A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma

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 morning, relative to 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 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.

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

“…Damato AR et al reported no significant difference in adverse events, quality of life, or OS in prospective randomized TMZ chronotherapy trials. 123 For high‐grade glioma patients, radiotherapy treatment time of the day (RT‐TTD) did not influence progression‐free survival and OS between patients treated in the morning or afternoon. 129 The heterogeneity of each study is worth our attention.…”

“…However, the results of chronotherapy for temozolomide and radiation therapy in glioma are currently controversial. Damato AR et al reported no significant difference in adverse events, quality of life, or OS in prospective randomized TMZ chronotherapy trials 123 . For high‐grade glioma patients, radiotherapy treatment time of the day (RT‐TTD) did not influence progression‐free survival and OS between patients treated in the morning or afternoon 129 .…”

“…Research has also shown that curcumin activates sirtuin 1, and binds to CLOCK: BMAL1 heterodimer to promote the deacetylation and degradation of PER2 69 . Although no effect on the circadian mechanism has been reported, 10 μM curcumin treatment did disrupt a single circadian oscillator within the clock unit or coupling between circadian clocks in apoptosis 123 . During anticancer treatment, curcumin or its analogs should be administered to tumor cells at the optimal stage in maximizing efficacy after determining the circadian phase.…”

“…Since mice are nocturnal animals, and their active and rest phases are out of phase with humans, there are obvious differences in circadian rhythms in mice and humans 130 . In addition, tumor cell‐intrinsic circadian rhythms can regulate TMZ cytotoxicity in mice, which showed a strong correlation between drug sensitivity and circadian rhythm, 82 while the effect of TMZ in glioma chronotherapy treatment is still controversial and needs further large‐population‐based trials for validation 17,123 . Despite being more complex and expensive than murine models, nonhuman primates share more closely activity patterns with humans, which may provide stronger evidence support for chronotherapy research 131 .…”

“… 130 In addition, tumor cell‐intrinsic circadian rhythms can regulate TMZ cytotoxicity in mice, which showed a strong correlation between drug sensitivity and circadian rhythm, 82 while the effect of TMZ in glioma chronotherapy treatment is still controversial and needs further large‐population‐based trials for validation. 17 , 123 Despite being more complex and expensive than murine models, nonhuman primates share more closely activity patterns with humans, which may provide stronger evidence support for chronotherapy research. 131 The generalization of these conclusions to other species will require additional systematic study.…”