Dataset Information

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

ABSTRACT:

Background

We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM).

Methods

We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3?+?3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis.

Results

From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51-86 y). The median target volume was 60 cm3 (range, 14.7-137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 mo). No grades 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6-10.5); overall survival, 14.8 months (95% CI: 10.9-19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5-33.5) versus 11.3 months (95% CI: 8.9-17.6) for no/unknown hypermethylation (P?=?0.03), and 27.2 months (95% CI: 11.2-48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9-17.6) for no ARE (P?=?0.08).

Conclusions

The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1-2 and did not statistically impact survival.

SUBMITTER: Azoulay M

PROVIDER: S-EPMC7594571 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

Azoulay Melissa M Chang Steven D SD Gibbs Iris C IC Hancock Steven L SL Pollom Erqi L EL Harsh Griffith R GR Adler John R JR Harraher Ciara C Li Gordon G Hayden Gephart Melanie M Nagpal Seema S Thomas Reena P RP Recht Lawrence D LD Jacobs Lisa R LR Modlin Leslie A LA Wynne Jacob J Seiger Kira K Fujimoto Dylann D Usoz Melissa M von Eyben Rie R Choi Clara Y H CYH Soltys Scott G SG

Neuro-oncology 20200801 8

<h4>Background</h4>We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM).<h4>Methods</h4>We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3-5 acute or late CNS ...[more]

PMID: 32002547

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Project description:PURPOSE:We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. METHODS:HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. RESULTS:With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01). CONCLUSION:On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.

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: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:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

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.

Project description:Abstract INTRODUCTION Standard of care for glioblastoma includes concurrent chemoradiation and maintenance temozolomide (TMZ) with tumor treatment fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report our experience evaluating toxicity of scalp-sparing radiation with concurrent TTFields. METHODS This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Patients (age≥ 18 years) with KPS≥ 60 with newly diagnosed glioblastoma were eligible. Patients received concurrent scalp-sparing radiation (60 Gy/30 fx), standard TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and TTFields continuation. Radiotherapy was delivered through TTFields arrays. Primary endpoint was safety and toxicity of concurrent TTFields with chemoradiation. RESULTS We report the first eighteen patients on trial. Majority were male (66.7%) with median age 59 years (34 to 77). Median KPS was 90 (70–100). Median follow-up was 6.0 months (1.4 to 18.0). Twelve (66.6%) patients had unmethylated MGMT, five (27.8%) were methylated, and one patient’s status was not obtained. Scalp dose constraints were achieved, with mean dose having a median value of 7.4 Gy (4.3–13.2), D20cc median 23.2 Gy (17.7–36.8), and D30cc median 20.3 Gy (14.8–33.4). Only one possible Grade 3 toxicity was observed in a patient who experienced a seizure in month six of the maintenance phase. Skin toxicity (erythema or dermatitis) was limited to Grade 1 (83.3%) or 2 (5.6%) during the concurrent phase and resolved spontaneously or responded to topical medications. Other Grade 1 events included fatigue (47.3%), cognitive impairment (31.6%), pruritis (52.6%), headache (26.3%), dizziness (15.8%), and nausea (26.3%). Other Grade 2 events included fatigue (21.1%) and headache (10.5%). Nine patients (50%) had progression, with median PFS of 7.6 months (2.2–9.6 months). CONCLUSIONS Concurrent TTFields with scalp-sparing chemoradiation is a safe and feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

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.

Dataset Information

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

Background

Methods

Results

Conclusions

Publications

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

Similar Datasets

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