Showing posts with label mindfulness. Show all posts
Showing posts with label mindfulness. Show all posts

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:

  • 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.






Thursday, October 19, 2017

How anticipating regret and quick decisions can lead to poor decision making

An essay in the New England Journal of Medicine describes the cognitive components of regret. They opine that regret always involves self-recrimination and not just disappointment over poorer than expected outcomes.

They breakdown treatment regret into different causes:

• "Process Regret" occurs when patients do not consider information about all available choices before making a decision.
• "Role Regret" arises when a patient gives in to pressure from others to change his decision.
• Active decisions can lead to more regret than passive decisions when the outcome turns out poorly.
• "Omission Bias" is the tendency to avoid active decisions, even when in our best interest.
• "Commission bias" may occur when the patient is distraught and believes that immediate decisive action is needed.
• Regret is lower when things are going poorly anyway; higher when there is a downturn of fortunes.

But there is another kind of regret that is equally counterproductive. In fact, it can lead to our making poor treatment decisions. "Anticipated regret," the fear of future self-recrimination, can cripple the patient's decision process, and ironically lead to "treatment regret" farther down the road. They offer the following advice to physicians, but I think that we as peers should heed it as well:
"We should recognize that anticipated regret can leave a patient mired in decisional conflict, unable to choose. For these patients, it is vital to bring anticipated regret to the surface by openly discussing their fears and helping them gain a clear perspective on the risks and benefits of their options in order to move forward. To mitigate the possibility of future experienced regret, we as doctors can try to reduce the emotional temperature and, when feasible, avoid having patients make their decisions while in a hot state. Except in the most urgent circumstances, physicians can set in motion a deliberate process, exploring all treatment options to avert process regret. When patients are heavily influenced by others in making a decision, we can also be alert to the possibility of role regret.
Here's their essay.

My personal belief is that regret - either of the past or anticipated - is a destructive emotion that causes distress. The best way I know to avoid it is by practicing Mindfulness to keep us in the present moment as much as possible and less in an a past that we can no longer change or a future that we cannot reliably anticipate.

I have also come to believe that no doctor ought to accept as final any prostate cancer primary treatment decision made by a low, intermediate or high risk patient within a month of receiving his diagnosis, and preferably within 3 months. The emotional temperature has too strong an effect on decision making, and time is our friend in this regard. Similarly, doctors should insist that second opinions have been acquired.

A new study by Hirasawa et al. confirms others that demonstrate that waiting 6 months or more (median 7.6 months) from biopsy to surgery among patients with localized prostate cancer (low risk to high risk) had no effect on 5 year rates of biochemical recurrence. It also had no effect on whether nerve bundles were spared, pathological upgrading or upstaging, positive margins, or positive lymph node detection. A similar study has demonstrated the same thing when the eventual treatment choice was radiation, comparing  those who waited more than 3 months with those who had treatment within 3 months,. There is no medical reason to rush this primary treatment decision.