thioguanine-anhydrous and Brain-Neoplasms

This article covers chemotherapy of malignant astrocytomas, ependymoma, and medulloblastoma. The future direction of anticancer drugs is discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Brain Stem; Child; Eflornithine; Ependymoma; Fluorouracil; Glioblastoma; Humans; Hydroxyurea; Lomustine; Medulloblastoma; Methotrexate; Mitoguazone; Mitolactol; Neoplasm Recurrence, Local; Ornithine; Prednisone; Risk; Thioguanine; Vincristine

To evaluate tumor responses, event-free survival (EFS), overall survival (OS), and toxicity of chemotherapy, children with neurofibromatosis type 1 (NF1) and progressive low-grade glioma were enrolled into the Children's Oncology Group (COG) A9952 protocol and treated with carboplatin and vincristine (CV).. Non-NF1 patients were randomized to CV or thioguanine, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine in COG A9952. NF1 patients were assigned to CV only. NF1 patients and non-NF1 patients who were treated with CV were compared with respect to baseline characteristics, toxicity, tumor responses, EFS, and OS.. A total of 127 eligible patients with NF1 were nonrandomly assigned to CV: 42 NF1 patients (33%) had events, and 6 (4.7%) died. The 5-year EFS rate was 69% ± 4% for the CV-NF1 group and 39% ± 4% for the CV-non-NF1 group (P < .001). In a univariate analysis, NF1 children had a significantly higher tumor response rate and superior EFS and OS in comparison with CV-treated children without NF1. NF1 patients and non-NF1 patients differed significantly in amount of residual tumor, extent of resection, tumor location, and pathology. According to a multivariate analysis, NF1 was independently associated with better EFS (P < .001) but not with OS. NF1 patients also had a decreased risk of grade 3 or 4 toxicities in comparison with non-NF1 patients. Three second malignant neoplasms occurred in NF1 patients receiving CV (CV-NF1 group) at a median of 7.8 years (range, 7.3-9.4 years) after enrollment, but there were none in the non-NF1 group.. Children with NF1 tolerated CV well and had tumor response rates and EFS that were superior to those for children without NF1. Cancer 2016;122:1928-36. © 2016 American Cancer Society.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Child; Child, Preschool; Female; Glioma; Humans; Male; Neurofibromatosis 1; Procarbazine; Thioguanine; Vincristine

PURPOSE Surgery is curative therapy for pediatric low-grade gliomas (LGGs) in areas of the brain amenable to complete resection. However, LGGs located in areas where complete resection is not possible can threaten both function and life. The purpose of this study was to compare two chemotherapy regimens for LGGs in children younger than age 10 years for whom radiotherapy was felt by the practitioner to pose a high risk of neurodevelopmental injury. PATIENTS AND METHODS Previously untreated children younger than age 10 years with progressive or residual LGGs were eligible. Children were randomly assigned to receive carboplatin and vincristine (CV) or thioguanine, procarbazine, lomustine, and vincristine (TPCV). Children with neurofibromatosis are reported separately. Results Of 274 randomly assigned patients who met eligibility requirements, 137 received CV and 137 received TPCV. The 5-year event-free survival (EFS) and overall survival (OS) rates for all eligible patients were 45% ± 3.2% and 86% ± 2.2%, respectively. The 5-year EFS rates were 39% ± 4% for CV and 52% ± 5% for TPCV (stratified log-rank test P = .10; cure model analysis P = .007). On multivariate analysis, factors independently predictive of worse EFS and OS were younger age and tumor size greater than 3 cm(2). Tumor location in the thalamus was also associated with poor OS. CONCLUSION The difference in EFS between the regimens did not reach significance on the basis of the stratified log-rank test. The 5-year EFS was higher for TPCV on the basis of the cure model analysis. Differences in toxicity may influence physician choice of regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Drug Administration Schedule; Female; Glioma; Humans; Infant; Lomustine; Male; Multivariate Analysis; Procarbazine; Prognosis; Risk Factors; Spinal Cord Neoplasms; Thioguanine; Treatment Outcome; Vincristine

Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria.. Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed.. The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses.. With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Female; Humans; Male; Methotrexate; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Remission Induction; Risk Factors; Salvage Therapy; Survival Rate; Thioguanine; Time Factors; Treatment Outcome

The aim of this study was to compare tolerance of a nitrosurea-based regime with 'standard' therapy of vincristine (VCR) and carboplatin for low-grade gliomas. Ten children with low-grade gliomas received second line therapy consisting of thioguanine, procarbazine, CCNU and vincristine (TPCV). Two groups were identified, i.e. patients who had either experienced significant toxicity with carboplatin (reaction group) or had re-growth of their tumor (re-growth group) following first line therapy. Patients were evaluated for toxicity. Data was available on nine patients. Patients in the reaction group completed a mean of 3 cycles of TPCV (range 2-4). One patient stopped after 2 cycles of TPCV due to tumor progression and died 3 months later and one remained on therapy at the time of analysis. Patients in the re-growth group received a mean of 5.5 cycles of TPCV (range 4-8). Treatment was discontinued in one patient after 4 cycles due to hematological toxicity, one experienced tumor progression after 4 cycles and one stopped after 6 cycles because of neurological toxicity. There was no difference in the incidence of grade 3/4 neutropenia or thrombocytopenia, transfusion requirements or delays in chemotherapy between TPCV and VCR/carboplatin in either group. There were no serious infections or toxic deaths. Seven of nine patients had stable disease at a mean of 13 months of follow up. TPCV therapy is a well-tolerated regime with comparable bone marrow toxicity to VCR/carboplatin. Significant disease stabilization was observed with TPCV and hence this regime may be used as second line therapy.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carboplatin; Child; Child, Preschool; Disease Progression; Drug Administration Schedule; Drug Tolerance; Female; Glioma; Humans; Infant; Lomustine; Male; Neoplasm Recurrence, Local; Procarbazine; Salvage Therapy; Thioguanine; Treatment Outcome; Vincristine

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Glioma; Humans; Lomustine; Male; Mitolactol; Procarbazine; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine

Between March 9, 1984 and January 29, 1992, 42 children with newly diagnosed symptomatic or previously diagnosed progressive low-grade gliomas received outpatient chemotherapy as their primary treatment. This study was a single arm, phase II trial designed to estimate the time to tumor progression and toxicity of this regimen. Procarbazine, 6-thioguanine, and dibromodulcitol were given before lomustine (CCNU) and vincristine was given 1 and 3 weeks after CCNU. Patients were treated for six treatment cycles or until the tumor progressed, whichever came first. Twenty-three patients had juvenile pilocytic astrocytomas, 11 had astrocytomas, one had oligodendroglioma, one had ganglioglioma, and six had radiographically diagnosed low-grade gliomas. The mean age of the patients was 5 years (median, 3 years). The median time to treatment failure was 132 weeks (95% confidence interval: 106, 186 weeks). Only eight patients have died the estimated 5-year survival rate is 78% (95% confidence interval, 60% 87%). There were two episodes of grade 4 neutropenia, and three episodes of grade 4 thrombocytopenia. This regimen was safe, able to be delivered in the outpatient setting, and produced prolonged periods of disease stabilization in children with low-grade gliomas.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Disease Progression; Female; Glioma; Humans; Infant; Lomustine; Male; Mitolactol; Procarbazine; Thioguanine; Treatment Outcome; Vincristine

To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors.. One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses.. Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients.. TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Female; Fluorouracil; Humans; Hydroxyurea; Lomustine; Lung Neoplasms; Male; Middle Aged; Mitolactol; Procarbazine; Prospective Studies; Thioguanine

Childrens Cancer Group 123 was a trial of intensive multidrug chemotherapy as well as cranial irradiation and bulk disease irradiation in children with acute lymphoblastic leukemia with lymphomatous presentation (bulk disease and either T-cell phenotype, high white blood count, or absence of anemia), a poor prognostic group with an increased risk of central nervous system (CNS) and other extramedullary recurrence.. Three hundred eight patients without CNS disease were randomized among three regimens: A--BFM chemotherapy (designed for high risk ALL patients) with 1800 cGy cranial irradiation; B--LSA2L2 chemotherapy (designed for non-Hodgkins lymphoma patients) with 1800 cGy cranial irradiation and 1500 cGy to nonabdominal bulk disease; C--Reg B without cranial irradiation. All patients received intrathecal methotrexate throughout therapy. Radiation treatment records were reviewed.. With a minimum 52-month follow-up, Regimen B and C patients had 5-year actuarial CNS relapses of 7% and 17% (p = 0.01) and event-free survivals of 53% and 39% (p = 0.04). Patients with white blood count < 50,000/mm3 did not benefit from cranial irradiation. Regimen A patients had the same CNS relapse rate as Regimen B patients but an improved event-free survival. Regimen B and C patients with large mediastinal masses who received their assigned chest radiation had a lower event rate than those who did not (p = 0.06). Patients whose cranial fields did or did not encompass the entire meningeal surface had equivalent CNS relapse rates.. Patients treated with LSA2L2 chemotherapy, a less than optimal regimen, benefited from cranial and mediastinal irradiation. Compliance with radiation volume guidelines was not essential for patients to receive the benefit of cranial irradiation.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Brain Neoplasms; Child; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Humans; Infant; Leukocyte Count; Lymphoma; Mediastinal Neoplasms; Meningeal Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Survival Rate; Thioguanine; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child, Preschool; Glioma; Humans; Lomustine; Male; Molecular Targeted Therapy; Mutation; Procarbazine; Prognosis; Proto-Oncogene Proteins B-raf; Salvage Therapy; Thioguanine; Vincristine

The NovoTTF-100A is a device that emits alternating electric fields and it is approved for the treatment of recurrent glioblastoma. It works by perturbing tumor cells during mitosis as they enter anaphase leading to aneuploidy, asymmetric chromosome segregation and cell death with evidence of increased immunogenicity. Clinical trial data have shown equivalent efficacy when compared to salvage chemotherapies in recurrent disease. Responders were found to have had a lower dexamethasone usage and a higher rate of prior low-grade histology. We treated a series of patients with NovoTTF-100A and bevacizumab alone (n = 34) or in combination with a regimen consisting of 6-thioguanine, lomustine, capecitabine, and celecoxib (TCCC) (n = 3). Compared to the former cohort, the latter cohort exhibited a trend for prolonged overall survival, median 4.1 (0.3-22.7) months versus 10.3 (7.7-13.6) months respectively (P = 0.0951), with one experiencing an objective response with a 50% reduction in tumor size on magnetic resonance imaging despite possessing a larger tumor size at baseline and more severe neurologic dysfunction than the median for either group. These observations illustrate the possibility of improving survival and achieving a response in patients with end-stage recurrent glioblastoma by biasing the tumor toward anti-tumor immunologic response with a combination of NovoTTF-100A and TCCC, as well as the continuation of bevacizumab in order to limit dexamethasone use due to its global immunosuppressive effect on the patient.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Capecitabine; Celecoxib; Combined Modality Therapy; Dacarbazine; Electric Stimulation Therapy; Female; Glioblastoma; Humans; Lomustine; Male; Middle Aged; Neoplasm Recurrence, Local; Temozolomide; Thioguanine; Treatment Failure

We evaluated the efficacy of temozolomide (TMZ) or lomustine (CCNU) in combination with 6-thioguanine, capecitabine, and celecoxib for the treatment of recurrent high-grade glioma. Forty-three patients with recurrent glioblastoma and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-thioguanine, capecitabine, and celecoxib. Endpoints were 12-month progression-free survival (PFS) for patients with AG, 6-month PFS for patients with glioblastoma, duration of PFS, and MRI-based objective response rates. Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. Thirty-eight patients with glioblastoma were treated with the lomustine-based regimen, and five received the TMZ-based regimen. For the 43 glioblastoma patients, the objective response rate was 12 and 33% had stable disease; the 6-month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined objective response rate was 26 and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated with hematological toxicity common and more frequent with CCNU than TMZ. The combination therapy with 6-thioguanine, capecitabine and celecoxib plus CCNU or TMZ does not appear to be more effective than other alkylating agent schedules for patients with recurrent glioblastoma. The combination, however, is promising for patients with recurrent high-grade AG.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Capecitabine; Celecoxib; Dacarbazine; Deoxycytidine; Female; Fluorouracil; Glioblastoma; Gliosarcoma; Humans; Lomustine; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Pyrazoles; Sulfonamides; Survival Rate; Temozolomide; Thioguanine; Treatment Outcome; Young Adult

The various members of the Trk tyrosine kinase family and p75 neurotrophin receptor (p75(NTR)) have been identified as signaling receptors for the structurally related members of the neurotrophins (NT) family. We have previously reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of extracellular-matrix degradative enzymes. These cells express aberrant levels of functional p75(NTR) and TrkC, the putative high-affinity receptor for the neurotrophin NT-3. Here we demonstrate that, by using sensitive immune-complex kinase assays in human brain-metastatic (70W) melanoma cells, TrkC receptors associate with a kinase activity exhibiting a dose-dependent susceptibility to inhibition by the purine-analogs 6-thioguanine and 2-aminopurine. The activity of this purine-analog-sensitive kinase (PASK) was induced by NT-3 in a time-dependent fashion, phosphorylating exogenous myelin basic protein (MBP) but not denatured enolase. It is similar to the one reported to relate with p75(NTR) and TrkA receptors and stimulated by the prototypic NT, nerve growth factor. Thus, PASKs may represent unique signaling components common to NT receptors that could engage joint downstream signaling effectors in brain-metastatic melanoma.

Topics: 2-Aminopurine; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Melanoma; Neoplasm Metastasis; Neurotrophin 3; Protein Kinases; Protein Serine-Threonine Kinases; Receptor, Nerve Growth Factor; Receptor, trkC; Receptors, Nerve Growth Factor; Signal Transduction; Thioguanine; Time Factors

The contributions of O6-methylguanine-DNA-methyltransferase(MGMT), p53 status, mismatch repair, and apoptotic response to the resistance of glial tumors to temozolomide (TMZ) were tested using seven established human glial tumor cell lines in culture and xenografts in athymic mice.. Resistance to TMZ was only marginally dependent on MGMT activity, because subtoxic doses of TMZ easily eliminated MGMT reserves for at least 18 h after treatment. Resistance to TMZ varied most notably with the p53 status of the tumor. Tumors with wild-type (wt) p53 and a functional p53 response to DNA damage (SWB40 and SWB61) were most sensitive. The p21-related cell cycle arrest was intimately linked to TMZ toxicity because tumors with wt p53 but lacking a robust increase in p21 protein level (D-54) were resistant to TMZ. In contrast, tumors with a dysfunctional p53 cycle and a weak cell cycle response to DNA damage (SWB39 and SWB77) were extremely unresponsive to treatment even with the aid of MGMT inactivators. Notable exceptions to the above were observed with the p53 mutated tumors SWB33 and SWB95, which were arrested by TMZ in G1-S and consequently underwent apoptosis despite their failure to express p21.. By testing a limited number of glial tumors in cell culture and also as xenografts, we have shown that mobilization of the p53 in response to TMZ damage is likely to induce a cell cycle arrest and apoptosis in glial tumors. Additional pathways linking cell cycle arrest and apoptosis contribute to the efficacy of TMZ against p53 mutated glial tumors. The unusual resistance of tumors, of which the cell cycle was not arrested in response to TMZ treatment, was associated with allelic losses during regrowth of treated tumors. Nevertheless such resistance was not related to dysfunctional mismatch repair.

Topics: Alleles; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Base Pair Mismatch; Blotting, Western; Brain Neoplasms; Cell Cycle; Cell Nucleus; Cytosol; Dacarbazine; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Glioma; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Temozolomide; Thioguanine; Time Factors; Tumor Cells, Cultured; Tumor Suppressor Protein p53

This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU.. Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival.. A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model.. This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Combined Modality Therapy; Disease Progression; Female; Glioblastoma; Glioma; Humans; Hydroxyurea; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Radiotherapy Dosage; Survival Analysis; Thioguanine

To determine the efficacy of the combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas after failure of either previous radiotherapy alone or previous radiotherapy plus nitrosourea-based chemotherapy.. Seventy-seven patients with recurrent malignant gliomas were studied. 6-Thioguanine was administered for 4 days before lomustine, and procarbazine was administered for 1 day before and 2 days after lomustine to potentiate lomustine's antitumor effect. Hydroxyurea was initiated 1 day before lomustine and continued for a total of 3 days.. Thirty patients with glioblastomas and 47 patients with anaplastic gliomas were eligible for evaluation. In the glioblastoma group, 2 of 30 patients had a partial response and 8 of 30 patients had stable disease. This group of patients who responded and had stable disease included 6 of 10 patients who had not undergone previous chemotherapy but only 4 of 20 who had undergone previous chemotherapy. The overall median time to disease progression for the glioblastoma group was 9 weeks. In the anaplastic glioma group, 11 of 47 patients had a partial response and 25 of 47 had stable disease, including 23 of 30 without previous chemotherapy and 13 of 17 who had undergone previous chemotherapy. The median time to disease progression for the whole anaplastic glioma group was 24 weeks; however, the time to disease progression was 50 weeks for responding patients who had not undergone previous chemotherapy and 25 weeks for those who had undergone previous chemotherapy.. Our results indicate that chemotherapy with a combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea is active for patients with recurrent anaplastic gliomas and glioblastomas not previously treated with nitrosourea-based chemotherapy but is inactive for patients with glioblastomas previously treated with chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Disease Progression; Drug Administration Schedule; Glioblastoma; Glioma; Humans; Hydroxyurea; Lomustine; Middle Aged; Neoplasm Recurrence, Local; Procarbazine; Radiography; Retreatment; Thioguanine

To investigate toxicity, and progression-free survival (PFS) of children and adults with newly diagnosed medulloblastoma, pineoblastoma, and other primitive neuroectodermal tumors (PNET) with a combined modality regimen of radiation therapy and adjuvant nitrosourea-based chemotherapy.. Between 1984 and 1992, 34 evaluable patients with newly diagnosed tumors were treated with chemotherapy and radiotherapy according to a single-arm phase II study. One cycle of chemotherapy was given prior to and for 6 cycles following craniospinal radiotherapy (CSA). Procarbazine, 6-thioguanine, and dibromodulcitol were given before lomustine (CCNU) to enhance CCNU-induced tumor cell kill and to reduce alkyltransferase repair of ethylated DNA. Vincristine was given 1 and 3 weeks after CCNU to kill cells that began to cycle after the challenge of the first four drugs. Chemotherapy was given in the outpatient setting. CSA radiation was planned to deliver a dose of 54 Gy to the primary tumor site and 24 Gy to the rest of the neuroaxis. Additional radiation was given to bulky disease outside the primary site if present. Hydroxyurea was used during radiotherapy as a radiosensitizer.. Patients treated included 27 with medulloblastoma, 5 with pineoblastoma, and 2 with supratentorial PNET. All but 3 medulloblastoma cases were considered high risk either because of bulky residual disease remaining after surgery and/or metastatic disease detected during staging. For the 34 patients, 24 have progressed, 20 have died. Overall estimated PFS was 55% at 3 years and 35% at 5 years. The 5-year survival estimate is 56%. One patient had inadequate staging to determine M stage. Of the remaining 33 patients, there were 19 patients who had metastatic disease at diagnosis (M1 or higher stage) who had a 3- and 5-year PFS of 42 and 21% respectively and 5-year survival of 42%. There were 14 patients who had negative staging (M0 stage) who had a 3- and 5-year PFS of 69 and 52% respectively and 5-year survival of 71%. Of the 27 patients with medulloblastoma, 15 had M1 or higher stage. These 15 patients had a 5-year PFS and overall survival of only 20 and 40% respectively. Medulloblastoma patients with M0 staging had a 5-year PFS and overall survival of 52 and 73% respectively. Overall toxicity was primarily due to mild hematological toxicity and related to the use of the chemotherapy.. The results using this therapy in high-risk groups of patients does not offer any improvement over results reported in other recent studies. The reason for these results may be due to the lowered craniospinal radiation dose.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Dose-Response Relationship, Radiation; Female; Follow-Up Studies; Humans; Infant; Male; Medulloblastoma; Middle Aged; Mitolactol; Neoplasm Staging; Neuroectodermal Tumors, Primitive; Nitrosourea Compounds; Procarbazine; Retrospective Studies; Risk Factors; Thioguanine; Vincristine

Pretreatment of 9L cells with either alpha-difluoromethylornithine (DFMO), which depletes intracellular levels of polyamines, or 6-thioguanine (6TG), which substitutes for guanine in DNA, potentiates the cytotoxic effects of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). We examined the effects of these 2 agents in combination on the cytotoxicity of BCNU in sensitive (9L) and resistant (BTRC-19) rat brain tumor cell lines. 9L cells were incubated with 0.2 microM 6TG for 72 hr; during the last 48 hr, 1 mM DFMO was added to cell cultures. The cytotoxicity of BCNU in pretreated cells was increased in an additive manner compared with the effects of each agent alone. Results of experiments in which the BCNU-resistant BTRC-19 cell line was treated similarly showed that only 6TG enhanced BCNU cytotoxicity. Flow cytometry studies showed that these effects are not related to cell-cycle processes.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carmustine; Cell Line; Drug Evaluation, Preclinical; Drug Resistance; Drug Synergism; Eflornithine; Flow Cytometry; Rats; Thioguanine; Tumor Cells, Cultured; Tumor Stem Cell Assay

9L Rat brain tumor cells were treated with 0.2 microM 6-thioguanine for 48 hr, which produced a 40% cell kill, a small (15%) inhibition of cell growth, and an accumulation of cells in S-phase. Maximum incorporation of [14C]6-thioguanine into cellular DNA occurred after 24 hr of incubation; 70% of the label was incorporated into DNA as 6-thio-2'-deoxyguanosine. Pretreatment of 9L cells for 48 hr with 0.2 microM 6-thioguanine potentiated the cytotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) by 50% with a dose enhancement ratio of 1.5, and caused a 30% increase in the number of BCNU-induced sister chromatid exchanges (SCEs) and a 50% increase in DNA crosslinks formed, compared to treatment with BCNU alone. Used as a single agent, 6-thioguanine induced a significant number of SCEs. Results suggest that these effects may be related to the increased formation of DNA crosslinks, possibly as the result of the formation of S6-(2-chloroethyl)-6-thioguanine in cellular DNA.

Topics: Animals; Brain Neoplasms; Carmustine; Cell Line; Cell Survival; Cross-Linking Reagents; DNA, Neoplasm; Drug Synergism; Rats; Sister Chromatid Exchange; Thioguanine

Complete remission was achieved in 11 of 22 children with acute myeloid leukaemia using at least two courses of a 24 hour infusion of cytosine arabinoside (Ara-C) 10 mg/kg, followed by push injections of daunorubicin (DNR) 45 mg/m2, and adriamycin (ADR) 45 mg/m2. Consolidation therapy consisted of three courses of Ara-C and 6-thioguanine (Tg) and one course of cyclophosphamide (CPA) and ADR. Central nervous system prophylaxis with intrathecal Ara-C was given in all patients and cranial irradiation of five. Maintenance therapy consisted of 5 day courses of Ara-C and Tg given 4 weekly with immunotherapy (BCG) vaccine and subcutaneous leukaemic cells) between courses. Median length of first complete remission was 99+ weeks, and median survival of all patients was 44 weeks. Median survival of remitters was 195+ weeks and non-remitters, 28 weeks. Two patients developed central nervous system disease, one at presentation and the other 46 weeks from presentation. Five patients have ceased therapy and remain in remission from 32 to 142 weeks after ceasing treatment.

Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cytarabine; Daunorubicin; Doxorubicin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Leukemia, Myeloid, Acute; Male; Thioguanine

The need for prophylactic therapy of the central nervous system in adult acute nonlymphoblastic leukemia has been suggested but no proven. Over a 4-year period from January 1973, to December 1976, we have maintained 40 patients achieving complete remission on a regimen consisting of monthly courses of Cytosine Arabinoside and 6-thioguanine. Twenty patients remain in remission with a predicted median remission duration for the entire group of 14.5 months. Thirty nine of the patients did not have central nervous system leukemia at diagnosis, and only one of these patients (2.6%) has had remission tenance regimen there is little need for central nervous system prophylaxis in adult acute nonlymphoblastic leukemia.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Cytarabine; Drug Therapy, Combination; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission, Spontaneous; Thioguanine

Twenty children with acute myeloblastic leukemia were given induction and maintenance regimens combining cytosine arabinoside (ARA-C) and 6-thioguanine (TG). Two died before completing induction therapy and were considered unevaluable. Of the 18 remaining patients, 3 died shortly after induction, 2 had no response, 1 had a partial response and 12 (66%) had a complete remission (CR) lasting 4 to 68 months. Six still survive: two in their initial CR and four who relapsed but were reinduced to CR. Although no prophylactic central nervous system (CNS) therapy was given, only one patient has developed CNS involvement after diagnosis. Two girls became pregnant while on maintenance therapy. One delivered a normal, full-term infant; both she and the child are well 24 months later.

Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cytarabine; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Recurrence; Remission, Spontaneous; Thioguanine; Time Factors

A number of chemotherapeutic agents have been shown to have anti-tumor activity against childhood medulloblastoma. Ten-year survival with optimal surgery and radiation therapy ranges from 5% to 25%. Carefully controlled clinical trials utilizing a combination of surgery, radiation therapy, and chemotherapy should be employed in the early stages of the disease in an attempt to define which drugs are most effective, and to improve the survival rate.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Gold Radioisotopes; Humans; Male; Medulloblastoma; Methotrexate; Nitrosourea Compounds; Podophyllotoxin; Procarbazine; Radioisotope Teletherapy; Semustine; Thioguanine; Triethylenemelamine; Vincristine

Twenty-three adult patients (ages greater than 15 years) and 75 children with acute lymphoblastic leukemia were treated with similar intensive, sequential cytotoxic protocols (L-2). The adult patients have lower remission rate (78%) than the children (98%). The duration of remission and the length of survival are also shorter in adults. The incidence of central nervous system (CNS) relapse in adults (27.7%) is higher than in children (7.1%) suggesting that prolonged prophylactic intrathecal methotrexate as given to the children is more effective than the schedule used for adults where intrathecal methotrexate was given only in the first 2 months of therapy. The low incidence of CNS involvement in children on the L-2 protocol compares favorably with other series reported using a combination of cranial irradiation and intrathecal methotrexate. In both adults and children there seemed to be a higher incidence of CNS involvement in patients with initial white blood cell counts greater than 25,000 cells/mm3.

Topics: Adolescent; Adult; Age Factors; Aged; Asparaginase; Brain Neoplasms; Carmustine; Child; Child, Preschool; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Infant; Injections, Spinal; Leukemia, Lymphoid; Male; Methotrexate; Middle Aged; Prednisone; Remission, Spontaneous; Spinal Neoplasms; Thioguanine; Vincristine

In a study of non-Hodgkin's lymphoma in children, 104 children were treated and followed at Memorial Sloan-Kettering Cancer Center from 1964 throughout June 1974. Forty-three patients, previously treated and untreated, received a nonspecific group of various chemotherapeutic agents and attained an 11% disease-free survival rate. A second group of 18 previously untreated patients, who received a chemotherapeutic regimen consisting of cyclophosphamide alone, achieved a 33% disease-free survival rate. The last group, 43 previously untreated patients (77% of whom had far advanced disease and 86% of whom had diffuse histological types) who received a new and intensive multiple-drug regimen (the LSA2-L2 protocol) consisting of induction, consolidation, and maintenance phases, has maintained an 81% disease-free survival rate after a median observation time of 21+ months. Although nervous system involvement and recurrence or metastases at any time are poor prognostic factors, initial marrow involvement and the amount of bulky disease are no longer considered negative prognosticators when intensive treatment is initiated immediately after diagnosis, is continued for 2--3 years, and includes radiation therapy to sites of bulky disease and CNS prophylaxis. The LS2-L2 treatment is effective in accomplishing the dual aims of not only increasing the numbers of disease-free patients but also prolonging their survival.

Topics: Adolescent; Asparaginase; Bone Marrow; Brain Neoplasms; Carmustine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Hydroxyurea; Lymphoma; Male; Methotrexate; Neoplasm Metastasis; Nitrogen Mustard Compounds; Peripheral Nervous System Neoplasms; Prednisone; Prognosis; Thioguanine; Vincristine