levoleucovorin and Kidney-Diseases

Methotrexate (MTX) is a highly renal and liver toxicity drug used in hematological malignancy treatment in children and adults. High-dose methotrexate (HD-MTX) therapy may cause impairment of kidney and decrease the elimination of MTX, at the same time, the serum concentration of MTX increased. Today the treatment for preventing MTX toxicity after renal shutdown is Carboxypeptidase. We report a patient who experienced nephrotoxicity after the HD-MTX infusions during the treatment for non-Hodgkin lymphoma (NHL) and received hemodiafiltration (HDF) with large dose of leucovorin (LV) to treat MTX intoxication. LV is very potent in the prevention of neurotoxicity and administration of LV could protect the normal cells, but the dosage and duration of LV should be according to the MTX concentration. Although a large dose of LV was applied, the patient's condition did not improve. It was found that the HDF with large dose of LV to save the patient and steadily improved the patient's clinical condition.

Topics: Antidotes; Antimetabolites, Antineoplastic; Hemodiafiltration; Humans; Kidney Diseases; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Treatment Outcome; Young Adult

Topics: Abnormalities, Drug-Induced; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Hematologic Diseases; Humans; Kidney Diseases; Leucovorin; Liver; Methotrexate; Pregnancy; Psoriasis; Skin

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

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Topics: Acyltransferases; Administration, Oral; Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Dose-Response Relationship, Drug; Drugs, Investigational; Enzyme Inhibitors; Female; Folic Acid; Folic Acid Antagonists; Gastrointestinal Diseases; Humans; Hydroxymethyl and Formyl Transferases; Kidney Diseases; Leucovorin; Male; Middle Aged; Phosphoribosylglycinamide Formyltransferase; Tetrahydrofolates

Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25-80 mg/m2/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Kidney Diseases; Leucovorin; Liver; Liver Neoplasms; Methotrexate; Neoplasms; Nervous System Diseases; Ovarian Neoplasms; Remission Induction; Spectrophotometry, Atomic; Tumor Cells, Cultured; Vinblastine

High-dose folinic acid with 5-fluorouracil (5-FU) is a novel combination chemotherapy used in the treatment of metastatic gastrointestinal cancer. One of the mechanisms of action of 5-FU is its conversion into fluorodeoxyuridylate (FdUMP), which inhibits thymidilate synthetase (TS). The rate of inhibition of TS is augmented by increasing concentrations of folinic acid. On the other hand, it is well known that treatment of animals with high doses of folinic acid results in acute renal failure due to tubular obstruction. In order to find out whether there are similar findings in the clinical setting, we investigated 8 patients (pts.) with metastatic gastrointestinal cancer who were treated with this chemotherapy. We used the following parameters: 1. excretion of four urinary enzymes (LDH, LAP, GGT, NAG); 2. creatinine clearance on days 1 and 5. Therapy consisted of folinic acid 200 mg/m2 i.v. on days 1-5 and 5-fluorouracil 400 mg/m2 on days 1-5. Each treatment cycle was repeated on day 28. We found a constant decrease in the excretion of all 4 enzymes from normal to subnormal values which was statistically significant (p less than .05) during the two treatment cycles. Creatinine clearance decreased about 50% in three patients from normal initial values. In conclusion, during therapy with high-dose folinic acid and 5-fluorouracil we found signs of tubular damage which are similar to those found in folate nephropathy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Kidney Diseases; Leucovorin; Male; Middle Aged

Fifty-three patients with metastatic osteogenic sarcoma were treated with vincristine, high-dose methotrexate with citrovorum factor rescue, and cisplatin. Metastases were surgically removed in most patients, either prior to chemotherapy or following initial response to therapy. Among 29 previously treated patients, responses to initial chemotherapy included two complete remissions, six partial remissions, and eight patients with stable disease. Twenty-three patients were disease-free, six for greater than 12 months. Toxicity was moderate, but usually reversible. There were two toxic deaths and one unexplained death 48 hours following a dose of cisplatin.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Neoplasm Metastasis; Neutropenia; Osteosarcoma; Thrombocytopenia; Time Factors; Vincristine

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

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cerebrospinal Fluid; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Kidney Diseases; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Mucositis; Neoplasm Invasiveness; Prednisone; Proportional Hazards Models; Prospective Studies; Recurrence; Rituximab; Vincristine

The authors present a case of an 18-year-old man with metastasized osteosarcoma, admitted for methotrexate (MTX) treatment combined with cisplatin and doxorubicin. During the first cycle, severe MTX toxicity was observed with increased MTX serum levels and delayed MTX clearance requiring rescue treatment with intensified leucovorin. In the following cycles, cisplatin and doxorubicin were discontinued, and MTX dose was reduced. The elimination half-life slowly improved over the following cycles suggesting a reversible cause responsible for reduced MTX clearance and toxicity during the first cycle. Cisplatin is well-known for its nephrotoxic effects and can induce reversible tubular injury. Previous treatment with cisplatin may well have been responsible for decreased MTX clearance, and combination treatment should be used with adequate monitoring of MTX levels. Other factors that may have contributed, such as urine alkalization, gene polymorphisms, and other drug-drug interactions are discussed.

Topics: Adolescent; Anti-Bacterial Agents; Antineoplastic Agents; Cisplatin; Doxorubicin; Drug Interactions; Female; Humans; Kidney Diseases; Leucovorin; Methotrexate; Morphine; Mucositis; Osteosarcoma

The authors report a case with spontaneous renal hemorrhage caused by invasive mole. The diagnosis was gestational trophoblastic disease (GTD), with metastasis to brain, kidneys, and lungs at Stage IV. The patient was given etoposide-methotrexate-actinomycin D plus cyclophosphamide-vincristine (EMACO) treatment regimen for 11 times including three times with consolidation chemotherapies. Laparoscopically-assisted vaginal hysterectomy (LAVH) + laparoscopic-assisted left renal excision + evacuation of the left perirenal hematoma were performed during the eighth chemotherapy.. Post-operational pathological examination revealed trophoblasts within the lesions present in uterine fundus and the residue images of a few trophoblasts present in the left renal mass.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dactinomycin; Doxorubicin; Etoposide; Female; Hemorrhage; Humans; Hydatidiform Mole, Invasive; Kidney Diseases; Leucovorin; Methotrexate; Pregnancy; Uterine Neoplasms; Vincristine

Aggressive chemotherapy protocols for non-metastatic limb osteosarcoma have improved histological response without affecting prognosis. This study evaluated the toxicity and outcome of a dose-intensive, high-dose 3- to 5-drug pilot protocol, SCOS 89.. The cohort included 26 patients (14 male; ages 6.5-22 years) with non-metastatic limb osteosarcoma treated at a tertiary pediatric medical center between 1989 and 2013. Preoperatively, patients received two courses of once-weekly pulses of high-dose methotrexate (12-30 g/m(2)) for 2 weeks; doxorubicin (90 mg/m(2)) with dexrazoxane, combined with cisplatin (200 mg/m(2)), was added in week 3. Following methotrexate, 760 mg/m(2) of folinic acid was administered. Postoperative chemotherapy was continued to a total of 14 courses of methotrexate, doxorubicin (up to a total dose of 360 mg/m(2)), and cisplatin (up to a total dose of 560 mg/m(2)). If toxicity occurred or <90 % tumor necrosis, ifosfamide (12 g/m(2)) plus etoposide (500 mg/m(2)) was substituted for doxorubicin, cisplatin, or methotrexate. Toxicity and death rates were calculated.. All patients underwent definitive limb salvage surgery. Six patients died of infection, recurrent disease, or secondary malignancy. Median follow-up was 100 months (range 2-290). Event-free and overall survival rates, respectively, were 88 and 96 % at 2 years, 80 and 87.6 % at 5 years, 80 and 78 % at 10 years. Eleven patients required ifosfamide/etoposide substitution. One patient had a transient decreased left ventricular ejection fraction. Two patients developed acute nephrotoxicity during therapy, but no neurotoxicity. Seven patients had hearing impairment.. The SCOS 89 yields a high event-free survival rate with reduced nephro-/neuro-/cardiotoxicity in patients with non-metastatic limb osteosarcoma.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Substitution; Etoposide; Female; Follow-Up Studies; Hearing Loss; Humans; Ifosfamide; Kidney Diseases; Leucovorin; Male; Methotrexate; Osteosarcoma; Pilot Projects; Stroke Volume; Survival Rate; Treatment Outcome; Young Adult

This observational study compares the effect of different radiotherapy techniques on late nephrotoxicity after postoperative chemoradiotherapy for gastric cancer.. Dosimetric parameters were compared between AP-PA, 3D-conformal and IMRT techniques. Renal function was measured by (99m)Tc-MAG-3 renography, glomerular filtration rate (GFR) and the development of hypertension. Mixed effects models were used to compare renal function over time.. Eighty-seven patients treated between 2002 and 2010 were included, AP-PA (n=31), 3D-conformal (n=25) and IMRT (n=31), all 45 Gy in 25 fractions. Concurrent chemotherapy: 5FU/leucovorin (n=4), capecitabine (n=37), and capecitabine/cisplatin (n=46). Median follow-up time was 4.7 years (range 0.2-8). With IMRT, the mean dose to the left kidney was significantly lower. Left kidney function decreased progressively in the total study population, however with IMRT this occurred at a lower rate. A dose-effect relationship was present between mean dose to the left kidney and the left kidney function. GFR decreased only moderately in time, which was not different between techniques. Six patients developed hypertension, of whom none in the IMRT group.. This study confirms progressive late nephrotoxicity in patients treated with postoperative chemoradiotherapy by different techniques for gastric cancer. Nephrotoxicity was less severe with IMRT and should be considered the preferred technique.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Cisplatin; Deoxycytidine; Female; Fluorouracil; Humans; Kidney; Kidney Diseases; Leucovorin; Male; Middle Aged; Radiation Injuries; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Stomach Neoplasms

There have so far been few reports of the pharmacokinetics of oxaliplatin in patients with renal impairment. This report describes the nephrotoxicity induced by repeated cycles of oxaliplatin in a Japanese colorectal cancer patient with moderate renal impairment(creatinine clearance(Ccr): 20-30mL/min). The patient was a 77-year-old male who had chronic renal impairment and received the modified FOLFOX6 repeated every 2 weeks. In cycle 8, the blood concentration of oxaliplatin(66 mg/m2)was measured as the platinum level to confirm the patient's safety. The serum ultrafiltrate concentrations of platinum were 800, 1, 000, 300, <200, and <200 ng/mLat 1, 2, 3 hr, 1 week, and 2 weeks after the start of infusion, respectively, which were closely comparable with the population pharmacokinetic data in Japanese patients with normal renal function. On the other hand, the serum creatinine value was gradually increased after cycle 6, resulting in a decrease of Ccr. The mean Ccr during day 1-59 and day 240-299were significantly different at 26. 5+/-2. 8(mean+/-SD)and 9. 6+/-1. 9mL/min, respectively. Consequently, the chemotherapy showed a complete response after 10 cycles, but the patient got dialysis on day 311. In conclusion, the repeated cycles of oxaliplatin cumulatively damaged the renal function in a Japanese patient with a moderate renal impairment.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Colorectal Neoplasms; Creatine; Fluorouracil; Humans; Kidney Diseases; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Renal Dialysis

To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity.. Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death.. Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity.. Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; gamma-Glutamyl Hydrolase; Humans; Infant; Kidney Diseases; Leucovorin; Male; Methotrexate; Middle Aged; Thymidine

Topics: Endothelium, Vascular; Humans; Hyperhomocysteinemia; Kidney Diseases; Leucovorin; Renal Dialysis; Stroke; Tetrahydrofolates; Vitamin B 12; Vitamin B 6

This study was performed to determine the prognostic factors of 102 nonresectable locally advanced or metastatic gastric cancer patients prospectively treated with a multimodulation of 5-fluorouracil (5FU), hydroxyurea, leucovorin, and cisplatin. Response rate in 85 patients with measurable disease was 62.4% (95% confidence interval 51.9% to 72.9%). A weight increase (5% or more) was observed in 47% of patients, performance status improved in 70.6%, and symptoms disappeared in 69%. Median times for progression-free survival and overall survival were eight and 11 months, respectively. Liver metastases, more than two involved sites, and increased carcinoembryonic antigen (CEA) were found to be univariate adverse prognostic factors for survival. In a multivariate analysis, only the presence of liver metastasis was found to be an independent prognostic factor. Response rate and survival in patients with gastric linitis or diffuse forms were in the same range as in patients with intestinal forms of gastric adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Cisplatin; Disease-Free Survival; Drug Evaluation; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxyurea; Karnofsky Performance Status; Kidney Diseases; Leucovorin; Life Tables; Liver Neoplasms; Male; Middle Aged; Nervous System Diseases; Prognosis; Proportional Hazards Models; Quality of Life; Risk Factors; Stomach Neoplasms; Survival Analysis; Treatment Outcome; Weight Gain

Toxicity from intermediate-dose methotrexate (MTX) is unusual. A severely obese adolescent with acute lymphoblastic leukemia experienced significant, delayed nephrotoxicity from intermediate-dose MTX. Altered MTX disposition may occur as a consequence of other ingestions or conditions such as obesity. The use of radioisotope renography established the diagnosis and followed the resolution of the patient's MTX-induced nephrotoxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radioisotope Renography

Methotrexate nephrotoxicity can lead to delayed methotrexate elimination and the development of life-threatening toxicity, which may not be preventable with the standard rescue agent leucovorin. In preclinical studies, we previously demonstrated that carboxypetidase-G2 (CPDG2) rapidly hydrolyzes methotrexate to nontoxic metabolites. A protocol for the compassionate use of CPDG2 in patients who develop nephrotoxicity while receiving high-dose methotrexate was therefore developed. The pharmacologic and clinical outcome of CPDG2 rescue administered with thymidine and leucovorin in 20 patients is presented here.. Patients with high-dose methotrexate-induced renal dysfunction received one to three doses of CPDG2, 50 U/kg body weight intravenously (i.v.), thymidine 8 g/m2/d by continuous i.v. infusion, and standard pharmacokinetically guided leucovorin rescue. Plasma concentrations of methotrexate and its inactive metabolite 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) were measured before and after CPDG2 using high-pressure liquid chromatography (HPLC). Tolerance of CPDG2 and thymidine, development of methotrexate toxicities, and recovery of renal function were monitored.. Twenty patients who received high-dose methotrexate for osteosarcoma (n = 11), lymphoid cancers (n = 8), and gastric cancer (n = 1) developed nephrotoxicity (median serum creatinine, 3.2 mg/dL) and elevated plasma methotrexate concentrations (median, 201 mumol/L at hour 46). CPDG2 and thymidine rescue was well tolerated and resulted in a rapid 95.6% to 99.6% reduction in the plasma methotrexate concentration. Methotrexate-related toxicity was mild to moderate. Serum creatinine returned to normal values at a median of 22 days.. CPDG2, thymidine, and leucovorin rescue was highly effective in 20 patients at high risk for developing life-threatening methotrexate toxicity after the onset of methotrexate-induced nephrotoxicity and delayed methotrexate excretion.

Topics: Adolescent; Adult; Antidotes; Antimetabolites, Antineoplastic; Carboxypeptidases; Child; Child, Preschool; Female; Humans; Infant; Kidney; Kidney Diseases; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sarcoma; Thymidine

The nephrotoxicity of low-dose methotrexate (MTX) and the rescue effect of leucovorin were studied by electron-microscopic examination of the kidney of guinea pigs. One group received MTX as a single weekly dose of 10 mg/kg, i.p.; a second group received a similar dose divided into three equal fractions. The third group received MTX rescued with an equal dose of leucovorin. The distal convoluted tubule showed cell swelling, fragmentation of the endoplasmic reticulum and loss of mitochondrial cristae and matrix. Leucovorin minimized these changes. The proximal tubule and the glomerulus were not affected. Low-dose MTX induced a nephrotoxicity in the distal convoluted tubule which could be minimized by leucovorin. Mild myelosuppression was also observed.

Topics: Animals; Antidotes; Antimetabolites, Antineoplastic; Blood Cell Count; Bone Marrow; Guinea Pigs; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Leucovorin; Methotrexate; Microscopy, Electron

Urinary N-acetyl-beta-D-glucosaminidase (NAG-ase) activity is a very sensitive parameter of kidney proximal tubular damage. Using urinary NAG-ase activity/urinary creatinine as the NAG index, the serum methotrexate (MTX) level and urinary pH were investigated simultaneously. These parameters were measured in 17 leukaemic children. During MTX treatment, NAG indices were normal in 5 children and only slightly elevated occasionally in 9 patients. Among them, transiently high serum MTX levels (Patient A) or low urinary pH (Patient B) were accompanied by high NAG indices. MTX toxicity has been diagnosed in 3 cases, when permanently high NAG indices were in accordance with other clinical signs.

Topics: Acetylglucosaminidase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Burkitt Lymphoma; Child; Creatinine; Diuresis; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Kidney Tubules, Proximal; Leucovorin; Leukemia; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Proteins; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Twenty-two patients with advanced head and neck carcinoma were treated with 5FU 400 mg-2 m-1 week and folinic acid 500 mg m-2 week-1 plus CDDP in escalating doses from 20 to 40 mg m-2 week-1 without forced diuresis. Reduced glutathione at the dose of 1.5 g m-2 was employed to protect patients from CDDP-related nephrotoxicity. The aims of the study were: a) to evaluate the therapeutic efficacy of this schedule, and b) to evaluate reduced glutathione as uroprotector. Out of 20 evaluable patients 14 (70%) had a major objective response. A CR with a mean duration of 9.0+ months was achieved in 15% of the patients, a PR of 5.8+ months in 55% of the patients, while 3 patients had stable disease and 4 progressed. It was possible to escalate CDDP up to 35 mg m-2 week-1, but at the dose of CDDP 40 mg m-2 week-1 the occurrence of grade 2 renal toxicity provoked a severe reduction of dose-intensity. Overall, this treatment has been very well tolerated by most patients with few cases of grade 3 gastrointestinal or hematological toxicity. In conclusion, the schedule seems effective and may be safely given to patients with advanced head and neck cancer on outpatient basis. Reduced glutathione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Glutathione; Head and Neck Neoplasms; Humans; Kidney Diseases; Leucovorin; Male; Middle Aged

Methotrexate (MTX) is a drug widely used in the treatment of patients with malignant disease. Its well-known side effects include myelosuppression, mucositis and renal damage. These problems are primarily dose-related, tending to occur more frequently when high doses (greater than 1 g/m2) are given. We present four cases in whom severe renal and mucosal toxicity occurred with intermediate doses (200 mg/m2) of MTX despite folinic acid rescue. Possible reasons for this occurrence are discussed and means of avoiding such toxicity are suggested. Three of four patients developed severe loin pain within a few hours of injection; the significance of this symptom in relation to subsequent renal toxicity has implications for early recognition of the problem.

Topics: Adult; Aged; Back Pain; Bicarbonates; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Leucovorin; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Mouth Mucosa; Mouthwashes; Sodium; Sodium Bicarbonate; Stomatitis

Fifteen patients with advanced or recurrent gynecologic malignancy were treated with high-dose methotrexate (HDMTX) (1-8 g/M2) and citrovorum factor rescue (10-100 mg/M2). One complete response (13%) and two improved responses occurred in eight patients (25%) with squamous cell carcinoma and one of seven patients (14%) with nonsquamous nontrophoblastic carcinoma had stable disease for 7 months. The median duration of survival in the squamous group was 9 months and in the nonsquamous groups 6.5 months. Mean serum MTX concentrations were proportional to the doses administered and typical two compartment plasma disappearance curves were seen. Adverse toxic reactions were not observed at serum MTX levels less than 7.8 X 10(-7) M at 24 hr and 1 X 10(-7) M at 48 hr post-MTX. Hematopoietic toxicity occurred most frequently with leukopenia observed in 19.5% of courses. Hepatic, renal, gastrointestinal, and dermatologic toxicities were observed infrequently. Drug-induced nephrotoxicity occurred in one patient and possibly related leukoencephalopathy occurred in another patient. On the basis of the relatively low response rate observed in this trial and the high expense of HDMTX therapy, the value of such therapy may be limited in advanced nontrophoblastic gynecologic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Drug Evaluation; Female; Genital Neoplasms, Female; Hematologic Diseases; Humans; Kidney Diseases; Kinetics; Leucovorin; Methotrexate; Middle Aged; Nausea; Time Factors

Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

Topics: Adolescent; Adult; Child; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Inulin; Kidney Diseases; Kinetics; Leucovorin; Methotrexate; Neoplasms; Thymidine

A new intensive methotrexate regimen for the treatment of advanced squamous carcinoma of the head and neck is presented, employing twice-weekly parenteral low-moderate doses of methotrexate and a single parenteral dose of leucovorin 24 hours following methotrexate. Toxicity and therapeutic results in 20 patients treated with this regimen favorably with results of weekly high-dose methotrexate-leucovorin in 36 patients treated immediately before initiation of the new regimen. Moderate nephrotoxicity and mild gastrointestinal/mucosal toxicity were common to both, while myelotoxicity was rarely seen with the low dose regimen and was more frequent with the high-dose regimen. Partial response was observed in 60% of patients treated on the intensive low-moderate dose schedule, and 50% of patients previously untreated with methotrexate on the weekly high-dose schedule. None of 12 patients previously failing low-moderate doses of methotrexate responded to high doses administered in this trial. The characteristics of antitumor response with low-moderate and high-dose schedules were similar except for the median dose required to attain response (50 mg/m2 vs. 3 g/m2) and the lesser toxicity of intensive lower dose therapy with leucovorin.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Gastrointestinal Diseases; Head and Neck Neoplasms; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Middle Aged; Myeloproliferative Disorders; Prognosis