levoleucovorin and Liver-Cirrhosis

We have previously reported that intra-arterial chemotherapy prolongs the survival of patients with advanced HCC (aHCC); however, whether the response to intra-arterial chemotherapy depends on the etiology of underlying liver cirrhosis (LC) is still unknown.. The aim of this study was to assess any influences of the etiology of LC on the response to combined intra-arterial chemotherapy for aHCC.. A total of 53 adult Japanese LC patients (46 men and 7 women) with aHCC were treated with combined intra-arterial chemotherapy between 2002 and 2007 at our hospital. All of the patients had a Japan Integrated Staging (JIS) score of 3 or 4. Their tumors were inoperable according to computed tomography findings. Combined intra-arterial chemotherapy was administered via the proper hepatic artery every 5 days for 4 weeks and the chemotherapy regimen was continued for as long as possible.. There were 15 patients with HBV infection (B-LC group), 29 patients with HCV infection (C-LC group), and nine patients with alcoholic cirrhosis (A-LC group). The percentage of patients with a complete or partial response after 4 weeks of chemotherapy was 0% in the B-LC group versus 31.0% in the C-LC group and 44.4% in the A-LC group. The survival of the A-LC and C-LC groups was significantly longer than that of the B-LC group with the median survival time being 688, 368, and 211 days, respectively.. Combined intra-arterial chemotherapy might be more effective for aHCC in patients with A-LC or C-LC than in patients with B-LC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Treatment Outcome

Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis and over-expression of VEGF has been detected in hepatocellular carcinoma (HCC). The aim of the present study was to clarify the usefulness of VEGF for monitoring the response to intra-arterial chemotherapy in patients with HCC.. Seventy-three patients with liver cirrhosis (LC) and advanced HCC (aHCC) received hepatic arterial infusion chemotherapy (HAIC: leucovorin (LV) at 12 mg/h, cisplatin (CDDP) at 10 mg/h and 5-fluorouracil (5-FU) at 250 mg/22 h) via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneous drug delivery system.. i) Serum VEGF levels were higher in patients with progressive disease than those in patients with a partial response or stable disease. ii) VEGF levels were higher in patients with alcoholic LC than those in patients with hepatitis C-related or hepatitis B-related LC. iii) VEGF levels were higher in stage IVB patients than those in patients with stage III or IVA disease. iv) VEGF levels were significantly higher in patients with giant or confluent multinodular tumors than those in patients with multiple discrete nodules. v) Serum VEGF levels were higher in patients with vascular invasion than in patients without vascular invasion.. Monitoring the serum VEGF level is useful for predicting the response of aHCC to HAIC, as well as for predicting metastasis, tumor type and vascular invasion.

Topics: Aged; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Treatment Outcome; Vascular Endothelial Growth Factor A

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC).. Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC.. Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC.. The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Predictive Value of Tests; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Treatment Outcome

Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.. C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.. FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.. We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Cycle; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Disease Models, Animal; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Inflammation Mediators; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Oxidative Stress; Serpin E2; Thrombosis

We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC.. Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers.. Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group.. These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Drug Combinations; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Paclitaxel; Retrospective Studies; Survival Rate; Treatment Outcome

Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and α-smooth muscle actin (α-SMA) were conducted with control group. The immunohistochemical stains for CD31 and α-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.

Topics: Actins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Hypertension, Portal; Immunohistochemistry; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Platelet Endothelial Cell Adhesion Molecule-1; Splenomegaly; Thrombocytopenia; Tomography, X-Ray Computed

The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib.. Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m(2) as a 2-hour infusion on day one, and leucovorin 200 mg/m(2) as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m(2) and a 48-hours infusion of 5-fluorouracil 2400 mg/m(2). Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred.. Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response.. In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Organoplatinum Compounds; Paris; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

A 64-year-old woman was introduced to our hospital with liver tumors. Our examination revealed that she had advanced colon carcinoma with multiple liver metastasis. Without symptoms from the primary cancer, she underwent chemotherapy of avastin FOLFOX. After 2 courses of chemotherapy, she suffered ileus and underwent operation. The resected specimen showed marked tumor necrosis and fibrosis, but few tumor cells remained in the primary lesion. We think this was a rare case of suffered ileus because of marked response of chemotherapy in primary colon carcinoma.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Cicatrix; Colorectal Neoplasms; Female; Fluorouracil; Humans; Ileus; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Middle Aged; Organoplatinum Compounds

The coexistence of liver cirrhosis with hepatocellular carcinoma (HCC) and colon cancer (Ca), which is a rare clinical condition, was treated in a liver transplant recipient.. A 46-year-old man, diagnosed incidentally during an ultrasound (US) examination with a 3.5-cm HCC in segment VII related to chronic hepatitis C virus (HCV), was referred for liver resection. He underwent a laparoscopic protocol evaluation for liver cirrhosis. Liver appearance and biopsy of the left lobe showed Child B/C liver cirrhosis. Because he fulfilled the Milan criteria, we suggested an orthotopic liver transplantation (OLT). During protocol colonoscopy, we discovered an ulcerative sigmoid colon Ca. Three weeks after completing the pre-OLT assessment he underwent an OLT and was discharged home on day 9 on an immunosuppressive regimen of Everolimus, Myfortic, and Prezolone. Two months after transplantation, the patient underwent a sigmoidectomy and for nearly 1 month thereafter received chemotherapy for colon Ca (6 cycles of FOLFOX:Folinic Acid+Fluorouracil+Oxaliplatin). One and a half years after OLT, patient was in good condition but presented with an increased alpha fetoprotein (a-FP) without other findings. A couple of months later we discovered a colon Ca recurrence and 3 small liver metastases. Patient underwent a bowel resection with Hartmann's procedure. Almost immediately after the last operation, he was found to suffer multiple myeloma. He underwent chemotherapy for both malignancies with good responses, but a few months later died of severe sepsis.. The relevant literature regarding treatment of liver cirrhosis complicated with HCC and synchronous colon Ca reveals poor and controversial outcomes. Our patient underwent chemotherapy immediately after colon resection in the presence of with a good functioning liver. Although his condition was satisfactory after OLT, the optimal treatment of such complicated patients is as yet uncertain.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Colonoscopy; Fatal Outcome; Fluorouracil; Hepatitis C, Chronic; Humans; Incidental Findings; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Organoplatinum Compounds; Sepsis; Time Factors; Treatment Outcome

We have previously reported that 24-h intra-arterial combination chemotherapy (IACC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, it has also been reported that 5-fluorouracil (5-FU) exacerbates liver damage in patients with liver cirrhosis (LC). The aim of this study was to clarify the hepatotoxicity of IACC in LC patients with aHCC.. Twenty-one adult Japanese patients (20 men and 1 woman) with aHCC and LC underwent IACC between 2004 and 2007 at our hospital. These patients showed multiple partial responses or stable disease, except for five patients who showed no response and three patients with tumors more than 30 mm in diameter. All patients had inoperable disease on the basis of computed tomography (CT) findings. IACC (leucovorin at 12 mg/h, cisplatin at 10 mg/h, and 5-FU at 250 mg/22 h) was delivered via the proper hepatic artery every 5 days for 4 weeks.. Twelve patients were in Child-Pugh class A (group A), and nine were in class B (group B). The Child-Pugh score was significantly increased after chemotherapy compared with before chemotherapy in both groups. Serum albumin was significantly decreased after chemotherapy, and the number of patients with ascites also increased after chemotherapy. Serum type IV collagen and N-terminal propeptide of type III procollagen were significantly increased after chemotherapy, although there was no significant change in serum aminotransferases.. IACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Hepatocellular; Cisplatin; Collagen Type IV; Female; Fluorouracil; Hepatic Artery; Humans; Hyaluronic Acid; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Peptide Fragments; Procollagen; Serum Albumin; Tomography, X-Ray Computed; Transaminases

It is known that tumors develop mechanisms to escape from the immune system and to inhibit antitumor responses. The aim of this study was to retrospectively assess changes of host immunity in relation to efficacy in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy.. Thirty-seven adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 19 adult Japanese patients with chronic hepatitis C diagnosed by pathological examination of liver biopsy specimens. All control patients were stage 1 according to the fibrosis score of Desment.. Ten of the 37 patients (group PR) showed a partial response and 17 of the 37 patients (group SD) showed stable disease, but 10 of the 37 patients (group PD) showed no response. There were no significant differences in the percentage of Th1 cells between any of the groups either before or after chemotherapy. The percentage of Th2 cells was significantly higher in group PD before and after chemotherapy than in the control group (P < 0.05 by Tukey's test). Although there was no significant difference, the percentage of Th2 cells was higher in group SD than in group PR.. The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Female; Flow Cytometry; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunity; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate; Th1 Cells; Th2 Cells; Treatment Outcome

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cells promotes antitumor immunity. However, the immunological features of liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by intra-arterial chemotherapy are still unclear. The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC.. Twenty-one adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 20 adult Japanese patients with chronic hepatitis C diagnosed from examination of liver biopsy specimens. All control patients were over 55 years old and were stage 1 according to the fibrosis score of Desment.. Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. There were no significant differences of Th1 cells between group R and group N either before or after chemotherapy. Although there was no significant difference from group R, group N had a significantly higher percentage of Th2 cells than the control group both before and after chemotherapy (p < 0.05 by Tukey's test).. These results indicate that the Th1/Th2 balance might be a useful indicator of the effect of intra-arterial combination chemotherapy in LC patients with aHCC. Inhibition of an increase of Th2 cells might be important for the efficacy of intra-arterial chemotherapy in such patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Monitoring; Female; Fluorouracil; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Infusions, Intra-Arterial; Interferon-gamma; Interleukin-4; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Lymphocyte Count; Male; Middle Aged; Th1 Cells; Th2 Cells

Topics: Female; Humans; Leucovorin; Liver Cirrhosis; Middle Aged; Pancytopenia; Triamterene