exercise intervention to modify physiologic risk factors in cancer survivors

Seminars in Oncology Nursing, Vol 23, No 4 (November), 2007: pp 275–284 275

OBJECTIVE:

To review the best current evidence

regarding the effects of exercise on

modifiable risk factors for adverse

physiologic outcomes of cancer and its

treatment.

DATA SOURCES:

Clinical practice guidelines, system-

atic reviews, meta-analyses, and

single studies.

CONCLUSION:

There is mounting evidence that exer-

cise improves fatigue, physical func-

tioning, and cardio-respiratory

fitness. Preliminary evidence suggests

that exercise also contributes to im-

provements in body weight and com-

position, metabolic risk factors, and

immune function. It may also influ-

ence disease-free and overall survival

in selected populations.

IMPLICATIONS FOR NURSING

PRACTICE:

Exercise appears to be a safe and well-

tolerated intervention that may mini-

mize or prevent adverse physiologic

outcomes of cancer and cancer

treatment.

KEYWORDS:Neoplasm, exercise, risk factor,

prevention and control, prospective

study

Carolyn Ingram, RN, DNSc, CON(C):

Associate Professor, Faculty of Health

Sciences, School of Nursing, McMaster

University, Hamilton, Ontario, Canada.

Constance Visovsky, RN, PhD, ACNP:

Associate Professor, University of Nebraska

Medical Center, College of Nursing, Omaha,

NE.

Constance Visovsky is supported by the

National Cancer Institute 5R03CA103488-

02. Carolyn Ingram is supported by Cana-

dian Breast Cancer Research Alliance grant

#16542.

Address correspondence to Carolyn In-

gram, RN, DNSc, School of Nursing, Faculty

of Health Sciences, McMaster University,

1200 Main St West, HSC – 2J32, Hamilton,

Ontario L8N 3Z5, Canada; e-mail: ingramc@

mcmaster.ca

� 2007 Elsevier Inc. All rights reserved.

0749-2081/07/2304-$30.00/0

doi:10.1016/j.soncn.2007.08.005

EXERCISE

INTERVENTION TO

MODIFY

PHYSIOLOGIC RISK

FACTORS IN CANCER

SURVIVORS

CAROLYN INGRAM AND CONSTANCE VISOVSKY

THE POTENTIAL of exercise to improve the lives of cancersurvivors is currently one of the foremost areas of researchin cancer control. In this context, the term cancer ‘‘survi-

vor’’ indicates any person who has or has had cancer, from the timeof diagnosis onward. Evidence of the benefits of exercise for cancersurvivors has mounted steadily over the past two decades particu-larly in the areas of psychological and quality-of-life outcomes1

and cancer-related fatigue.2 More recently, improvements in physi-cal functioning,3 body weight and composition,4 muscle strengthand endurance,5 and immune function6 have been reported. This ar-ticle reviews the effects of exercise on some of the adverse but poten-tially modifiable physiologic outcomes associated with cancer andits treatment; specifically, physical functioning and cardio-respira-tory fitness, fatigue, insulin regulation and metabolic syndrome,body weight and composition, and immune function. It will also dis-cuss the potential of exercise to influence disease recurrence andsurvival.

Our literature search was guided by the Oxford Centre for Evi-dence Based Medicine levels of evidence,7 which provide a systemfor ranking the strength of evidence used in clinical practice. Thissystem proceeds from the strongest evidence (level 1 ¼ high-qual-ity systematic reviews, meta-analyses, and randomized controlledtrials) to the weakest evidence (level 5¼ expert opinion, animal re-search, or inference from physiologic theory). The evidence for thisarticle included systematic reviews, meta-analyses, and high-qual-ity single studies. Systematic reviews appraise a group of similarstudies for content and quality and provide a narrative synthesis

mailto:[email protected]

mailto:[email protected]

276 C. INGRAM AND C. VISOVSKY

of the results. A meta-analysis is a systematic re-view that also provides a numeric summary of out-comes from several similar studies. This summaryyields a more precise estimate of the effect ofa given intervention than the findings of any onestudy.8 Meta-analyses use effect sizes (ES) to de-scribe how strong the effect of an intervention is.An effect of 0.2 to 0.5 is considered to be small tomoderate, 0.5 to 0.8 is moderate to large, and> 0.8 indicates a large intervention effect.9

PHYSICAL FUNCTIONING AND CARDIO-

RESPIRATORY FITNESS

D uring exercise, repetitive motion causes mus-cle hypertrophy and increased muscle mass.10

The psychological and physical symptoms result-ing from cancer and its treatment (such as depres-sion, anxiety, pain, fatigue, nausea, vomiting, andinsomnia) contribute to excessive patterns of restand precipitate muscle weakness, atrophy, andfunctional impairment. Immobility caused by com-plete or partial bed rest may further compromisethe patient’s functional ability and result in addi-tional adverse effects such as increased bone re-sorption. Some systemic treatments also inducemetabolic alterations in muscle cells, reduce theability of muscles to generate forceful contraction,and lead to muscle weakness and functional de-cline.11

Reductions in usual physical activity (PA) andexercise following the diagnosis and treatment ofcancer have been well-documented, often result-ing in physical deconditioning and functional de-cline. Furthermore, most cancer survivors do notresume their pre-diagnosis activity levels followingtreatment even if they are physically able to doso.12 Muscle weakness and atrophy following can-cer treatment can take weeks or even months toresolve.6 Diminished cardio-respiratory fitness re-sults from inactivity and is a key predictor of all-cause mortality in both men and women.13,14

Thus, cancer survivors are susceptible to a numberof inactivity-related chronic conditions that mayinfluence survival outcomes.6

Systematic Reviews and Meta-Analyses:

Physical Function and Fitness

Four systematic reviews and meta-analyses of ex-ercise interventions were found in which physicalfunctioning and cardio-respiratory fitness were

main outcomes.3,15-17 These reviews included ran-domized controlled trials and uncontrolled trials(eg, single group pretest-posttest designs) involvingpredominantly breast cancer survivors. Physicalfunctioning significantly improved in participantswho exercised.15,16 The ES ranged from 0.5 to 0.7,indicating a moderate effect of exercise on physio-logic functioning. Improvements in physical func-tioning were greater for breast cancer survivorscompared with the survivors of other cancers.15

Cardio-respiratory fitness also improved signifi-cantly for exercise participants (or, ‘for exercisers,’or ‘for those who exercised’), both during treatment(ES¼0.5) and post-treatment (ES¼0.7). However,post-treatment studies in the reviews involvedstronger research designs and methods comparedwith the during-treatment studies.

Single Studies: Physical Function

and Fitness

Four key studies that were not included in thepublished systematic reviews were also identi-fied.18-21 Two studies that included a 6-week com-bined aerobic and high-intensity resistanceexercise intervention18,19 used a single group pre-test-posttest design and reported pilot findings18

followed by a larger study.19 In these two studies,participants exercised 1.5 hours, 3 days perweek. In the pilot study (N ¼ 23), participantsexperienced a total mean increase in strength of32.5% (P < .001) and a mean increase in aerobiccapacity (VO2 max) of 16% (P< .001).18 In the fol-low-up larger study (N ¼ 82), participants experi-enced a total mean increase in strength of 40%(P < .001) and a significant increase in aerobiccapacity of 16% (P < .001).19 These were the firstknown studies that tested a high-intensity exer-cise intervention with cancer survivors. Comple-tion rates were 82.5% and 78%, respectively, anddemonstrated that cancer survivors can maintainand benefit from high-intensity exercise. Further-more, the participants reversed significant de-creases in non–intervention-related leisure timePA levels that had occurred between pre-illnessand the time of the study.

Thorsen et al20 conducted a 14-week home-based controlled clinical trial (N ¼ 111) on a sam-ple of cancer survivors with mixed diagnoses whohad completed treatment more than 1 month be-fore study enrollment. The aim was to evaluatethe effectiveness of a flexible exercise programon cancer-related fatigue. Participants received

EXERCISE INTERVENTION TO MODIFY PHYSIOLOGIC RISK FACTORS 277

exercise counseling from fitness instructors, chosetheir own modes of exercise, exercised at least twotimes per week for more than 30 minutes, and re-ceived bi-weekly follow-up calls. There was a 23%improvement in aerobic fitness (ie, VO2 max) forthe intervention group versus a 10% increase forthe control group.

Spruit et al21 examined the effects of an 8-weekpulmonary rehabilitation program in a pilot studyof 10 male and female lung cancer survivors whohad recently completed treatment. The programconsisted of daily cycling, treadmill walking, resis-tance exercise, and gymnastics. Participants be-gan the study with poor pulmonary function andexercise tolerance in addition to significant pre-existing co-morbidities. While pulmonary func-tion did not change, functional exercise capacityincreased by 43.2% (P ¼ .002) and peak exercisecapacity increased by 34.4% (P¼ .008). This studyis significant in that, to our knowledge, it is thefirst published exercise study to focus on objec-tively measured physiologic outcomes in lungcancer, which is a rarely included diagnosis in exer-cise and cancer research. Furthermore, it showedthat individuals who receive aggressive treatmentfor advanced malignancy can, given the proper sup-port, sustain and benefit from a vigorous supervisedexercise program.

FATIGUE

E xercise has been well-established as an effec-tive intervention to prevent, minimize, or de-

crease fatigue.22-24 The early pioneering work ofMacVicar and Winningham25,26 regarding the ef-fect of aerobic exercise on fatigue and functionalability made a substantial contribution to our un-derstanding of how exercise mitigates cancer-related fatigue. Home-based walking interventions,in particular, have shown effectiveness in relievingcancer-related fatigue.2,23,24 Winningham’s pro-posed Psychobiologic Entropy Model,27 based onthe relationship between deconditioning and func-tional ability, inspired a paradigm shift from restto exercise as a fatigue intervention for cancer sur-vivors. The phenomenon of cancer-related fatigueis complex and multifactorial and is not fully un-derstood. Nonetheless, there is strong evidencethat exercise mitigates the fatigue of survivorswho are experiencing a variety of cancers andtreatments, including those who have intensivetreatment or advanced disease, and regardless of

whether the intervention is supervised or unsu-pervised, aerobic or resistance, or implementedduring or after cancer treatment.22,24,28

INSULIN REGULATION AND THE

METABOLIC SYNDROME

I ncreased levels of insulin, insulin-like growthfactors (IGFs) and IGF binding protein 3

(IGFBP-3) have been associated with increasedrisk of premenopausal breast, prostate, and colo-rectal cancer through the mechanisms of en-hanced tumor growth and reduced apoptosis.29,30

In breast tissue, insulin is known to have a mito-genic effect on both normal and malignant cells,and high insulin levels have been associated witha poor breast cancer prognosis.31 Exercise hasbeen proposed as an intervention that may assistin normalizing insulin levels. It is thought to influ-ence insulin and glucose control by: increasingglucose transporter proteins, increasing post-re-ceptor insulin signaling, increasing glucose deliv-ery to muscles, and improving clearance of freefatty acids. A meta-analysis of individuals withtype II diabetes showed that exercise lowered gly-cosylated hemoglobin (H-A1c) levels by 66%.32

Similarly, in a sample of 2,996 healthy postmeno-pausal women randomly identified through theWomen’s Health Initiative, higher levels of PA,lower body mass index (BMI), and lower caloric in-take were related to lower fasting insulin levels.33

Several exercise studies have been publishedwith metabolic markers as outcomes. In onecontrolled trial,34 85 breast cancer survivors wererandomized to immediate or delayed strengthtraining over a 12-month period. Anthropometricmeasures (eg, BMI, waist circumference, weight),PA, fasting blood glucose, plasma insulin levels, in-sulin resistance, and IGFs were measured at base-line, 6 and 12 months. Immediate and delayedstrength training groups both experienced signifi-cant decreases in percentage of body fat andIGF-II and increases in lean body mass (LBM).No changes in plasma insulin, glucose, or IGF-Ilevels; insulin resistance; body weight or BMI;body fat mass or waist circumference were found.

An aerobic exercise intervention was conductedto examine the effect of exercise training on fast-ing insulin, plasma glucose, insulin resistance,IGFs I and II, and IGFBP-1 and -3 with 53 postmen-opausal breast cancer survivors.35 Women wererandomized to a 15-week aerobic program (n


¼ 25) or a control group (n ¼ 28). Exercise hadsignificant effects on IGF-I and IGFBP-3, but notthe other measures. It is possible that, becausethe intervention did not induce weight loss, thehyperinsulinemia and insulin resistance associ-ated with increased weight were not affected.Also, because blood collection took place 48hours post-exercise, the immediate effect of re-duced insulin resistance that follows exercisemay have been lost.

Metabolic syndrome, also known as ‘‘syndromeX,’’ is a cluster of metabolic abnormalities that in-cludes increased waist circumference (>102 cmin men and >88 cm in women); elevated fastingplasma glucose ($ 110 mg/dL); low levels ofhigh-density lipoprotein (HDL) cholesterol (<40mg/dL in men and<50 mg/dL in women); elevatedblood pressure ($130 and/or 85 mm Hg systolicand diastolic pressures, respectively); and high tri-glycerides ($150 mg/dL). The prevalence of meta-bolic syndrome among American adults over age20 is approximately 24%, with higher rates amongolder adults and Mexican Americans.36 Metabolicsyndrome is an important predictor for future de-velopment of diabetes and cardiovascular disease.

There is some evidence that metabolic syn-drome may be an important risk factor for cardio-vascular disease in survivors of testicular cancertreated with chemotherapy. The etiology of meta-bolic syndrome in this group is uncertain; how-ever, long-term gonadal dysfunction fromsurgery, chemotherapy, and radiation has been as-sociated with increased luteinizing hormone levelsin the presence of normal total testosterone. Nuverat al37 investigated gonadal and pituitary hor-monal function among long-term testicular cancersurvivors treated with unilateral orchiectomy andcisplatin-based chemotherapy (n ¼ 86), with or-chiectomy only (n ¼ 44), and healthy male con-trols (n ¼ 47). Median follow-up was 7 years andthe presence of metabolic syndrome was deter-mined by standard criteria. Men who received che-motherapy had significantly higher triglycerideand total cholesterol levels, total cholesterol:HDL ratios, increased BMI and waist-hip ratios,lower levels of total and free testosterone andhigher luteinizing hormone levels compared withthe healthy controls. Of those treated with chemo-therapy, 26% (n ¼ 22) developed metabolic syn-drome. Because only gonadal function wasaffected in the testicular cancer survivors, it waspostulated that it is these alterations that contrib-ute to the development of metabolic syndrome.

BODY WEIGHT AND COMPOSITION

A lthough weight loss characterizes the prevail-ing public image of cancer, weight gain and

sarcopenic body composition changes (ie, in-creased body fat mass with no increase in LBM)have been widely documented among cancer sur-vivors, particularly women who receive adjuvantsystemic therapy for breast cancer and men whoreceive androgen-deprivation therapies for pros-tate cancer.38-41 The reductions in PA followingthe diagnosis of and treatment for cancer thatplace survivors at risk for deconditioning andspiraling fatigue also increase the likelihood ofadverse weight and body composition changes.In addition, there are hormonal alterations relatedto some cancer treatments that are associatedwith changes in weight and body composi-tion.37,42,43 Maintenance of weight and preventionof increased body fat mass are important goals forreducing the risk of co-morbid illnesses such ashypertension, diabetes, and heart disease, andmay also be factors in reducing recurrence and im-proving survival.44

Body Composition

Body composition includes two compartments, fatmass and fat-free mass. Fat-free mass consists oftotal body water and LBM (eg, bone and muscle).4

Thus, alterations in body fluid, muscle, and boneare important components to consider when ex-amining body composition. Few exercise studieshave assessed changes in body weight and compo-sition.4 Of those that included body compositionas an outcome, most have targeted fat mass be-cause increased fat mass is a known risk factorfor chronic illness. In the meta-analysis by Connet al15 there was a small effect of exercise onbody composition (defined as percentage of bodyfat) in the controlled trials (ES ¼ 0.3), but nochange in body composition in the single grouppretest-posttest studies. Similar to the effect ofexercise on physical functioning,15 the effect ofexercise on body composition in breast cancersurvivors was superior to that of other cancer sur-vivors. Positive changes in body compositionamong breast cancer survivors who exercisedwere also supported by a systematic review of 14studies focused specifically on body weight andcomposition outcomes.4 In this review, four ofsix studies with body composition outcomes


reported significant differences between exer-cisers and non-exercisers. Exercisers lost 2.6% to11.7% of their body fat compared with controls,whose body fat actually increased.

Weight

Sedentary behavior contributes to weight gain.While increasing PA can have significant healthbenefits, the dose and intensity of exercise neededto induce weight maintenance or loss among can-cer survivors are not well-defined. In these indi-viduals, the hormonal and treatment factors thatmay influence metabolism are not well-under-stood, and this gap complicates our understandingof the relationship between exercise intensity andweight changes.

In four published reviews that examined theeffects of exercise on weight,3,4,16,17 participants’weight either remained stable or decreased veryslightly. It should be noted that, while weight lossis important for overweight or obese cancer survi-vors, weight maintenance is equally important forsome survivors, such as those diagnosed withbreast cancer who are at risk for weight gain. How-ever, even when weight is stable, body compositionis an important indicator of chronic illness risk,specifically, increased body fat and decreasedlean muscle mass. In a pilot study of a 16- to 24-week aerobic weight-loaded exercise intervention(supervised three times per week on a treadmill),women did not gain weight and there were no neg-ative changes in body composition except forwomen on adjuvant endocrine therapy.45 In a studyby Adamsen et al,18 subjects had a mean increasein body weight of 1% after an intensive, 6-week in-tervention (P< .009). However, there was a 2.6% (P< .03) mean decrease in skin fold measurements,the index of body fat, suggesting that the intensiveaerobic and resistance program increased partici-pants’ LBM (ie, muscle). These data underscorethe importance of assessing body composition asan outcome and not weight alone.

IMMUNE FUNCTION

C ancer treatments have adverse effects on theimmune system. Animal models and human

studies have shown that endurance training canprovide protection against cancer by increasingmacrophage and natural killer-cell cytotoxic activ-ity.46,47 The idea that exercise may enhance immu-

nity in cancer survivors has been a focus of severalinvestigations, but the results are equivocal.

Breast Cancer Studies

In a 6-month, single group pretest-posttest studyof immune function involving 24 women withearly stage breast cancer, a moderate-intensity su-pervised cycling intervention was conducted.48,49

The natural killer-cell cytotoxic activity and theconcentration of granulocytes increased (P <.05), the natural killer cell count and total whiteblood cell count remained unchanged and thelymphocytes decreased. Similarly, Fairey et al50

tested the effect of a 15-week controlled trial ofaerobic exercise on blood immune functionamong 53 postmenopausal breast cancer survi-vors. There was a significant improvement in exer-cisers’ natural killer-cell cytotoxic activity (P <.05) compared with the control group.

In contrast, Nieman et al51 investigated the im-mune effects of an 8-week combined aerobic andresistance program with 12 breast cancer survi-vors. There were no significant differences innatural killer-cell cytotoxic activity between theexercise and control groups. Hutnick et al52 testeda structured 6-month stretching, treadmill, andresistance program on lymphocyte activation inwomen with breast cancer who were receivingchemotherapy. Women were assigned to eithera formal exercise intervention (n ¼ 28) or a no-exercise control group (n ¼ 21). Exercise partici-pants had a greater percentage of CD4þ andCD69þ cells but there was no difference in plasmaand mitogen-stimulated cytokine production (in-terleukin-6 and interferon-gamma).

Non-Breast Cancer Studies

Natural killer-cell cytotoxic activity among stom-ach cancer survivors (N ¼ 35) was investigated ina randomized trial.53 Two days post-operatively,the exercise group began twice-daily moderate in-tensity aerobic exercise using arm and cycle ergom-eters. By day 14, the mean natural killer-cellactivity of the exercise group increased significantlycompared with that of the control group (P < .05).In contrast, a 3-month controlled trial of a moder-ate-intensity mixed aerobic and resistance programwith 12 peripheral blood stem cell transplant recip-ients reported that exercise had no effect on recov-ery of lymphocyte number or function.54


BONE MINERAL DENSITY

P roblems with decreased bone mineral density(BMD) in breast and prostate cancer survivors

have been well-documented.55,56 The benefits ofweight-bearing exercise for maintenance and im-provement of bone mass are also widely acceptedin non-cancer populations, especially for post-menopausal women. There are only three knownstudies that have investigated the effect of exerciseon bone outcomes in cancer survivors45,57,58 Ina small sample of postmenopausal breast cancersurvivors (N ¼ 21) with osteopenia or osteoporo-sis, a 12-month multi-component home-based in-tervention that included drug therapy, vitaminand mineral supplementation, home-basedstrength and weight training, and education on os-teoporosis resulted in improvements in BMD.57 Arandomized control trial of 66 early stage breastcancer patients receiving adjuvant chemotherapycompared aerobic and resistance exercise withusual care.58 Women in the usual care group hadthe greatest decline in lumbar spine BMD. A statis-tically significant difference was reported betweenthe aerobic exercise and usual care group (P ¼.02) but not the resistance exercise versus usualcare group or the two exercise groups. Aerobic ca-pacity and muscle strength was improved in bothexercise groups compared with usual care. Knobfet al45 conducted a 16- to 24-week weight-loadedaerobic exercise intervention with 26 womenwho were within 3 years of completing breast can-cer treatment. Women exercised on a treadmill for45 minutes three times a week with a 5-poundweight belt. There were no changes in bone re-modeling as assessed by serum biomarkers. BMDwas also assessed although dual-energy x-ray ab-sorptiometry (DEXA) is not a recommended mea-sure of change in BMD for a period of less than 12months. However, stabilization of BMD on DEXAcombined with serum biomarkers supporteda lack of change in bone turnover. Because nopharmacologic intervention is recommended forwomen at risk for osteopenia, further research topreserve bone mass and prevent bone loss amongcancer survivors is needed.

UPPER BODY FUNCTION

C ancer treatments that include lymph nodedissection and upper body radiation therapy

appear to be important risk factors for upper

body functional decline.59 Women treated forbreast cancer have traditionally been advised toavoid heavy lifting and vigorous exercises of thearm on the affected side because of a purported in-crease in risk for lymphedema. However, the sci-entific evidence for this advice is lacking.6,60,61

Lash and Silliman62 explored the effects of patientcharacteristics and cancer treatments on self-re-ported upper body function. Women newly diag-nosed with early breast cancer (N ¼ 303)completed telephone interviews 5 and 21 monthsfollowing surgery regarding their ability duringthe preceding month to push or pull large objects,lift objects weighing more than 10 lb, and reach orextend the arms above shoulder level. At 5months, 36% reported some decline in upperbody function, while 7% reported difficulties withall three tasks. At 21 months (n ¼ 250), 36% stillreported some decline in upper body function,while 4% reported difficulties with all three tasks.

Exercise that targets the upperbodyhas thepoten-tial to lessendisability, improvephysical functioning,and increase quality of life. In women with breastcancer, lymph node dissection and radiation treat-ments can leave the skin of the chest feeling tightand restrict movement. Stretching exercises alsohelp to maintain flexibility and are crucial for main-taining mobility of the shoulder and upper body.63,64

Women with breast cancer who are obese or whohave lymph node dissection with follow-up radiationtherapy or postoperative infections are particularlyprone to develop lymphedema. Bicego et al61

reviewed eight exercise studies that focused specifi-cally on the outcome of lymphedema; six examinedthe possibility that exercise precipitated lymphe-dema and two examined effects on pre-existinglymphedema. None of the reviewed studies showedsignificant effects for precipitation or exacerbationof lymphedema. Two studies that were pooled inMcNeely et al’s16 meta-analysis also indicateda non-significant difference between exercisers andcontrols. Similarly, in the systematic review by In-gram et al,4 of four studies that evaluated lymphe-dema, none detected any significant increases withexercise. However, compression garments wereused in many of these studies and may have contrib-uted to the non-significant findings.

DISEASE RECURRENCE AND SURVIVAL

T here is preliminary evidence to suggest thatexercise may prolong survival for individuals


with breast, prostate, and colon cancer.65-68 Ina prospective observational study of 832 patientswith stage III colon cancer enrolled in a NationalCancer Institute adjuvant chemotherapy trial,PA was assessed by calculating metabolic equiva-lent task (MET) scores. Subjects who reported 18MET hours per week of activity had a 47% im-provement in disease-free survival comparedwith those who remained inactive.68 For overallsurvival, increasing exercise following a diagnosisof non-metastatic colon cancer was associatedwith a 50% decrease in cancer-specific and overallmortality, which was not influenced by the level ofPA prior to diagnosis.67

In a landmark observational study of 2,987nurses with stage I-III breast cancer in the Nurses’Health Study, Holmes et al66 followed women for2 years post-diagnosis. Physical activity of 3 METhours of moderate exercise weekly was associatedwith a significant reduction in breast cancer recur-rence and mortality. The greatest improvement inmortality rates occurred among women with METhours of PA equivalent to 3 to 5 hours of moder-ately paced walking per week. Increasing PA hasbeen linked to lower levels of circulating estrogenin women with breast cancer, and thus, may leadto improved survival through reduction of estro-gen levels6,69,70

RECOMMENDATIONS FOR CLINICAL PRACTICE

T here is consistent evidence across studiesthat exercise improves fatigue, physical fit-

ness, and functional ability in cancer survivors.Promising results have also been reported forweight maintenance, body composition, metabo-lism, and immune function. Exercise appears tobe a safe and well-tolerated adjunct to treatmentwhen appropriately taught and monitored, and isa viable intervention to reverse or prevent the neg-ative effects of cancer treatment on physiologicoutcomes. It seems prudent to advise cancer sur-vivors to exercise within their tolerance limits,provided that they receive an adequate health as-sessment and have no contraindications to engag-ing in PA based on co-morbid health conditions.National guidelines recommend 30 minutes ofmoderate activity 5 or more days per week.71 Fur-thermore, the American College of Sports Medi-cine notes that, for weight management andimproved muscle strength, resistance training car-ried out 3 days per week is optimal.72 Stretching

before and after any exercise is critical for in-creased flexibility and prevention of injury.

Exercise recommendations for cancer survi-vors, like those for other individuals, should beindividually based on age, baseline fitness levels,and exercise experience. Additional considerationsfor cancer survivors are diagnosis, disease stage,medical treatment, and co-morbidities. McTiernan6

identifies factors that influence PA adoption in can-cer survivors such as reduced cardiac reserves orother cardiac conditions related to treatment, de-conditioning and loss of muscle mass, neuropathies,increased intracranial pressure, increased risk of in-fection, lymphedema, pain, amputations, and bonemetastases. While some survivors may be able to be-gin and sustain an appropriate exercise program ontheir own or with the help of a fitness instructor,those with specific health concerns may need refer-ral to a physical therapist or exercise physiologistfor assessment and monitoring.

RECOMMENDATIONS FOR FUTURE STUDY

T he majority of research focusing on physio-logic outcomes has examined fatigue and

physical function. Weight and body compositionhave commonly been reported, but are usually ofsecondary interest and are influenced by subopti-mal measurement and reporting.4 The outcomesof work in progress and future studies on preserv-ing and restoring bone mass, preventing lymphe-dema, and optimizing other components of bodycomposition will make a valuable contribution tothis body of knowledge. Exercise has the potentialto alter levels of insulin and IGF, and ultimately,the development of metabolic syndrome. The met-abolic abnormalities that accompany insulin resis-tance and metabolic syndrome have not beenstudied extensively in cancer survivors. As thesesurvivors age, there is a need to reduce the long-term effects of cancer treatment on the cardiovas-cular system to prevent co-morbid illness and,more importantly, reduce mortality. There are nu-merous physiologic outcomes related to exercisethat remain under-studied and require further at-tention, such as the effects of exercise on patientswith concurrent chronic illness.

The published systematic reviews and meta-analyses have advanced our knowledge of cancerand exercise by combining the results of small stud-ies with low statistical power. At the same time,they have identified significant methodologic


limitations. Larger randomized controlled trialswith objective measures and an increased focuson cancers other than breast cancer are needed

to substantiate the effects of exercise on physio-logic outcomes and the long-term endpoints of re-currence and survival.

REFERENCES

1. Knobf MT, Musanti R, Dorward J. Exercise and quality of

life outcomes in patients with cancer. Semin Oncol Nurs

2007;23:285-296.

2. Mock V, Pickett M, Ropka ME, et al. Fatigue and quality of

life outcomes of exercise during cancer treatment. Cancer Pract

2001;9:119-127.

3. Schmitz KH, Holtzman J, Courneya KS, et al. Controlled

physical activity trials in cancer survivors: a systematic review

and meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;

14:1588-1595.

4. Ingram C, Courneya KS, Kingston D. The effects of exer-

cise on body weight and composition in breast cancer survivors:

an integrative systematic review. Oncol Nurs Forum 2006;33:

937-947.

5. Visovsky C. Muscle strength, body composition and phys-

ical activity in women receiving chemotherapy for breast can-

cer. Integr Cancer Ther 2006;5:183-189.

6. McTiernan A. Physical activity after cancer: physiologic

outcomes. Cancer Invest 2004;22:68-81.

7. Oxford Centre for Evidence Based Medicine. Levels of

evidence and grades of recommendation. Oxford Centre for

Evidence Based Medicine 2001. Available at: http://www.cebm.

net/index.aspx?0¼1025 (accessed Sept. 21, 2007).

8. Ciliska D, Cullum N, Marks S. Evaluation of systematic

reviews of treatment or prevention interventions. Evid Based

Nurs 2001;4:100-104.

9. Cohen J. Statistical power analysis for the behavioral sci-

ences. Ed 2. Hillside, NJ: Lawrence Erlbaum Associates; 1988.

10. Willems ME, Stauber WT. Effect of resistance training on

muscle fatigue and recovery in intact rats. Med Sci Sports Exerc

2000;32:1887-1893.

11. Ojala BE, Page LA, Moore MA, et al. Effects of inactivity

on glycolytic capacity of single skeletal muscle fibers in adult

and aged rats. Biol Res Nurs 2001;3:88-95.

12. Irwin ML, Crumley D, McTiernan A, et al. Physical activ-

ity levels before and after a diagnosis of breast carcinoma: the

Health, Eating, Activity, and Lifestyle (HEAL) study. Cancer

2003;97:1746-1757.

13. Blair SN, Kampert JB, Kohl HW III, et al. Influences of car-

diorespiratory fitness and other precursors on cardiovascular

disease and all-cause mortality in men and women. JAMA

1996;276:205-210.

14. Blair S, Kohl H, Paffenbarger R, et al. Physical fitness and

all-cause mortality. A prospective study of healthy men and

women. JAMA 1989;262:2395-2401.

15. Conn VS, Hafdahl AR, Porock DC, et al. A meta-analysis

of exercise interventions among people treated for cancer. Sup-

port Care Cancer 2006;14:699-712.

16. McNeely ML, Campbell KL, Rowe BH, et al. Effects of

exercise on breast cancer patients and survivors: a systematic

review and meta-analysis. CMAJ 2006;175:34-41.

17. Markes M, Brockow T, Resch KL. Exercise for women re-

ceiving adjuvant therapy for breast cancer. Cochrane Database

Syst Rev 2006;(4):CD005001.

18. Adamsen L, Midtgaard J, Rorth M, et al. Feasibility, phys-

ical capacity, and health benefits of a multidimensional exercise

program for cancer patients undergoing chemotherapy. Sup-

port Care Cancer 2003;11:707-716.

19. Adamsen L, Quist M, Midtgaard J, et al. The effect of

a multidimensional exercise intervention on physical capacity,

well-being and quality of life in cancer patients undergoing che-

motherapy. Support Care Cancer 2006;14:116-127.

20. Thorsen L, Skovlund E, Stromme SB, et al. 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.

21. Spruit MA, Janssen PP, Willemsen SC, et al. Exercise

capacity before and after an 8-week multidisciplinary inpatient

rehabilitation program in lung cancer patients: a pilot study.

Lung Cancer 2006;52:257-260.

22. Mitchell SA, Beck SL, Hood LE, et al. Putting evidence

into practice: Evidence-based interventions for fatigue during

and following cancer and its treatment. Clin J Oncol Nurs

2007;11:99-113.

23. Mock V. Clinical excellence through evidence-based

practice: Fatigue management as a model. Oncol Nurs Forum

2003;30:790-796.

24. Stricker CT, Drake D, Hoyler K, et al. Evidence based

practice for fatigue management in adults with cancer: exercise

as an intervention. Oncol Nurs Forum 2004;31:963-974.

25. Winningham ML, Nail LM, Burke MB, et al. Fatigue and

the cancer experience: the state of the knowledge. Oncol Nurs

Forum 1994;21:23-36.

26. MacVicar MG, Winningham ML, Nickel JL. Effects of aer-

obic interval training on cancer patients’ functional capacity.

Nurs Res 1989;38:348-351.

27. Winningham ML. Fatigue. In: Yarbro CH, Frogge MH,

Goodman M, eds. Cancer symptom management. Ed 2. Boston:

Jones & Bartlett; 1999, pp 58-71.

28. Watson T, Mock V. Exercise as an intervention for can-

cer-related fatigue. Phys Ther 2004;84:736-743.

29. Kaaks R, Toniolo P, Akhmedkhanov A, et al. Serum C-

peptide, insulin-like growth factor (IGF)-I, IGF-binding pro-

teins, and colorectal cancer risk in women. J Natl Cancer Inst

2000;92:1592-1600.

30. Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insu-

lin-like growth factor-I (IGF-I), IGF binding proteins, their

biologic interactions, and colorectal cancer. J Natl Cancer

Inst 2002;94:972-980.

31. Goodwin PJ, Ennis M, Pritchard KI, et al. Insulin-like

growth factor binding proteins 1 and 3 and breast cancer out-

comes. Breast Cancer Res Treat 2002;74:65-76.

32. Boule NG, Haddad E, Kenny GP, et al. Effects of exercise

on glycemic control and body mass in type 2 diabetes mellitus:

a meta-analysis of controlled clinical trials. JAMA 2001;286:

1218-1227.

33. Chlebowski RT, Blackburn GL, Thomson CA, et al. Die-

tary fat reduction and breast cancer outcome: interim efficacy

http://www.cebm.net/index.aspx?0=1025

http://www.cebm.net/index.aspx?0=1025


results from the Women’s Intervention Nutrition Study. J Natl

Cancer Inst 2006;98:1767-1776.

34. Schmitz KH, Ahmed RL, Hannan PJ, et al. Safety and effi-

cacy of weight training in recent breast cancer survivors to alter

bodycomposition, insulin, and insulin-like growth factor axis pro-

teins. Cancer Epidemiol Biomarkers Prev 2005;14:1672-1680.

35. Fairey AS, Courneya KS, Field CJ, et al. Effects of exercise

training on fasting insulin, insulin resistance, insulin-like growth

factors, and insulin-like growth factor binding proteins in post-

menopausal breast cancer survivors: a randomized controlled

trial. Cancer Epidemiol Biomarkers Prev 2003;12:721-727.

36. Duncan GE. Exercise, fitness, and cardiovascular disease

risk in type 2 diabetes and the metabolic syndrome. Curr Diab

Rep 2006;6:29-35.

37. Nuver J, Smit AJ, Wolffenbuttel BH, et al. The metabolic

syndrome and disturbances in hormone levels in long-term sur-

vivors of disseminated testicular cancer. J Clin Oncol 2005;23:

3718-3725.

38. Demark-Wahnefried W, Hars V, Conaway MR, et al. Re-

duced rates of metabolism and decreased physical activity in

breast cancer patients receiving adjuvant chemotherapy. Am

J Clin Nutr 1997;65:1495-1501.

39. Demark-Wahnefried W, Peterson BL, Winer EP, et al.

Changes in weight, body composition, and factors influencing en-

ergy balanceamongpremenopausalbreast cancer patients receiv-

ing adjuvant chemotherapy. J Clin Oncol 2001;19:2381-2389.

40. Demark-Wahnefried W, Kenyon AJ, Eberle P, et al. Pre-

venting sarcopenic obesity among breast cancer patients re-

ceiving adjuvant chemotherapy: a feasibility study. Clin Exer

Physiol 2002;4:44-49.

41. Smith MR. Changes in fat and lean body mass during

androgen-deprivation therapy for prostate cancer. Urology

2004;63:742-745.

42. Chlebowski RT, Aiello E,McTiernanA. Weight loss in breast

cancer patient management. J Clin Oncol 2002;20:1128-1143.

43. Del Rio G, Zironi S, Valeriani L, et al. Weight gain in

women with breast cancer treated with adjuvant cyclophospha-

mide, methotrexate and 5-fluorouracil. Analysis of resting

energy expenditure and body composition. Breast Cancer Res

Treat 2002;73:267-273.

44. Eyre H, Kahn R, Robertson R, et al. Preventing cancer,

cardiovascular disease and diabetes. A common agenda for

the American Cancer Society, the American Diabetes Associa-

tion, and the American Heart Association. Circulation 2004;

109:3244-3255.

45. Knobf MT, Inosgna K, DiPietro L, et al. An aerobic weight-

loaded pilot exercise intervention for breast cancer survivors:

bone remodeling and body composition outcomes. Biol Res

Nurs (in press).

46. McTiernan A, Ulrich C, Kumai C, et al. Anthropometric

and hormone effects of an eight-week exercise-diet intervention

in breast cancer patients: results of a pilot study. Cancer Epide-

miol Biomarkers Prev 1998;7:477-481.

47. Woods JA, Davis JM, Mayer EP, et al. Exercise increases

inflammatory macrophage antitumor cytotoxicity. J Appl Phys-

iol 1993;75:879-886.

48. Peters C, Lotzerich H, Niemeier B, et al. Influence of

a moderate exercise training on natural killer cytotoxicity and

personality traits in cancer patients. Anticancer Res 1994;14:

1033-1036.

49. Peters C, Lotzerich H, Niemeir B, et al. Exercise, cancer

and the immune response of monocytes. Anticancer Res 1995;

15:175-179.

50. Fairey AS, Courneya KS, Field CJ, et al. Randomized

controlled trial of exercise and blood immune function in post-

menopausal breast cancer survivors. J Appl Physiol 2005;98:

1534-1540.

51. Nieman DC, Cook VD, Henson DA, et al. Moderate exer-

cise training and natural killer cell cytotoxic activity in breast

cancer patients. Int J Sports Med 1995;16:334-337.

52. Hutnick NA, Williams NI, Kraemer WJ, et al. Exercise and

lymphocyte activation following chemotherapy for breast can-

cer. Med Sci Sports Exer 2005;37:1827-1835.

53. Na YM, Kim MY, Kim YK, et al. Exercise therapy effect on

natural killer cell cytotoxic activity in stomach cancer patients

after curative surgery. Arch Phys Med Rehabil 2000;81:

777-779.

54. Hayes SC, Rowbottom D, Davies PS, et al. Immunological

changes after cancer treatment and participation in an exercise

program. Med Sci Sports Exer 2003;35:2-9.

55. Chen Z, Maricic M, Nguyen P, et al. Low bone density and

high percentage of body fat among men who were treated with

androgen deprivation therapy for prostate carcinoma. Cancer

2002;95:2136-2144.

56. Headley JA, Theriault RL, LeBlanc AD, et al. Pilot study

of bone mineral density in breast cancer patients treated with

adjuvant chemotherapy. Cancer Invest 1998;16:6-11.

57. Waltman NL, Twiss JJ, Ott CD, et al. Testing an interven-

tion for preventing osteoporosis in postmenopausal breast can-

cer survivors. J Nursing Scholarship 2003;35:333-338.

58. Schwartz AL, Winters-Stone K, Gallucii B. Exercise

effects on bone mineral density in women with breast cancer

receiving adjuvant chemotherapy. Oncol Nurs Forum 2007;34:

627-633.

59. Silliman RA, Prout MN, Field T, et al, Risk factors for a de-

cline in upper body function following treatment for early stage

breast cancer. Breast Cancer Res Treat 1999;54:25-30.

60. Harris SR, Hugi MR, Olivotto IA, et al. Steering Commit-

tee for Clinical Practice Guidelines for the Care and Treatment

of Breast Cancer. Clinical practice guidelines for the care and

treatment of breast cancer. Lymphedema. CMAJ 2001;164:

191-199.

61. Bicego D, Brown K, Ruddick M, et al. Exercise for women

with or at risk for breast cancer-related lymphedema. Phys Ther

2006;86:1398-1405.

62. Lash TL, Silliman RA. Patient characteristics and

treatments associated with a decline in upper-body function

following breast cancer therapy. J Clin Epidemiol 2000;53:

615-622.

63. Bendz I, Fagevik OM. Evaluation of immediate versus de-

layed shoulder exercises after breast cancer surgery including

lymph node dissection - A randomised controlled trial. Breast

2002;11:241-248.

64. Harris SR, Hugi MR, Olivotto IA, et al. Upper extremity

rehabilitation in women with breast cancer after axillary dissec-

tion: clinical practice guidelines. Crit Rev Phys Rehab Med

2001;13:91-103.

65. Giovannucci EL, Liu Y, Leitzmann MF, et al. A prospec-

tive study of physical activity and incident and fatal prostate

cancer. Arch Intern Med 2005;165:1005-1010.

66. Holmes MD, Chen WY, Feskanich D, et al. Physical activ-

ity and survival after breast cancer diagnosis. JAMA 2005;293:

2479-2486.

67. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Phys-

ical activity and survival after colorectal cancer diagnosis. J Clin

Oncol 2006;24:3527-3534.


68. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact

of physical activity on cancer recurrence and survival in

patients with stage III colon cancer: findings from CALGB

89803. J Clin Oncol 2006;24:3535-3541.

69. Holmberg L, Norden T, Lindgren A, et al. Pre-operative

oestradiol levels - relation to survival in breast cancer. Eur J

Surg Oncol 2001;27:152-156.

70. Lonning PE, Helle SI, Johannessen DC, et al. Influence of

plasma estrogen levels on the length of the disease-free interval

in postmenopausal women with breast cancer. Breast Cancer

Res Treat 1996;39:335-341.

71. Doyle C, Kushi LH, Byers T, et al. Nutrition and physical ac-

tivity during and after cancer treatment: an American Cancer Soci-

ety guide for informed choices. CA Cancer J Clin 2006;56:323-353.

72. American College of Sports Medicine. Position stand on

the recommended quantity andquality of exercise for developing

and maintaining cardiorespiratory and muscular fitness and flex-

ibility in healthy adults. Med Sci Sports Exerc 1998;30:975-991.

exercise intervention to modify physiologic risk factors in cancer survivors

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