Circadian rhythms (circa: about, dia: a day) organize biological functions in living organisms around an approximate 24-hour period to adjust organ and tissue physiology to the ever-changing demands of day and night [1]. Controlled by a molecular clockwork, they drive oscillations in a broad range of biological processes, ranging from the cellular level (eg, cell cycle regulation [2] and cellular metabolism [3]) to whole body physiology (eg, liver and renal activity [4]), which can therefore greatly affect drug responses [5].

Chemotherapy is used to treat many cancers and involves administration of cytotoxic drugs that either kill or interfere with the proliferation of rapidly dividing cells. The principle of conventional chemotherapy is to increase the chemotherapy dose until maximum cytotoxicity occurs and a maximum tolerated dose is reached. However, as both malignant and normal cells are affected, severe toxicities are often developed, in turn leading to interruption of chemotherapy treatments and decreased survival rates [6]. Therefore, finding ways to increase efficacy and reduce side effects would greatly improve cancer therapy potential.

The molecular mechanisms involved in regulating pharmacological processes such as drug absorption, distribution, metabolism, and excretion are controlled by the circadian clock. The clock thereby determines when the anticancer drug treatment should ideally be delivered as it controls the drug’s elimination and detoxification, affecting the efficacy and toxicity on tumor cells and healthy cells, respectively [7]. In addition to this, the sensitivity of molecular drug targets shows diurnal variations [7]. The tolerability of more than 40 anticancer drugs such as oxaliplatin have demonstrated a 10-fold variability in rodents as a function of dosing time [7]. Anticancer drugs have shown to have a 24-hour variability in drug toxicity as well as improved efficacy and tolerability in rodents kept in alternate exposure to 12h light and 12h darkness (LD12:12) [7]. The circadian rhythms of both drug toxicity and efficacy are defined in preclinical studies, and the optimal circadian time from rodents is extrapolated and translated to the most suitable time to administer chemotherapy according to the human’s circadian rhythms [8]. Together, these findings have led to the investigation of the time-dependent changes in the efficacy and safety of anticancer drug therapies [7].

Chronomodulated chemotherapy aims to exploit the circadian variation in drug response by administering anticancer drugs at specific times of the day, thereby hitting cancer cells when they are most vulnerable or normal cells when they are least vulnerable [9,10]. The terms chronomodulated and circadian-based have been used to describe similar strategies using parenteral or oral administration. For the sake of clarity, we will use the term chronomodulation for all therapeutic routes.

The goal of chronomodulated chemotherapy is to minimize toxic side effects while promoting the maximum achievable efficacy of the chemotherapy regimen to improve the cancer patients’ quality of life, survival time that is based on the different circadian rhythms of DNA synthesis, and cell growth between tumor and normal cells [11,12]. The impact of circadian rhythms on the outcome of cancer therapy has been the subject of several clinical trials over the past two decades. While conventional chemotherapy generally consists of constant-rate drug delivery, chronomodulated chemotherapy is administered as a variable rate infusion with peak drug delivery times set to vary according to circadian time or delivery restricted to specific time windows [13].

To date, several studies have established the association between circadian disruption caused by shiftwork and increased cancer risk [14-17]. In 2007, the International Agency for Research on Cancer classified “shiftwork that involves circadian disruption” as a probable carcinogenic risk [18]. Furthermore, both cancer and chemotherapy have been found to disturb circadian rhythmicity independently of each other [19]. These factors may be causing interpatient variability of circadian rhythms to a yet unknown extent. This leaves room for the exploration of optimizing chronotherapy by adjusting administration time to each patient’s individual circadian clock.

Although chronomodulated chemotherapy is a promising avenue of research that could contribute significantly to improve existing and future cancer treatments, no medical consensus has been reached to implement chronomodulated chemotherapy regimens, and conventional chemotherapy is most often administered in accordance with the hospital schedule and staff working hours [10]. Before this approach is integrated into clinical practice, its benefits must be adequately supported with evidence from well-designed randomized clinical trials.

This systematic review will evaluate the findings of randomized controlled trials (RCTs) that compare the safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy administration in adult cancer patients.

The systematic review and its protocol will comply with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines [20].

The search for the relevant studies on databases was performed on May 18, 2020. The systematic review is intended to be completed and ready for submission for publication by October 31, 2020.

This systematic review will have some limitations that will be discussed appropriately. The exclusion of papers not written in English, Dutch, and German may inhibit the identification of all important findings, and this will be taken into consideration in the discussion of the systematic review. However, the database searches of the appropriate studies will be extensive to ensure the required studies are captured for the systematic review.

We will produce a table with patient characteristics, including gender, age, ethnicity, and different cancer types. In this table, we will also include the type of chemotherapy used in the trial, the dose and half-life of these cytotoxic drugs, any significant differences between the conventional and chronomodulated chemotherapy treatment groups, optimal delivery time to administer the chemotherapeutic drug of choice, and the treatment group that produces the least side effects. In case of a sinusoidal infusion schedule, we will also state the circadian timing system function. The selected studies included in this review will provide information required to conclude whether chemotherapy regimens should be administered in accordance with the circadian clock and highlight the findings and quality of reporting these particular clinical trials. This systematic review will provide vital information on drug safety and drug efficacy in cancer patients administered chronomodulated chemotherapy versus conventional chemotherapy.