scholarly journals Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: A modelling study based on longitudinal tumor measurements

2021 ◽  
Author(s):  
Sarah C. Brüningk ◽  
Jeffrey Peacock ◽  
Christopher J. Whelan ◽  
Hsiang-Hsuan M. Yu ◽  
Solmaz Sahebjam ◽  
...  
Keyword(s):  
Treatment Option ◽  
Tumour Growth ◽  
Simulation Analysis ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Patient Specific ◽  
Tumor Control ◽  
Model Parameters ◽  
High Dose ◽  
High Grade

ABSTRACTRecurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, ≥ 6 Gyx5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering intermittent high dose treatment (iRT, ≥ 6 Gyx1 every six weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost (≥ 6 Gyx3 in daily fractions at time of progression) based on a mathematical model of tumour growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumour growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/-boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modelling results demonstrated that iRT+boost(-boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients.

scholarly journals Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: a modeling study based on longitudinal tumor measurements

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sarah C. Brüningk ◽  
Jeffrey Peacock ◽  
Christopher J. Whelan ◽  
Renee Brady-Nicholls ◽  
Hsiang-Hsuan M. Yu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Treatment Option ◽  
Radiation Treatment ◽  
Phase 1 ◽  
High Grade Glioma ◽  
Patient Specific ◽  
Tumor Control ◽  
Model Parameters ◽  
High Dose ◽  
High Grade

AbstractRecurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, $$\ge 6$$ ≥ 6 Gy $$\times$$ × 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, $$\ge 6$$ ≥ 6 Gy $$\times$$ × 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost ($$\ge 6$$ ≥ 6 Gy $$\times$$ × 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/− boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(− boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.

scholarly journals Image-based personalization of computational models for predicting response of high-grade glioma to chemoradiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
David A. Hormuth ◽  
Karine A. Al Feghali ◽  
Andrew M. Elliott ◽  
Thomas E. Yankeelov ◽  
Caroline Chung
Keyword(s):  
Mathematical Models ◽  
Computational Models ◽  
Tumor Response ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Information Criteria ◽  
Patient Specific ◽  
Model Parameters ◽  
High Grade ◽  
High Grade Gliomas

AbstractHigh-grade gliomas are an aggressive and invasive malignancy which are susceptible to treatment resistance due to heterogeneity in intratumoral properties such as cell proliferation and density and perfusion. Non-invasive imaging approaches can measure these properties, which can then be used to calibrate patient-specific mathematical models of tumor growth and response. We employed multiparametric magnetic resonance imaging (MRI) to identify tumor extent (via contrast-enhanced T1-weighted, and T2-FLAIR) and capture intratumoral heterogeneity in cell density (via diffusion-weighted imaging) to calibrate a family of mathematical models of chemoradiation response in nine patients with unresected or partially resected disease. The calibrated model parameters were used to forecast spatially-mapped individual tumor response at future imaging visits. We then employed the Akaike information criteria to select the most parsimonious member from the family, a novel two-species model describing the enhancing and non-enhancing components of the tumor. Using this model, we achieved low error in predictions of the enhancing volume (median: − 2.5%, interquartile range: 10.0%) and a strong correlation in total cell count (Kendall correlation coefficient 0.79) at 3-months post-treatment. These preliminary results demonstrate the plausibility of using multiparametric MRI data to inform spatially-informative, biologically-based predictive models of tumor response in the setting of clinical high-grade gliomas.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

scholarly journals PDCT-06. PHASE 1 STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH H3 K27M-MUTANT HIGH GRADE GLIOMA OR NEWLY DIAGNOSED DIPG

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi201-vi201
Author(s):  
Sharon Gardner ◽  
Fernando Suarez ◽  
James M Stafford ◽  
Rohinton S. Tarapore ◽  
Krystal Merdinger ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Phase 1 Study

scholarly journals ATIM-05. COMPLEMENTARY CLINICAL AND ANCILLARY DATA FROM 123 PATIENTS WITH RECURRENT HIGH GRADE GLIOMA FROM THREE PHASE 1 TRIALS OF TOCA 511 AND TOCA FC: UPDATE AND JUSTIFICATION FOR A PHASE 2/3 TRIAL

2016 ◽  
Vol 18 (suppl_6) ◽  
pp. vi18-vi18 ◽  
Author(s):  
Manish Aghi ◽  
Michael Vogelbaum ◽  
Steven Kalkanis ◽  
Daniela Bota ◽  
Bob Carter ◽  
...  
Keyword(s):  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Phase 2 ◽  
Ancillary Data ◽  
Phase 1 Trials ◽  
Three Phase

scholarly journals Revisiting the formalism of equivalent uniform dose based on the linear-quadratic and universal survival curve models in high-dose stereotactic body radiotherapy

2020 ◽  
Author(s):  
Mark Ka Heng Chan ◽  
Chi-Leung Chiang
Keyword(s):  
Linear Regression ◽  
Stereotactic Body Radiotherapy ◽  
Survival Curve ◽  
Dose Fractionation ◽  
Tumor Control ◽  
Model Parameters ◽  
High Dose ◽  
Linear Quadratic ◽  
Equivalent Uniform Dose ◽  
Prescription Dose

Abstract Purpose To examine the equivalent uniform dose (EUD) formalism using the universal survival curve (USC) applicable to high-dose stereotactic body radiotherapy (SBRT). Materials and methods For nine non-small-cell carcinoma cell (NSCLC) lines, the linear-quadratic (LQ) and USC models were used to calculate the EUD of a set of hypothetical two-compartment tumor dose–volume histogram (DVH) models. The dose was varied by ±5%, ±10%, and ±20% about the prescription dose (60 Gy/3 fractions) to the first compartment, with fraction volume varying from 1% and 5% to 30%. Clinical DVHs of 21 SBRT treatments of NSCLC prescribed to the 70–83% isodose lines were also considered. The EUD of non-standard SBRT dose fractionation (EUDSBRT) was further converted to standard fractionation of 2 Gy (EUDCFRT) using the LQ and USC models to facilitate comparisons between different SBRT dose fractionations. Tumor control probability (TCP) was then estimated from the LQ- and USC-EUDCFRT. Results For non-standard SBRT fractionation, the deviation of the USC- from the LQ-EUDSBRT is largely limited to 5% in the presence of dose variation up to ±20% to fractional tumor volume up to 30% in all NSCLC cell lines. Linear regression with zero constant yielded USC-EUDSBRT = 0.96 × LQ-EUDSBRT (r2 = 0.99) for the clinical DVHs. Converting EUDSBRT into standard 2‑Gy fractions by the LQ formalism produced significantly larger EUDCFRT than the USC formalism, particularly for low $$\alpha /\beta$$ α / β ratios and large fraction dose. Simplified two-compartment DVH models illustrated that both the LQ- and USC-EUDCFRT values were sensitive to cold spot below the prescription dose with little volume dependence. Their deviations were almost constant for up to 30% dose increase above the prescription. Linear regression with zero constant yielded USC-EUDCFRT = 1.56 × LQ-EUDCFRT (r2 = 0.99) for the clinical DVHs. The clinical LQ-EUDCFRT resulted in median TCP of almost 100% vs. 93.8% with USC-EUDCFRT. Conclusion A uniform formalism of EUD should be defined among the SBRT community in order to apply it as a single metric for dose reporting and dose–response modeling in high-dose-gradient SBRT because its value depends on the underlying cell survival model and the model parameters. Further investigations of the optimal formalism to derive the EUD through clinical correlations are warranted.

Procarbazine and High-Dose Tamoxifen as a Second-Line Regimen in Recurrent High-Grade Gliomas: A Phase II Study

1999 ◽  
Vol 17 (2) ◽  
pp. 645-645 ◽  
Author(s):  
Alba A. Brandes ◽  
Mario Ermani ◽  
Sergio Turazzi ◽  
Elvira Scelzi ◽  
Franco Berti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Chemotherapy Regimen ◽  
Phase Ii Study ◽  
Tumor Control ◽  
High Dose ◽  
High Grade ◽  
Second Line ◽  
First Line ◽  
High Grade Gliomas

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.

scholarly journals OS12.2 Targeting epigenetic pathways in the treatment of recurrent high-grade glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii22-iii22
Author(s):  
A Hau ◽  
L Houben ◽  
E Klein ◽  
A Oudin ◽  
D Stieber ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Drug Response ◽  
High Grade Glioma ◽  
Differential Sensitivity ◽  
Targeted Sequencing ◽  
Patient Specific ◽  
Comparative Genomic ◽  
High Grade ◽  
Evolutionary Trajectory ◽  
Tumor Organoids

Abstract BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification of distinct genomic abnormalities. Furthermore, using large patient cohorts of longitudinal tumor samples, comprehensive genomic profiling studies emerged to investigate therapy-associated evolution of gliomas. All together, those studies point out the need for personalised treatment strategies, where applied drugs will be adapted to the unique patient-specific genetic abnormalities. MATERIAL AND METHODS We collected fresh samples of more than 800 brain tumors containing almost 300 glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. By now, we have successfully established 34 patient-derived orthotopic xenografts (PDOXs) in mice. We performed comprehensive molecular profiling using array comparative genomic hybridisation, DNA methylation analysis and targeted DNA sequencing on patient specimen and their derivatives such as 3D tumor organoids and PDOXs. The custom-design sequencing panel comprises 234 genes that reflect both established genetic identifiers for individual glioma subtype classification and novel genes encoding mainly epigenetic effector genes. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed by targeted sequencing. RESULTS We succeeded in generating a live biobank of HGG patient-derived xenografts and 3D organoids that neatly recapitulates the mutational spectrum including structural DNA variation and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from a total of 9 glioma patients. A detailed analysis of the paired longitudinal samples indicated that PDOX models closely recapitulate the evolutionary trajectory of the parental tumors. Targeted sequencing of longitudinal HGG PDOXs suggests that relapse tumors accumulate somatic mutations in epigenetic effectors compared with the Initial. Differential drug responses between initial and relapse tumors were observed after screening of in vitro 3D tumor organoids. CONCLUSION Response assessment of naïve initial gliomas and recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalised therapeutic options in the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.

scholarly journals Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone Protein

2012 ◽  
Vol 19 (1) ◽  
pp. 205-214 ◽  
Author(s):  
Courtney A. Crane ◽  
Seunggu J. Han ◽  
Brian Ahn ◽  
Jessica Oehlke ◽  
Valerie Kivett ◽  
...  
Keyword(s):  
High Grade Glioma ◽  
Patient Specific ◽  
Autologous Tumor ◽  
High Grade ◽  
Specific Immunity ◽  
Chaperone Protein

Phase I dose escalation of temozolomide with thiotepa and carboplatin with autologous hematopoietic cell reinfusion in patients with recurrent/refractory malignant brain tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2060-2060 ◽  
Author(s):  
S. Gardner ◽  
M. Fisher ◽  
J. Belasco ◽  
P. Phillips ◽  
J. Finlay
Keyword(s):  
Brain Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Standard Dose ◽  
Treatment Options ◽  
High Grade Glioma ◽  
High Dose ◽  
High Grade ◽  
Malignant Brain Tumors ◽  
Dose Limiting Toxicity

2060 Background: The prognosis for most patients with recurrent malignant brain tumors is dismal. Treatment options are limited especially for patients who have already received irradiation. TMZ is an oral alkylating agent which is approved for use in patients with high grade glioma and has also been shown to have activity in patients with recurrent medulloblastoma. It’s primary dose-limiting toxicity is non- cumulative bone marrow suppression. In the present study, TMZ is given in a dose escalation fashion with fixed doses of high dose thiotepa and carboplatin with AHCR in the treatment of patients with recurrent or refractory malignant brain tumors. Methods: Treatment consisted of TMZ twice daily on days -10 to -6 followed by thiotepa 300 mg/m2/day and carboplatin AUC=7/day on days -5 to -3 with AHCR on day 0. Filgrastim was given day +1 and continued until engraftment. Results: 27 patients (18M; 9F) ages 3–46 years were treated from 11/00 until 10/04. Diagnoses included high grade glioma (n=12); medulloblastoma/PNET (n=9); CNS germ cell tumor (GCT) (n=4); and 1 each ependymoma and spinal cord PNET. TMZ doses ranged from 50 mg/m2 twice daily (100 mg/m2/day) to 200 mg/m2 twice daily (400 mg/m2/day) for 5 days. One patient had dose limiting toxicity consisting of reversible veno-occlusive disease at dose level 3 (TMZ 100 mg/m2 twice daily). Two patients had dose limiting toxicity at dose level 7 (TMZ 200 mg/m2 twice daily) consisting of transient encephalopathy (n=1) and severe mucositis (n=1). Additional toxicities included bacteremia (n=11), C. difficile enteritis (n=6) and grade 4 elevation of bilirubin and/or liver transaminases (n=2). There were no toxic deaths. Survival included 3 patients with glioma (38–48 months); two of whom had relapsed following standard dose TMZ; 3 patients with PNET/MB (48–72 months) and 3 patients with CNS GCT (26–71 months). Conclusions: Increased doses of TMZ are feasible when given with AHCR. There is presently a phase II study underway through the Pediatric Blood and Marrow Transplant Consortium evaluating the efficacy of TMZ at a dose of 175 mg/m2/day twice daily for 5 days with high dose thiotepa and carboplatin and AHCR. No significant financial relationships to disclose.

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