levoleucovorin and Kidney-Failure--Chronic

As pharmacokinetics in patients undergoing haemodialysis is different from patients with normal renal function, it remains unclear whether chemotherapy can be performed safely for patients with haemodialysis as well as those who have normal renal function. Here, we report a case with recurrence of rectal cancer who received FOLFIRI with bevacizumab chemotherapy under haemodialysis, and obtained good tumor control. A 47-year-old woman had undergone haemodialysis for 10 years due to chronic renal failure. At 45 years of age, she received abdominoperineal resection due to rectal cancer (pStage II). Four months after the surgery, liver metastasis was found, for which partial resection of the liver and adjuvant chemotherapy [UFT (400 mg/body)/UZEL (75 mg/body)] were performed. Eighteen months after the liver resection, multiple lung metastases were found. Therefore, intensive chemotherapy using FOLFIRI (CPT-11: 90 mg/m2) with bevacizumab (2.5 mg/m2) was performed. Severe neutropenia (grade 3, 4), but not non-hematologic adverse events such as diarrhea and bevacizumab-specific adverse events, was observed. As she did not recover easily from neutropenia in spite of treatment with G-CSF, a dose reduction of the FOLFIRI regimen was gradually performed. Although chemotherapy was conducted approximately monthly, the tumor response reflected a stable disease 8 months after 8 courses of chemotherapy. We suggest that it is important to investigate the pharmacokinetics of toxic agents such as CPT-11, (SN38) for dose modification, and for the safe and continuous chemotherapy of patients receiving haemodialysis.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Rectal Neoplasms; Recurrence

Topics: Adolescent; Adult; Alkalies; Aminopterin; Animals; Bone Marrow; Bone Neoplasms; Drug Therapy, Combination; Female; Folic Acid Antagonists; Humans; Kidney; Kidney Failure, Chronic; Leucovorin; Leukemia L1210; Methotrexate; Neoplasm Metastasis; Osteosarcoma; Thymidine; Vincristine

Abnormalities of endothelial function are likely to contribute to the accelerated atherosclerotic risk in subjects with end-stage renal disease (ESRD). While folates can improve endothelial function, their role in ESRD has not been fully studied. The objective was to determine the acute and 12 week-effect of folinic acid on endothelium-dependent vasodilation in subjects with ESRD.. Forearm blood flow (FBF) was assessed by strain gauge plethysmography at baseline and after 12 weeks in 34 ESRD patients (57 +/- 14 years). Vascular function was assessed with acetylcholine (ACh), and sodium nitroprusside (SNP). Patients were randomized to receive folinic acid (50 mg i.v. once weekly) or a matching placebo. A subset of 25 subjects also received folinic acid (500 microg/min intra-arterially) or placebo to determine the acute effect on ACh and SNP mediated dilation at the time of the baseline vascular study.. Folinic acid acutely improved the maximum change in ACh mediated FBF (10.0 +/- 2.4 to 12.8 +/- 2.2 ml/min/100 ml, P = 0.017), but did not change SNP responses. Chronic active therapy did not change ACh or SNP-mediated increases in FBF. Folinic acid resulted in a non-significant decrease in homocysteine (21 +/- 6 vs 28 +/- 18 micromol/l, P = 0.16) and diastolic blood pressure was significantly reduced (P = 0.05).. The present study demonstrated that folinic acid acutely improved endothelium-dependent vasodilatation in patients with ESRD suggesting a direct vascular effect. Chronic treatment with folinic acid did not show benefit in endothelial function, but did lower diastolic blood pressure. Further work is required to determine the optimal regime to protect vascular health in subjects with ESRD.

Topics: Acetylcholine; Aged; Atherosclerosis; Endothelium, Vascular; Female; Folic Acid; Forearm; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Nitroprusside; Placebos; Regional Blood Flow; Time Factors; Vitamin B Complex

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy.. Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients.. In a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin.. Folinic acid and pyridoxine i.v. supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse effects attributable to folinic acid treatment were observed during this time.. Intravenous folinic acid therapy (50 mg) once per week associated with pyridoxine supplementation appears to be an effective and safe strategy to normalize plasma tHcy levels in the majority of chronic HD patients.

Topics: Adult; Aged; Erythrocytes; Female; Humans; Hyperhomocysteinemia; Injections, Intravenous; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Pyridoxine; Renal Dialysis; Tetrahydrofolates; Vitamin B 12

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3 h prior to the start of a 4 h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7 L and 30.0 μg·h/mL, respectively. A dose reduction of L-OHP by 30%-50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Renal Dialysis; Stomach Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Renal Dialysis

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Pelvic Neoplasms; Prognosis; Renal Dialysis; Time Factors

A 61-year-old man on hemodialysis due to chronic renal failure caused by diabetes mellitus was diagnosed as having ascending colon cancer with multiple liver metastases. Colonoscopy revealed a Type 2 tumor located in the ascending colon. Abdominal CT showed hepatic tumors in S8 measuring 8×7 cm and in S6 measuring 5×4 cm, with a number of small tumors in the other sites. In order to prevent a hemorrhage from the colonic tumor, laparoscope-assisted right colectomy was performed. Seventeen days after the operation, oral administration of tegafur uracil(300mg/body/day)and calcium folinate(75mg/body/day)was initiated for the treatment of hepatic metastases. After three courses of treatment, size reduction of the hepatic metastases(the S8 4×3. 5 cm and the S6 2. 5×2. 5 cm)was obtained. Although nine months with seven courses of chemotherapy had passed without significant side effects, the size of hepatic metastases increased. Currently, therefore, CPT-11 and cetuximab are being administered as second-line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Neoplasm Staging; Renal Dialysis; Tegafur; Tomography, X-Ray Computed; Uracil

A 76-year-old man with renal dysfunction received FOLFIRI due to a relapse in his pelvis after surgery for sigmoid colon cancer. FOLFIRI was continued for approximately 21 months with stabilization of disease observed on CT scans, but his tumor marker levels increased and tumors showed progression. He then began treatment with cetuximab/CPT-11, but disease progression was observed. XELOX in a low-dose was then administered, but this therapy was discontinued because of progression. He could not receive the other antitumor agents, due to mutations of the KRAS gene and renal dysfunction. Therefore, FOLFIRI was restarted, because it can be continued for long periods of time. Consequently, his tumor marker levels decreased with stabilization of disease on CT scans, and he continued the therapy for 7 months while maintaining quality of life. Ultimately, this case suggested that if there was effectiveness from a previous treatment, retreatment would be successful as chemotherapy for colon cancer in the difficult situation of selecting the other effective antitumor agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Salvage Therapy; Tomography, X-Ray Computed

A 71-year-old man receiving maintenance dialysis because of diabetic nephropathy presented with hematemesis at another hospital in January 2008. A gastrointestinal endoscopy demonstrated a II a-like lesion in the angle of the stomach, and he was admitted to our hospital. A diagnosis of gastric adenocarcinoma (cT2N2M0, Stage IIIA) was made. An operation could not be performed because of the high risk, so combination chemotherapy with 5-FU and l-LV was initiated. After 3 courses of treatment, the size of the primary tumor was markedly reduced. After 6 courses, the primary lesion had changed to a scar, and an endoscopic biopsy revealed no cancer cells. His performance status did not deteriorate, and no serious adverse events occurred during the course of treatment. Chemotherapy was continued because the overall response was SD. 5-FU/l-LV therapy should be considered as a safe and useful treatment for a hemodialysis patient with advanced gastric cancer.

Topics: Aged; Biopsy; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Neoplasm Staging; Renal Dialysis; Stomach Neoplasms

A 58-year-old woman, who was undergoing peritoneal dialysis( PD) for chronic kidney disease (CKD) and had been operated by sigmoidectomy for early colonic cancer, was diagnosed as peritoneal recurrence of the colonic cancer. Her treatment for CKD was switched from PD to hemodialysis. She was administered mFOLFOX6 therapy(reducing the dose to 70%). Hemodialysis was performed 1 hour after administration of oxaliplatin on day 1 and repeated two days later after the completion of drug administration. No serious adverse events were observed. After 10 courses of mFOLFOX6, an ovarian metastasis was appeared. We then changed the regimen to FOLFIRI (70% dose)/bevacizumab (BV). Neutropenia (grade 4) was observed after the second treatment. After some rest, 21 courses of FOLFIRI/BV therapy were performed safely by reducing the dose to 60%. We thought that a reduced dose of FOLFIRI/BV therapy appeared to be safe for a patient with chronic kidney disease who is on hemodialysis.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Middle Aged; Organoplatinum Compounds; Peritoneal Dialysis; Peritoneal Neoplasms

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Rectal Neoplasms; Treatment Outcome

A 68-year-old woman was on dialysis for the treatment of chronic renal failure. FOLFOX 4 therapy was performed following CPT-11+UFT+Leucovorin for liver metastasis after resection of cancer of the sigmoid colon. The dose of oxaliplatin was 40 mg/m2, while 5-FU was given as a bolus of 300 mg/m2, and a continuous intravenous infusion of 500 mg/m2. Hemodialysis was performed 1 hour after administration of oxaliplatin on day 1 and was repeated two days later after the completion of drug administration. Vomiting (grade 2),anorexia and leukopenia (both grade 3) were observed after the first treatment. A total of 4 courses were administered thereafter by reducing the dose of oxaliplatin to 32 mg/m2, the intravenous bolus of 5-FU to 240 mg/m2, and continuous infusion of 5-FU to 400 mg/m2. Measurement of drug concentrations showed that free platinum was immediately eliminated by dialysis. It was considered possible to safely perform FOLFOX 4 therapy in patients with chronic renal failure by reducing the doses and by providing dialysis. It is desirable to measure drug concentrations in these patients. Also,more cases should be monitored to investigate the safe dose,the blood drug concentration profile, and the accumulation of chemotherapy agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Routes; Female; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Platinum; Renal Dialysis; Sigmoid Neoplasms

Haemodialysis patients have elevated levels of the atherogenic amino acid homocysteine. We wanted to assess the effects of small doses of intravenous folinic acid (the active form of folic acid) on some biochemical risk factors of cardiovascular disease.. Longitudinal and open intervention study.. Two dialysis units in the County of Rogaland.. All patients on maintenance haemodialysis were invited, and 32 of 35 patients gave their informed consent.. After each dialysis session, the patients were given 1.0 mg of folinic acid intravenously thrice a week for a period of 3 months. Prior to and during the study, all patients were on maintenance supplementation with small doses of vitamins B1, B2, B3, B5, B6 and B12.. Changes in the levels of (i) plasma total homocysteine (p-tHcy) and folate, (ii) circulating endothelium related proteins--markers of endothelial activation and (iii) serum malondialdehyde (S-MDA)--a marker of oxidative stress and lipid peroxidation.. The p-tHcy levels were reduced by 37% (P < 0.0001), whilst the serum and erythrocyte folate levels increased by 95 and 104%, respectively (P < 0.0001 for both). The circulating levels of endothelium related cellular adhesion molecules and haemostatic factors remained high and unchanged, except the thrombomodulin (TM) levels increased (P = 0.0004). The high levels of S-MDA were reduced by 26% (P = 0.003).. Low doses of folinic acid given intravenously to dialysis patients reduced their levels of p-tHcy and S-MDA and thus improved their cardiovascular risk profile. The concurrent increment in TM levels was unexpected and of unknown clinical significance.

Topics: Creatinine; Endothelium, Vascular; Female; Hemoglobins; Homocysteine; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Leucovorin; Longitudinal Studies; Male; Malondialdehyde; Middle Aged; Mutation; Renal Dialysis; Serum Albumin

5-fluorouracil (5-FU), widely used for chemotherapy of colorectal carcinoma, requires intracellular anabolic conversion to cytotoxic nucleotides and exhibits a narrow therapeutic range with dose-dependent and concentration-dependent effects. 5-FU undergoes extensive metabolic degradation to several catabolites, which are excreted mainly by the kidneys. Alteration of the pharmacokinetics of 5-FU and its catabolites as a result of renal dysfunction might augment systemic toxicity. Because no data are available for patients with severe renal failure, the pharmacokinetic parameters of 5-FU and its catabolites were determined for a patient with colorectal carcinoma and end-stage renal disease on maintenance hemodialysis therapy. Plasma was analyzed by 19F nuclear magnetic resonance spectroscopy for the first 5-day treatment cycle (daily bolus injections of 5-FU for 5 days in combination with low-dose folinic acid). On days 1 and 5, the pharmacokinetic parameters for 5-FU (total area under the plasma concentration-time curve, terminal half-life, total plasma clearance, volume of distribution based on the terminal phase) and its initial catabolite dihydrofluorouracil (total area under the plasma concentration-time curve, terminal half-life) were in the ranges reported in the literature for patients with normal renal function, implying no need for primary dose adjustment. In contrast, the final 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) accumulated to a concentration of 276 micromol/L on day 5 (approximately twofold higher than expected from the literature) despite good removal by hemodialysis with extraction ratios of 0.6 to 0.85 over the filter membrane. Negative effects of FBAL or enhancement of 5-FU-related toxicity could not be judged in this individual case, but further study is warranted to determine the possible benefits of more intensive dialysis treatment.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colonic Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Magnetic Resonance Spectroscopy; Male; Middle Aged; Renal Dialysis

Topics: Folic Acid; Homocysteine; Humans; Kidney Failure, Chronic; Leucovorin

A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.

Topics: Antimetabolites, Antineoplastic; Area Under Curve; Carcinoma, Squamous Cell; Fatal Outcome; Humans; Infusions, Parenteral; Injections, Intravenous; Kidney Failure, Chronic; Laryngeal Neoplasms; Leucovorin; Male; Methotrexate; Middle Aged; Palliative Care; Renal Dialysis; Terminal Care