Treatment of malignant gliomas with surgery,intraarterial chemotherapy with ACNU and radiation therapy

Summary Forty-five patients with malignant gliomas were treated after aggressive surgical resection with alternating intravenous carmustine and cisplatin both during and after radiation therapy. Thirty-three patients were considered evaluable for responses, 17 had glioblastoma multiforme (GBM),14 had anaplastic astrocytoma (AA) and 2 had anaplastic oligodendroglioma (AO). The median age of the evaluable patients was 47 years. The median time to tumor progression was 34.5 weeks, and the median survival for the entire group was 76 weeks. Early progression occurred more frequently in patients with glioblastoma than in those with AA or AO. Seventeen patients (55%) were alive at 18 months (6 GBM, 9 AA, 2 AO). Toxicity was mainly hematologic, otic and tolerable. The results suggest that further trial is warranted to assess the efficacy of alternating carmustine and cisplatin in conjunction with radiation therapy postoperatively in patients with malignant gliomas.     

Benefit from prolonged dose-intensive chemotherapy for infants with malignant brain tumors is restricted to patients with ependymoma: a report of the Pediatric Oncology Group randomized controlled trial 9233/34

Background

The randomized controlled Pediatric Oncology Group study 9233 tested the hypothesis that dose-intensive (DI) chemotherapy would improve event-free survival (EFS) for children <3 years of age with newly diagnosed malignant brain tumors.

Methods

Of 328 enrolled eligible patients, diagnoses were medulloblastoma (n = 112), ependymoma (n = 82), supratentorial primitive neuroectodermal tumor (sPNET, n = 38) and other malignant brain tumors (n = 96), and were randomized to 72 weeks of standard dose chemotherapy (Regimen A, n = 162) or DI chemotherapy (Regimen B, n = 166). Radiation therapy (RT) was recommended for patients with evidence of disease at completion of chemotherapy or who relapsed within 6 months of chemotherapy completion.

Results

Distributions of EFS for Regimens A and B were not significantly different (P = 0.32) with 2- and 10-year rates of 22.8% ± 3.3% and 15.4% ± 3.7%, and 27.1% ± 3.4% and 20.8% ± 3.8%, respectively. Thus, the study hypothesis was rejected. While distributions of EFS and OS were not significantly different between Regimens A and B for patients with medulloblastoma and sPNET, DI chemotherapy resulted in significantly improved EFS distribution (P = .0011) (2-year EFS rates of 42.1% vs. 19.6% with SD chemotherapy), but not OS distribution, for patients with centrally confirmed ependymoma. The degree of surgical resection affected EFS, OS or both for most tumor groups. Approximately 20%, 40% and 20% of patients with medulloblastoma, ependymoma treated with DI chemotherapy, and sPNET, respectively appear to have been cured without RT. Of 11 toxic deaths on study, 10 occurred on the DI chemotherapy arm.

Conclusions

Prolonged dose-intensive chemotherapy given to infants with malignant brain tumors resulted in increased EFS only for patients with ependymoma.     

Phase 11 study of aziridinylbenzoquinone (AZQ: NSC-182986) in the treatment of malignant gliomas recurrent after radiation

Seventeen patients with malignant gliomas recurrent after chemotherapy and/ or radiation failure were treated with aziridinylbenzoquinone (AZQ) at a dose of 20-15 mg/M² weekly for four weeks followed by a two week rest. Regression of disease was observed in four patients, 4/17 (24%) for 35, 15+,40+, and 10 weeks. Toxicity was limited to moderate reversible myelosuppression. AZQ in this dose and schedule has limited but definite activity in patients with malignant gliomas progressive after primary radiation therapy failure.     

Metabolic patterns in malignant gliomas

Summary Changes of mitochondrial and cytoplasm tumor metabolism were studied in malignant gliomas and normal cortex probesin vitro. By spectrophotometric methods marker enzymes of different mitochondrial (whole respiratory chain, citrate acid cycle, fatty oxidation) and cytoplasm (glycolysis, pentose phosphate shunt) metabolic energy pathways were analysed. Generally, the activities of intramitochondrial key enzymes were significantly decreased in gliomas when compared with enzyme activities of normal cortex tissue (p < 0.01). Glycolytic enzymes and a representative of the pentose phosphate shunt were unchanged or increased. Ratios of marker enzymes of the glycolytic pathway (lactate dehydrogenase) and glycose-6-P dehydrogenase revealed a significant difference between glioblastomas (p < 0.05) and grade III (p < 0.05) tumors in comparison to normal astrocytic tissue and astrocytomas WHO grade II. Thus, biochemical analyses allow metabolic grading of gliomasin vitro and may be a useful tool for understanding tumor biology.     

Intra arterial chemotherapy with ACNU and radiotherapy in inoperable malignant gliomas

Summary For the non-operable malignant glioma patients, prognosis remains poor, with a survival of 8 months for the glioblastomas (G), and 15 months for anaplastic astrocytomas (AA). 27 histologic proven malignant gliomas (17 AA and 10 G) were treated between April 1991 and June 1992. Median age was 48 years. The therapeutic protocol consisted of three courses of intra arterial chemotherapy (IAC) with ACNU, at intervals of six weeks, and a localised 60 Gy radiotherapy between the first and the second IAC course. 72 courses of IAC were delivered (2,4 per patient). Response rate was 51,8%. Median survival (MS) was 13 months, with a survival rate of 28% at 24 months. For the AA, MS was 21 months, with a survival rate of 37% at 24 months. For the G, median survival was 10 months. Responders were 65 % for AA, 30% for G. Non responders all died before 24 months had relapsed with a MS of 9 months. 54% of responding patients had a 2 years survival. Toxicity were acceptable with 7% of haematological toxicity and a partial loss of visual acuity in 11% of the cases. No chronic neurological sequellae were noted. We compare theses results with two previous trials, concerning inoperable patients, treated by an association of radiotherapy and systemic chemotherapy. Survival seems to be equivalent with HeCNU and with this treatment, but toxicity decreases with ACNU. Early radiotherapy does not increase complications. This treatment can be used for patients with inoperable malignant gliomas.     

The expanding role of chemotherapy for pediatric supratentorial malignant gliomas

Summary Supratentorial malignant gliomas are among the most difficult tumors to treat in children. With a combination of surgery and irradiation, the median survival for children with malignant gliomas is only 9 months. Even among survivors, irradiation causes long-lasting neurological impairment, especially in young children. These disappointing results have stimulated interest in adjuvant chemotherapy as a more effective treatment for pediatric gliomas. In 1976, the first pediatric randomized trial of adjuvant chemotherapy incorporated CCNU, vincristine and prednisone. The addition of these agents to standard irradiation and surgery enhanced the 5-year survival rate from 18% to 43%. Other trials with multiple drug regimens, now considered to be suboptimal in dosing, have not further enhanced disease-free survival. Current trials of high-dose chemotherapy combined with autologous bone marrow rescue for children with recurrent malignant gliomas have produced some durable survivors, but long-term benefits for children with newly diagnosed malignant gliomas are yet to be realized.     

Phase II evaluation of high-dose intravenous cisplatin for treatment of adult malignant gliomas recurrent after chloroethylnitrosourea failure

Summary Twenty-one patients with recurrent malignant glioma who had failed prior chemotherapy with nitrosoureas were treated with high-dose intravenous cisplatin on days 1 and 8 of successive 4 week cycles. Fourteen patients were evaluable for response. Four patients showed partial responses; mean time to tumor progression (MTP) was 8 weeks. Six patients stabilized; MTP was 11 weeks. Four patients showed no response. There were no infectious or hemorrhagic complications, but partial hearing loss occurred in 7 patients and severe vomiting in 8 patients. High-dose intravenous cisplatin demonstrates substantial activity against malignant gliomas recurrent after chloroethylnitrosourea (CENU) failure.     

Arachidonic acid metabolic profiles in human meningiomas and gliomas

We determined arachidonic acid (AA) cyclooxygenase metabolic profiles in specimens of human intracranial tumors (gliomas and meningiomas) and, when available, normal brain tissue. Samples were collected at surgery and immediately frozen in liquid nitrogen. The five stable metabolites of AA (PGE2, PGD2, PGF2, 6-keto-PGF1 and TXB2) were measured by high-resolution gas chromatography-mass spectrometry after ex vivo metabolism of endogenous AA by tissue homogenates. The absolute amounts of AA metabolites varied widely between samples, though meningiomas and gliomas showed characteristic profiles. Compared to the slow-growing benign meningiomas, the rapidly-growing infiltrating gliomas had higher synthesis of TXA2 (reported as a procancer metabolite) and lower synthesis of PGD2 and PGI2 (reported as anticancer metabolites). A higher overall synthesis capacity, preferentially toward TXA2, was found in glioblastomas than in nonpathological brain tissue.This paper was presented in part at the Sixth International Conference on Brain Tumor Research and Therapy, Asheville, North Carolina, October 20–23, 1985.     

An integrated approach to the treatment of chiasmatic-hypothalamic gliomas

The treatment of visual pathway gliomas is controversial. The many retrospective studies reporting outcome data for patients with chiasmatic/hypothalamic gliomas are difficult to interpret for several reasons. First the natural history of these tumors is erratic with some reports suggesting that most visual pathway gliomas are hamartomas and follow an indolent course, and others reporting 10-year survival rates of close to 60%. Second, earlier studies did not clearly indicate which patients had neurofibromatosis type 1 (NF1) and recent evidence suggests that the natural history of optic gliomas is more favorable in patients with NFL Third the methods and accuracy of diagnosis have changed dramatically and patients diagnosed before and after the[/p] advent of CT/MR imaging have often been included in the same series.While surgical resection is usually not a viable option for definitive treatment of these tumors, recent studies have shown favorable results after subtotal resection in selected patients. The efficacy of radiotherapy has not been unequivocally demonstrated and treatment-related morbidity has become a major concern, in particular, adverse effects on cognition and growth. Chemotherapy has been advanced as an viable alternative to avoid or delay the adverse affects of RT, but the long-term outcome benefits and adverse effects of treatment are just being defined. Despite the limitations of currently available information, sufficient data are now available to rational management quotelines for the majority of children with chiasmatic/hypothalamic gliomas.     

Management of malignant gliomas during pregnancy: a case series

BACKGROUND.

Limited data are available on the management of glioma in pregnant women. Therefore, the aim of the current article was to describe the outcome of women with malignant gliomas who were exposed to chemotherapy early in the gestation period of their pregnancies.

METHODS.

The authors presented a case series of 6 women with malignant gliomas who during glioma‐directed treatment were discovered to have an unplanned pregnancy. All patients elected to discontinue chemotherapy and carry their pregnancy to term.

RESULTS.

All women had uneventful pregnancies with no glioma‐related complications. All women delivered healthy newborns without evidence of congenital malformations despite exposure to cytotoxic chemotherapy and anticonvulsant medications.

CONCLUSIONS.

Management of malignant glioma during pregnancy is challenging; however, normal delivery and healthy live birth is possible. Cancer 2008. © 2008 American Cancer Society.     

A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study

Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m²) weekly × 3 + vinblastine (4.5 or 3.5 mg/m²) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m²) on day 1 + vinblastine (4.0 mg/m²) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7–14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m² carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m² carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m²/dose on day 1, and vinblastine, 4 mg/m²/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.     

Phase II study of a radiotherapy/etoposide combination for patients with newly malignant gliomas

Purpose: Etoposide, a semisynthetic derivative of podophyllotoxine, is a topoisomerase II inhibitor. This drug is currently used in several types of human cancer. The aim of this study was to evaluate the efficacity and tolerance of a near-concurrent association of radiotherapy and etoposide for newly malignant gliomas. Methods: From May 1995 to December 1996, 30 malignant glioma patients were included in this phase II study; 16 patients underwent surgical tumor resection, and a stereotactic biopsy was performed in 14 patients. Standard cranial irradiation and six courses of etoposide (100 mg/m², ×days 1–3) were administered. The first course of etoposide was administered on days 1–3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. Results: Only 26 patients could be evaluated for the purpose of our study. The median age was 60.1 years, and the median Karnofsky performance score (KPS) was 80.2. The rate of objective response for evaluable patients was 34.6%, and four complete responses (CR) and five partial responses (PR) were noted. The median survival (MST) was 12 months, and the average overall survival was 12.5 months. Hematological toxicity was mild, and grade 3 or 4 neutropenia (white blood cell count <1500/ml) was noted in three patients, without any sepsis or bleeding. Conclusions: The results obtained in this study are comparable to the best reported results on the combination of radiotherapy and nitrosoureas. The near-concurrent combination of radiotherapy and etoposide seems to be effective and well tolerated in the treatment of newly malignant gliomas. Received: 7 December 1998 / Accepted: 5 February 1999     

A comparison of treatment results for recurrent malignant gliomas

Retreatment of malignant gliomas may be performed with palliative intent after careful consideration of the risks and benefits, and with special regards to iatrogenic neurotoxicity and quality of life (QOL). This review compares studies of several retreatment strategies (published between 1987 and 2000) based on the quality of their evidence. Depending on both established prognostic factors and previous treatment, individually tailored retreatment strategies are possible. In all studies that included a multivariate analysis of prognostic factors, performance status was the most important. So far, predictive factors for response, which might facilitate patient selection, have not been unequivocally defined.In terms of QOL, single-agent chemotherapy (temozolomide, nitrosoureas, platinum and taxane derivatives) may offer a better therapeutic ratio than polychemotherapy. For glioblastoma multiforme, progression-free survival and QOL were more favourable after temozolomide than procarbazine (level 1 evidence).The survival of patients after various radiotherapy techniques is broadly similar. However, considerable toxicity is associated with radiosurgery or brachytherapy. Fractionated stereotactic radiotherapy plus radio-sensitizing cytostatic agents has shown promising initial results in small groups of selected patients and awaits further evaluation. Level 2 evidence derived from non-randomized studies does not suggest a substantial prolongation of survival by re-resection as compared with chemotherapy or radiotherapy alone. Level 1 evidence derived from a randomized trial suggests that application of BCNU polymers significantly improves the outcome after re-resection. However, most studies reported median survival in the range of only 25-35 weeks, thereby emphasizing the need for the development and clinical evaluation of new innovative treatment approaches.     

Pilot study of 6 weeks of chemoradiotherapy with 5 FU and hydroxyurea in malignant gliomas

Summary In an attempt to improve the primary treatment of malignant gliomas we used a concomitant 6-week course of chemoradiotherapy with 5 fluorouracil (5 FU) and hydroyxurea (HU) in 24 adults with anaplastic astrocytoma (AA) (7 cases) or glioblastomas (GLB) (17 cases). This patient population was characterised by a poor prognostic profile; 50% of cases had biopsic or subtotal surgery and 70% had GLB. Patients received 2 Gy/day 18 MV photons with 300m² of 5 FU in continuous infusion and 500 mg x 4/day per os of HU, five days per week during 6 weeks. Treatment was poorly tolerated in terms of toxicity and implied heavy logistics (hospitalization, central venous access) worsening the quality of life which is already bad in malignant gliomas. Unfortunately we did not improve median survival which does not exceed 26 weeks with 7 long survivors (> 49 weeks). This pilot study does not offer any benefits over current standard approaches. Aggressive locoregional approaches such as this should perhaps be attempted in patients with a better profile.     

Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group

To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.     

Role of tyrosine kinase inhibitors in the management of high-grade gliomas

Recent years have witnessed an explosion of promising therapies for cancer patients. New insights into the biology of malignancies have led to the development of targeted agents with the potential to improve survival and quality of life. One of the most important classes of these compounds are tyrosine kinase inhibitors. These agents are beginning to offer a clinically relevant benefit to patients with tumors that until recently have been refractory to medical therapies. High-grade gliomas represent one class of medically refractory solid tumors. This article summarizes the state of the art of tyrosine kinase inhibitors in the management of patients with high-grade gliomas.     

Factor analysis of the immunophenotypes of astrocytomas and malignant gliomas: Correlations with tumor grade and patient survival

Summary Our previous investigations correlated the degree of cytogenetic and immunophenotypic heterogeneity of cultured normal glia, astrocytomas and malignant gliomas. The possible significance was suggested by the statistical correlation of individual antigens with diagnosis and patient survival [1]. The present study has established the patterns of covariation of titers of monoclonal antibody reactivity with a panel of cell surface antigens among normal glia (8), astrocytomas (4), anaplastic astrocytomas (12), mixed malignant gliomas (8) and glioblastomas (21). A mean aggregate titer across 43 antigens was computed for each culture and then subtracted from the observed individual titers. Factor analysis was performed to determine a small number of Factors, derived as the weighted average of the 43 mean-adjusted antigens, which accounted for a significant proportion of the covariation of immunophenotypic expression in the sample of 53 cultures. Clusters of antigens were found to independently segregate in their deviation from the aggregate phenotype. Adjusting for age and diagnosis, Factors 1 and 4 correlated with patient survival among recurrent and primary neoplasms, respectively. Factor 2 additionally discriminated between primary and recurrent gliomas. Factor 3 was associated with age at diagnosis. Factors 1 and 2 correlated with the histopathologic grade of glial tumor. Scatter plots of Factor 1 vs. 2 revealed the minimal immunophenotypic diversity of the normal glia. Astrocytomas were similar but not identical. Progressive divergence was evident between the immunophenotypes of anaplastic astrocytomas, mixed gliomas and glioblastomas. These data suggest that qualitative and quantitative differences in antigenic heterogeneity may identify stages in glial tumor progression. Furthermore, the aggregate immunophenotype may be a useful prognostic indicator, which is independent of established clinical variables such as age at diagnosis and pathologic grade of neoplasm. Factor analysis has been shown to be an efficient means of reducing the dimensionality of the data without sacrificing its informative character.     

Altered therapy schedules in postoperative treatment of patients with malignant gliomas

Results of altered therapy schedules obtained in postoperative treatment of 294 patients with malignant gliomas over last 20 years are presented. During this period 135 patients received Conventional Irradiation and Chemotherapy (CICH), 61 patients received Conventional Irradiation (CI), 59 patients received Split Course High Fractional Dose Irradiation (SCHFDI), and 39 patients received Twice a Day Accelerated Irradiation (TDAI). Actuarial survival rates at 2, 3 and 5 years were 19%, 7%, 0% respectively for patients treated with CICH, and they were 21%, 10%, 0% for CI group, 24%, 12%, 0% for SCHFDI option and 15%, 8%, 0% for TDAI schedule. According to the Cox proportional hazard model, only age was significant factor in prognosis.     

Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas

A prospective, randomized trial evaluates the effects of two postoperative treatment regimens on survival in 198 adult patients with supratentorial gliomas. All patients were irradiated with 6 000 rads after possibly radical removal of tumors. CCNU administration in the dosis of 100 mg/sq m of body surface every 6–8 weeks following surgery proved to have no significant effect on the survival of patients. The median survival time in patients receiving radiation therapy alone was 61±7 weeks, while in those receiving additional chemotherapy was 56±4 weeks. Tumor histological malignancy and patients age were found to be the only important prognostic factors, irrespective of the treatment modality. Address for offprints: T Trojanowski, Department of Neurosurgery, Medical School, Jaczewskiego 8, 20-950 Lublin, Poland     

Oncogene-related growth factors and growth factor receptors in human malignant glioma-derived cell lines

Oncogenes induce malignant transformation of cells. Two oncogenes are closely related to genes coding for a mitogenic growth factor (v-sis to the PDGF gene) and a receptor for a mitogenic growth factor (v-erb B to the EGF receptor gene). We studied the possibility that cells derived from malignant gliomas produce mitogenic factors that bind to cell surface receptors, the activation of which could lead to excessive stimulation of cell proliferation. All six cell lines tested secrete into their medium factors that stimulate DNA synthesis. The factor secreted by one cell line was characterized and found to resemble PDGR Six of 11 cell lines had receptors for PDGF demonstrable by binding and receptor autophosphorylation assays. Six of six cell lines tested had EGF receptors demonstrable by binding and receptor autophosphorylation experiments. The extremely high levels of EGF receptor in one cell line may reflect excessive expression of the erb B oncogene associated with abnormalities of chromosome 7 that occur in this cell line.