Therapy For High-grade Glioma Research Articles

Surviving Fraction (SF2) and Clonogen Cell Density (CCD) are the Dominant Predictors of Tumor Control Probability (TCP) in High Grade Glioma

Surviving Fraction (SF2) and Clonogen Cell Density (CCD) are the Dominant Predictors of Tumor Control Probability (TCP) in High Grade Glioma

Feasibility of Using Bevacizumab With Radiation Therapy in High Grade Gliomas

Use of Bevacizumab, an anti-VEGF monoclonal antibody with Irinotecan has shown promise in the treatment of recurrent high grade gliomas. The purpose of this study was 1. To test the feasibility of using Bevacizumab with radiation therapy in the primary management of recurrent and unresectable high grade gliomas and 2. To correlate the blood volume and vascular permeability changes with tumor volume measurements to assess the response.

123I-IMT SPECT for evaluation of the response to radiation therapy in high grade gliomas: a feasibility study

Assessing response to radiation therapy in patients with high grade gliomas is needed upon making decisions toward further therapy strategies. Currently used standard imaging tools such as CT and MRI are not sensitive enough to detect early therapy effects. We prospectively investigated if single photon emission computed tomography (SPECT) using radiolabelled amino acid derivate (123)I-methyltyrosine (IMT) would be useful for this aim. 10 patients with histologically proven high grade gliomas, who were candidates for radiation therapy, were enrolled in this investigation. All patients were examined by IMT SPECT before radiation therapy and 4 weeks after the initiation of the hypofractionated application of 40 Gy. Patients were followed up for 39 months; the tumours to background ratios (T/B) for IMT under/before radiation therapy were correlated to survival times. Initially, SPECT depicted an abnormal intratumoural IMT uptake in all patients (mean T/B ratios 1.37-1.87). In four out of 10 patients, the mean T/B ratios decreased by more than 10% under radiation therapy. In six other patients, the BQ decreased by less than 10% or increased. There were no significant correlations between the degree of changes in T/B and survival (r = -0.1, p = 0.973). Serial IMT SPECT measurements allow detection of changes in amino acid accumulation in high-grade gliomas under radiation therapy. However, these changes seem to possess no prognostic value in respect to survival prediction.

2059: Biologically Targeted Therapy for High Grade Gliomas Using Inverse-Planned Intensity Modulated Radiotherapy and Diffusion Tensor Imaging

To examine the role of Diffusion Tensor Imaging (DTI) in implementing biologically targeted radiotherapy, using IMRT to deliver synchronous dose boosts to the GTV and adjacent areas of abnormality on DTI. In this dosimetry study of seven patients, IMRT based synchronous boost therapy was compared to standard conformal radiotherapy (CRT). CRT plans were prepared using a 2.5cm CTV margin added to the GTV, and a 0.5cm margin for the planning target volume. A dose of 60Gy in 30 fractions was specified to the PTV. For IMRT synchronous boost plans, a class solution was used to determine doses to the GTV, DTI abnormality and PTV, for a fixed 30 fraction schedule. Multiple normal tissue complication probability models were applied to each plan, specifically to assess the effect of biological dose transformation, and exclusion of the GTV from the volume of brain at risk of radionecrosis. Morphology analysis was used to assess the eccentricity of treatment volumes. Small (GTV<20cc, PTV<380cc) and medium sized (GTV<100cc, PTV<750cc) tumours could be boosted to achieve doses of 80Gy and 74Gy to the GTV respectively, without violating specified normal tissue dose constraints. In 6 of 7 cases, the estimated NTCP for the IMRT boost plan was lower than that of the standard CRT plan. Excluding the GTV from the NTCP calculation resulted in a 32% mean reduction in estimated NTCP. Morphology analysis demonstrated that adequate spatial conformation to the treatment volumes could be achieved without the need for specialist hardware such as micro-multileaf collimators. Dose inhomogeneity was observed in the outer concentric boost volumes, but at a level that compares favourably with previously published clinical studies. DTI based planning is a feasible technique for the implementation of IMRT based biologically targeted therapy.

Cytotoxic and molecular chemotherapy for high-grade glioma: an emerging strategy for the future

Maximal surgical debulking and radiotherapy have been the cornerstone of therapy for high-grade gliomas. The impact of chemotherapy on outcome has been marginal and, until recently, its usage has been debatable. The development of new drugs and an improved understanding of chemoresistance have reinvigorated interest in this treatment modality. Furthermore, increasing knowledge of gliomagenesis has also led to novel non-cytotoxic approaches to targeting the molecular machinery that is responsible for tumour development and progression. These new strategies, which are currently being evaluated in clinical trials, provide new hope for the future.

Photodynamic therapy of high grade glioma – long term survival

Haemetaporphyrin derivative (HpD) mediated photodynamic therapy (PDT) has been investigated as an adjuvant treatment for cerebral glioma. This study records the survival of patients at the Royal Melbourne Hospital with residences in the State of Victoria, utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT following surgical resection of the tumour. For primary (newly diagnosed) tumours, median survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 months for glioblastoma multiforme (GBM). Seventy-three percent of patients with AA and 25% with GBM survived longer than 36 months. For recurrent tumour, median survival from the time of surgery was 66.6 months for AA and 13.5 months for GBM. Fifty-seven percent of patients with recurrent AA and 41% of patients with recurrent GBM survived longer than 36 months. Older age at the time of diagnosis was associated with poorer prognosis. Laser light doses above the sample median of 230 J/cm2 were associated with better prognosis in the 136 patients studied (primary tumour patients - (HR=0.50[0.27,0.95],p=0.033); recurrent tumour patients (HR=0.75[0.42,1.31],p=0.312). There was no mortality directly associated with the therapy, three patients had increased cerebral oedema thought to be related to photodynamic therapy that was controlled with conventional therapies.

439 TGF-beta2 suppression by the antisense oligonucleotide AP 12009 as therapy for high-grade glioma: safety and efficacy results of phase I/II clinical studies

A major obstacle in successful cooled semen storage is the reactive oxygen species generated in the media by the sperm cells. Recently, many reports document the antioxidant, anti-carcinogenic and anti-mutagenic properties of flavonoids when used in vitro or in vivo. The objective of this study was to determine whether supplementing diluents with the flavonoids, silibinin or catechin, would aid in maintaining the viability of caprine sperm during cooling and storage at 5 °C. Semen samples were collected from seven post-pubertal bucks using electro-ejaculation and aliquots of sperm (40×106 cells, replicated 3 times), were diluted in 9% non-fat dried skim milk extender supplemented with 0 (control), 25, 50, 75, or 100 μM of either silibinin or catechin. Diluted samples were cooled and maintained at 5 °C prior to microscopic analysis (250×) using a Makler counting chamber. A minimum of 200 sperm cells per sample were counted to determine the percentage of motile sperm following 24, 48, 72 and 96 h of incubation. An ANOVA was performed on arcsine-transformed data to determine differences in sperm motility between control and treatment levels for each flavonoid. No differences in motility were detected for the silibinin-treated samples at any of the concentrations across the four time periods. Significant differences (P<0.05) in motility were detected between the 0 (control, 34%) and the 25, 50, 75 and 100 μM concentrations of catechin (57, 53, 55 and 64% motile cells, respectively) at 96 h. These results demonstrate that the flavonoid catechin, but not silibinin, aids in maintaining the motility of cooled goat sperm in a dose dependent manner.

TGF-β2 suppression by the antisense oligonucleotide AP 12009 as treatment for pancreatic cancer: preclinical efficacy data

4106 Background: With a 5-year-survival rate of less than 1% pancreatic cancer is one of the most aggressive human cancers. Overexpression of TGF-beta2 in malignancies correlates with decreased survival and is associated with advanced tumor stage due to its pivotal role in malignant progression by inducing key mechanisms including immunosuppression, metastasis, angiogenesis and tumor cell proliferation. In pancreatic cancer patients TGF-beta2 levels were significanty elevated (median: 1,198 pg/ml; range: 319–1,713 pg/ml) as compared to healthy controls (median: 378 pg/ml; range: 241–575 pg/ml). Methods: Aiming at a highly specific anti-tumor therapy, AP 12009, a phosphorothioate antisense oligonucleotide specific for the human TGF-beta2 mRNA, has been developed and tested for its anti-tumor activity in a variety of preclinical studies with pancreatic cancer cells. Results: AP 12009 significantly reduced the TGF-beta2 secretion in several human pancreatic cancer cell lines (Hup-T3, Hup-T4, PA-TU 8902). In functional assays AP 12009 inhibited pancreatic tumor cell proliferation in a dose-dependent manner by up to 76%. Migration of PA-TU 8902 cells was completely blocked as compared to untreated controls in a spheroid migration model while TGF-beta2 antibody had no effect. Additionally, AP 12009 reversed TGF-beta2 mediated immunosuppression in an allogenic PA-TU 8902 system targeted by IL-2 activated PBMC (LAK cells) derived from healthy donors. After AP 12009 treatment LAK cell cytotoxicity was increased in a donor-dependent manner up to 708% of the untreated control (effector/target ratio 20:1). Conclusions: AP 12009 has already shown efficacy in phase I/II clinical studies as therapy for high-grade glioma. Based on this successful application of AP 12009 in clinical studies and the presented preclinical efficacy in tumor proliferation, migration and inhibition of escape from immunosurveillance in pancreatic cancer a multi-site dose-escalation trial with AP 12009 in pancreatic carcinoma is currently being initiated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma

Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-β2 specific antisense oligonucleotide AP 12009

1514 Background: High-grade gliomas are highly aggressive tumors showing marked transforming growth-factor-beta2 (TGF-β2) overexpression inducing proliferation, metastasis, angiogenesis and in particular immunosuppression. Methods: In 3 phase I/II dose escalation studies adult high-grade glioma patients (WHO III/IV) with recurrent tumor and evidence of tumor progression on MRI were treated with AP 12009, a TGF-β2 specific phosphorothioate antisense oligonucleotide. AP 12009 was administered intratumorally by convection enhanced delivery (CED) in 3 studies in up to 12 cycles. In the 3rd study, an indwelling pump system was used that allowed repeated treatment cycles with a single catheter placement on an out-patient basis. Safety and tolerability were primary endpoints. Secondary endpoint was clinical efficacy. Results: In only 5 of the total 24 patients “possibly” related adverse events were observed, mostly of grade 1 or 2, one was classified as serious. There were no relevant changes in laboratory value...

Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-β2 specific antisense oligonucleotide AP 12009

Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-β2 specific antisense oligonucleotide AP 12009

TGF-beta2 suppression by the antisense oligonucleotide AP 12009 as therapy for high-grade glioma: safety and efficacy results of phase I/II clinical studies

TGF-beta2 suppression by the antisense oligonucleotide AP 12009 as therapy for high-grade glioma: safety and efficacy results of phase I/II clinical studies

Advances in the therapy of high-grade glioma at relapse: pegylated liposomal doxorubicin

Approaches to improve the prognosis of patients with high-grade glioma, which is still grim despite combined therapy and major advances in the development of new drugs, are highly important. Chemotherapeutic agents have not consistently produced favorable results in the relapse setting so far, with tumor responses reported in a minority of cases. Among them, doxorubicin has not shown significant efficacy, despite being one of the most effective substances in vitro and in animal models. Nevertheless, encapsulation of doxorubicin using polyethylene-glycol significantly improves penetration across the blood–brain barrier. Moreover, recent clinical trials in other entities have demonstrated that similar clinical responses can be achieved using approximately half of the dose of polyethylene-glycol-liposomes compared with conventional liposomes. Considering these facts, polyethylene-glycol-liposomal doxorubicin with and without tamoxifen was evaluated within two sequential Phase II trials performed at our institution. Polyethylene-glycol-liposomal doxorubicin (Caelyx™) was efficient in a reasonable number of patients with equivalent results in comparison with other successful Phase II studies. This article will discuss the literature and our own results on polyethylene-glycol-liposomal doxorubicin, with a special focus on toxicity and efficacy data raised in clinical trials on patients with high-grade glioma.

Use of 201Tl SPECT imaging to assess the response to therapy in patients with high grade gliomas.

To assess the potential role of 201Tl single photon emission tomography (201-Thallium SPECT) when compared to other imaging modalities in the evaluation of the response to therapy in high grade gliomas. Twenty patients with histologically proved high grade glioma have been included: 15 with glioblastoma (GBM), 3 with anaplastic astrocytoma (AA) and 2 with anaplastic oligoastrocytoma (AOA). Patients were assessed by 201Tl SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) at (a) either at the moment of maximum response to first line chemotherapy, or after the completion of radiotherapy and chemotherapy if post-surgical residual disease was present, and (b) after the completion of second line chemotherapy if disease persisted, or either a relapse or disease progression was confirmed. Final response was evaluated according to the McDonald criteria, and by comparing SPECT, CT and MRI results. According to the McDonald criteria, clinical response after first line chemotherapy was 5 partial response, 7 stable disease and 8 progressive disease. Evaluation by 201Tl SPECT was in agreement with such criteria in nearly all patients (90%). MRI findings closely agreed with the clinical follow-up. CT findings clearly differed from those observed by SPECT and MRI. After second line therapy, 10 patients progressed, 3 had stable disease and 7 had partial response. 201Tl SPECT agreed with the clinical status in 89% cases, whereas MRI and, specially CT, fared significantly lower. Compared to conventional neuroimaging, 201Tl SPECT added valuable information in the assessment of the response to therapy in our patient population; whenever findings were not conclusive and in the case of disagreement between CT and MRI findings.

Adults with newly diagnosed high-grade gliomas.

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.

A phase 2 study with concurrent and sequential temozolomide combined with radiation therapy in high grade gliomas

A phase 2 study with concurrent and sequential temozolomide combined with radiation therapy in high grade gliomas

211At-alpha-dose dependence of poly-ADP-ribosylation of human glioblastoma cells in vitro. Suitability in cancer therapy?

It was intended to test the biological response (poly-ADP-ribosylation of cellular proteins) of alpha-particles from extracellular 211At for enhanced damage to human glioblastoma cells in vitro and to discuss its suitability for potential application in therapy of high-grade gliomas. Confluent cultures of human glioblastoma cells were exposed to different doses of alpha-radiations from homogeneously distributed extracellular 211At. Cellular poly-ADP-ribosylation of all proteins including histones was monitored since it is an indirect but sensitive indicator of chromatin damage and putative repair in both normal and malignant mammalian cells. A significant diminution (average 85.6%) in poly-ADP-ribosylation of total cellular proteins relative to that for non-irradiated glioblastoma cells was observed following 0.025 to 1.0 Gy alpha-radiations. In the dose range of 0.0025 to 0.01 Gy there was an increase with a maximum value of approximately 119.0% at 0.0025 Gy. Below 0.0025 Gy no change in poly-ADP-ribosylation was observed. Level of cellular poly-ADP-ribosylation of proteins at 0.025 to 1.0 Gy of alpha-radiation dose from 211At appears to cause enhanced damage by creating molecular conditions which are not conducive to repair of DNA damages in human glioblastoma cells in vitro. Therefore, it is assumed that clinical application of 211At at least in this dose range might enhance clinical efficacy in radiotherapy of cancer.

Phase I and pharmacokinetic study of preirradiation chemotherapy with BCNU, cisplatin, etoposide, and accelerated radiation therapy in patients with high-grade glioma

Purpose: We conducted a Phase I study of bischloroethylnitrosourea (BCNU), cisplatin, and oral etoposide administered prior to and during accelerated hyperfractionated radiation therapy in newly diagnosed high-grade glioma. Pharmacokinetic studies of oral etoposide were also done.Methods and Materials: Patients started chemotherapy after surgery but prior to definitive radiation therapy (160 cGy twice daily × 15 days; 4800 cGy total). Initial chemotherapy consisted of BCNU 40 mg/m2 days 1–3, cisplatin 30 mg/m2 days 1–3 and 29–31, and etoposide 50 mg orally days 1–14 and 29–42, repeated in 8 weeks concurrent with radiation therapy. BCNU 200 mg/m2 every 8 weeks × 4 cycles was given after radiation therapy.Results: Sixteen patients, 5 with grade 3 anaplastic astrocytoma and 11 with glioblastoma were studied. Grade 3–4 leukopenia (38%) and thrombocytopenia (31%) were dose-limiting. Other toxicities were anorexia (81%), nausea (94%), emesis (56%), alopecia (88%), and ototoxicity (38%). The maximum tolerated dose was BCNU 40 mg/m2 days 1–3, cisplatin 20 mg/m2 days 1–3 and 29–31, and oral etoposide 50 mg days 1–21 and 29–49 prior to radiation therapy and repeated in 8 weeks with the start of radiation therapy followed by BCNU 200 mg/m2 every 8 weeks for 4 cycles. Median time to progression and survival were 13 and 14 months respectively. Responses occurred in 2 of 9 (22%) patients with evaluable disease. In pharmacokinetic studies, all patients achieved plasma concentrations of >0.1 μg/ml etoposide (the in vitro radiosensitizing threshold), following a 50 mg oral dose. The mean ± SD 2 hr and 6 hr plasma concentrations were 0.92 ± 0.43 μg/ml and 0.36 ± 0.12 μg/ml, respectively. Estimated duration of exposure to >0.1 μg/ml etoposide was 10–17 hr.Conclusions: Preirradiation chemotherapy with BCNU, cisplatin, and oral etoposide with accelerated hyperfractionated radiation therapy in high-grade gliomas is feasible and merits further investigation. Sustained radiosensitizing concentrations can be achieved with low oral doses of etoposide.

Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma

A Phase I study to determine the safety, toxicity, and maximum tolerated dose (MTD) of carmustine (BCNU) and interferon alpha-2a (IFN-a) when combined with radiation as initial therapy in high-grade glioma. Patients with newly diagnosed Grade 3 or 4 astrocytoma, oligoastrocytoma, or gliosarcoma were enrolled after surgery. All received radiation therapy to the brain (64.8 Gy/36 fractions), combined with a single dose of BCNU (200 mg/m2) at the start of radiation. Chemotherapy after completing radiation consisted of BCNU 150 mg/m2 once every 7 weeks, and IFN-a 12 x 10(6) units/m2 subcutaneously Days 1-3 each week of a 7-week cycle. Subsequent dose modification was based on constitutional symptoms for IFN-a and on myelosuppression for BCNU. Fifteen patients were entered on the study. Four were excluded because they did not receive IFN-a (3 refused treatment and 1 patient left the study due to multiple medical problems). Eleven were evaluable for toxicity and efficacy. Nonhematological toxicity, mainly lethargy and flu-like symptoms, were dose-limiting for IFN-a. After the first 6 patients were treated per the initial protocol, the frequency of IFN-a administration was decreased to Days 1-3 on weeks 1, 3, and 5 of the 7-week cycle for 5 additional patients. Lethargy, fever, chills, myalgias, alopecia, and anorexia occurred in all patients. Other toxicities included nausea and vomiting (91%), central-nervous-system depression or mood changes (64%), headaches (55%), and elevation of liver enzymes (36%). Grade 3-4 leukopenia occurred in 4 (45%) of 11 patients, and Grade 3-4 thrombocytopenia in 3 (27%) of 11 patients. Due to myelosuppressive effects, BCNU dose was not escalated. Median survival of the cohort was 44 months. Objective responses occurred in 5 (56%) of 9 patients and median duration of response was 33 months. The MTD of this combination after radiation therapy is IFN-a 12 x 10(6) units/m2 Days 1-3, on Weeks 1, 3, and 5 of a 7-week cycle and BCNU 150 mg/m2 Day 1, every 7 weeks. Treatment with radiation, IFN-a, and BCNU is feasible and effective in patients with high-grade gliomas, although constitutional symptoms from IFN-a are substantial.

P-5-556 - Induction and maintenance therapy for high grade glioma of cerebral hemisphere using ACNU, platinum and CSF (PARM + JAM therapy)

P-5-556 - Induction and maintenance therapy for high grade glioma of cerebral hemisphere using ACNU, platinum and CSF (PARM + JAM therapy)

Mechanisms of glioma invasion: role of matrix-metalloproteinases.

One of the most lethal properties of high grade gliomas is their ability to invade the surrounding normal brain tissue, as infiltrated cells often escape surgical resection and inevitably lead to tumour recurrence. The consequent poor prognosis and survival rate underscore the need to further understand and target the cellular mechanisms that underly tumour invasiveness. Proteases which degrade the surrounding stromal cells and extracellular matrix proteins have been demonstrated to be critical effectors of invasion for tumours of both central and peripheral origin. Within the nervous system, the role of metalloproteinases as well as other classes of proteases in mediating the invasive phenotype of high grade gliomas has been an intense area of research. We present in this article a review of this literature and address the possibility that these proteases and the biochemical pathways that regulate their expression, such as protein kinase C, may represent potential targets in the therapy of high grade gliomas.