Cancer-Related Fatigue: History
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Subjects: Oncology | Immunology
Contributor:
Amy Shaver

Cancer treatments can cause adverse effects such as cancer-related fatigue. Immune checkpoint inhibitors (ICIs) are a relatively new therapy for some cancers and have shown great promise in helping people. Physical activity has been shown to aid many cancer patients to overcome adverse effects in traditional chemotherapy, but along with ICIs, it hasn’t been fully examined.

  • immune checkpoint inhibitors
  • physical activity
  • exercise
  • exercise therapy
  • adverse events
  • tumor growth

1. Introduction

Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy in multiple cancer settings. Since the initial Food and Drug Administration (FDA) approval for an ICI (ipilimumab) in 2011 for advanced stage melanoma, efficacy has been demonstrated in a broad range of both solid tumors and hematologic malignancies. ICIs are now indicated in the neoadjuvant, adjuvant, advanced/metastatic, and recurrent settings for various tumor types [1]. Additionally, pembrolizumab became the first anti-neoplastic medication approved across solid tumors solely based on a biomarker, as a result of early studies including the phase 2 KEYNOTE-158 trial [2]. As the indications for ICIs expand, so too must the medical community’s understanding of their effects, both on tumor biology and patient-reported outcomes.
While the use of ICIs has improved outcomes in cancer, ICIs are also associated with multiple adverse effects, such as cancer-related fatigue (CRF), which occurs in up to 25% of patients. Physical activity has been previously shown to be effective in the milieu of chemotherapy for decreasing the severity of chemotherapy- and cancer-related side effects [3][4][5]. Similarly, physical activity has been shown to reduce CRF and modulate the immune system through multiple mechanisms in cancer patients [6][7].
Therefore, it has been postulated that physical activity may impact the outcomes of those being treated with ICIs. Current recommendations are to be as physically active as an individual’s abilities will allow [8]. Cancer patients are recommended to follow guidelines for healthy populations, which may not always be appropriate [9], even though many cancer survivors have reportedly reaped great benefits from individualized fitness regimens [10].
The utilization of ICIs has increased exponentially, and along with this use there have been immune-related adverse events. Previous work indicates that physical activity concurrent with cancer therapy may be useful for alleviating adverse events in cancer patients; however, this is as yet unknown.

2. Physiology of Exercise and Immunology

There is a growing body of evidence investigating the mechanisms by which exercise modulates immunity. Much of this research points to effects on natural killer (NK) and T cells, rather than to components of humoral immune responses [7]. These are also the immune cells that are targeted by ICIs, indicating that the anti-tumor effects of both exercise and checkpoint blockade may be synergistic.
It has been shown that sedentary patients have higher proportions of both CD4+ and CD8+ T cells that express PD-1, a negative immunologic regulator [11]. Meanwhile, CD8+ cytotoxic T cells are mobilized by acute exercise, and thus more able to participate in active immunity [12]. Exercise further induces the proliferation and activation of T cells against tumors, likely through adrenergic stimulation [13]. Finally, T cells that undergo repeated stimulation suffer from both senescence (a decreased ability to replicate partially due to telomere shortening) and exhaustion (the loss of vital functions). However, these two processes of immune impairment are attenuated by the effects of exercise [14].
As the blockade of PD-L1, PD-1, and CTLA-4 by ICIs results in the activation of T cells, it stands to reason that this effect would be augmented by exercise through the above mechanisms. In fact, this was demonstrated in a mouse model of breast cancer, which showed that exercise slowed immunosuppressive elements of the tumor microenvironment and induced increases in CD8+ T cell activation [15]. This was tested in the presence of radiotherapy (RT) plus PD-1 blockade. The investigators found that the addition of exercise to RT+PD-1 blockade increased splenic CD8+ T cells, decreased PD-1 expression on NK cells, increased markers of NK-cell activation, and ultimately slowed tumor growth.
Although there are clearly physiologic reasons for synergism with immunotherapies, physical activity has also been shown to improve outcomes when combined with chemotherapy. One study in breast cancer patients found that a physical activity regimen was adhered to more closely while patients were undergoing therapy, as compared with when after therapy was complete; and higher adherence occurred during chemotherapy than during radiotherapy [16]. In lung cancer, across the cancer continuum, increased physical activity was found to be safe and sought-after by patients, and shown to improve quality of life [17].
Similarly, a recent study indicated that the combination of diet, physical activity, and chemotherapy improved the efficacy of chemotherapy in patients with acute lymphoblastic leukemia [18]. Compared to usual care, those patients who participated with a diet and physical activity program during treatment saw a reduction in minimal residual disease.
Similarly to the murine results of the Martín-Ruiz et al. study, Reis et al. found an increase in in both functional and aerobic capacity in human breast cancer patients undergoing treatment [19][20]. Reis et al. also found a decrease in pain scores and an increase in strength for those undergoing a physical activity regimen during their chemotherapy. There was no significant finding for fatigue. Likewise, the OptiTrain group found lower rates of thrombocytopenia in their exercising group compared to usual care [21].

3. Conclusions

The results suggest that the current availability of research is lacking to inform the use of concurrent administration of physical activity or increased physical activity and ICIs. Pre-clinical studies suggest that the addition of physical activity, whether as a prescribed regimen or as a voluntary practice, has benefits both in tumor growth rate and volume. Those studies also show an improvement in strength and in immune response. The clinical pilot study showed efficacy for the addition of physical activity to immunotherapy. Prior studies indicate that the addition of physical activity benefits chemotherapy. There is a need now to perform more clinical studies combining physical activity with immunotherapy, so as to inform clinicians and improve outcomes for patients.

This entry is adapted from the peer-reviewed paper 10.3390/cancers13246364

References

  1. Vaddepally, R.K.; Kharel, P.; Pandey, R.; Garje, R.; Chandra, A.B. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers 2020, 12, 738.
  2. Marabelle, A.; Le, D.T.; Ascierto, P.A.; Di Giacomo, A.M.; De Jesus-Acosta, A.; Delord, J.-P.; Geva, R.; Gottfried, M.; Penel, N.; Hansen, A.R.; et al. Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results from the Phase II KEYNOTE-158 Study. J. Clin. Oncol. 2020, 38, 1–10.
  3. McNeely, M.L.; Courneya, K.S. Exercise programs for cancer-related fatigue: Evidence and clinical guidelines. J. Natl. Compr. Cancer Netw. 2010, 8, 945–953.
  4. Chiu, H.-Y.; Huang, H.-C.; Chen, P.-Y.; Hou, W.-H.; Tsai, P.-S. Walking Improves Sleep in Individuals with Cancer: A Meta-Analysis of Randomized, Controlled Trials. Oncol. Nurs. Forum 2015, 42, E54–E62.
  5. Streckmann, F.; Zopf, E.M.; Lehmann, H.C.; May, K.; Rizza, J.; Zimmer, P.; Gollhofer, A.; Bloch, W.; Baumann, F.T. Exercise Intervention Studies in Patients with Peripheral Neuropathy: A Systematic Review. Sports Med. 2014, 44, 1289–1304.
  6. Mustian, K.M.; Peppone, L.J.; Palesh, O.G.; Janelsins, M.C.; Mohile, S.G.; Purnell, J.Q.; Darling, T.V. Exercise and Cancer-related Fatigue. US Oncol. 2009, 5, 20–23.
  7. Gustafson, M.P.; Wheatley-Guy, C.M.; Rosenthal, A.C.; Gastineau, D.A.; Katsanis, E.; Johnson, B.D.; Simpson, R.J. Exercise and the immune system: Taking steps to improve responses to cancer immunotherapy. J. Immunother. Cancer 2021, 9, e001872.
  8. Patel, A.V.; Friedenreich, C.M.; Moore, S.C.; Hayes, S.C.; Silver, J.K.; Campbell, K.L.; Winters-Stone, K.; Gerber, L.H.; George, S.M.; Fulton, J.E.; et al. American College of Sports Medicine Roundtable Report on Physical Activity, Sedentary Behavior, and Cancer Prevention and Control. Med. Sci. Sports Exerc. 2019, 51, 2391–2402.
  9. Gil-Rey, E.; Quevedo-Jerez, K.; Maldonado-Martin, S.; Herrero-Román, F. Exercise Intensity Guidelines for Cancer Survivors: A Comparison with Reference Values. Int. J. Sports Med. 2014, 35, e1–e9.
  10. Campbell, K.L.; Winters-Stone, K.M.; Wiskemann, J.; May, A.M.; Schwartz, A.L.; Courneya, K.S.; Zucker, D.S.; Matthews, C.E.; Ligibel, J.A.; Gerber, L.H.; et al. Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Med. Sci. Sports Exerc. 2019, 51, 2375–2390.
  11. Campbell, J.P.; Riddell, N.; Burns, V.; Turner, M.; van Zanten, J.J.V.; Drayson, M.; Bosch, J.A. Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype. Brain Behav. Immun. 2009, 23, 767–775.
  12. Gustafson, M.P.; DiCostanzo, A.C.; Wheatley, C.M.; Kim, C.-H.; Bornschlegl, S.; Gastineau, D.A.; Johnson, B.D.; Dietz, A.B. A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood. J. Immunother. Cancer 2017, 5, 30.
  13. Baker, F.L.; Bigley, A.B.; Agha, N.H.; Pedlar, C.R.; O’Connor, D.P.; Bond, R.A.; Bollard, C.M.; Katsanis, E.; Simpson, R.J. Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells. Front Immunol. 2019, 10, 3082.
  14. Donovan, T.; Bain, A.L.; Tu, W.; Pyne, D.B.; Rao, S. Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review. Front. Physiol. 2021, 12.
  15. Wennerberg, E.; Lhuillier, C.; Rybstein, M.D.; Dannenberg, K.; Rudqvist, N.-P.; Koelwyn, G.J.; Jones, L.W.; Demaria, S. Exercise reduces immune suppression and breast cancer progression in a preclinical model. Oncotarget 2020, 11, 452–461.
  16. Kirkham, A.A.; Bonsignore, A.; Bland, K.A.; McKenzie, D.C.; Gelmon, K.A.; Van Patten, C.L.; Campbell, K.L. Exercise Prescription and Adherence for Breast Cancer: One Size Does Not FITT All. Med. Sci. Sports Exerc. 2018, 50, 177–186.
  17. Bade, B.C.; Thomas, D.D.; Scott, J.B.; Silvestri, G.A. Increasing Physical Activity and Exercise in Lung Cancer: Reviewing Safety, Benefits, and Application. J. Thorac. Oncol. 2015, 10, 861–871.
  18. Orgel, E.; Framson, C.; Buxton, R.; Kim, J.; Li, G.; Tucci, J.; Freyer, D.R.; Sun, W.; Oberley, M.J.; Dieli-Conwright, C.; et al. Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: The IDEAL trial. Blood Adv. 2021, 5, 1853–1861.
  19. Martín-Ruiz, A.; Fiuza-Luces, C.; Rincón-Castanedo, C.; Fernández-Moreno, D.; Gálvez, B.G.; Martínez-Martínez, E.; Martin-Acosta, P.; Coronado, M.J.; Franco-Luzón, L.; González-Murillo, A.; et al. Benefits of exercise and immunotherapy in a murine model of human non-small-cell lung carcinoma. Exerc. Immunol. Rev. 2020, 26, 100–115.
  20. Reis, A.D.; Pereira, P.T.V.T.; Diniz, R.R.; Filha, J.G.L.D.C.; dos Santos, A.M.; Ramallo, B.T.; Filho, F.A.A.; Navarro, F.; Garcia, J.B.S. Effect of exercise on pain and functional capacity in breast cancer patients. Health Qual. Life Outcomes 2018, 16, 1–10.
  21. Mijwel, S.; Bolam, K.A.; Gerrevall, J.; Foukakis, T.; Wengström, Y.; Rundqvist, H. Effects of Exercise on Chemotherapy Completion and Hospitalization Rates: The OptiTrain Breast Cancer Trial. Oncologist 2019, 25, 23–32.
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