5 Things to Know About Chronotherapy

Ariel Harsinay

Disclosures

August 17, 2018

Chronotherapy—treatment of an illness that incorporates the body's natural rhythms and cycles—has been studied since the 1980s, but has recently gained momentum due in part to the awarding of the 2017 Nobel Prize in Physiology or Medicine to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young for their work on circadian rhythms.[1,2] Their discovery of the molecular mechanisms controlling circadian rhythm has caused chronotherapy to become a topic of paramount interest for those investigating the therapeutic implications of this circadian-cancer connection.[3]

1. Chronotherapy aims to mitigate the side effects of chemotherapy by aligning drug administration with the body's circadian rhythm.

Also known as a sleep/wake cycle, the circadian rhythm is an internal clock that causes the brain and all biological cycles to cycle between intervals of alertness and sleepiness.[4] Circadian rhythms comprise various elements that influence these intervals, including eating habits, body temperature, and duration of sleep, as well as external factors such as darkness and lightness. Chronotherapy involves syncing the time at which cancer drugs are administered with a patient's natural circadian rhythm with the goal of mitigating side effects as well as maximizing the effectiveness of the drug. This involves administering drugs when healthy cells are least prone to the toxicity of these drugs or when cancer cells are most vulnerable to the effects of the drug.

2. Working graveyard shifts or experiencing frequent jet lag may be carcinogenic.

A study by Davis, Mirick, and Stevens at the Fred Hutchinson Cancer Research Center in Seattle, Washington, found that exposure to light during the nighttime is associated with an increased risk of developing breast cancer.[5] The investigators observed the sleeping habits of 813 women who worked graveyard shifts 10 years prior to diagnosis. Compared with controls, women who worked night shifts during the decade prior to diagnosis had a 60% greater chance of developing breast cancer. There was also a direct correlation between number of hours worked during night shifts and the risk for breast cancer. The study observed that avoiding sleep during the time in which your nocturnal melatonin levels are at their peak is a possible carcinogen.

Frequent jet lag is another possible carcinogen relating to disrupted circadian rhythms. A study conducted by Kettner and colleagues at the Baylor College of Medicine in Houston, Texas, observed that mice that were jet lagged were more frequently diagnosed with ovarian tumors, B-cell lymphoma, pancreatic tumors, and hepatocellular carcinoma, among other cancers.[6] This study observed that chronic circadian disruption was associated with increased risk for cancer, neoplastic growth, and genomic instability. Because mice have different circadian rhythms than humans, the role of jet lag on cancer risk in humans still requires investigation; however, it is proposed that the repetitive circadian disruption associated with jet lag leads to neuroendocrine dysfunction and overall metabolic debilitation, leading to increased risk of developing cancer.

3. There is currently only one active clinical trial on chronotherapy in the United States.

Despite the growing interest in chronotherapy following the Nobel Prize award last year, there is currently only one study being conducted in the United States on chronotherapy. This clinical trial, titled "A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade Glioma," is being conducted at Washington University in St. Louis, Missouri, by Jian Campian and her colleagues and is expected to be completed in 2020.[7] Temozolomide was chosen as the chemotherapy drug for the trial because of its association with DNA damage. Through the use of chronotherapy, researchers hope to uncover whether the time at which temozolomide is administered influences its toxicity or effectiveness. The 30 participants in the trial will take temozolomide at either 8 AM or 8 PM, and, while it is too early for conclusive results, Campian states that, so far, taking temozolomide at 8 PM rather than 8 AM has led to reduced side effects of the drug.[8]

4. Whether you're a morning person or night person can influence the effectiveness of chemotherapy.

While Campian's study has been observing that the 8 PM dosage time seems to be optimal for most patients, the most effective time for a drug's administration is not universal but rather specific to a patient's individual circadian rhythm. Your individual circadian rhythm is known as your chronotype, which, at its most basic, is whether you're a morning person or a night person. Each person has individual intervals of alertness and sleepiness, which correlate to internal molecular activity. Thus, chronotherapy must be personalized to each specific patient even if a certain time is better for most patients on average. Decoding personal chronotype can help uncover the optimal time to go to bed in order to get the best night's sleep, or in this case the optimal time to take antineoplastic drugs for their toxicity to be at their lowest and their effectiveness to be at its greatest.

Not only do humans have optimal times for drug administration, but the drugs themselves have specific times in which they will be most effective. Because each class of chemotherapy has an individualized method of killing cells, each drug also has a window of time in which it is most productive. For example, fluorouracil, a chemotherapy given to treat a number of cancers, has been observed to work best at nighttime, while oxaliplatin, a drug most frequently used to treat advanced colorectal cancer,[9,10] has been observed to work best during the afternoon. Francis Lévi, MD, PhD, a chronotherapy researcher at the University of Warwick in Coventry, United Kingdom, has researched the role of these drugs in metastatic colorectal cancer and observed that chronotherapy resulted in significantly lower toxicities.[11]

5. You can shift the body's circadian rhythm or even disrupt a tumor's clock to make chronotherapy feasible for everyday implementation.

While the subject of chronotherapy has gained popularity recently, there are many pitfalls in researching chronotherapy that have been a roadblock to clinical results. One main factor has been the invasive nature of acquiring tumor biopsies, as well as the expense and time involved. For this reason, many researchers are looking at biomarkers rather than tumor samples to investigate the effects of chronotherapy. For example, wrist actigraphy, skin temperature, and blood and saliva samples have been identified as relatively effective ways of identifying if a patient's body is alert or at rest. However, more accurate and comprehensive biomarkers are necessary to research individualized chronotherapy.

In an attempt to circumvent the pitfalls that have made chronotherapy less feasible for everyday implementation, researchers have investigated ways to manipulate circadian rhythms to make chronotherapy more practical for patient use. This can involve ambient lighting, gradually shifting sleeping schedules, taking melatonin supplements, or altering dietary or exercise habits.

In addition to shifting a patient's circadian rhythm, the circadian clock of the tumor itself can be manipulated. Kiessling and colleagues at the Douglas Mental Health University Institute in Montreal, Canada, discovered that injecting tumors with steroids can restore clock function in cancer cells and consequently reduce tumor growth.[12] The injection of the glucocorticoid dexamethasone was found to restore clock gene expression in B16 melanoma cells, which resulted in a 33% reduction in tumor size in just over a week. The use of steroids was observed to inhibit the proliferation of cancer cells, which suggests that patients can reap the benefits of chronotherapy without disrupting their daily schedules.

Moving Forward

While chronotherapy has been primarily associated with cancer treatments, there are benefits to its use in other medical fields as well. Chronotherapy was observed to be effective in the treatment of hypertension in a study conducted by Hermida and colleagues at the University of Vigo in Pontevedra, Spain.[13] Hermida used wrist actigraphy as a biomarker to identify the circadian rhythms of patients while also monitoring their blood pressure through 48-hour sessions. Administering antihypertensive drugs before going to sleep resulted in 37% of patients having controlled blood pressure after 3 months, as opposed to only one of the 125 patients who received antihypertensive drugs in the morning. Chronotherapy may also be useful in psychiatric conditions like bipolar disorder. Wu and colleagues at the University of California, Irvine, found significant benefits in taking antidepressants at three specific intervals in patients' circadian rhythms to achieve sustained responses to the drugs.[14] Studies like these contribute to the wide applicability of chronotherapy and its potential across a spectrum of drug therapies.

The relatively low number of chronotherapy clinical trials has been a barrier to advancements in the field. Advocates for chronotherapy, like Chi Van Dang, MD, PhD, a cancer researcher from The Wistar Institute in Philadelphia, Pennsylvania, hope that recent research on circadian rhythms will propel chronotherapy toward becoming a widely researched field with a plethora of controlled trials to prove its effectiveness. In his keynote presentation last September at the National Institutes of Health's National Cancer Institute in Bethesda, Maryland, Dang called upon oncologists to encourage chronotherapy research and implementation: "I would argue that the evidence shows there is a benefit and we can't ignore it. We just need to be more clever on how to approach the challenges."[15]

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