While percentages vary, studies have consistently demonstrated that cancer-related fatigue is one of the most common debilitating side effects associated with both radiation and chemotherapy, as well as the malignant process itself. Quality of life can be significantly and negatively impacted in cancer survivors who experience fatigue and other commonly associated symptoms including sleep disturbance, pain, depression, and anxiety. Presently, pharmacological options are limited and are often associated with further side effects. An integrative approach that, in addition to optimizing lifestyle, employs specific natural agents can safely and effectively enhance energy levels following conventional cancer treatments. While much of the data associated with these natural interventions are considered preliminary, the benefit-to-risk profile is appealing and thus should be considered in clinical practice. While there are many ways to mitigate symptoms, including fatigue, during active conventional treatment, the focus of this article is on posttreatment cancer-related fatigue.
The fatigue associated with cancer or cancer treatment is broadly referred to as cancer-related fatigue (CRF). The National Comprehensive Cancer Network defines CRF as persistent, subjective fatigue that interferes with the patient’s ability to carry out normal daily activities.1 This is different than other forms of fatigue such as overexertion or flu-related fatigue, which are typically resolved with rest and sleep. In cases of CRF, the fatigue becomes pathological when it occurs during normal activities, does not improve, and severely impacts a patient’s quality of life.
A multicenter patient survey conducted by Stone et al demonstrated that CRF affects more patients for a longer period of time than any other posttreatment symptom and that patients view this symptom as being more significant than any other symptom, including pain or nausea.2 The authors also report that CRF is consistently underreported and often untreated.
Because of its subjective nature and the broad definition often used in clinical studies, CRF prevalence data vary. Hofman et al reported that up to 80% of patients treated with chemotherapy experienced fatigue, and up to 90% of those treated with radiation experienced fatigue.3 These percentages are consistent with other research.4 A small study by Nail et al showed that 81% of the patients who had received chemotherapy reported fatigue as a significant side effect.5
The onset of CRF typically coincides with treatment but in as many as 40% of patients, it can start as an early symptom of malignancy beginning prediagnosis.3 CRF can persist for months or even years after treatment ends. Bower et al reported in 2006 that 34% of their breast cancer study participants had significant fatigue even 5 to 10 years after diagnosis.6 Another study involving patients who had a previous diagnosis of Hodgkin’s lymphoma found that fatigue was still present in 60% of the participants even 5 years after diagnosis.7 A more recent study by Oerlemans et al reported that 44% to 54% of non-Hodgkin’s lymphoma patients reported constant fatigue 10 years postdiagnosis.8 In some cases, especially during active chemotherapy and radiation, there is a large subset of patients who experience an energy pattern with sharp dips and plateaus sometimes referred to as “roller coaster” fatigue.9
While reporting of fatigue can be subjective, it is often accompanied by objective physical symptoms such as pain, weakness, depression, nausea, impaired cognitive function, and sleep disturbance.4,10
There are several comorbid factors and other issues that can increase a patient’s risk of developing CRF11,12:
- advanced age,
- advanced disease,
- previous conventional treatment,
- electrolyte and fluid disturbances,
- nutrient deficiencies,
- depression and/or anxiety,
- high body mass index, and
- lack of physical activity.
Comorbidity and a lack of clear etiological mechanisms make this condition multifactorial and more complex to treat and reverse.
Possible Underlying Mechanisms
Causal factors associated with CRF are not fully understood; however, it is becoming clear that the etiology of posttreatment fatigue is related, at least in part, to underlying mechanisms associated with activation of the proinflammatory cytokine network, hypothalamic-pituitary-adrenocortical (HPA) axis dysfunction, circadian rhythm disruption, and mitochondrial dysregulation.13,14
The contribution of inflammatory cytokines to CRF has been demonstrated in a number of investigational studies. Collado-Hidalgo et al (2008) examined single nucleotide polymorphisms in fatigued and nonfatigued breast cancer survivors and found that polymorphisms in the interleukin-(IL) 1β genotype may be a potential risk factor in the development of CRF.14 Previously, these same researchers demonstrated that circulating inflammatory markers and functional alterations in the proinflammatory cytokine network were associated with increased fatigue in breast cancer survivors.15 Higher levels of c-reactive protein and IL-6 have also been correlated with the presence of fatigue in women diagnosed with breast cancer before the initiation of treatment,16 suggesting that the inflammatory underpinnings are the result of the malignancy itself and perhaps later aggravated by treatment. Bower et al (2011) demonstrated that fatigue was positively associated with higher plasma levels of soluble tumor necrosis factor receptor II in breast cancer patients who were treated with chemotherapy (P<0.05).13 In that study, 25% of the participants also reported elevated depressive symptoms and 60% reported corresponding sleep disturbances; however, increased inflammatory markers were not correlated with those 2 comorbid factors. Cytokine and IL-mediated fatigue has been postulated to be the result of cytokine-induced central nervous system (CNS) inflammation that in turn alters hypothalamic and hippocampal functioning.17
One result of hypothalamic and hippocampal dysfunction is disruption of the HPA axis. HPA axis dysfunction, aggravated by the inflammatory stress of cancer treatment, as well as the psychological distress associated with a cancer diagnosis, is proposed as a discrete cause of post–cancer treatment fatigue. Chemotherapy and radiation are known to alter HPA axis function leading to endocrine alterations that can cause fatigue.18 In a study involving children with brain cancer, Schmiegelow et al demonstrated that radiation and chemotherapy negatively impacted HPA axis function that resulted in secondary adrenal insufficiency.19 Preliminary studies indicate that reduced cortisol output and disturbances in HPA axis function correlate with CRF.18 Bower et al (2002) also demonstrated that CRF was associated with reduced cortisol output in breast cancer survivors.20
The loss of the sleep-wake cycle in cancer survivors may also represent a central mechanism for fatigue, insomnia, and depression/anxiety.
Endocrine disruption and circadian rhythm are closely related. Alterations in circadian function as it relates to CRF are linked in part to cortisol secretion. Bower et al (2005) demonstrated that breast cancer survivors with CRF had a significantly flatter diurnal cortisol slope when compared to women without fatigue and that the severity of the fatigue correlated closely with the flatter slope plots.21 Rich et al demonstrated that patients with inconsistent and/or dampened circadian rhythms also had greater fatigue compared to patients with better-defined rhythms.22 This reflects a heightened hypothalamic sensitivity to the negative feedback of cortisol or more likely, given the cytokine-induced CNS inflammation, a reduced central HPA axis drive and impaired responsiveness. The loss of the sleep-wake cycle in cancer survivors may also represent a central mechanism for fatigue, insomnia, and depression/anxiety experienced by some cancer survivors.
Mitochondrial dysregulation is also a logical contributing factor for CRF.23 One of the characteristics of cytotoxic cancer therapies is the generation of high levels of oxidative stress.24 High levels of intracellular oxidative stress cause cellular hypoxia that limits oxidative phosphorylation in the mitochondrial inner membrane, the primary cellular process used to generate adenosine triphosphate (ATP). This inhibition of mitochondrial oxidative phosphorylation can occur as a result of oxidatively induced mitochondrial fission and ultimately mitochondrial uncoupling.25 Another oxidatively mediated cause of reduced oxidative phosphorylation is direct impairment of the electron transport chain,26 primarily the result of oxidative damage to mitochondrial DNA along with ubiquinone deficiency.27 Furthermore, several drugs used in cancer treatment, such as anthracyclines, damage mitochondria and inhibit mitochondrial biogenesis,28 thereby stunting cellular energy recovery posttreatment.
Successfully impacting and even reversing CRF requires attention to the potential underlying mechanistic factors. Fortunately, there are several botanicals and nutrients that may positively influence posttreatment CRF. Adaptogenic herbs are among the most potentially impactful strategies in the alleviation of CRF.
The primary mechanism of action of botanical adaptogens is to normalize the output of the HPA axis. Most adaptogens increase adrenocorticotropic hormone (ACTH) and cortisol with single high-dose administration and normalize ACTH and cortisol with longer-term administration.29 The use of adaptogens causes normalization of stress-induced alteration in plasma corticosterone and monoamines such as norepinephrine, 5-hydroxytryptamine, and dopamine in the cortex and hippocampus regions of the brain.30 Another key point of action of adaptogens appears to be their upregulating and stress-mimetic effects on the “stress-sensor” 70 kilodalton heat shock proteins, which interact with glucocorticoid receptors and, in so doing, affect the levels of circulating cortisol and nitric oxide (NO).31 Prevention of stress-induced increases in NO and the associated decrease in ATP production, results in increased performance and endurance.31 Adaptogens specifically can increase energy and stamina, improve mood, and enhance cognition.32
Ginseng has been used in Asian countries for thousands of years. The active medicinal components of the plants are ginsenosides. There are 2 major species of ginseng: Asian/Korean ginseng (Panax ginseng) and American ginseng (Panax quinquefolius). Both species have similar constituents, including ginsenosides Rb1 and Rg1. P ginseng is one of the most researched ginsengs and has been shown to have anti-inflammatory, antioxidant, and anticancer effects with clinical research also revealing that it can improve psychological and immune function.33,34
Safety data regarding P ginseng demonstrate good toleration with mild adverse events such as dyspepsia, hot flash, insomnia, and constipation being reported.35 There are no confirmed drug-botanical interactions; however, P ginseng does induce cytochrome P450, family 3, subfamily A (CYP3A) and therefore caution with drugs that are CYP3A substrates is advised.36 Additionally, use during pregnancy and lactation should be avoided.34 Preliminary data show that ginseng can offer protection against cancer37 and while there are no human studies on the interaction of ginseng with chemotherapy or radiation, preclinical studies indicate synergism of P ginseng with various chemotherapeutics.38 Some caution is warranted in presence of estrogen receptor–positive cancer as in vitro assays have demonstrated estrogen-receptor activation and proliferation effects of human breast cancer cells.39
A literature review by Choi et al revealed 1,415 relevant studies with 30 randomized clinical trials and found that although many of the studies were poorly designed, ginseng appears to be effective for a variety of conditions.40 Kim et al found that P ginseng (1 g/d or 2 g/d) reduced fatigue severity in patients with idiopathic chronic fatigue compared to placebo; however, this failed to reach statistical significance (P>0.05).41 Nonetheless, the interesting aspect of another study was the noteworthy antioxidant effects that were measured in the P ginseng group.42 In that study, reactive oxygen species and malondialdehyde were lowered and total glutathione was increased significantly when compared to placebo. The researchers concluded that the antifatigue effects of P ginseng are due in part to its antioxidant properties, perhaps favorably impacting mitochondrial function.
A pilot study conducted by Kim et al looked at quality of life (QoL) scores in cancer patients. After 12 weeks, the patients who took 3,000 mg of P ginseng showed improvement in mental and physical functioning compared to placebo as indicated by subjective QoL scores.41 Improvement in QoL could be due in part to the demonstrated anxiolytic effects ginsenosides have by their interactions with GABA receptors.43
Specific to CRF, a randomized, double-blind, multisite trial featuring fatigued cancer survivors conducted by Barton et al demonstrated that P quinquefolius at a dose of 2,000 mg daily for 8 weeks produced statistically significant improvement in fatigue scores compared to placebo (P=0.003).44
Rhodiola rosea is a traditional botanical medicine that has been used for centuries to increase physical endurance, improve resistance to altitude sickness, enhance longevity, and treat depression, anemia, fatigue, and other health issues. Scientific research on this botanical has increased dramatically over the past several decades. Since 1960, there have been more than 180 different Rhodiola studies published in the scientific literature.45 The majority of these studies were done on the R rosea species of the genus Rhodiola, and most of the human studies utilized a standardized dose that contained 3% rosavins and 0.8% to 1% salidroside, which coincides with the naturally occurring ratio of 3:1 in R rosea.45,46
From a mechanistic standpoint, R rosea has different effects on the CNS depending on dose. Larger doses have a more sedative effect while smaller doses promote the release of brain monoamines, which then activate the cerebral cortex and limbic system.47
R rosea is considered safe because of its low toxicity level and low side effects profile, although dizziness and dry mouth have been reported in a clinical trial setting.48 A review by Ishaque et al concluded that there are few side effects associated with R rosea supplementation and that adverse effects such as headache and insomnia were mild and rare.46 Specific to cancer, preliminary in vivo studies have shown that R rosea may enhance the effects of chemotherapy in general and potentially reduce universal side effects such as fatigue and cognitive impairment.45 Animal studies have failed to show interactive effects between Rhodiola and medications, although Rhodiola may contribute to hypoglycemia and hypotension.49
There have been no studies conducted to date specifically involving patients with CRF; however, there have been several human clinical trials evaluating efficacy in both mental and physical fatigue. Olsson et al looked at individuals suffering from stress-related fatigue in a randomized, double-blind, parallel-group study and found that R rosea decreased cortisol response to stress and had a positive effect on fatigue levels when compared to placebo.50 The study also demonstrated that there were improvements in cognitive function when patients receiving the extract were placed under stressful conditions.
The review of 11 clinical trials by Ishaque et al found contradictory evidence due to study bias or reporting flaws. While results were inconsistent, 2 of the 6 trials looking at physical fatigue demonstrated R rosea to be effective and 3 of the 5 studies evaluating R rosea for mental fatigue showed that it was effective.46
Preliminary animal data also indicate that R rosea has cytokine-reducing antiinflammatory properties, which could explain in part how it can help reverse mental and physical fatigue. Lee et al found that oral administration in vivo suppressed several proinflammatory factors including IL-1B, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF-a).51 The same study showed a neuroprotective effect from R rosea as well.
Mushrooms have a long history of use as medicines in many cultures. Many of these mushrooms are immunomodulators that can help prevent and treat many illnesses. Mushrooms have also been shown to produce antiinflammatory effects by downregulation of iNOS, cytochrome c oxidase-2, IL-1B, and TNF-a.52 The safety profile of these medicinal mushrooms is also very positive.53 In addition to their anticancer effects, some mushrooms have been shown to increase the cytotoxic effects of chemotherapy.54
Mushrooms are biological response modifiers, so their overall therapeutic actions may benefit cancer survivors who are experiencing chronic fatigue. Animal studies have demonstrated various mechanisms by which mushrooms improve energy. One study found that a mushroom extract increases endurance by increasing liver and muscle glycogen deposition.55 Another animal study found that an extract of Ganoderma lucidum enhances Krebs cycle dehydrogenases and mitochondrial electron transport chain complex IV activities, thereby contributing to increased cellular energy.56 A 3-month double-blinded clinical trial of 7 healthy male cyclists demonstrated increased free radical scavenger capacity in the athletes’ serum after daily dosing of 1,335 mg standardized extract of Cordyceps sinensis and 1,170 mg pure extract of Ganoderma lucidum. This effect correlated with enhanced recovery and overall performance.57 A 1-year randomized control trial of 73 obese adults assessed various metabolic impacts of substituting meat with mushroom in the diet. At the end of a year, participants on the mushroom diet experienced weight loss, lower body mass index, and improved lipid and inflammatory markers.58These improvements are consistent with improved metabolism and energy.
Of note, mushroom extracts exert significant immune-enhancing activities and a meta-analysis by Eliza et al demonstrated that Coriolus versicolor produced a 9% absolute reduction in 5-year mortality in cancer patients, which equated to 1 additional patient alive for every 11 patients treated.59 All trials used mushroom extracts standardized to 1 g to 3.6 g of polysaccharide-K or polysaccharide peptide daily with range duration of therapy from 1 month to 36 months. The trials included patients with cancers of the nasopharynx, breast, colorectum, stomach, and esophagus.
One of the key roles that nutrients have in energy regeneration is to reduce inflammatory cytokines and to optimize mitochondrial function. While an exhaustive list is beyond the scope of this article, the following deserve mention.
- Acetyl-L-carnitine: Supports oxidative phosphorylation from fatty acids. Fatty acids in cytoplasm are transformed to long-chain acyl-coenzyme A (CoA) and 3 carnitine-dependent enzymes transfer the fatty acids into the mitochondrial matrix where they undergo beta-oxidation to produce acetyl-CoA, which enters the Kreb’s cycle.60
- Alpha lipoic acid: Studies performed in rats have also shown that supplementation with alpha-lipoic-acid and acetyl-L-carnitine synergistically reduced oxidative stress and improved mitochondrial function.61
- CoenzymeQ10 (as ubiquinol): CoQ10 is an integral component of the electron transport chain, and it modulates mitochondrial permeability and is thus necessary for optimal mitochondrial function. Of note, a recent randomized, double-blind, placebo-controlled study of 300 mg of oral CoQ10 (as ubiquinol) failed to show relief of self-reported treatment-related fatigue in newly diagnosed patients with breast cancer when taken for 24 weeks concurrent with chemotherapy.62 The favorable impact of CoQ10 may be more evident when ubiquinone levels are depleted (ie, posttreatment).
There is no question that CRF is a significant problem for many cancer survivors and it is absolutely critical that it be addressed in clinical practice. The integrative practitioner—whether in general practice, naturopathic oncology, or any form of complementary medicine—can play an important role in filling the gap for these patients.
A treatment strategy should begin by assessing and addressing potential underlying causal factors associated with activation of the proinflammatory cytokine network, HPA axis dysfunction, circadian rhythm disruption, and mitochondrial dysregulation. There are many tools that address these underlying factors, including the botanical adaptogens P ginseng and R rosea, medicinal mushrooms, and mitochondrial nutrients. In addition to these supplemental strategies, regular exercise, optimal nutrition, and stress management should also be considered in this patient population.
Conflict of Interest Disclosure
Lise Alschuler, ND, FABNO, is an independent contractor providing educational services to healthcare and dietary supplement companies and nonprofit professional associations. She is on the Medical Advisory Board of Integrative Therapeutics and the Executive Director of TAP Integrative, an educational non-profit that receives sponsorship support from Integrative Therapeutics. She is also a co-principle of Thrivers, LLC, a multimedia consumer educational corporation that derives a percentage of revenue from sponsorships and consultation services associated with dietary supplement products.
Karolyn A. Gazella provides educational consulting services to healthcare and dietary supplement companies and is a co-principle of Thrivers, LLC, a multimedia consumer educational corporation that derives a percentage of revenue from sponsorships and consultation services associated with dietary supplement products.
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