[The role of alpha-tocopherol and retinol in correcting disorders of lipid peroxidation in patients with malignant liver neoplasms]. / Rol' al'fa-tokoferola i retinola v korrektsii narushenii perekisnogo okisleniia lipidov bol'nykh so zlokachestvennymi opukholiami pecheni.

Patients with liver tumors are known to reveal antioxidant system disorders which lead to accumulation of products of lipids peroxidation and lower resistance. Levels of malonic dialdehyde as well as the antioxidant system (superoxide dismutase, catalase, alpha-tocopherol and retinol) in liver and tumor have been followed in 28 patients in whom liver was removed to treat malignant tumors. Liver and tumor tissue were shown to contain more dialdehyde and less superoxide dismutase and catalase than in the livers of accident victims. Treatment with alpha-tocoferol (600 mg), retinol (100,000 MU) and ascorbic acid (1.5 g) for 7 days before surgery was found to significantly reduce dialdehyde level in the liver. Also, the catalase level increased. Treatment with alpha-tocoferol and retinol resulted in their selective accumulation in the liver. No changes in lipid peroxidation or accumulation of alpha-tocoferol in tumor were recorded. Purulent and septic complications were 1.6 times less frequent after preoperative antioxidant treatment than in controls. It is recommended that said antioxidant treatment should be used to correct lipid peroxidation and to improve the effectiveness of therapy of liver cancer.

Percutaneous hepatic vein isolation and high-dose hepatic arterial infusion chemotherapy for unresectable liver tumors.

PURPOSE: This prospective, nonrandomized trial evaluated a percutaneous isolated chemotherapy perfusion approach for treating advanced primary and metastatic liver tumors. Chemotherapy was administered via hepatic artery catheter and hepatic venous blood isolated by a novel percutaneous double-balloon inferior vena cava (IVC) catheter was passed through a detoxification/filtration cartridge in a venovenous bypass circuit. PATIENTS AND METHODS: Among 23 patients enrolled onto the study, 58 procedures were performed on 21 patients. Twelve patients received dose escalations of fluorouracil (5-FU) (1,000 mg/m2 to 5,000 mg/m2), and nine received dose escalations of doxorubicin (50 mg/m2 to 120 mg/m2). Pharmacokinetic studies included drug accumulation in the liver, extraction by detoxification filters, systemic exposure, and alterations of half-life. Each patient received two treatments at 3-week intervals. Those showing stabilization or response received additional treatments. RESULTS: There was a direct relationship between dose and peak concentration of drug entering the hepatic veins. The system functioned efficiently throughout the dose range, with extraction efficiencies ranging from 64% to 91% (P < .001). The hepatic vein drug levels showed a sixfold increase in 5-FU with dose escalation from 1,000 to 5,000 mg/m2, and a twofold increase in dox with dose escalation from 50 to 120 mg/m2 (P < .001, filter-mediated drug extraction). The treatments were accomplished with only an overnight hospital stay and no mortality. The common procedure-related toxicity was transient hypotension (grade I to II), due to catecholamine depletion by the filter. Dose-limiting toxicity (leukopenia) was observed in patients receiving 5-FU at a dose of 5,000 mg/m2 and doxorubicin at a dose of 120 mg/m2. Significant tumor response (> 95% reduction) was obtained in two patients receiving doxorubicin at 90 mg/m2 and 120 mg/m2. CONCLUSION: The use of a double-balloon catheter to isolate and detoxify hepatic venous blood during intraarterial therapy is technically feasible, safe, and allows administration of large doses of intrahepatic chemotherapy at short intervals. This approach should allow new dose-intensification strategies to increase tumor responses in primary and metastatic liver tumors.

The 11-year Pittsburgh experience with liver transplantation for hepatocellular carcinoma: 1981-1991.

Experience with liver transplantation over a period of 11 years at the University of Pittsburgh is presented. The application of liver transplantation to cases of hepatocellular carcinoma has changed considerably over this 11-year period with the sequential introduction of adjuvant and, more recently, neoadjuvant chemotherapy. Results with the combination of chemotherapy plus surgery appear to be better than results with either agent alone. Moreover, the early results with neoadjuvant therapy appear to be better than those achieved with adjuvant therapy. As a result of this experience, conceptual changes in the approach to the problem of hepatic cancer and the role of both chemotherapy and liver transplantation in its management have changed at the University of Pittsburgh. These changes are identified and discussed.

Analysis of failure after curative irradiation of extrahepatic bile duct carcinoma.

Thirty-four patients with subtotally resected or unresectable carcinoma of the extrahepatic bile ducts received radiation therapy; a minimum of 45 Gy (external beam) to the tumor and regional lymph nodes +/- 5-fluorouracil (5-FU). Seventeen patients received an external beam boost of 5 to 15 Gy to the tumor, and a specialized boost was used in the remaining 17 patients (iridium-192 transcatheter seeds in 10 and intraoperative radiation therapy [IORT] with electrons in seven). The median time to death in all 34 patients was 12 months (range, 4 to 98-months). The only patients who survived longer than 18 months were those either with gross total or subtotal resection before external irradiation (2 of 6) or who received specialized boosts (192Ir, 3 of 10; IORT, 3 of 7). Local failure was documented in 9 of 17 patients who received external beam irradiation alone +/- 5-FU, 3 of 10 patients who received an 192Ir boost, and 2 of 6 patients who received an IORT boost with curative intent.

[Combined moving strip whole liver irradiation and traditional Chinese medicine for large liver cancer].

This paper reports the result of large liver cancer treated by moving strip whole liver irradiation from 1980 to 1988. The 5-year survival rate was 30.83% +/- 7.77% and the median survival time was 25.8 months. Analysis of factors affecting prognosis showed: 1. The higher the midplane tissue irradiation dose, the longer the survival (P less than 0.001) and 2. Patients with greater than or equal to 8 less than 13 cm tumor diameter and/or greater than or equal to 50% less than 75% tumor/liver volume ratio had longer survival than those with greater than or equal to 13 cm diameter and/or greater than or equal to 75% tumor/liver volume ratio (P less than 0.001). Traditional Chinese medicine was indispensable as a supplement to this treatment. Both clinical and experimental study suggested that this technique could improve the patient's final outcome.

[Cases of advanced cholangiocarcinoma showing partial response by the combination chemotherapy including protracted continuous infusion of 5-FU combined with intravenous administration of low-dose leucovorin and intra-arterial administration of MMC and CQ].

We treated a patient with advanced cholangiocarcinoma with a new combination chemotherapy (modified MQF). The regimen consisted of intra-arterial administration of MMC (20 mg/body) and CQ (4 mg/body), protracted continuous infusion of 5-FU (500 mg/body) and intravenous administration of low-dose leucovorin (30 mg/body). More than 50% reduction in the liver tumor for over 4 weeks was obtained by the therapy. As for toxicity, diarrhea and stomatitis were observed.

Variable low dose rate irradiation (131I-anti-CEA) and integrated low dose chemotherapy in the treatment of nonresectable primary intrahepatic cholangiocarcinoma.

Previous experience using 131I anti-CEA antibody, which irradiates at a variable low dose rate in combination with a multimodality treatment program, has demonstrated acceptable toxicity and response in primary intrahepatic cholangiocarcinoma. In attempting to improve therapy, Cis-platin was added to the prior regimen. Induction therapy was unchanged. One month later, chemotherapy was given (doxorubicin, 15 mg, 5-fluorouracil, 500 mg, plus Cis-platin, 20 mg/M2) followed the next day by outpatient administration of 20 mCi 131I anti-CEA by i.v. bolus. Five days later, 10 mCi was administered. The latter regimen (chemotherapy plus 20 + 10 mCi 131I anti-CEA) was repeated every 2 months using polyclonal antibodies derived from different species (rabbit, pig, baboon, and horse). Twenty-four patients (29% with prior chemotherapy and/or metastases) were prospectively treated according to this regimen. Toxicity was limited to hematologic toxicity and was manifested by thrombocytopenia and leukopenia (17% and 4% grade 4, respectively, according to RTOG toxicity criteria). Tumor remission was evaluated by CT volumetric analysis and demonstrated a 14% response rate for the induction portion of therapy, 24% for the radioimmunoglobulin portion of treatment, and 50% remission rate when all subsequent tumor volumes were compared to the pre-treatment volume (entire program). The median survival for the entire group of patients was 10.1 months. This result is superior to previously reported trials and, in comparison to our previous study (10.1 vs 6.5 months median survival), further advancement in protocol design appears to have been made. In view of the rarity of this disorder, a randomized trial is not possible and strict statistical analyses cannot be made. The mechanism of 131I-anti-CEA variable low dose irradiation and chemotherapy interaction is discussed as well as further potential modifications for treatment improvement.

Etiologic and clinical characteristics of peripheral and hilar cholangiocarcinoma.

A 20-year experience with 112 patients with cholangiocarcinoma was reviewed with reference to the demographic, etiologic, and clinical features and prognosis in the following two types: peripheral (originating from the intrahepatic small duct radicles) and hilar (originating from the major hepatic ducts at or near the junction of the right and left hepatic ducts). Seventy of the 112 patients were in the hilar group, and 42 were in the peripheral group. Prolonged high alcohol consumption was a prominent feature in both categories (45% and 37%, respectively). Among the women, 35% of those with the peripheral tumor had used oral contraceptive preparations. The major identifiable etiologic factor among the hilar tumors was ulcerative colitis, with or without sclerosing cholangitis, which was documented in 20 of 70 cases (28.6%), with an additional 4 patients having Crohn's disease. The hilar group mainly had obstructive jaundice initially, whereas abdominal pain and weight loss were the predominant symptoms in the peripheral type. Tumor recurrence was frequent in those undergoing resection or transplantation, and none of those undergoing chemotherapy or radiation therapy showed any objective evidence of response. Overall median survival time was poor in both groups at 12 months.

Rifampicin as cytotoxic agent for cholangiocarcinoma: preliminary report of seven cases.

Seven consecutive patients with unresectable cholangiocarcinoma of the major bile ducts, referred to one surgical department with a hepatobiliary interest, were treated by biliary decompression and with the antibiotic rifampicin in an uncontrolled preliminary study. Three patients were also given tamoxifen. Five of the seven are dead, the mean survival being 26 months (expected mean survival 8 months), and two are alive and well in May 1991, 48 and 30 months respectively from the time of presentation. A controlled study of rifampicin with and without tamoxifen is indicated in unresectable cholangiocarcinoma.

Subrenal capsule assay using liver cancer specimens obtained by fine needle biopsy.

Twenty-seven liver cancer biopsies (20 hepatocellular carcinomas, 4 metastatic liver cancers and 3 cholangiocellular carcinomas) were obtained using a 21-gauge fine needle biopsy guided by ultrasonography. These cancers were subcutaneously transplanted to the subrenal capsular region of BDF1 mice premedicated with immunosuppressive agents to modulate the host immune reaction. The SRCA was based on the change in tumor size (delta TS) and the tumor growth inhibition rate (TGIR). The transplantation rate of the 27 liver cancer specimens was 85% by delta TS and 67% by TGIR. The efficacy rates of Adriamycin, cis-platinum, and mitomycin were respectively 71%, 58%, and 43% by delta TS, and 73%, 56% and 50% by TGIR. Thus, liver cancer specimens obtained by fine needle biopsy and examined by SRCA had a fairly high transplantation rate, and this method can be useful for patients with inoperable liver cancer, as a general chemosensitivity test for anticancer drugs.

[Hepatic arterial infusion of etoposide in the treatment of primary liver neoplasms].

A phase 1 study of etoposide for hepatocellular carcinoma and cholangiocarcinoma was undertaken by single arterial infusion (9 cases; range of doses levels; step 1: 50 mg/m2, step 2: 75 mg/m2, step 3: 120 mg/m2). Mild leukopenia (2500/mm3 in step 2 and 2400/mm3 in step 3) was observed in 2 cases. Thrombocytopenia or anemia was not observed in these doses. Hypotension was experienced 2 hrs. after infusion in one case of step 2. The post-infusion plasma decay of etoposide was biphasic with t1/2 alpha ranging from 0.59 approximately 0.63 h and t1/2 beta ranging from 5.40 approximately 6.57 h. AUC0-24 increased in association with the increase of the doses. Hepatic artery infusion of etoposide was performed without serious complication and the dose limiting toxicity was leukopenia.

[Intra-arterial infusion chemotherapy in non-resectable pancreatic cancer using angiotensin-II and implantable drug delivery system].

Over the past 6 years, we have treated 25 cases of pancreatic cancer, 6 cases of cholangioma in pancreas-head and 3 cases of cancer in duodenal papilla (2 cases Stage I, 5 cases stage II, 2 cases stage III, 25 cases stage IV). Twelve cases (10 unresectable cases, 1 hepatic metastasis case, 1 recurrent case) were treated with intra-arterial infusion chemotherapy using implantable Drug Delivery System, combined with angiotensin-II to increase the concentration of anti-cancer agents in cancer tissue. Twenty-four cases (70%) died in less than one year, so operation is not effective except for curative resection of cholangioma and duodenal papilla cancer. But exploratory laparotomy or inoperable cases given intermittent transcatheter arterial infusion chemotherapy (5-FU + ADM + MMC + angiotensin-II), showed favorable results (decrease of tumor size and pain in 2 cases; recanalization of obstruction in choledochus of 1 case). Especially trans-femoral or left subclavian arterial catheterization proved to be effective therapy for possibly giant or recurrent inoperable pancreatic cancer and hepatic metastasis. Using the drug delivery system, the technical approach to arterial infusion therapy and angiography has been readily undertaken. Quality of life has been improved, and course observation of the patient has been possible by imaging diagnosis and multidisciplinary treatment for advanced pancreatic cancer.

[Intra-arterial and intraportal therapy combined with decollateralization in unresectable cholangiocellular carcinoma--a case report].

A 45-year-old man was referred to our hospital due to obstructive jaundice by intrahepatic cholangiocellular carcinoma. At laparotomy, he was assessed as unresectable because of multiple foci in both lobes. Therefore, two catheters connected to implantable access devices were placed in both the hepatic artery and the portal vein following decollateralization using silicone rubber sheeting, in addition to choledochectomy and choledocho-jejunostomy. After the surgical procedure, he underwent chemoembolization twice using Lipiodol, cisplatin, and Gelfoam, and two intraportal infusions of cisplatin at a dose of 50 mg. Moreover, a total dose of 4 g of 5-FU and 20 mg of MMC was administered through the arterial and portal catheters, respectively. Administration of G-CSF was remarkably effective for severe thrombocytopenia, and leukopenia resulted from this active chemotherapy. He is still alive 7 months after the surgical procedure with the regression of the lesions.

[A case of cholangiocarcinoma with marked reduction of tumor after oral administration of UFT].

A 54-year-old male complaining mainly of pain in the right terminal rib area was admitted to hospital for hepatic tumor examination. Cholangiocarcinoma was diagnosed by various imaging techniques, and the patient was started on a program of daily oral administrations of 600 mg of UFT after abdominal arterial injection of 30 mmg of MMC. The tumor continued to decrease in size on CT image during two years of UFT administration. The patient continues to be monitored as an outpatient. A marked reduction in the size of a cholangiocarcinoma was observed in the case, and administration of UFT has proved effective in prolonging life for over two years.

Hepatic perfusion with FUdR utilizing an implantable system in patients with liver primary cancer or metastatic cancer confined to the liver.

Nineteen patients with colorectal adenocarcinoma, three with cholangiocarcinoma, two with hepatocellular carcinoma, and one with carcinoid were treated with hepatic artery infusion chemotherapy. An implantable pump system was used to deliver floxuridine (FUdR), starting at 400 mg for 2 weeks with 2 weeks of rest. Eleven of 15 (73%) measurable patients with colorectal carcinoma responded. Of 6 complete responses, 4 were documented by laparotomy, including 1 with cholangiocarcinoma. Toxicity included dyspepsia and elevated liver function tests in all patients, gastric ulcer in 2, cholecystitis in 2, and sclerosing cholangitis in 3. Overall median survival for the colon cancer patients has not been reached at 16 months. Regional disease was controlled in the majority of patients treated with this regimen with acceptable toxicity and good quality of life.

[Combined hepatic arterial infusion chemotherapy with transcatheter arterial embolization and hyperthermia in primary liver cancer].

Intrahepatic arterial infusion chemotherapy (HAI) was performed for 20 hepatocellular cancer (HCC) patients and 7 cholangiocellular cancer (CC) patients. HAI combined transcatheter arterial embolization (TAE) and/or hyperthermia were performed for 10 HCC and 3 CC patients. The effective responses were shown in 6 HCC and 1 CC patients who were treated with HAI-TAE-hyperthermia combination therapy, and 2 CC patients who were treated with HAI-hyperthermia combination therapy. The 1 and 2-year cumulative survival rate was 100% and 33.3%, respectively, for HCC patients treated with HAI-TAE-hyperthermia therapy. The 1 and 2-year survival rate for HCC patients treated with HAI therapy was 19.5%, and 7.3%, respectively. Generalized Wilcoxon test revealed that the survival was favorable for patients treated with HAI-TAE-hyperthermia therapy as compared with patients given with HAI therapy. Almost the same results were obtained in CC patients. These results suggest that the HAI-TAE-hyperthermia combination therapy was favorable for the treatment of advanced liver cancer.

Regional lipiodolized chemotherapy for cholangiocarcinoma associated with oral contraceptives.

We describe a case of cholangiocarcinoma in a young woman, who presented with cholestatic jaundice following oral contraceptive ingestion. Following diagnostic laparotomy she received intra-arterial 'lipiodolized' chemotherapy. Intravenous mitozantrone was given for 2 years and she is asymptomatic, with computed tomographic evidence of tumour response, 27 months after diagnosis. We suggest that this form of treatment is of value for cholangiocarcinoma.

Chemotherapy and radiotherapy of malignant hepatic tumours.

Cure of primary liver tumours remains possible only by surgery and early diagnosis will therefore continue to be important; the value of regular screening of cirrhotic patients for development of HCC by ultrasound scanning and estimation of AFP is now established. Prognosis of irresectable HCC depends largely on the general condition of the patient at the time of diagnosis and is better in the absence of cirrhosis. Radiotherapy has little role in the management of patients with HCC, but benefit with acceptable morbidity may be obtained from parenteral chemotherapy, with doxorubicin or its derivatives used as single agents, or with a combination of 5-FU and methyl-CCNU. There may be advantage from regional therapy given via the hepatic artery and early results from the combination of embolization with arterial doxorubicin are encouraging. The use of radiolabelled antibodies to tumour-related determinants of hormonal manipulation show promise. Worthwhile results from the non-surgical management of peripheral (intrahepatic) cholangiocarcinoma and primary hepatic sarcoma remain scarce. Isolated hepatic metastases from colorectal primaries may be resectable; for those that are not, results from regional chemotherapy with 5-FU or FUDR are encouraging, but cost and high morbidity currently limit more general application.