Exercise and immunity

Exercise is good for the immune system but what about high volume, high intensity, chronic (long-term) exercise?  For cancer patients, a couple of things may be worth considering, but first a few things about immune cells.  In a general sense, cancer is a failure of the immune system to detect and eliminate defective cells, or maybe more accurately, the ability of cancer cells to evade detection from immune cells.

Two categories of immune cells are: innate immune cells; and, adaptive immune cells.  Natural Killer cells (NK cells) are a part of the innate immune system and they respond quickly to tumor formation and virally infected cells.  T-cells are a part of the adaptive immune system.  T-cells remember previous invaders, and cancer, and respond faster the second time to the same invader.  Moderate intensity exercise and life long aerobic fitness improves aspects of both of these immune cell types.  However, high volume, high intensity, long-term extreme exercise can have negative effects (1,2).

A study (3) followed Ironman competitors training for 6 months prior to the event and for a few weeks afterwards.  The researchers found that by the end of study period the ratio of  some T-cell subtypes changed to a composition that an older person is more likely to have.  Naive T-cells, which are highly responsive mature T-cells, decreased, while terminally differentiated T-cells (senescence) increased.  Terminally differentiated T-cells are not as ‘nimble’ as naive T-cells in responding to invaders, and the ratio between the two can change as one ages – more terminally differentiated T-cells accumulate and less naive T-cells are found.  This change is thought to make the elderly more susceptible to infections.  However, increasing aerobic fitness can lower the proportion of age-related senescent T-cells and increase naive T-cells, regardless of age (4), but maybe only to a point, as elite endurance athletes are known to get more upper respiratory infections and changes in immune cells are thought to play a role in this (5).

streaming blood cells

Another piece in this exercise puzzle is a virus, Cytomegalovirus (CMV).  CMV is a common herpes virus infecting approximately 50% of American adults, and that percentage increases with age.  CMV affects the exercise response of NK cells, increasing their numbers and cytotoxicity (killing ability).  However, that changes at exercise intensities eliciting a blood lactate concentration of 4 millimoles, which is about +15% of the blood lactate threshold (as defined by Weltman, A., 1995).  This is an intensity that many endurance athletes periodically train at in order to improve performance – tempo runs for marathon runners are an example.  After exercise that induces 4 millimoles blood lactate, NK cell numbers and cytotoxicity are decreased, but not in healthy individuals, only in CMV infected individuals, and regardless of sex (6).

So what does this mean for cancer patients wanting to do a triathlon, marathon, or ultra?  Right now there isn’t enough evidence to change the general American College of Sports Medicine (ACSM) guidelines of 150 minutes per week of moderate intensity exercise or 75 minutes per week of vigorous exercise.  Although a recent breast cancer study (7) found that 300 minutes per week of moderate intensity exercise was best for post-menopausal breast cancer patients who were not on hormones.  Surprisingly, another study found that higher levels of cardiorespiratory fitness was associated with higher risk of prostate cancer (8), the CMV status of those subjects was not reported and may not be known.  Outside Magazine recently did an article (9) on the deleterious effects ultra-marathons has had on some participants.  Perhaps CMV status or changes in T-cell proportions may be emerging as important markers to follow.  Exercise can help protect us against infection and fight tumors but that does not also mean greater amounts of exercise is better.  Until more evidence is presented, the ACSM exercise recommendations, as generic as they are, appear to be about right for cancer patients, and maybe particularly for those who are CMV positive.

For more in-depth information about exercise and immunity, a couple of recent articles are worth reading (10,11,12), if you can get full access (12).

  1. Special issue on exercise immunology: Current perspectives on aging, health and extreme performance. Richard J. Simpson, Jos A. Bosch. Brain Behav Immun. 2014 Jul;39:1-7.
  2. Is immunosenescence influenced by our lifetime ‘‘dose’’ of exercise? Jmes E. Turner. Biogerontology (2016) 17:581–602.
  3. The impact of 6-month training preparation for an Ironman triathlon on the proportions of naïve, memory and senescent T cells in resting blood.  Coagrove, C., et al. Eur J Appl Physiol (2012) 112:2989–2998.

  4. Aerobic fitness is associated with lower proportions of senescent blood T-cells in man.  Spielmann, G., et al.  Brain, Behavior, and Immunity 25 (2011) 1521–1529.

  5. Upper respiratory tract infections and exercise.  D.C. Nieman. Thorax. 1995 Dec; 50(12): 1229–1231.
  6. Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Part II: Impact of latent cytomegalovirus infection and catecholamine sensitivity.  Bigley, A.B., et al. (Article in Press) Brain, Behavior, and Immunity xxx (2015) xxx–xxx.

  7. Effects of a High vs Moderate Volume of Aerobic Exercise on Adiposity Outcomes in PostmenopausalWomen. A Randomized Clinical Trial.  Friedenreich C.M., et al.,  JAMA Oncol. doi:10.1001/jamaoncol.2015.2239.

  8. Midlife Cardiorespiratory Fitness, Incident Cancer, and Survival After Cancer in Men. The Cooper Center Longitudinal Study.  Lakoski, S.G., et al.,  JAMA Oncol. 2015;1(2):231-237. doi:10.1001/jamaoncol.2015.0226.

  9.  Running on empty.  Meaghan Brown.  Outside, June 12, 2015.
  10. Human cytomegalovirus infection and the immune response to exercise. Simpson, R.J., et al., Exerc Immunol Rev. 2016;22:8-27.
  11. Does Regular Exercise Counter T Cell Immunosenescence Reducing the Risk of Developing Cancer and Promoting Successful Treatment of Malignancies? James E. Turner and Patricia C. Brum. Oxidative Medicine and Cellular Longevity Volume 2017, Article ID 4234765, 18 pages.
  12. Mobilizing Immune Cells With Exercise for Cancer Immunotherapy. Simpson, R.J., et all., Exerc. Sport Sci. Rev., Vol. 45, No. 3, pp. 163–172, 2017.
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A little exercise for me, a lot for you?

 

bikes,vintage  Cycling on twilight time

I often read stories about cancer patient’s (survivor, warrior, thriver, whatever we want to be called) physical accomplishments before, during, or after treatments – marathons, triathlons, ultras, century rides – all impressive stuff, even outside the realm of cancer.  The accomplishments seem understandable too, since exercise has been found to:

  • Improve survival in breast (1) and colorectal cancers by 50% (2).
    • Brisk walking of 2 1/2 hours per week produced the breast cancer results, but more vigorous exercise of 6 hours per week was needed for colon cancer;
  • Other researchers found moderate intensity physical activity to reduce risk of death from all causes by 60% among breast cancer patients (5);
  • and, cancer specific mortality from brain (4),andhigh grade, advanced, or fatal prostate cancers (3), were also reduced 43% and 70% respectively.
    • running 7.5 to 15.5 miles per week or walking briskly 12 to 23 miles per week for the brain cancer results, and 3 hours per week of vigorous exercise for prostate cancer.

Interestingly, more exercise did not reduce risk any further in the breast (1) or brain cancer studies.  However, for their results, the brain cancer subjects had to exceed the recommended physical activity levels (6) of 150 minutes of moderate intensity exercise per week.  Walking was also as good as running in the brain cancer study, subjects just had to walk farther.

What does this all mean for those of us affected by cancer?  Well, for the cancers mentioned above, if you’re not moving at the levels showing significance, perhaps it is time to get clearance from your physician, and start.  Practically, make exercise or physical activity a part of your weekly schedule.  It is easy to fill up your calendar with other things and people but forget to plan you into your week. Take a good look at your week, find days and times that work best to accomplish what you want, then write you into those time slots, and keep the appointment.  Book others to meet with you if needed, guilt can be the right motivator sometimes.

African American Family Parents and Children Cycling  Walking_2

Hypothetically, what if completing an Ironman Triathlon improved survival by 80%, would cancer patients, the majority of whom are sedentary, start training?  I wouldn’t be surprised if many did, determination can be great when faced with a cancer diagnosis.  However, even if willing to simply change their lifestyle, or intensely train for an Ironman, are we already hindering patients’ ability to do so by not pre-habilitating (8) them for the insult some treatments inflict on the body?  If most cancer patients do not already like to exercise, how are we ever going to convince them to start if we let their physical function decline further prior to or during the treatment process?

For those of us already in the exercise choir, and for cancer types other than those listed above, how much exercise is enough, and what may warrant caution (9) or be too much?  Unfortunately, most fitness stories remain just that, stories, unless we happen to be in a study, because, until physical activity is routinely recorded in oncology we will never know to what extent many physical accomplishments affect cancer survivorship (the ‘survivorship beginning at diagnosis’ definition).  Most of us in the cancer exercise choir, myself included, are just figuring it out as we go along, sometimes overdoing it (7), or maybe we’re not doing enough, and we share what we’ve learned with others.  Ironically, in spite of all the data we generate when training with our consumer fitness tools, there still isn’t the right statistical data to guide many of us.

senior man exercising in wellness club

Missing data …

A physical activity profile (using a short, scientifically validated, questionnaire) is not routinely recorded when extracting biopsy tissue from patients.  Is there evidence in tissue samples that could correlate physical activity to cancer treatment response rates and survival?  How are tissue samples different, if at all, between those who exercise versus those who don’t?  If different, can the differences be exploited to improve cancer treatment outcomes or to develop new drugs?  Exercise and physical activity are positively affecting survival for those cancers listed above, but how is this happening?  What are the physiological mechanisms, and are we overlooking routine biopsies as sources of evidence?  Exercise physiologists sometimes pay study volunteers and take muscle biopsy samples to find out what exercise did.  In oncology, other than pathology, how much thought is given to our biopsy samples, which patients pay for, and exorbitantly too?

I wouldn’t limit recording patients’ physical activity to biopsies only, we should be updating fitness profiles at diagnosis, first treatment, scans, and subsequent healthcare visits too.  The studies mentioned above were observational ones done over a number of years, some only assessing physical activity every two years (1,3), which doesn’t allow for teasing out information in the weeks specifically surrounding a cancer diagnosis or treatment.  Some physical activity questionnaires have gone electronic, but collecting data using paper forms, interviews, and calls to subjects is still done.  In today’s electronic world this sounds archaic, but this is how the best observational evidence has been obtained so far.Exercising on gym bikes.

Or … data to nowhere

With all the new consumer fitness products available we are still unable to get much of the data they generate into our electronic health records (EHRs).  My Garmin data, Moves data, and the information I type into my training and treatment log, all just sit there in electronic form somewhere in cyberspace.  My information cannot be pooled with the fitness data from others to search for statistical significance.  You can be sure the consumer fitness developers know a lot of things about me, but the products they have developed are generating data that goes nowhere – lots of data rather than ‘Big Data’ – my cancer and fitness story has no statistical power even though plenty of Information Technology (IT) is attached to it.

Recent announcements regarding consumer fitness and IT may change this and move us closer to continuously updated physical activity profiles by using data automatically uploaded through privacy ensured patient portals (EPIC’s ‘MyChart’ would be a good example).  Physical activity information could then be accessible when needed by clinicians from EHRs, and more importantly, tied to pathology, treatment, and other information within EHRs.  Apple’s collaboration with The Mayo Clinic, Nike, and the prominent EHR system, EPIC, appears to be headed in this direction.  However, without the broad use of internationally standardized exercise and physical activity codes for the common measures most exercise stakeholders are recording – steps, calories, heart rate, etc. – integrating the fitness data into EHRs will remain problematic.  Medicine wants valid standardized data and evidence before they will change clinical practice.  Our fitness stories, with isolated data on only one person, will not change clinical practice.

There is interest among cancer patients in allowing their data to be shared for research purposes, 87% reporting a willingness to do so (10) as long as privacy was adequately addressed.  How many of them have stories on the extreme ends of the physical activity spectrum and how is cancer survivorship going for them out there?  Fitness stories may motivate or guide others, but we also need statistical significance in order to impact clinical practice.

Swimming competition  Young Couple Jogging in Park

 

References:

1.  Holmes MD, et al., Physical activity and survival after breast cancer diagnosis. JAMA. 2005;393:2479-86.

2.  Meyerhardt JA, et al., Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.  J. Clin Oncol. 2006: 24:3535-41.

3.  Giovannucci EL, et al., A prospective study of physical activity and incident and fatal prostate cancer.  Arch. Intern. Med.  2005:165:1005-10.

4.  Williams PT, Reduced risk of brain cancer mortality from walking and running. Med. Sci. Sports Exerc. 2014 May;46(5):927-32.

5.  Irwin ML, et al., Influence of pre and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study.  J. Clin. Oncol. 2008:26:3958-64.

6.  Schmitz K.H, et al., American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors. Med Sci Sports Exerc. 2010 Jul;42(7):1409-26.

7.  Kano S, et al., [A case with myositis as a manifestation of chronic graft-vs-host-disease (GVHD) with severe muscle swelling developed after aggressive muscular exercise.] Rinsho Shinkeigaku. 2003 Mar;43(3):93-7.

8.  Julie K. Silver, MD and Jennifer Baima, M.D.  Cancer Prehabilitation: An opportunity to Decrease Treatment-Related Morbidity, Increase Cancer Treatment Options, and Improve Physical and Psychological Health Outcomes. Am J Phys Med Rehabil. 2013 Aug;92(8):715-27.

9.  Stan, D, et al., Pilates for Breast Cancer Survivors: Impact of Physical Parameters and Quality of Life After Mastectomy. Clinical Journal of Oncology Nursing. Volume 16, Number 2; pp:131-141.

10. Rechis, R, et al., The Promise of Electronic Health Information Exchange: A LIVESTONG Report.

 

Update:

The Future of Medicine Is in your Smartphone.  Eric J. Topol, MD.  The Wall Street Journal, 1/9/2015.

http://www.wsj.com/articles/the-future-of-medicine-is-in-your-smartphone-1420828632

Time to consider ditching the chemo recliner?

IMG_0224

A cancer study published earlier this year found some very interesting results regarding the blood flow of tumors at rest versus during exercise.  For some of you, it may be a surprise to learn that this had not yet been studied in animals or in humans.  For me, I have been waiting for something like this for the past 2 1/2 years, since I began looking into exercise and cancer survivor research.  In spite of all the cancer fundraising events where people exercise to raise money for cancer research, little is know about what all that exercise may be doing to tumors.

The study (only in rats) examined prostate tumor tissue at rest and during low to moderate intensity exercise.  At rest, the blood flow to prostate tumor tissue was less than that of the surrounding prostate tissue and less than that of the control animals’ prostate tissue.  However, during exercise, the prostate tumor tissue blood flow increased 200%, significantly above that of the surrounding prostate tissue or that of the control animals’ prostate tissue, both of which remained the same as at rest.

If you’ve ever had chemotherapy or accompanied someone who has, you may remember those nice, comfortable, recliners for resting in while the drugs pump into the veins.  Well, if we could extrapolate the results of this study, resting in recliners would seem to limit blood flow into tumors at the very time that we want it to be at its maximum – while the drugs are flowing in.  Now, before you get too concerned about infusion nurses yelling at chemotherapy patients to ‘push it’ for 30 more seconds on the treadmill, remember, the study used low to moderate intensity, and as I wrote previously, intensity is relative to each cancer patient’s fitness level.  For many patients, I would not be surprised if strolling around the infusion ward was low to moderate intensity exercise, and for some, maybe even near maximal intensity.  Currently, one of the best parts of chemo infusions could actually be the walking out of the infusion ward when it’s over, plus, any ‘exercise’ (shopping, walking, work/household duties) done afterwards until the chemotherapy drugs are metabolized or eliminated.

They let us walk into and out of the chemotherapy infusion wards, why not walk during infusion?  Some concerns may be over balance due to any sedatives administered as a part of the infusion process.  True, but some sedative doses can be decreased.  When I had to drive myself home after a series of infusions, they cut my Benadryl in half so that I wouldn’t be woozy for the drive home.  There must be other sedatives as well that could be similarly adjusted.

An editorial that accompanied the cancer study I cited above, mentioned how emerging evidence is ‘beginning to challenge the current perception of exercise as a “soft” intervention that “cannot hurt.” ‘  This is similar to what cardiology went through decades ago.  Then, patients were sent home to bed rest for weeks after a heart attack.  Once more research started coming in, showing that patients did better if they started exercising soon after their heart attack, cardiology started getting patients moving.  This may be where we are with cancer treatments and exercise – leaving the ‘soft’ intervention realm and moving into the “A Team’ of evidence that shows improvements in existing cancer treatments.   But we need human studies first, this is why I started WorkOut Cancer.

I hope you’ll help us to move evidence like this along into human studies.  This is not rocket science but basic physiology, much of which has been overlooked in favor of billion dollar drug development.  Fair enough, there are many effective cancer drugs, I’m not opposed to them, but can we improve the delivery of those drugs with something as simple as switching from recliners to strolling the infusion ward halls?  Furthermore, what else might we discover about these physiological mechanisms that might improve cancer treatments?  We will never know unless we do more research like this.  Please donate.

Thank you!

 

References:

Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise.  McCullough, D.J.,  et al.  J Natl Cancer Inst 2014 Mar 13. [Epub ahead of print]

Therapeutic Properties of Aerobic Training After a Cancer Diagnosis: More Than a One-Trick Pony?  Lee W. Jones, Mark W. Dewhirst.   JNCI J Natl Cancer Inst (2014)dju042doi: 10.1093/jnci/dju042First published online: March 13, 2014