mercaptopurine and Brain-Neoplasms

The authors review and discuss the basic concepts of cell kinetics as applied to brain tumors. Uncontrolled growth of a neoplasm represents an expanding tumor cell population. Four growth parameters characterize the behavior of a neoplastic population: cell cycle time, growth fraction, tumor doubling time, and cell loss. The concept of provisionally nondividing cells explains the disparity between cell cycle time and tumor doubling time. Human gliomas, like many non-neural solid tumors, contain variable proportions of actively proliferating and nonproliferating tumor cells; this ratio is expressed by the growth fraction. The major kinetic difference between glioblastomas and differentiated astrocytomas resides in their respective growth fractions, in all likelihood an inherent biological characteristic of each tumor. Glioblastoma proliferates at a rapid rate, and only a high rate of cell loss prevents this tumor from doubling its volume in less than 1 week. The selection of drugs and design of drug schedules for treatment of glioblastomas should be made with the knowledge that 60% to 70% of the cells in this tumor are resting (nonproliferating). If experience with other solid tumors is any guide, judicious selection and combined use of drugs according to kinetically sound schedules will produce more effective chemotherapy of brain tumors.

Topics: Alkylating Agents; Anti-Bacterial Agents; Antimetabolites; Astrocytoma; Brain; Brain Neoplasms; Cell Survival; DNA, Neoplasm; Glioma; Humans; Kinetics; Mercaptopurine; Mitosis; Neoplasm Metastasis; Prednisolone; Remission, Spontaneous; RNA, Neoplasm; Time Factors; Vincristine

The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkin's lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates.. From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months.. The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity.. The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Infant; Infusions, Intravenous; Injections, Spinal; Lymphoma, Large B-Cell, Diffuse; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Prednisone; Vincristine

This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%.. In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001).. (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Combined Modality Therapy; Female; Glioblastoma; Humans; Karnofsky Performance Status; Male; Mercaptopurine; Middle Aged; Mitomycin; Prospective Studies; Quality Assurance, Health Care; Survival Rate

To assess the effect of treatment intensification and that of extended intrathecal methotrexate substitution for cranial irradiation in intermediate-risk acute lymphoblastic leukemia (ALL) children treated with a Berlin-Frankfurt-Münster (BFM)-based intensive chemotherapy.. Three hundred ninety-six children with non-B-ALL were enrolled onto the Associazione Italiana di Ematologia ed Oncologic Pediatrica (AIEOP) ALL 88 study. Standard risk (SR) included patients with low tumor burden (BFM risk index [RI], < 0.8); intermediate risk (IR) were patients with an RI > or = 0.8 but less than 1.2; and high risk (HR) were those with an RI > or = 1.2 or CNS involvement at diagnosis. The treatment schedule was a modified version of the ALL-BFM 86 study. CNS-directed treatment consisted of high-dose methotrexate (HD-MTX; 5 g/m2 for four courses) plus intrathecal methotrexate (IT-MTX; nine doses); IR patients additionally received extended IT-MTX (nine doses during continuation therapy); cranial irradiation was given only to HR patients.. Of the 375 (94.7%) children who achieved remission, 1.3% had an adverse event other than relapse. The estimated event-free survival (EFS) at 6 years was 66.6% (SE 2.4) overall; 80.7% (4.5) in the SR patients, 77.5% (3.9) in the IR patients, and 54.5% (3.7) in the HR patients. Relapse occurred in 107 children (27.0%). Isolated CNS relapse occurred in 20 children (5.0%): 5 (6.3%) in the SR group, 1 (0.8%) in the IR group, and 14 (7.1%) in the HR group. The estimated 6-year CNS leukemia-free survival was 94.6% (1.2) overall: 93.5% (2.8) in the SR group, 99.1% (0.9) in the IR group, and 92.3% (2.0) in the HR group.. Cranial irradiation may be omitted safely in IR ALL patients treated with BFM-based intensive chemotherapy when extended intrathecal chemotherapy is given. Because the CNS disease control was less complete in the SR group, these data challenge the effectiveness of HD-MTX for protection from CNS disease and support the protective role of extended intrathecal chemotherapy.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Infant; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Regression Analysis; Remission Induction; Survival Analysis; Vincristine

On the basis of response rates of up to 50%, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] is the primary drug used in the chemotherapy of anaplastic gliomas. Preclinical data obtained in several experimental systems show that the cytotoxicity of chloroethylnitrosoureas can be increased by the concomitant use of thiopurines. In this phase I trial, patients with anaplastic gliomas received standard-dose BCNU (200 mg/m2 x 1) in combination with escalating doses of intravenous 6-mercaptopurine (200, 350, 500, and 750 mg/m2 daily x 3), with BCNU being given on day 3 to maximize the effect of the drugs on cellular DNA. No increase in hematologic toxicity was demonstrated as the dose of 6-mercaptopurine was increased. Responses and stabilization of disease were observed in several patients. Due to the safety of and the evidence of activity found for this regimen in the present trial, 750 mg/m2 6-mercaptopurine has been incorporated into subsequent studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Brain Stem; Carmustine; Child; Dose-Response Relationship, Drug; Drug Evaluation; Drug Synergism; Female; Glioma; Humans; Injections, Intravenous; Male; Mercaptopurine; Middle Aged

On study CCG-161 of the Childrens Cancer Study Group (CCSG), 631 children with acute lymphoblastic leukemia (ALL) at low risk for relapse were randomized to receive monthly pulses of vincristine-prednisone (VCR-PDN ) during maintenance therapy in addition to standard therapy with mercaptopurine (6MP) and methotrexate (MTX), and either cranial irradiation during consolidation or intrathecal (IT) MTX every 3 months during maintenance. All patients received six doses of IT MTX during induction and consolidation. With a minimum follow-up time of 4.25 years, 76.7% receiving VCR-PDN were in continuous complete remission at 5 years, in contrast to 63.9% receiving GMP-MTX alone (P = .002). The difference in relapse-free survival was due primarily to bone marrow relapse (P = .0008), and in boys also to testicular relapse (P = .003). Among the nonirradiated patients, the 5-year disease-free survival (DFS) was 79.4% for patients randomized to the VCR-PDN pulses, in contrast to 61.2% for the patients randomized to receive 6MP-MTX alone (P = .0002). Among the irradiated patients, the DFS was not significantly different. Of the four combinations of maintenance and CNS therapy studied, the highest DFS was achieved with VCR-PDN pulses and maintenance IT MTX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Brain Neoplasms; Child, Preschool; Combined Modality Therapy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Spinal; Male; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Random Allocation; Recurrence; Remission Induction; Survival Rate; Testicular Neoplasms; Vincristine

Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bone Marrow; Brain Neoplasms; Central Nervous System Diseases; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Prednisone; Probability; Prognosis; Random Allocation; Testicular Neoplasms; Vincristine

The progressive improvement in the prognosis of acute lymphocytic leukemia has been a result of two major developments: 1) the more efficient use of chemotherapeutic agents, particularly the use of combinations of agents and the discovery that agents effective at one stage of disease may be inappropriate at another stage, and 2) the prevention with irradiation of central nervous system relapse. As many as one-half of children with this disease may enjoy long-term leukemia-free survival. However, further studies are needed to improve the efficacy and reduce the toxicity of therapy. This paper reviews the evolution of some of these studies.

Topics: Age Factors; Antineoplastic Agents; Asparaginase; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Prednisone; Radiotherapy; Remission, Spontaneous; Spinal Cord Neoplasms; Vincristine

Topics: Adolescent; Adult; Blood Transfusion, Autologous; Brain Neoplasms; Child; Child, Preschool; Cobalt Isotopes; Cyclophosphamide; Female; Humans; Infant; Infections; Injections, Intravenous; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Radiation Dosage; Radiation Effects; Remission, Spontaneous; Spinal Cord Neoplasms; Time Factors

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow Neoplasms; Brain Neoplasms; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cranial Irradiation; Cytarabine; Drug Administration Schedule; Female; fms-Like Tyrosine Kinase 3; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Mutation; Nuclear Proteins; Oxides; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Translocation, Genetic; Transplantation, Autologous; Treatment Outcome; Tretinoin; Tumor Suppressor Proteins

Topics: Aged; Antibodies, Monoclonal; Brain; Brain Neoplasms; Crohn Disease; Diagnosis, Differential; Epstein-Barr Virus Infections; Fatal Outcome; Female; Groin; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infliximab; Lymph Nodes; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Magnetic Resonance Imaging; Mercaptopurine; Tomography, X-Ray Computed; Unconsciousness

The effects of vincristine (VC) and 6-mercaptopurine (6-MP) on body weight, regional weights, and the contents of putrescine, spermidine, and spermine in six regions of the brain were examined in rats that had been given these drugs for 5 consecutive days. VC is recommended for management of tumors in the corpus striatum and/or hippocampus, and cortex although its efficacy is dependent on the doubling time of the tumor cells, whereas 6-MP is recommended for the management of tumors in the cortex, thalamus and/or hypothalamus, and diencephalon. VC and 6-MI are chosen for treatment of the brain tumors because they reduce polyamines which are associated with the reduction of drug-sensitive cells and an inhibition of tumor growth.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Chromatography, High Pressure Liquid; Male; Mercaptopurine; Polyamines; Putrescine; Rats; Rats, Sprague-Dawley; Spermidine; Spermine; Vincristine

Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP.. A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment.. A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day.. In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Breast Neoplasms; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Intestinal Neoplasms; Leukemia; Lymphoma, Non-Hodgkin; Male; Mercaptopurine; Middle Aged; Neoplasms; Risk Factors; Time Factors

Extramedullary relapse outside the testes and CNS is rare in children with acute lymphoblastic leukemia (ALL). We describe a case of a recurrence of ALL in the uterine cervix during hematopoietic remission.. Primary recurrence in the uterine cervix was diagnosed by cytology with immunochemistry 43 months after initial diagnosis. She was successfully treated with systemic chemotherapy, without hysterectomy or irradiation. She remains in second complete remission 54 months after relapse.. Immunocytochemistry using monoclonal antibodies against cell surface antigens made the cytologic diagnosis of leukemic relapse in the uterine cervix possible. Systemic chemotherapy is the first treatment of choice for ALL recurrence in the genital tract in a patient without poor prognostic factors in order to spare gonadal function and reproductive potential.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Cyclophosphamide; Daunorubicin; Female; Follow-Up Studies; Humans; Mercaptopurine; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Ultrasonography; Uterine Cervical Neoplasms; Vaginal Smears; Vincristine

We studied the prescription patterns of maintenance therapy for children with acute lymphoblastic leukemia and their association with duration of complete remission. Both 6-mercaptopurine and methotrexate (MTX) were prescribed in doses significantly lower than those recommended (75 mg/m2 daily 6-mercaptopurine; 20 mg/m2 weekly MTX) during maintenance therapy. Of 212 evaluated patients, patients who had relapses (n = 101) received significantly less MTX compared with patients who did not have relapses (n = 111) during the first 2 years of maintenance therapy. In the group of standard-risk patients who received the same induction therapy (n = 92), 11 of 17 who received less than 50% of the recommended MTX dose (64%) and 28 of 75 who received greater than 50% of the dose (37%) had relapses (P less than 0.05). The two groups had comparable periods of interruption of MTX therapy. Further analysis revealed that the lower maintenance dose stemmed from a continuous low prescribed dose and not from more frequent interruption of therapy in relapse. Physicians' inability or failure to adhere to the recommended protocol was associated with a higher relapse rate of acute lymphoblastic leukemia. Improved physicians' compliance may improve the prognosis of the disease.

Topics: Administration, Oral; Brain Neoplasms; Child; Humans; Injections, Spinal; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Practice Patterns, Physicians'; Radiotherapy Dosage; Remission Induction

Twenty-one patients with recurrent malignant central nervous system gliomas were treated with a combination of 5-fluorouracil, CCNU, hydroxyurea, and 6-mercaptopurine. Thirteen patients had brain stem gliomas, 3 patients had spinal cord gliomas, 3 patients had thalamic gliomas, and 2 patients had cerebellar astrocytomas. All patients had received radiation therapy, and 4 brain stem patients had also been treated with chemotherapy. Sixteen patients (76%) responded to treatment with either stabilization of disease or improvement. Nine of the 13 patients with brain stem gliomas (71%) had response or stabilization of disease. The median time to tumor progression (TTP) for the brain stem patients who responded or had stabilization of disease was 25 weeks. The median survival from recurrence for the brain stem glioma patients was 27 weeks. Patients with cerebellar, thalamic, and spinal cord tumors did very well, with an 87% response or stabilization of disease and a median TTP of 122 weeks.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Brain Stem; Child; Child, Preschool; Ependymoma; Female; Fluorouracil; Glioma; Humans; Hydroxyurea; Lomustine; Male; Mercaptopurine; Neoplasm Recurrence, Local; Spinal Cord Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers, Tumor; Blood Proteins; Brain Neoplasms; Doxorubicin; Humans; Mercaptopurine; Methotrexate; Orosomucoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

We prospectively assigned 289 consecutive children with acute lymphoblastic leukemia to receive one of two treatment programs on the basis of the presence or absence of certain risk factors at the time of diagnosis. Patients at high risk (62 percent of the total) had one or more of the following risk factors: age below two or above nine years, a white-cell count of 20,000 per cubic millimeter or more, the presence of T-cell immunologic markers, radiologic evidence of a mediastinal mass, and involvement of the central nervous system. Patients in both the standard-risk and high-risk groups were treated for two years, receiving intensive remission-induction therapy, central nervous system prophylaxis, weekly administration of high-dose asparaginase, and multiple-drug continuation therapy (which in the high-risk group included doxorubicin and a larger dose of prednisone). At a median follow-up of 35 months, the mean (+/- SE) event-free survival rates at four years among the patients in the standard-risk and high-risk groups were 86 +/- 4 percent and 71 +/- 4 percent, respectively (P = 0.003), for a total event-free survival of 77 +/- 3 percent. Within the high-risk group, the white-cell count at diagnosis and the sex of the patient were not significant prognostic indicators, but age below 12 months at diagnosis was associated with a very poor outcome. As compared with previous methods, this treatment program using four-drug induction and intensive asparaginase therapy has resulted in improved event-free survival in children with acute lymphoblastic leukemia.

Topics: Adolescent; Age Factors; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Child, Preschool; Doxorubicin; Drug Administration Schedule; Female; Humans; Infant; Infant, Newborn; Leukemia, Lymphoid; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Neprilysin; Prednisone; Prognosis; Prospective Studies; Risk; Vincristine

The Neuro-oncology Service of the University of California Brain Tumor Research Center conducted a nonrandomized phase II study to evaluate, in patients with recurrent malignant glioma, the benefit of a four-drug combination (BFHM) consisting of carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea), 5-fluorouracil, hydroxyurea, and 6-mercaptopurine. There were 29 evaluable glioblastoma multiforme patients and 45 nonglioblastoma anaplastic glioma patients available for analysis. Tumor progression was analyzed as the primary study endpoint. Of the glioblastoma patients, 16 of 29 (55%) responded or stabilized on therapy; of the other anaplastic gliomas, 32 of 45 (71%) responded or stabilized. For patients who stabilized or responded to treatment, BFHM achieved a median time to tumor progression of 46 weeks with a 25th percentile time to tumor progression of 68 weeks for anaplastic gliomas and a median time to tumor progression of 23 weeks with a 25th percentile time to tumor progression of 36 weeks for glioblastoma multiforme patients. A Cox multivariate analysis demonstrated that age and Karnofsky score were important prognostic variables for these patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Drug Evaluation; Fluorouracil; Glioblastoma; Glioma; Humans; Hydroxyurea; Mercaptopurine; Middle Aged; Neurologic Examination; Statistics as Topic; Tomography, X-Ray Computed

9L rat brain tumor cells were continuously exposed to "low" (2.9 microM) and "high" (18 and 35 microM) doses of 6-mercaptopurine (6-MP); cell kill was measured with a colony forming efficiency assay. The low dose of 6-MP killed more cells than the high doses, as measured by surviving fraction, when they were treated for greater than 48 hours. Even though the total number of cells increased during the 72-hour treatment period, the number of clonogenic cells decreased most when cells were treated with the low dose of 6-MP. Data obtained with flow cytometry suggest that for the high dose there was a drug-induced block of cells in the G1 phase that prevented them from progression into S phase where they would be killed.

Topics: Animals; Brain Neoplasms; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Flow Cytometry; Interphase; Mercaptopurine; Rats

A patient, a 46-year-old female, with a malignant thymoma spreading to the extrathoracic region is described. She underwent a thoracotomy and received radiation therapy, but the myasthenic symptoms did not disappear. A metastatic thymoma of the right mandibula was removed 9 months after thoracotomy. Further examination revealed metastatic thymomas of the bone and liver. After the operation the patient received combination chemotherapy (vincristine, cyclophosphamide, 6-mercaptopurine, prednisone) and remained asymptomatic for 31 months. She was found to have a metastatic thymoma in the occipital lobe of the brain 3.5 years after thoracotomy, and died from infection of the lung. Distant metastases and chemotherapy in malignant thymoma are reviewed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Cyclophosphamide; Female; Humans; Liver Neoplasms; Mandibular Neoplasms; Mercaptopurine; Middle Aged; Neoplasm Metastasis; Prednisone; Thymoma; Thymus Neoplasms; Vincristine

A four-drug regimen, based on cell kinetic principles, induced complete remissions in 68 of 95 children (72%) with acute nonlymphocytic leukemia (ANLL). Patients entered remission after 2-5 weekly cycles of vincristine-daunorubicin (day 1) followed by sequential cytosine arabinoside and 6-azauridine (days 4-7). With continuation therapy of monthly vincristine-doxorubicin-cyclophosphamide, weekly cytosine arabinoside, and daily 6-mercaptopurine, the median duration of complete remission was 10 mo and the median survival time 21 mo. Portal triaditis, evident in 11 of 23 patients with liver biopsies, was associated with long remissions. A larger spleen size (greater than 5 cm) and a higher myeloblast labeling index (greater than 10%) at diagnosis were clearly related to shorter durations of remission. Splenectomy within 1 mo of remission had no statistically significant effect on the frequency of relapse or length of remission. Patients without central nervous system (CNS) leukemia at diagnosis, all treated prophylactically with intrathecal methotrexate, had a low frequency of initial CNS relapse (3/56, 5%). The 2-yr disease-free survival rate is 29% (20 of 68 patients attaining complete remission). fifteen patients have completed 2.5 yr of therapy, and each remains in continuous complete remission, off treatment, for 1+ -36+ mo. This induction chemotherapy was as effective as more intensive regimens, with the advantage of less toxicity and shorter periods of hospitalization.

Topics: Acute Disease; Adolescent; Asparaginase; Brain Neoplasms; Child; Cyclophosphamide; Cytarabine; Doxorubicin; Humans; Injections, Spinal; Leukemia; Mercaptopurine; Methotrexate; Prednisone; Splenectomy; Vincristine

We describe two adolescent girls with acute lymphoblastic leukemia (ALL) whose leukemia cells were near-haploid. Their lymphoblasts stained in a block pattern with periodic acid Schiff and had "common ALL" surface markers confirmed by indirect immunofluorescence. Each patient had two populations of blasts, one near-haploid and one hyperdiploid, which was an exact doubling of the near-haploid karyotype. The first patient had a predominant population of cells with 26 chromosomes and a few with 52, while the second had a predominance of cells with 56 and a minority with 28. Flow cytometric analysis of DNA content initially detected the minor near-haploid population in the second patient, which was confirmed later by cytogenetic review of the marrow sample. In addition to our two patients, only four patients have been reported with near-haploid ALL. Of these six, five were girls, five were adolescents, and five had short survivals (median, 10 mo). All six had disomy of chromosome 21 with or without disomy for chromosomes 10, 14, 18, or X (four patients each). Thus, near-haploid ALL may represent a unique subgroup of ALL with a poor prognosis. To detect these and other possible subgroups, we have included cytogenetic analysis and flow cytometric analysis of DNA content in our initial evaluation of patients with ALL.

Topics: Acute Disease; Adolescent; Bone Marrow Examination; Brain Neoplasms; Child; Daunorubicin; Female; Haploidy; Humans; Injections, Spinal; Karyotyping; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Prednisone; Prognosis; Vincristine

The in vivo effect of various cytotoxic drugs and cranial irradiation on neutrophil chemotaxis was tested in 62 children with acute lymphoblastic leukaemia and in 10 patients with other malignant disease. Cranial radiotherapy had a transient adverse effect on neutrophil chemotaxis after completion of the course which was most marked in children. Methotrexate (MTX) and 6-mercaptopurine (6-MP) alone and in combination had a variable effect of chemotaxis, which was most marked nine days after the end of the course. The effect of 6-MP was clearly dose-related, but continuous therapy (75 mg/m2 day) had the greatest inhibitory effect of all the regimens tested. The in vitro effect was studied in 48 leukaemics and in 85 controls (adults and children); all the patients with leukaemia had been off treatment for at least six months. No difference was found between the effects of drugs tested on control or leukaemic cells. The greatest inhibitory effect was found in vinblastine, adriamycin, 6-MP, and vincristine, all of which were closely dose-dependent, MTX, prednisolone, and asparaginase had no effect on chemotaxis when tested in this way.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Chemotaxis, Leukocyte; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Neutrophils; Time Factors

Comparative results of chemo- and chemoimmunotherapy with Soviet strain of BCG vaccine in children with acute leukemia are presented. The immunotherapeutical regimen includes 20 intracutaneous injections of 0.1 mg BCG vaccine given weekly during 5--6 months with subsequent 5--6 months intervals simultaneously with maintenance chemotherapy. In the control group children were only given conventional chemotherapy. The median duration of remission and survival in patients who had received BCG chemoimmunotherapy was 25.2 +/- 1.5 and 32.3 +/- 1.2 months respectively. In the group of patients with chemotherapy alone--13.2 +/- 0.9 and 21.8 +/- 1.1 months respectively (p less than 0.01). The best results were obtained in children who had received before BCG immunotherapy neuroleukemia prophylactic treatment.

Topics: Adolescent; Antineoplastic Agents; BCG Vaccine; Brain Neoplasms; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Prednisolone; Remission, Spontaneous; Time Factors; Vincristine

This report describes the results of a study of central nervous system (CNS) prophylaxis and combination chemotherapy for the maintenance of remission in adult acute lymphoblastic leukemia. Adults with acute lymphoblastic leukemia who achieved complete remission were treated with 2,400 rads cranial irradiation and intrathecal methotrexate for CNS prophylaxis followed by continuation systemic chemotherapy with oral methotrexate, 6-mercaptopurine and cyclophosphamide. There were no CNS relapses following treatment. One-half of the patients relapsed within 11 months, with 5 patients remaining in remission for 27+ to 31+ months. The toxicity was acceptable with no treatment-related deaths. This regimen is capable of producing long remissions in a significant proportion of adults with acute lymphoblastic leukemia and appears to be effective in reducing the incidence of CNS relapse. It has the additional advantage of ease of administration and can be largely administered in the community.

Topics: Adolescent; Adult; Brain Neoplasms; Cyclophosphamide; Female; Head; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission, Spontaneous; Spinal Cord Neoplasms

For the purpose of evaluating the efficiency of an unspecific immunostimulation in acute leukaemias the results of treatment obtained from two groups of patients (a total of 55 children) were compiled. In the first group an unspecific immunostimulation with vaccination (BCG, diphtheria-tetanus-pertussis, measles) could be observed after the induction of remission during a cytostatic maintenance therapy. In the second group a polychemical therapy and the CNS-irradiation was applied according to the treatment scheme developed by the working team of Donald Pinkel. The group of patients treated with unspecific immunostimulation involved a high percentage of surviving children. In total there was no essential difference between the treatment results of both schemes of therapy during our period of observation. As before, the treatment of hyperleukocytic forms of leukaemias will cause particular difficulties.

Topics: Acute Disease; BCG Vaccine; Brain Neoplasms; Child; Cyclophosphamide; Diphtheria Toxoid; Drug Therapy, Combination; Gold Radioisotopes; Humans; Injections, Spinal; Leukemia; Mercaptopurine; Methotrexate; Pertussis Vaccine; Prednisone; Tetanus Toxoid; Vincristine

In accordance with the recommendations of Pinkel, 147 children with acute lymphoblastic leukemia were treated by a combined cytostatic and radiation therapy during a joint study between May 1971 and Jan. 1, 1974. After a primary cytostatical treatment which brought about a remission of 94% of the patients within four to six weeks, the cranial irradiation was performed, depending on age, with a focal dose of 1500 up to 2400 rd in the course of three or four weeks. Simultaneously, the patients were given methotrexate intrathecally which was followed, later on, by a long-term therapy with cytostatics. By means of this combined treatment, a three-year survival was obtained in 50% (8 of 16) and a complete remission in 44% (7 of 16). The prognosis is the same for boys as for girls. A less favorable prognosis concerns the patients with an initial leukocytosisf more than 50 000 leukocytes/mm3 of blood, an age of more than ten years, and leukemic cells already demonstrable in the cerebrospinal fluid.

Topics: Acute Disease; Adolescent; Age Factors; Alopecia; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Prednisone; Premedication; Prognosis; Radiotherapy; Radiotherapy Dosage; Remission, Spontaneous; Skull; Vincristine

Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Humans; Infant; Injections, Spinal; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Netherlands; Prednisolone; Prednisone; Vincristine

Topics: Adolescent; Adult; Black People; Brain Neoplasms; Choriocarcinoma; Female; Humans; Jamaica; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm Metastasis; Pregnancy; Prognosis

The effects of six clinically active drugs were tested against a ttansplantable leukemia in inbred strain 2 guinea pigs. Cytoxan and 6-mercaptopurine were found to elicit a therqeutic response against this leukemia based on complete tumor regression of the established tumor as well as a substantial increase in survival time. Animals dying in the untreated control and drug-treated groups revealed typical generalized lymphoblastic leukemia. However, only Cytoxan-treated animals that had relapsed exhibited central nervous system involvement originating from the arachnoid membrane. A tow-drug combination of Cytoxan and 1-(2-chloroethyl)-3(trans-4-methylcyclohexyl)-1-nitrosourea was found not only to prevent meningeal leukemia development but also to result in "curing" all animals from their leukemia. This observation was based on a complete clinical, hematological, and histopathological "remission" period up to 176 days. The administration of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea alone was observed not only to control the systemic leukemia but also to prevent central nervous system involvement. No relapses occurred after the first "remission" period was achieved in the groups of animals that received 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cyclohexanes; Cyclophosphamide; Drug Therapy, Combination; Guinea Pigs; Leukemia, Experimental; Leukemia, Lymphoid; Male; Meninges; Mercaptopurine; Neoplasm Transplantation; Nitrosourea Compounds; Prednisolone; Remission, Spontaneous; Vincristine

Topics: Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cystitis; Drug Therapy, Combination; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Infant; Infections; Leukemia; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Pneumonia, Viral; Prednisone; Remission, Spontaneous; Skin Diseases; Vincristine; Viral Vaccines; Virus Diseases

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Astrocytoma; Blood-Brain Barrier; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Fluorouracil; Glioblastoma; Glioma; Humans; Male; Mercaptopurine; Methotrexate; Middle Aged; Monomethylhydrazine; Neoplasm Metastasis; Vinblastine

Topics: Adenocarcinoma; Adolescent; Age Factors; Autopsy; Brain Neoplasms; Cyclophosphamide; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Neoplasms, Multiple Primary; Pancreas; Pancreatic Neoplasms; Prednisone; Vincristine

Topics: Brain Neoplasms; Child; Child, Preschool; Cross Infection; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Infant; Injections, Intravenous; Leukemia; Leukemia, Lymphoid; Male; Measles; Mercaptopurine; Methotrexate; Prednisolone; Remission, Spontaneous; Spinal Neoplasms; Vincristine

Topics: Arachnoid; Asparaginase; Brain Neoplasms; Cerebrospinal Fluid; Child; Cyclophosphamide; Daunorubicin; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunotherapy; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Prednisolone; Prednisone; Remission, Spontaneous; Vincristine

Topics: Autopsy; Brain Neoplasms; Child; Child, Preschool; Daunorubicin; Humans; Leukemia; Male; Mercaptopurine; Neoplasm Metastasis; Prednisone; Time Factors; Vincristine

Topics: Adult; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Hydrazines; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Vinblastine

Topics: Adult; Blood Transfusion; Brain; Brain Neoplasms; Cerebral Angiography; Cerebrovascular Disorders; Choriocarcinoma; Dactinomycin; Encephalitis; Female; Headache; Hemiplegia; Humans; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm Metastasis; Neurologic Manifestations; Pregnancy; Seizures; Uterine Neoplasms

Topics: Adult; Brain Neoplasms; Chorionic Gonadotropin; Dactinomycin; Female; Humans; Hysterectomy; Kidney Neoplasms; Mercaptopurine; Methotrexate; Middle Aged; Pregnancy; Prognosis; Time Factors; Trophoblastic Neoplasms

Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Female; Humans; Infant; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Methotrexate; Neurologic Manifestations; Prednisone; Prognosis; Vincristine

Topics: Adult; Blood Cell Count; Bone Marrow Examination; Brain Neoplasms; Carotid Arteries; Cobalt Isotopes; Craniotomy; Electroencephalography; Humans; Intracranial Pressure; Leukemia, Myeloid; Lymphoma; Male; Mercaptopurine; Methotrexate; Microscopy, Phase-Contrast; Prednisolone; Radiography

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Chemical Phenomena; Chemistry; Leukemia L1210; Lipids; Mercaptopurine; Methods; Mice; Solubility

Topics: Bone Marrow Examination; Brain Neoplasms; Cerebrospinal Fluid Proteins; Humans; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Meninges; Mercaptopurine; Methotrexate; Neoplasms; Prednisone

Topics: Antineoplastic Agents; Brain Neoplasms; Castration; Choriocarcinoma; Female; Humans; Hydatidiform Mole, Invasive; Hysterectomy; Lung Neoplasms; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Neoplasms; Pregnancy; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Animals; Azaguanine; Brain; Brain Neoplasms; Glycols; Guanine; Mercaptopurine; Neoplasms, Experimental; Purines