Chemotherapy in the treatment of malignant gliomas

Malignant gliomas are one of the most difficult tumors to treat, with only modest advances being made in the past few decades. Surgery and radiation have had the greatest impact, increasing survival. Chemotherapy modestly increases survival. The use of chemotherapy in the treatment of malignant gliomas is the focus of this paper and the more commonly used agents at diagnosis and relapse are reviewed. Since most patients fail first-, second- and even third-line agents that are commercially available, some of the more relevant new biological compounds will also be discussed. As treatments for brain tumors evolve, it is likely that optimal therapies will come from combination therapies that incorporate target-specific and chemotherapeutic agents.     

Inhibition of angiogenesis and invasion in malignant gliomas

Malignant gliomas confer a dismal prognosis. As the molecular events that underlie tumor angiogenesis are elucidated, angiogenesis inhibition is emerging as a promising therapy for recurrent and newly diagnosed tumors. Data from animal studies suggest that angiogenesis inhibition may promote an invasive phenotype in tumor cells. This may represent an important mechanism of resistance to antiangiogenic therapies. Recent studies have begun to clarify the mechanisms by which glioma cells detach from the tumor mass, remodel the extracellular matrix and infiltrate normal brain. An array of potential therapeutic targets exists. Combination therapy with antiangiogenic and novel anti-invasion agents is a promising approach that may produce a synergistic antitumor effect and a survival benefit for patients with these devastating tumors.     

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.     

Mechanisms of angiogenesis in gliomas

Summary Gliomas are the most frequent primary tumors of the central nervous system in adults. Glioblastoma multiforme, the most aggressive form of astrocytic tumors, displays a rapid progression that is accompanied by particular poor prognosis of patients. Intense angiogenesis is a distinguishing pathologic characteristic of these tumors and in fact, glioblastomas are of the most highly vascularized malignant tumors. For this reason, research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenic blood vessels in order to develop new approaches that effectively block angiogenesis and cause tumor regression. We discuss here some important features of glioma angiogenesis and we present molecules and factors and their possible functions and interactions that play a role in neovascularization. In spite of the great progress that molecular biology has achieved on investigating tumor angiogenesis, many aspects remain obscure and the complexity of the angiogenic process stands for an obstacle in identifying the exact and complete molecular pathways orchestrating new blood vessels formation, which are necessary for the survival and expansion of these tumors.     

The basis for current treatment recommendations for malignant gliomas

Although primary brain tumors represent an important cause of cancer related mortality in the United States, advances in the treatment of these tumors has been slow and has generally lagged behind that of most systemic tumors. One of the major reasons for this is the paucity of well conducted, prospective radiation and chemotherapy trials. For the brain tumor trials that have been conducted, small patient numbers, heterogeneous patient populations, and non-uniformity of response criteria, have made the current clinical data base difficult to interpret. Data from several prospective, multi-institutional randomized trials have defined a role for radiation therapy in the treatment of malignant gliomas and on-going trials will help define refinements in technique. Although there does appear to be a place for the use of chemotherapy in the treatment of a subgroup of patients with malignant gliomas, its role for the majority of patients remains unclear. Only through better understanding of the biology of these tumors, more effective therapies, and the implementation of better clinical trial design can we hope to make significant progress in the treatment of malignant gliomas.     

Convection enhanced delivery for the treatment of malignant gliomas: symposium review

Summary In January 2003 a symposium was held to discuss the current state of progress and future challenges for the recently described technique of convection enhanced delivery (CED). The focus of the CED symposium was on the potential use of this novel drug delivery technology to enhance the delivery of chemotherapy to malignant brain tumors. The international panel of invited speakers included individuals who had a significant role in pioneering the concept of CED, were actively pursuing new areas of investigation into the uses of CED and/or who were directing the first clinical trials using CED in patients with malignant brain tumors. Topics covered included the physiology of the blood brain barrier, basic principles of CED, application of CED to the treatment of brain tumors, and research models that have been developed to further refine the technique of CED. Each speakers talk has been abstracted and a list of relevant references has been compiled.     

Molecularly targeted therapies for malignant gliomas: advances and challenges

The identification of molecular markers associated with tumor but not with normal tissue has allowed the development of highly specific, targeted therapies for the treatment of cancer. Over the last several years, tremendous advances in our understanding of the genetic and molecular changes involved in the progression of malignant gliomas have triggered a large effort in the development of targeted therapies to treat these tumors. However, to date only a modest clinical benefit, limited to subsets of patients, has been demonstrated. Furthermore, despite a high degree of target selectivity, the use of targeted therapies often has systemic toxicity. The reasons behind this limited clinical success are complex and include the intricacy of the signaling pathways in gliomas and the heterogeneity of the disease process, compounded by existing limitations in assessing the efficacy of these novel agents when conventional end points and clinical trial designs are utilized. However, despite these difficulties targeted therapies remain a very attractive avenue of treatment for malignant gliomas. Three basic approaches are needed to overcome the hurdles associated with targeted therapies: first, further development of genetic profiling techniques will help to better determine the genetic changes and molecular pathways involved in gliomas and will potentially allow the design of individualized therapies based on the genetic and molecular signature of each tumor. Second, there is a need for the development of better combination strategies (complementary targeted agents or targeted agents with chemotherapy drugs) directed towards disease heterogeneity. Third, we need to optimize the design of preclinical and clinical trials to obtain the maximum amount of information in the shortest period of time.     

A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas

BACKGROUND:

Hypericin is a potent inhibitor of glioma growth in vitro. To examine whether synthetic oral hypericin can be tolerated by patients with recurrent malignant gliomas (anaplastic astrocytoma and glioblastoma) and to investigate its efficacy against these tumors, the authors undertook an open‐label, sequential dose escalation/de‐escalation tolerance study.

METHODS:

Patients with documented recurrent or progressive malignant gliomas who had received standard radiation therapy with or without chemotherapy were included. Patients were excluded for previous treatment with agents known to contain hypericin or treatment within 30 days with medications known to cause photosensitivity. Enrolled patients were given gradually increasing dosages of oral synthetic hypericin (0.05‐0.50 mg/kg) for up to 3 months if no toxicity was observed, and patient response to treatment was noted. The patients were examined each month and underwent magnetic resonance imaging to evaluate tumor status at 3 months.

RESULTS:

Synthetic hypericin administered orally appeared to provide stabilization or a slight (<50%) decrease in tumor volume (coded as stable disease) at 3 months for 7 of 42 patients (17%) and produced a tumor reduction >50% (partial response) in 2 patients (5%). Seventeen patients (40%) survived for 3 months on daily synthetic hypericin at dose levels of 0.33 ± 0.070 mg/kg daily. The mean maximum tolerated dose was 0.40 ± 0.098 mg/kg daily. Twelve patients continued on hypericin therapy beyond 3 months. The median survival was 26 weeks (Kaplan‐Meier method).

CONCLUSIONS:

The results of this study indicated that synthetic, oral hypericin is well tolerated in this patient group. The response results were comparable to those reported from other studies of salvage therapies for recurrent malignant brain tumors. Cancer 2011;. © 2011 American Cancer Society.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma muhiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma multiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Several low molecular weight signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials. The efficacy of these agents as monotherapies has been modest, at best; however, small subsets of patients who harbor specific genetic changes in their tumors may display favorable clinical responses to defined small molecule inhibitors. Multitargeted kinase inhibitors or combinations of agents targeting different mitogenic pathways may overcome the resistance of tumors to single-agent targeted therapies. Well designed studies of small molecule kinase inhibitors will include assessment of safety, drug delivery, target inhibition and correlative biomarkers to define mechanisms of response or resistance to these agents. Predictive biomarkers will enrich for patients most likely to respond in future clinical trials. Additional clinical studies will combine novel targeted therapies with radiation, chemotherapies and immunotherapies.     

Targeted therapies in the treatment of gastric cancer

Gastric cancer (GC) constitutes a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant and neoadjuvant radiotherapy and chemotherapy approaches have increased the survival of patients with loco-regional disease. However most patients with GC have advanced disease either at diagnosis or at follow up. Despite recent advances in the treatment of advanced disease, these patients still have poor outcomes. An emerging understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of GC. These therapeutic strategies include epidermal growth factor receptor inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis, promoters and matrix metalloproteinases inhibitors.     

Phase II trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas

We conducted a phase II trial to evaluate the efficacy and toxicity of radiotherapy immediately after hyperbaric oxygenation (HBO) with chemotherapy in adults with high-grade gliomas. Patients with histologically confirmed high-grade gliomas were administered radiotherapy in daily 2 Gy fractions for 5 consecutive days per week up to a total dose of 60 Gy. Each fraction was administered immediately after HBO with the period of time from completion of decompression to irradiation being less than 15 min. Chemotherapy consisted of procarbazine, nimustine (ACNU) and vincristine and was administered during and after radiotherapy. A total of 41 patients (31 patients with glioblastoma and 10 patients with grade 3 gliomas) were enrolled. All 41 patients were able to complete a total radiotherapy dose of 60 Gy immediately after HBO with one course of concurrent chemotherapy. Of 30 assessable patients, 17 (57%) had an objective response including four CR and 13 PR. The median time to progression and the median survival time in glioblastoma patients were 12.3 months and 17.3 months, respectively. On univariate analysis, histologic grade (P=0.0001) and Karnofsky performance status (P=0.036) had a significant impact on survival, and on multivariate analysis, histologic grade alone was a significant prognostic factor for survival (P=0.001). Although grade 4 leukopenia and grade 4 thrombocytopenia occurred in 10 and 7% of all patients, respectively, these were transient with no patients developing neutropenic fever or intracranial haemorrhage. No serious nonhaematological or late toxicities were seen. These results indicated that radiotherapy delivered immediately after HBO with chemotherapy was safe with virtually no late toxicity in patients with high-grade gliomas. Further studies are required to strictly evaluate the effectiveness of radiotherapy after HBO for these tumours.     

Changing boundaries in the treatment of malignant gliomas

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.     

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00671970","term_id":"NCT00671970"}}NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.     

A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas

Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525–900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy.     

Clinical trials of viral therapy for malignant gliomas

Despite recent scientific advances in the understanding of the biology of malignant gliomas, there has been little change in the overall survival for this devastating disease. New and innovative treatments are under constant investigation. Starting in the 1990s, there was an interest in using viral therapeutics for the treatment of malignant gliomas. Multiple strategies were pursued, including oncolytic viral therapy, enzyme/pro-drug combinations and gene transfer with viral vectors. Multiple Phase I and II trials demonstrated the safety of these techniques, but clinically showed limited efficacy. However, this led to a better understanding of the pitfalls of viral therapy and encouraged the development of new approaches and improved delivery methods. Here we review the prior and ongoing clinical trials of viral therapy for gliomas, and discuss how novel strategies are currently being utilized in clinical trials.     

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.     

恶性脑胶质瘤术后放疗联合替莫唑胺化疗的疗效观察

目的比较单纯放射治疗及放疗联合替莫唑胺治疗高级别胶质瘤的有效性以及不良反应。方法 86例术后病理证实间变性星形细胞瘤及胶质母细胞瘤随机分为单纯放疗（RT）以及放疗联合替莫唑胺治疗组,研究两组患者治疗有效率、生活质量和药物安全性。结果两组间各项临床病理特征相似,其中病灶未完全切除患者共62例。术后放疗联合替莫唑胺组（RT-TMZ）以及单纯放射治疗（RT）组的近期总有效率分别为87.5%和60.0%（P〈0.05）。RT-TMZ组中位生存期为16.2月,RT组仅10.7月（P〈0.05）。RT-TMZ组的1、2年生存率分别为74.4%和46.5%,明显高于单纯RT组（P〈0.05）。而RT-TMZ组患者对治疗的耐受性良好,常见不良反应是骨髓抑制和呕吐。结论术后放疗联合替莫唑胺化疗治疗高级别胶质瘤能有效提高治疗有效率及生活质量,提高患者无瘤生存期,且患者耐受性较好。     

Emerging clinical principles on the use of bevacizumab for the treatment of malignant gliomas

Despite advances in adjuvant therapy, the prognosis for most patients with high‐grade glioma (HGG) is poor, and almost all HGGs have a likelihood of disease recurrence. HGGs are highly vascularized tumors with elevated expression levels of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. A compelling biologic rationale, a pressing need for improved therapeutics and positive results from studies of bevacizumab in other tumor types, led to the evaluation of bevacizumab in the treatment of HGG. It was demonstrated previously that bevacizumab, which is a humanized monoclonal antibody that targets VEGF, improved outcomes when combined with chemotherapy (most commonly irinotecan) in patients with recurrent HGG; and, on the basis of an improved objective response rate in 2 prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration as a single agent in patients with previously treated glioblastoma (GB). Bevacizumab‐containing therapy has been associated with manageable, class‐specific toxicity; however, severe treatment‐related adverse events are observed in a minority of patients. Preliminary data on bevacizumab‐based therapy in recurrent anaplastic gliomas, in the frontline treatment of GB, and in additional patient populations are also encouraging. With the goal of addressing unanswered questions regarding the optimal use of bevacizumab, the objective of the current review was to provide a summary of the clinical efficacy and safety data on bevacizumab in patients with HGG, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in additional brain tumor treatment settings. Cancer 2010. © 2010 American Cancer Society.     

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.