It is a prevalent morbidity associated with external beam radiation therapy (EBRT) for every kind of cancer. Hickok et al. reported it among 372 EBRT patients treated for a variety of cancers. The incidence of fatigue for those treated for prostate cancer was 42% at baseline, increasing to 71% by week 5. Fatigue severity of at least 4 on a 5-point scale increased from 13% at baseline to 20% by week 5. They also found that:
- Prostate cancer patients had lower incidence of fatigue compared to other cancers
- Fatigue severity was not associated with age, gender or total dose of EBRT
Chao et al. examined the records of 681 prostate radiation patients treated with 6-9 weeks of radiation therapy for prostate cancer at the University of Pennsylvania. Their fatigue level (on a scale of 0-3) was assessed at baseline and at the end of radiation therapy. They found that fatigue was higher :
- in younger men (<60 years of age)
- in men who were depressed
- in men who started hormone therapy before radiation
- in men who did not get anti-nausea medication
Fatigue returned to baseline levels by 3 months post-EBRT in the vast majority of patients.
Miaskowski et al. also found that younger men and those suffering from depression were more susceptible.
Luo et al. did not detect any correlation with age among locally advanced patients, but did detect an association with PSA, Gleason score and stage. Since all 97 patients in their study received androgen deprivation therapy, it is impossible to isolate the effects of each. Tumor burden has always been associated with fatigue in cancer patients.
There is a psycho/social dimension to radiation-induced fatigue. Stone et al. found that there were associated deteriorations in global quality of life, cognitive functioning, and social functioning, most likely as a result of the fatigue. Nausea/vomiting, pain, insomnia, diarrhea, were associated morbidities. Financial difficulties were associated as well. Baseline levels of fatigue and anxiety were associated with higher levels of post-radiation fatigue.
Others have found that fatigue increases with the number of treatments (but not the dose), and the size of the radiation field. In fact, with 5-treatment SBRT, fatigue scores were never meaningfully elevated. Chao found there was no difference between photons and protons in inducing fatigue.
It is impossible to separate cause from effect in these associational studies. Muscle weakness has been associated with fatigue (see this link and this one), but is that because the radiation causes muscle weakness, or because fatigue makes men less likely to exercise with resultant muscle weakness? Our minds may interpret the feeling of muscle weakness as fatigue. It is also difficult to separate the effect of adjuvant hormone therapy, which may cause lassitude and muscle loss from lack of testosterone.
Emotional status is another variable that may both contribute to fatigue and result from it. Stress causes increased production of cortisol at first, but over time, negative feedback may cause adrenal insufficiency, creating a feeling of fatigue. Depression and anxiety are normal reactions to a cancer diagnosis, and the process of going through multiple treatments undoubtedly exacerbate those emotions. Whether psychogenic or somatogenic, the mind changes the body, and the body changes the mind.
Biochemical pathways
We know surprisingly little about the physical process that leads to the feeling of fatigue. The hope is that by learning more, we can design interventions that may block the fatigue process. Holliday et al. hypothesized that fatigue was caused by sleeplessness or by inflammatory cytokines (which can cause flu-like symptoms). In their small study of 28 men at MD Anderson, they found that sleep actually increased, and there was no relationship between cytokines and degree of fatigue (this contradicted a mouse model).
Radiation may induce anemia in susceptible individuals. Feng et al., in a study of 35 men, found that red blood cells, hematocrit, and hemoglobin levels dropped as radiation therapy and adjuvant androgen deprivation therapy progressed. Perceptions of fatigue correlated with reduction in those "heme" markers.
Mitochondria are the energy factories of our cells. They mostly use a process called "oxidative phosphorylation" to generate energy. Hsiao et al. found that genes necessary for the patency of mitochondrial energy production were significantly more impaired in men who received radiation than in men on active surveillance. Mitochondrial enzymes have been shown to play a role as well.
There is some evidence that nerve inflammation from radiation may cause fatigue. Saligan et al. found that the SNCA gene, which is over-expressed as a result of neural inflammation, overexpressed the protein alpha-synuclein, a neuroprotectant. This may one day become a biomarker for radiation-induced fatigue. "Neurotrophic factors" are released by nerves that have been exposed to radiation. They have been implicated in psychological states like fatigue and depression.
Hsiao et al. found that worsening fatigue scores were associated with impairment of genes related to B-cell immune response, antigen presentation, and protection from oxidative damage. The same group also found an association with IFI27, a gene responsible for inducing cell death in irradiated cells.
What can be done about it?
Unfortunately, we do not yet have a pill for it. Ritalin had been proposed, but placebo-controlled studies have proven it to be ineffective in brain tumor patients receiving EBRT and in cancer patients in general (interestingly, a placebo was effective). It is doubtful that a stimulant will be effective in prostate cancer patients receiving EBRT, although patients have anecdotally reported some success with modafinil.
Erythropoietin may be useful off-label in some cases if significant anemia is detected, but there are no clinical trials supporting such use.
Anti-nausea medication may be beneficial, but the ones that cause drowsiness should be avoided.
Until there is a pill, the best interventions are:
(1) Avoid protracted radiation therapy. Now that eight randomized clinical trials have proven that moderately hypofractionated EBRT (20-26 treatments) is no less effective than conventionally fractionated EBRT (39-44 treatments), there is no longer any reason, other than in exceptional cases, to endure the longer fatiguing schedule. SBRT (4 or 5 treatments) entails no meaningful increase in fatigue. High-risk patients may avail themselves of brachy-boost therapy that includes only 20 EBRT treatments. Patients getting salvage radiation will still have to endure 35-40 treatments, although current and past clinical trials suggest that that may no longer be necessary in the future.
(2) Exercise. In a small randomized controlled trial, Monga et al. found that an 8-week structured cardiovascular exercise program prevented fatigue, while improving depression, cardiovascular fitness, strength, flexibility and sense of well-being. Hojan et al. found that those high-risk patients randomized to supervised moderate intensity physical exercise had significantly less fatigue compared to controls. Their levels of inflammatory cytokines were lower, as was their functional capacity, blood counts, and quality of life. Steindorf et al. compared outcomes among 160 women undergoing radiation for breast cancer who were randomly assigned to 12-week muscle resistance training or muscle relaxation training. Resistance exercise resulted in significantly lower radiation-induced fatigue and better quality of life. Segal et al. showed that the combination of cardiovascular and resistance exercise in men with prostate cancer decreased fatigue, with longer lasting improvements attributable to resistance training. Windsor et al. found that even moderate walking throughout the duration of EBRT treatments prevented fatigue and improved physical functioning.
Exercise has another important benefit during radiation therapy -- it may improve the effectiveness of radiation and reduce its toxicity. Some tumors are radioresistant due to hypoxia -- not enough oxygen penetrates the deepest tumor tissue. Oxygenation is necessary for radiation to create the free radicals that destroy the cancer DNA. This positive effect of exercise has so far only been studied in rats and awaits clinical verification. Paradoxically, good oxygenation is what keeps healthy cells healthy. Kapur et al. showed that aerobic exercise reduced rectal toxicity during EBRT.
Patients complain that exercise is the last thing they feel like doing when they are fatigued and depressed. Well-meaning friends and loved ones may offer deleterious advice to rest and take things easy. In all of the above clinical trials, patients had supervised exercise training. If one can afford it, this would be a good time to hire a personal trainer who would force one to work out, whether one wants to or not. Perhaps family and friends can be enlisted to "crack the whip" rather than encourage relaxation. Both cardiovascular training and muscle resistance training are important. Some hospitals and cancer support organizations offer exercise programs for cancer patients. Of course, permission from one's doctor is required.
(3) Stress reduction. Patients and their physicians should be alert to signs of depression and anxiety. Antidepressant medications (e.g., Lexapro) may serve double duty because they have been found to reduce the severity of hot flashes in patients who are on androgen deprivation therapy. Wellbutrin (bupropion) is an antidepressant that also has stimulant side effects. Most anxiolytic drugs (e.g., benzodiazepines) will only increase fatigue. However, practicing mindfulness-based stress reduction has been shown to reduce anxiety and depression in cancer patients. Yoga may be useful as well.
