The Time for Chronotherapy in Radiation Oncology

Abstract

Five decades ago, Franz Halberg conceived the idea of ​​a circadian-based therapy for cancer, given the differential tolerance to treatment derived from the intrinsic host rhythms. Nowadays, different experimental models have demonstrated that both the toxicity and efficacy of several anticancer drugs vary by more than 50% as a function of dosing time. Accordingly, it has been shown that chemotherapeutic regimens optimally timed with the circadian cycle have jointly improved patient outcomes both at the preclinical and clinical levels. Along with chemotherapy, radiation therapy is widely used for cancer treatment, but its effectiveness relies mainly on its ability to damage DNA. Notably, the DNA damage response including DNA repair, DNA damage checkpoints, and apoptosis is gated by the circadian clock. Thus, the therapeutic potential of circadian-based radiotherapy against cancer is mainly dependent upon the control that the molecular clock exerts on DNA repair enzymes across the cell cycle. Unfortunately, the time of treatment administration is not usually considered in clinical practice as it varies along the daytime working hours. Currently, only a few studies have evaluated whether the timing of radiotherapy affects the treatment outcome. Several of these studies show that it is possible to reduce the toxicity of the treatment if it is applied at a specific time range, although with some inconsistencies. In this Perspective, we review the main advances in the field of chronoradiotherapy, the possible causes of the inconsistencies observed in the studies so far and provide some recommendations for future trials.

ncRNAs-mediated TIMELESS overexpression in lung adenocarcinoma correlates with reduced tumor immune cell infiltration and poor prognosis

“…As TIMELESS is a circadian gene, immune checkpoint inhibitor regimens may need to be optimally timed with a patient's intrinsic rhythms to improve outcomes. Currently, only chronoradiotherapy and chronochemotherapy have been investigated across several cancers [34][35][36].…”

Does timing matter in radiotherapy of hepatocellular carcinoma? An experimental study in mice

“…Differences in times of sensitivity/resistance to irradiation were also observed in many clinical studies reviewed in. 47,48 Thus, morning radiotherapy tended to be best tolerated by the oral mucosa patients. 49 Patients with breast cancer who received radiotherapy early morning showed less skin reaction as compared with the group who received the radiotherapy late afternoon (after 3 PM).…”

Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology

“…Although individual studies demonstrated statistical significance, study designs varied widely, and the differences in how patients were grouped presents a major obstacle to forming a consensus of strong conclusions [131]. It has been suggested that future time-of-day studies should compare groups of patients who received radiation within different narrow time windows that are separated by a few hours [149], rather than dividing groups by arbitrary cutoff times. This would ensure consistent differences in the timing of doses between patients of different groups.…”