levoleucovorin and Central-Nervous-System-Diseases

The comprehensive use of methotrexate is possible because there is an easy way of reducing the toxic effects of this drug. Effective in the antidotic action are alkalinization of the urine, increasing hydration of the patient, and "rescue" of purine and pyrimidine metabolism in the tissues by use of reduced folates. Only intravenous administration, by means of infusion given over a long period (24 hours or more), results in reliable and reproducible concentrations in the plasma. Oral administration should be abandoned because of the variable resorption and the different concentrations reached in plasma by different individuals. Local administration, such as by intrathecal injection, is useful only when the interval between two succeeding injections is 14 days or more. On the basis of known pharmacokinetic constants, the dose of methotrexate and of citrovorum factor (leucovorin) which will result in the desired concentration in plasma, and possibly also in tissues, can easily be calculated. Use of the principle of concentration X time in dosage calculations will result in the avoidance of giving unnecessarily high doses of methotrexate.

Topics: Administration, Oral; Central Nervous System; Central Nervous System Diseases; Child; DNA; Drug Therapy, Combination; Humans; Infusions, Parenteral; Injections, Spinal; Kinetics; Leucovorin; Leukemia; Methotrexate

Patients with malignant lymphoma, diffuse type, have an unfavorable prognosis when compared to those patients with modular patterns. Prior to the introduction of combination chemotherapy, 50% survival rates for MC-D or PDL-D were about 2 years, HL-D about 1 year. Aggressive combination chemotherapy for advanced MC-D or PDL-D results in complete remission rates of 22-82%, with median survivals of 1-2 years. Patients with localized HL-D are probably curable with radiotherapy alone in 75% of cases. Patients with advanced disease are best treated with intensive combination chemotherapy, achieving a long-lasting complete remission in over one-half of cases, with median survivals now at 1-3 years. Many of these patients are probably cured, central nervous system relapse may now be a concern. The results of treatment of advanced histiocytic lymphoma are now approaching the results reported for advanced Hodgkin disease.

Topics: Antineoplastic Agents; Central Nervous System Diseases; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Humans; Leucovorin; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Methotrexate; Neoplasms; Prednisone; Remission, Spontaneous; Vincristine

To describe the incidence of acute neurotoxicity (NT) in children with lower risk B-precursor acute lymphoid leukemia (ALL) treated with intermediate-dose methotrexate (MTX) or divided dose oral MTX with or without intravenous (i.v.) mercaptopurine (MP) and extended intrathecal triple therapy.. Thirteen hundred four patients were entered onto Pediatric Oncology Group (POG) 9005, a randomized phase III trial, between January 11, 1991 and September 1, 1994. After remission induction, patients were randomized to one of three 24-week intensification schedules: regimen A, MTX 1,000 mg/m2 i.v. infused over 24 hours and MP 1,000 mg/m2 i.v. infused over 6 hours; regimen B, low-dose repetitive MTX 30 mg/m2 orally every 6 hours for six doses and i.v. MP; or regimen C, i.v. MTX alone. Intensification was given every 2 weeks for 12 courses. CNS prophylaxis was age-adjusted intrathecal MTX (ITM). In August 1992, the CNS prophylaxis was changed to age-adjusted triple intrathecal therapy (TIT). Reports of grades 3 and 4 acute NT were reviewed.. Acute NT was reported in 95 of 1,218 (7.8%) eligible patients treated on POG 9005. The incidence by regimen was regimen A, 46 of 543 patients (8.3%); regimen B, 13 of 354 patients (3.7%); and regimen C, 36 of 321 patients (11.2%) (P < .001). The majority of events were seizures and the median number of days to first occurrence of symptomatic NT after ITM or TIT was 10 to 11 days. Computed tomography (CT) or magnetic resonance imaging (MRI) evidence consistent with leukoencephalopathy (LE), with or without the presence of cerebral calcifications, was observed in 75% and 77.1 % of symptomatic patients treated on regimens A and C, respectively, but in only 15.4% of symptomatic patients treated on regimen B (P < .001). Factors associated with an increased incidence of NT included increased cumulative exposure with repeated i.v. MTX (regimens A and C v B), increased MTX-leucovorin (LCV) ratio (regimens A and C v B), and choice and timing of TIT therapy. The use of i.v. MP during intensification did not appear to contribute to these complications. The switch to TIT CNS prophylaxis was associated with an inferior overall 4-year continuous complete remission (CCR) (P=.031) when compared with ITM.. Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

Topics: Acute Disease; Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Diseases; Child; Child, Preschool; Female; Humans; Infant; Infusions, Intravenous; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Factors; Tomography, X-Ray Computed

--To ascertain if low-dose multiagent chemotherapy, with central nervous system prophylaxis and antiretroviral therapy, might be associated with increased efficacy and decreased risk of intercurrent infection in patients with malignant lymphoma related to the acquired immunodeficiency syndrome (AIDS).. --A phase II prospective clinical trial, with median follow-up of 33 months.. --Eight university hospitals, within the context of the AIDS Clinical Trials Units, sponsored by the National Institute of Allergy and Infectious Diseases.. --Forty-two patients with AIDS-related malignant lymphoma. All were evaluable for toxicity assessment, and 35 for response.. --A low-dose modification of the M-BACOD regimen (day 1): cyclophosphamide, 300 mg/m2 intravenously (IV); doxorubicin, 25 mg/m2 IV; vincristine sulfate, 1.4 mg/m2 IV; bleomycin, 4 mg/m2 IV; dexamethasone, 3 mg/m2 orally on days 1 through 5; methotrexate, 500 mg/m2 IV on day 15, with leucovorin rescue. Intrathecal cytosine arabinoside (50 mg) to all on days 1, 8, 21, and 28, with radiation therapy to a helmet field to those with central nervous system involvement. Zidovudine for 12 months after completion of four to six cycles of chemotherapy.. --Response rate and number of opportunistic infections.. --Response rate was 51% with a complete response of 46%. Of 16 complete responses, relapse occurred in four, none isolated to the central nervous system. Opportunistic infections occurred in 21% of those receiving treatment. Median duration of survival among all 42 patients is 5.6 months, 6.5 months in 35 patients evaluable for response, and 15 months in patients with complete response. Lower concentration of CD4 cells, history of prior AIDS, bone marrow involvement, and stage IV disease were independently associated with decreased survival.. --Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance may be associated with durable remissions in AIDS-related lymphoma with fewer opportunistic infections than noted in prior reports.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Diseases; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; HIV Seropositivity; Humans; Leucovorin; Lymphoma; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Opportunistic Infections; Prospective Studies; Vincristine; Zidovudine

One hundred thirty-four assessable patients with stage II-IV large-cell lymphoma (LCL) were treated with the combination chemotherapy regimen methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) between July 1981 and May 1986. The m-BACOD regimen substituted moderate-dose methotrexate (200 mg/m2 x 2) for the high-dose methotrexate used in the preceding M-BACOD regimen; all other drugs were administered as with m-BACOD. Eighty-two patients (61%) in the completed m-BACOD trial achieved a complete response (CR). With a median follow-up of 3.6 years, 62 patients (76%) continue in CR. Predicted survivals of 1, 3, and 5 years for the entire m-BACOD group are 80%, 63%, and 60%, respectively, with a 5-year disease-free survival (DFS) of 74% for the patients who achieve CR. The results obtained with m-BACOD are comparable with those obtained in the preceding M-BACOD trial, which now has a median follow-up of 8.0 years. The reduction in methotrexate dosage in m-BACOD patients was not associated with an increased incidence of CNS relapse. Long-term follow-up of the 215 M/m-BACOD patients indicates that the regimens are not associated with an increased incidence of secondary malignancy. Prolonged follow-up also indicates that advanced-stage patients have a persistent rate of late relapse of about 7.0% per year for years 2 to 5 of their follow-up and that stage II patients have an approximate 2.1% per year rate of late relapse. Application of the previously described prognostic factor model to the 215 M/m-BACOD patients from the completed trials identifies a high-risk group of patients with a CR rate and predicted 5-year survival (38% and 24%, respectively) that are significantly worse than those of the group as a whole (65% and 57%, respectively).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Central Nervous System Diseases; Clinical Trials as Topic; Cyclophosphamide; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Recurrence, Local; Prognosis; Remission Induction; Survival Analysis; Time Factors; Vincristine

Thirty-eight adults with acute lymphocytic leukemia (ALL), 24 previously untreated and 14 previously treated, were entered into a study in which sequential, moderate-dose methotrexate and asparaginase were added to vincristine and dexamethasone (MOAD) for remission induction therapy. Eighteen of 24 previously untreated patients (75%) and 11 of 4 previously treated patients (79%) achieved a complete remission (CR). Once in CR, patients were given remission continuation therapy, which included intravenous high-dose methotrexate that was used without prophylactic cranial irradiation and without intrathecal methotrexate because of its potential activity alone as prophylaxis against central nervous system (CNS) leukemia. The median duration of CR was 11.1 mo (range 0.7-55.9+) and median survival 17.0 mo (range 0.4-55.9+) for the 24 previously untreated patients. The median duration of CR was 7.5 mo (range 1.9-55.3+) for the 14 previously treated patients. Only 2 of 24 previously untreated patients (8.3%) developed CNS leukemia at 3.3 and 42.7 mo from start of MOAD. None of the previously treated patients developed CNS leukemia as the initial site of relapse. MOAD is useful as induction therapy for previously untreated adults with ALL, as well as for previously treated patients, and is superior to other regimens that we have used for the treatment of adult ALL.

Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Central Nervous System Diseases; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leucovorin; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Vincristine

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Diseases; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Central Nervous System; Central Nervous System Diseases; Child; Child, Preschool; Electroencephalography; Female; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tomography, Emission-Computed, Single-Photon

Topics: Adenocarcinoma; Central Nervous System Diseases; Colonic Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Nervous System

Most infants with congenital Toxoplasma gondii infection have no symptoms at birth, but many will have retinal disease or neurologic abnormalities later in life. Early detection and treatment of congenital toxoplasmosis may reduce these sequelae.. In Massachusetts since January 1986, and in New Hampshire since July 1988, newborns have been screened for intrauterine infection with T. gondii by means of an IgM capture immunoassay of blood specimens routinely collected for screening for metabolic disorders. Congenital infection is confirmed by assays for specific IgG and IgM antibodies in serum from infants and their mothers. For this study, infants with serologic evidence of infection underwent extensive clinical evaluation and received one year of treatment.. Through June 1992, 100 of 635,000 infants tested had positive screening tests. Congenital infection was confirmed in 52 infants, 50 of whom were identified only through neonatal screening and not through initial clinical examination. However, after the serologic results became available, more detailed examinations revealed abnormalities of either the central nervous system or the retina in 19 of 48 infants evaluated (40 percent). After treatment, only 1 of 46 children had a neurologic deficit (hemiplegia attributable to a cerebral lesion present at birth). Thirty-nine treated children had follow-up ophthalmologic examinations when one to six years old; four (10 percent) had eye lesions that may have developed postnatally (a macular lesion in one child and minor retinal scars in three).. Routine neonatal screening for toxoplasmosis identifies congenital infections that are subclinical, and early treatment may reduce the severe long-term sequelae.

Topics: Antibodies, Protozoan; Central Nervous System Diseases; Follow-Up Studies; Humans; Immunoglobulin G; Immunoglobulin M; Infant, Newborn; Leucovorin; Neonatal Screening; Pyrimethamine; Retinal Diseases; Spiramycin; Sulfadiazine; Toxoplasmosis, Congenital

Thirty-four symptomatic cases of inherited transcobalamin II (TCII) deficiency were analysed in order to determine the frequency and nature of neurologic manifestations. In no instance was there definite evidence of a neurologic disorder at the time of presentation as a young infant. One child of 2 1/2 years transiently lost deep tendon reflexes at a time of suboptimal treatment. A syndrome of mental retardation and other neurologic manifestations was observed in three cases, all with the following in common: (1) an extended duration of illness of 2-17 years; (2) inadequate or not treatment with Cbl; (3) treatment with folic of folinic acid. TCII deficiency rarely if ever presents with neurologic manifestations. However, neurologic disorders can be produced subsequently by improper treatment.

Topics: Central Nervous System Diseases; Folic Acid; Humans; Infant; Infant, Newborn; Intellectual Disability; Leucovorin; Nervous System Diseases; Time Factors; Transcobalamins; Vitamin B 12

Two patients treated with high dose methotrexate otrexate with citrovorum rescue (HDMTX-CF) for osteogenic sarcoma developed the acute onset of neurologic deficits. Prior to the onset of symptoms, one child suffered brief episodes of altered consciousness. Both patients developed hemiparesis and then steadily improved over 72 hours. Laboratory evaluations disclosed normal coagulation parameters and nontoxic serum methotrexate levels at onset of symptoms. Computed tomography in one child disclosed a large low absorption abnormality. This patient represents the first reported case of positive radiologic findings associated with this syndrome. The two patients recovered completely and received further HDMTX-CF without sequelae. This condition may result from transient demyelination or embolic cerebrovascular disease.

Topics: Adolescent; Brain; Central Nervous System Diseases; Child; Female; Femoral Neoplasms; Humans; Leucovorin; Methotrexate; Osteosarcoma; Tomography, X-Ray Computed

Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.

Topics: Adolescent; Adult; Asparaginase; Central Nervous System Diseases; Cyclophosphamide; Doxorubicin; Female; Humans; Leucovorin; Leukemia, Myeloid; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Vincristine

Urinary alkalinization with oral sodium bicarbonate has decreased the incidence of acute nephrotoxicity and subsequent myelotoxicity in 18 adults receiving high-dose methotrexate with calcium leucovorin rescue (MTX-LCV) weekly in doses of 1-7.5 g/m2. Close monitoring of 24-hour serum creatinine and MTX levels can predict patients at risk for serious toxicity. By a prompt (24-36 hours) increase in the LCV dose rate, hematologic and biochemical evidence of myelosuppression has been prevented. Kinetic parameters in serum and lumbar cerebrospinal fluid (CSF) were studied in two patients following iv injection of 3 and 7.5 g/m2 respectively. Lumbar CSF MTX concentrations greater than 1 muM are achieved. The half-life of MTX in the CSF (11.95 hours) is twice as long as the serum half-life. In the presence of carcinomatous meningitis, further delay in the clearance of MTX from the CSF was seen. With weekly MTX-LCV, there have been four objective responses in six patients with non-Hodgkin's lymphoma in CNS relapse, including complete regression in two. It is suggested that therapeutic concentrations can be achieved in the central nervous system following MTX-LCV.

Topics: Adult; Aged; Bone Marrow; Central Nervous System Diseases; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Humans; Hydrogen-Ion Concentration; Injections, Intravenous; Kidney; Kinetics; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Urine