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ACTR-03. FINAL RESULTS OF A PHASE II STUDY OF HYPOFRACTIONATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN PATIENTS OVER 70 YEARS OLD WITH NEWLY DIAGNOSED GLIOBLASTOMA

ABSTRACT: Abstract BACKGROUND We sought to determine the efficacy and tolerability of hypofractionated radiotherapy (HFRT), 34Gy given over two weeks with concurrent and adjuvant temozolomide, in patients over 70 years old with newly diagnosed GBM. METHODS Patients ? 70 years of age with newly diagnosed GBM received HFRT to a dose of 34 Gy in 10 fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. Quality of life (QOL) data using the validated functional assessment of cancer therapy-brain (FACT-BR) questionnaire was collected. Kaplan-Meier methods and log-rank tests were used for survival analyses. A random intercepts growth model with baseline and linear effect in time terms was used to assess QOL with relation to protocol treatment. RESULTS Eleven patients were enrolled from 12/1/2015 to 2/5/2018. Median age and KPS of the cohort was 74 years (range 70 -81) and 80 (range 60–100). Eight patients have died. Median follow-up of the cohort was 13.8 months (range 3 – 26 months). The median progression free survival (PFS) was 6.0 months (CI 4.7 months -not achieved (NA) and the median overall survival (OS) was 24.5 months (CI 10.2 months –NA). MGMT methylation status was significantly associated with both PFS (p =0.02) and OS (p =0.02). All patients completed HFRT with no patients developing ? grade 3 adverse treatment events. QOL did not significantly worsen over time with therapy (p =0.75). CONCLUSIONS This completed phase II trial suggest a HFRT schedule of 34Gy delivered over 2 weeks with concomitant and adjuvant TMZ is well tolerated in elderly GBM patients without compromising clinical outcomes. This result compares favorably to the longer HFRT regimen of 40Gy over 3 weeks. ClinicalTrials.gov identifier: NCT01985087

SUBMITTER: Yusuf M

PROVIDER: S-EPMC6847443 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Project description:PurposeBevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Experimental designPatients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.ResultsForty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.ConclusionsThis aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma.

Project description:Although concurrent radio-chemotherapy and adjuvant temozolomide (TMZ) treatment for 6 cycles has been established as a standard of care for newly diagnosed glioblastoma multiforme (GBM) patients, the recommended duration of adjuvant TMZ remains a matter of debate. Hereby, we aimed to report for the first time our experience from Upper Egypt through comparing survival and toxicity profile between two treatment modalities of adjuvant TMZ (> six cycles versus six cycles) and delineating factors of prognostic significance in Egyptian patients with newly diagnosed GBM treated by radiation therapy with concomitant and adjuvant TMZ. Between June 2016 and February 2018, the medical records of 121 patients were eligible to be retrospectively reviewed to extract the study relevant data. All patients received concurrent radio-chemotherapy, followed by TMZ for 6 cycles in 29 patients (Group 1) and for >6 cycles in 26 patients (Group 2). Patients in Group 1 had a median PFS of 15 months (95% CI: 10.215-19.785), while those in Group 2 had a median PFS of 18 months (95% CI: 16.611-19.389). After a median follow up duration of 20 months (range: 12-41), the median OS was 18 months (95% CI: 13.420-22.580) in Group 1 and 22 months (95% CI: 18.777-25.223) in Group 2. There was no statistically significant correlation between the number of chemotherapy cycles and PFS (P=0.513) or OS (P=0.867). The extent of surgical resection was the only independent prognostic factor for both PFS (P=0.015) and OS (P=0.028) by multivariate analysis. Three grade ≥3 hematologic toxicity were encountered in 3 patients. One in the six-cycle group (neutropenia), and two in the extended cycles group (one had neutropenia and the other one developed thrombocytopenia). No statistically significant difference in the toxicity profile between both groups. The results of our study suggest that extended TMZ therapy is safe and tolerable, however it did not significantly improve PFS or OS as compared to the standard six-cycle course. Larger randomized studies are required to shed more light on this issue.

Project description:PurposeDespite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).MethodsSixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.ResultsSurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.ConclusionSurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Project description:Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2-32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization.

Project description:IntroductionStandard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation.MethodsThis is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment.ResultsThere were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%).ConclusionsConcurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling.Clinical trial registrationClinicaltrials.gov, identifier NCT03477110.

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ACTR-03. FINAL RESULTS OF A PHASE II STUDY OF HYPOFRACTIONATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN PATIENTS OVER 70 YEARS OLD WITH NEWLY DIAGNOSED GLIOBLASTOMA

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