Exercise and Cancer Related Fatigue: An Evidence- Based Analysis

Transcription

1 University of New Mexico UNM Digital Repository Doctor of Physical Therapy Capstones Spring Exercise and Cancer Related Fatigue: An Evidence- Based Analysis Andrea Kerstin Pfaff Follow this and additional works at: Recommended Citation Pfaff, Andrea Kerstin. "Exercise and Cancer Related Fatigue: An Evidence-Based Analysis." (2017). dpt/129 This Capstone is brought to you for free and open access by UNM Digital Repository. It has been accepted for inclusion in Doctor of Physical Therapy Capstones by an authorized administrator of UNM Digital Repository. For more information, please contact

2 Exercise and Cancer Related Fatigue: An Evidence-Based Analysis Andrea Pfaff Doctoral Candidate University of New Mexico School of Medicine Division of Physical Therapy Class of 2017 Advisor: Marybeth Barkocy, PT, DPT, PCS

3 Exercise and Cancer Related Fatigue 1 Table of Contents Section Header Page Number ABSTRACT SECTION 1: Background and Purpose SECTION 2: Case Description SECTION 3: Evidence Based Analysis Methodologies of Search Table 1: Methodologies of Search Reference Summaries Table 2: Systematic Literature Review Process Discussion Conclusion REFERENCES APPENDIX Evidence Appraisal Worksheets

4 Exercise and Cancer Related Fatigue 2 ABSTRACT Purpose: The following paper presents a case of a 56-year-old female who presented to physical therapy following adjuvant treatment for breast cancer. This paper provides an evidence-based analysis to answer the following PICO question: Is exercise an effective intervention for reducing cancer-related fatigue in individuals diagnosed with cancer, receiving adjuvant treatment for cancer, or are successfully in remission? Background: Fatigue is one of the most common effects of cancer and its various treatments. This condition affects 60% to 90% of cancer patients, who describe feeling weak, listless, paralyzed, and too exhausted to perform basic activities such as eating, toileting, or general movement 19. The condition may persist for months or years following completion of treatment 9, and is not relieved by rest or sleep. As a result, many patients find cancer-related fatigue to be more distressing than more visible cancer therapy sequelae. This is especially concerning because moderate to severe distress can play a role in the development or recurrence of cancer 5. Case Description: The patient in this case was a 56-year-old female who was referred to outpatient physical therapy for generalized weakness following a recent battle against stage IIIA breast cancer. Following successful treatment, the patient was still experiencing persistent cancer-related fatigue that limited her ability to participate in most activities. She also experienced global muscle wasting, weakness, and significant scar tissue formation that limited her right neck and shoulder mobility. Outcomes: There is a growing body of research aimed at determining the effects of exercise and different exercise parameters on cancer-related fatigue. An in-depth analysis of 8 articles selected from current available research demonstrated that exercise can improve cancer-related fatigue as well as quality of life, activity avoidance, strength, aerobic capacity and general physical function in many different cancer populations. There is still conflicting evidence regarding how statistically and clinically significant these exercise-induced changes are, but there is an overall trend towards the positive nonetheless. Discussion: Though the author did not observe the full treatment of the patient presented in this case study, the initiation of an individualized exercise program supported by research showed promising progress that supported the use of exercise to improve cancer-related fatigue.

5 Exercise and Cancer Related Fatigue 3 SECTION 1: Background and Purpose The patient was a 56-year-old female who was referred to outpatient physical therapy for evaluation with a diagnosis of generalized weakness. Her medical history revealed that she had recently been diagnosed and treated for stage IIIA breast cancer with a multimodal treatment including neo-adjuvant chemotherapy, mastectomy, and postoperative radiation therapy. Eighteen months after successful treatment, the patient was still experiencing persistent fatigue that limited her ability to participate in most activities. She exhibited global muscle wasting, weakness, and significant scar tissue formation that limited her right neck and shoulder mobility. Though uncertain she would be able to follow through with physical therapy due to her fatigue and low tolerance for activity, the patient agreed to participate. She was evaluated and treated 1 to 2 times per week over an 8-week period that extended beyond the period the author was observing her. Fatigue is one of the most common effects of cancer and its various treatments. The condition affects 60% to 90% of cancer patients and is described as feelings of weakness, listlessness, paralysis, and exhaustion inhibiting performance of basic activities such as eating, toileting, or general movement 19. As a result, fatigue can have a profound negative impact on a person's ability to function and his or her quality of life 3. Cancer-related fatigue can be unpredictable, as it does not result from activity or exertion and is not relieved by rest or sleep. The condition may persist for months or years following completion of treatment 9. As a result, many patients find cancer-related fatigue to be more distressing than more visible cancer therapy sequelae such as pain, nausea, vomiting, alopecia, and scarring. This

6 Exercise and Cancer Related Fatigue 4 is especially concerning because moderate to severe distress, which affects approximately 50% of breast cancer patients, can play a role in the development or recurrence of cancer 5. The exact cause of cancer-related fatigue is unknown, but it is believed to be a multifactorial phenomenon linked to both the disease and the treatment 19. Demographic, medical, psychosocial, behavioral, and biological factors can all influence the degree to which cancer-related fatigue is experienced. Both cancer and its associated treatments can change normal protein and hormone levels, resulting in altered inflammatory processes that can contribute to fatigue. One study that examined patients undergoing radiation therapy found associations between fatigue and increases in serum levels of inflammatory markers CRP and IL-1 receptor antagonist 2. Another study described associations between fatigue and elevations in plasma levels of soluble TNF receptor type II following chemotherapy treatment of breast cancer. Additionally, elevated leukocyte counts post-treatment were found to be predictive of persistent fatigue over a 2-3 year follow-up in breast cancer survivors 2. Further research is necessary to better understand how inflammatory and cellular immunity responses influence cancer-related fatigue. Cancerous tumors can also cause fatigue by forming toxic substances that alter normal cellular function. Uncontrolled tumor growth can also cause fatigue by depleting the body s nutrient stores as the cancer cells compete for energy, protein, vitamins, and oxygen to supply the tumors own growth. If an individual s cancer metastasizes in bone marrow, it can further cause fatigue by decreasing red blood cell production and causing anemia 19.

7 Exercise and Cancer Related Fatigue 5 Another proposed mechanism for the development of cancer-related fatigue is the widespread cellular destruction caused by cancer treatments. This cellular destruction creates a surplus of cellular waste that requires increased energy to remove and repair. Red blood cell counts plummet as a result of the widespread cellular destruction that occurs during treatment 19. An insufficient red blood cell count decreases the blood s ability to supply sufficient oxygen to meet the body s needs. Anemia which causes fatigue results once hemoglobin levels drop below 12g/dL 1. The cancer treatment induced cellular destruction also affects the rapidly reproducing cells that compose the lining of the digestive tract. This can decrease the body s ability to extract nutrients and cause fatigue associated with poor nutrition 19. Other proposed mechanisms for the development of cancer-related fatigue include pain, emotional distress, sleep disturbances, other medications, pre-existing medical conditions, and lack of exercise. Though counterintuitive, prolonged rest and inactivity can contribute to fatigue through physical deconditioning, which makes everyday tasks more challenging and potentially contributes to fatigue persistence 2. One study found that cancer survivors experiencing fatigue after treatment had decreased cardiorespiratory fitness 13. Elevated body mass index has also been found to be a key predictor of post-treatment fatigue in patients with breast cancer 7. Because the etiology of cancer-related fatigue is multi-factorial and still not well understood, a gold standard treatment protocol has yet to be developed. In past and present practice, standard care typically prescribed rest to address fatigue in

8 Exercise and Cancer Related Fatigue 6 cancer patients. However, treatment of this symptom has begun to incorporate a wide range of other approaches including pharmacological, mind-body, psychosocial, nutritional, and physical activity interventions 19. A variety of pharmacologic agents have been evaluated for the treatment of cancer- related fatigue including: hematopoietic growth factors, progestational steroids, methylphenidate (psychostimulant), modafinil (nonamphetamine-based stimulant), and paroxetine (antidepressant) 2. Hematopoietic growth factors have been shown to produce improvements in fatigue caused by chemotherapy-induced anemia, but progestational steroids, paroxetine, and sertraline have not produced beneficial effects on fatigue. Some studies have found psychostimulants to be more effective than placebos in improving fatigue, but few have yielded statistically significant effects 11. The potential link between inflammatory processes and cancerrelated fatigue has prompted research into anti-inflammatory drugs such as etanercept (TNF-decoy receptor) and infliximab (anti-tnf antibody), which have shown some improvements on patient-reported fatigue 2. Other pharmacological agents continue to be investigated, but their efficacy has not yet been determined. Research trials examining the effects of mind-body interventions on cancerrelated fatigue have focused on acupuncture, mindfulness meditation, yoga, and biofield therapy. Acupuncture trials have produced results that range from nonexistent to significant between group differences. Other studies that investigated mindfulness meditation, yoga, or biofield healing have shown significant reductions in fatigue when compared to a non-active control group 2. Psychosocial interventions used to address cancer-related fatigue have

9 Exercise and Cancer Related Fatigue 7 included patient education, support groups, hypnosis, cognitive-behavioral therapy, stress and distress management, and energy conservation techniques. Metaanalyses of psychosocial intervention trials have shown reductions in fatigue relative to control, with small to moderate effect sizes (ES = 0.10 to 0.30) 2. Despite the long history of rest being prescribed for fatigue in cancer patients, there is a growing body of research aimed at investigating the effects of exercise on cancer-related fatigue. This research has identified beneficial effects of exercise on fatigue for patients at different stages of the disease and its treatment 2. New guidelines from the American College of Sports Medicine recommend that cancer patients and survivors engage in at least 150 minutes of moderate intensity aerobic activity each week, consistent with recommendations for the general population 14. However, this recommendation has yet to be globally integrated into typical care programs for cancer patients. As cancer becomes an ever-greater concern, physical therapists will inevitably work with a growing number of patients at varying stages of the disease progression. Because treatment of the disease itself is beyond the scope of physical therapy, it is necessary to find ways to address and potentially ameliorate some of the most distressing symptoms of cancer, including fatigue. Therefore, the aim of this case report was to further examine the question: Is exercise an effective intervention for reducing cancer-related fatigue individuals currently diagnosed with cancer, receiving adjuvant treatment, or are successfully in remission?

10 Exercise and Cancer Related Fatigue 8 SECTION 2: Case Description The patient was a 56-year-old female who was referred to outpatient physical therapy for evaluation with a diagnosis of generalized weakness. Per documentation and verbal history, the patient had a rather benign past medical history until recent years when she was diagnosed with stage IIIA hormone receptor negative breast cancer in her right breast. The patient s medical records indicated a 3.5cm mass with lymph node involvement requiring neo-adjuvant chemotherapy followed by surgery and postoperative radiation therapy. The patient received 5 cycles of chemotherapy treatment over 4 months via a port to shrink the tumor prior to surgery. A mastectomy with sentinel lymph node dissection was then performed and followed by 5 weeks of postoperative radiation therapy to the ipsilateral neck, breast, and axilla. Treatment was successful but costly in terms of symptom production, which included: extreme fatigue, alopecia, loss of appetite, vomiting, low blood cell count, hyperpigmentation, and pain at radiation sites during and after treatment. The patient s physical therapy evaluation occurred eighteen months after she was declared to be in remission and revealed significant fatigue, low activity tolerance, global muscle wasting, weakness, and significant scar tissue formation over the right neck, shoulder, axilla, and chest cavity that reduced mobility. Upon reviewing the evaluative findings with the patient, she indicated that her persistent fatigue and resulting activity intolerance was the most distressing symptom because it prevented her from participating in work and home duties, performing basic activities of daily living, and even socializing. Though uncertain that she would be

11 Exercise and Cancer Related Fatigue 9 able to follow through with physical therapy due to her fatigue and low tolerance for activity, the patient agreed to participate. She was treated 1 to 2 times per week over an 8-week period that extended beyond the period that the author was observing her.

12 Exercise and Cancer Related Fatigue 10 SECTION 3: Evidence Based Analysis Methodologies of Search: The following search methodology was used to answer the PICO question: Is exercise an effective intervention for reducing cancer-related fatigue in individuals diagnosed with cancer, receiving adjuvant treatment for cancer, or who had cancer and are now in remission.? Three major databases were searched including: CINAHL, PEDro, and PubMed. Boolean searches were carried out on each of the databases using consistent terminology: cancer related fatigue AND exercise. A variety of filters were used to eliminate extraneous results. The filters were database-specific and included language, publication dates, and so on. Studies were selected for review based on title relevance and type, which was restricted to randomized control trials and reviews. Table 1 details the search process including filters used, articles that were included or excluded, and articles selected for final review.

13 Exercise and Cancer Related Fatigue 11 Table 1: Methodologies of Search Search Terms Number of Articles Excluded/Included CINAHL Cancer related fatigue 819 Too many AND exercise 179 Limit scope Filter English 177 Multi-lingual results Filter Publication date: excluded on title irrelevance. 8 excluded duplicates. 7 selected for review of abstracts. 4 excluded after review of abstracts. 3 selected after review of abstracts: Meneses-Echávez et al, Velthius et al, Cantarero- Villanueva et al (2013) PEDro Cancer related fatigue 209 Too many AND exercise excluded on title irrelevance. 20 excluded due to low level of evidence. 5 excluded duplicates. 5 selected for review of abstracts. 3 excluded after review of abstracts. 2 selected after review of abstracts: Kampshoff et al, Cantarero-Villanueva et al (2011) PubMed Cancer related fatigue 5361 Far too many Filter Free full text 1904 Too many to review Filter Publication date 1637 Too many to review within last 10 years Filter Species: human 1306 Too many to review Filter English language 1270 Too many to review Filter Randomized Control Trial OR Review excluded on title irrelevance. 20 excluded due to low level of evidence. 5 excluded duplicates. 5 selected for review of abstracts. 3 excluded after review of abstracts. 3 selected after review of abstracts: Dimeo et al, Eyigor et al, Travier et al

14 Exercise and Cancer Related Fatigue 12 Reference Summaries Reference #6: Dimeo, F., Schwartz, S., Wesel, N., Voigt, A., & Thiel, E. (2008). Effects of an endurance and resistance exercise program on persistent cancer-related fatigue after treatment. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 19(8), Level of Evidence: Oxford: 2b Pedro: N/A (3/10) Purpose: The purpose of this study was to assess the effects of an exercise program on persistent cancer-related fatigue after treatment. Methods: 32 oncology patients with mild to severe persistent fatigue were selected based on their fulfillment of specific inclusion criteria to participate in a 3-week exercise program. The exercise program was performed 5 times per week with supervision and consisted of 30 minutes of endurance walking and resistance exercises for all major muscle groups using body weight, rubber bands, and dumbbells. Fatigue, mood, and anxiety were assessed with the following questionnaires: Brief Fatigue Inventory, Functional Assessment of Cancer Therapy- Fatigue Scale, and Multidimensional Fatigue Inventory. Physical performance was measured with a stress test before and after the program. No follow-up assessment was performed. Results: Global fatigue was reduced by 25% as measured by the BFI (p=0.0007) and FACT-F (p < ) questionnaires. Mental and physical fatigue decreased by 27% (p=0.01) and 17% (p=0.004) respectively. Changes in cognitive fatigue were not statistically different (p=0.09). Depression and anxiety scores were relatively unchanged based on results from the HADS A (P=0.15) and HADS D questionnaires (p=0.37).

15 Exercise and Cancer Related Fatigue 13 Bottom Line: Even an exercise program of limited duration appears to reduce fatigue, improve functional status, and increase endurance in cancer survivors suffering from persistent fatigue. Findings also suggest that fatigue in cancer patients is multifactorial and not solely driven by impairment of physical performance. This is applicable to the patient presented in this case study due to the age range of the subjects, the use of multiple adjuvant treatments, and the chronicity of their cancer-related fatigue.

16 Exercise and Cancer Related Fatigue 14 Reference #12: Meneses-Echávez, J. F., González-Jiménez, E., & Ramírez-Vélez, R. (2015). Effects of Supervised Multimodal Exercise Interventions on Cancer-Related Fatigue: Systematic Review and Meta-Analysis of Randomized Controlled Trials. BioMed Research International, 2015, Level of Evidence: Oxford: 1a Pedro: N/A Purpose: The purpose of this study was to determine the effects of supervised multimodal exercise interventions on cancer-related fatigue through a systematic review and meta-analysis. Methods: 2 independent, blinded authors searched the PubMed, CENTRAL, EMBASE, and OVID databases to retrieve randomized controlled trials. Articles that met the selection criteria were evaluated and data was extracted using a standardized form. Results: The pooled data showed that supervised multimodal exercise reduced fatigue in cancer survivors (p=0.001). The most significant improvements in fatigue were seen in patients still receiving adjuvant treatment (p<0.0001). Post-treatment patients presented non-significant differences in fatigue with exercise (p=0.10). Exercise interventions including a combination of aerobic, resistance, & stretching exercises reduced CRF symptoms significantly (p= 0.01). The effects of resistance training alone on fatigue were not statistically significant (p=0.30). Length, frequency, and session duration of the supervised multimodal exercise interventions were associated with improvements in CRF levels (p=0.04). Bottom Line: The results of this analysis demonstrated that supervised multimodal exercise can improve cancer-related fatigue in cancer survivors during and after cancer treatment, especially in patients receiving chemotherapy when compared with conventional care alone. Clinically, this suggests that exercise may promote

17 Exercise and Cancer Related Fatigue 15 functional performance, reduce development of CRF, and improve perceived energy, mental capacity, and psychological status. These results are applicable to the patient presented in this case study due to the mean age range of the subjects, the use of multiple adjuvant treatments, the type of cancer considered, and the goals for therapy.

18 Exercise and Cancer Related Fatigue 16 Reference #8: Eyigor, S., Karapolat, H., Yesil, H., Uslu, R., & Durmaz, B. (2010). Effects of pilates exercises on functional capacity, flexibility, fatigue, depression and quality of life in female breast cancer patients: a randomized controlled study. European Journal of Physical and Rehabilitation Medicine, 46(4), Level of Evidence: Oxford: 1c Pedro: 5/10 Purpose: The purpose of this study was to investigate the impact of pilates exercises on physical performance, flexibility, fatigue, depression and QoL in breast cancer survivors. Methods: 52 women diagnosed with breast cancer were randomly allocated into treatment and control groups. Subjects in the treatment group performed supervised pilates exercises for 1 hour, 3 times a week for 8 weeks in addition to a home exercise program. The control group only performed the home exercise program, which consisted of minutes of walking and specific exercises to be performed 3 times a week for 8 weeks. All subjects were tested for functional capacity (6MWT), flexibility (modified sit and reach test), fatigue (BFI), depression (BDI), and quality of life (EORTC QLQ-C30 and EORTC QLQ BR23). Results: Significant improvements in functional capacity, depression, and quality of life (p<0.05) were found in the pilates group compared to the control group. No significant changes (p>0.05) in fatigue or flexibility were noted in either group. Bottom Line: Though fatigue decreased in both groups, it was not statistically significant. This suggests that though pilates may be beneficial when incorporated into an exercise regimen, it should not be a stand-alone intervention for cancerrelated fatigue. That said, the statistically significant changes reported in this study would still be applicable to the patient in this case study because they aligned with some of her goals.

19 Exercise and Cancer Related Fatigue 17 Reference #10: Kampshoff, C. S., Chinapaw, M. J. M., Brug, J., Twisk, J. W. R., Schep, G., Nijziel, M. R., Buffart, L. M. (2015). Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study. BMC Medicine, 13, Level of Evidence: Oxford: 1b Pedro: 8/10 Purpose: The purpose of this study was to evaluate the effectiveness of a high intensity and low-to-moderate intensity resistance and endurance exercise program compared to a wait list control group on physical fitness and fatigue in a mixed group of cancer survivors who completed primary cancer treatment. Methods: 277 cancer survivors were randomized into 3 groups. One group performed high intensity exercise (n=91), the second group performed low-tomoderate intensity exercise, and the control group was on a wait list (n=91) and received usual care. The high intensity and low-to-moderate intensity regimens were performed for 12 weeks and included the same type of exercise, duration and frequency. Outcome measurements included cardiorespiratory fitness (peakvo2), strength (grip strength & 30-second chair-stand test), fatigue (MFI), health-related quality of life, physical activity, daily functioning, body composition, mood, and sleep disturbances. Results: Compared to the control group, the high intensity and low-to-moderate intensity protocols produced significant improvements in general fatigue, physical fatigue, and reduced anxiety, with no significant differences between the 2 intervention groups. Improvements in physical function and peakvo2 were better in both exercise groups compared to the control, with no significant differences between the exercise programs. Quality of life improvements were larger for

20 Exercise and Cancer Related Fatigue 18 patients that were younger (p= 0.03), had breast cancer (p=0.02), and/or were women (p= 0.02). Bottom Line: Both the high intensity and low-to-moderate intensity exercise protocols improved cancer-related fatigue, QoL, and physical function equally well. PeakVO2 and motivation were more responsive to the high intensity exercise protocol. The most promising results were seen in patients that resembled the patient being considered in this case study: female and diagnosed with breast cancer. Both exercise protocols could be used with the patient presented in this case depending on tolerance and secondary goals.

21 Exercise and Cancer Related Fatigue 19 Reference #16: Travier, N., Velthuis, M. J., Steins Bisschop, C. N., van den Buijs, B., Monninkhof, E. M., Backx, F., May, A. M. (2015). Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial. BMC Medicine, 13, Level of Evidence: Oxford: 1b Pedro: 7/10 Purpose: The purpose of this study was to examine the effects of an 18-week exercise program on cancer-related fatigue when introduced within 6 weeks after diagnosis of breast cancer. Methods: 204 breast cancer patients beginning chemotherapy treatment were randomly assigned to a treatment group receiving supervised aerobic and resistance training or to a control group receiving usual care for 18 weeks. Fatigue, quality of life, anxiety, and depression were assessed with questionnaires and physical fitness was assessed with stress tests at baseline, 18 weeks, and 36 weeks. Results: The intervention group experienced a significantly lower increase in physical fatigue compared to the control group (ES=-0.30). There were significant between-group differences at 18-weeks for the change in health category on the SF-36 favoring the intervention group (ES=0.47). VO2 (ES=0.31), power output at ventilatory threshold (ES=0.29), and muscle strength (ES= ) were significantly higher for the intervention group at 18 weeks than the control group. Bottom Line: Compared to standard treatment alone, early initiation of an 18-week exercise intervention following diagnosis of breast cancer has statistically significant benefits on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. The exercise intervention did not show statistically significant effects on QoL, anxiety, or depression. Fatigue levels returned to baseline for both groups at 36 weeks. In practice, this suggests that exercise may benefit the physical

22 Exercise and Cancer Related Fatigue 20 aspects of fatigue and deconditioning associated with breast cancer and its corresponding treatments early on in the disease.

23 Exercise and Cancer Related Fatigue 21 Reference #18: Velthuis MJ, Agasi-Idenburg SC, Aufdemkampe G, & Wittink HM. (2010). The effect of physical exercise on cancer-related fatigue during cancer treatment: a metaanalysis of randomised controlled trials. Clinical Oncology, 22(3), Level of Evidence: Oxford: 1a Pedro: N/A Purpose: The purpose of this meta-analysis was to evaluate the effects of different exercise prescription parameters during cancer treatment on cancer-related fatigue, and to gain insight into the safety and feasibility of exercise during treatment. Methods: CINAHL, Cochrane Library, Embase, Medline, Scopus and PEDro databases were searched for randomized controlled trials studying the effects of exercise during cancer treatment on cancer-related fatigue. 18 studies met inclusion criteria and were assessed by 2 independent reviewers. Results: The results of all studies in breast cancer patients showed a small, significant reduction in CRF in favor of the exercise group. Results of home-based exercise programs showed a small, non-significant reduction in CRF. Aerobic exercise programs showed a medium, significant reduction in CRF, resistance training programs showed a small, non-significant reduction in CRF, and combination exercise programs showed a large, non-significant reduction in CRF in favor of the exercise groups. Studies examining the effects of exercise on patients with prostate cancer, multiple myeloma, or acute myelogenous leukaemia showed medium to small, non-significant reductions in CRF in favor of the exercise group. Bottom Line: Pooled results from 3 studies in patients with breast cancer showed a significant reduction in CRF in favor of the aerobic exercise groups. Supervised aerobic exercise programs were more effective in reducing CRF than home-based exercise programs, which did not lead to significant reductions. This suggests that

24 Exercise and Cancer Related Fatigue 22 supervised exercise programs might be superior to home-based exercise programs to ensure proper adherence and intensity to yield physiological benefits. Homebased, supervised aerobic, and resistance exercise programs in prostate cancer patients showed no significant reduction in CRF in favor of the exercise group, which may be due to limited data. Insufficient statistical power may have resulted in the lack of significant effects on CRF in patients with other cancer diagnoses.

25 Exercise and Cancer Related Fatigue 23 Reference #5: Cantarero-Villanueva, I., Fernández-Lao, C., Díaz-Rodriguez, L., Fernándezde-las-Peñas, C., del Moral-Avila, R., & Arroyo-Morales, M. (2011). A multimodal exercise program and multimedia support reduce cancer-related fatigue in breast cancer survivors: A randomised controlled clinical trial. European Journal of Integrative Medicine, 3(3), e189 e Level of Evidence: Oxford: 1b Pedro: 8/10 Purpose: The purpose of this study was to evaluate the effects of an 8-week multimodal PT program with multimedia support on CRF, cortisol and IgA salivary concentrations, α-amylase activity, and neck-shoulder mobility in women with breast cancer. Methods: 78 breast cancer survivors in their first year post treatment were randomized in a treatment group that received a multimodal exercise program, or a control group that received usual care. The multimodal program consisted of individual physical training incorporating endurance and resistance exercises, stretching, and massage interventions that were conducted for 90 minutes each, 3 times per week. The Piper Fatigue Scale, cortisol and IgA salivary levels, α-amylase activity, and active cervical/shoulder range of motion were measured at baseline, 8 weeks, and at a 6-month follow-up. Results: There were significant improvements in all dimensions of fatigue (PFS): affective (p=0.002), sensory (p=0.010), cognitive (p=0.001), severity (p=0.044) and total fatigue score (p<0.001). The inter-group effect size after treatment was moderate for the severity, sensory, and cognitive dimensions of fatigue, and for total fatigue score. The inter-group effect size at the 6mo follow-up was small for the affective, severity, sensory, cognitive dimensions and the total fatigue score

26 Exercise and Cancer Related Fatigue 24 compared to pre-intervention values. There were significant improvements for shoulder flexion (p= 0.004) and horizontal abduction (p=0.020). Bottom Line: Compared to the control group, the treatment group experienced a greater decrease of fatigue in all dimensions and the total score and maintained these improvements after a 6-month follow-up. Subjects in the treatment group also experienced greater increases in cervical mobility (all directions) and shoulder flexion and horizontal abduction than those within the control group. Statistically speaking, this suggests that a multi-modal and multi-media PT intervention would be beneficial for the patient being considered in this case study.

27 Exercise and Cancer Related Fatigue 25 Reference #4: Cantarero-Villanueva, I., Fernández-Lao, C., Cuesta-Vargas, A. I., Del Moral- Avila, R., Fernández-de-las-Peñas, C., & Arroyo-Morales, M. (2013). The Effectiveness of a Deep Water Aquatic Exercise Program in Cancer-Related Fatigue in Breast Cancer Survivors: A Randomized Controlled Trial. Archives of Physical Medicine & Rehabilitation, 94(2), Level of Evidence: Oxford: 1b Pedro: 7/10 Purpose: The purpose of this study was to investigate the effectiveness of an 8- week aquatic program on cancer-related fatigue, physical outcomes, and psychological outcomes in breast cancer survivors. Methods: 68 breast cancer survivors were randomized to a treatment group or a control group receiving usual care following their oncologist s recommendations for a healthy lifestyle. The treatment group attended aquatic exercise sessions 3 times per week for 8 weeks in a heated deep-water swimming pool. Each session was 60 minutes long and included a combination of aerobic and endurance exercises. Results: The treatment group demonstrated significant improvements in all dimensions of the PFS with large to moderate inter-group effect sizes: affective (p<.001), sensory (p<.001), cognitive (p<.001), severity (p<.040), and total fatigue score (p<.001). The intergroup effect size at 6-month follow-up was large for affective, sensory, cognitive, and the total fatigue score compared to preintervention scores. The treatment group also demonstrated significant improvements for tension (p=0.048), depression (p=0.029), anger (p=0.014), and mental fatigue (p=0.002). Intergroup effect sizes were large for the mental fatigue scale at 8 weeks and moderate at the 6-month follow-up. Bottom Line: The improvements in fatigue, leg-abdominal muscle endurance, and mood states were greater for the aquatic exercise group than the control group. The

28 Exercise and Cancer Related Fatigue 26 aquatic exercise group maintained these improvements at the 6-month follow-up except for mood state. This intervention is appropriate for the patient s abilities and goals. Potential barriers include the difficulty of procuring facilities with a heated pool, minimizing the therapist-subject ratio decreases cost-effectiveness, and questionable reimbursement for group therapy.

29 Exercise and Cancer Related Fatigue 27 Systematic Literature Review Process Table 2: Systematic Literature Review Process # Author Oxford Pedro General Purpose Outcome Measures Results 6 Dimeo, F., et al. 1 2 Menese s- Echáve z, J. F., et al. 8 Eyigor, S., et al. 1 0 Kamps hoff, C. S., et al. 2b 3/10 Assess the effects of an exercise program on persistent cancer-related fatigue after treatment 1a N/A Meta-analysis to determine the effects of supervised multimodal exercise interventions on CRF 1c 5/10 Investigate the impact of pilates exercises on physical performance, flexibility, fatigue, depression and QoL in breast cancer survivors 1b 8/10 Evaluate the effectiveness of a HI and LMI resistance & endurance Functional Assessment of Cancer Therapy- Fatigue Scale (FACT-FS), Multidimension al Fatigue Inventory (MFI), Hospital Anxiety and Depression Scale (HADS), workload at anaerobic threshold FACT-FS, EORTC QLQ- C30, PFS, Schwartz Cancer Fatigue Scale (SCFS), MFI BFI, 6MWT, BDI, EORT-C30, EORTC QLQ BR23 MFI, peakvo2, grip strength 30-sec chairstand test, Health-related Mental & physical fatigue, & physical performance were significantly improved with exercise in cancer patients after treatment. Depression, anxiety, & cognitive fatigue were not significantly affected. Supervised aerobic exercise, resistance training, and stretching significantly improved CRF symptoms during & after cancer treatment. Resistance exercises alone produced nonsignificant changes. Statistically non-significant decrease in fatigue in both groups. Pilates may be beneficial, but not a standalone intervention for CRF. HI & LMI exercise significantly reduced general & physical Answer PICO Yes Yes No Yes

30 Exercise and Cancer Related Fatigue Travie r, N., et al. Velthui s, M. J., et al. 5 Cantar ero- Villanu eva, I., et al. 4 Cantar ero- Villanu exercise program on physical fitness and fatigue cancer survivors posttreatment 1b 7/10 Examine the effects of an 18- week exercise program on CRF early on in diagnosis of breast cancer 1a N/A Meta-analysis to evaluate the effects, safety, & feasibility of different types of exercise on CRF during cancer treatment 1b 8/10 Evaluate the effects of an 8- week multimodal PT program on CRF, cortisol and IgA salivary concentrations, α-amylase activity, and neck-shoulder mobility in women with breast cancer 1b 7/10 Investigate the effectiveness of an 8-week aquatic QoL, physical activity, daily functioning, body comp, mood, and sleep disturbances. FQL, MFI, SF- 36, EORT-C30, continuous breathing gas analysis, Cybex dynamometer, handgrip dynamometer, Short Questionnaire to Assess Health enhancing physical activity (SQUASH) Not specified: patientreported fatigue by means of reliable and valid measurement instruments PFS, cortisol and IgA salivary levels, α- amylase activity, and cervical/should er AROM PFS, PMS, trunk curl static endurance test, sit-to-stand test fatigue compared to control. No significant differences between both interventions. Physical fatigue, submax cardiorespirato ry fitness, & strength had statistically significant improvements with intervention. Effects were no longer statistically significant at 36 week f/u Home-based exercises = small, nonsignificant reductions in CRF. Supervised aerobic exercised = med, significant decrease in CRF. No significant reductions in CRF for prostate cancer survivors. Improved fatigue, α- amylase activity, & cervical/should er AROM in breast cancer survivors at end & 6mo f/u Fatigue, LEabdominal endurance, & mood improved Yes Yes Yes Yes

31 Exercise and Cancer Related Fatigue 29 eva, I., et al. program on CRF, physical outcomes, and psychological outcomes in breast cancer survivors more for aquatic exercise group than control, even at 6-mo f/u Discussion: The development of standardized therapeutic interventions that adequately address all aspects of cancer-related fatigue has been difficult due to the multi-factorial nature of fatigue and other compounding features, such as cancer type, severity, treatment regimen, and so on. Despite this complexity, exercise is slowly gaining recognition as a potential treatment among others for cancerrelated fatigue. Research is ongoing to better understand the effectiveness of exercise on cancer-related fatigue and which parameters maximize that effect. The research presented in this case study examined a variety of exercise types including: pilates, aquatic, aerobic, resistance, stretching, and multi-modal exercises. Though studies examining resistance-only and pilates-only exercise protocols reported improvements in functional capacity, depression, and quality of life, improvements in fatigue were not statistically significant 8,12. Several studies reported statistically significant reductions in cancer-related fatigue after implementing aerobic exercises such as walking 12. However, multi-modal exercise protocols that incorporated aerobic, resistance, and stretching exercises produced the greatest improvements in fatigue regardless of cancer type, severity, or chronicity 5,6,12,16. Aquatic exercises were also found to produce large to moderate, statistically significant improvements in cancer-related fatigue 4. Several studies examined the effects of different exercise parameters such as intensity, frequency, duration, and level of supervision. One study found that high

32 Exercise and Cancer Related Fatigue 30 intensity and low-to-moderate intensity exercise protocols produced equally statistically significant improvements in cancer-related fatigue, quality of life, and physical function. However, secondary outcomes such as peakvo2 and motivation were more responsive to the high intensity exercise protocol 10. This suggests that exercise intensity can be somewhat patient-dependent and still produce progress in terms of fatigue. Each of the studies evaluated exercise protocols with a frequency and duration that was sufficient to yield physiological change: 1 hour of exercise performed 3-5 times per week for a duration of 8-18 weeks. The improvement in fatigue and relatively low incidence of reported adverse events suggests that this frequency and duration of exercise is tolerable and safe for patients battling cancer and cancer-related fatigue. One study that evaluated a 3-week multi-modal exercise intervention still demonstrated statistically significant decreases in cancer-related fatigue in newly diagnosed breast cancer patients despite the brevity of the intervention. Each exercise protocol regardless of exercise type, intensity, or duration produced significantly greater improvements in fatigue when performed as in-clinic, supervised programs rather than as home exercise programs 18. However, home exercise programs were found to be more effective when offered with multimedia resources such as instructional videos than without 5. Understanding which type of patient will be most responsive to certain interventions is an important step in developing an appropriate treatment plan. The studies evaluated in this paper included subjects with a wide variety of cancer diagnoses, stages of severity, types of treatment, age, and etc. Though exercise was found to decrease cancer-related fatigue in all of the populations considered in these

33 Exercise and Cancer Related Fatigue 31 studies, some populations were more responsive than others. One study suggested that patients diagnosed with prostate cancer, multiple myeloma, or acute myelogenous leukemia may have less statistically significant decreases in fatigue in response to an exercise protocol than patients diagnosed with breast cancer. However, the authors of this meta-analysis believed that insufficient statistical power may have resulted in the lack of significant effects on fatigue in these patient populations 18. One RCT found that initiating a multi-modal exercise protocol earlier in the disease trajectory can provide preventative improvement in cancer-related fatigue 6,16. However, exercise was still found to produce improvements in fatigue at later stages of the disease progression as well 5,18. Another study found that quality of life improvements following an exercise protocol were larger for patients that were younger, had breast cancer, and/or were women 10. The patient presented in this case study was a middle-aged female breast cancer survivor battling persistent fatigue 18 months after her final treatment, which included chemotherapy, surgery, and radiation. As such, she fell into the patient population thought to be most responsive to exercise as a treatment for cancer-related fatigue with the exception of the chronicity of the symptoms. One point that each of the research articles stressed was that the therapeutic exercises being evaluated were personalized and graded to the patient s tolerance level. The importance of this personalization was made explicitly clear with the patient presented in this case study. Meeting the patient at her level was a key step to enabling her to progress. The lack of specialized equipment to directly measure VO2max, 1RM, and other markers of performance in the clinical setting necessitated

34 Exercise and Cancer Related Fatigue 32 the use of less precise measures such as patient reported levels of perceived exertion and etc. This, in combination with consistent monitoring, was sufficient to establish a baseline and a basic understanding of how the patient would respond to different activities. Though multi-modal exercise programs incorporating aerobic, resistance, and stretching exercises were found to be the most effective in decreasing cancer-related fatigue, the patient was uncertain of her ability to participate in such an ambitious program. To earn patient buy-in, a slow progression towards exercise had to be initiated with gentle manual therapy to address the scar tissue restrictions on her right shoulder, neck, and torso. Gentle stretches were soon incorporated to complement the manual therapy and increase patient participation. One aspect of therapy that was not presented in the aforementioned articles is the emotional toll that cancer has on people. For the patient presented in this case study, cancer had obliterated her sense of control. To address this lost sense of control, the patient was given a choice of exercises that steadily increased her participation and intensity. Thus, gentle exercises including pilates were incorporated in the early phases of the patient s plan of care due to her comfort and familiarity with them. Despite the lack of evidence to support the effects of pilates on cancer-related fatigue, these exercises proved to be an invaluable building block for progression towards more intense and effective exercises. From that point, slow progressions with resistance exercises and aerobic conditioning were made. During this time, the patient acknowledged slight decreases in her sense of fatigue and progressive increases in her willingness to attempt different therapeutic activities.

35 Exercise and Cancer Related Fatigue 33 The patient s continued care and progress was made in the absence of the author and therefore cannot be reported at this time. Conclusion/Clinical Bottom Line: Due to the complex and multifactorial nature of cancer-related fatigue, no single treatment is sufficient to address all aspects of the symptom. A multi-disciplinary approach is likely the best way to address a multifactorial problem. Identifying the most effective and safe ways to address this highly prevalent and distressing condition is a key step in improving care and quality of life for cancer patients. Although the statistical and clinical significance of the effects of exercise on cancer-related fatigue are still being researched, current evidence suggests a trend towards improvement. Is exercise an effective intervention for reducing cancer-related fatigue in individuals currently diagnosed with cancer, receiving adjuvant treatment for cancer, or who had cancer and are now in remission? The evidence presented in this case study suggests that exercise would be an appropriate and effective intervention for the patient upon whom this paper was based and other patients that currently have cancer or have previously experienced cancer and its associated treatments. Individualized, multi-modal exercise protocols during and after cancer treatment are safe and effectively improve fatigue, quality of life, activity avoidance, strength, aerobic capacity and general physical function in patients with a variety of different cancer diagnoses, disease stages, and adjuvant treatments approaches. Secondary benefits of exercise to address cancer-related fatigue include reducing distress and the increased risk of cancer recurrence associated with elevated levels of distress 5. Despite the benefits of exercise, there are some limitations. The improvements in

36 Exercise and Cancer Related Fatigue 34 fatigue produced by exercise are not always statistically significant and the need for individualized programs may potentially decrease the cost-effectiveness of the intervention. Further research is needed to better understand the full extent to which exercise can improve cancer-related fatigue, how generalizable it is to a wider range of cancer types and stages, and the feasibility of implementing programs directed at addressing cancer-related fatigue within a physical therapy setting. With the current evidence considered, exercise should not be used as a stand-alone intervention to address cancer-related fatigue. Rather, it should be incorporated as a safe and effective component of a multi-disciplinary approach to address the symptom.

37 Exercise and Cancer Related Fatigue 35 REFERENCES 1. Anemia. (n.d.). Retrieved January 12, 2017, from 2. Bower, J. E. (2014). Cancer-related fatigue--mechanisms, risk factors, and treatments. Nature Reviews. Clinical Oncology, 11(10), Cancer Fatigue Causes, Treatment & More. (n.d.). Retrieved January 11, 2017, from 4. Cantarero-Villanueva, I., Fernández-Lao, C., Cuesta-Vargas, A. I., Del Moral-Avila, R., Fernández-de-las-Peñas, C., & Arroyo-Morales, M. (2013). The Effectiveness of a Deep Water Aquatic Exercise Program in Cancer-Related Fatigue in Breast Cancer Survivors: A Randomized Controlled Trial. Archives of Physical Medicine & Rehabilitation, 94(2), Cantarero-Villanueva, I., Fernández-Lao, C., Díaz-Rodriguez, L., Fernández-de-las- Peñas, C., del Moral-Avila, R., & Arroyo-Morales, M. (2011). A multimodal exercise program and multimedia support reduce cancer-related fatigue in breast cancer survivors: A randomised controlled clinical trial. European Journal of Integrative Medicine, 3(3), e189 e Dimeo, F., Schwartz, S., Wesel, N., Voigt, A., & Thiel, E. (2008). Effects of an endurance and resistance exercise program on persistent cancer-related fatigue after treatment. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 19(8), Donovan, K. A., Small, B. J., Andrykowski, M. A., Munster, P., & Jacobsen, P. B. (2007). Utility of a cognitive-behavioral model to predict fatigue following breast cancer treatment. Health Psychology: Official Journal of the Division of Health Psychology, American Psychological Association, 26(4), Eyigor, S., Karapolat, H., Yesil, H., Uslu, R., & Durmaz, B. (2010). Effects of pilates exercises on functional capacity, flexibility, fatigue, depression and quality of life