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

• Published in: Journal of cancer research and clinical oncology 2019-02, Vol.145 (2), p.337-344
• Main Authors: Cramer, Christina K., Alphonse-Sullivan, Natalie, Isom, Scott, Metheny-Barlow, Linda J., Cummings, Tiffany L., Page, Brandi R., Brown, Doris R., Blackstock, Arthur W., Peiffer, Ann M., Strowd, Roy E., Rapp, Stephen, Lesser, Glenn J., Shaw, Edward G., Chan, Michael D.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - radiotherapy; Brain Neoplasms - secondary; Brain tumors; Cancer Research; Chemotherapy; Clinical trials; Cognitive ability; Diabetes mellitus; Diabetic neuropathy; Fatigue; Female; Follow-Up Studies; Hematology; Humans; Hypoglycemic Agents - therapeutic use; Internal Medicine; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Oncology; Original Article – Cancer Research; Patient Safety; Patients; Pioglitazone; Pioglitazone - therapeutic use; Prognosis; Radiation therapy; Radiotherapy, Conformal; Safety; Survival Rate; Toxicity; Tumors
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-018-2791-5

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.