Exercise and Cancer Treatments

Exercise Training Manages Cardiopulmonary Function and Fatigue During and Following Cancer Treatment in Male Cancer Survivors Carole M. Schneider, PhD, City C. Hsieh, PhD, Lisa K. Sprod, MS, Susan D. Carter, MD, and Reid Hayward, PhD

This investigation determined the cardiopulmonary function and fatigue alterations in male cancer survivors during treatment as well as following treatment utilizing similar exercise assessment protocols and individualized, prescriptive exercise interventions. The study included 45 male cancer survivors that were referred by local oncologists. Following a comprehensive screening and physical examination, cardiovascular endurance, pulmonary function, and fatigue were assessed leading to the development of 12-week individualized exercise prescriptions and exercise interventions. The cancer survivors were divided into during treatment (DTm) and following treatment (FTm) groups. Repeated-measures analysis of variance and analyses of covariance were used to compare pre- versus postintervention and between groups. Cardiopulmonary function was maintained in the DTm, whereas the FTm showed significant reductions in resting heart rate (P < .05) with concurrent increases in predicted VO2max and time on treadmill (P < .05) postexercise intervention. Fatigue levels did not increase in the DTm group, whereas the FTm group showed significant reductions in behavioral fatigue, affective fatigue, sensory fatigue, cognitive/mood fatigue, and total fatigue (P < .05) after the exercise intervention. The results of the current study suggest that moderate intensity, individualized, prescriptive exercise intervention maintains or improves cardiovascular and pulmonary function with concomitant reductions in fatigue in cancer survivors during and following cancer treatment. Exercise appears to be a safe, efficacious strategy for improving physical fitness in cancer survivors during and following treatment. Keywords: cancer survivorship; exercise training; cardiopulmonary function; fatigue

Worldwide 5.8 million males are diagnosed with cancer each year. Cancers of the lung, prostate, stomach, colon, and liver account for the majority of cancer in males worldwide,1 whereas prostate, lung, and colon DOI: 10.1177/1534735407305871

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compose the major cancer types in the United States.2 However, the mortality rate from cancer is significantly decreasing, thus there are increasing numbers of cancer survivors. In the past 5 years, it is estimated that worldwide there are 10.2 million male cancer survivors living with a history of cancer.3 The decline in death rate is, in part, due to early detection and advancements in treatments.4 Cancer treatments are effective in destroying abnormal cancer cells; however, in the process there is destruction of normal, healthy tissue. The destruction of cells in healthy tissue and organ systems can be debilitating.5 For example, surgery (eg, radical prostatectomy), radiation therapy, chemotherapy, and hormonal therapy (eg, androgen deprivation therapy) have acute and chronic effects on physiological systems such as the cardiovascular and pulmonary systems.5-9 Cardiovascular toxicity can lead to cardiomyopathy, pericarditis, electrocardiographic abnormalities, mucosa epithelial cell injury, inflammatory responses in the vasculature leading to vascular dilation, increased capillary permeability, and decreased perfusion of body tissues. Pulmonary toxicity can result in abnormal development of the pulmonary tissue and pulmonary fibrosis.5,7 The effects of these toxicities manifest into symptoms such as reduced cardiac output and stroke volume, leading to lower oxygen and nutrient delivery, decreased lung capacity causing reduced functional work capacity, and psychological alterations such as depression and severe debilitating

CMS, LKS, SDC, and RH are at Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Greeley; CCH is at the National HsinChu University of Education, Hsinchu City, Taiwan; SDC is at the Regional Breast Center of Northern Colorado, Greeley. Correspondence: Carole M. Schneider, PhD, Rocky Mountain Cancer Rehabilitation Institute, University of Northern Colorado, Campus Box 6, Greeley, CO 80639. E-mail: carole.schneider @unco.edu.

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Schneider et al fatigue. These toxicities and concomitant symptoms profoundly influence the quality of life of cancer survivors.5,9,10 A growing body of research is showing that exercise interventions can help cancer survivors during treatment and following treatment. Studies11-15 on exercise benefits have documented improvements in functional (work) capacity and cardiopulmonary function with concomitant decreases in depression, fatigue, and other symptoms in cancer survivors during or following various types of cancer therapies. Thus far, research investigating the effects of exercise on cancer survivors reports results during treatment or following treatment utilizing different assessment criteria, and yet compares exercise outcomes across investigations. Additionally, a vast majority of studies11-14 implement generalized exercise interventions that are not based on the health of each cancer survivor. Generalized exercise interventions have the potential to exacerbate the negative side effects of cancer treatments.15 Therefore the purpose of this investigation was to determine cardiopulmonary function and fatigue alterations in male cancer survivors during treatment as well as following treatment utilizing similar exercise assessment protocols followed by individualized, prescriptive exercise prescriptions and individualized exercise interventions.

Methods Participants The study included 45 male cancer survivors, mean age 65.6 ± 10.9 years with the during treatment (DTm) group averaging 67.1 ± 9.5 years and the following treatment (FTm) group averaging 64.0 ± 12.5 years. Thirty-seven participants had completed radiation and/or chemotherapy treatments, whereas 8 participants were undergoing cancer treatments concurrent with the exercise intervention. The university institutional review board approved all study procedures. Detailed written and verbal information was provided to participants concerning the assessment and training protocols. Participants were informed of the voluntary and confidential nature of the study and were free to discontinue at any time. Informed consent was obtained prior to participation in the study. Assessment Participants received comprehensive screening followed by an initial medical examination prior to inclusion into the study. Cardiovascular endurance, pulmonary function, and fatigue were assessed, leading to the development of individualized exercise prescriptions. Cardiovascular endurance was evaluated using

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the 3-minute stage Bruce Exercise Test, a multistage, variable speed, and elevation treadmill protocol. Heart rate, blood pressure, oxygen consumption (predicted VO2max), time on treadmill, and oxygen saturation were obtained from the Bruce Treadmill Test results. Participants continued to a predetermined heart rate or volitional fatigue, dependent on the recommendation of the physician. Pulmonary function was assessed using a Flowmate™ spirometer, which measures forced vital capacity (FVC) and forced expiratory volume (FEV1). The participant’s measured result was compared to the predicted normal for FVC and FEV1 based on the participant’s age, gender, height, and weight to obtain the percentage of predicted.15 This yielded a percentage of the predicted FVC (FVC %pred) and a percentage of the predicted FEV1 (FEV1 %pred). The Piper Fatigue Inventory was used to assess the subscales of behavioral, affective, sensory, cognitive/mood, and total cancer-related fatigue. The behavioral fatigue subscale was used to assess the impact of fatigue on school/work, interacting with friends, and the overall interference with activities that are enjoyable. The affective fatigue subscale was used to assess the emotional meaning attributed to fatigue. The sensory fatigue subscale was used to assess the mental, physical, and emotional symptoms of fatigue. The cognitive/mood fatigue subscale was used to assess the impact of fatigue on concentration, memory, and the ability to think clearly.16 Reassessments were obtained following a 6-month individually prescribed exercise intervention. The same physiological and psychological parameters were assessed using identical protocols during the initial assessment and reassessment to obtain program effectiveness outcomes.

Exercise Intervention Certified cancer exercise specialists developed individualized exercise prescriptions and exercise interventions to meet the specific needs of each cancer survivor, based on results from the medical and cancer history, the physical examination, and the initial physiological and psychological assessments. Participants attended individualized, supervised exercise sessions 2 or 3 days per week for 6 months. Prior to each training session, the cancer exercise specialist asked each participant a series of questions that would clarify the need to alter the exercise intervention, if necessary. Questions focused on how the participant felt after the last exercise session, if the participant had any soreness or specific problems that would affect training, and if changes in medication or treatment had been implemented since the last exercise session. The exercise sessions lasted 60 minutes based on a “wholebody” approach.15 Table 1 presents an example of an

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Exercise and Cancer Treatments Table 1.

Prostate Cancer Survivor Following Treatment15 BRIEF HISTORY

Patient Name: John Age: 51 RHR: 74 bpm BP: 130/90 mm Hg Piper Fatigue Index Score: 6.5 Cancer: Prostate cancer Stage: Gleason 2 Treatment: Radical prostatectomy Adjuvant Treatment: None Treatment Status: Treatment complete

Ht: 5’8”

Wt: 199 lbs

CARDIOVASCULAR ASSESSMENT RESULTS Protocol: Bruce treadmill test Time on Treadmill (min:sec): 5:49 Predicted V02 max: 21.82 mL.kg.min

Fitness category: Low PULMONARY FUNCTION RESULTS

Protocol: Forced vital capacity (FVC) Percent of predicted: 86% Fitness category: Within Normal Limits Protocol: Forced expiratory volume (FEV1) Percent of predicted: 89% Fitness category: Within Normal Limits MEDICAL/PHYSICAL CONCERNS 1. 2. 3. 4.

Radical prostatectomy Persistent fatigue, adjust exercise intensity daily if needed to accommodate fatigue. Surgery to repair meniscus tear in left knee, weakness in left leg Medications: Zyrtec (10 mg/day); Lipitor (10 mg/day); Lunesta (2 mg/day) HEALTH STATUS

Patient completed treatment for prostate cancer 6 months ago; however, fatigue persists. Patient underwent arthroscopic surgery to repair torn meniscus in left knee 1 year ago but has not regained full strength in left knee. SAMPLE PROGRAM MONTH 1, WEEK 1 Aerobic 40%-45% HRR; 114-117 bpm; RPE: 3; 3 days per week; 20 minutes duration Strength/Endurance Resistance bands and weight machines; 2 sets; 10 repetitions; RPE: 3 Begin with weight machines to learn movements and set neuromuscular patterns. As strength and comfort increase, progress to resistance bands and dumbbells to improve unilateral strength. Avoid deep squatting, bending, or twisting movements. Emphasize whole-body workouts each training session. Exercise Intervention Monitor the patient prior to each session, assessing his health and fatigue status. Adjust the workload (duration and intensity) accordingly. Frequency, duration, and intensity will vary dependent on the patient’s fatigue status. Monitor form on all exercises, neutral back, soft knees while standing, firm but not tight grip on weights and rails of treadmill, and proper breathing. The workout should consist of a warm-up, short stretch, the exercise activity phase (cardiovascular & strength training), and the cooldown/stretching phase. The patient should have a water bottle with him at all times for hydration. The patient will wear a heart rate monitor, use a pulse oximeter, and blood pressure will be taken before and after the workout. Warm-up: Walking on the AquaCiser underwater treadmill at 1.0 mph for 5-10 minutes, RPE: 2 Aerobic Activity: Walking on the AquaCiser underwater treadmill at 1.3 mph for 5 minutes, RPE: 3 Walking on the AquaCiser underwater treadmill at 1.5 mph for 10 minutes, RPE: 3 Walking on the AquaCiser underwater treadmill at 1.3 mph for 5 minutes, RPE: 3 Standing stretches: Be sure to hang on to something for support.

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Schneider et al Table 1.

(continued)

Resistance Activity: Right side is always worked first unless complications on right side RPE: 3 70 lb; 10 repetitions; 2 sets Chest Press machine: 70 lb; 10 repetitions; 2 sets Shoulder Press machine: 55 lb; 10 repetitions; 2 sets Shoulder External and Internal Rotation while standing 10 lb dumbbells; 10 repetitions; 2 sets Lat Pulldown machine: Bicep Curls while seated on Fit Ball 25 lb dumbbells; 10 repetitions; 2 sets Overhead Tricep Extension while seated on bench: 10 lb dumbbell; 10 repetitions; 2 sets Step-ups onto 12” bench: Have patient use wall for support Alternate legs 10 repetitions (5/leg); 2 sets Hamstring Curl on Floor with Fit Ball: 10 repetitions; 2 sets Standing Calf Raises: Standing on floor, have patient come up on toes then lower down to the floor 10 repetitions; 1 set Fit Ball Pelvic Motions: Anterior-posterior tilts Lateral movements Circular motions, both directions 10 repetitions each action; 1 set Crunches on Fit Ball: Hands crossed over chest; 10 repetitions; 2 sets Cool-Down: Walk on treadmill at 2.0 mph for 5-10 minutes, RPE: 2 Follow treadmill walking with stretching. Assist, if needed, for correct positioning. Stretch hamstrings and quadriceps, latissimus dorsi, biceps, triceps, shoulders, calves, lower back and abdominals, neck and chest. Be sure to monitor heart rate, blood pressure, and pulse oximetry before patient leaves facility. Reassessment: Following 6 months of exercise training, John was able to significantly improve on all fitness parameters. Initial Assessment: Time on Treadmill (min:sec): 5:49; Predicted V02 max: 21.82 mL.kg.min Percent of predicted Forced vital capacity (FVC): 86% Percent of predicted Forced expiratory volume (FEV1): 89% Post 6-month exercise intervention following treatment assessment: Time on Treadmill (min:sec): 9:30: Predicted V02 max: 30.22 mL.kg.min Percent of predicted Forced vital capacity (FVC): 95% Percent of predicted Forced expiratory volume (FEV1): 94% RPE = rating of perceived exertion (Borg 0-10 scale); ROM = range of motion.

individualized exercise intervention for a prostate cancer survivor following cancer treatment. Each exercise session was individualized for the cancer survivor but generally included a 10-minute warm-up and 40 minutes of aerobic exercise, resistance training, and flexibility, and concluded with a 10-minute cool-down. Exercise intensity was based on the cancer survivors’ treadmill assessment results and ranged from 30% to 55% of heart rate reserve (HRR) depending upon the participants’ health status. The Karvonen, or percent

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HRR method, was used to determine exercise heart rate utilizing the formula (exercise target heart rate = [(220 – age) – HRrest] × %exercise intensity + HRrest).15 The mode of aerobic exercise selected for each participant was based on the mode offering the greatest anticipated benefit. Options included outdoor or treadmill walking, stationary cycling, recumbent stepping, and walking on an AquaCiser underwater treadmill. Resistance training and flexibility consisted of exercises emphasizing all of the major

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Exercise and Cancer Treatments Table 2.

Initial Characteristics of Male Cancer Survivors

Variable

DTm Group (n = 8)

FTm Group (n = 37)

67.1 ± 9.5 175.4 ± 9.9 96.1 ± 19.8 75 75 38 3 2 1 0 0 0 1 0 1 0

64.0 ± 12.5 175.7 ± 7.3 87.7 ± 17.2 73 46 41 18 7 4 4 1 1 0 1 0 1

Table 3.

Variable Age (yr) Height (cm) Weight (kg) Surgery (%) Chemotherapy (%) Radiation (%) Prostate (n) Colon (n) Hodgkin’s (n) Lung (n) Bladder (n) Melanoma (n) Pancreatic (n) Rectal (n) Testicular (n) Throat (n)

DTm = during treatment; FTm = following treatment.

muscle groups. The exercise sessions concluded with an extremely low-intensity cool-down targeting all of the major muscle groups. Follow-up examinations revealed that participants’ adherence to the exercise intervention was 74.2%.

Statistical Analyses Data are presented as means ± SD. Participants’ characteristics in the 2 groups were compared using independent t tests. The main effect of supervised exercise training was determined pre- to postexercise intervention using repeated-measures analysis of variance (ANOVA). Following main effects significance, Tukey HSD post hoc tests were used to determine where significance occurred. The primary analyses compared changes from pre- to postexercise intervention and between treatment groups using univariate analyses of covariance (ANCOVA) procedures in which the postvalue was the dependent variable, the prevalue of the same variable was the covariate, and treatment group was the grouping variable. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software package (SPSS Inc, Chicago, IL). Significance was set at a probability of ≤ .05.

Results Forty-five male cancer survivors were referred by their oncologists for participation in this study. Thirty-seven participants had completed treatment (surgery, radiation, and/or chemotherapy) (FTm), whereas 8 men were undergoing cancer treatment (DTm) during the exercise intervention. The cancer survivors’ initial characteristics are shown in Table 2. There were no significant age, height, or weight differences between groups (P > .05). Types of cancer and cancer treatments are also presented in Table 2. As can be seen,

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Cardiopulmonary Function Pre- and Post-Exercise Intervention

N

Systolic blood pressure (mm Hg) DTm group 8 FTm group 37 Diastolic blood pressure (mm Hg) DTm group 8 FTm group 37 Rest heart rate (beats/min) DTm group 8 FTm group 37 FVC %pred DTm group 8 FTm group 37 FEV1 %pred DTm group 8 FTm group 37 pVO2max (mL/kg/min) DTm group 6 FTm group 28 Treadmill time (min:sec) DTm group 6 FTm group 29

Pre

Post

132 ± 14 127 ± 13

124 ± 10 126 ± 10

84 ± 9 77 ± 9

80 ± 8 74 ± 8

85 ± 17 81 ± 16

76 ± 8 75 ± 9*

93.4 ± 24.8 93.5 ± 20.1 95.6 ± 21.0 96.9 ± 24.6 96.9 ± 27.8 97.5 ± 20.6 88.4 ± 25.4 88.6 ± 26.9 25.6 ± 5.0 27.1 ± 4.4 21.3 ± 5.0 24.8 ± 5.0* 6:20 ± 1:43 6:07 ± 2:26** 5:38 ± 2:29 7:17 ± 2:09*

DTm = during treatment; FTm = following treatment; FVC %pred = forced vital capacity % of predicted; FEV1 %pred = forced expiratory volume % of predicted; pVO2max = predicted maximal oxygen consumption. *P < .05 pre to post. **P < .05 DTm vs FTm.

many of the cancer survivors had multiple adjuvant treatments. Table 3 shows the cardiopulmonary function changes in DTm and FTm groups from pre- to postexercise intervention. Resting heart rate, pVO2max, and time on treadmill showed significant improvement in the FTm group after the supervised exercise intervention (P < .05), whereas there were no significant improvements in any of the cardiopulmonary variables for the DTm group after the supervised exercise intervention (P > .05). Furthermore, the ANCOVA analysis between the DTm and FTm groups showed that the exercise time on the treadmill in the FTm group was significantly increased compared to the DTm group. Table 4 displays alterations in the 4 fatigue domains and total fatigue from pre- to postexercise intervention for the DTm and FTm groups. The exercise intervention resulted in significant reductions in behavioral fatigue, affective fatigue, sensory fatigue, cognitive/ mood fatigue, and total fatigue (P < .05) in the FTm group. However, the male cancer survivors in the DTm group showed no significant reductions in the 4 fatigue domains or in total fatigue (P > .05) after the exercise training intervention.

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Schneider et al Table 4.

Fatigue Pre- and Post-Exercise Intervention

Variable Behavioral fatigue DTm group FTm group Affective fatigue DTm group FTm group Sensory fatigue DTm group FTm group Cognitive/mood fatigue DTm group FTm group Total fatigue DTm group FTm group

N

Pre

Post

7 36

4.10 ± 3.20 3.62 ± 2.68

3.33 ± 3.50 2.12 ± 2.22*

7 37

4.69 ± 3.40 4.30 ± 2.89

4.14 ± 3.69 3.01 ± 2.69*

7 37

5.11 ± 2.66 4.69 ± 2.47

4.63 ± 3.54 2.96 ± 2.18*

7 37

4.09 ± 2.53 3.70 ± 2.21

3.24 ± 2.80 2.89 ± 1.94*

7 37

3.78 ± 2.90 4.04 ± 2.33

3.79 ± 3.22 2.67 ± 2.06*

DTm = during treatment; FTm = following treatment; Fatigue scores = 0 (no fatigue) to 10 (severe fatigue). *P < .05 pre to post.

Discussion This investigation determined cardiopulmonary function and fatigue alterations in male cancer survivors during treatment as well as following treatment utilizing similar exercise assessment protocols followed by individualized, prescriptive exercise prescriptions and individualized exercise interventions. Researchers17,18 investigating the physiological and psychological outcomes of exercise in cancer survivors compare their findings across investigations regardless of where survivors are in their cancer experience (eg, during treatment versus following treatment). Additionally, researchers use different assessment protocols that give varying results (eg, field assessments such as the 12-minute walk test versus controlled laboratory treadmill protocols). Once fitness assessments are completed, the same generalized exercise interventions are implemented for the cancer survivors without taking into account health status. It is imperative that exercise be individualized to the specific needs of the cancer survivor to prevent exacerbation of the physiological toxicities and psychological stress that occur as a result of cancer treatments. It is well documented15,19,20 that the exercise dose (frequency, duration, intensity) has a profound influence on the immune system in a healthy population. Moderate exercise has a positive effect on the immune system, whereas intense exercise has a negative effect on the immune system. Therefore it seems prudent to exercise cancer survivors at a moderate intensity inasmuch as many survivors have an already compromised immune system due to treatment. To date, there is little information regarding the specific effects of various exercise

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intensities on cancer survivors, and thus it remains a fertile ground for future research. In addition, because the fitness and health status of each cancer survivor is variable, it necessitates individualizing the exercise regimen. As a result of a moderate-intensity individualized, prescriptive exercise intervention, the current study found that cardiopulmonary function was improved with concomitant reductions in fatigue in male cancer survivors following treatment and was maintained in survivors during cancer treatment. Male cancer survivors who had completed treatment showed cardiopulmonary improvements in resting heart rate (−7.4%), predicted maximal oxygen consumption (+16.4%), and the length of exercise time on the treadmill (+29.1%) as a result of the exercise intervention. Additionally, male cancer survivors who were currently undergoing cancer treatment were able to maintain their prior cardiopulmonary fitness and fatigue level. Although survivors in the DTm group did not demonstrate measurable improvements in cardiopulmonary fitness or fatigue, the fact that cardiopulmonary fitness and fatigue did not decline indicates that the exercise intervention was safe for these cancer survivors and that it may offset the deleterious effects of treatment. One of the most significant obstacles for effective cancer treatment is the potential for debilitating treatment toxicities. These toxicities limit the utilization of many cancer drugs because of dose-dependent cardiopulmonary toxicity. As a result, many cancer survivors who may benefit from continued use of an effective chemotherapy drug must switch to less effective therapies, thus compromising the probability of cure. Based on the results of the current study, exercise appears to be a successful strategy for limiting the toxicities and symptoms that occur in cancer survivors both during and following treatment, leading to an improved quality of life. The mechanisms by which exercise training benefits cancer survivors during or following treatment continue to be elusive. Our laboratory21 investigated potential cardiovascular benefits of exercise training in an animal model following androgen deprivation therapy. We found that exercise training protected against cardiac dysfunction by preserving the distribution of cardiac myosin heavy chain distribution. Likewise, other studies from our laboratory demonstrate a cardioprotective effect of exercise training during doxorubicin chemotherapy treatment.22 In these experiments, the preservation of cardiac function coincided with the prevention of chemotherapy-induced activation of apoptotic signaling. Additionally, we have shown that exercise training preserved intrinsic cardiovascular function following treatment with various

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Exercise and Cancer Treatments chemotherapeutic agents.23,24 These protective effects were associated with an exercise-induced increase in endothelial nitric oxide synthase, myocardial heat shock protein content, a prevention of chemotherapyinduced myocardial lipid peroxidation, and reduced mortality following treatment. These findings provide a starting point for future mechanistic studies in human cancer survivors to determine the therapeutic value of exercise training during or following cancer treatment.

Conclusion According to the current study, cancer survivors respond differently to exercise depending on where they are on the cancer continuum. Regardless of when exercise is initiated, it appears to be a safe, efficacious strategy to maintain or improve physical and mental well-being in cancer survivors. However, it is critical that exercise be individualized to the specific needs of the cancer survivor to prevent exacerbation of the physiological toxicities and psychological stress that occur as a result of cancer treatments. References 1. Cancer Research UK. Cancer Worldwide⎯The Global Picture. Available at: http://info,cancerresearchuk.org/cancerstats/ geographic/world. Accessed March 1, 2007. 2. American Cancer Society. Statistics 2007. Available at: http://www.cancer.org/docroot/stt/stt_0.asp. Accessed March 2, 2007. 3. Global Cancer Statistics, 2002. Incidence and Mortality by Sex and Cancer Site Worldwide. Available at: http://caonline.amcancersoc .org/cgi/content/full/ 55/2/74/TBL1. Accessed March 1, 2007. 4. Ries LAG, Wingo PA, Miller DS, et al. Annual report to the nation on the status of cancer. Cancer. 2000;88:2398-2424. 5. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 6. Brockstein BE, Smiley C, Al-Sadir J, Williams SF. Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transpl. 2000;25:885-894. 7. Chabner BA, Longo DL. Cancer Chemotherapy & Biotherapy. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. 8. Wilson JK. Pulmonary toxicity of antineoplastic drugs. Cancer Treat Rep. 1978;62:2003-2008. 9. National Cancer Institute. Information From PDQ for Patients. Available at: http://www.graylab.ac.uk/cancernet/504461.html .Accessed January 31, 2007.

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10. Fatigue Coalition. Fatigue Is Most Prevalent and Longest-Lasting Cancer-Related Side Effect. Available at: http://www.cancercareinc.org. Accessed May 5, 2000. 11. Dimeo F, Bertz H, Finde J, Fetscher S, Mertelsmann R, Keul J. An aerobic exercise program for patients with haematological malignancies after bone marrow transplantation. Bone Marrow Transpl. 1996;18:1157-1160. 12. Durak EP, Lilly PC, Hackworth JL. Physical and psychosocial responses to exercise in cancer patients: a two year follow-up survey with prostate (sic), leukemia, and general carcinoma. JEPonline. 1999;2(1). Available at: http://www.css.edu/users/ tboone2/asep/jan12b.htm. Accessed May 2000. 13. Dimeo F, Stieglitz R, Fischer-Novelli U, Fetscher S, Keul J. Effects of activity on fatigue and psychologic status of cancer patients during chemotherapy. Cancer. 1999;85:2273-2277. 14. Thorsen L, Skovlund E, Stromme SB, Hornslien K, Dahl AA, Fossa SD. Effectiveness of physical activity on cardiorespiratory fitness and health-related quality of life in young and middle-aged cancer patients shortly after chemotherapy. J Clin Oncol. 2005;23:2378-2388. 15. Schneider CM, Dennehy CA, Carter SD. Exercise and Cancer Recovery. 1st ed. Champaign, IL: Human Kinetics; 2003. 16. Piper BF, Dibble SL, Dodd MJ, Weiss MC, Slaughter RE, Paul SM. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum. 1998;25:677-684. 17. Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ, Fairey AS. Randomized controlled trial of exercise training in postmenopausal breast caner survivors: cardiopulmonary and quality of life outcomes. J Clin Oncol. 2003;21:1660-1668. 18. Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R. Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomark Prev. 2005;14:1588-1595. 19. Kajiura JS, MacDougall JD, Ernst PB, Younglai EV. Immune response to changes in training intensity and volume in runners. Med Sci Sports Exerc. 1995;27:1111-1117. 20. Nieman DC, Johanssen LM, Lee JW, Arabatzis K. Infectious episodes in runners before and after the Los Angeles Marathon. J Sports Med Phys Fitness. 1990;30:316-328. 21. Hydock DS, Wonders KY, Schneider CM, Hayward R. Androgen deprivation therapy and cardiac function: effects on endurance training. Prostate Cancer Prostatic Dis. 2006;9:392-398. 22. Chicco AJ, Hydock DS, Schneider CS, Hayward R. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. J Appl Physiol. 2006;100:519-527. 23. Chicco AJ, Schneider CM, Hayward R. Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. J Cardiovasc Pharmacol. 2006;47:182-189. 24. Hayward R, Ruangthai R, Schneider CM, Hyslop RM, Strange R, Westerlind KC. Training enhances vascular relaxation after chemotherapy-induced vasoconstriction. Med Sci Sports Exerc. 2004;36:428-434.

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