Physical Activity is Medicine

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Alfredo Carrato
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The frequent lack of appropriate statistical evidence regarding physical activity benefits in patients with cancer has meant that either epidemiologic or retrospective observational studies have provided the basis for our knowledge. The level of evidence for results has been weak and the basis of a controversial and not well-established issue. Scientific and clinical evidence is much more limited for less frequent and low survival cancers such as pancreatic cancer. Conducting randomized controlled trials on physical activity implementation in individuals with cancer is challenging due to the low observed adherence to trial recommendations and completion of quality-of-life questionnaires; the interference of environmental, social, and structural barriers; comorbidities as well as symptoms derived from cancer and its treatment; and the high number of patients needed, which is difficult to achieve in uncommon and deadly cancers. In the article by Neuzillet et al1 elsewhere in this issue, we can learn from a well-designed randomized trial on the positive effects of increasing physical activity in quality-of-life parameters for patients with advanced pancreatic cancer who are receiving treatment.

We have known that healthy habits contribute to a healthier life. Patients with heart disease, type 2 diabetes, hypertension, and cancer, which are quite frequent and major causes of morbidity and mortality in our Western world, do benefit from a systematic increase in physical activity. Patients desire to be more active and would like help and guidance from their doctor. The American Cancer Society recommends that individuals maintain healthy behaviors regarding diet and physical activity in order to reduce cancer risk.2 Indeed, in a recent analysis, the combination of risk factors (excess body weight, physical inactivity, poor diet, and alcohol consumption) accounted for at least 18.2% of cancer cases and 15.8% of cancer deaths in the United States.3 Feeling fit could help patients physically and psychologically cope with the development of cancer, as well as with the therapeutic strategies needed to cure or control this disease. The beneficial effect of physical activity implementation in cancer prevention and during cancer treatment has been demonstrated.4 This finding is potentially the result of a dose–response association5 and independent of critical confounders such as smoking or increased body mass index.6 Even individuals who were sedentary throughout most of their adult life (age 19–60 years) but routinely increased physical activity in their 50s or 60s showed a lower risk for all-cause mortality (hazard ratio [HR], 0.65; 95% CI, 0.62–0.68), cardiovascular disease–related mortality (HR, 0.57; 95% CI, 0.53–0.61), and cancer-related mortality (HR, 0.84; 95% CI, 0.77–0.92).7

A systematic review and meta-analysis of hundreds of epidemiologic studies with several million participants showed that there was a 10% to 20% reduction in bladder, breast, endometrial, renal, colon, and gastroesophageal cancers in people with a dynamic lifestyle. A 40% to 50% reduction in mortality was also seen in people with prostate, breast, and colorectal cancer who were physically active.8

On the other side, cancer treatments damage patient’s tissues and can contribute to accelerated biological aging. Psychological stress from cancer and its treatments favors prolonged toxicities, impairs essential repair mechanisms, and promotes a lack of will to do what has been recommended. Therapeutic objectives are to control disease growth and dissemination, reduce stress, improve sleep, increase physical activity according to patient’s performance status, improve self-esteem, preserve mental well-being, sustain a healthy diet, and maintain a healthy body weight.

Benefits of regular physical activity include stress reduction, sleep quality improvement, mood enhancement, muscle strength and tone enhancement, and cardiovascular and lung fitness augmentation for improving quality of life and aging outcomes. This is especially relevant for patients with sedentary lifestyles. More recently, the use of smart devices has increased adherence to physical exercise programs.

At the molecular level, the enhancement of immune function is a strong candidate to explain these effects, at least partly. Evidence has shown a stimulating effect of vigorous physical activity on immune effectors, mainly natural killer (NK) cells and CD8+ T cells, against tumors, as well as a decrease in inflammatory markers such as prostaglandin E2 and an increase in gut microbiota diversity, while also potentially reducing the levels of tumor-promoting bacteria.9

During physical exercise, skeletal muscle secretes myokines into the bloodstream, such as IL-6, IL-7, and IL-15, that can circulate free or are packaged into exosomes. IL-6 causes an anti-inflammatory effect by inducing the release of IL-1 receptor antagonist (IL-1RA), and it can also bind to NK cells to accelerate their mobilization into the bloodstream. IL-7 helps to preserve thymic mass and enhances the output of naive T cells. IL-7, together with IL-15, plays a relevant role in T-cell survival and CD8+ T-cell homoeostasis. As recently reported in pancreatic cancer,9,10 regular physical activity may act on inflammation and immunity through IL-15–mediated activation of CD8+ T cells, decreasing tumor growth and enhancing sensitivity to chemotherapy and anti–PD-1 antibodies. These molecular findings underline the potential benefit of constant physical exercise and point to IL-15 as a useful resource for pancreatic cancer treatment.9 The diminution in myokine secretion owing to the aging-related decline in skeletal muscle mass is a fact that triggers immune senescence, a condition linked to cancer immune evasion.11

The cognitive benefits of systematic physical activity are tied to an increased plasticity and reduced inflammation within the hippocampus, and to a decelerated neurodegeneration. One of the underlying mechanisms is an increase in clusterin, a complement cascade inhibitor, that reduces neuroinflammatory gene expression.12

A highly disease-specific microbiota-based classification model confined to pancreatic cancer–enriched species has been identified and could be useful as a control group for future randomized trials and for the early detection of pancreatic cancer.13 In contrast to dysbiosis, changes toward increased microbial abundance, diversity, and composition observed with physical activity training significantly change the function of the gut microbiota in favor of the patient, including improvements in immune function and inflammatory profiles.14 Many other physical activity mechanisms of action remain to be discovered.

Physical activity programs must be properly tailored to a patient’s characteristics by an expert team. In this way, a positive impact can be made on the health status of patients with cancer, even those with advanced-stage cancer, as well as persons living beyond cancer. All should have a lifestyle as active as possible to avoid complications that could occur when physical activity is not adequately prescribed and closely followed. In clinical practice, rehabilitation professionals must ask patients about their daily or weekly physical activity, and must record the information. Patients should then be given a written prescription specifying the type of exercise, frequency, and duration appropriate for them. Patients can start small and low, and increase duration and frequency over time. It is crucial for patients to measure the physical activity performed. Health monitoring wearables are helpful and support adherence to the recommendations. Clinicians should follow up on their patients’ physical activity program, asking about it at every contact. Reinforcement of this advice is relevant, and pointing out that physical activity can help preserve functional independence can be particularly motivating for patients. If rehabilitative services are not available, patients should be referred to another institution that provides them.

And last but not least, there is room for improvement, given that exercise is the most cost-effective medical intervention for patients with cancer. No financial toxicity is associated with it. Our health teams will not be properly organized until physical exercise and the professionals involved in it are part of the pancreatic cancer treatment circuit within the multidisciplinary team.

References

  • 1.

    Neuzillet C, Bouché O, Tournigand C, et al. Effect of adapted physical activity in patients with advanced pancreatic cancer: the APACaP GERCOR randomized clinical trial. J Natl Compr Canc Netw 2023;21:12351243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Rock CL, Thomson C, Gansler T, et al. American Cancer Society guideline for diet and physical activity for cancer prevention. CA Cancer J Clin 2020;70:245271.

  • 3.

    Islami F, Goding Sauer A, Miller KD, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin 2018;68:3154.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Rock CL, Thomson CA, Sullivan KR, et al. American Cancer Society nutrition and physical activity guideline for cancer survivors. CA Cancer J Clin 2022;0:133.

  • 5.

    Emery A, Moore S, Turner JE, Campbell JP, et al. Reframing how physical activity reduces the incidence of clinically-diagnosed cancers: appraising exercise-induced immuno-modulation as an integral mechanism. Front Oncol 2022;12:788113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Moore SC, Lee IM, Weiderpass E, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med 2016;176:816825.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Saint-Maurice PF, Coughlan D, Kelly SP, et al. Association of leisure-time physical activity across the adult life course with all-cause and cause-specific mortality. JAMA Netw Open 2019;2:e190355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    McTiernan A, Friedenreich CM, Katzmarzyk PT, et al. Physical activity in cancer prevention and survival: a systematic review. Med Sci Sports Exerc 2019;51:12521261.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Fiuza-Luces C, Valenzuela PL, Gálvez BG, et al. The effect of physical exercise on anticancer immunity. Nat Rev Immunol. Published online October 4, 2023. doi: 10.1038/s41577-023-00943-0

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Kurz E, Alcantara Hirsch C, Dalton T, et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 202211;40:720737.e5.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    López-Otín C, Pietrocola F, Roiz-Valle D, et al. Meta-hallmarks of aging and cancer. Cell Metab 2023;35:1235.

  • 12.

    De Miguel Z, Khoury N, Betley MJ, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 2021;600:494499.

  • 13.

    Kartal E, Schmidt TSB, Molina-Montes E, et al. A fecal microbiota signature with high specificity for pancreatic cancer. Gut 2022;71:13591372.

  • 14.

    Boytar AN, Nitert MD, Morrision M, et al. Exercise-induced changes to the human gut microbiota and implications for colorectal cancer: a narrative review. J Physiol 2022;600: 51895201.

    • PubMed
    • Search Google Scholar
    • Export Citation

ALFREDO CARRATO, MD, PhD

Alfredo Carrato, MD, PhD, is Professor of Medical Oncology at Alcala University, Madrid, Spain, and the Chairperson of Pancreatic Cancer Europe.

Dr. Carrato is involved in clinical and translational research projects on molecular epidemiology and biology of solid tumors, mainly in pancreatic cancer, in national, European, and United States networks.

Dr. Carrato has served as a member on multiple editorial boards for international journals, and has contributed to more than 350 publications in peer-reviewed journals. He is an active member of the European Society of Medical Oncology (ESMO), serves as an ESMO Faculty Member for the Gastro-Intestinal Tumors group, and serves as member of the ASCO Quality Oncology Practice Initiative (QOPI) Certification Program.

Disclosures: Dr. Carrato has disclosed not having any financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Alfredo Carrato, MD, PhD, Alcala University, Department of Medicine, Calle Princesa 43, 11D, 28008 Madrid, Spain. Email: acarrato@telefonica.net

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  • 1.

    Neuzillet C, Bouché O, Tournigand C, et al. Effect of adapted physical activity in patients with advanced pancreatic cancer: the APACaP GERCOR randomized clinical trial. J Natl Compr Canc Netw 2023;21:12351243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Rock CL, Thomson C, Gansler T, et al. American Cancer Society guideline for diet and physical activity for cancer prevention. CA Cancer J Clin 2020;70:245271.

  • 3.

    Islami F, Goding Sauer A, Miller KD, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin 2018;68:3154.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Rock CL, Thomson CA, Sullivan KR, et al. American Cancer Society nutrition and physical activity guideline for cancer survivors. CA Cancer J Clin 2022;0:133.

  • 5.

    Emery A, Moore S, Turner JE, Campbell JP, et al. Reframing how physical activity reduces the incidence of clinically-diagnosed cancers: appraising exercise-induced immuno-modulation as an integral mechanism. Front Oncol 2022;12:788113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Moore SC, Lee IM, Weiderpass E, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern Med 2016;176:816825.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Saint-Maurice PF, Coughlan D, Kelly SP, et al. Association of leisure-time physical activity across the adult life course with all-cause and cause-specific mortality. JAMA Netw Open 2019;2:e190355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    McTiernan A, Friedenreich CM, Katzmarzyk PT, et al. Physical activity in cancer prevention and survival: a systematic review. Med Sci Sports Exerc 2019;51:12521261.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Fiuza-Luces C, Valenzuela PL, Gálvez BG, et al. The effect of physical exercise on anticancer immunity. Nat Rev Immunol. Published online October 4, 2023. doi: 10.1038/s41577-023-00943-0

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Kurz E, Alcantara Hirsch C, Dalton T, et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 202211;40:720737.e5.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    López-Otín C, Pietrocola F, Roiz-Valle D, et al. Meta-hallmarks of aging and cancer. Cell Metab 2023;35:1235.

  • 12.

    De Miguel Z, Khoury N, Betley MJ, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 2021;600:494499.

  • 13.

    Kartal E, Schmidt TSB, Molina-Montes E, et al. A fecal microbiota signature with high specificity for pancreatic cancer. Gut 2022;71:13591372.

  • 14.

    Boytar AN, Nitert MD, Morrision M, et al. Exercise-induced changes to the human gut microbiota and implications for colorectal cancer: a narrative review. J Physiol 2022;600: 51895201.

    • PubMed
    • Search Google Scholar
    • Export Citation
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