Cancer-Related Fatigue and Disrupted Sleep

Cancer-related fatigue is one of the most common and challenging side effects experienced by people with cancer. Unlike the everyday tiredness that improves with rest, cancer-related fatigue is persistent, overwhelming, and can profoundly affect every aspect of daily life—from relationships and work to emotional wellbeing and hope for the future.

Many patients don't realize that effective treatments are available, or they hesitate to mention their exhaustion, assuming it's simply something they must endure. However, both fatigue and sleep disturbances can be addressed, and doing so can significantly improve quality of life during and after cancer treatment.

This page explores what makes cancer-related fatigue different, why it often goes unrecognized, and most importantly, how it can be managed to help you reclaim your energy and vitality.

Introduction

People going through treatment and recovery from cancer find that sleep and fatigue are so interrelated that it is often difficult to casually separate them from each other.  Both are associated with radiation and chemotherapy, biologic and hormonal therapies, and while they each have different causes and symptoms,  they seem to have a synergistic and additive effect on each other.

 Fatigue is one of the most common and disruptive symptoms associated with cancer and its treatment. It affects somewhere between 25% and 100% of patients during treatment, depending on the type of cancer and the treatments given, and often persists after treatment is completed.

It is also recognized that in people having pre-existing sleep or fatigue-related issues, cancer treatment will increase this problem dramatically, making it more severe and more difficult to resolve.

Fatigue in normal day-to-day life is usually a transient or short-lived experience of feeling out of sync or tired. This is distinct from the fatigue of cancer or serious illness, as, rather than a temporary inconvenience, it is persistent, unremitting, and unresolved.

Both problems significantly impact quality of life measures, affecting enjoyment of life, normal interactions with family and friends, and the ability to work and maintain financial stability, along with their effect on mood, cognitive function, focus, and the ability to remain buoyant and optimistic. 

These effects on lifestyle can be overlooked if not specifically inquired about, as patients often don't mention or complain about their fatigue or sleep issues, and their consequences in their lives, believing they have to live with it or are unaware that treatments are available. 

One impediment to quantifying fatigue is that it is a subjective description of feelings, based on both cultural background and language. As a result, no test or image can diagnose it. As a result, they must be specifically asked about. There are questionnaires that help characterize it,  which in western cultures, people describe as feeling weary, tiredness that has never been experienced, a sapping of vitality, low energy, or exhausted, which reference how the body feels, or the emotional state, or mental brightness or clarity. In other cultures, often the context and description are different and won't uncover the problem as often their concepts and expressions about fatigue are different than the western representation.

Fatigue associated with the cancer and its treatments is also distinct from physical overuse or overactivity, as any level of activity tends to cause greater aggravation than would be expected, and rest and sleep generally do not alleviate it.

Fatigue

In evaluating sources of cancer-related fatigue (CRF), looking for specific treatable causes should be the initial step.

These include:

  • Any acute community-acquired  Infections, like flu or COVID, can result from immune impairments secondary to therapy, but there can also be the reactivation of lurking dormant pathogens, like the herpes family, which includes Epstein-Barr and oral or genital herpes. 

  • One breast cancer study revealed that the pre-existing presence of the herpes family virus, cytomegalovirus (CMV), was associated with higher inflammatory markers and greater fatigue during and after treatment. See below for the inflammatory effects related to fatigue.

  • Nutrient deficiencies from diminished appetite and food intake reduce the needed essentials for cellular repair and recovery. 

  • Anemia reduces available oxygenation to tissues and mitochondrial energy generation.

  • Hormonal dysregulation, including cortisol and thyroid functions.

  • Diminished  organ activity from treatment toxicity 

  • Neurocognitive impairment

  • Psychological impacts of mood changes 

  • Fatigue from medications, such as opioids or antidepressants

  • Focal neurologic problems from nerve damage

  • Mitochondrial damage impacts cellular energy production secondary to inflammation-generated oxidative stress and low oxygen.

  • The new onset of medical problems or exacerbation of existing diseases. 

  • There is evidence that suggests that with certain genetic predispositions, some people will experience greater levels of fatigue when receiving cancer treatments.

The Challenges in Cancer-Related Fatigue and Its Connection  to: Chronic Inflammation and Sleep Disruption

In the presence of malignancy, the treatment modalities of surgery, drugs, and radiation all activate inflammatory responses that both disrupt normal circadian sleep rhythms and contribute to fatigue. 

They play off each other in an inverse relationship; when fatigue is high, sleep time is low, and when fatigue is low, sleep time is high. Too often, they are looked at and treated as separate entities, but to achieve improvement, both need to be approached in combination.

Inflammation

The effects of radiation and pharmaceutical drug therapies in cancer treatment affect both active cancer and the surrounding healthy cells, resulting in localized damage. In response, injured tissues release cellular fragments, recognized by the immune system as damage-associated molecular patterns (DAMPs), which activate its inflammatory response and the subsequent release of pro-inflammatory cytokines, TNF-alpha, IL1, and IL6, which support the removal of killed cancer cells and the repair of collateral damage to normal cells. 

These pro-inflammatory cytokines also enter the circulation and travel throughout the body, impacting the nervous system by crossing the blood-brain barrier. 

  • These cytokines can activate the brain microglia cells that initiate neuroinflammation within the central nervous system, affecting sleep, mood, energy, and exacerbating fatigue.

  • Neuroinflammation then alters the neurotransmitter actions of serotonin and dopamine, which regulate mood and motivation, also causing a sense of fatigue.

  • Neuroinflammation disrupts hormonal functions that affect the actions of the hypothalamus, see below. 

Chronobiology of Sleep

This is the study of biological rhythms based on the timing and duration of repetitive cycles, with a central one being the circadian rhythm, the body's 24-hour cycle of physiologic processes.

This circadian rhythm is synchronized to the suprachiasmatic nucleus  (SCN) of the hypothalamus, which is considered the master clock. It responds to the changes in light and dark. When light hits the eye, it triggers the SCN to awaken the body and bring alertness. With darkness, the SCN signal changes and decreases, which then signals the release of melatonin in preparation for the sleep cycle.

Besides wakefulness and sleep, many other of our cellular processes are coordinated by genes which also work on this "clock" rhythm, in coordination between day and night, including:

  • Regulation of glucose and fat metabolism

  • Immune production of cytokines and immune cells

  • Production and secretion of neurotransmitters 

  • Effects on processing reactive oxidative molecules 

Non Rapid Eye Movement Sleep (NREM) is our restorative sleep, which is divided into three stages: (1) passing from wakefulness to light sleep, then into (2) true sleep with diminished awareness of surroundings, with the lowering of body temperature and slowing of the heart. It is here that memory consolidation and information processing from the day occur. The last part (3) is deep sleep, essential for restoration and recovery within the body. It is here that tissue repair, muscle recovery, and immune system strengthening occur. It is also during this cycle that hormones and metabolism are harmonized and balanced.

It is generally about a 90-minute cycle.

Rapid Eye Movement Sleep (REM) describes sleep in which eye movements beneath the closed eyelids occur. It implies an awakened, active brain that is creating vivid,  complex dreams. During this time, the voluntary muscles in the body become temporarily paralyzed while the brain is active, as measured by its increased oxygen consumption and its metabolism.

During this cycle, emotions are processed, memories consolidated, and creative solutions revealed, and daily experiences are moved into long-term storage for future retrieval. 

The essence and importance of sleep need repeating! It is vital for resting the brain and body to:

  • Download our daily experiences and store them in memory files

  • Update the new information

  • Restore energy reserves

  • Initiate repair 

  • Reboot the system

  • Harmonize hormonal balances 

  • Enhance immune functions

Chronobiologic Applications for Cancer Therapies

The circadian rhythm, our 24-hour sleep-wake cycle, includes within its chronobiological rhythm a series of 15" clock" associated genes that cycle according to this rhythm; regulating and modulating, interacting and interconnecting to multiple cellular functions controlling.

  • The timing of cellular replication or cell cycle phases, DNA repair, apoptosis (programmed cell death), and autophagy (the breakdown and recycling of cellular components )

and

  • Bioactivation of cellular processes such as detoxification, elimination, and immune regulation

These are sequentially connected, mutually dependent cycles of communication, and because of their discrete timing of specific effects, they are currently being recognized as offering potential benefits in cancer therapeutics.   Research has uncovered chronobiological rhythms related to the optimum timing of these therapies to maximize their effectiveness and minimize side effects, which appear to be associated with the timing of these clock genes.

  • In a review of data from 18 clinical patient studies, and 3250 patients, the infusion of immune checkpoint inhibitor drugs in the early am enhanced progression-free and overall survival by up to fourfold as compared to treatments given late in the day.

  • Doxorubicin and Cyclophosphamide showed greater effectiveness when administered in the morning.

  • Oxaliplatin, a platinum drug, causes cell death by causing DNA cross-linking. International patient studies using chronomodulation infusion timing found that there was a fivefold improvement in its tolerability and a near doubling of its antitumor effects, when compared to giving it at a constant rate, in combination with 5-FU and Leucovorin. 

  • In another clinical study, 114 patients with metastatic colorectal cancer and 45 patients with non-small cell lung cancer, the incidence of severe adverse events varied up to fivefold depending on when in a 24-hour period the dose of chemotherapy was timed. The optimum chronobiological rhythms for chemotherapy delivery were 5-FU and Leucovorin at 1 am or 4-5 am, and oxaliplatin or carboplatin at 1 pm or 4 pm.

  • A study in patients who had head and neck cancer and received chrono chemo-radiation had  73%less risk of a lower objective response compared to non-timed chemo-radiation therapy.

  • It was also noted that patients with head and neck cancer who underwent chrono-chemotherapy had a 41% lower risk of overall toxicity and other adverse events compared with those with no time range of treatment.

  • Cisplatin infusion, in studies with animal models, suggests that administering it in the am may reduce kidney toxicity.

Radiation Chronobiology

Radiation is designed to kill cancer cells by interrupting cell replication, causing breaks in the DNA. This process also does damage to the surrounding healthy cells.

Studies suggest that timing radiation to the circadian rhythm can maximize its benefit, for better outcomes, while limiting damage to healthy cells.

Cancer cells follow no fixed circadian rhythm in their replication, while healthy ones follow a strict cycle. By following specific markers, it is known that at 6 am, the G1 phase, healthy cells begin synthesizing mRNA and proteins as the initial step in preparation for cellular division. Since the DNA is not yet dividing,  it is the least vulnerable time in which radiation will cause adverse events in normal tissues, compared to later in the day.

The Cortisol and Sleep Circadian Rhythm

Cortisol is an important hormone for the modulation of inflammation and for its effect on the regulation of the sleep cycle, both of which impact the repair and recovery from the effects of cancer treatment, and potentially also reduce the risk of recurrence. 

Cortisol synthesis follows the circadian cycle, with its regulation occurring  via 

  • The hypothalamic-pituitary axis, the HPA,  which regulates cortisol through the stimulation of the hypothalamus secretion of corticotropin-releasing hormone, CRH. This hormone signals the pituitary to produce and release adrenocorticotropic hormone, ACTH, triggering the release of cortisol from the adrenal glands, located on the top of the kidneys.

  • Cortisol in its normal cycle begins to elevate in the early morning light,  specifically the blue light spectrum, and rises till midafternoon and declines toward evening and reaches a low point during the night. During daytime activity, it is influential in regulating blood sugar and many metabolic pathways, controls inflammation, contributes to memory formation, and regulates salt and water metabolism.

Lowering evening levels sets the stage for the uptick in melatonin, from the pineal gland, which releases melatonin, the sleep-inducing hormone, throughout the night.

And normally,  the cycle then repeats.

The Effect of Chronic Stress on Cortisol Levels

The classic acute fight or flight response to acute danger or a perceived threat results in a series of responses that are out of conscious control and happen spontaneously and instinctually. 

In acute situations, whether physical or emotional, there is a transient surge of cortisol, which results in its transient elevation.

Cortisol's physiologic preparation for flight or fight responses includes:

  • Increased arterial and heart sensitivity designed to specifically increase our core and brain blood flow 

  • Repurposing amino acids to ultimately produce more sugar for energy

  • Activating the liver to release more sugar

  • Decrease inflammation

  • Hypervigilance

  • An energy surge

When that stressful situation passes, the system re-equilibrates and rebalances to pre-fight or flight status, and cortisol levels decrease.

Chronic situations of continued stress cause persistent elevations of cortisol, which disrupts its normal circadian cycle, affecting sleep patterns and increasing fatigue. 

It is also commonly assumed that it is the physical effects and side effects of cancer therapy that are the source, but importantly,  chronic emotional triggers contribute substantially as initiators and sustainers of cortisol imbalances.

There are the outward responsibilities that generate questions, many of which are unanswerable; will I survive, can I manage to keep working to pay my bills and support my loved ones, can the family cope and provide the support I will need, will surgery be required, will chemotherapy make me ill and what if it doesn't work, will insurance cover the cost of drugs and if not, can I afford them.   

And there are the internal struggles of emotion and mood. Feelings of despondency, anger, hopelessness, isolation, and resentment. Often wondering, why did this happen to me, or did I do something wrong to deserve this, and tendencies toward guilt, fear, anxiety, and depression.

Even with the successful completion of treatment,

Even with success in their cancer treatment, concerns of a possible recurrence always linger, with people becoming fearful and anxious at any minute, temporary symptoms being the harbinger of cancer's return. 

After treatment, people are also uneasy over whether a return to a "normal" life can be achieved, and yes, a quality can be attained, but it will be a new normal as a cancer survivor.  

In situations of emotional and/or physical stress, the amygdala in the brain, the regulator of emotion, mood, and survival, communicates with the hypothalamus, which regulates the autonomic nervous system and endocrine system, triggering the release of cortisol and adrenaline to prepare for fight or flight.

When the stress is chronic and ongoing, the circadian cortisol rhythm is disrupted and cortisol is continually released, resulting in poor sleep and high levels of fatigue.

To evaluate cortisol, laboratory testing can be used to measure levels, which in situations of chronic inflammation and stress, are elevated above the normal levels expected in the early morning, suggesting its ongoing presence during the night when levels decrease.

People often feel wired from its excessive stimulation of the autonomic nervous system and tired, exhausted from sleep disruption, yet unable to sleep. With the persistence of cortisol into the evening and night, the expected rise in melatonin to initiate sleep does not occur.

Persistent cortisol elevations can result in:

  • Poor sleep initiation

  • Night waking

  • Daytime sleepiness

  • Restlessness

  • Lower sleep efficiency, or the time that you stay in bed

  • Minimal or no relief of fatigue, even with napping 

However,  this pattern can be sustained for only so long, and eventually, the adrenals become unable to sustain this level of cortisol production, and levels start to decrease below normal from adrenal burnout. This diminution results in dizziness, low blood pressure, and again more fatigue symptoms.