Background: Chronomodulated chemotherapy aims to achieve maximum drug safety and efficacy by adjusting the time of treatment to an optimal biological time as determined by the circadian clock. Although it is a promising alternative to conventional (non–time-stipulated) chemotherapy in several instances, the lack of scientific consensus and the increased logistical burden of timed administration limit the use of a chronomodulated administration protocol.
Objective: With the goal to increase scientific consensus on this subject, we plan to conduct a systematic review of the current literature to compare the drug safety and efficacy of chronomodulated chemotherapy with those of conventional chemotherapy.
Methods: This systematic review will comply with the PRISMA (Preferred Reporting Items for the Systematic Reviews and Meta-Analysis) guidelines. In order to identify relevant studies, we conducted a comprehensive search in PubMed and Embase on May 18, 2020. We included clinical studies that compare either the safety or efficacy of chronomodulated chemotherapy with that of conventional chemotherapy. Potential studies will be reviewed and screened by 2 independent reviewers. Quality assessment will be performed using the National Institutes of Health’s Study Quality Assessment Tool (Quality Assessment of Controlled Intervention Studies). Disagreements will be resolved by consulting a third independent reviewer.
Results: This protocol has received funding, and the search for studies from databases commenced on May 18, 2020. The systematic review is planned to be completed by October 31, 2020.
Conclusions: In this systematic review, we will compare drug safety and drug efficacy for cancer patients who were administered either chronomodulated chemotherapy or conventional chemotherapy. Moreover, we will highlight the outcomes and quality of the selected trials for this review.
Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42020177878; https://tinyurl.com/y53w9nq6
International Registered Report Identifier (IRRID): PRR1-10.2196/18023
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 . Controlled by a molecular clockwork, they drive oscillations in a broad range of biological processes, ranging from the cellular level (eg, cell cycle regulation [ ] and cellular metabolism [ ]) to whole body physiology (eg, liver and renal activity [ ]), which can therefore greatly affect drug responses [ ].
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 . 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 . In addition to this, the sensitivity of molecular drug targets shows diurnal variations [ ]. 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 [ ]. 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) [ ]. 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 [ ]. Together, these findings have led to the investigation of the time-dependent changes in the efficacy and safety of anticancer drug therapies [ ].
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 [, ]. 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 [, ]. 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 [ ].
To date, several studies have established the association between circadian disruption caused by shiftwork and increased cancer risk [- ]. In 2007, the International Agency for Research on Cancer classified “shiftwork that involves circadian disruption” as a probable carcinogenic risk [ ]. Furthermore, both cancer and chemotherapy have been found to disturb circadian rhythmicity independently of each other [ ]. 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 . 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 .
Inclusion and Exclusion Criteria
Studies in English, Dutch, or German will be included in the systematic review. Clinical trials that compare the safety or efficacy of chemotherapy administered to adult cancer patients in accordance with conventional and chronomodulated chemotherapy regimens will be included. Only RCTs will be included in the systematic review. There will be no restrictions on inclusion of studies by time frame or type of setting. We will provide a list of all excluded clinical trials as a supplemental file.
Adult patients (≥18 years old) of all ethnicities and genders that are diagnosed with any type of cancer will be included. No restrictions will be imposed with respect to participants having received other treatment prior to inclusion in the trial.
RCTs that compare the clinical safety or efficacy of chemotherapy administered according to circadian delivery schedules with standard delivery schedules will be included. Single agent and combination chronotherapy regimens delivered through oral administration, bolus injection, or infused according to a flat or sinusoidally chronomodulated schedule will be included. In addition, trials with concomitant radiotherapy will be included in this systematic review.
The outcome of this systematic review will be analyzed as per the following measures.
This will include changes in chemotherapy administration, like a delay or a reduction of chemotherapy treatment, maximum tolerable dose, termination of treatment, or early withdrawal from the clinical trial. Toxicity will be assessed by either of the following toxicity grading scales: World Health Organization standard toxicity criteria , Common Toxicity Criteria [ ], Eastern Cooperation Oncology Group criteria for toxicity [ ], Radiation Therapy Oncology Group criteria [ ], and Gynecologic Oncology Group standard toxicity criteria.
This will include objective response rate (also known as response rate), disease control rates, progression free survival, and overall survival, taking into account salvage therapies if reported. In the case of neoadjuvant and adjuvant studies, efficacy will be measured by recurrence rate and disease-free and overall survival.
Studies published on or before May 18, 2020, were identified by performing a comprehensive search in PubMed and Embase (Elsevier). A literature search strategy was developed in collaboration with an information specialist from Utrecht University unconnected to this study. The search strategy was composed of the following terms and their synonyms: cancer, circadian rhythms, and chemotherapy. For chemotherapy, alongside its synonyms, specific terms for chemotherapy classes, individual drug names, and brand names were included. The World Health Organization’s list of essential medicines 2019  was utilized to confirm inclusion of all essential chemotherapies. Appropriate MeSH (Medical Subject Headings) and Embase subjects headings (Emtree terms) were added to the search strategy for PubMed and Embase searches, respectively. No limits on publication dates were imposed on the search. The search results were narrowed down to show only articles in English, Dutch, or German, due to resource limits. For Embase, conference abstracts were filtered from the search results. The complete search is listed in . The reference lists of all selected articles were handsearched, and their titles and abstracts will be assessed based on the inclusion and exclusion criteria.
The appropriate references and trials for the review will be deduplicated in Endnote (Clarivate Analytics) and afterwards uploaded to Rayyan  to be screened on title and abstract and will be reviewed independently by 2 different reviewers (ABK and MIP). Disagreements will be resolved by consulting a third independent reviewer (LWL). Full texts that contain studies that could be suitable for the systematic review will be screened based on the inclusion and exclusion criteria. If there is no full text available for a relevant trial, the corresponding author(s) will be contacted in order to request it.
Risk of Bias and Quality Assessment
The quality and the risk of bias for selected trials and studies will be assessed using the Quality Assessment of Controlled Intervention Studies tool from the National Heart, Lung, and Blood Institute . All included studies will be categorized as being of good, fair, or poor quality. Studies judged as being of poor quality will be excluded from this review. The risk of bias and quality assessment will be performed by 2 reviewers (ABK and MIP). Any inconsistencies between the 2 reviewers will be resolved by consulting a third reviewer (LWL).
Selective reporting within studies will be assessed by verifying if a protocol was published for each included study and evaluating whether all specified outcomes were published. Other possible risks of meta-bias such as publication bias will be discussed appropriately.
The confidence in the cumulative evidence obtained will be assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations)  for each primary outcome measure.
A data extraction sheet will be developed to store information about the selected studies and trials. Each paper will be assessed independently by 2 reviewers (MIP and ABK) to reduce bias. Data from the selected studies and trials will be extracted independently by the 2 reviewers. The data extraction form will be made and piloted before final implementation by both reviewers. The following parameters will be extracted:
- Publication information: authors, year, country, and journal.
- Study information: trial size, subject characteristics, type of cancer, duration and frequency of follow-up, chemotherapy, and trial objectives.
- Treatment information: type of treatment schedule for each patient.
- Primary outcome variables: efficacy (objective response rate, overall survival, and progression-free survival); toxicity (incidence of side effects and severity of side effects based on either World Health Organization’s standard toxicity criteria [ ] or the National Cancer Institute’s Common Terminology Criteria for Adverse Events [ ]).
- Secondary outcome variables: efficacy (disease control rate, reduction in tumor marker, complete response, pathological complete response, disease-free survival, event-free survival, recurrence rate, reoperation rate, rate of microscopically complete resection, time to progression of cancer symptoms, subjective tumor-related symptoms, minimal residual disease, metastasis-free survival); toxicity (duration of side effect, reversibility of side effect, dose limiting toxicity, treatment modifications, treatment delays, and treatment discontinuations); efficacy and toxicity (quality of life, time to treatment failure).
All factors influencing toxicity and efficacy will be explored appropriately. In order to compare the endpoints in both study arms, we will collect the corresponding hazard ratios, relative risks, risk differences, mean/median differences, and their statistical significance, as far as availability allows.
Any amendments made to the protocol will be documented in PROSPERO (the International Prospective Register of Systematic Reviews) by MIP. The methods section of the systematic review will include a summary of any protocol amendments accompanied by date and rationale.
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.
This research received funding from the EU’s H2020 Research and Innovation Programme under Marie S Curie cofund RESCUE grant agreement no. 801540 and from the Netherlands Heart Foundation, Dekker Senior Clinical Scientist 2019, grant agreement no. 2019T056.
LWL is the guarantor of this review. LWL conceived the study and acquired funding. ABK, US, and MIP developed and drafted the protocol. AMM, CJAP, MP, JPGS, and LWL critically revised the protocol and manuscripts and approved the final version.
Conflicts of Interest
Search terms.PDF File (Adobe PDF File), 65 KB
- Roenneberg T, Merrow M. The Circadian Clock and Human Health. Curr Biol 2016 May 23;26(10):R432-R443 [FREE Full text] [CrossRef] [Medline]
- Chaix A, Zarrinpar A, Panda S. The circadian coordination of cell biology. J Cell Biol 2016 Oct 10;215(1):15-25 [FREE Full text] [CrossRef] [Medline]
- Putker M, Crosby P, Feeney KA, Hoyle NP, Costa ASH, Gaude E, et al. Mammalian Circadian Period, But Not Phase and Amplitude, Is Robust Against Redox and Metabolic Perturbations. Antioxid Redox Signal 2018 Mar 01;28(7):507-520 [FREE Full text] [CrossRef] [Medline]
- Marcheva B, Ramsey K, Peek C, Affinati A, Maury E, Bass J. Circadian clocks and metabolism. Handbook of Experimental Pharmacology 2013:127-155. [CrossRef] [Medline]
- Musiek ES, Fitzgerald GA. Molecular clocks in pharmacology. Handb Exp Pharmacol 2013(217):243-260 [FREE Full text] [CrossRef] [Medline]
- Aldred EM. Chapter 39 - Chemotherapy. In: Pharmacology: A Handbook for Complementary Healthcare Professionals. Edinburgh; New York: Churchill Livingstone, Elsevier; 2009:307-313.
- Ozturk N, Ozturk D, Kavakli IH, Okyar A. Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy. Int J Mol Sci 2017 Oct 17;18(10) [FREE Full text] [CrossRef] [Medline]
- Hrushesky WJ. Circadian timing of cancer chemotherapy. Science 1985 Apr 05;228(4695):73-75. [CrossRef] [Medline]
- Eriguchi M, Levi F, Hisa T, Yanagie H, Nonaka Y, Takeda Y. Chronotherapy for cancer. Biomed Pharmacother 2003 Oct;57 Suppl 1:92s-95s. [CrossRef] [Medline]
- Ballesta A, Innominato PF, Dallmann R, Rand DA, Lévi FA. Systems Chronotherapeutics. Pharmacol Rev 2017 Apr;69(2):161-199 [FREE Full text] [CrossRef] [Medline]
- Lévi F, Okyar A, Dulong S, Innominato PF, Clairambault J. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 2010;50:377-421. [CrossRef] [Medline]
- Lévi F. Chronotherapeutics: the relevance of timing in cancer therapy. Cancer Causes Control 2006 May;17(4):611-621. [CrossRef] [Medline]
- Erkekoglu P, Baydar T. Chronopharmacodynamics of drugs in toxicological aspects: A short review for clinical pharmacists and pharmacy practitioners. J Res Pharm Pract 2012 Oct;1(2):41-47 [FREE Full text] [CrossRef] [Medline]
- Lie JS, Roessink J, Kjaerheim K. Breast cancer and night work among Norwegian nurses. Cancer Causes Control 2006 Feb;17(1):39-44. [CrossRef] [Medline]
- Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, et al. Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. J Natl Cancer Inst 2001 Oct 17;93(20):1563-1568. [CrossRef] [Medline]
- Papantoniou K, Castaño-Vinyals G, Espinosa A, Aragonés N, Pérez-Gómez B, Burgos J, et al. Night shift work, chronotype and prostate cancer risk in the MCC-Spain case-control study. Int J Cancer 2015 Sep 01;137(5):1147-1157 [FREE Full text] [CrossRef] [Medline]
- Papantoniou K, Castaño-Vinyals G, Espinosa A, Turner MC, Alonso-Aguado MH, Martin V, et al. Shift work and colorectal cancer risk in the MCC-Spain case-control study. Scand J Work Environ Health 2017 May 01;43(3):250-259 [FREE Full text] [CrossRef] [Medline]
- Palmer K. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 98: Painting, Firefighting and Shiftwork. International Agency for Research on Cancer. Occupational Medicine 2011 Oct 04;61(7):521-522. [CrossRef]
- Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Lévi FA. The circadian timing system in clinical oncology. Ann Med 2014 Jun;46(4):191-207. [CrossRef] [Medline]
- Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009 Aug 18;151(4):264-9, W64. [Medline]
- World Health Organization. WHO handbook for reporting results of cancer treatment.: World Health Organization; 1979. URL: https://apps.who.int/iris/handle/10665/37200 [accessed 2020-02-04]
- National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. 2017 Nov 27. URL: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf [accessed 2020-02-04]
- Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982 Dec;5(6):649-655. [Medline]
- Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995 Mar 30;31(5):1341-1346. [CrossRef] [Medline]
- World Health Organization Model List of Essential Medicines: 21st List 2019. World Health Organization. Geneva: World Health Organization URL: https://apps.who.int/iris/handle/10665/325771 [accessed 2020-02-04]
- Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016 Dec 05;5(1):210 [FREE Full text] [CrossRef] [Medline]
- Study Quality Assessment Tools. National Heart, Lung, and Blood Institute (NHLBI). 2014. URL: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools [accessed 2020-02-04]
- Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. alfkdsn: The GRADE Working Group; Oct 2013. URL: https://gdt.gradepro.org/app/handbook/handbook.html
|GRADE: Grading of Recommendations, Assessment, Development and Evaluations|
|MeSH: Medical Subject Headings|
|PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis|
|PROSPERO: International Prospective Register of Systematic Reviews|
|RCT: randomized controlled trial|
Edited by G Eysenbach; submitted 04.02.20; peer-reviewed by P Innominato, F Levi; comments to author 31.03.20; revised version received 30.05.20; accepted 02.06.20; published 21.10.20Copyright
©Aoife B Kilgallen, Urška Štibler, Markella I Printezi, Marrit Putker, Cornelis J A Punt, Joost P G Sluijter, Anne M May, Linda W van Laake. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.10.2020.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included.