Showing posts with label fatigue. Show all posts
Showing posts with label fatigue. 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.






Tuesday, August 30, 2016

Patient compliance with radiation schedules

A new study by Ohri et al. (with additional information in the ASCO Post) found that for certain cancers, there was a 22% non-compliance rate at the Montefiore/Albert Einstein Cancer Center in NY. Non-compliant patients extended their total treatment time by about a week. The recurrence rate was 7% among compliant patients, but was significantly higher, 16%, among non-compliant patients. Now, the authors only looked at compliance with radiation schedules for head and neck, breast, lung, cervix, uterus and rectal cancers. Should prostate cancer radiation oncologists and their patients be concerned?

All cancers are different. It is impossible to generalize from one cancer to another. This is as true for radiation treatments as it is for medical treatments. Prostate cancer has some very unique characteristics that affect radiation treatments:

(1) Prostate cancer is very slow growing. For certain cancers like some head and neck cancers, the tumor growth is so fast that multiple radiations sessions must be scheduled each day (called hyperfractionation) in order to keep ahead of the high cancer cell repopulation rate. In fact, the repopulation rate increases as radiation progresses for such cancers. In contrast, even high-risk prostate cancers repopulate so slowly that delays of a few days to a week are insignificant. In fact, some treatment schedules for SBRT and HDR brachytherapy are a week apart with no apparent loss of efficacy.
(2) Prostate cancer responds to fewer, higher doses of radiation – hypofractionation. Prostate cancer has a peculiarly low radiobiological characteristic, called an alpha/beta ratio, which means it is killed more effectively by hypofractionated radiation. Two major randomized clinical trials have proved that shortened radiation schedules (20 fractions or 28 fractions) have equivalent effectiveness and no worse toxicity than the traditional fractionation of 40-44 treatments. The most extreme kinds of hypofractionation, SBRT and HDR brachytherapy, typically only need 4 or 5 treatments. Recent HDR brachytherapy protocols are using as few as 2 treatments. Therefore, patient compliance isn’t much of an issue. For cancers with a high alpha/beta ratio, more fractions with lower dose per fraction are needed to kill the cancer. Showing up every day for many weeks can be burdensome to the patient.
(3) Fatigue increases with the number of fractions, so reducing the number of prostate cancer treatments helps maintain vigor. With normally fractionated prostate radiation, fatigue peaks at 4-6 weeks after the start of therapy (See this link.). While fatigue scores increased a month after SBRT, it was not a clinically meaningful change (See this link.). Fatigue reported from prostate cancer radiation is less than from radiation to head and neck, alimentary and lung cancers (See this link.); therefore, non-compliance due to fatigue from radiation is probably less important for prostate cancer, particularly with hypofractionation. Other issues sometimes associated with extended fractionation include anxiety, nausea, lost days of work and financial burden. Ohri et al. found that compliance was worse among those of lower socio-economic class.
(4)    Prostate cancer’s alpha/beta ratio is much lower than the ratio attributable to healthy surrounding tissues – a therapeutic advantage. This means that prostate cancer cells are more efficiently killed by the hypofractionated regimen, but the healthy tissues of the bladder and rectum that respond quickly to radiation are not killed at all efficiently. So a total SBRT dose of, say, 40 Gy in 5 fractions, has much more cancer killing power than an IMRT dose of, say 80 Gy in 40 fractions, but less acute toxicity to healthy tissues.   This contrasts with other cancers where the alpha/beta ratio of the cancer is similar to that of nearby healthy tissues. In that case, the only way to mitigate damage to healthy tissues is to deliver the radiation in much smaller fractions, and allow time in between for sub-lethally damaged healthy tissues to self-repair. It doesn’t take long, only a few hours, but for practical purposes, treatments are a day apart.
(5) Prostate cancer is multi-focal in at least 80% of men. Tumors are almost always distributed throughout the entire prostate, so the entire organ is irradiated. This contrasts with many other cancers where there is a single large tumor growing in the organ, at least for a long time. For non-prostate cancers, it is rare for the entire organ to be treated.
(6) There are many important organs (including the bladder, rectum, penile bulb and femur) that fall, at least in part, within the radiation field. Prostate radiation requires sophisticated image-guidance and intensity modulation to treat the prostate and nothing else. Unlike radiation for other cancers where there are toxic effects due to treating the organ itself, there is almost no toxicity due to irradiation of the prostate itself (other than loss of seminal fluid). Discomfort from bladder and rectal toxicity arrives only towards the end or after the end of treatments, so there is little reason to discontinue or miss treatments.
(7) Unlike the other organ cancers that were treated in the study, the prostate is deep within the body. Higher energy X-rays are needed for that depth, and that spares closer-to-surface organs. Consequently, radiation burns of the skin rarely occur, and there is no discomfort associated with each treatment. There are exceptions in men who are hypersensitive to radiation, but burns, necrosis, and fistulas have rarely been reported.
There are some radiobiological considerations that are similar to other cancers that respond to radiation (not all of them do). Some cancer cells may self-repair sub-lethal damage to the DNA, and poor tumor-tissue oxygenation (hypoxia) may protect the tumor from radiation damage. For these reasons, it is important to deliver enough radiation to overcome the hypoxia and kill all the cancer cells. Dose escalation has improved the curative potential of radiation for prostate cancer.
An argument in favor of longer treatment regimens is that cancer cells are more vulnerable during certain phases of their cell cycle; therefore, there will be more opportunities to kill them over a longer treatment schedule. Another argument for longer schedules is that hypoxic protection of the tumor is worn away by the treatments, and subsequent growth of blood vessels around the tumor will re-oxygenate it, thus radio-sensitizing it. The greater local control we’ve seen with extreme hypofractionation suggests that it may elicit unique radiobiological mechanisms that might overcome hypoxia and cell cycle phase issues.


Because of prostate cancer’s low repopulation rate, higher quality of life during treatment, and with increasing use of hypofractionation (both moderate and extreme) there is no reason why patient compliance with prostate cancer treatment schedules should be a problem as it is for other cancers.