A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma.
Anna R. Damato,Ruth Katumba,Jingqin Luo,Himachandana Atluri,Grayson Talcott,Ashwin Govindan,Emily A. Slat,Katherine N. Weilbaecher,Yu Tao,Jiayi Huang,Omar H. Butt,George Ansstas,Tanner M. Johanns,Milan G. Chheda,Erik D. Herzog,Joshua B. Rubin,Jian Campian +16 more
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TL;DR: A retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma and concluding Chronotherapy with TMZ is feasible.
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Abstract: Background
Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792).
Methods
Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms.
Results
A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms.
Conclusions
Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy.
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Citations
Chronotherapy in Glioblastoma: State of the art and future perspectives
TL;DR: In this article , the authors discuss recent advances in using chronotherapy regimens in the treatment of Glioblastoma multiforme (GBM) and discuss novel treatments with drugs of short half-life or circadian phase specific activity, and examine the therapeutic potential of new approaches that target elements of the core circadian clock.
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Temozolomide Chronotherapy in Glioma: A Systematic Review
TL;DR: A systematic review of literature following PRISMA guidelines looking at clinical outcomes on TMZ chronotherapy on gliomas was performed as discussed by the authors , which indicated a trend for improved overall survival, but possibly increased toxicity when TMZ was administered in the morning (vs. evening).
Watching the Clock in Glioblastoma.
TL;DR: The role of the circadian clock in GBM tumorigenesis is discussed in this paper , where the authors highlight the critical role the clock plays in brain tumor biology and the strategies by which the clock can be leveraged for GBM treatment in the clinic.
Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs
Zongqi Wang,Gang Chen +1 more
TL;DR: The association between cell cycle and circadian clock is discussed and provided a prominent molecular theoretical basis for tumor therapy and the internal characteristics concerning the circadian clock in glioma involve stemness, metabolism, radiotherapy sensitivity, and chemotherapy sensitivity.
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Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma
Maria Felicita Gonzalez‐Aponte,Anna R. Damato,Laura Lucía Trebucq,T. Simon,Sandra P. Cárdenas-García,Kevin Cho,Gary J. Patti,Diego A. Golombek,Juan José Chiesa,Erik D. Herzog +9 more
TL;DR: It is concluded that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity.
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