levoleucovorin and Meningeal-Neoplasms

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Boston; Brain Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Dexamethasone; Doxorubicin; Eye Neoplasms; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Meningeal Neoplasms; Methotrexate; Prednisone; Radiotherapy, Adjuvant; Remission Induction; Time Factors; Treatment Outcome; Vincristine

Radiation therapy has a broad range of applications in the management of patients with non-Hodgkin's lymphoma. It has curative potential for patients with Stage I to II low-grade lymphoma (small lymphocytic, follicular small cleaved, and follicular mixed) and has substantial palliative efficacy in patients with more advanced stage low-grade lymphoma. Low-dose whole-body irradiation may be used as palliative therapy even in patients with bone marrow involvement by these lymphomas. In the management of the large cell lymphomas (diffuse large cell, diffuse mixed, and immunoblastic), radiation alone has curative potential in only the most favorable early-stage presentations. However, since radiation can achieve significant responses in these tumors, it should be considered for inclusion in combined-modality programs. Reports that have appeared in the literature as well as results of treatment at Stanford that bear upon these issues are reviewed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Meningeal Neoplasms; Methotrexate; Mycosis Fungoides; Palliative Care; Prednisone; Radiotherapy Dosage; Skin Neoplasms; Time Factors; Vincristine; Whole-Body Irradiation

To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis.. Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease.. Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF.. This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

Topics: Adult; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leucovorin; Lung Neoplasms; Male; Meningeal Neoplasms; Methotrexate; Neoplasm Metastasis; Osteosarcoma

This retrospective study evaluates the results of a regimen of high-dose intrathecal methotrexate and the prognostic factors for the response in patients with meningeal from breast carcinoma.. From 1979 to 1994, 68 breast carcinoma patients were diagnosed with meningeal carcinomatosis at a mean age of 52 years. All but two had previous metastatic involvement. The proportion of lobular and ductal carcinomas was balanced. Malignant cells were present in cerebrospinal fluid (CSF) samples from 61 patients, whereas the 7 remaining patients had increased CSF protein associated with computerized tomographic scan evidence of meningeal metastases. From 1989, 41 of the patients received a regimen of high-dose intrathecal methotrexate with systemic folinic acid rescue (HD-MTX+FA): intrathecal MTX, 15 mg daily x 5 days, repeated every 2 weeks, and intrathecal hydrocortisone acetate, 125 mg on Day 1, and folinic acid, 10 mg intramuscularly 12 hours after each MTX injection. Systemic treatment and radiation therapy were usually associated. Patients treated before 1988 received intrathecal MTX in conventional doses (15 mg once a week).. Clinical objective response, defined as a neurological improvement for at least one month, was achieved in 17 patients (41%) and stabilization in 14 (34%) treated with the HD-MTX+FA regimen. The response rate was significantly higher compared with that of the group treated with the conventional doses (P = 0.03). Median survival was 14 weeks for patients treated with the HD-MTX+FA regimen, compared with 7 weeks for patients who received conventional doses of MTX (P = 0.01). Grade 3 or 4 neutropenia was the main toxicity that occurred in 16 16 patients (39%) treated with the HD-MTX+FA regimen, and in 7 patients (33%) treated with conventional doses of MTX. In a univariate analysis, three parameters were singled out as having a favorable prognostic value for response to therapy; controlled systemic disease at diagnosis (P < 0.05), low initial CSF protein level (P < 0.05), and concomitant systemic chemotherapy during intrathecal therapy (P < 0.02). Multivariate analysis was not performed because the sample size was too small.. Although this study was retrospective, the intrathecal HD-MTX+FA regimen appears to be a more efficient strategy than conventional doses of MTX to induce neurologic improvement and perhaps better survival. It should be recommended in combination with systemic chemotherapy for selected patients with meningeal carcinomatosis from breast carcinoma who are likely to benefit from intensive therapy, i.e., patients with a CSF protein level less than 5 g/L and in whom systemic disease has been controlled.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Injections, Spinal; Leucovorin; Meningeal Neoplasms; Methotrexate; Middle Aged; Prognosis; Retrospective Studies

A multicenter prospective study was conducted in 114 children with acute lymphoblastic leukemia receiving 4 intravenous methotrexate (MTX) courses (5 g/m2 as a 24 hour-infusion) to determine the diffusion of MTX in cerebrospinal fluid (CSF) and to correlate the drug levels to central nervous system (CNS) relapse occurrence. Serum and CSF levels were measured at the end of 446 MTX courses. A significant correlation was found between CSF and serum MTX concentration. CSF MTX level was greater than 1 mumol/l in 66% of the courses. Twelve patients (11%) failed to achieve this potentially cytotoxic drug level at the end of the 4 consecutive MTX courses: only one CNS relapse was observed and the mean age of these children was lower than that of the others. To date 9 (7.8%) children had CNS relapse and no difference was observed in terms of CSF MTX levels when compared to data of children free of CNS relapse. With a median follow up of 32 months, pharmacokinetic data during high-dose MTX therapy do not seem to be an exclusive predictive factor of CNS relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Blood-Brain Barrier; Child; Child, Preschool; Cytarabine; Female; Follow-Up Studies; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Risk Factors

Using the CCLSG-S811 protocol for children with standard-risk acute lymphoblastic leukemia (ALL), late intensification therapy (LIT) with high-dose methotrexate (HD-MTX) was conducted without randomization. Of 118 eligible patients, 114 attained complete remission and 82 maintained continuous complete remission (CCR) for at least 3 years, completing the entire S811 regimen. Among the latter, 74 patients received LIT with HD-MTX between 2-3 years after CCR onset. MTX (2,000 mg/m2 per dose per week) was administered by 24 h infusion and three doses were given every 12 weeks. Leucovorin rescue (15 mg/m2 i.v.) every 6 h was initiated 12 h after the end of MTX infusion for seven doses. As regular maintenance chemotherapy, intermittent (Regimen A) or continuous (Regimen B) MTX plus 6-mercaptopurine (6MP) combined with pulses of prednisolone and vincristine was administered (Koizumi S, Fujimoto T, Takeda T, et al. Cancer 1988; 61: 1292-1300). Retrospective analysis revealed that patients on Regimen A who started LIT earlier (within 2 years of CCR onset (n = 23)) showed a higher rate of event-free survival (EFS) at 8 years (95.5% +/- 4.4%, mean +/- S.E.) than patients who started LIT later (2.5 years after CCR onset (n = 18, 66.2% +/- 11.3%, p less than 0.01)). In addition, the superiority of four or five courses of the LIT (n = 39) as compared to 2 or 3 courses (n = 35) was noted for both regimens. The data suggest that early and aggressive LIT with HD-MTX may improve the long-term survival of childhood ALL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cranial Irradiation; Humans; Infant; Leucovorin; Life Tables; Meningeal Neoplasms; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Remission Induction; Retrospective Studies; Survival Rate; Vincristine

Radiation therapy has a broad range of applications in the management of patients with non-Hodgkin's lymphoma. It has curative potential for patients with Stage I to II low-grade lymphoma (small lymphocytic, follicular small cleaved, and follicular mixed) and has substantial palliative efficacy in patients with more advanced stage low-grade lymphoma. Low-dose whole-body irradiation may be used as palliative therapy even in patients with bone marrow involvement by these lymphomas. In the management of the large cell lymphomas (diffuse large cell, diffuse mixed, and immunoblastic), radiation alone has curative potential in only the most favorable early-stage presentations. However, since radiation can achieve significant responses in these tumors, it should be considered for inclusion in combined-modality programs. Reports that have appeared in the literature as well as results of treatment at Stanford that bear upon these issues are reviewed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Follow-Up Studies; Humans; Leucovorin; Lymphoma, Follicular; Lymphoma, Non-Hodgkin; Meningeal Neoplasms; Methotrexate; Mycosis Fungoides; Palliative Care; Prednisone; Radiotherapy Dosage; Skin Neoplasms; Time Factors; Vincristine; Whole-Body Irradiation

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bleomycin; Bone Marrow Transplantation; Carcinoma; Cells, Cultured; Child; Cisplatin; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Cytarabine; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Hepatic Artery; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Mechlorethamine; Melanoma; Meningeal Neoplasms; Methotrexate; Neoplasms; Osteosarcoma; Peritoneal Cavity; Pleura

Among all solid tumors breast cancer is the most common cause of meningeal carcinomatosis (MC). The purpose of this study was to analyze clinical and biological responses as well as overall survival in MC patients (pts) of breast primary treated with intrathecal methotrexate (MTX).. Single-center retrospective series of MC pts treated between 2000 and 2007. Chemotherapy regimen was: MTX (15 mg/day; day 1-5) and depomedrol (40 mg, day 1) plus leucoverin (12 mg IV or 25 mg PO; day 1-5). Treatment cycles were repeated every 2 weeks. The survival was analyzed according to the characteristics of the tumor considering clinical and cytological response rates to treatment.. The median survival was 4.5 months (range 0-53). In multivariate analysis, poor prognostic factors at diagnosis were: Performans status greater than 2 [P = 0.006, RR = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra-21-1 level [P = 0.048, RR = 0.09-0.99]. The clinical progression after one cycle and the biological response after two cycles were independently correlated with OS [P<0.001, RR = 0.09 (0.02–0.37) and P = 0.003, RR = 3.6 (1.5–8.5), respectively]. A prognostic score designed to define three groups of patients is proposed.. Although prognosis of patients with MC is poor, 1-year overall survival rate is 25%. The proposed prognostic score may be helpful in decision but warrants further assessment and validation in prospective trials.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Breast Neoplasms; Female; Humans; Leucovorin; Meningeal Carcinomatosis; Meningeal Neoplasms; Methotrexate; Methylprednisolone; Middle Aged; Neuroprotective Agents; Retrospective Studies; Vitamin B Complex

We describe a 61-year-old man with a multiple neurologic complication of Merkel cell carcinoma, a rare skin cancer. An enhancing brain mass, and cytologically proven leptomeningeal disease produced a succession of symptoms including seizures, bilateral radiculopathies, myoclonus, a cauda equina syndrome and altered mental status. Aggressive treatment prolonged his survival marginally.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Merkel Cell; Cytarabine; Fatal Outcome; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Nervous System Diseases; Skin Neoplasms

Radiological and clinical evidence of acute necrosis in a meningioma following one cycle of chemotherapy with 5-fluorouracil, folinic acid, and levamisole was observed in a patient being treated for invasive rectal carcinoma. The possible mechanisms and implications of this occurrence are discussed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Embolization, Therapeutic; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Necrosis; Neoplasms, Multiple Primary; Radiotherapy Dosage; Rectal Neoplasms

Between April 1981 and May 1984, 61 patients with advanced diffuse large-cell lymphoma completed treatment with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), an innovative pilot chemotherapy program emphasizing weekly treatment, antibiotic prophylaxis, daily corticosteroid treatments, and brief duration (12 weeks). Fifty-one patients (84%) achieved a complete response and 10 patients (16%) had a partial response. Over a median follow-up after treatment of 23 months, the actuarial overall survival for the entire group has been 76%; for complete responders the relapse-free survival has been 90%. Toxicity was modest with one treatment-related death and seven episodes of serious infection. The most frequent toxicity was mucositis. Thus, MACOP-B is an effective treatment for large-cell lymphoma that can be delivered in 12 weeks with an acceptable incidence of toxicity. This regimen can achieve results similar and possibly superior to those of other presently used regimens of longer duration.

Topics: Actuarial Analysis; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Arachnoid; Bleomycin; Bone Marrow; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Inflammation; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Mucous Membrane; Neoplasm Staging; Pia Mater; Prednisone; Vincristine

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow; Cyclophosphamide; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Female; Follow-Up Studies; Humans; Leucovorin; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Prognosis; Vincristine

Serum and cerebrospinal fluid (CSF) concentrations of citrovorum factor (CF) and 5-methyltetrahydrofolic acid (5-MTHFA) were measured after i.v. infusion of leucovorin (50 or 100 mg/sq m) in seven patients undergoing treatment for meningeal carcinomatosis by intra-Ommaya reservoir injection of methotrexate (MTX). Serum CF levels rapidly rose after leucovorin administration as did 5-MTHFA, its conversion product. A small amount of CF entered the CSF, but peak CSF 5-MTHFA increased about 10-fold. The concentration X time (C X t) of additional 5-MTHFA in the CSF was greater [114.4 +/- 36.1 (S.E.) microgram/ml X min] after 100-mg/sq m doses of leucovorin than after 50 mg/sq m [14.2 +/- 4.3 micrograms/ml X min] (p less than 0.05). The CSF MTX concentration exceeded CSF 5-MTHFA by 2 to 3 logs throughout the 48 hr of observation, while serum 5-MTHFA and CF exceeded serum MTX by 0.5 to 2 logs. This study demonstrates that leucovorin administered i.v. to patients receiving intra-Ommaya MTX does not increase CSF concentrations of "rescue" folate above those of CSF MTX and are unlikely to interfere with MTX action against meningeal tumor. On the other hand, i.v. leucovorin does permit serum "rescue" folate to operate, thus reducing the systemic toxicity that may follow intraventricular administration of MTX.

Topics: Aged; Carcinoma; Female; Humans; Injections, Intravenous; Injections, Intraventricular; Leucovorin; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Tetrahydrofolates; Time Factors

Forty breast cancer patients with meningeal carcinomatosis were treated with a combined program of whole brain irradiation therapy with intrathecal and intraventricular methotrexate and citrovorum factor rescue. Responses were seen in 26 patients (65%); 13 patients (35%) failed to respond. The median survival time for the responding patients was six months, and for the nonresponders, one month. Factors affecting response and survival included pretreatment spinal fluid glucose, protein, and duration of CNS-related symptomatology prior to onset of therapy. In contrast, pretreatment CSF tumor cell count, CEA and initial CNS functional status did not appear to have prognostic significance. The authors conclude that following intensive therapy there can be much improvement in the quality of life and disease-free survival in breast cancer patients with meningeal carcinomatosis.

Topics: Brain; Breast Neoplasms; Carcinoma; Female; Humans; Injections, Intraventricular; Injections, Spinal; Leucovorin; Meningeal Neoplasms; Methotrexate; Palliative Care; Prognosis; Quality of Life

Subcutaneous cerebrospinal fluid reservoirs (Ommaya) were placed in 27 children and adolescents with acute lymphoblastic leukemia. Eleven of the reservoirs were used for administration of preventive central nervous system therapy and the remaining 16 reservoirs were used in the management of overt meningeal leukemia. Seven of the 11 patients treated prophylactically had recurrence of leukemia. The first site of recurrence was the central nervous system in three (42%) cases. Four of the 16 patients with reservoirs placed for the treatment of overt meningeal leukemia have not had recurrent disease. Of the 12 patients who relapsed, the site of first recurrence was the central nervous system in five cases. The incidence of major complications was 26%.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Cerebral Ventricles; Cerebrospinal Fluid; Child; Cytarabine; Dexamethasone; Drainage; Drug Therapy, Combination; Humans; Infant; Leucovorin; Leukemia, Lymphoid; Meningeal Neoplasms; Methotrexate; Skull

We reviewed 33 cases of meningeal carcinomatosis seen at the Mount Sinai Hospital, New York, from 1970 through 1979. The major sources of meningeal disease were carcinoma of the breast (21 cases), carcinoma of the lung (five), and malignant melanoma (five). Seventy-eight percent of the patients had widespread metastases at the time of neurologic diagnosis. A combination of radiotherapy and intrathecal administration of methotrexate was the most successful treatment, and 14 of 22 treated patients showed at least symptomatic improvement; however, mean survival in the most improved group was still less than six months.

Topics: Adrenal Cortex Hormones; Carcinoma; Female; Humans; Leucovorin; Meningeal Neoplasms; Methotrexate; Outcome and Process Assessment, Health Care; Radiotherapy; Time Factors

Topics: Adult; Drug Combinations; Female; Humans; Leucovorin; Lymphoma; Male; Meningeal Neoplasms; Methotrexate; Middle Aged