A prospective randomized evaluation of a compound of tegafur and uracil as an adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization

A prospective randomized trial was conducted to evaluate the efficacy of long-term oral administration of low-dose tegafur combined with uracil as an adjuvant chemotherapy, following transcatheter arterial embolization (TAE) in 40 patients with hepatocellular carcinoma (HCC). Forty eligible patients were randomized into two groups: 20 with TAE plus UFT (a compound of tegafur 200 mg and uracil 448 mg per day) and 20 with TAE alone. A good necrosis rate or decrease in size of more than 70% of the original tumor mass was attained in 10 by TAE plus UFT arm and in 12 by TAE arm alone. As for the "responded" patients, there was no significant difference in the time from tumor response to tumor regrowth between the two groups. The appearance rate of ascites and/or encephalopathy in patients with chemotherapy was slightly higher than that in control patients. The median survival time was 22.7 months for TAE plus UFT arm and 28.2 months for TAE arm alone. There was no significant difference in the cumulative survival curves. In conclusion, these results indicated no substantial benefit for this chemotherapy regimen, as an adjuvant therapy for patients with HCC during repeated TAE.     

Transcatheter arterial embolization of hepatocellular carcinoma using CO2-US

Enhanced ultrasonography under the injection of microbubbles of carbon dioxide into the hepatic artery (CO2-US) contributed to the treatment of hepatocellular carcinoma in the selection of indication of transcatheter arterial embolization (TAE). Judging from the accumulation of the lipiodol after TAE with the combination of lipiodol, TAE was thought to be effective in the tumor which was enhanced by CO2 microbubbles more strongly and the enhancement was prolonged more longer compared to the surrounding parenchyma, even the tumor had no tumor staining on the hepatic angiography. In none of the tumor which had no enhancement, TAE was effective. In most of the tumor with isoenhancement compared with surrounding parenchyma TAE was not effective.     

A case of renal pelvic cancer with recurrence of liver metastasis showing partial response by injection of methotrexate and intraarterial infusion of cisplatin and pirarubicin

The patient was a 71-year-old man who had been diagnosed as having a left renal pelvic cancer with liver metastasis. We performed total left nephroureterectomy with lymphnode cleaning and partial resection of the liver. Because abdominal CT 5 months after the operation revealed multiple metastasis of the liver, we performed chemotherapy with a regimen consisting of methotrexate 50 mg (intravenous injection), cisplatin 30 mg and pirarubicin 20 mg (intraarterial infusion), and leucovorin 3 mg (intramuscular injection), three times at intervals of 6 hours. Ten days after chemotherapy, CT revealed the disappearance of most of the liver metastatic lesions, and a partial response was obtained. We are now performing the regimen at an interval of a month to a month and one-half to control the metastatic lesions.     

Zinc metabolism after transcatheter arterial embolization for hepatocellular carcinoma

BACKGROUND/AIMS: Zinc metabolism after transcatheter arterial embolization (TAE) was studied in 15 cases of hepatocellular carcinoma (HCC) with liver cirrhosis (LC). METHODOLOGY: Serum zinc concentrations, 24-hr urinary excretion of zinc, blood ammonia (NH3) and plasma endotoxin (Et) levels were measured before and one, three and seven days after TAE. RESULTS: Serum zinc levels one day after TAE were decreased (p<0.05) as compared to those before TAE and then returned to pretreatment values three days or more after TAE. Urinary excretion of zinc increased (p<0.01) one day after TAE, but then returned to the pretreatment value three days after TAE. Although blood NH3 and plasma Et levels increased (P<0.05) the day after TAE, these parameters recovered on the third day. CONCLUSIONS: Decrease in the serum zinc concentration after TAE is considered to be due to changes in the zinc distribution in the body associated with endotoxemia, as well as increased urinary zinc excretion.     

Hepatic arterial infusion chemotherapy (HAI) for advanced hepatocellular carcinoma inefficacious with transcatheter arterial embolization (TAE)

For 6 patients with advanced hepatocellular carcinoma (HCC) in whom TAE was inefficacious, we tried hepatic arterial infusion chemotherapy. 5-FU 500 mg/day + CDDP 10 mg/day was administered during 5 days. The AFP level was decreased for 4 patients, and 2 patients showed a partial response in CT image. These 2 patients have been alive over 22 and 18 months, respectively. These results suggest that 5-FU + CDDP HAI might be a useful treatment of HCC inefficacious with TAE.     

Effect of 5-fluorouracil and UFT on experimental liver metastasis model of colorectal cancer using mouse colon 26 cells

Effects of 5-fluorouracil (5-FU) and UFT on an experimental liver metastasis model were compared at equi-effective dosage levels against subcutaneous tumor of mouse colon 26. 5-FU at the dosage level of 40 mg/kg suppressed the subcutaneous tumor growth by 70.0% and 45.0% on day 13 and day 18, respectively, and UFT at 20 mg/kg provided almost equal suppression (63.0% and 48.0%). In the liver metastasis model, 5-FU at 40 mg/kg showed more potent prevention of the formation of metastatic foci (94.9%) than did UFT (60.4%) at 20 mg/kg. 5-FU at 40 mg/kg produced a much higher peak serum level of 5-FU than did UFT at 20 mg/kg and also showed a much higher AUC (area under the curve) level in the portal blood. These results suggest that oral administration of 5-FU might be useful in prevention of liver metastasis of colorectal cancer.     

A case of untreatable progressive bladder carcinoma effectively treated by single administration of tegafur and uracil

Bloody urine was grossly observed and multinodular shadow confirmed in both lungs of an 81-year-old male, who had been referred to our department. The diagnosis was bladder cancer (TCC, G3, T4N3M1) from detailed examination. With his advanced age and lowered ADL, the family did not wish for aggressive treatment, so no combination multidrug chemotherapy was attempted. Instead he was given 300 mg/day UFT per os. After 4 weeks administration, the metastatic focus decreased and tended to contract; at the same time gross observation revealed no more bloody urine. Moreover, following 7 weeks of administration, the bladder tumor disappeared, the lung metastatic focus showed overall shrinkage of over 50%, the lymph node metastasis also was more than 50% less, and the case was considered to be PR. The literature reveals UFT was efficacious in only 2 other cases of progressive bladder carcinoma. Since UFT has fewer complications, such as myelosuppression, among antitumor agent, it is considered worth trying in cases where intensive treatment is not feasible.     

Bone metastases responsive to pamidronate therapy in breast cancer

A 66-year-old woman with locally advanced and metastatic breast carcinoma received combination chemotherapy, which comprised mitomycinC (total 84 mg) and anthracyclines (total : epirubicin 350 mg and pirarubicin 450 mg). She had been alive without tumor progression for more than one year thanks to these chemotherapies. Nevertheless, she thereafter complained of severe bone pain due to progression of bone disease. Since morphine administration could not give her sufficient pain relief, we tried to treat her bone pain with pamidronate in a dose of 30 mg weekly or biweekly. The pamidronate markedly relieved her bone pain and improved osteolytic bone lesions. In conclusion, pamidronate therapy can be a promising therapeutic modality for bone-derived pain in terminal patients.     

Induction of gene expression of antibacterial proteins by chitin oligomers in the silkworm, Bombyx mori

A 71-year-old male with advanced gastric carcinoma with paraaortic lymph node metastases underwent distal gastrectomy. Cisplatin (CDDP) 50 mg/body was administered intravenously (i.v.) on day 1 followed by the administration of 5-fluorouracil 500 mg/body/day i.v. on day 2 through day 7. After two courses of this regimen, further enlargement of paraaortic lymph nodes was revealed by CT scan, and chemotherapy was suspended. Multiple liver and lung metastases were diagnosed 6 months after initial diagnosis, and mitomycin C (MMC) 10 mg/body i.v. was administered on day 1 followed by CDDP 50 mg/body i.v. on day 2. After three courses of this regimen, partial response of the liver metastases and complete response of the lung metastases were observed, and the general condition was markedly improved without any adverse effect except slight nausea. Though the patient died of brain metastases one year after initial diagnosis, the combination chemotherapy with MMC and CDDP was nevertheless thought to improve his quality of life.     

The incidence of solitary pulmonary metastasis from carcinoma of the large intestine

Two hundred and two consecutive patients who underwent resection of an adenocarcinoma of the colon or rectum from January 1958 to December 1972 were evaluated for the development of a metastatic tumor in the lungs. In the 185 patients who survived the 30 day postoperative period, 30 malignant pulmonary lesions were subsequently recognized. Six of these were a solitary lesion and 24 were multiple lesions. Three of these malignant lesions were proved to be other than metastatic disease. Metastatic adenocarcinoma from the colon or rectum was proved to be present in 27 patients, an incidence of 14.5 per cent. Only four of these lesions were solitary, 14.8 per cent of the metastatic pulmonary lesions. The solitary metastatic tumors represented an incidence of 2.1 per cent in this patient population, but long term tumor-free survival was possible with appropriate pulmonary resection of the metastatic disease. It is suggested that periodic roentgenographic examination of the chest, every four to six months, be an integral part of the postoperative follow-up study carried out on these patients.     

Type-oriented intraoperative and adjuvant chemotherapy and survival after curative resection of advanced gastric cancer

Recent observations and our experience that histologic types of gastric cancer related significantly to patterns of recurrence prompted us to develop intraoperative and postoperative chemotherapy based on the preoperatively diagnosed histologic types of cancer and to evaluate its effectiveness by a prospective randomized trial. This chemotherapy regimen consisted of the intraoperative administration of mitomycin C (MMC) and postoperative administration of cisplatin (80 mg/patient, day 14), and tegaful and uracil (UFT) (300-600 mg/day for 2 years). Patients with a diffuse type of cancer were randomly assigned to one of three treatment groups: no intraoperative chemotherapy and UFT 300 mg/day (P0 group, n = 16); intraoperative chemotherapy and UFT 300 mg/day (P1 group, n = 13); or UFT 600 mg/day (P2 group, n = 17). Patients with an intestinal type of cancer were randomly assigned to one of three treatment groups: H0 (n = 17), H1 (n = 12), and H2 (n = 12); each group was subjected to the same protocols as the P0, P1, and P2 groups, respectively, except for the MMC administration route. MMC (10 mg/patient) was administered intraoperatively into the intraperitoneal cavity (P1 and P2 groups) or the portal vein (H1 and H2 groups). All patients underwent curative resection. Background factors did not differ significantly among the treatment groups. The overall survival rates were progressively worsened in the order of P2, P1, and P0 or H2, H1, and H0, respectively. The survival rate of the P2 group was statistically higher than that of the P0 group (p < 0.05). The intermediate-term survival rate of the P2 group or H2 group was significantly higher than that of the P0 group (p < 0.05) or H0 group (p < 0.05), respectively. These results suggest the effectiveness of this therapy and the possible eradication of potential micrometastatic foci outside the surgical field by the direct administration of chemotherapeutic agents to the predicted recurrence site.     

Successful treatment of recurrent multiple lung metastasis from colon cancer with combination chemotherapy using methotrexate, 5-fluorouracil, and high-dose leucovorin: a case report

A 66-year-old man, who had received sigmoidectomy for sigmoid cancer in 1985, was diagnosed as having multiple lung and liver tumors in September 1988. When celiac-angiography was performed, recurrent liver metastases from sigmoid cancer were suspected and he received a transarterial embolism with ADM 30 mg and MMC 20 mg. In addition, he was treated with a sequential chemotherapy with methotrexate (MTX), 1,200 mg intravenously (6 h-infusion) followed by 5-fluorouracil (5-FU), 600 mg/m2/day and leucovorin, 300 mg/body/day in continuous infusion for 5 days from day 2 with concomitant oral administration of dipyridamole (300 mg/day) over 14 days. Treatment was repeated every 28 days for two courses. For the third course, administration of only 5-FU, leucovorin and dipyridamole was performed. As a result, the size of pulmonary lesions was prominently reduced on computed tomography. Although mucositis, anal erosion, diarrhea and thrombocytopenia were noted, no severe side effects were observed. This sequential chemotherapy appears useful for metastatic lesions from colon cancer.     

Lipiodol avidity of neuroendocrine liver metastases

AIMS: Lipiodol has been shown to concentrate in most hepatocellular carcinomas as well as in some liver metastases, including those of neuroendocrine origin. Our aim was to determine the proportion of neuroendocrine liver metastases that take up lipiodol and to identify tumour characteristics that predict avidity. METHODS: Avidity was assessed in 12 patients with neuroendocrine liver metastases by performing an abdominal CT scan immediately after selective hepatic arterial injection of 5 ml of unlabelled lipiodol and this was correlated with number and size of lesions as well as angiographic and plain CT scan features. RESULTS: In seven patients the tumours displayed lipiodol avidity (four solitary, three multiple); five patients had non-avid lesions (all multiple). A large dominant liver tumour was the only predictor of avidity (mean diameter of largest lesion 9 cm vs. 3 cm for patients with non-avid tumours: P=0.01). Avidity was not related to vascularity or CT density of lesions. CONCLUSIONS: Although this is a small study, it would appear that approximately 50% of neuroendocrine liver metastases selectively concentrate lipiodol, which could have implications for targeted cancer therapy.     

Usefulness of enhanced US by CO2 microbubbles for segmental-subsegmental TAE for hepatocellular carcinoma

Enhanced US by intraarterial infusion of CO2 microbubbles is useful for segmental to subsegmental TAE of hepatocellular carcinoma for several reasons. First, we can obtain better recognition of the tumor stain of hepatocellular carcinoma which is even faint on DSA. Secondly, we can recognize the co-relation between tumor stain and its related segment or subsegment well. Therefore, subsegmental or segmental TAE can be performed easily and precisely using enhanced US by CO2 microbubbles. We noted the bigger advantage of enhanced US by CO2 microbubbles especially in the repeated treated cases of TAE for hepatocellular carcinoma.     

Cisplatin and epirubicin plus oral lonidamine as first-line treatment for metastatic breast cancer: a phase II study of the Southern Italy Oncology Group (GOIM)

Lonidamine (LND) is a unique antineoplastic drug derived from indazole-3-carboxylic acid which inhibits oxygen consumption and aerobic glycolysis, interfering with energy metabolism of neoplastic cells. LND has been experimentally shown to potentiate the cytotoxic effects of epirubicin (EPI) in human breast cancer cell lines, cisplatin activity in both platinum-sensitive and -resistant human ovarian carcinoma cell lines, and EPI antineoplastic activity in some recent phase III trials carried out in advanced breast cancer. A multicenter phase II trial was carried out with the combination of cisplatin 60 mg/m2, EPI 100 mg/m2 and LND 450 mg/day p.o. in three refracted doses/day starting 2 days before cisplatin and EPI (day -2 and -1), stopping 2 days after chemotherapy (day 0, +1 and +2). Thirty patients with metastatic breast cancer were enrolled into the study. Twenty-nine patients were evaluable for objective response. The overall response rate accordingly to an intent-to-treat analysis was 73% (95% CL 54-88%). Four patients achieved complete response (13%; 95% CL 4-31%) with a median duration of 9.5 months (range 4-16) and 18 patients had partial response (60%; 95% CL 41-77%) with a median duration of 9.8 months. Stable disease was obtained in five cases (17%) and progressive disease was recorded in three patients. One patient died of progressive cancer before restaging. The overall median survival of the whole series of patients was 14+ months. The most frequent toxicities were represented by gastrointestinal and hematological side effects. The combination of cisplatin + EPI plus oral LND is active against metastatic breast carcinoma. The antineoplastic activity of the cisplatin + EPI + LND regimen is as high as that reported for more aggressive regimens such as the fluorouracil + doxorubicin + cyclophosphamide combinations without an increase in toxic effects.     

Correlation of cytologic and pathohistologic findings in ultrasonically-guided thin-needle biopsy of abdominal and retroperitoneal organs

A 71-year-old woman with loss of appetite was referred to our hospital. Imaging diagnosis revealed a large, cystically dilated left kidney with a solid tumor inside the cavity and right hydronephrosis. A chest X-ray revealed multiple metastatic lesions. A horseshoe kidney was found intraoperatively and left nephroureterectomy with partial cystectomy was performed. Histological diagnosis was poorly differentiated transitional cell carcinoma. She died of progressive pulmonary metastases 2 weeks after operation. This is the 19th case of a renal pelvic tumor associated with a horseshoe kidney reported in the Japanese literature. The diagnosis was confounded by the extreme dilation and deformity of the hydronephrotic kidney.     

Intraperitoneal chemo-hyperthermia with mitomycin C in cancer of the stomach with peritoneal carcinosis

We report 42 cases of gastric cancer with peritoneal carcinosis treated with intraperitoneal chemohyperthermia. Intraperitoneal chemohyperthermia was achieved with a closed sterile circuit containing mitomycin C, 10 mg/l producing an input temperature varying from 46 to 49 degrees C for 90 minutes. There were three postoperative deaths: one pulmonary embolism at day 4, one multiple organ failure et day 4, and one septic shock at day 25 due to a colonic fistula. Two patients suffered complications: one opening of the duodenal stump requiring reoperation on day 5, and one prolonged postoperative ileus lasting to day 10. Of the 12 patients with ascites, resorption was achieved in 8. In patients with early-stage peritoneal carcinosis (granulations less than 5 mm) survival at 1, 2 and 3 years was 90%, 61% and 41% respectively. For those with more extensive carcinosis, survival at 1 year was 10%. Five patients survived more than 30 months, three have survived to 34, 43 and 73 months. Intraperitoneal chemohyperthermia is a new treatment for carcinosis of gastric origin. These early results must be assessed further with larger controlled.     

A changing psychiatry for the future

A 66-year-old man presented with an epigastric tumor demonstrated by both ultrasonography and computed tomography as hepatocellular carcinoma. He referred himself to a specialist at another hospital who performed transarterial embolization (TAE) of the hepatic artery. But the serum alpha fetoprotein (AFP) concentration gradually rose after the procedure. A right adrenal metastasis was discovered by computed tomography 9 months after his presentation, 8 months after first embolization. When TAE was performed for this metastasis, there was transverse palsy of the lower limb secondary to spinal artery embolization. He returned to our hospital where a right adrenectomy was performed 14 months after his first presentation. The operation was successful and he was discharged 6 weeks later. But he was readmitted in 8 months with an elevated serum AFP concentration and died within 2 weeks. The details of this case are presented, and the indications for resection of adrenal metastasis from hepatocellular carcinoma are discussed.     

Chylous ascites following heart transplantation

BACKGROUND: Hepatocellular carcinoma is highly refractory to most chemotherapeutic agents. Clofazimine, a riminophenazine compound used to treat leprosy since 1962, inhibits various cancer cell lines, including hepatocellular carcinoma cell lines, via phospholipase A2 dependant processes. Clofazimine also inhibits p170-glycoprotein, the mdr1 gene product. PATIENTS AND METHODS: Thirty patients (26 males and four females) with unresectable (25) or metastatic (5) hepatocellular carcinoma received oral clofazimine 600 mg daily for two weeks, followed by 400 mg daily until progression or death. RESULTS: There were three responses (10%)--one of a soft tissue metastasis, and two of local disease, with 13 patients disease stabilizing for up to 20 months. The overall median survival was 13 weeks. Adverse events included hyperpigmentation, eczematous skin rashes and palpitations. CONCLUSIONS: Although only three patients had an objective response (10%), the 13 patients with stable disease for up to 20 months, and an overall median survival of 13 weeks, suggest that clofazimine, or other riminophenazine compounds may prove to be of value in hepatocellular carcinoma.     

Hepatic embolization through extrahepatic collateral pathways after hepatic arterial embolization for the hepatocellular carcinoma

Extrahepatic collateral pathways developing after repeated transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) make therapeutic arterial embolization for recurrent lesions extremely difficult. TAE was performed through the collateral pathways using a sophisticated micro-catheter with good trackability and pushability and a coaxial system. Twenty-three TAEs were undertaken through the collateral pathways in 13 patients with recurrent HCC who had extrahepatic collateral pathways after the previous hepatic arterial TAE. There were 69 extrahepatic collateral pathways, with partially obstructed hepatic arteries. On the average, three feeding arteries were seen in the liver. The main extrahepatic collateral pathways were the inferior phrenic artery and epicholedocal artery, 18 vessels and 29 vessels, respectively, accounting for about 80% of the total collateral pathways. TAEs were successful in all cases and the number of embolized vessels was 2.1 on average. The average time of the first collateral TAE after the initial conventional hepatic arterial TAE was 2.3 years. Excellent prognosis was observed with a one-year survival rate of 77% and 3-year survival rate of 38% after the collateral TAE. We consider that collateral TAE for recurrent HCC with obstruction of the hepatic artery is the procedure of choice, is technically feasible, and provides better prognosis for the patients.