Speaker
Description
Administration time-of-day may modulate antitumor treatment efficacy both in preclinical and clinical studies, likely due to the circadian regulation of physiological processes (\cite{fey},\cite{levi}). However, appropriate biostatistical methods to analyze such periodic variables in clinical studies are lacking. This project aims to identify robust survival analysis methods integrating treatment timing into chronotherapy studies.
Starting from real-world data (\cite{cato}), we conducted a simulation study to evaluate statistical approaches (discrete, sinusoidal, and spline-based models) for modeling the effect of administration timing on patient survival. Simulation scenarios examined the combined impact of (i) cohort size, (ii) observation time windows and (iii) potential confounding factors on model performance, assessed through likelihood ratio tests or Wald delta method–based tests for sinusoidal models.
First, we observed a limited ability of discrete methods to detect circadian effects. Moreover, we showed that the delta method could falsely detect such effects (inflated type 1 error) and overestimate their amplitude. Next, all methods lacked sufficient power to detect interaction effects with patient characteristics for cohort sizes typically encountered in clinical trials (e.g 100-300 patients), advocating for large trials or meta-analysis.
Overall, these results guide the choice of the most appropriate methods to study patient survival’s dosing time dependencies.
Bibliography
@article{fey,
title = {Personalization of {Cancer} {Treatment}: {Exploring} the {Role} of {Chronotherapy} in {Immune} {Checkpoint} {Inhibitor} {Efficacy}},
volume = {17},
copyright = {https://creativecommons.org/licenses/by/4.0/},
issn = {2072-6694},
shorttitle = {Personalization of {Cancer} {Treatment}},
url = {https://www.mdpi.com/2072-6694/17/5/732},
doi = {10.3390/cancers17050732},
abstract = {In the era of precision medicine, mounting evidence suggests that the time of therapy administration, or chronotherapy, has a great impact on treatment outcomes. Chronotherapy involves planning treatment timing by considering circadian rhythms, which are 24 h oscillations in behavior and physiology driven by synchronized molecular clocks throughout the body. The value of chronotherapy in cancer treatment is currently under investigation, notably in the effects of treatment timing on efficacy and side effects. Immune checkpoint inhibitor (ICI) therapy is a promising cancer treatment. However, many patients still experience disease progression or need to stop the therapy early due to side effects. There is accumulating evidence that the time of day at which ICI therapy is administered can have a substantial effect on ICI efficacy. Thus, it is important to investigate the intersections of circadian rhythms, chronotherapy, and ICI efficacy. In this review, we provide a brief overview of circadian rhythms in the context of immunity and cancer. Additionally, we outline current applications of chronotherapy for cancer treatment. We synthesize the 29 studies conducted to date that examine the impact of time-of-day administration on the efficacy of ICI therapy, its associated side effects, and sex differences in both efficacy and side effects. We also discuss potential mechanisms underlying these observed results. Finally, we highlight the challenges in this area and future directions for research, including the potential for a chronotherapeutic personalized medicine approach that tailors the time of ICI administration to individual patients’ circadian rhythms.},
language = {en},
number = {5},
urldate = {2025-03-04},
journal = {Cancers},
author = {Fey, Rosalyn M. and Billo, Avery and Clister, Terri and Doan, Khanh L. and Berry, Elizabeth G. and Tibbitts, Deanne C. and Kulkarni, Rajan P.},
month = feb,
year = {2025},
pages = {732},
}
@article{cato,
title = {Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer: {An} {In}-depth chronotherapeutic study},
volume = {199},
issn = {09598049},
shorttitle = {Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0959804924000479},
doi = {10.1016/j.ejca.2024.113571},
language = {en},
urldate = {2025-03-03},
journal = {European Journal of Cancer},
author = {Catozzi, Simona and Assaad, Souad and Delrieu, Lidia and Favier, Bertrand and Dumas, Elise and Hamy, Anne-Sophie and Latouche, Aurélien and Crochet, Hugo and Blay, Jean-Yves and Mullaert, Jimmy and Ballesta, Annabelle and Heudel, Pierre},
month = mar,
year = {2024},
pages = {113571},
file = {Full Text PDF:C\:\Users\srevillon\Zotero\storage\ZIIM748T\Catozzi et al. - 2024 - Early morning immune checkpoint blockade and overall survival of patients with metastatic cancer An.pdf:application/pdf},
}
@article{levi,
title = {Circadian {Regulation} of {Drug} {Responses}: {Toward} {Sex}-{Specific} and {Personalized} {Chronotherapy}},
volume = {64},
copyright = {http://creativecommons.org/licenses/by/4.0/},
issn = {0362-1642, 1545-4304},
shorttitle = {Circadian {Regulation} of {Drug} {Responses}},
url = {https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-051920-095416},
doi = {10.1146/annurev-pharmtox-051920-095416},
abstract = {Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.},
language = {en},
number = {1},
urldate = {2026-03-06},
journal = {Annual Review of Pharmacology and Toxicology},
author = {Lévi, Francis A. and Okyar, Alper and Hadadi, Eva and Innominato, Pasquale F. and Ballesta, Annabelle},
month = jan,
year = {2024},
pages = {89--114},
file = {Texte intégral:C\:\Users\srevillon\Zotero\storage\RT5B7ERA\Lévi et al. - 2024 - Circadian Regulation of Drug Responses Toward Sex-Specific and Personalized Chronotherapy.pdf:application/pdf},
}
