levoleucovorin and Liver-Diseases

Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.. We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate.. Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.. Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable.. Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Topics: Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Drug Eruptions; Folic Acid; Gastrointestinal Diseases; Hematologic Diseases; Humans; Immunosuppressive Agents; Leucovorin; Liver Diseases; Methotrexate; Psoriasis; Randomized Controlled Trials as Topic

Capecitabine is a novel oral fluoropyrimidine carbamate that is preferentially converted to the cytotoxic moiety fluorouracil (5-fluorouracil; 5-FU) in target tumour tissue through a series of 3 metabolic steps. After oral administration of 1250 mg/m2, capecitabine is rapidly and extensively absorbed from the gastrointestinal tract [with a time to reach peak concentration (tmax) of 2 hours and peak plasma drug concentration (Cmax) of 3 to 4 mg/L] and has a relatively short elimination half-life (t(1/2)) [0.55 to 0.89 h]. Recovery of drug-related material in urine and faeces is nearly 100%. Plasma concentrations of the cytotoxic moiety fluorouracil are very low [with a Cmax of 0.22 to 0.31 mg/L and area under the concentration-time curve (AUC) of 0.461 to 0.698 mg x h/L]. The apparent t(1/2) of fluorouracil after capecitabine administration is similar to that of the parent compound. Comparison of fluorouracil concentrations in primary colorectal tumour and adjacent healthy tissues after capecitabine administration demonstrates that capecitabine is preferentially activated to fluorouracil in colorectal tumour, with the average concentration of fluorouracil being 3.2-fold higher than in adjacent healthy tissue (p = 0.002). This tissue concentration differential does not hold for liver metastasis, although concentrations of fluorouracil in liver metastases are sufficient for antitumour activity to occur. The tumour-preferential activation of capecitabine to fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phosphorylase, key enzymes in the conversion process. As with other cytotoxic drugs, the interpatient variability of the pharmacokinetic parameters of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine and fluorouracil, is high (27 to 89%) and is likely to be primarily due to variability in the activity of the enzymes involved in capecitabine metabolism. Capecitabine and the fluorouracil precursors 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine do not accumulate significantly in plasma after repeated administration. Plasma concentrations of fluorouracil increase by 10 to 60% during long term administration, but this time-dependency is assumed to be not clinically relevant. A potential drug interaction of capecitabine with warfarin has been observed. There is no evidence of pharmacokinetic interactions between capecitabine and leucovorin, docetaxel or paclitaxel.

Topics: Antacids; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Docetaxel; Dose-Response Relationship, Drug; Drug Interactions; Fluorouracil; Food; Humans; Intestinal Absorption; Leucovorin; Liver Diseases; Paclitaxel; Protein Binding; Taxoids

Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice.. Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient.. Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients. These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance.. Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Bilirubin; Creatinine; Dose-Response Relationship, Drug; Fatigue; Female; Fluorouracil; Humans; Infusions, Intravenous; Kidney Diseases; Leucovorin; Liver Diseases; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia

Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Dehydration; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Infant; Kidney Diseases; Kidney Function Tests; Leucovorin; Liver Diseases; Liver Function Tests; Male; Methotrexate; Neoplasms; Pleural Effusion; Prognosis; Time Factors; Vomiting

The purpose of this study was to evaluate the efficacy of the combination of hepatic arterial infusion therapy and FOLFOX for colorectal cancer with multiple unresectable liver metastases causing severe liver dysfunction.. The subjects were 13 colorectal cancer patients who had undergone resection of the primary tumor, and showed multiple, unresectable liver metastases and severe liver dysfunction. They consisted of 8 men and 5 women, with a median age of 63(29-77)years. Of these patients, 7 and 6 had colon and rectum cancers, respectively. They had an average of 8(3-22)liver metastases of 4.6(1.5-14.5)cm in diameter. During surgery, extrahepatic lesions were found in 3 patients(P in 2, and CY in 1). The preoperative serum LDH and ALP levels were high, at 1,099 (322-1,418)and 1,011(644-2,384), respectively. The follow-up period was approximately 500(248-928)days. Only 5-FU in FOLFOX4 or 6 m therapy was infused into the hepatic artery, and LV and L-OHP were injected into the central venous port about every two weeks. Response rates and adverse events were evaluated according to the RECIST criteria and CTCAE ver 3.0, respectively.. The therapy was performed 14(6-22)times, with a response rate of 84.6% for liver metastases, facilitating hepatectomy in 1 patient. The overall response rate was 61.5%, with 1 patient dying of the primary cancer on the 265th day. Grade 3 adverse events were neutropenia and anorexia in only 1 patient each, and no adverse events were specific to hepatic arterial infusion.. Since the follow-up period after this therapy was still short, only 13 patients have received the therapy. However, it appears that it can be performed relatively safely, and is effective for the control of extrahepatic lesions as well. Therefore, this therapy provides good control, and can be a treatment option.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Tomography, X-Ray Computed; Treatment Outcome

Oxaliplatin has been shown to be valuable in the treatment of patients with colorectal cancer. Many of these patients will develop liver metastases during the course of their disease, with, in some cases, severe hepatic dysfunction. Although single agent oxaliplatin can be administered safely in patients with severely compromised liver function (as it is not metabolized by the liver), little is known of its safety in these patients when administered in the preferred combination with 5-fluorouracil (which is metabolized by the liver) and leucovorin (FOLFOX protocol). We report on a very sick patient with major liver dysfunction, a bilirubin of 11.2 mg/dl (190 micromol/dl) and an open abdominal wound, for whom palliative hospice care alone was originally proposed, who responded dramatically to the combination. His bilirubin fell to 0.6 mg/dl (10.2 micromol/dl) and his liver function tests returned to near normal levels. The combination was well tolerated and clinical improvement continued for more than 11 months before disease progression was observed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

We report a case of rectal cancer with unresectable multiple liver metastases, which was worried about the transition from liver dysfunction to liver failure. The male patient in his 70s was diagnosed as advanced rectal cancer with severe liver dysfunction because of multiple liver metastases. Hepatic arterial infusion (HAI) chemotherapy, which was effective to reduce the size of metastatic liver tumors, was initially started. During HAI chemotherapy, sigmoid colostomy was performed. He recovered from liver dysfunction after he had been treated with 13th cycle HAI chemotherapy. He was treated with the modified FOLFOX6 regimen following a resection of rectal cancer. Although the standard therapy for colorectal cancer with unresectable liver metastases is firstly systemic chemotherapy such as FOLFOX or FOLFIRI, it might be better to control the liver metastases by HAI chemotherapy when a liver function is severely damaged by extensive liver tumors.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms

Bevacizumab (Avastin) in combination with intravenous 5-fluorouracil-based chemotherapy as first-line as well as second-line treatment of metastatic colorectal cancer improves survival. Although skin rash (type unspecified) has been described in some patients following infusion of bevacizumab, it is not a common toxicity of bevacizumab, while acneiform rash occurs in more than 90% of patients who receive cetuximab (Erbitux), the severity of which appears to be predictive of response. We report a patient with colorectal cancer who developed a rash secondary to bevacizumab that correlated with response. A 40-year-old patient with stage IV colorectal cancer received FOLFOX-4 and bevacizumab, which he tolerated very well except for a skin rash related to bevacizumab. The rash cleared every time bevacizumab was eliminated from the chemotherapy regimen. When use of bevacizumab was resumed, similar rash reappeared. Therefore, we believe that this observation of the rash emergence was linked to bevacizumab administration. The most common toxicities associated with bevacizumab include hypertension, hemorrhage, gastrointestinal perforation, arterial thromboembolism, wound healing and proteinuria. Exfoliative dermatitis and a nonspecific rash have been reported with bevacizumab. This case report, we believe, is the first report of a possible correlation between a rash and a positive drug response associated with bevacizumab, and may initiate further investigation of similar observation.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Exanthema; Fluorouracil; Humans; Leucovorin; Liver Diseases; Male; Organoplatinum Compounds; Radiography

Liver cryosurgery is one of the treatment options for unresectable liver metastases. Indications for the use of this treatment instead of classic surgery are bilobar disease, location of the tumor at an irresectable anatomic site, and comorbid conditions of the patient. Possible complications of cryosurgery are hemorrhage, coagulopathy, pneumonia, pleural effusion, abdominal abscess, and bile fistula. We describe a patient in whom a hepatobronchial fistula developed after cryosurgery. The patient had cryosurgery because of an unresectable liver metastasis in a Dukes' C rectal carcinoma. More details are given in the case report. To our knowledge, a hepatobronchial fistula as a complication of cryosurgery has never been reported. It therefore should be added to the list of possible cryosurgery complications.

Topics: Antimetabolites, Antineoplastic; Bronchial Fistula; Carcinoma; Cryosurgery; Fistula; Fluorouracil; Humans; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Postoperative Complications; Rectal Neoplasms; Ultrasonography

Topics: Child; Child, Preschool; Evaluation Studies as Topic; Humans; Infant; Injections, Intravenous; Leucovorin; Liver; Liver Diseases; Methionine; Nucleosides; Vitamins

Topics: Animals; Chemical and Drug Induced Liver Injury; Female; Folic Acid; Hepatectomy; Hydroxocobalamin; Leucovorin; Lipid Metabolism; Liver; Liver Cirrhosis, Experimental; Liver Diseases; Liver Regeneration; Male; Rats

Topics: Adolescent; Adult; Aged; Humans; Leucovorin; Liver Diseases; Methionine; Middle Aged; Niacinamide; Nucleosides; Vitamin B 12

Topics: Biochemical Phenomena; Biomedical Research; Folic Acid; Leucovorin; Liver Diseases