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Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

ABSTRACT: INTRODUCTION:Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation. METHODS:We enrolled patients?>?18 years old with primary or metastatic brain tumors slated to receive at least 10 treatments of RT (??3 Gy per fraction). We evaluated the safety of pioglitazone at 22.5 mg and 45 mg with a dose-escalation phase and dose-expansion phase. Pioglitazone was taken daily during RT and for 6 months after. RESULTS:18 patients with a mean age of 54 were enrolled between 2010 and 2014. 14 patients had metastatic brain tumors and were treated with whole brain RT. Four patients had primary brain tumors and received partial brain RT and concurrent chemotherapy. No DLTs were identified. In the dose-escalation phase, there were only three instances of grade???3 toxicity: one instance of neuropathy in a patient receiving 22.5 mg, one instance of fatigue in a patient receiving 22.5 mg and one instance of dizziness in a patient receiving 45 mg. The attribution in each of these cases was considered "possible." In the dose-expansion phase, nine patients received 45 mg and there was only one grade 3 toxicity (fatigue) possibly attributable to pioglitazone. CONCLUSION:Pioglitazone was well tolerated by brain tumor patients undergoing RT. 45 mg is a safe dose to use in future efficacy trials.

SUBMITTER: Cramer CK

PROVIDER: S-EPMC6805132 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

Cramer Christina K CK Alphonse-Sullivan Natalie N Isom Scott S Metheny-Barlow Linda J LJ Cummings Tiffany L TL Page Brandi R BR Brown Doris R DR Blackstock Arthur W AW Peiffer Ann M AM Strowd Roy E RE Rapp Stephen S Lesser Glenn J GJ Shaw Edward G EG Chan Michael D MD

Journal of cancer research and clinical oncology 20181112 2

<h4>Introduction</h4>Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation.<h4>Methods</h4>We enrolled patients > 18 years old with primary or metastatic brain tumors slated to r ...[more]

PMID: 30417218

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Project description:PurposeRadiation pneumonitis remains a major limitation in the radiation therapy treatment of patients with lung cancer. Functional avoidance radiation therapy uses functional imaging to reduce pulmonary toxic effects by designing radiation therapy plans that reduce doses to functional regions of the lung. Lung functional imaging has been developed that uses 4-dimensional computed tomography (4DCT) imaging to calculate 4DCT-based lung ventilation (4DCT-ventilation). A phase 2 multicenter study was initiated to evaluate 4DCT-ventilation functional avoidance radiation therapy. The study hypothesis was that functional avoidance radiation therapy could reduce the rate of grade ≥2 radiation pneumonitis to 12% compared with a 25% historical rate, with the trial being positive if ≤16.4% of patients experienced grade ≥2 pneumonitis.Methods and materialsLung cancer patients receiving curative-intent radiation therapy (prescription doses of 45-75 Gy) and chemotherapy were accrued. Patient 4DCT scans were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose. Pneumonitis was evaluated by a clinician at 3, 6, and 12 months after radiation therapy.ResultsSixty-seven evaluable patients were accrued between April 2015 and December 2019. The median prescription dose was 60 Gy (range, 45-66 Gy) delivered in 30 fractions (range, 15-33 fractions). The average reduction in the functional volume of lung receiving ≥20 Gy with functional avoidance was 3.5% (range, 0%-12.8%). The median follow-up was 312 days. The rate of grade ≥2 radiation pneumonitis was 10 of 67 patients (14.9%; 95% upper CI, 24.0%), meeting the phase 2 criteria.Conclusions4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra procedure necessary. This first report of a multicenter study of 4DCT-ventilation functional avoidance radiation therapy provided data showing that the trial met phase 2 criteria and that evaluation in a phase 3 study is warranted.

Project description:ImportancePalliative thoracic radiotherapy (RT) can alleviate local symptoms associated with advanced non-small cell lung cancer (NSCLC), but esophagitis is a common treatment-related adverse event. Whether esophageal-sparing intensity-modulated RT (ES-IMRT) achieves a clinically relevant reduction in esophageal symptoms remains unclear.ObjectiveTo examine whether ES-IMRT achieves a clinically relevant reduction in esophageal symptoms compared with standard RT.Design, setting, and participantsPalliative Radiation for Advanced Central Lung Tumors With Intentional Avoidance of the Esophagus (PROACTIVE) is a multicenter phase 3 randomized clinical trial that enrolled patients between June 24, 2016, and March 6, 2019. Data analysis was conducted from January 23, 2020, to October 22, 2021. Patients had up to 1 year of follow-up. Ninety patients at 6 tertiary academic cancer centers who had stage III/IV NSCLC and were eligible for palliative thoracic RT (20 Gy in 5 fractions or 30 Gy in 10 fractions) were included.InterventionsPatients were randomized (1:1) to standard RT (control arm) or ES-IMRT. Target coverage was compromised to ensure the maximum esophagus dose was no more than 80% of the RT prescription dose.Main outcomes and measuresThe primary outcome was esophageal quality of life (QOL) 2 weeks post-RT, measured by the esophageal cancer subscale (ECS) of the Functional Assessment of Cancer Therapy: Esophagus questionnaire. Higher esophageal cancer subscale scores correspond with improved QOL, with a 2- to 3-point change considered clinically meaningful. Secondary outcomes included overall survival, toxic events, and other QOL metrics. Intention-to-treat analysis was used.ResultsBetween June 24, 2016, and March 6, 2019, 90 patients were randomized to standard RT or ES-IMRT (median age at randomization, 72.0 years [IQR, 65.6-80.3]; 50 [56%] were female). Thirty-six patients (40%) received 20 Gy and 54 (60%) received 30 Gy. For the primary end point, the mean (SD) 2-week ECS score was 50.5 (10.2) in the control arm (95% CI, 47.2-53.8) and 54.3 (7.6) in the ES-IMRT arm (95% CI, 51.9-56.7) (P = .06). Symptomatic RT-associated esophagitis occurred in 24% (n = 11) of patients in the control arm vs 2% (n = 1) in the ES-IMRT arm (P = .002). In a post hoc subgroup analysis based on the stratification factor, reduction in esophagitis was most evident in patients receiving 30 Gy (30% [n = 8] vs 0%; P = .004). Overall survival was similar with standard RT (median, 8.6; 95% CI, 5.7-15.6 months) and ES-IMRT (median, 8.7; 95% CI, 5.1-10.2 months) (P = .62).Conclusions and relevanceIn this phase 3 randomized clinical trial, ES-IMRT did not significantly improve esophageal QOL but significantly reduced the incidence of symptomatic esophagitis. Because post hoc analysis found that reduced esophagitis was most evident in patients receiving 30 Gy of RT, these findings suggest that ES-IMRT may be most beneficial when the prescription dose is higher (30 Gy).Trial registrationClinicalTrials.gov Identifier: NCT02752126.

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Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

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Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

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