Gene transfer technologies for malignant gliomas.

Although early clinical gene therapy trials for recurrent central nervous system neoplasms showed the proof-of-principle, they did not fulfill the high expectations suggested by the preclinical experimental data. Insufficient distribution of vectors in human brain tumors and very low transduction efficiency require that we reevaluate gene transfer concepts for brain tumor treatment. Major steps to improve gene transfer into the central nervous system and the efficacy of gene therapy for malignant brain tumors include: 1) the design of more effective vector systems; 2) the development of new or improved prodrug/suicide systems, gene replacement approaches, or strategies targeting the immune response or tumor angiogenesis; 3) the study of new techniques to enhance delivery of genetic vectors into brain tumors and for monitoring gene delivery into tumors; and 4) assessment of the role of gene therapy as part of a combined treatment approach.     

Novel radiation-enhancing agents in malignant gliomas

Malignant gliomas represent among the most aggressive of all known human neoplasms. These tumors show high levels of resistance to conventional therapies (ie, surgery, radiation, and chemotherapy). For many decades, significant improvements in clinical outcomes of newly diagnosed glioblastoma (GBM) patients have not been observed until recently. A landmark European Organization for Research and Treatment of Cancer (EORTC) phase III study showed significant improvements in median and 2-year survivals in newly diagnosed GBM patients treated with a combination of radiation and temozolomide chemotherapy versus radiation alone. The results of this study have certainly defined practice standards for this patient population. This article will review the role of both traditional nitrosurea-based and newer-generation chemotherapeutic and biotherapeutic agents when combined with radiation therapy for the treatment of malignant glioma patients.     

Intraoperative radiation therapy (IORT) for previously untreated malignant gliomas

Background  

Intraoperative radiation therapy (IORT) is one of the methods used to deliver a large single dose to the tumor tissue while reducing the exposure of normal surrounding tissue. However, the usefulness of intraoperative electron therapy for malignant gliomas has not been established.     

High dose radiation therapy in the treatment of malignant gliomas: final report.

One hundred patients with supratentorial malignant gliomas were prescribed to receive postoperative whole brain irradiation with doses ≥5000 rad; 41 had astrocytoma grade III and 59 had grade IV tumors. The median survival was 91 weeks for patients with grade III tumors and only 42 weeks for those with grade IV (p < 0.01). For both grades, patients who were ≤45 years of age survived significantly better than patients who were older at diagnosis (p < 0.05). Patients with tumors at each grade were divided into three groups depending on the total dose delivered to the tumor; 5000, 6000, 7500 rad (median doses).For patients with grade IV tumors the median survival was 30, 42 and 56 weeks respectively, these differences were significant (p < 0.05) between the extremes but not between consecutive dose groups and were maintained only up to 2 years from the initiation of treatment. For patients with grade III tumors, the median survival was 43, 82 and 204 weeks respectively; these differences were significant (p < 0.05) between consecutive dose groups and between extremes and were maintained up to 4 years from the initiation of treatment. For 22 patients with grade IV who were treated with high-doses (7500 rad), the median time for recurrence was 43 weeks while for six patients with grade III tumors it was 158 weeks.The use of higher radiation doses was well tolerated; it did not compromise the quality of survival, and did not yield normal brain tissue necrosis. However, these doses did not seem to alter the total survival of patients, nor did they seem capable of sterilizing these tumors. Histopathological changes that were observed in normal brain tissue that was irradiated with 7000–8000 rad suggest that increasing total doses beyond this range might attain tumor sterilization, but could also lead to frank radiation necrosis in these patients.     

Cranial radiation and concomitant cisplatin and mitomycin-C plus resistance modulators for malignant gliomas

We studied the toxicity and efficacy of adding in sequence 4 resistance modulators to combination chemotherapy and radiotherapyin the treatment of glioblastoma multiforme and poor prognosis anaplastic astrocytomas. Patients received cisplatin plus mitomycin-C concurrently with and following 60 Gy of radiotherapyadministered over 6 weeks. Resistance modulators were added in sequence to chemotherapy in each cohort of 6 patients as follows: metronidazole + pentoxifylline (cohort 1); + dipyridamole(cohort 2); + beta carotene (cohort 3). Central nervous system toxicity (which ranged from drowsiness to seizures and lossof consciousness) was frequent. The incidence of gastrointestinal symptoms was substantial, but was usually mild to moderatein severity. Three of 11 patients evaluable for response achieved a partial remission with treatment. The median survival duration for all patients was 26 weeks from initial diagnosis. The study was terminated prematurely because of significant toxicity (in this study as well as in parallel concurrent studies of similar design in other tumor types) and apparent lack of benefit.     

Chemosensitivity assays for malignant gliomas

Chemosensitivity assays including colony forming assay (CFA), MTT dye reduction assay (MTT assay) and thymidine incorporation assay (TIA) for cultured rat and human glioma cells were conducted to determine the correlation among them and the in vivo antitumor efficacy of anticancer drugs using rats implanted glioma cells. Cytotoxicity of various agents such as ACNU, ACR, CDDP, VCR or BLM, was estimated from the concentrations which caused 50% inhibition of the cell growth at the peak plasma concentration. The survival time of tumor bearing rats was assessed after ip treatment with these agents at their estimated clinical doses. This parameter was greater in the drugs that were shown to be highly sensitive in CFA and was consistent with the data for CFA. In the chemosensitivity assays, CFA closely correlated to MTT assay for all agents except VCR, but poorly so to TIA. The results in this study indicate that MTT assay seemed to be useful for determining the chemosensitivity of anticancer drugs and that chemosensitivity assay should be conducted depending on the nature of anticancer drug.     

Novel targeted agents for platelet-derived growth factor receptor and c-KIT in malignant gliomas

Malignant gliomas are a heterogeneous group of tumors with a varying natural history and response to treatment. Despite current therapeutic strategies, these tumors almost universally recur after excision and are associated with a poor survival. Increasingly, the true heterogeneity of these tumors is being correlated with distinct molecular subgroups. Platelet-derived growth factor receptor (PDGFR) alpha is almost universally expressed on glioma cells; expression of the proto-oncogene c-KIT has also been reported. These findings have led to the clinical investigation of inhibitors of this pathway, such as imatinib and dasatinib, for the treatment of recurrent malignant glioma. To date, this approach in unselected patients has been disappointing. However, isolated responses have been seen, which may correlate with constitutive activation of one or more of the corresponding tyrosine kinases. In the future, it is hoped that an increasing knowledge of glioma biology will translate into the more judicious use of these and other targeted therapies, resulting in improvements in patient outcomes. This review describes the preclinical science behind PDGFR and c-KIT, the clinical importance of these molecular pathways and the available data from translational clinical trials.     

Blood-based biomarkers for malignant gliomas

Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood–brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.     

Molecular pathogenesis of malignant gliomas.

De novo glioblastomas develop in older patients without prior clinical history of less malignant tumors. Progressive glioblastomas are common among younger patients and arise through progression from lower-grade astrocytomas. CDKN2A deletions, PTEN alterations, and EGFR amplification are more prevalent among de novo glioblastomas, whereas p53 mutations are more common among progressive glioblastomas. Loss of heterozygosity (LOH) for chromosome 10 is seen uniformly among both de novo and progressive high-grade astrocytomas. The inactivation of the PTEN gene is found in approximately 30% to 40% of astrocytomas with chromosome 10 loss, and LOH pattern in the remaining astrocytomas strongly supports the presence of another yet unidentified tumor suppressor gene telomeric to PTEN. More than 80% of oligodendrogliomas exhibit LOH for 1 p and 19q alleles. Oligoastrocytomas with 1p/19q LOH are related to oligodendrogliomas, and those with p53 mutations are related to astrocytomas.     

Treatment of recurrent malignant gliomas with stereotactic intensity modulated radiation therapy

Malignant gliomas are usually refractory to aggressive combined-modality therapy, and the incidence of recurrence and death after treatment is very high. State-of-the-art techniques such as stereotactic intensity-modulated radiation therapy (IMRT) are now available to deliver a high dose of radiation to the tumor with relative preservation of surrounding tissues to achieve optimal tumor coverage with minimal toxicity. We report 10 patients (median age 48 years) with recurrent malignant gliomas that were treated with stereotactic directed IMRT. Initial tumor histologies included one low grade glioma (upgraded to anaplastic astrocytoma at recurrence), four anaplastic astrocytomas, and four glioblastomas multiforme. One patient was originally presumed to have a brain metastasis secondary to renal cell carcinoma but was pathologically confirmed as having glioblastoma multiforme at the time of recurrence. Before recurrence, all patients had been treated with external beam radiation therapy (median 59.7 Gy). All recurrences were confirmed by a subtotal resection (5/10) or by imaging (5/10). The median Karnofsky performance score at the time of IMRT was 80. The median tumor volume was 34.69 cm. Treatment was delivered on a 10-MV linear accelerator with a mini-multileaf collimator, MIMiC, and planned with Peacock/Corvus software. Radiation was delivered in daily fractions of 5 Gy, to a total median dose of 30 Gy at the 71% to 93% median isodose line. Median overall survival time was 10.1 months from the date of stereotactic treatment, with 1- and 2-year survival rates of 50% and 33.3%, respectively. Fractionated stereotactic intensity modulated radiation therapy is a novel technique used in the treatment of recurrent malignant gliomas, which produces results comparable to other currently used stereotactic techniques.     

Boron neutron capture therapy for murine malignant gliomas.

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.     

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.     

Promising new therapies for malignant gliomas

Since the publication of the 7th edition of Cancer, Principles & Practice of Oncology, there have been several potentially important advances in the treatment of patients with high-grade gliomas. These advances have occurred in the area of molecular targeting of the epidermal growth factor receptor and in attempts to inhibit glioma-associated angiogenesis. For the first time ever, drugs are being used that can cause reproducible and clinically meaningful tumor responses in patients with recurrent malignant gliomas. Unfortunately, the number of patients with long-term responses to these agents remains relatively low. Identification of biomarkers that will allow a more accurate prediction of which patients are likely to benefit from a specific treatment and new radiographic criteria of true drug-mediated antitumor effects will be increasingly important as new molecular targeted agents are evaluated in patients with primary brain tumors.     

恶性胶质瘤的综合治疗现状

恶性胶质瘤是常见的肿瘤,其死亡率和致残率均很高,手术、放疗及化疗的综合治疗已经成为恶性胶质瘤治疗常规。近年来,术后放疗及化疗出现了许多进展。本文就恶性胶质瘤的综合治疗现状及进展作一综述。     

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.     

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 molecular therapy for malignant gliomas

Opinion statement Advances in our understanding of the molecular changes and resultant cellular effects in malignant glioma are expanding the opportunities for novel targeted therapies. At present, chemotherapy and radiation followed by chemotherapy with nonselective cytotoxic agents is emerging as a standard treatment option for patients with malignant glioma. Unfortunately significant improvements in response and survival have not occurred for the majority of patients. The continued improvement in patient outcomes will require the incorporation of glioma-specific therapies either in the form of compounds specifically targeted to glioma-specific receptors or that inhibit signaling pathways promoting glioma survival and progression.     

Cisplatin does not enhance the effect of radiation therapy in malignant gliomas

The aim of this randomised trial was to test the effect of cisplatin given during radiation therapy in adults with supratentorial malignant gliomas. Of 285 patients included, 246 were evaluable. The main reasons for exclusion were: inadequate pathology or no pathology review (24 patients), exclusion of the institution (11 patients), and inadequate follow-up (4 patients). For 121 patients randomised to receive cisplatin 50 mg/m² on days 1, 8, 15 and 22 of radiation therapy, 81 were given the full dose. Radiation therapy alone was given to 125 control patients. All patients were followed until the recurrence of clinical signs (free interval) and until death (survival). Neither of these two parameters was modified by cisplatin. No signs of major toxicity were reported. It is concluded that at the doses used, cisplatin does not enhance the effects of radiation therapy in malignant gliomas.     

Radiosensitivity testing of human malignant gliomas.

Radiotherapy remains the main treatment modality for patients with malignant gliomas and is the only treatment which significantly prolongs survival. Clonogenic and tetrazolium based colorimetric assays (MTT) of early passage cultures have been performed following 2 Gy doses of x-rays in order to determine if in vitro radiosensitivity is a factor in response to treatment. Of 47 biopsies received, 39 were established in primary culture. A value of surviving fraction to 2 Gy (SF2) was obtained in 85% of growth assays and 64% of clonogenic assays. The mean SF2 value for the MTT was 0.56 which was significantly higher than the 0.42 obtained for the clonogenic assay. There was, however, reasonable qualitative agreement in assessing relative radiosensitivity/radioresistance (r = 0.7). Mean SF2 values for grade 3 tumors were 0.52 (MTT) and 0.35 (clonogenic) as against mean SF2 values of 0.63 (MTT) and 0.47 (clonogenic assay) for grade 4 tumors. In 24 patients with adequate follow-up, no direct correlation was found between SF2 and survival, although mean SF2 values for patients surviving greater than 18 months was significantly less (p = 0.01) than patients surviving less than 18 months as determined by the MTT assay.