Tumor Growth Rate Determines the Timing of Optimal Chronomodulated Treatment Schedules

In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy. We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that 24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy

Relevance of internal time and circadian robustness for cancer patients

International audienceAbstractBackgroundAdequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.MethodsTwenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.ResultsThree circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.ConclusionsThe integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers

Systems chronotherapeutics

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system–resetting strategies for improving chronic disease control and patient outcomes

Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer

Backround: Sleep disorders are prevalent in patients with advanced cancer. Their impact on clinical outcomes is not well understood. Methods: A post-hoc analysis was conducted in 361 chemo-naïve patients with metastatic colorectal cancer completing twice the EORTC QLQ-C30 questionnaire within a randomized international phase III trial. The study assessed the effect on overall survival (OS) of subjective sleep complaint, used as a normal or a time-dependent covariate (TDC), using a multivariate Cox proportional hazard model. Prognostic analysis was conducted on the whole study population and separately in each treatment arm (conventional FOLFOX2, or chronomodulated chronoFLO4). Results: Sleep problems were reported by 202 patients (56%) at baseline and by 188 (52%) on treatment. Sleep problems at baseline were independently associated with a higher risk of earlier death (HR: 1.36; p = 0.011), progression (HR: 1.43; p = 0.002) and poor treatment response (RR: 0.58; p = 0.016). TDC analysis confirmed the independent prognostic effect of sleep problems on OS (HR: 1.37; p = 0.008), while on treatment this effect was only observed using univariate analysis. The negative prognostic value of sleep problems on OS at baseline, on treatment, and as a TDC was greatest on chronoFLO4 compared to FOLFOX2. Conclusions: Subjective sleep problems are associated with poor clinical outcomes in metastatic colorectal cancer patients and affect chronotherapy effectiveness. There is a need for a well-tuned circadian timing system in order to increase chronotherapy activity. Prospective studies are needed for determining the impact of therapeutic approaches on sleep disorders upon quality of life and survival of cancer patients

Hidden Markov models for monitoring circadian rhythmicity in telemetric activity data

Wearable computing devices allow collection of densely sampled real-time information on movement enabling researchers and medical experts to obtain objective and non-obtrusive records of actual activity of a subject in the real world over many days. Our interest here is motivated by the use of activity data for evaluating and monitoring the circadian rhythmicity of subjects for research in chronobiology and chronotherapeutic healthcare. In order to translate the information from such high-volume data arising we propose the use of a Markov modelling approach which (i) naturally captures the notable square wave form observed in activity data along with heterogeneous ultradian variances over the circadian cycle of human activity, (ii) thresholds activity into different states in a probabilistic way while respecting time dependence and (iii) gives rise to circadian rhythm parameter estimates, based on probabilities of transitions between rest and activity, that are interpretable and of interest to circadian research

Fully Explorable Horned Particles Hiding Charge

The charge-hiding effect by a horned particle, which was studied for the case where gravity/gauge-field system is self-consistently interacting with a charged lightlike brane (LLB) as a matter source, is now studied for the case of a time like brane. From the demand that no surfaces of infinite coordinate time redshift (horizons) appear in the problem we are lead now to a completly explorable horned particle space for traveller that goes through the horned particle (as was the case for the LLB) but now also in addition to this, the horned region is fully visible to a static external observer. This requires negative surface energy density for the shell sitting at the throat. We study a gauge field subsystem which is of a special non-linear form containing a square-root of the Maxwell term and which previously has been shown to produce a QCD-like confining gauge field dynamics in flat space-time. The condition of finite energy of the system or asymptotic flatness on one side of the horned particle implies that the charged object sitting at the throat expels all the flux it produces into the other side of the horned particle, which turns out to be of a "tube-like" nature. An outside observer in the asymptotically flat universe detects, therefore, apparently neutral object. The hiding of the electric flux behind the tube-like region of a horned particle is the only possible way that a truly charged particle can still be of finite energy, in a theory that in flat space describes confinement. This points to the physical relevance of such solutions, even though there is the need of negative energy density at the throat of the horned particle, which can be of quantum mechanical origin.Comment: The new version has been accepted for publication in Classical and Quantum Gravity. Title changed to "Fully Explorable Horned Particles Hiding Charge". Horned Particles terminology is used now instead of "wormholes" to dscribe the solutions here. arXiv admin note: text overlap with arXiv:1108.373