Evidence-based physical activity guidelines for cancer survivors: Current guidelines, knowledge gaps and future research directions

Cancer Treatment Reviews 40 (2014) 327–340

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

General and Supportive Care

Evidence-based physical activity guidelines for cancer survivors: Current guidelines, knowledge gaps and future research directions L.M. Buffart a,⇑, D.A. Galvão b,1, J. Brug a,2, M.J.M. Chinapaw c,3, R.U. Newton b,4 a EMGO Institute for Health and Care Research and the VU University Medical Center, Department of Epidemiology and Biostatistics, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands b Edith Cowan University Health and Wellness Institute, Edith Cowan University, Joondalup, WA 6027, Australia c EMGO Institute for Health and Care Research and the VU University Medical Center, Department of Public and Occupational Health, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

a r t i c l e

i n f o

Article history: Received 7 February 2013 Received in revised form 20 June 2013 Accepted 25 June 2013

Keywords: Exercise Health Neoplasms Physical activity Quality of life Review

a b s t r a c t Physical activity during and after cancer treatment has beneficial effects on a number of physical and psychosocial outcomes. This paper aims to discuss the existing physical activity guidelines for cancer survivors and to describe future research directions to optimize prescriptions. Studies on physical activity during and after cancer treatment were searched in PubMed, Clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, and Dutch Trial registry. Physical activity guidelines for cancer survivors suggest that physical activity should be an integral and continuous part of care for all cancer survivors. However, the development of these guidelines has been limited by the research conducted. To be able to develop more specific guidelines, future studies should focus on identifying clinical, personal, physical, psychosocial, and intervention moderators explaining ‘for whom’ or ‘under what circumstances’ interventions work. Further, more insight into the working mechanisms of exercise interventions on health outcomes in cancer survivors is needed to improve the efficacy and efficiency of interventions. Finally, existing programs should embrace interests and preferences of patients to facilitate optimal uptake of interventions. In conclusion, current physical activity guidelines for cancer survivors are generic, and research is needed to develop more personalized physical activity guidelines. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction In developed countries, approximately one in three persons will be directly affected by cancer before the age of 75 years, with breast cancer, prostate cancer, lung cancer and colorectal cancer the most common diagnoses [1]. It has been estimated that 12.7 million cancer cases and 7.6 million cancer deaths occurred worldwide in 2008 [1]. Advances in early detection and treatment have improved survival rates over the past decades, with approximately 60% of patients living over 5 years after diagnosis [2,3]. However, cancer and its treatment are often associated with physical and psychosocial problems, negatively affecting quality of life (QoL) [4,5]. Anyone who has been diagnosed with cancer, from the time of diagnosis through the rest of life, is considered a cancer survivor ⇑ Corresponding author. Tel.: +31 20 444 9931; fax: +31 20 444 8387. E-mail addresses: [email protected] (L.M. Buffart), [email protected] (D.A. Galvão), [email protected] (J. Brug), [email protected] (M.J.M. Chinapaw), [email protected] (R.U. Newton). 1 Tel.: +61 8 6304 3420; fax: +61 8 6304 2499. 2 Tel.: +31 20 444 8192; fax: +31 20 444 8171. 3 Tel.: +31 20 444 8203; fax: +31 20 444 8387. 4 Tel.: +61 8 6304 3443; fax: +61 8 6304 5106. 0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctrv.2013.06.007

[6]. Several reviews and meta-analyses demonstrate beneficial effects of physical activity (PA) and exercise (i.e. form of PA that is planned, structured and repetitive and aims to improve fitness, performance or health [7]) in cancer survivors during and after treatment on physical and psychosocial outcomes, [8,9] including increased aerobic fitness, [10] reduced fatigue [11,12] and depression, [13] and improved QoL [14,15]. Sufficient levels of PA may also be important to improve disease free and overall survival. Observational studies showed higher levels of moderate-tovigorous PA to be associated with lower mortality risk in survivors [16] of breast, [17–19] colon, [20,21] and prostate cancer, [22,23] with physically active survivors having approximately 50% lower mortality. However, to establish a causal relationship between PA and survival, randomized controlled trials (RCTs) are needed. The first RCT evaluating the effects of PA on survival is currently being conducted among survivors with colon cancer who have completed adjuvant chemotherapy in the Colon Health and Life-Long Exercise Change (CHALLENGE) trial [24]. Given the increasing number of studies showing the safety and benefits of PA, it should be part of standard care for all cancer survivors. Evidence-based PA guidelines have been published, but the development of these guidelines is limited by the research

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conducted in this area. This paper reviews the current evidencebased PA guidelines for cancer survivors, identifies current knowledge gaps and describes the research needed to fill these gaps. This synopsis may inform future studies evaluating exercise as medicine for cancer, as well as the development of more personalized PA guidelines for cancer survivors. Current guidelines and their empirical basis In 2003, the American Cancer Society (ACS) published a report intended to present health care providers with the best possible information on which to assist cancer survivors and their families to make informed choices related to nutrition and PA [25]. This was ACS’s second report on nutrition, but the first to also include information on PA. Although evidence was generally insufficient to draw conclusions about the benefits and risks of PA, a probable beneficial effect of PA on QoL was found for survivors of breast and colorectal cancer during and after cancer treatment, and for survivors of prostate cancer after cancer treatment, as well as for overall survival after treatment for colorectal, lung, and prostate cancer. Importantly, no evidence of harm was reported. The ACS report was updated in 2006 [26]. Despite methodological limitations and small sample sizes, evidence strongly suggested that exercise is safe and feasible during cancer treatment and can improve physical functioning and some aspects of QoL [26]. It was also suggested that regular PA after cancer treatment is essential for recovery and to improve fitness. Also, after recovery it was concluded that PA is important to promote overall health, QoL and longevity. For the prevention of cancer, the ACS recommends at least 30 min, and preferably 45–60 min, of moderate-to-vigorous PA above usual activities, on 5 or more days of the week (Table 1). Although these PA levels have not been studied systematically in cancer survivors, these recommendations may also benefit cancer survivors, as it may reduce the risk of recurrence or developing secondary cancers and extend survival. Therefore, ACS recommended that daily and regular PA is preferred, but any steps that are taken to move from a sedentary to a more active lifestyle should be encouraged, with higher levels of PA leading to more health benefits [25,26] (Table 1). However, specific precautions should be heeded for survivors with severe anemia, compromised immune function, severe fatigue, indwelling catheters and peripheral neuropathies or ataxia [25,26] (Table 2). In 2009, Exercise and Sport Science Australia (ESSA) published exercise guidelines for cancer survivors with the intention of guiding exercise practitioners in their work with cancer survivors [27]. The document provided specific recommendations for aerobic exercise and for the first time, also for resistance exercise (Table 1), particularly important for cancer survivors experiencing loss of lean mass during and following treatment. The ESSA position statement indicated that the optimal exercise prescription remains unknown, and may depend on the type of cancer, treatment and characteristics of the patient. It was recognized that participation in some PA is better than none, and that more is generally better than less, at least up to levels meeting national PA guidelines [27]. It was also recommended to avoid certain types of aerobic or resistance exercises (e.g. high impact activities) during periods of increased risk of infection, ataxia, dizziness, peripheral sensory neuropathy, low platelet counts, bone pain, or in patients with primary or metastatic bone cancer (Table 2). In 2010, the American College of Sports Medicine (ACSM) organized a roundtable on exercise guidelines for cancer survivors given the proliferation of exercise programs, and the lack of structured exercise guidelines for health and fitness professionals to draw upon in working with cancer survivors [28]. Evidence was reviewed for adult survivors of breast, prostate, colon, hematologic, and gynecologic cancers. This was the first time that evaluation of the evidence in exercise oncology for development of guidelines was

conducted more systematically and based on categories A–D, outlined by the National Heart, Lung and Blood Institute. Overall, the ACSM guidelines fall into evidence category level B, indicating that few RCTs exist or they are small and results are inconsistent. The expert panel reported consistent evidence regarding the safety of exercise during and after cancer treatment (including intensive treatments such as bone marrow transplant) and reported that improvements can be expected in aerobic fitness, muscle strength, QoL and fatigue in survivors of breast, prostate, and hematologic cancer. The expert panel acknowledged that the extent to which these findings may generalize to other cancer survivor groups remains unknown, and that exercise prescriptions should be individualized according to cancer survivors’ pre-treatment aerobic fitness, medical co-morbidities, response to treatment, and the immediate or persistent negative effects of treatment. The ACSM generally recommends avoiding inactivity, returning to normal daily activities as quickly as possible after surgery, and to continue normal daily activities and exercise as much as possible during and after nonsurgical treatments. Recommendations for aerobic, resistance, and flexibility exercises are the same as the age-appropriate PA guidelines for the general population [28,29] (Table 1), with several alterations for patients with and at risk for lymphedema, skeletal fractures or infections. In addition, several contraindications for exercise were identified, including arm and shoulder problems secondary to breast cancer treatment, having an ostomy after colon cancer, or swelling or inflammation in the abdomen, groin, or lower extremity following gynecologic cancer (Table 2). In 2011, PA guidelines for cancer survivors were developed in the Netherlands recommending at least moderate intensity exercise to all cancer survivors and to tailor exercise programs to individual fitness levels to obtain optimal training effects [30,31]. Individual cardiopulmonary fitness levels can be assessed by measuring peak oxygen uptake (peakVO2) which is feasible and safe for cancer survivors prior to an exercise program [32]. In case of logistical problems related to cost, lack of appropriate equipment or experienced health care professionals to use this test in clinical practice, [32] a 6 min walk-test, shuttle walk test, or steep ramp test [33] is recommended [32]. To adequately tailor resistance exercises to individual patients, the Dutch guidelines recommend using indirect 1-repetition maximum (1-RM) assessments to assess muscle strength (Table 1) [33,31]. In 2012, the ACS updated their report from 2006 and 2003 [34]. Generally, they recommended cancer survivors to engage in regular PA, to avoid inactivity and return to normal daily activities as soon as possible following diagnosis. The ACS recommends cancer survivors to aim for exercising at least 150 min per week and to include strength exercises following the comprehensive guidelines suggested by the ACSM expert panel, after consideration of specific precautions (Table 2). In the same year, the British Association of Sport and Exercise Science (BASES) published an expert statement on exercise and cancer survivorship [35]. They reported that there is consistent evidence confirming that exercise is safe during and after cancer treatment, provided that individual limitations and specific side effects associated with cancer therapies are considered and monitored, and that improvements in aerobic and muscular fitness, QoL and fatigue can be expected. They recommended all cancer survivors be encouraged to avoid being sedentary, and unless advised otherwise, follow the PA guidelines of the general UK population [36] (Table 1), as no formal guidelines for cancer survivors have been published in the UK. Knowledge gaps to be addressed Although the significant work conducted to formulate the above mentioned guidelines is important and has changed clinical practice for management of cancer, current recommendations are

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Table 1 Overview of PA guidelines for cancer survivors. Year

Institute

PA recommendations

2003/ ACS 2006 [25,26]

2009

ESSA [27]

 Follow guidelines for the general population for cancer prevention, i.e. at least 30 min of moderate-to-vigorous PA, above the usual activities, on 5 or more days of the week. Forty-five to 60 min of intentional PA are preferable  Daily and regular activity may be preferred and may be the goal. Any steps that are taken to move from a sedentary to an active lifestyle should be encouraged Aerobic exercise:

 Type: exercises involving large muscle groups  Frequency: at least 3–5 times per week, but daily exercise may be preferable for deconditioned patients who do lower intensity and shorter duration exercise sessions  Intensity: moderate, depending on current fitness level. Guidelines recommend 50–75% VO2max, or HRreserve, 60–80% HRmax, or a RPE of 11–14 (original Borg scale)  Duration: at least 20–30 min continuous exercise; however, deconditioned patients or those experiencing severe side effects of treatment may need to combine short bouts (e.g. 3–5 min) with rest intervals  Progression: would be slower and more gradual for deconditioned patients or those who are experiencing severe sideeffects of treatment

Resistance exercise:  Type: exercises using machine-weights, free weights, body weight and/or elastic bands that involve major functional lower- and upper-body muscle groups. Targeting large muscle groups. Exercises should be dynamic in nature using both concentric and eccentric muscle contractions  Frequency: 1–3 times per week, with minimum one rest day between sessions  Intensity: 50–80% of 1-RM or 6–12 RM  Duration: 6–10 exercises, 1–4 sets per muscle group  Progression: as described for aerobic exercise 2010

ACSM [28]

Aerobic exercise:

 Avoid inactivity and be as physically active as abilities and conditions allow  For patients with breast, prostate, colon, hematologic (no HSCT) and gynaecologic cancer, recommendations are the same as age-appropriate guidelines for the general American population, i.e. to engage in at least 150 min per week of moderate intensity or 75 min per week of vigorous intensity aerobic PA or an equivalent combination of moderate and vigorous intensity aerobic PA, for adults aged 18–64 years. Activity should be done in episodes of at least 10 min per session and preferably spread throughout the week; some activity is better than nothing and exceeding the guideline is likely to provide additional health benefits  For patients with HSCT, it is ok to exercise everyday, however lighter intensity and lower progression of intensity is recommended  Women with gynaecologic cancer who are morbidity obese may require additional supervision and altered programming

Resistance exercise:  For patients with prostate, colon, and hematologic cancer, recommendations for resistance training are the same as ageappropriate guidelines for the general American population, i.e. Muscle-strengthening activities involving all major muscle groups at least 2 days per week for adults aged 18–64 years  For patients with breast cancer, start with a supervised program of at least 16 sessions and very low resistance; progress resistance at small increments  For patients with prostate cancer: add pelvic floor exercises for those who undergo radical prostatectomy  For patients with colon cancer with a stoma, start with low resistance and progress resistance slowly to avoid herniation at the stoma  For bone marrow transplant patients, resistance exercises might be more important than aerobic exercise 2011

CCCN [30,31]

 Systematically identify physical and psychosocial problems using for example the distress thermometer  At least moderate intensity physical exercise should be recommended to all patients with cancer, using the Dutch physical activity norms as a guideline: at least 30 min moderate intensity (4 MET, and 3 MET for people aged P55 years) on at least 5 but preferable all days per week  Physical exercise programs should be tailored to patients’ individual cardiopulmonary fitness levels to obtain optimal training effects  Assessments of CPET, 6-min walk test, shuttle walk test or steep ramp test should be performed to tailor aerobic exercises to individual disease characteristics, preferences and goals  Assessments of 1-RM should be performed to tailor resistance exercises to individual disease characteristics, preferences and goals

2012

ACS [34]

    

2012

BASES [35]

 All cancer survivors should be encouraged, as a minimum, to avoid being sedentary  Unless advised otherwise, cancer survivors should follow the health-related PA guidelines provided for the general UK population i.e. 150 min each week of moderate to vigorous intensity PA for adults (and adults should aim to do some PA every day) and include muscle strengthening activities twice a week

Engage in regular PA Avoid inactivity and return to normal daily activities as soon as possible following diagnosis Aim to exercise at least 150 min per week Include strength training exercises at least 2 days per week Follow the survivor-specific guidelines written by the ACSM expert panel

ACS = American Cancer Society; ACSM = American College of Sports Medicine; BASES = British Association of Sport and Exercise Science; CCCN = Comprehensive Cancer Center the Netherlands; CPET = cardiopulmonary exercise testing; ESSA = Exercise and Sport Science Australia; HR = heart rate; HSCT = hematopoietic stem cell transplantation; MET = metabolic equivalent; RM = repetition maximum; RPE = rating of perceived exertion; UK = United Kingdom; VO2 = oxygen uptake.

rather general due to gaps in specific areas of exercise oncology. The ultimate aim is to have specific guidelines to inform a given exercise intervention (e.g. mode, frequency, intensity, duration), for a given cancer site at a particular phase of the cancer trajectory (e.g. during treatment, survivorship, end of life), for specific end points (e.g. fatigue, physical function, QoL, survival) and to address specific treatment side-effects and co-morbidities (e.g. osteoporosis, metabolic syndrome, sarcopenia, functional decline) [28]. A

meta-analysis by Speck et al. [9] concluded that the current volume of literature was not large enough to summarize findings per time point within PA across the Cancer Continuum (PACC) framework, [37] which proposes four post-diagnosis (pre-treatment, treatment, survivorship, and end of life) cancer-related time periods [37]. Nevertheless, results of exercise during and post cancer treatment were separately presented in this meta-analysis. During treatment, small-to-moderate effects of PA were reported

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Table 2 Precautions for exercise. Year

Institute

Precautions

2003/ 2006

ACS [25,26]

 Survivors with severe anemia should delay exercise, other than activities of daily living, until the anemia is improved  Survivors with compromised immune function should avoid public gyms and public pools until their white blood cell counts return to safe levels. Survivors who have completed a bone marrow transplant are usually advised to avoid such exposures for one year after transplantation  Survivors suffering from severe fatigue from their therapy may not feel up to an exercise program, so they may be encouraged to do 10 min of stretching exercises daily  Survivors undergoing radiation should avoid chlorine exposure to irradiated skin (e.g. from swimming pools)  Survivors with indwelling catheters or feeding tubes should be cautious or avoid pool, lake, or ocean water or other microbial exposures that may result in infections, as well as resistance training of muscles in the area of the catheter to avoid dislodgment  Survivors with significant peripheral neuropathies or ataxia may have a reduced ability to use the affected limbs because of weakness or loss of balance. They may do better with a stationary reclining bicycle, for example, than walking on a treadmill

2009

ESSA [27]

 Patients are recommended to avoid swimming or the use of public facilities such as machine-weights in gymnasiums during periods of increased infections (e.g. low absolute neutrophil counts, when catheters are being used, during wound recovery from surgery)  Patients with primary or metastatic bone cancer, patients with low platelet counts, or patients experiencing bone pain should avoid highimpact activities or contact sports  Patients with ataxia, dizziness, or peripheral sensory neuropathy are recommended to avoid activities requiring balance and coordination (e.g. treadmill exercise, cycling) and specific resistance exercises such as those using free weights  Patients should avoid the use of public facilities (e.g. local gymnasium) during periods of increased infection risk  When nausea, dyspnoea, fatigue and/or muscle weakness exist, exercise intensity and duration should be prescribed to tolerance

2010

ACSM [28]

 Beware of fracture risk in patients with breast and prostate cancer who are treated with hormone of androgen deprivation therapy, respectively, or diagnosed with osteoporosis or bone metastases  Women with immediate arm or shoulder problems secondary to breast cancer treatment should seek medical care to resolve those issues before exercise training with the upper body  If an ostomy is present in patients with colon cancer, physician permission is recommended before participation in contact sport and weight training, excessive intra-abdominal pressure should be avoided, and modifications will be needed for swimming and contact sports  In adults with HSCT, care should be taken to avoiding overtraining given immune effects of vigorous exercise  If peripheral neuropathy is present in patients with gynaecologic cancer, a stationary bike might be preferable over weight bearing exercise  Women with gynaecologic cancer with swelling or inflammation of the abdomen, groin or lower extremities should seek medical care to resolve these issues before exercise training with the lower body  Patients with bone metastases may need to alter their exercise program given the increased risk for skeletal fractures  Care should be taken to reduce infection risk in fitness centers for patients who are currently undergoing chemotherapy or radiation treatment or have compromised immune function  Patients with cardiac conditions will require modifications and may require increased supervision for safety

2012

ACS [34]

 See also precautions from ACS published in 2003 and 2006  Survivors with multiple or uncontrolled comorbidities need to consider modifications to their exercise program in consultation with their physicians

ACS = American Cancer Society; ACSM = American College of Sports Medicine; ESSA = Exercise and Sport Science Australia.

for aerobic fitness, upper and lower body muscle strength, body weight, functional QoL, anxiety, and self-esteem. Post treatment, large effects were found for upper and lower body muscle strength and breast cancer-specific concerns, and small to moderate effects for PA level, aerobic fitness, overall QoL, insulin-like growth factor (IGF)-1, and symptoms and side effects [9]. For many outcomes, there have been too few studies to draw conclusions. Similar small-to-moderate effect sizes were reported in other metaanalyses on this topic [12–15,38,39]. Explanations for small-to-moderate effects of exercise in cancer survivors include problems with program participation and adherence, and the use of one-size-fits-all approaches in a heterogeneous group of cancer survivors. Thus, similar to developments in personalized primary cancer treatment, exercise prescription for cancer survivors should be optimally tailored to the individual characteristics, states, needs, capabilities and preferences of a patient. To be able to shift towards personalized PA and exercise programs, it is essential to know which mode of exercise, at which frequency, intensity and duration is best for whom, and under what circumstances, for example the timing with respect to the treatment phase (i.e. treatment moderators). To further optimize exercise interventions, it is essential to gain insight into the working mechanisms and to identify effective intervention components (i.e. treatment mediators). Moderators of exercise intervention effects Specific treatment moderators can help determine which patients should receive a particular treatment [40]. Few previous studies have examined moderators of exercise intervention effects

on QoL in cancer survivors. Greater QoL benefits were found in lymphoma patients who had no preference for exercise, were unmarried, had normal weight or were obese, or had poor/fair health [41]. During chemotherapy for breast cancer, aerobic training was most beneficial for patients who had no exercise preference, were unmarried, aged <50 years and had more advanced disease stage [42]. Resistance exercise was most beneficial for patients who preferred it, were unmarried, received nontaxane-based chemotherapy and had more advanced disease stage [42]. Prostate cancer patients with lower psychosocial function at baseline showed higher improvements in QoL after completing a lifestyle PA program [43]. These studies indicate that demographic, clinical and personal factors may help us to understand differences in exercise responses. Insight into moderators of interventions is needed to maximize benefits of interventions for individual patients. Future studies should focus on identifying relevant moderators of exercise intervention effects. Exercise mode, frequency, intensity and duration RCTs directly comparing different exercise modes, frequencies, intensities and durations in cancer survivors are necessary to identify optimal exercise prescriptions. Unfortunately, few RCTs have been published (Table 3). Regarding exercise mode, Courneya et al. [44] found peak oxygen uptake (peakVO2) to be superior after aerobic exercise training (AET) compared with usual care (UC) and resistance exercise training (RET), and lower and upper body strength to be superior after RET compared with AET and UC in women with breast cancer during chemotherapy. Neither exercise interventions prevented weight gain, but they both altered body

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Table 3 Overview of studies directly comparing different exercise modes, frequencies, intensities, durations, and timing. Author Trial identification

Population Diagnosis, n

Study design

Main findings

Breast cancer during chemotherapy; n = 242

3-armed RCT:

Men with prostate cancer during radiation therapy; n = 121

3-armed RCT:

Newton et al. [48](ACTRN12609000200280)

Men with prostate cancer during ADT; n = 195

3-armed RCT:

 PeakVO2 (ml/kg/min): AET > RET (4 1.4, 95% CI = 0.1; 2.7, p = 0.031) RET = UC (4 0.5, 95% CI = -0.8; 1.8, N.S.) AET > UC (4 2.0, 95% CI = 0.6; 3.3, p = 0.004)  Lower body strength (1 RM in kg): RET > AET (4 5.2, 95% CI = 2.5; 7.9, p = 0.001) RET > UC (4 6.8, 95% CI = 4.2; 9.5, p = 0.001) AET = UC (4 1.6, 95% CI = 1.1; 0.12, N.S.)  Upper body strength (1 RM in kg): RET > AET (4 6.8, 95% CI = 4.5; 9.0, p = 0.001) RET > UC (4 7.7, 95% CI = 5.5; 9.9, p = 0.001) AET = UC (4 1.0, 95% CI = 1.3; 3.2, N.S.)  Body weight (kg): AET = RET (4 -0.7, 95% CI = 0.4; 0.9, N.S.) RET = UC (4 0.5, 95% CI = 1.6; 0.6, N.S.) AET = UC (4 0.2, 95% CI = 0.9; 1.4, N.S.)  Body fat (%): AET = RET (4 0.0, 95% CI = 1.0; 1.0, N.S.) RET = UC (4 0.9, 95% CI = 0.1; 1.9, N.S.) AET > UC (4 0.9, 95% CI = 0.1; 1.9, p = 0.076)  Lean mass (kg): RET = AET (4 0.6, 95% CI = 0.1; 1.3, N.S.) RET > UC (4 1.0, 95% CI = 0.3; 1.6, p = 0.004) AET = UC (4 0.3, 95% CI = 0.3; 1.0, N.S.)  Chemotherapy completion rate: RET = AET (4 3.3, 95% CI = 2.5; 9.2, p = 0.266) RET > UC (4 5.7, 95% CI = 0.4; 11.0, p = 0.033) AET = UC (4 not reported, N.S.) Self esteem: RET = AET (4 0.0, 95% CI = 1.1; 1.1, N.S.) RET > UC (4 1.2, 95% CI = 0.2; 2.3, p = 0.025) AET > UC (4 1.2, 95% CI = 0.1; 2.3, p = 0.026)  QoL*: RET > UC (4 4.3, 95% CI = 0.9; 7.8, p = 0.015) AET > UC (4 2.5, 95% CI = -0.9; 5.9, p = 0.141) Fatigue*: RET > UC (4 4.8, 95% CI = 1.8; 7.8, p = 0.002) AET > UC (4 2.7, 95% CI = 0.3; 5.6, p = 0.08)  PeakVO2 (ml/kg/min) RET > UC (4 1.6, 95% CI = 1.0; 3.1, p = 0.037) AET > UC (4 1.4, 95% CI = 0.1; 2.8, p = 0.063) Lower body strength (8 RM in kg): RET > UC (4 25.1, 95% CI = 15.3; 34.9, p < 0.001) AET = UC (4 3.7, 95% CI = 6.0; 13.4 p = 0.45)  Upper body strength (8 RM in kg): RET > UC (4 13.7, 95% CI = 10.7; 16.6, p < 0.001) AET > UC (4 4.0, 95% CI = 1.2; 6.9, p = 0.006)  Body fat (%): RET > UC (4 1.5, 95% CI = 3.1; 0.03, p = 0.055) AET = UC (4 0.2, 95% CI = 1.7; 1.4, p = 0.847)  Triglyceride (mmol/L): RET > UC (0.1 (SD = 0.6) decrease in RET vs 0.3 (SD = 0.7) increase in UC, p = 0.036) AET = UC (0.3 (SD = 0.7) increase in AET and UC, N.S.) Study is ongoing

Jones et al. [46]The Lung Cancer Exercise Training (LUNGEVITY) study (NCT00018255)

Histologically confirmed stage I-IIIA post-operative NSCLC; n = 160

 RET + impact loading  RET + AET  UC 4-armed RCT:

Study is ongoing

Winters-Stone [50](NCT00662103)

Older (>65 years) female breast cancer after treatment. n = 141

RET AET RET + AET Attention-control (progressive stretching) 3-armed RCT:

Study is ongoing

Exercise mode Courneya et al. [44]Supervised Trial of Aerobic versus Resistance Training (START) trial

Segal et al. [45]

 AET  RET  UC

 AET  RET  UC

   

 AET  RET  Flexibility and relaxation (control) (continued on next page)

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Table 3 (continued) Author Trial identification

Population Diagnosis, n

Young-McCaughan [51](NCT00237926)

2-armed RCT: Sedentary adults after treatment with  AET chemotherapy or radiation  RET therapy n = 58 Adult survivors of solid 3-armed RCT: tumours. n = 76  Tai Chi  AET  UC Breast cancer after 3-armed RCT: treatment n = 114  QuiGong  AET (line dancing)  UC

Study is ongoing

Survivors of breast and colon cancer n = 18

Differences at post-test between moderate (n = 6) and low AET (n = 6):

National Institutes of Health Clinical Center [47](NCT00246818) Siew Yim [49](ACTRN12611000093987)

Exercise frequency – Exercise intensity Burnham and Wilcox [54]

Study design

3-armed RCT:  Moderate AET  Low AET  UC

3-armed RCT:

Gibbs et al. [55](ACTRN12612000256875)

Breast cancer patients with lymphedema after cancer treatment; n = 73

Cormie et al. [56](ACTRN12610000788077)

Women with breast cancer 3-armed RCT: related lymphedema.  High intensity RET n = 60  Low intensity RET  UC Mixed group after 3-armed RCT: chemotherapy; n = 400  High intensity RET + AET  Low-moderate intensity RET + AET  Wait-list

Kampshoff et al. [57]Resistance and Endurance exercise After ChemoTherapy (REACT) study.(NTR2153)

 High intensity RET  Low intensity RET  UC

Main findings

Study is ongoing

Study is ongoing

 PeakVO2 (ml/kg/min): p = 0.824  Body fat (%): p = 0.512  Sit and reach (cm): p = 0.722 Exercise (n = 12) vs UC (n = 6) " PeakVO2 (ml/kg/min): p < 0.001 ; Body fat (%): p < 0.001 " Sit and reach (cm): p = 0.027 " QoL: p < 0.001 " Energy: p = 0.038 Lymphatic relative volume (%): High vs Low: N.S. High vs UC: 4 8.6; p = 0.001 Low vs UC: 4 7.8; p = 0.001  Chest press (kg): High vs Low: N.S. High vs UC: 4 4.7; p = 0.001 Low vs UC: 4 3.8; p = 0.001  Seated row (kg): High vs Low: N.S. High vs UC: 4 9.7; p = 0.001 Low vs UC: 4 4.9; p = 0.001  Leg extension (kg): High vs Low: N.S. High vs UC: 4 5.6; p = 0.001 Low vs UC: 4 3.9; p = 0.001  400 m walk (sec): High vs Low: 4 16.3; p = 0.020 High vs UC: 4 36.2; p = 0.025 Low vs UC: 4 18.9; p = 0.004  General fatigue (%) High vs Low: N.S. High vs UC: 4 28.2; p = 0.001 Low vs UC: 4 25.3; p = 0.001  Body image (%) High vs Low: N.S. High vs UC: 4 20.8; p < 0.05 Low vs UC: 4 23.4; p < 0.05  Breast symptoms (%) High vs Low: N.S. High vs UC: 4 9.5; p < 0.05 Low vs UC: 4 10.8; p < 0.05  Arm symptoms (%) High vs Low: N.S. High vs UC: 4 15.2; p < 0.05 Low vs UC: 4 13.6; p < 0.05 Study is ongoing      

Study is ongoing

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L.M. Buffart et al. / Cancer Treatment Reviews 40 (2014) 327–340 Table 3 (continued) Author Trial identification

Population Diagnosis, n

Study design

Main findings

Jones et al. [58]Exercise Intensity trial (EXCITE)(NCT01186367)

Postmenopausal, operable breast cancer after treatment; n = 174

3-armed RCT:

Study is ongoing

Breast cancer survivors; n = 114

3-armed RCT:

Breast cancer survivors scheduled for radiotherapy; n = 63.

3-armed RCT:

Exercise duration Sprod et al. [59]

Timing of exercise Gibbs et al. [60](ACTRN1212000646842)

 High intensity aerobic  Moderate-high intensity aerobic  Attention control

 3 months exercise  6 months exercise  UC

 RET + AET during treatment  RET + AET post treatment  UC

 Cardiovascular endurance (treadmill time): 6M=3M 6 M > UC (p < 0.05) 3 M > UC (p < 0.05)  Forced Vital Capacity: 6 M > 3 M (p < 0.05) 6 M > UC (p < 0.05) 3 M = UC  Upper body muscle endurance (bench press) : 6 M > 3 M (p < 0.05) 6 M = UC 3 M = UC  Crunches: 6M=3M 6 M > UC (p < 0.05) 3 M > UC (p < 0.05)  Affective fatigue: 6 M > 3 M (p < 0.05) 6 M = UC 3 M = UC 12 weeks/3 months follow-up  MFI, general fatigue (%) During vs Post: N.S./N.S. During vs UC: 4 17.2; p = 0.042/4 10.8; p = 0.012 Post vs UC: 4 14.4; p = 0.031/4 9.2; p = 0.031  MFI, physical fatigue (%) During vs Post: 4 5.5; p = 0.045/N.S. During vs UC: 4 18.7; p = 0.034/4 11.1; p = 0.034 Post vs UC: 4 13.0; p = 0.038/4 10.3; p = 0.035  Chest press (1-RM in kg) During vs Post: N.S./4 3.2; p = 0.026 During vs UC: 4 6.5; p = 0.001/4 2.3; p = 0.002 Post vs UC: 4 5.3; p = 0.002/N.S.  Seated row (1-RM in kg) During vs Post: N.S./4 3.5; p = 0.002 During vs UC: 4 7.3; p = 0.002/4 1.5; p = 0.045 Post vs UC: 4 4.4; p = 0.001/N.S.  Leg extension (1-RM in kg) During vs Post: N.S./N.S. During vs UC: 4 5.8; p = 0.006/4 1.4; p = 0.042 Post vs UC: N.S./N.S.  Upper body endurance (rep) During vs Post: N.S./N.S. During vs UC: 4 6.3; p = 0.011/4 2.9; p = 0.038 Post vs UC: 4 4.5; p = 0.025/N.S.  Lower body endurance (rep) During vs Post: N.S./N.S. During vs UC: 4 7.1; p = 0.022/4 3.9; p = 0.032 Post vs UC: 4 6.9; p = 0.021/N.S.  Global health (%): During vs Post: N.S./N.S. During vs UC: 4 23.5; p = 0.006/N.S. Post vs UC: N.S./N.S.  Physical functioning (%) During vs Post: N.S./N.S. During vs UC: 4 12.0; p = 0.010/N.S. Post vs UC: N.S./N.S.  Role functioning (%) During vs Post: N.S./N.S. During vs UC: 4 13.3; p = 0.010/N.S. Post vs UC: N.S./N.S.  Emotional functioning (%) During vs Post: N.S./N.S. During vs UC: 4 20.1; p = 0.002/N.S. Post vs UC: N.S./N.S. (continued on next page)

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Table 3 (continued) Author Trial identification

Population Diagnosis, n

Study design

Main findings

Newton et al. [61](ACTRN12612000097842)

Prostate cancer during ADT; n = 124

2-armed RCT

Study is ongoing

Testicular, colon and Walenkamp & Gietema [62] Optimal timing of PA in Cancer breast cancer n = 206 Treatment (ACT) study(NCT01642680)

 Commence exercise simultaneously with ADT  start after 6 months 2-armed RCT Study is ongoing  PA program during (3 months) and after chemotherapy (3 months)  PA after chemotherapy (6 months)

ACTRN = Australian New Zealand Clinical Trials Registry Number; ADT = androgen deprivation therapy; AET = aerobic exercise training; NCT = ClinicalTrials.gov Identifier; N.S. = not significant; NSCLC = non-small cell lung cancer; RCT = randomized controlled trial; RET = resistance exercise training; RM = repetition maximum; UC = usual care; VO2 = oxygen uptake. * Unadjusted for covariates. > = more benefits.

composition compared to UC: AET prevented fat gain, and RET added lean body mass. Further, compared to AET (87.4%) and UC (84.1%), chemotherapy completion rate was higher during RET (89.8%) [44]. Both RET and AET improved self-esteem compared to UC, but no differences were found between AET and RET. Also cancer-specific QoL, fatigue, anxiety, depression and arm volumes did not differ between groups. QoL and lower body strength were higher, and body fat and triglycerides lower after 24 weeks of RET compared to UC in men receiving radiotherapy for prostate cancer [45]. No significant differences were found between AET and UC (Table 3) [45]. Compared with UC, both RET and AET improved upper body strength and peakVO2, and reduced fatigue. No significant differences between groups were found for prostate-specific symptoms, body weight, body fat, hemoglobin, testosterone, and prostate-specific antigen. Although both RET and AET were compared with UC, with RET showing longer-term improvements and additional benefits for QoL, strength, triglycerides and body fat, direct comparisons between RET and AET were not reported. To be able to tailor exercise interventions to individual cancer-related sequelae, more studies evaluating the effects of different exercise modes on specific outcomes are needed. Few studies are currently underway [46–51] (Table 3). In addition to RET and AET, specific clinical exercises may be recommended for specific cancer diagnoses. For example, for survivors of prostate cancer, pelvic floor training before surgery and during radiation and ADT may be important to reduce incontinence and to improve QoL [52,53]. RCTs directly comparing different exercise frequencies among cancer survivors have not been published. The majority (59%) of studies evaluating effects of PA in cancer survivors focused on a frequency of 3–5 times per week, [9] corresponding with general PA guidelines. Interventions focusing on structured supervised exercise generally offered two sessions per week with or without additional PA counseling. Two studies compared responses to different exercise intensities [54,55] (Table 3). Comparisons of 10 weeks of moderate and low intensity AET with UC in a small group (n = 18) of breast and colon cancer survivors after completion of treatment showed no differences in peakVO2, lower-body flexibility and body fat between the two exercise groups [54]. Both exercise groups combined showed increased peakVO2, lower-body flexibility, QoL, and energy, and decreased body fat compared to UC [54]. A three-armed RCT among 73 women with breast cancer-related lymphedema showed that 12 weeks of both high and low intensity RET are safe and effective in reducing lymphatic relative volume, improving upper and lower body muscle strength, 400 m walk test, general fatigue, body image, and breast and arm symptoms [55]. High intensity RET was superior to low intensity RET on the 400m walk [55]. Three [56–58] RCTs comparing effects of different exercise intensities are currently being conducted (Table 3).

Regarding exercise duration, physiological and psychological outcomes following 3 or 6 months of prescriptive, individualized exercise were compared with UC in a non-randomized controlled trial among 114 breast cancer survivors [59] (Table 3). Exercising for 6 months showed additional improvements in pulmonary function (forced vital capacity) and upper body muscle endurance (bench press) compared with 3 months. No significant differences between the exercise groups were found in cardiovascular endurance (treadmill time) and abdominal muscle endurance (crunches), but both showed improvements compared to UC. No differences between groups were found for forced expiratory volume in one second, leg press, lateral pull-down, shoulder press, fatigue and depression, except for affective fatigue, which improved more after 6 months than after 3 months, but showed no differences compared to UC [59]. Optimal timing of interventions Although studies have shown beneficial effects of exercise both during and after cancer treatment, little is known about the optimal timing of starting exercise interventions. A three-armed RCT in 63 survivors of breast cancer scheduled for radiotherapy comparing RET + AET during treatment with RET + AET post treatment and UC showed that both exercise groups reduced general and physical fatigue, and improved muscle strength and endurance compared to UC at 12 weeks and 3 months follow-up [60] (Table 3). In patients who exercised during treatment, improvements in global health, physical functioning, role functioning and emotional functioning compared to UC were found at 12 weeks, but not at 3 months follow-up. Improvements in physical fatigue at 12 weeks, and improvements in upper body muscle strength at 3 months follow-up were superior after exercising during treatment compared to exercising post treatment, [60] indicating that it may be more beneficial to start exercising during treatment. Two RCTs comparing early versus delayed onset of exercise are currently being conducted [61,62] (Table 3). Although it may be expected that early initiation of exercise is better, patients may experience specific barriers to exercise at different time points in the cancer trajectory, limiting them to comply with specific exercise programs early in the trajectory. Starting later would then be more effective and efficient. Therefore, more insight into the optimal timing of interventions is warranted. Mediators of exercise effects Insight into mediators of exercise programs is important for identifying and subsequently targeting critical intervention components to improve effectiveness and efficiency and to reduce the costs [40,63,64]. Few studies examined mediators of exercise interventions in cancer survivors. In uncontrolled trials and a

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L.M. Buffart et al. / Cancer Treatment Reviews 40 (2014) 327–340 Table 4 Cancer survivors’ interests and counseling and program preferences regarding PA and exercise. Reference number

[134] [135]

[136] [137]

Characteristics n Country Diagnosis

588 1284 307 106 Can Nor Can USA Mixed Mixed Mixed Brain

[138]

[139]

[140]

[141]

[142] [143]

386 397 90 50 192 90 Can Can USA Can USA USA Endometrial Bladder Breast Palliative Breast Head Neck 52 (32) 74 14.9 62.5 (14.7) (25.9) 64.5 (10.6) 30% < 65 57.1 61.5 64 65% < 65 (12.0) (13.1) (11.5) 0 74.3 0 40 100 78

Months since diagnosis, mean (SD) 73.6 (52.1) Age in years, mean (SD) 38.2 (5.6) Gender, % male 30

42.9 (15.5) 56.6 (13.8) 44

28; 6– 18 60.8 (11.5) 41.1

28; 6– 178 44.8 (12.0) 49.1

COUNSELLING Interest Yes No Maybe

b

c

51.7 19.5 28.8

55 24 21

60.3 15.9 23.7

29.2 37.7 16

55.7 22.6 14.2

17.2 2.2 49.6

12 7 53

9.8 4.6 76.8

18.7 12.7 40.9

20.5 12.7 40.1

4 3 71

5 2 25

11 6 11

13.8

27

4.9

17.3

15.9

12

26

6.5

2

3.6

10.4

11

9

47.2 11.2 15.1 63.5 38.5 45.9

95 0 2 2 1

85.3 1.7 6.5 6.5 0

82.8 3.4

77.7 3.5

55 3

11.8

17.7

Source Physician Nurse Exercise specialist from cancer center Exercise specialist from health club or community center Cancer patient/survivor Delivery Face-to-face Telephone (self-help) video Print material Internet By e-mail Other

1

2

[144]

[145]

[146]

[147] Total

483 USA Breast (rural) 39.0 (21.5) 63 (12)

345 703 431 5452 Can Can Can Ovarian Kidney NHL Mean  73.6 (52.6) 60.2 (12.6) 0

69.0 (55.5) 65.0 (11.1) 63

62 (25) 61 (13) 52

47.5 29.6 22.9

44 24.8 31.2

51.7 51 22.9 23 25.4 25

9 0.6 18

21.9 12.2 55.7

16 7 47

6

22

19.1

19

2

0

2

19.6

7

7 6

61 0 7 5 0

40 0 9 3 1

47 0.8 6 11 3

34 6.1 13.5 50 13.9 19.5

30

3

68 3 6 21 8 9 2

0

3

50 57 39

PROGRAM Interested Yes No Maybe

48 21.7 30.3

67 9 24

29 38 16

56 23 14

41.5 18.3 35.3

44.5 18.8 36.6

78 8 14

38 26 36

33 25 42

33 26 41

53.8 13.3 32.9

34.2 28.5 37.3

55.4 49 18.9 19 25.7 31

Able to Yes No Maybe

62.2 12.5 25.3

74 6 20

30.2 32.1 17

65.1 46.4 8.5 18.3 18.9 35.3

47 15.7 37.3

58 8 34

64 14 22

51 17 32

55 15 30

64.6 6.6 28.9

48 18.9 33.1

52.9 59 15.5 13 31.6 28

25.8

10

32

18.1

21.4

17.9

17

27.7 19

10.1 16.6 33.5 14.1

14 46 26 5

17 24 23 5

6 26.8 39.3 9.7

10.6 39.1 21.4 7.5

12.6 25.5 25.8 18.2

4.7 22.4 36.5 20.9

16.6 11 29 38.2 30 18.1 12

17 26

44 34

35.8 6

21 25

54 0

50

41

4.7

23.8 11.7

41

4.7

29 15.9

39.1 20.6

30.8 29 12.7 16

26

4

26.4

51.9 31.8

22

30

16

35

30

38

30.5

46.3 43.5 53.5

20 35

16 40 13

25.5 9.4

43.4 32.7 22.6 24.3

53.7 11.4

37 16

84 0

29 36 15

47 33 8

25 38 19

48.9 20.9

46.8 52 32.5

16 42.6 38 17.3 27

11.2

23

19

10.2

7.8

33

0

6

0

3

6.9

7.3

12.6 12

34 32 16

48 23 5

51.3 12.3 12.9

36.6 15.6 11.4

40 32 4

52 13 20

47 17 15

53 11 20

48.9 15 17.4

58.3 25.9 30.3

41.3 45 17.4 22 18.7 18

*

*

*

33 14 14 23

81 4 4 4

72

55.5 7.5 7.5 3

45.5 4.5

48.5 8.5 8.5 5

62.7 3.3 4.4

69.4 23.8 16.9

55 12 10 12

Preferred timing At the time of diagnosis, before treatment During treatment Immediately after treatment At 3–6 months after treatment At least 1 year after treatment

Company Alone 16.7 With other cancer patients/ 16.9 survivors Family/ friends/ spouse/ coworker 31.6 Location Outside around my neighborhood At home At a community/local fitness center At a cancer center Time of the day Morning Afternoon Evening Mode Walking Cycling Swimming Resistance training

*

45.7 16.6 20.8

51 19

53

68.6

81.1 16.1

44

36

26.9

20.5

61 24 15 24

12

9.5

22.5 24

Intensity (continued on next page)

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L.M. Buffart et al. / Cancer Treatment Reviews 40 (2014) 327–340

Table 4 (continued) Reference number

[136] [137]

[138]

[139]

[140]

Light Moderate Vigorous

[134] [135] 11 77 9

35 56 4

26.3 61.1 7.7

26.1 61.7 6.7

45 47 3

Variability Same each time Different each time

34 66

51 49

40.9 59.1

49.1 50.9

22 78

Supervision Supervised Unsupervised

64 36

43 57

53.1 46.9

29.4 70.6

66 34

Structure Spontaneous/Flexible Structured/scheduled

21 79

47 53

35.5 64.5

56.9 43.1

46 54

[141]

[142] [143]

[144]

[146]

[147] Total

22 64 7

26 50 6

26 65 4

35.3 58.4 6.3

23.1 23 62 64 9.7 7

27 21

35 23

64.7

28 38.9 54

12 55

22 47

40.8 59.2

41.5 45 58.5 49

66 10

62 24

49.2 50.8

45 55

25 49

[145]

41 57

NHL = Non-Hodgkin lymphoma. aBefore diagnosis. b During treatment. c After treatment. * Summer and winter averaged.   weighted according to sample size. Proportions do not add up to 100 due to missing categories (e.g. no preference, other).

cross-sectional study, exercise effects on QoL were found to be mediated by fatigue [65–67]. As another example, the effects of an 8-week mixed modality community-based group exercise and information support intervention on QoL of patients with breast cancer was mediated by exercise familiarity and self-efficacy but not by social support [68]. In addition to personal and psychosocial working mechanisms, biological factors (e.g. function of immune and endocrine systems) and physiological factors (e.g. neuromuscular function) may mediate the effect of PA and exercise on relevant health outcomes, including fatigue, QoL and survival.

Immune system function Cancer and its treatments may alter immune system function [69]. C-reactive protein (CRP) is a sensitive marker of low-grade systemic inflammation [70]. In cancer survivors, elevated concentrations of CRP have been found to be associated with fatigue [71] and reduced overall and disease-free survival [72]. Exercise can have a beneficial effect on the immune system, [73–76] including cancer survivors [16,69]. Reductions in CRP after exercise [16] were found in an observational study among breast cancer survivors [77] and RCTs among survivors of breast, [78] lung, [79] and prostate cancer [80]. Pro-inflammatory cytokines (e.g. tumor necrosis factor-alpha (TNF-a) and Interleukin (IL)-6) may be released in response to the tumor or cancer treatment, and may promote tumor growth and angiogenesis [81–83]. TNF-a and IL-6 have been associated with cancer-related anemia, [83] cachexia, [84] loss of muscle mass, [84,85] and cancer-related fatigue [86,87]. PA and exercise may have an anti-inflammatory effect in cancer survivors, [88] as cytokines may be expressed and released by muscle fibers [89– 92]. However, no change in IL-6 levels after exercise was found in 20 patients with breast cancer [93]. Comparably, a study in 10 patients with prostate cancer did not find changes in resting serum concentrations of IL-6 and TNF-a after a 20-week resistance exercise program, but increased IL-6 levels were found after acute resistance exercise [94]. Exercise improved Natural Killer cell cytotoxity among cancer survivors, [16,69] indicating improved immune function. Other beneficial effects included increased lymphocyte proliferation and granulocyte cell counts. Although evidence is still preliminary, PA and exercise may be associated with beneficial changes in inflammation and immunity [16]. Future studies among cancer survivors should examine immune system responses to exercise and their mediating role on reducing fatigue, and improving QoL and survival.

Endocrine function Insulin, IGF, and IGF binding proteins (IGFBP) are important regulators of energy metabolism and growth, and may also be involved in tumor development and progression. High insulin levels have been associated with increased risk of tumor recurrence or death in survivors of breast [95,96] and colon cancer [97,98]. In addition, increasing evidence suggests that insulin, IGF and IGFBP may have an important mediating role in the effect of exercise on cancer risk and prognosis. Recently, Ballard-Barbash et al. [16] systematically reviewed studies among cancer survivors examining associations between PA and biomarkers. One observational study [77] and four RCTs [99–102] evaluated effects of PA on insulin, IGF and IGFBP among breast cancer survivors [16]. Higher levels of PA were found to be associated with lower levels of C-peptide (marker of insulin secretion) and leptin, and higher levels of IGF-1, but no association was found for IGFBP-III [77]. Results from RCTs provide preliminary evidence that PA may result in beneficial changes in the circulating levels of insulin and insulin-related pathways, which may be more pronounced for obese or sedentary women who generally have higher serum insulin levels at baseline, and for women who are not taking Tamoxifen [16]. Weighted-mean effect size of the effect of post-treatment PA on IGF-1 was found to be significant but small-to-moderate [9]. No changes were reported for insulin and IGFBP-III, and evidence was insufficient for IGF-II and IGFBP-I [9]. The number of studies on the effects of PA on insulin, IGF and IGFBPs during treatment was too small to draw conclusions [9]. Three RCTs in prostate cancer survivors on androgen deprivation therapy (ADT) [45,80,103] showed consistent evidence that exercise does not alter prostate-specific antigen (PSA) or testosterone levels, [16] however, the effect on survivors not on ADT is unclear. Studies on the effect of PA on biomarkers, such as serotonin, cortisol, bilirubin [93] or others are limited or nonexistent [16]. Future studies among cancer survivors should further explore the effects of PA on biomarkers of endocrine function and their mediating role in the association between PA and health outcomes. Neuromuscular function Cancer and its treatment may affect neuromuscular function. Peripheral neuropathy has emerged as a side effect of several chemotherapeutic agents including thalidomide, [104,105] paclitaxel [106,107], and oxaliplatin [108–110]. Cancer treatment may also damage the muscle itself. Several case reports describe chemotherapy-induced myopathy or myopathy-related disorders among cancer survivors [111–113]. Deconditioning, neuropathy and myopathy may lead to PA avoidance and consequently to

L.M. Buffart et al. / Cancer Treatment Reviews 40 (2014) 327–340

muscle atrophy. Sarcopenia (age-related loss of skeletal muscle mass and strength) is present in many cancer survivors, and may be associated with poor outcomes including increased fatigue, reduced QoL, and higher mortality risk. Sarcopenia has been associated with time to tumor progression and overall survival after breast cancer [114–115]. Also, androgen deprivation therapy (ADT), which is used as adjuvant therapy for patients with prostate cancer, may result in toxicity-related musculoskeletal deficits, including loss of skeletal muscle and strength, reducing physical function and QoL[116–119]. Exercise may improve muscle strength [9] and reverse muscle loss, [116] thereby reducing the acceleration of sarcopenia. Combined resistance and aerobic exercise has been demonstrated to improve muscle mass and strength in patients undergoing ADT for prostate cancer [80,120]. Further knowledge on the detrimental effects of various types of cancer treatment on muscle mass and neuromuscular function, and potential counteractive effects of PA and exercise is necessary. The use of voluntary and electrically stimulated contractions may be helpful in identifying these changes in contractile muscle properties (e.g., force production and rate of force development and relaxation) [121]. How to motivate cancer survivors to exercise? Traditionally, exercise trials were designed as efficacy trials to examine whether the intervention produced the intended effect on health outcomes under ideal circumstances [122]. The effectiveness, which refers to whether an intervention works in ‘‘real-world’’ conditions, largely depends on the motivation and adherence of patients [122]. To improve the effectiveness of exercise, it is essential to improve the uptake, dissemination and maintenance of PA and exercise interventions. Common barriers to PA among cancer survivors include physical discomfort, feeling sick, having low mood, feelings of self-consciousness relating to physical appearance, fatigue, fear of overdoing it, and being too busy [123–128]. Also, socio-demographic and clinical variables, smoking, alcohol consumption, obesity as well as attitude, self-efficacy, and intention may play a role [129–131]. Specific PA barriers may vary between patient groups [128] and exercise modes. To be able to increase adoption and maintenance of a physically active lifestyle, we need to obtain insight into barriers to specific modes of exercise, to develop strategies that help patients overcome these barriers, and to identify the most effective formats of delivering PA and exercise interventions (e.g. home-based, supervised, hospital-based, internet-based) and whether or not this should be combined with nutrition and/or psychosocial support interventions. Incorporation of behavior change techniques may further assist with PA adoption and maintenance [122]. Development of interventions to improve PA behavior – i.e. behavior change trials-, should be theory-based incorporating a clearly defined set of behavioral change techniques [132,133]. PA participation and adherence can also be influenced by patients’ preferences. Previous studies have investigated patients’ interests in PA and exercise and their preferences regarding exercise programs in various groups of cancer survivors [134,147] (Table 4). A summary of these studies showed that most patients were interested in receiving PA information, preferably by an exercise specialist from a cancer center, and face-to-face (Table 4). Most patients were interested in an exercise program, feel able to participate, prefer to start exercising after completion of therapy, at moderate intensity, alone, at home, and in the morning. Walking is the preferred type of exercise for most patients, both in summer and in winter. Some patients prefer a different activity each session, whereas others prefer the same activity each time. Most patients prefer unsupervised exercise with a flexible structure (Table 4). However, patients’ interests, counseling and program

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preferences depend on age, current PA level, employment status, education, income, the presence of overweight or obesity, and medical variables including the type and stage of cancer, time since diagnosis, type of treatment, and the presence of comorbidities [134–139,141–147]. Also self-efficacy, enjoyment, social support, perceived barriers, and the presence of depressive symptoms and fatigue determine exercise preferences [142,144]. For optimal participation in and adherence to PA and exercise programs, it is necessary that they fit with patients’ interests, abilities, opportunities, and preferences while being aware of the therapy intent of the exercise prescription. Conclusions Current PA guidelines for cancer survivors are generic. It is necessary to move from a one-size fits all approach to specific PA guidelines tailored to the characteristics, needs, capabilities and preferences of individual patients. More research is needed to be able to develop specific guidelines for a given exercise prescription (e.g. mode, frequency, intensity, duration), for a given cancer site at a particular phase of the cancer trajectory, disease impact and treatment side-effects, and for specific outcomes. These studies should focus on identifying clinical, personal, physical, psychosocial, and intervention moderators explaining ‘which’ interventions work ‘for whom’ and ‘under what circumstances.’ It is time to move towards second generation studies that compare different exercise modes, frequencies, intensities, duration and timing. Further, more insight into the working mechanisms of exercise interventions on health outcomes in cancer survivors is needed to improve the efficacy and efficiency of interventions. Future studies should identify the mediating role of personal, psychosocial, immunological, endocrine, and physiological factors in the exercise intervention effects on health outcomes among cancer survivors. For optimal uptake of PA and exercise interventions, it is necessary that existing programs embrace interests and preferences of individual patients or patient groups. Conflict of interest statement All authors have declared no conflicts of interest. Authorship All authors have made a substantial contribution to the conception and design of the study, drafting or critically revising the manuscript, and approved the version to be submitted. Acknowledgements The contribution of LMB was funded by a ‘Bas Mulder’ grant of the Alpe d’HuZes foundation, which is part of the Dutch Cancer Society, a fellowship granted by the EMGO Institute for Health and Care Research, and a travel grant funded by the Edith Cowan University. The contribution of DAG was funded by a Movember New Directions Development Award obtained through Prostate Cancer Foundation of Australia’s Research Program. All sponsors had no involvement in the content of the manuscript and in the decision to submit the manuscript for publication. References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. [2] Australian Institute of Health and Welfare. Cancer survival and prevalence in Australia. Cat no CAN 38, 2008, Canberra.

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