction in this level within 1 month after treatment. Toxicity was quite acceptable, although grade 4 toxicity (WHO) was observed as liver dysfunction in 1 patient. Transarterial chemotherapy with SMANCS, which is well tolerated, appears to have moderate antitumor effect in patients with HCC.

A novel dosage approach for evaluation of SMANCS [poly-(styrene-co-maleyl-half-n-butylate) - neocarzinostatin] in the treatment of primary hepatocellular carcinoma.

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.

[Advantages and disadvantages of SMANCS-Lipiodol intrahepatic arterial infusion chemotherapy for unresectable hepatocellular carcinoma].

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.

[Arterial infusion of SMANCS for multiple recurrent tumors after hepatic resection].

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.

[Arterial infusion of SMANCS-Lipiodol for advanced hepatocellular carcinoma].

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.

[Intra-arterial infusion of SMANCS for treatment of patients with hepatocellular carcinoma--adverse reactions and complications].

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.

[Comparative studies on the antitumor activities and side effects of segmental SMANCS/Lip-TAE with segmental SMANCS/Lip-TAI for hepatocellular carcinoma].

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.