levoleucovorin and Medulloblastoma

To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas.. From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue.. Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively.. This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms; Child; Child, Preschool; Cisplatin; Cyclophosphamide; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Etoposide; Female; Humans; Leucovorin; Male; Medulloblastoma; Mesna; Methotrexate; Risk Factors; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Vincristine

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Etoposide; Humans; Leucovorin; Medulloblastoma; Methotrexate; Mitolactol; Procarbazine

This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cerebellar Neoplasms; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Etoposide; Female; Follow-Up Studies; Humans; Infant; Leucovorin; Magnetic Resonance Imaging; Male; Medulloblastoma; Methotrexate; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Radiotherapy; Remission Induction; Survival Rate; Vincristine

Between 1975 and 1991, 40 patients with newly diagnosed medulloblastoma were treated at the authors' institutions. After aggressive surgical resection 39/40 (98%) received craniospinal radiation therapy with a local boost to the posterior fossa and other macroscopically involved areas. A group of 29 patients was treated with adjuvant chemotherapy. The five-year actuarial survival and event-free survival were 75% and 65%, respectively. Survival was significantly better for patients treated after 1981 as compared to those treated between 1975 and 1980 (p = .02). Younger age (two to four years) was associated with a better prognosis (p = .02). The extend of resection, Chang-stage, radiation dose to posterior fossa and the use of chemotherapy did not significantly impact on survival and relapse-free survival.

Topics: Actuarial Analysis; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cerebellar Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Female; Germany, West; Humans; Ifosfamide; Leucovorin; Lomustine; Male; Medulloblastoma; Methotrexate; Postoperative Care; Procarbazine; Prognosis; Radiotherapy Dosage; Vincristine

A case of treatment-related leukoencephalopathy is presented. A patient with medulloblastoma was postoperatively treated with craniospinal axis irradiation. One month after irradiation, weekly intrathecal administration of methotrexate was performed 4 times to treat cerebrospinal fluid dissemination of the tumor. Two months after the initiation of intrathecal chemotherapy, the patient became somnolent and developed decerebrate posturing. Magnetic resonance imaging showed diffuse leukoencephalopathy. Positron emission tomography revealed a diffuse decrease in glucose uptake in the deep white matter. Auditory evoked potential also showed diffuse abnormalities, not only in the cerebrum, but also in the brain stem. High dose intravenous leucovorin rescue was attempted without any neurologic improvement.

Topics: Blood Proteins; Brain Damage, Chronic; Brain Diseases; Cerebellar Neoplasms; Cerebrospinal Fluid Proteins; Cerebrospinal Fluid Shunts; Child; Combined Modality Therapy; Cranial Irradiation; Decerebrate State; Diagnostic Imaging; Female; Humans; Injections, Spinal; Leucovorin; Magnetic Resonance Imaging; Medulloblastoma; Methotrexate; Radiation Injuries; Tomography, Emission-Computed; Tomography, X-Ray Computed

Thirteen patients with primary and metastatic CNS tumors have been treated with methotrexate (MTX) using three different approaches: (a) high-dose MTX with leucovorin (LV) rescue; (b) high-dose MTX with carboxypeptidase (CPDG) rescue; and (c) intraventricular administration of low doses of MTX for extended periods (concentration X time [CXT]). Eleven patients had central nervous system (CNS) lymphoma (one primary, one patient had recurrent medulloblastoma, and another patient had metastatic breast carcinoma. All 13 patients received high-dose MTX-LV rescue, while 3 patients were subsequently given MTX-CPDG. One patient received MTX by all three modalities. In patients with CNS lymphomas, complete responses (45%) and partial responses (36%) produced CNS disease-free intervals ranging from 1 to 23+ months. Survival for the complete responders has thus far ranged from 2.5 to 35 months, while the partial responders survived from 3 to 5 months. Two patients failed to respond and survived 2.5 and 3 months. Responses were obtainable with high-dose MTX-CPDG in patients resistant to MTX-LV. One patient who became sensitized to CPDG subsequently responded to MTX by intraventricular CXT administration. Thus, MTX can be effectively administered to patients with CNS tumors by several different approaches.

Topics: Adolescent; Adult; Aged; Brain Neoplasms; Breast Neoplasms; Carboxypeptidases; Female; Humans; Injections, Intraventricular; Leucovorin; Lymphoma; Male; Medulloblastoma; Methotrexate; Middle Aged; Time Factors

A comparison between citrovorum factor (CF) and carboxypeptidase G1 (CPDG1) rescue with respect to cerebrospinal fluid (CSF)-methotrexate (MTX) disappearance was studied in a patient with recurrent medulloblastoma who had a ventriculoperitoneal shunt. CPDG1 rescue resulted in a prolonged CSF-MTX half-life of 16.5-23 hours in comparison with CF rescue where the CSF-MTX half-life was 6.5-7.2 hours. There was a positive clinical response measured by loss of bone pain, increased physical activity, and almost complete clearing of CSF blast cells. CPDG1 rescue after high-dose MTX may provide more intense and selective treatment for meningeal neoplasms.

Topics: Adolescent; Brain Neoplasms; Carboxypeptidases; Drug Interactions; Drug Therapy, Combination; Humans; Kinetics; Leucovorin; Male; Medulloblastoma; Methotrexate

Eleven patients with brain tumors recurrent after surgery and radiation therapy were treated with high-dose methotrexate (MTX) (300-500 mg/kg) with citrovorum factor rescue (CFR). MTX was given as an iv infusion over 4 hours followed 2 hours later by oral CFR (10 mg every 6 hours X 12). MTX levels were measured in the serum, lumbar cerebrospinal fluid (CSF), and ventricular CSF at 0, 4, 12, 24, 48, and 72 hours from the start of the MTX infusion. MTX concentrations of greater than 10(-6) M were measured in the CSF over a period of 24 hours after the iv infusion. Peak CSF concentrations reached were greater than 10(-5) M. After the response to high-dose MTX with CFR was evaluated, vincristine (1.5 mg/m2) and a nitrosourea (methyl-CCNU or BCNU) were added to this treatment regimen. Two of four patients with recurrent pontine glioma and five of seven patients with recurrent medulloblastoma had favorable objective responses to treatment. It is suggested that high-dose MTX with CFR be cautiously considered for the primary treatment of intracranial neoplasms in children with the hope of increasing the cure rate for children with malignant brain tumors.

Topics: Brain Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Glioma; Humans; Leucovorin; Male; Medulloblastoma; Methotrexate; Neoplasm Recurrence, Local; Pons