Chemotherapy For High-grade Gliomas Research Articles

Late-line treatment with bevacizumab alone or in combination with chemotherapy in recurrent high-grade gliomas.

Bevacizumab's use in recurrent high-grade glioma is controversial. This study evaluates outcomes in recurrent high-grade glioma patients receiving bevacizumab alone or combined with chemotherapy as a late-line treatment. We retrospectively analyzed patients treated with bevacizumab alone or combined with chemotherapy for high-grade gliomas who showed tumor progression after multiple treatment attempts. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier curves. Predictors of PFS according to prognostic variables were assessed with regression analysis. Between 2010 and 2022, 31 consecutive patients received bevacizumab alone or combined with chemotherapy as a late-line treatment for recurrent high-grade gliomas. Of these patients, 14 (45.2%) were responders according to RANO criteria, and 17 (54.8%) showed progressive or stable disease. OS at 3, 6, and 12months was 80.3%, 62.1%, and 43.5. PFS was 48.4%, 34.3%, and 21.8%, respectively. In the multivariate survival analysis, the only factor independently associated with PFS was smaller 2D tumor size in post-contrast T1-weighted MRI at bevacizumab initiation (p = 0.02). Median time-to-progression was 3months (95%CI: 1-4) in the unmethylated MGMT promoter group and 6 (95%CI: 1-11) in the methylated MGMT promoter group. This difference was not statistically significant (p = 0.37). Bevacizumab alone or in combination with chemotherapy could be beneficial as a late-line therapy in a subset of patients with recurrent high-grade glioma. Small 2D tumor size in post-contrast T1 weighted MRI at bevacizumab initiation was independently associated with prolonged time to progression.

Intra-arterial chemotherapy for high-grade gliomas

Reason for withdrawal from publication Withdrawn from Issue 5, 2017; editorial decision not to proceed with full review as author team unable to complete the review.

AT-25 * A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by the blood brain barrier. Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in animal models and shows superior anti-tumor activity. An advance in the use of CED is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action. METHODS: With support from an R21 we're conducting a phase I study of CED of liposomal-irinotecan using real-time imaging in patients with recurrent HGG. This is a 3 + 3 dose escalation trial; dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral location. Concentration of gadoteridol will be 2 mM for all groups; both agents will be co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG.

A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by poor activity of available agents and compromised delivery across the blood brain barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection established as a result of a pressure gradient, obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in rat, dog, and primate models. A recent study in mice with intracranial glioblastoma xenografts compared routes of delivery for liposomal irinotecan by CED or IV and showed superior anti-tumor activity of CED. A major clinical advance in the use of CED over recent trials is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action for technical complexities. METHODS: With support from an R21 we will conduct the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. This is a single center, prospective, 3 + 3 dose escalating, single-arm, phase I trial with a four-level dose escalation, expecting to enroll at least 3 patients in each level and expanding the highest level to 12 patients total. Dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral (IT) location. Concentration of gadoteridol will be 2 mM for all dose groups; both agents will be combined and co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group will have tumor volume 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG. SECONDARY CATEGORY: Imaging.

PTPN6 expression is epigenetically regulated and influences survival and response to chemotherapy in high-grade gliomas

The prognosis of high-grade glioma patients is poor, and the tumors are characterized by resistance to therapy. The aims of this study were to analyze the prognostic value of the expression of the protein tyrosine phosphatase non-receptor type 6 (PTPN6, also referred to as SHP1) in high-grade glioma patients, the epigenetic regulation of the expression of PTPN6, and the role of its expression in chemotherapy resistance in glioma-derived cells. PTPN6 expression was analyzed with immunohistochemistry in 89 high-grade glioma patients. Correlation between PTPN6 expression and overall survival was analyzed with Kaplan-Meier univariate analysis and Cox regression multivariate analysis. Differences in drug sensitivity to a panel of 16 chemotherapeutic drugs between PTPN6-overexpressing clones and control clones were analyzed in vitro with the fluorometric microculture cytotoxicity assay. Cell cycle analysis was done with Krishan staining and flow cytometry. Apoptosis was analyzed with a cell death detection ELISA kit as well as cleaved caspase-3 and caspase-9 Western blotting. Autophagy was analyzed with LC3B Western blotting. Methylation of the PTPN6 promoter was analyzed with bisulfite pyrosequencing, and demethylation of PTPN6 was done with decitabine treatment. The PTPN6 expression correlated in univariate analysis to poor survival for anaplastic glioma patients (p = 0.026). In glioma-derived cell lines, overexpression of PTPN6 caused increase resistance (p < 0.05) to the chemotherapeutic drugs bortezomib, cisplatin, and melphalan. PTPN6 expression did not affect bortezomib-induced cell cycle arrest, apoptosis, or autophagy. Low PTPN6 promoter methylation correlated to protein expression, and the protein expression was increased upon demethylation in glioma-derived cells. PTPN6 expression may be a factor contributing to poor survival for anaplastic glioma patients, and in glioma-derived cells, its expression is epigenetically regulated and influences the response to chemotherapy.

Clinical trials in cellular immunotherapy for brain/CNS tumors

High-grade gliomas are the most common type of primary malignant brain/CNS tumor. There have been only modest advances in surgical techniques, radiotherapy and chemotherapy for high-grade gliomas over the past several decades. None of these have provided a major improvement in survival for patients. Recently, immunotherapy has been explored for the treatment of high-grade gliomas. Immunotherapy capitalizes on the specificity of the host immune system to selectively target tumor cells for destruction, while sparing normal brain parenchyma, thus making it a particularly attractive option. This article provides a comprehensive review of published clinical trials evaluating cellular immunotherapy in primary brain/CNS tumors.

Modification of loco-regional microenvironment in brain tumors by spinal cord stimulation. Implications for radio-chemotherapy

The effectiveness of radiotherapy and chemotherapy in high grade gliomas (HGG) depends on tumor micro-environment. We summarize our experience of the influence of spinal cord stimulation (SCS) on this micro-environment. Patients with HGG (n = 26) were assessed pre- and post-SCS, using: (1) Doppler in middle cerebral arteries (MCA) and (2) in common carotid arteries (CCA); (3) tumor blood-flow using single photon emission computed tomography (SPECT); (4) tumor-pO(2) (mmHg) using polarographic probes (eight tumor areas from five patients); and (5) tumor glucose metabolism using (18)F-fluoro-2-deoxyglucose ((18)FDG) positron emission tomography ((18)FDG-PET). Pre-SCS: tumor blood-flow was lower (P < 0.001) than peri-tumor areas and healthy contra-lateral areas. Tumor-pO(2) was lower (P < 0.042) than healthy tissue. Tumor glucose metabolism was higher than peri-tumor areas (P = 0.017) and healthy contra-lateral areas (P = 0.048). Post-SCS: there were increases in: MCA blood-flow (P ≤ 0.002), CCA blood-flow (P ≤ 0.013), tumor blood-flow (P = 0.033), tumor glucose metabolism (P = 0.027) and tumor-pO(2) (P = 0.022). The percentage of hypoxic values decreased (P = 0.007). SCS can modify tumor micro-environment. The potential usefulness of SCS in improving the effectiveness of radio-chemotherapy in HGG needs to be evaluated.

Modification of Brain Tumor Microenvironment by Applying Cervical Spinal Cord Stimulation (cSCS)

The effect of radiotherapy and chemotherapy in high grade gliomas (HGG) depends of tumor microenvironment. This work summarizes our experience about the effect of cervical spinal cord stimulation (cSCS) on brain tumor microenvironment.

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.

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.

Role of natural lycopene and phytonutrients along with radiotherapy and chemotherapy in high grade gliomas

1561 Objective: The present study was conducted to determine the effect of adding lycopene (antioxidant with potential anticancer activity), to radiotherapy (RT) and chemotherapy in the adjuvant treatment of high grade gliomas, with response at 6 months and time to progression being end points. Methods: The study was conducted from Nov’02-Nov’03. Fifty patients with anaplastic astrocytoma (AA) or GBM were enrolled who had undergone surgical excision but had residual disease. All of them received RT to a dose of 60Gy in 30 fractions over 6 weeks with concomitant Paclitaxel, 60 mg/m2 i/v weekly. They were randomized into two groups: Group A: (n=25) received 8mg of oral lycopene daily, Group B: (n=25) received placebo; along with RT. Informed consent was taken prior to enrollment. Response was evaluated with MRI and brain SPECT at 3 and 6 months post treatment; and 6monthly thereafter. Pre and post RT plasma lycopene levels were monitored using high precision liquid chromatography. Results: Out of 50 patients, 38 were males and 12 females with a mean age of 38 years. 32 patients had GBM while 18 had AA Response at six months post treatment was analyzed using WHO criteria. All patients were alive at 6 months. Pre and post treatment plasma lycopene levels in patients of Group A were 152 and 316 ng/ml and in Group B were 93 and 98 ng/ml. Among Group A (lycopene group): 10 (40%) patients had complete response (CR), 10 (40%) had partial response (PR), 1 (4%) had stable disease (SD), 3 (12%) had progressive disease (PD) while response was not available for 1 patient (4%). Among Group B (placebo group); 5 (20%) patients had CR, 6 (24%) had PR, 1 (4%) had SD, 8 (32%) had PD while response was not available for 5 patients (20%). Overall response in Group A was superior to Group B but was not statistically significant (p = 0.1). Median time to disease progression was 39 wks for Group A and 21 wks for Group B patients (p = 0.14). Conclusions: The addition of lycopene to radiotherapy and chemotherapy in patients with high grade glioma results in positive outcome; both in terms of response rates at 6 months post treatment and time to progression. Further larger studies would be required to arrive at a more definitive Conclusion: No significant financial relationships to disclose.

Arguments against the routine use of currently available adjuvant chemotherapy in high-grade gliomas

The results of adjuvant chemotherapy in high-grade gliomas are disappointing. Carmustine (BCNU) wafers placed in the resection cavity provide a modest increase in median survival. However, the overall benefit of this approach is small, it offers no potential for cure, and the results are not statistically significant in patients with glioblastoma multiforme. During the past three decades, controlled clinical trials of systemically administered adjuvant chemotherapy have consistently failed to show significant benefit in patients with glioblastoma multiforme. Furthermore, as of 2003, no randomized studies convincingly document improved survival from adjuvant chemotherapy in anaplastic astrocytomas or anaplastic oligodendrogliomas, which are the most chemotherapy sensitive gliomas. These findings result from the limited efficacy of available chemotherapy in malignant gliomas and the current design of adjuvant brain tumor trials that allow accrual of patients with bulky residual disease. Until further information becomes available, it is reasonable to use radiation alone as adjuvant therapy and to reserve chemotherapy for the treatment of recurrences. This approach minimizes toxicities and ensures that chemotherapy is administered when its effect can be assessed using measurable disease. Improving outcome in high-grade gliomas requires an emphasis on discovering novel therapies and improving the design of adjuvant trials.

Benefits of adjuvant chemotherapy in high-grade gliomas

The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving ≥18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.

Prospective trial of radiotherapy after hyperbaric oxygenation with chemotherapy for high-grade gliomas.

Twenty-one patients with high-grade gliomas were enrolled in a prospective trial of radiotherapy after hyperbaric oxygenation (HBO). Radiotherapy was administered in daily 2-Gy fractions up to a total dose of 60 Gy, and each fraction was delivered immediately after HBO. The current study indicated that radiotherapy immediately after HBO with chemotherapy was feasible for high-grade gliomas.

Chemotherapy for high-grade glioma.

Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence. To compare radiotherapy plus chemotherapy with radiotherapy alone in completely resected adults with high-grade glioma. To investigate whether or not pre-defined patient subgroups benefit more or less from chemotherapy. MEDLINE and CancerLit searches were supplemented with information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists and organisations. These searches were carried out in June 1997, June 1999 and December 2000. Trials comparing radiotherapy versus radiotherapy + chemotherapy were eligible for inclusion provided that they randomized adult patients using a method which precluded prior knowledge of treatment assignment. A quantitative meta-analysis using updated information from individual patients from all available randomized trials was carried out. Data from all patients randomized in all eligible trials were sought directly from those responsible. Updated information on survival and date of follow-up were obtained, as were details of treatment allocation, date of randomization, age, sex, histological cell type, stage and performance status. To avoid potential bias, information was requested for all randomized patients including those who had been excluded from the investigators' original analyses. All analyses were done on an intention to treat basis on the endpoint of survival. For trials using cisplatin-based regimens, subgroup analyses by age, sex, histological cell type, tumour stage and performance status were also done. Data from 12 randomized trials and 3004 patients were included. The results show a significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI 0.78-0.91, p=0.00004) or 15% relative decrease in the risk of death. This is equivalent to an absolute increase in one year survival rate of 6% (95% confidence interval 3% to 9%) from 40% to 46% and a two-month increase in median survival time (95% confidence interval one month to three months). There was no evidence that the effect of chemotherapy was different in any group of patients defined by age, sex, histology, performance status or extent of resection. This small but clear improvement in survival from chemotherapy encourages further study of drug treatment of these tumours

Chemotherapy for high-grade gliomas.

Chemotherapy for high-grade gliomas.

Chemotherapy for high-grade gliomas of childhood.

Astrocytomas are the most common group of childhood brain tumors. Approximately 20% of these lesions are histologically malignant tumors that often prove fatal within 2 years of diagnosis, despite the use of surgery and conventional radiotherapy. During the last 15 years, considerable attention has been focused on evaluating the potential role of chemotherapy as a means of improving survival. Although several agents have been observed to have modest therapeutic activity against these tumors, the optimal strategies for improving disease control have yet to be defined. This article will review the results that have been achieved in previous studies using a variety of single and multi-agent chemotherapeutic regimens, and also the rationale for ongoing trials of the major cooperative groups, and will discuss the challenges that are inherent in designing and interpreting therapeutic studies for these tumors. Ways in which currently available approaches may be incorporated into future therapeutic strategies will also be discussed and a brief review of the extensive array of promising new treatment approaches will be presented.