Chronotherapy: introducing the circadian rhythms into treatment landscapes

Article by Aida Sánchez-Bretaño Sánchez, PhD; Associate Science Liaison at EPG Health

Daily light/dark cycles have led to the evolution of an endogenous system that allows organisms to predict those cyclic changes in order to optimise the use of the resources available in nature. This is the circadian system¹.

It is well known that this system is involved in modulating cellular and molecular responses to physiological cues, pathological events and medical interventions, generally involving a multisystemic response. This modulatory action includes an influence on the disposition and action of various drugs that can result in changes in efficacy and toxicity patterns along the day/night cycle².

Chronotherapy was described five decades ago by the doctor Franz Halberg, whose studies in cancer seemed to indicate a differential tolerance of treatment that was associated with the circadian rhythms of the patient³. This science is applicable to a wide spectrum of specialties, including cancer, immune, cardiovascular and skin diseases, and even neurological disorders, as depression. However, current clinical practice is rarely aligned with these implications.

Chronotherapeutics is the science that involves the prevention or treatment of different diseases while taking into consideration the role of biological rhythms, including a timing of pharmacological and non-pharmacological interventions to optimise their outcomes²

Possibly, the best-known applications of chronotherapy are the use of light therapy to ease seasonal depression symptoms or time-restricting diets to manage gastrointestinal disorders. However, the potential applications are a lot more extensive. There are two main approaches to the inclusion of a chronobiological angle to therapies⁴.

Modern life has implemented changes in our daily routines that can have a strong negative effect on the clockwork of our endogenous rhythms. A clear effect of this is the exposure to blue light at night that acts as a strong inhibitor for the secretion of melatonin⁵. These disruptions often increase the risk of pathologies such as cardiovascular or neurological conditions, cancer, or inflammatory disorders^4,6. Therapies like light-therapy, or the so-called chrono-diets are aimed at modulating the circadian system itself by directly targeting the endogenous clocks presents in the organism, with the intention to correct the disruption created by a modern lifestyle.

The second approach to chronotherapy does not involve direct action to modulate the circadian system itself, but it learns from its functioning in order to improve the use of certain pharmacological and non-pharmacological interventions.

Targets of many medications are expressed rhythmically

In recent decades, studies of transcriptomics have shown that rhythmicity is not a quality limited to the molecules that are part of the circadian system. On the contrary, it seems to be a common characteristic for many other molecules across the entire organism.

For drugs whose targets are controlled by the circadian rhythm and have different levels of expression across the day/night cycle, a better understanding on the peaks of expression could help to determine optimal dosage when accompanied by a correct intake timing; this could help to reduce toxicity and increase effectiveness at lower doses⁴

Timing cancer therapies can be a deal-breaker

Cancer has been one of the first areas of medicine where chronotherapy was implemented and continues to strengthen its ties even now. The high cytotoxicity of anti-cancer drugs requires laborious efforts to identify scenarios where the benefits (higher efficacy, improved dose/effect ratio) outweigh the risks (adverse events, resistance). This work included understanding the circadian variations in cancer pathophysiology.

For decades, it has been known that the some of the most common anti-cancer drugs have different toxicities across the day/night cycle⁷

Chemotherapy provided with a chronotherapeutic component has shown improvement in the outcome of several types of cancer. For instance, children with lymphoblastic leukaemia showed a 2-fold increase in disease-free survival rate after 5 years when the chemotherapy sessions occurred in the evening⁸. In a study of head and neck cancer patients treated with cisplatin, the positive effect of chronotherapy was linked to a reduction in the adverse events associated with the treatment, when it was administered in a chronomodulated way, peaking at 4pm⁹ versus a more standard constant rate of infusion.

A more profound knowledge about the circadian variations in the different targets selected in multi-drug treatments can provide an opportunity to build complex chronomodulated cocktails that could improve outcomes. A chronomodulated chemotherapy consisting in fluorouracil/leucovorin peaking at 4am and oxaliplatin peaking at 4pm administered to male patients with colorectal cancer showed a better response than those patients that were provided with conventional chemotherapy sessions¹⁰. Interestingly, results were opposite in females in this study, indicating the relevance of studying the effects of chronotherapy in both genders to fully understand its potential use in clinical practice¹⁰.

Circadian rhythms in the cell cycle are of critical importance when talking about cancer. Understanding the rhythms associated with cancer cells and finding differences with normal cell cycles can become a powerful tool to target cancer cells in both chemotherapy and radiotherapy contexts. As one of the most common targets in chemotherapy is the cell cycle, optimal timing in treatment administration can improve the chances of affecting preferentially tumorous cells, being less toxic for normal tissue.

Recent advances in immunotherapy for different types of cancer have led to the investigation of the potential circadian regulation of these new targets. A small study on patients with metastatic non-small-cell lung cancer (NSCLC) showed that, when treated with a second-line nivolumab, the time of the day had a striking impact on efficacy, favouring those patients treated in the morning¹¹.

Whilst evidence to support the benefits of implementing a chronotherapeutic approach to chemotherapy sessions is extensive and continues to grow, the consideration of timing radiotherapy is more recent and still developing, with limited available literature. Similar to chemotherapy, the main aim of radiotherapy is to disrupt the circadian-driven cell cycle in cancerous cells.

Interestingly, the cancer origin seems to be relevant for the selection of the correct time of the day for the radiation treatment. Thus, some studies have indicated a better outcome, with lower adverse events when the radiation session takes place in the morning, whereas in other cases evening sessions seem to benefit from better outcomes. Within the cancer types that benefit from morning radiotherapy, targeting adenocarcinoma at this time preferentially attacks cancer cells over normal tissue¹² and, similarly, using proton beam therapy in patients with prostate cancer at this time produced less severe adverse events in the lower urinary tract ¹³. On the other hand, cervical cancer treated in the morning led to a higher gastrointestinal mucositis¹⁴.

Rhythms and chronotherapy in cardiovascular and metabolic diseases

Cardiovascular physiology is closely linked to the circadian system, with many components showing circadian patterns, including blood pressure, heart rate or cholesterol metabolism⁴. Even some pathologies have been observed to have a time preference, as occurs with the myocardial infarction¹⁵.

Due to the close relationship between the circadian and cardiovascular systems, cardiovascular disease care is one of the areas where efforts to implement chronotherapy have been widely investigated. An example of these approaches includes timing of anti-thrombotic agents, which have been shown to be more effective when taken at night, as a consequence of the circadian control of platelet activation^16,17.

Several clinical studies performed on the study of the correct timing for blood pressure medication showed conflicting results, with some of them indicating a potential advantage in the use of anti-hypertension and vasodilatory drugs at night¹⁸ while others have found no differences between the use of these drugs in the morning or evening¹⁹.

Where there is a pathology, there is potential for chronotherapy

Each cell in an organism has the required molecular machinery to be part of the circadian system, allowing them to all be synchronised with each other, with other systems in the organism and with the environment.

Inside of each cell, there are elements that are continuously cycling, and for that reason, any disruption/pathology is a potential target for chronotherapy

In the lungs, the circadian system modulates lung resistance, lung functional residual capacity and peak expiratory flow²⁰. Similar to other conditions, respiratory diseases involve targets that show a circadian oscillation. Asthma gets worse overnight and peaks early in the morning. Recently, studies identifying its connections with the circadian system had defined its relationship with the endogenous molecular oscillators in the lungs. Utilising chronotherapy in asthmatic patients provided better outcomes for several pharmacological treatments than conventional treatment. For instance, patients treated with inhaled triamcinolone once daily at 3pm had a better response compared with patients that were administered the same inhaled drug four times a day²¹.

Another disease that has been widely investigated in the context of its relationship with daily oscillations is psoriasis. Skin is known to be under a strong influence of external cues, as well as internal cyclic signals. Psoriasis has been shown to have itself a strong cyclic component with symptoms being worse in the evening and at night and a recent study demonstrated that topical corticosteroids have greater efficacy when applied to plaques in the evening²².

Chronotype and personalised medicine

Chronotherapy opens the treatment landscape to explore the horizons of the personalised medicine. A better understanding on the circadian rhythms of the disease, as well as the interactions between the pathologies and the circadian rhythm in patients and the patients’ chronotype can offer healthcare professionals with optimised tools to tackle the symptoms, reduce the adverse events related to treatment options and, in the best scenario possible, cure the disease. 

Learn more about cancer treatments

Learn more about non-small cell lung cancer

Learn more about prostate cancer

Learn more about antiplatelet therapy in ACS

Learn more about respiratory diseases

Learn more about dermatology

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