Radiation therapy does not often fail in prostate cancer patients who are not already metastatic. Many had thought that most radiation failures are attributable to undetected micrometastases. However, two recent studies (see this link and this one) showed that about half of all failures of IMRT as primary therapy were due to failure to kill all the cancer within the prostate. One of the reasons that radiation may not destroy all the cancer is due to a condition called hypoxia.
Hypoxia refers to tissues that are not well oxygenated. Most solid tumors are hypoxic to some degree. The tumor tissue is denser than benign tissue, and although the tumor does generate its own blood supply, the blood vessels are leaky and haphazard. Cancer can often thrive in an hypoxic environment that would atrophy healthy tissue.
Good tissue oxygenation is essential for radiation to work. X-rays cause a chemical reaction with water and oxygen to generate what is called "reactive oxygen species (ROS)." The most important ROS is a molecule called a hydroxyl radical. The hydroxyl radical (a free radical) is powerful enough to tear apart DNA in a reaction called a "double strand break." This is where the magic of radiation happens. Healthy cells can repair double strand breaks or commit suicide (apoptosis) if they can't. Cancer cells lack the ability to repair double strand breaks. Then, when they eventually try to replicate (and that may be delayed for years), they fail to do so and die trying. So radiation irreversibly kills cancer cells but leaves most benign cells intact. But under hypoxic conditions not enough hydroxyl radicals are formed, and some of the cancer is left alive.
(Incidentally, it should be
obvious from this that supplements that are marketed as antioxidants or
free-radical absorbers (e.g., Vitamin E, Vitamin C, glutathione, alpha-lipoic
acid, etc.), which are of questionable value at any time, should be especially
avoided during radiation therapy.)
The most common solutions to overcome hypoxia are to increase the radiation dose and to use some fractionation. Increasing the dose blasts through the tumor like a steam blaster cleaning debris. Fractionation - smaller, multiple doses - kills the outer, oxygenated layer of the tumor. Then, as the outer layer falls away and the next layer gets a fresh blood supply, the next fraction kills that layer. It's like peeling away the layers of an onion. Prostate cancer is particularly vulnerable to a more intense radiation dose, which is why radiation techniques that increase dose per fraction (i.e., SBRT, HDR brachytherapy, and hypofractionated IMRT) are so effective. But at least some fractionation seems to be important too. Attempts to use just one fraction of HDR brachytherapy seem to have higher-than-expected failure rates (see this link).
Good tissue oxygenation seems to play a role in keeping healthy cells healthy following radiation. Kapur et al. in one small study found that moderate aerobic exercise throughout the radiation treatments reduced the incidence of acute rectal side effects. We recently saw that exercise reduces radiation-induced fatigue (see this link). Hyperbaric oxygen therapy has been used to reverse radiation-induced cystitis and proctitis (see this link) and hematuria, although one randomized controlled trial found it did not improve bowel inflammation or rectal bleeding.
So far, the evidence that exercise reduces tumor hypoxia has been limited to a study in rats (see this link). In the first study in humans that I'm aware of, a group at the University Hospital of North Norway are conducting a small clinical trial among 32 men who plan to have a prostatectomy. Half will undergo 4-5 weeks of moderate to intense supervised aerobic exercise. Half will not be told to exercise. They hypothesize that the aerobic exercise will increase the vascularity of the prostate tumors and thereby cause a sustained reduction in hypoxia. Before prostatectomy, they will all be injected with pimonidazole, a non-toxic drug that has particular affinity for hypoxic tissue. In post-prostatectomy pathology, it will be detected in prostate tissue using a specific antibody. They will also look at blood flow in the tumor prior to prostatectomy using MRI.
While this trial may prove that exercise reduces prostate cancer tumor hypoxia, it will remain for a future clinical trial to prove that radiation oncological and toxicity outcomes are improved by it. That will take several years, if it ever gets studied.
Meanwhile, this intervention is harmless for most patients (with doctor's permission, of course), and may improve the results of their prostate radiation treatment. While it may be ideal to undertake a 4-5 week supervised aerobic exercise program to permanently increase tumor vasculature or undergo hyperbaric oxygen therapy, as little as 15 minutes on a treadmill or an exercise bike within an hour of radiation treatment may be enough to temporarily increase tumor oxygenation.
Showing posts with label exercise. Show all posts
Showing posts with label exercise. Show all posts
Friday, December 8, 2017
Saturday, November 4, 2017
Radiation-induced fatigue
One of the annoyances associated with radiation treatments given over a long duration is a growing feeling of fatigue. Radiation-induced fatigue reaches a peak by the end of therapy, but may not completely disappear for a year (see this link). There are many open questions about exactly what it is, what causes it, and what can be done about it.
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:
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 :
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.
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.
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