If you are a person living with cancer, a cancer survivor, or supporting someone affected by cancer, your life can feel as though it has been turned upside down. Our days and nights start to blur together, and sometimes just feel out of our control. Take this as an opportunity, or even a call to action, whether impacted by cancer or just wanting to better understand preventative strategies, use sleep and circadian health as a tool to optimize the cancer journey and take control of what you can. 

In the Basics of Sleep and Circadian Rhythm section, we learned about our body’s natural daily rhythm (the circadian rhythm) and how there are both genetic, or literally a DNA blueprint, as well as behavioral and environmental influences on what those rhythms should be. These rhythms direct almost every function we experience and every action our body performs to live. When the circadian rhythm is out of sync, as is seen with circadian rhythm sleep-wake disorders, the risk of developing some cancers increases. The evidence for the link between circadian disruption and breast, prostate, and colorectal cancers is particularly strong.¹

Circadian rhythm and sleep-wake patterns have been found to have an association, and some research has suggested as a cause, of being a risk factor for cancer development, a symptom at time of diagnosis, contributory to a more aggressive, invasive cancer, and even a strong influence to therapeutic timing, response, and survivorship.

But WHY? For the same reason that WSCN exists. Sleep-Wake and Circadian health are critical to all areas of health and wellness. When disturbed, they result in unregulated cell cycles and growth, increased vulnerability of our DNA to damage, and impaired mechanisms that are supposed to function as safety checks or valves. 

For instance, some studies^3,4 have shown that circadian disruption interferes with our melatonin production. Although many think about melatonin as a factor that solely plays a role in our sleep, it actually has very significant antioxidant and energy-metabolism properties as well. Melatonin has been shown to be oncostatic, meaning it can decrease how quickly cancerous cells grow, develop, or spread. In fact, there are current studies looking at the use of tamoxifen, a chemotherapy used for breast cancer, given in combination with the use of melatonin as an adjunctive or add-on therapy. Similarly, melatonin is also being studied in glioblastoma multiforme (GBM), the most common and fatal form of brain cancer in adults. In GBM, it has been suggested that the cancer itself gains its super-malignant potential by hijacking the brain’s circadian machinery, and the use of melatonin has been shown to not only impact the tumor itself but also reduce chemotherapy drug resistance, making treatments like temozolomide more impactful.

If we bring it back to basics, our genes that are involved in maintaining our circadian rhythm influence the timing, amount, and regularity of all our cellular actions. If these genes have an abnormality or if we start living a life that is a conflicting day-night pattern, it is going to result in dysregulated timing, amount, or regularity of what our cells do. Never a good thing! Driving and car maintenance can provide a great illustrative analogy. As drivers, we may know that a regular alignment can improve safety, enhance handling, and reduce stress on the suspension of our vehicle, and we may even recognize the early signs of a misalignment, like poorer gas mileage or even having the vehicle tend to pull to one side while driving. But, we may not be doing anything about it because the vehicle still “drives fine” and still takes us from A to B. “It does the job.” That is, until the misalignment damages our suspension, and we are looking at costly repairs, or perhaps something even irreparable. We don’t get away with less sleep or irregular schedules. It’s more like we are just waiting for the suspension to give out and see what our individual related cost is.

Cancer and Circadian Rhythms 

Although many types of cancer have been found to have a sleep-wake and circadian component, let’s take a deeper dive into glioblastoma multiforme (GBM) and its relationship with the circadian rhythm. GBM is a very aggressive and difficult-to-treat brain cancer. GBM has been found to hijack our normal circadian machinery to be more aggressive⁵ How? Well, scientists have found that GBM tumors actually use clock genes to grow and even exhibit their own circadian rhythms and synchronize to our circadian rhythm to optimize their growth! 

Timing Matters! Not Convinced? 

Not only do we have a circadian influence on tumor growth and progression, but we have a growing body of research that underscores that TIMING MATTERS in treatment. 

We repeatedly discuss the idea that every single thing our body does has a sleep-wake or circadian relationship, and pretty much all cell functions have a peak time of action or expression across a 24-hour period. But what about when you have a genetic difference that doesn’t impact a clock gene but may impact a gene that makes an important enzyme your body needs to be able to use a certain drug or chemotherapy? 

Since the late 1980s, this is exactly what has been discovered with the use of the chemotherapy agent 5-fluorouracil (5-FU), whose metabolism is dependent on the enzyme dihydropyrimidine dehydrogenase (DPD), a product of the dihydropyrimidine dehydrogenase (DPYD) gene.⁶ People with a mutation or change in DPYD produced have a deficiency in DPD, and when receiving the same protocol as others, would have intolerable side effects and poorer outcomes. 

We now know that using chronotherapy to time the infusions of cisplatin and 5-FU—two commonly used cancer drugs—not only decreases side effects, like gastrointestinal toxicity, bone marrow suppression, and damage to the heart, but also boosts the anticancer activity of the drugs.¹ Doctors and scientists can harness this information to treat cancer more effectively. Healthcare providers can also use chronotherapy to time radiation or other cancer treatments.

Recent research has shown that the timing of glucocorticoid (GC) infusions, commonly used during chemotherapy, may indeed affect the outcome of treatment. In a study evaluating the timing of administration of synthetic GC in mice with GBM,⁷ researchers found that if GC was given at the beginning of the resting phase, the tumors grew more quickly, but if it was given in alignment with when the mice naturally produced the most GC, the tumors shrank. This concept of aligning treatment time of use to the body’s circadian timing of relevant factors to optimize its effect is called chronotherapy. But do humans experience a similar difference in treatment response based on the timing of treatments?

Many research studies are underway looking at the impact of using chronotherapy in oncology. Particular attention and study have been demonstrated in a form of cancer treatment called immune checkpoint inhibitor (ICI). When researchers collectively assessed 29 studies that included time of day as a factor in giving ICIs in a variety of cancers, most of the studies showed that when ICIs were administered early in the day, patient outcomes were improved and, perhaps even more of an impact, that later administration potentially increased the risk of worse outcomes.⁸

We at WSCN want our community to be educated, empowered, and active in their journey. Therefore, it is critical that we discuss not just the science and a bunch of facts, but understandable useable information that gives a better understanding of the bidirectional relationships, highlighting research that has shown the impact of sleep and circadian rhythm on disease and the effects of disease on sleep and circadian rhythm, as well as what you can do today to be the best at getting better every day. The intimate relationship of sleep and circadian health with cancer represents an actionable response we can have. Currently, sleep and circadian disorders are accepted as a consequence of cancer and its treatments, but we now understand that sleep and circadian health are a potential biomarker and therapeutic strategy that has yet to be fully taken advantage of in oncology. 

There is a stigma associated with being a cancer survivor. Be grateful you are alive. As if the expectation is you should only expect to survive, NOT “THRIVE.” We get it. We don’t want to exist, we want to excel. You are not alone. 

It is first important to note that sleepiness and fatigue are not the same thing, but can coexist. Both can make it difficult to live the life you desire. Sleepiness, however, is the disability associated with the desire to sleep, unexpected intrusion of sleep, and excess need of sleep, and is frequently only improved with sleep- or wake-promoting strategies. Whereas fatigue is not sleep-motivated, but is a difficulty in doing physical or cognitive actions despite the capability to do so. Fatigue may be worsened with repeated or ongoing attempts. 

Despite such significant differences, much of the research done in this area of cancer-related impairment doesn’t distinguish the two, which can make it a bit difficult to not only interpret your own experience, but also have it appropriately acknowledged and treated. Based on these limitations, we will use the term fatigue to be consistent with published literature, but we recognize the limitations and want to call out that this is an area of needed clarity and research. 

Fatigue during and after chemotherapy for cancer is common, even for 5 years or longer. The fatigue can also start even before a cancer diagnosis. In fact, one study found that 14-28% of people had been experiencing severe fatigue in the year before their diagnosis of prostate, breast, or gastrointestinal cancer.^9,10

Although most people think that these symptoms are related to their treatment, it may actually be a consequence of the cancer itself. Cancer can change the body’s metabolism and inflammatory status. Tumors often release inflammatory signals or cytokines, which can increase sleepiness and fatigue. Factors associated with fatigue include decreased physical activity, depression, and disturbed sleep,¹⁰ which may be a cause or effect of the symptoms of fatigue.

Fatigue in people with cancer varies based on individual factors, the type of cancer, and the treatment. To better guide your healthcare partner on what YOU need, keep a symptom diary to understand your sleep-wake quality and schedule, as well as the circadian distribution of your daily symptoms.  This can help you have a better understanding of what you are experiencing as well as better determine with your healthcare partner if you are experiencing sleepiness, fatigue, or both. This will hopefully allow for personalized suggestions or treatments to improve your function and quality of life. Stop surviving! Start Thriving!

References

1. El-Tanani M, Rabbani SA, Ali AA, et al. Circadian rhythms and cancer: implications for timing in therapy. Discov Oncol. 2024;15(1):767.
2. Straif K, Baan R, Grosse Y, et al. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8(12):1065-1066.
3. Vasey C, McBride J, Penta K. Circadian rhythm dysregulation and restoration: the role of melatonin. Nutrients. 2021;13(10).
4. Fishbein AB, Knutson KL, Zee PC. Circadian disruption and human health. J Clin Invest. 2021;131(19).
5. Chan P, Rich JN, Kay SA. Watching the clock in glioblastoma. Neuro Oncol. 2023;25(11):1932-1946.
6. Granados J, Pasternak AL, Henry NL, Sahai V, Hertz DL. Risk of toxicity from topical 5-fluorouracil treatment in patients carrying DPYD variant alleles. Clin Pharmacol Ther. 2024;115(3):452-456.
7. Gonzalez-Aponte MF, Damato AR, Simon T, et al. Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host. Cancer Cell. 2025;43(1):144-160 e147.
8. Fey RM, Billo A, Clister T, et al. Personalization of cancer treatment: exploring the role of chronotherapy in immune checkpoint inhibitor efficacy. Cancers (Basel). 2025;17(5).
9. Ancoli-Israel S, Liu L, Rissling M, et al. Sleep, fatigue, depression, and circadian activity rhythms in women with breast cancer before and after treatment: a 1-year longitudinal study. Support Care Cancer. 2014;22(9):2535-2545.
10. Goedendorp MM, Gielissen MF, Verhagen CA, Peters ME, Bleijenberg G. Severe fatigue and related factors in cancer patients before the initiation of treatment. Br J Cancer. 2008;99(9):1408-1414.