Treatment of VX2 carcinoma implanted in the liver with arterial and intraperitoneal administration of oily anticancer agents.

PURPOSE: Long-term survival and cure cannot be achieved in patients with unresectable, advanced abdominal cancer, because no chemotherapeutic treatment has definite antitumor activity for malignant solid tumor and its dissemination. In this study, arterial and intraperitoneal administration of oily anticancer agents, which have properties that permit targeted chemotherapy for VX2 carcinoma implanted in the liver, was attempted to achieve long-term survival. MATERIALS AND METHODS: Rabbits bearing VX2 tumors in the liver measuring 1-2 cm in diameter received an arterial injection of 0.2 ml of nitrogen mustard N-Oxide (HN2-O) dissolved in Lipiodol (7.5 mg/ml), a newly developed oily anticancer agent, for the tumor and an intraperitoneal injection of a cocktail of oily anticancer agents for the prevention of intraperitoneal dissemination. RESULTS: Twelve out of thirteen rabbits survived and VX2 cancer was not observed in these 12 rabbits. The controls received a sham operation, an intraperitoneal injection of the cocktail of oily anticancer agents alone, or an arterial injection of HN2-O/Lipiodol alone. In these control groups, 27 out of 29 rabbits died of cancer. To examine the dose form for arterial injection, 14 rabbits received an arterial injection of the simple mixture of HN2-O dissolved in physiological saline and Lipiodol, with an additional intraperitoneal injection of the cocktail. Eight of these 14 rabbits died of enlargement of the hepatic tumor and peritoneal dissemination. CONCLUSION: Long-term survival and cure was achieved in almost all rabbits bearing VX2 tumor in the liver by simultaneous arterial and intraperitoneal injection of oily anticancer agents.

[Targeted chemotherapy of hepatocellular carcinoma with SMANCS/Lipiodol--how to use SMANCS/Lipiodol].

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.

Targeted cancer chemotherapy for VX2 tumour implanted in the colon with lipiodol as a carrier.

In this study, we examined the possibility of targeting drug delivery to tumours by dissolving the cytotoxic drug in a lipid fluid that is selectively deposited in tumours. Rabbits bearing VX2 tumour 10-20 mm in diameter in the large bowel received arterial injections of 0.2 ml of mitomycin C (MMC) dissolved in Lipiodol (MMC/Lipiodol), and the antitumour activity and adverse effects were examined. One week after treatment complete necrosis of the tumour was observed in 8 of 10 rabbits that received MMC/Lipiodol (3 mg/ml) without severe adverse effects on the surrounding caecum. In comparison 3/12 control animals that received MMC in saline and Lipiodol also showed complete necrosis. 6 of 7 rabbits killed eight weeks after the injection of MMC/Lipiodol were cured, with no viable tumour cells and with a normal appearance of the surrounding large bowel. In conclusion, MMC dissolved in Lipiodol may be adaptable for the treatment of colon cancer and may achieve antitumour activity without severe adverse effects.

Targeted vinblastine chemotherapy with two preparations of lipiodol contrast medium.

BACKGROUND: Long-term survival and cure can not be achieved in patients with unresectable metastatic liver cancer. In this study, to improve the antitumor activity of oily anticancer agents, which enable targeted cancer chemotherapy, various concentrations of vinblastine dissolved in Lipiodol ultrafluid (vinblastine/Lipiodol U) or Lipiodol F, which has three times the viscosity of Lipiodol ultrafluid, were used. MATERIALS AND METHODS: Rabbits bearing VX2 tumors measuring 1 to 2 cm in diameter in the liver received arterial injections of 0.2 ml of these drugs, and antitumor activity were examined. RESULTS: Complete necrosis of the tumor was observed in three of nine rabbits received vinblastine/Lipiodol U at 2.5 mg/ml. Complete necrosis of the tumor was observed in all eleven rabbits which received vinblastine/Lipiodol U at 5 mg/ml. At concentrations of 7.5 and 10 mg/ml, the necrotic area spread from the tumor to the liver parenchyma surrounding the tumor. The antitumor activity of vinblastine dissolved in Lipiodol F was increased compared with that of vinblastine dissolved in Lipiodol ultrafluid. CONCLUSIONS: The antitumor activity of a kind of the oily anticancer agents, vinblastine/Lipiodol increased with increasing amounts of vinblastine dissolved in Lipiodol ultrafluid and with the increasing viscosity of the carrier, Lipiodol.

[Targeted chemotherapy of hepatocellular carcinoma using Lipiodol as a carrier].

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.