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

Cramer, Christina K.; Alphonse-Sullivan, Natalie; Isom, Scott; Metheny-Barlow, Linda J.; Cummings, Tiffany; Page, B.R.; Brown, Doris R.; Blackstock, A. William; Peiffer, Ann M.; Strowd, Roy E.; Rapp, Stéphen R.; Lesser, Glenn J.; Shaw, Edward G.; Chan, Michael D.

doi:10.1007/s00432-018-2791-5

Cited by 13 publications

(9 citation statements)

References 51 publications

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“…For example, in rats, the PPAR-gamma agonist, pioglitazone, and the ACE inhibitor, ramipril, have been shown to indirectly improve neurocognitive dysfunction, although without directly improving the already damaged brain vasculature [108][109][110]. In patients with brain tumors, pioglitazone and ramipril have been, or are currently being, tested in phase I and II clinical trials [111] (ClinicalTrials.gov Identifier: NCT03475186). Fig.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Prevention and treatment of radiotherapy‐induced side effects

2020

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Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. Highprecision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Prevention and treatment of radiotherapy‐induced side effects

2020

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“…The administration of PPARg agonists prevent radiationinduced toxicity and cognitive impairment in animal models [38][39][40][41][42][43] . The PPARg agonist pioglitazone, normally used as antidiabetic medication, has recently been experimented as neuroprotective agent in patients receiving brain irradiation, with good results in terms of tolerance 44 , paving the way to the experimentation of other drugs with PPARg agonist properties such as sartans 45 .…”

Section: Discussionmentioning

confidence: 99%

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

Terziev

Psimaras

Marie

et al. 2021

Sci Rep

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The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

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“…There are emerging data that PPAR-γ agonists can be neuroprotective in stroke, Alzheimer’s disease and Parkinson’s disease [91–95]. An initial safety study of pioglitazone in brain tumor patients has been completed [96] and there are plans for a cooperative group trial evaluating the efficacy of pioglitazone in the prevention of RICD.…”

Section: Preventionmentioning

confidence: 99%

Treatment of Radiation-Induced Cognitive Decline in Adult Brain Tumor Patients

Cramer

Cummings

Andrews

et al. 2019

Curr. Treat. Options in Oncol.

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Opinion statement Patients with either primary or metastatic brain tumors quite often have cognitive impairment. Maintaining cognitive function is important to brain tumor patients and a decline in cognitive function is generally accompanied by a decline in functional independence and performance status. Cognitive decline can be a result of tumor progression, depression/anxiety, fatigue/sleep dysfunction, or the treatments they have received. It is our opinion that providers treating brain tumor patients should obtain pre-treatment and serial cognitive testing in their patients and offer mitigating and therapeutic interventions when appropriate. They should also support cognition-focused clinical trials.

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

Cited by 13 publications

References 51 publications

Prevention and treatment of radiotherapy‐induced side effects

Prevention and treatment of radiotherapy‐induced side effects

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

Treatment of Radiation-Induced Cognitive Decline in Adult Brain Tumor Patients

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