Cochrane Database of Systematic Reviews (Reviews) || Exercise for women receiving adjuvant therapy...

Exercise for women receiving adjuvant therapy for breast

cancer (Review)

Markes M, Brockow T, Resch KL

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Exercise for women receiving adjuvant therapy for breast cancer (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Exercise versus control, Outcome 1 Cardiorespiratory fitness. . . . . . . . . . . 27

Analysis 1.2. Comparison 1 Exercise versus control, Outcome 2 Strength. . . . . . . . . . . . . . . . 28

Analysis 1.3. Comparison 1 Exercise versus control, Outcome 3 Fatigue. . . . . . . . . . . . . . . . . 28

Analysis 1.4. Comparison 1 Exercise versus control, Outcome 4 Weight change. . . . . . . . . . . . . . 29

Analysis 1.5. Comparison 1 Exercise versus control, Outcome 5 Cancer specific quality of life. . . . . . . . . 29

Analysis 1.6. Comparison 1 Exercise versus control, Outcome 6 Cancer site-specific quality of life. . . . . . . . 30

Analysis 1.7. Comparison 1 Exercise versus control, Outcome 7 Anxiety. . . . . . . . . . . . . . . . . 30

Analysis 1.8. Comparison 1 Exercise versus control, Outcome 8 Mood disturbance. . . . . . . . . . . . . 31

Analysis 1.9. Comparison 1 Exercise versus control, Outcome 9 Depression. . . . . . . . . . . . . . . 31

Analysis 1.10. Comparison 1 Exercise versus control, Outcome 10 Natural killer cells. . . . . . . . . . . . 32

Analysis 1.11. Comparison 1 Exercise versus control, Outcome 11 T-cells. . . . . . . . . . . . . . . . 32

Analysis 1.12. Comparison 1 Exercise versus control, Outcome 12 Oxidative stress. . . . . . . . . . . . . 33

Analysis 1.13. Comparison 1 Exercise versus control, Outcome 13 Nausea relief. . . . . . . . . . . . . . 33

Analysis 1.14. Comparison 1 Exercise versus control, Outcome 14 Sleep disturbances. . . . . . . . . . . . 34

34ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

39INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iExercise for women receiving adjuvant therapy for breast cancer (Review)


[Intervention Review]

Exercise for women receiving adjuvant therapy for breastcancer

Martina Markes1, Thomas Brockow2 , Karl-Ludwig Resch3

1Rehabilitation Research Institute, FBK German Institute for Health Research, Bad Elster, Germany. 2Physical medicine and reha-

bilitation, Rehabilitation Research Institute, Bad Elster, Germany. 3Physical Medicine and Rehabilitation, FBK German Institute for

Health Research, Bad Elster, Germany

Contact address: Martina Markes, Rehabilitation Research Institute, FBK German Institute for Health Research, Lindenstr. 5, Bad

Elster, 08645, Germany. [email protected].

Editorial group: Cochrane Breast Cancer Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.

Review content assessed as up-to-date: 15 July 2004.

Citation: Markes M, Brockow T, Resch KL. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database ofSystematic Reviews 2006, Issue 4. Art. No.: CD005001. DOI: 10.1002/14651858.CD005001.pub2.


A B S T R A C T

Background

A huge clinical research database on adjuvant cancer treatment has verified improvements in breast cancer outcomes such as recurrence

and mortality rates. On the other hand, adjuvant therapy with agents such as hormone therapy, chemotherapy and radiotherapy impacts

on quality of life due to substantial short- and long-term side effects.

Objectives

To assess the effect of aerobic or resistance exercise interventions during adjuvant treatment for breast cancer on treatment-related side

effects such as physical deterioration, fatigue, psychosocial distress and physiological, morphological and biological changes.

Search methods

We searched the Cochrane Breast Cancer Specialised Register (16 July 2004) and the following electronic databases: MEDLINE (1966

to 2004), EMBASE (1988 to 2004), CINAHL (1982 to 2004), SPORTDiscus (1975 to 2004), PsycINFO (1872 to 2003), SIGLE

(1880 to 2004), ProQuest Digital Dissertations (1861 to 2004) and Conference Papers Index (1973 to 2004). Furthermore, we screened

references in relevant reviews and clinical trials and handsearched relevant journals.

Selection criteria

We included randomised and non-randomised controlled trials that examined aerobic or resistance exercise, or both, in women

undergoing adjuvant treatment for breast cancer.

Data collection and analysis

Two authors independently extracted data and assessed methodological quality and adequacy of the training stimulus following a set

of standardised criteria. Meta-analyses were performed for physical fitness, fatigue and weight gain using a random-effects model.

1Exercise for women receiving adjuvant therapy for breast cancer (Review)


mailto:[email protected]

Main results

Nine trials involving 452 women met the inclusion criteria. Meta-analysis for cardiorespiratory fitness (involving 207 participants)

suggested that exercise improves cardiorespiratory fitness (SMD 0.66, 95% CI 0.20 to 1.12). Meta-analysis for fatigue (317 partici-

pants) found statistically non-significant improvements for participants in the exercise intervention groups compared to control (non-

exercising) groups (SMD -0.12, 95% CI -0.37 to 0.13); the same applied for the meta-analysis of weight gain (147 participants) (SMD

-1.11, 95% CI -2.44 to 0.22). Evidence for other outcomes remains limited. Adverse effects (lymphedema and shoulder tendonitis)

were observed in two trials. The results from non-randomised controlled trials are similar to those of randomised controlled trials and

do not appear to produce any bias. This review is based on a small number of trials with a considerable degree of clinical heterogeneity

regarding adjuvant cancer treatments and exercise interventions.

Authors’ conclusions

Exercise during adjuvant treatment for breast cancer can be regarded as a supportive self-care intervention which results in improved

physical fitness and thus the capacity for performing activities of daily life, which may otherwise be impaired due to inactivity during

treatment. Improvements in fatigue were ambiguous and there was a lack of evidence for improvement with exercise for other treatment-

related side effects. Since exercise interventions (for sedentary participants) require behaviour change, strategies for behaviour change

should underpin these interventions. Furthermore, long-term evaluation is required due to possible long-term side effects.

P L A I N L A N G U A G E S U M M A R Y

Exercise for women receiving adjuvant therapy for breast cancer

In the past, cancer patients were usually advised to rest and avoid physical effort. However, it is now well established that excessive

rest and lack of physical activity may result in severe deconditioning and thus reduced physical functioning. Furthermore, women

undergoing chemotherapy or radiation therapy as adjuvant treatment for breast cancer commonly experience debilitating side effects.

One of the main side effects of radiation therapy is fatigue; common side effects of chemotherapy are nausea and vomiting, fatigue,

weight gain and mood disturbances. These side effects interfere with daily activities such as self-care or return to work. Physical exercise

has been reported to improve the underlying conditions in people with a range of chronic diseases.

This review evaluated physical exercise as a means of counteracting several of the side effects that cancer treatments (chemotherapy

and radiation therapy) induce. It included nine controlled clinical trials with a total of 452 participants. Results suggest that physical

exercise can improve physical function even during cancer treatment. Also, fatigue may be lessened through exercise although there

is insufficient evidence to conclude this. There is still not enough evidence about the effect of exercise on outcomes such as mood

disturbances, immune function and weight gain. Moreover, there is a lack of evidence for harms of exercise during adjuvant cancer

treatment.

B A C K G R O U N D

Breast cancer detection and management have undergone dra-

matic changes over the past three decades. Women are increasingly

diagnosed with early-stage disease leaving them with treatment

choices ranging from breast conserving options to mastectomy

(Newman 2003). With the majority of breast cancers diagnosed at

an early stage, treatment is focused on cure and the prevention of

relapse due to micrometastatic disease. Because systemic adjuvant

therapy effectively prevents or delays some relapses and deaths in

early-stage disease, this treatment approach has become standard

practice throughout most of the Western world (Hudis 2003).

The mainstay of care is local therapy, consisting of surgery (with

or without radiotherapy), along with systemic adjuvant therapy,

which includes chemotherapy (cytotoxic agents), hormonal ther-

apy or a combination of these treatments.

Besides these major advances in managing both early and locally

advanced breast cancer, patients still have to deal with severe side

effects and psychological distress during adjuvant therapy. This has

a substantial impact on their quality of life. Side effects that appear

with adjuvant cancer treatment differ depending on the mode

of treatment, that is, radiotherapy, chemotherapy or hormonal



therapy.

Radiotherapy is associated with short-term side effects such as fa-

tigue and skin erythema and long-term side effects including lym-

phedema, cardiac and pulmonary toxicities and brachial plexopa-

thy (Truong 2004). Chemotherapy is associated with short-term

side effects such as emesis, nausea, stomatitis, alopecia, myelosup-

pression, thromboembolism, myalgias, neuropathy and fatigue.

Long-term side effects of chemotherapy are premature menopause,

weight gain, fatigue, cardiac dysfunction and cognitive dysfunc-

tion (Partridge 2001). Furthermore, patients receiving radiother-

apy or chemotherapy report anxiety and depression prior to, dur-

ing and after therapy due to treatment side effects (Spiegel 1997).

Adjuvant hormonal therapy produces symptoms secondary to oe-

strogen withdrawal, such as hot flushes, bone demineralisation and

psychosexual effects (Rutqvist 2004).

Although research is producing increasingly hopeful insights into

the causes and cures for cancer, efforts to manage the side effects

of adjuvant therapy have not kept pace (Patrick 2003). Exercise

interventions may be effective in managing some of these side

effects, such as fatigue, weight gain, emotional distress, nausea and

vomiting and premature menopause.

Cancer-related fatigue is defined by the National Comprehensive

Cancer Network as a “persistent, subjective sense of tiredness re-

lated to cancer or cancer treatment that interferes with usual func-

tioning” (NCCN 2004). Fatigue results in substantial physical,

psychosocial, cognitive and socioeconomic consequences (Holley

2000). Acute and chronic radiotherapy-related fatigue occurs in up

to 80% and 30% of patients, respectively (Jereczek-Fossa 2001).

During and after adjuvant chemotherapy the prevalence of fatigue

is high and fluctuating (de Jong 2002), with a frequency of 60%

to 90% (Feyer 2001). Fatigue is also associated with factors such

as depression, impaired quality of sleep or pain (de Jong 2002).

The rationale supporting exercise interventions for cancer-related

fatigue is based on the proposition that the combined effects of a

toxic treatment and a decreased level of activity during treatment

cause a reduction in the capacity for physical performance. Pa-

tients must, therefore, use greater effort and expend more energy

to perform daily activities, which leads to fatigue (NCCN 2004).

Physical exercise training programmes may increase functional ca-

pacity leading to reduced effort and decreased fatigue.

Weight gain is also common among breast cancer patients receiv-

ing adjuvant chemotherapy, with gains ranging from 0 to 22 kg,

influenced by menopausal status, nodal status and the type, dura-

tion and intensity of treatment (Demark-Wahnefried 97). Weight

gain not only has a similar profound effect on quality of life as fa-

tigue but in addition it indicates a potentially poor prognosis, with

higher relapse rates and poorer survival (Camoriano 1990). Evi-

dence suggests that overeating is not a cause of weight gain among

breast cancer patients who receive chemotherapy but is the result

of reduced physical activity. Chemotherapy induced weight gain

shows the distinctive pattern of sarcopenic obesity that is weight

gain in the presence of lean tissue loss or absence of lean tissue gain

(Demark-Wahnefried 01). The development of sarcopenic obesity

with evidence of reduced physical activity supports the need for

interventions focused on exercise, especially resistance training.

Women treated for breast cancer frequently experience higher

levels of emotional distress than the general population (Spiegel

1997). The rationale for considering exercise as an intervention

to reduce distress in women receiving adjuvant therapy for breast

cancer is based upon the literature that has demonstrated amelio-

rating effects of exercise on these problems. Results of studies with

non-cancer populations indicate that aerobic exercise training has

antidepressant and anxiolytic effects and protects against harm-

ful consequences of stress (Salmon 2001). There is evidence that

cognitive dysfunction may also occur in women receiving adju-

vant chemotherapy for breast cancer (O’Shaughnessy 2003; Rugo

2003; Tchen 2003). A meta-analytic study conducted to examine

the hypothesis that aerobic fitness training enhances the cognitive

vitality of healthy but sedentary older adults indicated that fitness

training has robust benefits for cognition (Colcombe 2003).

The incidence and severity of nausea and vomiting in patients re-

ceiving chemotherapy are affected by numerous factors including

the specific chemotherapeutic agents used, their dosage, the sched-

ule and route of administration and individual patient variability.

Although standard chemotherapy regimens for breast cancer are

considered to be mildly to moderately emetogenic (Dibble 2003),

nausea and vomiting do occur with these regimens: 73 to 82% of

women receiving chemotherapy for breast cancer experience nau-

sea (Dibble 2003). If emesis is severe it can in turn lead to antic-

ipatory nausea and vomiting (Morrow 1998). Winningham et al

suggested that aerobic exercise may serve as a potential interven-

tion for controlling or mitigating chemotherapy induced nausea

(Winningham 1988).

Currently, exercise does not appear as an inherent part of cancer

care. Exercise is actually considered an essential component in car-

diopulmonary rehabilitation; however, its role in oncological reha-

bilitation programmes has thus far been mostly limited to physical

treatment addressing specific impairments caused, for example, by

amputation or surgery (Dimeo 2000). Evidence concerning the

natural progression of physical activity suggests that women with

breast cancer significantly decrease physical activity and exercise

from pre-diagnosis to post-diagnosis (Irwin 2003). These decreases

are associated with adjuvant cancer treatment: observed decreases

in physical activity were greater among women who were treated

with radiation and chemotherapy (50% decrease) compared with

women who underwent surgery only (24% decrease) or who were

treated with radiation only (23% decrease) (Irwin 2003).

The role of exercise in breast cancer was examined in retrospective,

cross-sectional and prospective studies (Courneya 2001; Courneya

2002; Courneya 2003; Pinto 1999) with the majority of research



focused on rehabilitation and health promotion in women who

had completed cancer treatment. This review aims to evaluate

the role of exercise in managing common side effects of adjuvant

therapy for breast cancer.

O B J E C T I V E S

To systematically assess the effectiveness and safety of exercise

training (aerobic or resistance exercise, or both) during adjuvant

treatment for breast cancer in reducing treatment-related side ef-

fects. These include physical deterioration, fatigue, psychosocial

distress and physiological, morphological and biological changes.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We considered randomised and non-randomised controlled trials

of exercise training during adjuvant treatment (radiotherapy, che-

motherapy, hormonal therapy) for women with non-metastatic

breast cancer.

We defined a controlled trial as a trial with at least two groups

where the trial investigator assigned participants to the experimen-

tal or control group using randomisation, a quasi-randomisation

procedure or some other method of allocation. We excluded trials

if group assignment was based on self selection.

Types of participants

We included trials with women who were diagnosed with breast

cancer stages I, II and III and who were undergoing adjuvant (in-

cluding neo-adjuvant) chemotherapy, hormonal therapy or radio-

therapy concurrently with an exercise intervention in the active

group.

Types of interventions

Studies that assessed the effects of all forms of repeatedly per-

formed aerobic or resistance exercise, or both, with programme

duration of at least six weeks were considered for inclusion. To

be included in this review, the exercise intervention had to coin-

cide with the adjuvant treatment regimen rather than follow it.

We excluded studies where the exercise intervention was part of

a complex intervention (for example complete decongestive lym-

phatic therapy). Trials with interventions restricted to local mus-

cular endurance (for example training of shoulders, back or legs

only) instead of including all major muscle groups or restricted to

stretching exercises were also excluded.

We included trials making the following comparisons:

• exercise versus no exercise;

• exercise versus other interventions (e.g. psychosocial

interventions).

Types of outcome measures

Trials that assessed measures related to any of the following out-

comes were considered for inclusion:

• physical fitness (e.g. cardiorespiratory fitness, physical

performance, muscular fitness);

• physiological outcomes;

• multidimensional outcomes (e.g. pain, fatigue, quality of

life);

• psychological distress outcomes;

• biological outcomes (e.g. related to immune function);

• morphological outcomes (e.g. body weight or lean body

mass);

• physical activity behaviour;

• harms.

Search methods for identification of studies

1. Electronic databases

a) The Cochrane Breast Cancer Specialised Register (16 July 2004)

Details of the search strategy applied by the Group to create the

register, and the procedure used to code references, are described

in the Group’s module on The Cochrane Library. We extracted

studies coded as ’exercise’ and ’early’, ’locally advanced’, local re-

currence’ and ’locoregional’ on the Specialised Register for con-

sideration.

b) MEDLINE (1966 to 2006)

The MEDLINE search strategy incorporated the sensitive search

strategy for randomised and controlled trials by Dickersin (

Dickersin 1994), the Cochrane Breast Cancer Group’s strategy for

the identification of populations with ’breast neoplasms’ (Simes

2004) and key words to identify exercise interventions. We mod-

ified this strategy for searching the other databases. In order to

apply the most sensitive approach, we allowed for all breast cancer

survivors instead of limiting our search to breast cancer survivors

currently undergoing cancer treatment. This inclusion criterion

of cancer treatment was accounted for in the process of selecting

studies (see Appendix 1).

c) EMBASE (1988 to 2004)

d) CINAHL (1982 to 2004)

e) SPORTDiscus (1975 to 2004)

f ) PsycINFO (1872 to 2003)

g) SIGLE (1880 to 2004)

h) ProQuest Digital Dissertations (1861 to 2004)

i) Conference Papers Index (1973 to 2004)



2. References from published studies

We screened references in relevant reviews and in published clinical

trials for further trials.

3. Handsearching

a) Psycho-Oncology (1997 to 2004)

b) Cancer (1990 to 2004)

c) Breast Cancer Research and Treatment (1990 to 2004)

d) Nursing Research (1996 to 2004)

e) Applied Nursing Research (1994, 2000 to 2004)

f ) International Journal of Sports Medicine (1990 to 2004)

g) Medicine & Science in Sports & Medicine (1980 to 2004)

h) Clinical Journal of Sport Medicine (2000 to 2004)

i) Deutsche Zeitschrift für Sportmedizin(1985 to 2004)

j) Oncology Nursing Forum (2000 to 2004)

k) The Physician and Sportsmedicine (1990 to 2003)

l) European Journal of Sport Science (2000 to 2004)

4. Other

We consulted 31 experts in the field of cancer and exercise to

identify additional trials. No language restrictions were applied.

Data collection and analysis

Selection of trials

Initially, two review authors (TB, MM) independently selected

reports potentially fulfilling the inclusion criteria of this review

based on title and abstract. Full articles of any possibly relevant

reports were retrieved for more detailed evaluation. Both authors

then independently performed a final selection of trials to be in-

cluded in the review using a standardised form (eligibility form

plus instruction sheet for assessing eligibility) that was designed

for this review. The decision algorithm required the fulfillment of

our predefined eligibility criteria (see Table 1). A report was ex-

cluded according to the first criterion that it did not fulfill. Dis-

agreements were resolved by consensus; if necessary a third person

was consulted to reach a final decision.

Data extraction

Two review authors (TB, MM) independently extracted data (in-

cluding study characteristics, study results and point estimates to-

gether with measures of variability for selected outcome variables)

using a data extraction form together with coding instructions

for data collection, both designed for this review. Where further

or missing data were required, authors of studies were contacted.

All discrepancies were reviewed and consensus achieved by discus-

sion.

Methodological quality assessment

Methodological quality was assessed independently by two review

authors (TB, MM) each applying a study quality form as well as a

code of practice for implementing quality criteria, both designed

for this review. Disagreement was resolved by consensus and, if dis-

agreement persisted, a third review author (KLR) was consulted for

a final decision. We applied the van Tulder methodological quality

criteria (van Tulder 1997) with all criteria carrying equal weight,

but we customised these criteria with two deviations regarding

blinding requirements: we regarded blinding of care providers and

participants as not applicable to exercise interventions and thus

omitted these items (see Table 2). However, blinding of outcome

assessment was included as a quality criterion. Each criterion was

answered with ’yes’, ’no’ or ’n/a’ (not available); answers were coded

with: ’yes’ as ’+’, ’no’ as ’-’ and ’n/a’ as ’?’. A quality score was cal-

culated for each study by summing positive scores for individual

items, resulting in a possible score from 0 to 17. Moderate quality

was defined as fulfilling a score between 9 and 12 (50 to 74%)

of all methodological quality criteria; high quality was defined as

fulfilling at least 13 (> 75%) of all methodological quality criteria.

Analysis of training stimulus

Analysis of the training stimulus roughly followed the American

College of Sports Medicine (ACSM) guidelines for exercise pre-

scription for the elderly (ACSM 2000), the ACSM references for

exercise programming for cancer patients (Schwartz 1997) and the

exercise prescription guidelines for early-stage cancer patients and

cancer survivors as recommended by Courneya (Courneya 2000).

We classified studies as trials with an adequate training stimulus

if they met three of four predefined requirements (see Table 3).

Each criterion was answered with ’yes’, ’no’ or ’n/a’ (not available);

answers scored as ’yes’ were coded as ’+’, ’no’ as ’-’ and ’n/a’ as ’?

’. A quality score was then calculated for each study by summing

scores for individual items, resulting in a possible score from 0

to 4. In trials using exercise interventions with both aerobic and

resistance modules we assessed training stimulus for each module

and then calculated the corresponding mean.

Classification of high quality training studies (HQTS)

Moderate and high quality studies, that provided an adequate

training stimulus were classified as high quality training studies.

Data analysis

Reliability

Inter-rater agreement for the overall methodological quality as-

sessment was measured using the intraclass correlation coefficient

(ICC) based on the two-way mixed model with measures of ab-

solute agreement (Shrout 1997). We described the level of relia-

bility for the ICC using categories suggested by Landis and Koch

(Landis 1977) for Kappa, as another measure of inter-rater agree-

ment. ICC values of 0.21 to 0.40 were considered as ’fair agree-

ment’, values from 0.41 to 0.60 as ’moderate agreement’, from

0.61 to 0.80 as ’substantial agreement’ and from 0.81 to 1.00 as

’almost perfect agreement’.

Statistical pooling

Outcome measurements were presented as continuous data across

included studies. As the first step, we extracted data on outcomes

in the format in which they were reported. For selected outcomes

we extracted group means for final values and change scores with

the corresponding measures of variability such as standard devia-

tions (SD) or confidence intervals (CI) and the number of partici-

pants on whom the outcome was assessed per group. Missing data



were requested from authors. In a subsequent step we transformed

data. If variability was presented by measures other than stan-

dard deviations we obtained standard deviations using standard

approaches for transforming data. We transformed confidence in-

tervals, t-values, and P values into standard deviations as described

in the Cochrane Handbook for Systematic Reviews of Interven-

tions (Deeks 2005); when F-statistics were reported for compar-

ing two groups, we transformed F-statistics into T-statistics using

the following formula: T=√

F and continued transforming the T-

statistic into standard deviations.

As a summary statistic for meta-analysis of continuous outcomes,

we either used the standardised mean difference (SMD) or the

weighted mean difference (WMD). We chose the standardised

mean difference in cases where different assessment instruments

measuring the same construct were used across studies (for exam-

ple for fatigue and physical fitness outcomes). We did not combine

final values and change scores in meta-analyses since the difference

in standard deviation does not reflect “differences in measurement

scale, but differences in the reliability of the measurements” (Deeks

2005). The instruments used for the particular outcomes as well as

the base for calculating summary statistics (final values or change

scores) are summarised in Table 4. As a summary statistic for di-

chotomous outcomes we chose the relative risk (RR). Nausea was

the only outcome that was analysed as a dichotomous outcome: for

every participant the nausea outcome was either improvement or

no improvement (no change or nausea worsened). The only study

that assessed nausea (Winningham 1988) compared three groups;

for calculating the summary statistic we compared the index exer-

cise intervention with the combined reference groups (placebo and

untreated control). For those outcomes with data available from

only one study, we calculated and presented a summary statistic

for this particular study.

We used the random-effects model to obtain the average effect of

exercise because, in addition to the presence of random error, dif-

ferences between exercise studies during adjuvant cancer treatment

can also result from real differences between study populations,

adjuvant cancer treatment and the training stimulus. The random-

effects model considers these additional sources of between-study

variability as well as within-study variability.

Inconsistency of results across studies was evaluated by the I2 statis-

tic; I2 describes the percentage of variability in the point estimates

that is due to heterogeneity rather than sampling error (Higgins

2002). Following Higgins (Higgins 2003), we considered I2 values

of 25% as indicating low heterogeneity, I2 values of 50% as indi-

cating moderate heterogeneity and I2 values of 75% as indicating

large heterogeneity.

One trial (Segal 2001) contributed to the meta-analysis of physical

functioning with two exercise groups: one group performed self-

directed exercise (referred to as Segal 2001 SD) and one group

attended supervised exercise sessions (referred to as Segal 2001SU).

We incorporated both exercise arms into the meta-analysis and

allocated a control group to each of them, as half the number of

participants and events observed in the control group.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

Through a comprehensive literature search, 1612 potentially rel-

evant references were identified and screened for retrieval. A total

of 1580 references were excluded based on the title and abstract

with 32 references retrieved for more detailed evaluation. From

these, 22 publications were excluded, one trial is awaiting assess-

ment (pending publication) and nine controlled clinical trials were

selected as appropriate to be included in the meta-analyses.

Excluded studies

The exercise intervention was not concurrent with adjuvant can-

cer treatment in six trials: exercise was either part of a complex

intervention or no exercise intervention was implemented in three

trials; in four trials the participants were not predominantly breast

cancer patients; five trials could not be characterised as controlled

trials (they were study protocols or reviews). Three more trials did

not compare two groups assigned by the investigator (they com-

pared high exercisers with low exercisers) and one trial did not

assess health-related outcome measures. For a detailed description

of the reasons for exclusion see the table of ’Characteristics of ex-

cluded studies’. Note that this table does not only contain clinical

studies but also review articles etc which were part of our full text

retrieval in order to assure our decision of exclusion when abstracts

were ambiguous.

Included studies

The final selection based on consensus resulted in nine trials being

included in this review. For trial characteristics and outcomes seethe table of ’Characteristics of included studies’.

Participants

The distinctive feature of each of the trials appeared to be the mode

of adjuvant cancer treatment received by the participants. Women

obtained different regimens of adjuvant treatment across these

nine exercise intervention studies: one trial (Segal 2001) included

patients on chemotherapy, radiotherapy or hormonal therapy; pa-

tients received either chemotherapy or radiotherapy in two trials

(Campbell 2005; Mock 2004); chemotherapy only in four trials

(Crowley 2003; MacVicar 1986; MacVicar 1989; Winningham

1988); and two trials (Drouin 2002; Mock 1997) included pa-

tients undergoing radiotherapy only.

Intervention

Mode of exercise differed across trials. Seven trials tested aero-

bic exercise interventions, with three trials using cycle ergometer

interval training (MacVicar 1986; MacVicar 1989; Winningham

1988) and four trials offering walking programmes (Drouin 2002;



Mock 1997; Mock 2004; Segal 2001). The remaining two trials

(Campbell 2005; Crowley 2003) applied a combined aerobic-re-

sistance programme which was implemented as a group exercise

programme in one of the trials (Campbell 2005).

Apart from one trial (Drouin 2002) that used a stretching inter-

vention as the comparison arm, trials compared an exercise inter-

vention with no intervention.

Exercise interventions lasted six to seven weeks for women un-

dergoing radiation treatment in three trials (Drouin 2002; Mock

1997; Mock 2004), 10 weeks in three trials (MacVicar 1986;

MacVicar 1989; Winningham 1988) and more than 12 weeks

for women undergoing chemotherapy treatment in four trials

(Campbell 2005; Crowley 2003; Mock 2004; Segal 2001). The

longest intervention period of any trial was 26 weeks (Segal 2001).

Trials with shorter intervention periods (six to seven weeks) were

those with breast cancer patients receiving radiation treatment,

which is of shorter duration than chemotherapy. In one trial (Mock

2004) the exercise intervention was implemented to span the pe-

riod of time from initiation to cessation of the participant’s ad-

juvant therapy and subsequently participants in the intervention

arm of the trial had intervention periods of variable length (either

six weeks with radiation treatment or three to six months with

chemotherapy).

In four trials (Campbell 2005; MacVicar 1986; MacVicar 1989;

Winningham 1988) and in one of the two intervention arms in one

further trial (Segal 2001) the exercise intervention was supervised;

participants’ exercise (walking) was self-directed in another four

trials (Crowley 2003; Drouin 2002; Mock 1997; Mock 2004) and

in the second intervention arm of Segal 2001.

Outcomes

Physical fitness and fatigue were the outcome measures most

frequently assessed, with eight trials measuring physical fitness

(Campbell 2005; Crowley 2003; Drouin 2002; MacVicar 1986;

MacVicar 1989; Mock 1997; Mock 2004; Segal 2001) and seven

studies measuring fatigue (Campbell 2005; Crowley 2003; Drouin

2002; MacVicar 1986; Mock 1997; Mock 2004) or vitality (Segal

2001), as a related construct. Other outcomes assessed were body

composition, quality of life, psychological distress, side effects re-

lated to adjuvant cancer treatment, immune functioning, adher-

ence and adverse effects. For detailed information on outcome

measures see the table of ’Characteristics of included studies’.

Other study characteristics

Small sample size was common among included trials. Only two

trials (Mock 2004; Segal 2001) had more than 30 participants per

group; sample size was based on power calculations in only three

trials (Mock 1997; Mock 2004; Segal 2001). The median sample

size was 42 patients, interquartile range (IQR) 22 to 82. Two trials

were controlled clinical trials (CCT) without random allocation of

women to intervention and control group (MacVicar 1986; Mock

1997); the other trials were randomised controlled trials.

Risk of bias in included studies

Methodological quality

For results of the methodological assessment see the table of

’Methodological scores’ (Table 5). The intraclass correlation coef-

ficient (ICC 0.82, 95% CI - 0.03 to 0.97) indicated an almost per-

fect agreement among the two review authors; all disagreements

could be resolved by discussion.

On average, the quality of the studies was moderate with a mean

quality score of 11 (range 7 to 14 points). The methodological

quality score was associated with year of publication. The mean

overall methodological score in the three studies published in the

1980s was 8.3, compared to a mean of 12.5 in the studies published

later than 1990.

The following methodological issues relating to the included stud-

ies are of special interest in exercise studies. Firstly, although feasi-

ble, lack of observer blinding was common and was attempted in

only one study (Crowley 2003), however, the success of blinding

activities was not evaluated in that study.

Secondly, adherence problems which would continue to occur in

routine practice are of concern. Non-adherence was included in

the estimated benefit of exercise in all studies by including non-

adherent participants in the intervention group to which they were

assigned. Mock (Mock 2004) applied an innovative valid statistical

analysis and estimated the complier average causal effect (CACE)

which maintains randomisation-based properties and addresses

non-adherence to the exercise intervention. Potentially long-term

side effects of adjuvant cancer treatment are fatigue and weight

gain and so long-term follow up was considered in our quality

score. However, none of the included studies assessed outcomes

beyond the period of adjuvant therapy. In two ongoing studies a

six-month follow up is planned (Courneya 2005; Mutrie 2005).


The training stimulus was adequate in all included studies.

High quality training studies (HQTS)

Seven studies that had methodological quality scores of nine points

or greater and provided adequate exercise training stimuli were

classified as HQTS (Campbell 2005; Crowley 2003; Drouin 2002;

Mock 1997; Mock 2004; Segal 2001; Winningham 1988).

Effects of interventions

Effectiveness of exercise programmes

We performed meta-analyses for physical fitness, fatigue and body

composition (weight gain). Trials that were included in the meta-

analysis for cardiorespiratory fitness either measured performance,

for example distance walked in a given time, or maximum oxygen

uptake. Trials that were included in the meta-analysis for fatigue

predominantly applied the (revised) Piper fatigue scale. Moreover,

the symptom assessment scale (Mock 1997) and the vitality scale

of the 36-item short form (SF-36) of the Medical Outcomes Study

(MOS) (Segal 2001) were used as assessment instruments for fa-



tigue and vitality as a related construct, respectively.

Physical fitness

Five trials reported small but statistically significant improvements

in tests of cardiorespiratory fitness (Crowley 2003; Drouin 2002;

MacVicar 1989) or in physical performance assessed via timed

walking distances (Campbell 2005; Mock 1997). One controlled

clinical trial, a pilot study presented descriptive statistics only

(MacVicar 1986). In one trial (Segal 2001) improvements in car-

diorespiratory fitness (assessed via oxygen uptake) did not reach

statistical significance. However, improvement in physical func-

tioning (assessed via the physical functioning scale of the 36-

item short form (SF-36) of the Medical Outcomes Study (MOS)

reached statistical significance in the self-directed arm of this trial

(but not in the supervised arm). The authors’ interpretation of

these findings was that improvements in physical functioning (as

measured by the SF-36 physical functioning scale) may occur even

without changes in physiologic fitness measures (as measured by

oxygen uptake).

Meta-analysis of four trials yielding five comparisons (Campbell

2005; Drouin 2002; Mock 1997; Segal 2001 SD; Segal 2001SU)

provided some evidence that exercise improved cardiorespiratory

fitness: SMD 0.66, 95% CI 0.20 to 1.12 (see: Comparison and

data, figure 1). There was moderate heterogeneity with an I² of

54.7%. One trial (with two comparisons) predominantly con-

tributed to the heterogeneity and I2 was reduced to 0% when this

trial (Segal 2001) was excluded from the meta-analysis. Possible

causes for this finding are proposed in the Discussion section.

Two HQTS studies (Crowley 2003; Drouin 2002) evaluated

changes in muscular strength following aerobic exercise and aer-

obic-resistance exercise, respectively. In both trials no statistically

significant differences in strength were found and thus there is

no evidence that exercise is effective in increasing strength dur-

ing adjuvant cancer treatment. Data could be extracted from one

trial only (Drouin 2002): SMD -0.10, 95% CI -0.99 to 0.78 (seeComparison and data, figure 2).

Fatigue

Meta-analysis of five trials yielding six comparisons (Campbell

2005; Drouin 2002; Mock 1997; Mock 2004; Segal 2001 SD;

Segal 2001SU) found a statistically non-significant improvement

in fatigue for participants in the exercise intervention groups com-

pared to control (non-exercising) groups: SMD -0.12, 95% CI -

0.37 to 0.13 (see: Comparison and data, figure 3).

Body Composition

Several approaches for measuring the effects of exercise on body

composition were applied across studies, including body weight,

BMI, skinfold measurement and lean body mass. The result of

the meta-analysis of weight change was a statistically non-signif-

icant reduction in weight for participants in the aerobic exercise

intervention groups compared to a non-exercising control group:

SMD -1.11, 95% CI -2.44 to 0.22 (see: Comparison and data,

figure 4). One other trial (Drouin 2002) that also assessed weight

as an outcome could not be included in the meta-analysis since

only final values for weight were available.

Adherence and contamination

Different approaches were used among the included studies to

measuring adherence, that is, the level of exercise participation

achieved once the individual had agreed to undertake it. First, ad-

herence was assessed via the proportion of possible exercise ses-

sions attended by participants, on average; the total number of

possible exercise sessions resulted from frequencies per week that

ranged from two to five sessions. Second, adherence was assessed

as the proportion of adherent participants with cut-points of 60

and 90 minutes of exercise per week (Mock 1997; Mock 2004).

Adherence to exercise was said to be 70% or more of possible exer-

cise sessions (supervised or self-directed) in four trials (Campbell

2005; Crowley 2003; Drouin 2002; Segal 2001). Adherence may

be of a similar magnitude in one trial (MacVicar 1989) since they

let participants repeat missed sessions. The proportion of adher-

ent participants was 86% in (Mock 1997) and 72% in (Mock

2004). No information was given in the remaining two trials

(MacVicar 1986; Winningham 1988). Exercise levels in non-exer-

cising control groups (contamination) were reported in only two

trials (Crowley 2003; Mock 2004). Whereas Crowley 2003 stated

a significant difference in activity levels between the two groups

two groups in terms of frequency and duration of exercise, Mock

2004 observed 39% of the control group beginning regular walk-

ing during the study, at a level greater than 45 minutes per week,

which demonstrates considerable contamination. However, when

adopting the underlying cut-point of 45 minutes per week (Mock

2004), contamination can also be observed in the trial of Crowley

2003 (mean of 53 minutes per week walked in the control group).

Exercise adherence regarding exercise intensity was not reported

in any of the included trials; exercise adherence regarding duration

of single exercise sessions was reported in Mock 2004only.

Adverse effects

Adverse effects due to exercise were reported for six trials (

Campbell 2005; Crowley 2003; Drouin 2002; Mock 1997; Mock

2004; Segal 2001). Some adverse effects were observed in two tri-

als: Crowley (Crowley 2003) reported lymphedema in one par-

ticipant; Drouin (Drouin 2002) reported shoulder tendonitis and

decreases in strength due to overtraining in one participant. None

of the trials described how relevant information was collected or

whether surveillance of adverse effects was passive (spontaneously

reported by participants) or active (based on structured question-

naires or interviews).

Quality of life

Cancer- and cancer site-specific quality of life

Two HQTS (Campbell 2005; Segal 2001) examined effects of ex-

ercise on cancer- and cancer site-specific quality of life. Camp-

bell (Campbell 2005) found statistically significant differences be-

tween groups in general quality of life, particularly in physical and

functional subscales of the general version of the functional as-

sessment of cancer therapy scale (FACT-G). However, no statisti-



cally significant differences between groups were found for breast

cancer specific quality of life using the functional assessment of

cancer therapy scale for breast cancer patients (FACT-B). On the

other hand, no statistically significant differences between groups

were reported for either general or breast cancer specific quality of

life (FACT-G and FACT-B), over a 26 week intervention period,

in the trial of Segal (Segal 2001). Thus, evidence is conflicting as

to whether exercise interventions are effective in increasing can-

cer- and cancer site-specific quality of life. Data could be extracted

from one trial only (Campbell 2005): FACT G SMD 0.95, 95%

CI -0.01 to 1.91; FACT B SMD 0.78, 95% CI -0.16 to 1.72 (see:Comparison and data, figures 5 and 6).

Generic health-related quality of life

Generic health-related quality of life (assessed via MOS SF-36) was

examined by Segal (Segal 2001) and Crowley (Crowley 2003) and

no statistically significant differences between groups were found.

Thus, there is limited evidence for the effectiveness of exercise

programmes for generic health-related quality of life (assessed via

MOS SF-36) during breast cancer treatment. Quantitative syn-

thesis was not performed because only data for subscales, but no

data for physical and mental health summary measures, were pre-

sented.

Psychological distress outcomes: anxiety, mood, depression

Anxiety

Anxiety was reduced in one trial (Mock 1997) suggesting limited

evidence for the effects of exercise in reducing anxiety: SMD -

0.66, 95% CI -1.25 to - 0.06 (see: Comparison and data, figure

7).

Mood disturbances

There is no evidence for the effect of exercise on mood disturbances

with data from only one study that found no statistically significant

difference between groups (Drouin 2002): SMD -0.69, 95% CI

-1.60 to 0.22 (see: Comparison and data, figure 8).

Depression

There was only one trial that examined group differences for de-

pression and no statistically significant difference was found (Mock

1997): SMD -0.48, 95% CI -1.07 to 0.10 (see: Comparison and

data, figure 9). There is no evidence that exercise is effective in

reducing depression during adjuvant cancer treatment.

Other outcomes

No statistically significant differences between groups were found

for satisfaction with life (Campbell 2005), physical self-efficacy

and attention performance (Crowley 2003) as well as for satisfac-

tion with body (Mock 1997).

Biological outcomes

Immune functioning

Immune parameters (T-cells and natural killer cells) as well as ox-

idative stress were assessed in only one trial (Drouin 2002). No

statistically significant differences were observed during radiother-

apy (see: Comparison and data, figure 10, 11, 12). Thus, there

is no evidence for an effect of exercise programmes on immune

functioning during breast cancer treatment.

Other side effects relating to adjuvant cancer treatment: nausea

and sleep disturbances

Nausea was measured in one trial only (Winningham 1988); the

data from this trial show that moderate aerobic exercise may pro-

vide relief from the symptom of chemotherapy-associated nausea

in some patients. The relative risk (RR) for nausea relief was 4.33,

95% CI 1.34 to 13.99 (see: Comparison and data, figure 13). Thus,

there is limited evidence for an effect of exercise programmes on

reduction of nausea.

Sleep disturbances were reduced in one trial (Mock 1997) which

provided limited evidence for an effect of exercise programmes on

reduction of sleep disturbances: SMD -0.67, 95% CI -1.27 to -

0.08 (see: Comparison and data, figure 14).

D I S C U S S I O N

This review offers little evidence that women with breast cancer

may benefit through improved physical fitness from exercise dur-

ing adjuvant cancer treatment. Statistically significant improve-

ments for cardiorespiratory fitness, anxiety, sleep disturbance and

nausea relief were found. No statistically significant differences

were found for the other outcomes examined (fatigue, weight,

quality of life, depression, strength, immune function or mood).

However, these results are based on a small number of trials and

usable data could be extracted from only one study for the major-

ity of these outcomes. Only one of the two non-randomised tri-

als (Mock 1997) was included in quantitative analyses; results are

similar to those of randomised trials and do not appear to produce

any bias.

Limitations of the review

This review is based on a small number of small trials with limited

numbers of participants and with a considerable degree of clinical

heterogeneity between trials regarding adjuvant cancer treatment

and exercise intervention. It remains to be explored whether dif-

ferences in adjuvant cancer treatment and exercise intervention

actually affect results. In spite of our comprehensive attempts to

identify all relevant studies, predominantly English language stud-

ies were retrieved for inclusion in this review (one German trial is

awaiting assessment after its completion). This may reflect selec-

tive publication of English language studies with statistically sig-

nificant findings. The policy of registration of trials may provide

an interesting basis for addressing publication bias in the future

(Antes 2004).

The assessment of training stimulus was based on two scores, one

for aerobic and one for resistance exercise. For exercise interven-

tions with both aerobic and resistance modules, applicability of

these two single scores (developed for assessing training stimulus



of aerobic or resistance interventions only) may lead to the under-

estimation of the strength of the training stimulus.

Limitations of included studies

There was a clear trend toward a higher methodological quality in

studies published after 1990; this trend coincides with the devel-

opment of recommendations for the reporting of RCTs, for ex-

ample the CONSORT statement (Altman 2001). On the other

hand, the early studies are really pioneers in the field of exercising

during adjuvant cancer therapy. The effect of improved quality on

trial outcomes could not be assessed in this review due to limited

usable data from these trials.

Reporting of outcome measures

A wide range of outcome measures was assessed across the studies,

which made it difficult to combine outcomes in meta-analysis. For

example, psychosocial distress was assessed via mood, anxiety, de-

pression, satisfaction with life, satisfaction with body, self-efficacy

and sleep disturbances; and body composition was evaluated via

weight, body mass index (BMI), subcutaneous fat and lean body

mass. Moreover, data reporting was very poor and did not provide

estimates of effect size that could be pooled. Reporting of harms-

related data from exercise intervention trials during adjuvant can-

cer treatment also needs improvement.

Statistical power

Benefits of exercise interventions may be relatively small. Sub-

sequently, the number of participants included should be great

enough for allowing the detection of small differences between

groups. The sample sizes in the included studies ranged from 6 to

60 in the intervention group.


The individual’s level of fitness is an important factor to consider

before determining the level of exercise intensity (ACSM 2000).

According to ACSM (ACSM 2000), deconditioned individuals

may demonstrate increases in their cardiorespiratory fitness with

exercise intensities at the lower end of the intensity continuum;

whereas more fit individuals need to work at the higher end of the

intensity continuum to improve fitness. The initial fitness level

was considered in three studies only, which limited participation

to sedentary individuals; however, definitions of sedentary varied.

Adherence and contamination

For sedentary individuals, a change in personal health behaviour

is required in order to take up regular exercise. Thus, any exercise

intervention can additionally be evaluated according to the degree

of behavioural change achieved in the intervention group; a lack

of adherence can compromise the training stimulus as well as the

sustainability of exercise behaviour. According to the American

College of Sports Medicine (ACSM 2000) the art of exercise pre-

scription is the “successful integration of exercise science with be-

havioral techniques that result in long-term program compliance”.

Only one trial (Campbell 2005) applied theory-based methods

focused on changing behaviour. Adherence problems do not only

arise in terms of participation in exercise sessions and frequency

of sessions but also in terms of the training intensity and duration

actually achieved during each exercise session. Insufficient exercise

intensity or duration may compromise the training stimulus as a

whole. However, these two facets of the training stimulus were

poorly evaluated and reported in the included studies.

Besides adherence, the extent to which the control group performs

exercise (contamination) is a second critical component in exercise

studies. Exercise contamination is rarely reported and often only

when the exercise programme is home based.

Results

Physical fitness

Moderate heterogeneity across studies was observed for physical

fitness outcomes. It was one trial that predominantly contributed

to this heterogeneity (Segal 2001). The trial characteristics that

may have contributed to the heterogeneity were as follows. The

exercise intensity of 50 to 60% maximum heart rate was rather low

and may have resulted in a modest effect that was not statistically

significant; the intervention period was relatively long (26 weeks)

compared with other trials included in this meta-analysis, possibly

resulting in the cumulative side effects of cancer treatment over

time counteracting the physiological exercise response. Regarding

muscular strength, there was no evidence for positive effects of ex-

ercise. However, in Drouin (Drouin 2002) the intervention (walk-

ing) was not intended to produce effects on this outcome (mus-

cular strength in upper extremities) and subsequently the effect of

exercise on muscular strength should be evaluated in future trials.

Fatigue

Additional exercise studies are required to assess the effect of exer-

cise on cancer-related fatigue.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Receiving adjuvant treatment for breast cancer should no longer

be seen as a rigid contraindication for exercise, which should be

regarded as a feasible, supportive self-care intervention. Based on

current evidence, improvement can be expected in physical fitness

and the resulting capacity for performing activities of daily life.

An improvement for other outcome variables is still tenable, due

to a lack of evidence.

Exercise adherence during cancer treatment constitutes a challenge

and thus programmes are needed to foster exercise participation.

For behaviour changes to occur (the adoption of regular exercise in

this instance) it is essential that intervention programmes focus on



underlying principles from theories about why people change their

behaviours. The social cognitive theory appears to be a promising

theoretical framework for promoting exercise behaviour in breast

cancer patients (Pinto 2002; Rogers 2004; Rogers 2005). The key

construct in the social cognitive theory is self-efficacy. Exercise self-

efficacy can be described either as the confidence to overcome bar-

riers to exercise or as confidence in the ability to perform certain

exercise tasks. Self-efficacy has proven to be an important corre-

late of exercise among breast cancer patients. Exercise self-efficacy

among breast cancer patients during cancer treatment is reported

as lowest when patients are nauseated, tired, not interested, lack-

ing time and lacking exercise enjoyment (Rogers 2006).

Future exercise interventions should target the exercise barriers.

Exercise enjoyment, for example, may be addressed through pick-

ing up recent trends in the field of fitness, such as Pilates, Nordic

walking, Tai Chi, step aerobics and dancing; of course adequately

adjusted to the needs and limitations of the target group. Group

exercise or partner assisted exercises may also increase exercise en-

joyment. Time management may be addressed by exercise classes

taking place in different locations, choosing venues that are ac-

cessible by public transport and by timetabling classes at various

times in the day and evening.

Implications for research

At this stage there is a lack of evidence for relevant benefits of

exercise as well as for harms. Results of ongoing trials have to be

awaited and further trials with adequate power are needed.

Consensus of researchers on outcome measures for exercise stud-

ies involving breast cancer patients receiving adjuvant treatment

is needed in order to facilitate interpretation and comparison of

results across various interventions. The long-term follow up of

exercise interventions requires attention because some side effects

of adjuvant cancer treatment are either long term, such as fatigue

or deconditioning, or may be related to recurrence and mortality,

such as weight gain. Besides health related outcome measures, ad-

herence and contamination as well as potential harms should be

assessed and reported. Reporting standards for harms (Ioannidis

2004) should help to inform practitioners and the public on poten-

tial harms of exercise interventions during adjuvant cancer treat-

ment.

As described above, the actual training stimulus may substantially

deviate from the assigned exercise regimen. If participants allo-

cated to the exercise group do not exercise (non-adherence), and

at the same time participants allocated to the control group do

exercise (contamination), the originally intended trial groups are

distorted into groups with participants who exercise and those who

do not (moreover in unknown proportions). If those groups are

analysed as ’randomised’, effects may be underestimated. In effi-

cacy trials investigators need to ensure adherence to the interven-

tion to determine whether exercise interventions in this popula-

tion work. Subsequently, exercise programmes should be designed

to address exercise facilitators such as exercise enjoyment; this may

be achieved by offering a variety of alternating exercise modes that

assure an adequate training stimulus. Inclusion of sedentary par-

ticipants only may be a way to deal with contamination issues,

utilising the observation that physical activity and exercise decline

during cancer treatment (Irwin 2003). In effectiveness trials, we

recommend that both adherence and contamination are reported

as an outcome measure because poor adherence can render an ef-

ficacious intervention ineffective. As a format for reporting adher-

ence we regard the following specification as helpful: the propor-

tion of participants who achieved a cut-point of 60 minutes of

moderate to strenuous exercise per week.

Finally, regarding recruitment problems and thus the problem of

small sample sizes, multi-site trials may be advisable.

A C K N O W L E D G E M E N T S

We would like to thank Sharon Parker who rendered assistance in

her role as Assistant Review Group Coordinator of the Cochrane

Breast Cancer Group and the Editorial Base of the Cochrane Breast

Cancer Group. Moreover, we would like to thank the referees who

provided valuable feedback during the peer review process, the

authors of primary trials for additional information about their

trials and the expert who contributed to identifying studies for

inclusion. Anne Franke and Horst Müller rendered support in

statistics and Katja Borodulin assisted with one Finish language

publication.



R E F E R E N C E S

References to studies included in this review

Campbell 2005 {published data only}

Campbell A, Mutrie N, White F, McGuire F, Kearney N.

A pilot study of a supervised group exercise programme as

a rehabilitation treatment for women with breast cancer

receiving adjuvant treatment. European Journal of Oncology

Nursing 2005;9(1):56–63.

Crowley 2003 {published data only}

Crowley SA. The effect of a structured exercise program

on fatigue, strength, endurance, physical self-efficacy, and

functional wellness in women with early stage breast cancer.

Ann Arbor, Michigan: University of Michigan, 2003:127.

Drouin 2002 {published data only}

Drouin J. Aerobic exercise training effects on physical function,

fatigue and mood, immune status, and oxidative stress in

subjects undergoing radiation treatment for breast cancer.

Detroit: Wayne State University, 2002:142.

MacVicar 1986 {published data only}∗ MacVicar MG, Winningham ML. Promoting the

functional capacity of cancer patients. Cancer Bulletin 1986;

38:235–9.

MacVicar 1989 {published data only}

MacVicar MG, Winningham ML, Nickel JL. Effects of

aerobic interval training on cancer patients’ functional

capacity. Nursing Research 1989;38(6):348–51.

Winningham ML, MacVicar MG, Bondoc M, Anderson

JI, Minton JP. Effect of aerobic exercise on body weight

and composition in patients with breast cancer on adjuvant

chemotherapy. Oncology Nursing Forum 1989;16:683–9.

Mock 1997 {published data only}

Mock V, Dow KH, Meares CJ, Grimm PM, Dienemann

JA, Haisfield Wolfe ME, et al.Effects of exercise on fatigue,

physical functioning, and emotional distress during

radiation therapy for breast cancer. Oncology Nursing Forum

1997;24(6):991–1000.


Mock V, Frangakis C, Davidson NE, Ropka ME, Pickett

M, Poniatowski B, et al.Exercise manages fatigue during

breast cancer treatment: A randomized controlled trial.

Psychooncology 2004;14:14.

Segal 2001 {published and unpublished data}∗ Segal R, Evans W, Johnson D, Smith J, Colletta S, Gayton

J, et al.Structured exercise improves physical functioning

in women with stages I and II breast cancer: results of a

randomized controlled trial. Journal of Clinical Oncology

2001;19:657–65.

Segal 2001 SD {published and unpublished data}

Segal R, Evans W, Johnson D, Smith J, Colletta S, Gayton




2001;19(3):657–65.

Segal 2001SU {published and unpublished data}

Segal R, Evans W, Johnson D, Smith J, Colletta S, Gayton




2001;19:657–65.

Winningham 1988 {published data only}

Winningham ML, MacVicar MG. The effect of aerobic

exercise on patient reports of nausea. Oncology Nursing

Forum 1988;15(4):447–50.

References to studies excluded from this review

Burnham 2002 {published data only}

Burnham TR, Wilcox A. Effects of exercise on physiological

and psychological variables in cancer survivors. Medicine

and Science in Sports and Exercise 2002;34(12):1863–7.

Courneya 2003a {published data only}

Courneya KS, Friedenreich CM, Sela RA, Quinney HA,

Rhodes RE, Handman M. The group psychotherapy and

home-based physical exercise (group-hope) trial in cancer

survivors: physical fitness and quality of life outcomes.

Psychooncology 2003;12(4):357–74.

Courneya 2003b {published data only}

Courneya KS, Mackey JR, Bell GJ, Jones LW, Field CJ,

Fairey AS. Randomized controlled trial of exercise training in

postmenopausal breast cancer survivors: cardiopulmonary

and quality of life outcomes. Journal of Clinical Oncology

2003;21(9):1660–8.

Demark-Wahnefried 02 {published data only}

Demark-Wahnefried W. Randomized study of a diet

and exercise-based counseling program versus a standard

counseling program for patients with early-stage breast

or prostate cancer. http://www.clinicaltrials.gov/ct/show/

NCT00044980?order=128. National Cancer Institute,

assessed 08.05.2002. [: Ref Type: Unpublished Work]

Demark-Wahnefried 03 {published data only}

Demark-Wahnefried W, Morey MC, Clipp EC, Pieper

CF, Snyder DC, Sloane R, Cohen HJ. Leading the way in

exercise and diet (Project LEAD): intervening to improve

function among older breast and prostate cancer survivors.

Controlled Clinical Trials 2003;24(2):206–23.

Dimeo 1999 {published data only}

Dimeo FC, Stieglitz RD, Novelli-Fischer U, Fetscher

S, Keul J. Effects of physical activity on the fatigue and

psychologic status of cancer patients during chemotherapy.

Cancer 1999;85(10):2273–7.

Fairey 2003 {published data only}

Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW,

Mackey JR. Effects of exercise training on fasting insulin,

insulin resistance, insulin-like growth factors, and insulin-

like growth factor binding proteins in postmenopausal

breast cancer survivors: a randomized controlled trial.

Cancer Epidemiology, Biomarkers & Prevention 2003;12(8):

721–7.



Given 2002 {published data only}

Given B, Given C, McCorkle R, Kozachik S, Cimprich

B, Rahbar M, Wojcik C. Pain and Fatigue Management:

Results of a Nursing Randomized Clinical Trial. Oncology

Nursing Forum 2002;29(6):949–56.

Ho 1986 {published data only}

Ho C. Psychological adaptation and coping resources

of breast cancer patients: Comparisons across three

treatment modalities. Dissertation-Abstracts-International.

Dissertation–Abstracts–International, Vol 47 (6–B): 2617,

1986; Vol. 47:2617.

Latikka 1997 {published data only}

Latikka P, Pukkala E, Vihko V. [Exercise and breast cancer].

Duodecim 1997;113(4):317–22.

McKenzie 2003 {published data only}

McKenzie DC, Kalda AL. Effect of upper extremity exercise

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Schwartz 1999 {published data only}

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Campbell 2005

Methods RCT, 2 groups, computer-generated numbers, stratification by adjuvant cancer treatment

Participants 22 breast cancer patients, after surgery, receiving chemotherapy or radiotherapy

Interventions Group exercise: aerobic and resistance training (walking, cycling, low-level aerobics, muscle-strengthening

exercises, circuits),

behaviour change communication, supervised,

60 - 75% HRmax,

10 - 20 min per session exercise, plus warm-up, cool-down, relaxation,

2/week,

12 weeks.

Control: no intervention.

Outcomes Quality of life (cancer specific, cancer site-specific),

fatigue,

physical performance,

physical activity,

expectation of treatment,

satisfaction with life.

Notes Methodological quality score: 13.

Training stimulus: adequate.

High quality training study: yes.

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Crowley 2003

Methods RCT, 2 groups, random numbers table; Intention-to-treat analysis

Participants 22 breast cancer patients, stage I, II; after surgery, receiving adjuvant chemotherapy (Adriamycin, Cytoxan)

Interventions Aerobic training (walking) and resistance training (tubing),

self-directed,

Aerobic training: 60% of HRmax, 20 - 60 min. per session, 3 - 5 d/week, 13 weeks.

Resistance training: 12 - 15 repetitions, ca. 20 min, 1 - 2 sets, 2 - 3 d/week, 13 weeks




Crowley 2003 (Continued)

Outcomes Cardiorespiratory fitness,

muscular fitness,

fatigue,

physical self-efficacy,

attention performance,

functional wellness,

quality of life,

physical activity.




Risk of bias


Allocation concealment? Yes A - Adequate

Drouin 2002

Methods RCT, 2 groups, random number chart.

Participants 23 breast cancer patients, stages 0 - III; after surgery, receiving radiotherapy, sedentary

Interventions Aerobic training (walking), self-directed,

50 - 70 % HRmax

20 - 45 min per session,

3 - 5/week,

7 weeks.

Control: Stretching, 3 - 5/week, 7 weeks.

Outcomes Fatigue,

cardiorespiratory fitness,

muscular fitness,

mood,

body composition,

immune function (CD4+/ CD8+ ratio, natural killer cytotoxic activity) ,

oxidative stress (8-isoprostane).




Risk of bias




Drouin 2002 (Continued)


MacVicar 1986

Methods CCT, 2 groups.

Participants 10 breast cancer patients, after surgery, receiving chemotherapy

Interventions Aerobic training (cycling, interval training),

60 - 85% HRmax,

20 - 30min per session,

3/week,

10 weeks.



mood.

Notes Only descriptive statistics presented.

Methodological quality score: 7.


High quality training study: no.

Risk of bias


Allocation concealment? Unclear D - Not used

MacVicar 1989

Methods RCT, 3 groups, stratified by functional capacity.

Participants 45 breast cancer patients, stage II; after surgery, receiving chemotherapy

Interventions (1) Aerobic training (cycling, interval training),

60 - 85% HRmax,


3 /week,

10 weeks.

(2) Control 1:

flexibility and stretching exercises.

(3) Control 2: no intervention.


Body composition (described in Winningham 1989) via secondary analysis, comparing intervention to

no intervention group with n=24)



MacVicar 1989 (Continued)

Notes Description includes Winningham 1989 (2 publications).

Methodological quality score: 8.


High quality training study: no.

Risk of bias



Mock 1997

Methods CCT, 2 groups, alternating assignment.

Participants 46 breast cancer patients, stages I and II; after surgery, receiving radiotherapy

Interventions Aerobic training (walking),

self-directed,

Rate of perceived exertion: 11 - 13,


4 - 5/week,

6 weeks.


Outcomes Physical activity,

fatigue,


emotional distress,

symptom experience: sleep disturbances, depression, anxiety, satisfaction with body




Risk of bias


Allocation concealment? Unclear D - Not used



Mock 2004

Methods RCT, 2 groups, computer-generated randomisation; Complier Average Causal Effect (CACE); Intention-

to-treat effect of assignment that focuses only on ’full compliers’

Participants 119 breast cancer patients, stages 0 - III, after surgery, receiving chemotherapy or radiotherapy, sedentary

Interventions Aerobic training (walking), self-directed,

50 - 70% HR max,

15 min per session, increased to 30 min as training progressed,

5 - 6 /week,

radiotherapy: 6 weeks exercise;

chemotherapy: 3 - 6 month exercise.


Outcomes Fatigue,


physical activity.




Risk of bias



Segal 2001

Methods RCT, 3 groups.

Participants n=123.

Interventions (1) ’Segal 2001 SD’ performed self-directed aerobic training; (2) ’Segal 2001 SU’ performed supervised

training;

(3) Control group.

Outcomes Generic and cancer-, cancer site-specific quality of life,


body composition.

Notes Trial compared 2 exercise groups (self-directed and supervised) to 1 control group;

for meta-analysis control group was split into halves in order to compare with the particular intervention

group.

Described separately in Segal 2001 SD and Segal 2001 SU

Risk of bias



Segal 2001 (Continued)



Segal 2001 SD

Methods RCT, 2 groups (total: 3 groups), random numbers table; Intention-to-treat analysis

Participants 60 (total: n=123) breast cancer patients, stages I and II, receiving radiotherapy or hormonal therapy or

chemotherapy

Interventions IIntervention (n=40): self-directed aerobic training (walking),

50 - 60% VO2max,

35 - 40 min per session (including warm-up, walking, cool down),

5/weeks,

26 weeks.

Control (n=20): no intervention.



body composition.




Risk of bias



Segal 2001SU

Methods RCT, 2 groups (total: 3 groups), random numbers table; Intention-to-treat analysis

Participants 63 (total: n=123) breast cancer patients, stages I and II, receiving radiotherapy or hormonal therapy or

chemotherapy

Interventions Intervention (n=42): supervised aerobic training (walking), supervised,

50 - 60% VO2max,

35 - 40 min per session (including warm-up, walking, cool down),

5/weeks,

26 weeks.

Control (n=21): no intervention.



Segal 2001SU (Continued)



body composition.




Risk of bias



Winningham 1988

Methods RCT, 3 groups; Intention-to-treat analysis.

Participants 42 breast cancer patients, after surgery, receiving chemotherapy

Interventions Aerobic training (cycling, interval training),

60 - 85% HRmax,

20 - 30min per session,

3/week,

10 weeks.

Control 1: no intervention.

Control 2: mild stretching, conversation, 1/week.

Outcomes Nausea,

somatisation.




Risk of bias



HRmax: maximum heart rate

VO2max: maximal oxygen uptake



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Burnham 2002 Exercise intervention not concurrent with adjuvant cancer treatment

Courneya 2003a Participants not predominantly breast cancer patients (40%), exercise as part of a complex intervention

(group psychotherapy plus exercise)

Courneya 2003b Exercise intervention not concurrent with adjuvant cancer treatment (<50 % under current hormone

therapy)

Demark-Wahnefried 02 No clinical trial, protocol status,

exercise as part of a complex intervention (diet and exercise based counseling program)

Demark-Wahnefried 03 No clinical trial, design paper

Dimeo 1999 Participants not predominantly breast cancer patients (cancer patients with solid tumors and lymphomas)

,

no chemotherapy, radiotherapy or hormonal treatment (high dose chemotherapy followed by peripheral

stem cell transplantation)

Fairey 2003 Exercise intervention not concurrent with adjuvant cancer treatment

Given 2002 Participants not predominantly breast cancer patients (BC stages 0 - IV; colon and lung cancer),

no exercise intervention

Ho 1986 No exercise intervention

Latikka 1997 No clinical trial, review

McKenzie 2003 Intervention and adjuvant treatment not concurrent

Mock 1994 Exercise as part of a complex intervention (walking plus support group)

Mock 2001 Trial does not compare two groups as assigned by investigator

Mock 2002 No exercise intervention

Mustian 2002 No clinical trial, review

Pickett 2002 No health-related outcome measure (adherence study)

Pinto 2003 Exercise intervention not concurrent with adjuvant cancer treatment

Schwartz 1999 Trial does not compare two groups as assigned by investigator

Schwartz 2001 Trial does not compare two groups as assigned by investigator



(Continued)

Segar 1998 Exercise intervention not concurrent with adjuvant cancer treatment

Shaw 2003 No clinical trial, protocol status,

exercise as part of a complex intervention (calcium-rich diet and exercise)

Wilkie 2003 Participants not predominantly breast cancer patients (63% female),

duration of intervention programme 4 weeks

Characteristics of ongoing studies [ordered by study ID]

Chetiyawardana 2004

Trial name or title A pilot study to investigate the effects on fitness and quality of life of an individualised exercise programme

for breast cancer patients undergoing radiotherapy

Methods

Participants 10 breast cancer patients, receiving a 3 week course of radiotherapy at the Queen Elizabeth Hospital, University

Hospital Birmingham Trust

Interventions Intervention: individualised exercise programme;


Outcomes Fitness, quality of life (the European Organisation for Research and Treatment of Cancer - EORTC QLQ-

C3O, version 3)

Starting date November 2003

Contact information Dr A D Chetiyawardana

Queen Elizabeth Hospital

Birmingham

B15 2TH

United Kingdom

+44 (0)121 472 1311

Notes

Courneya 2005

Trial name or title Comparison of aerobic versus resistance exercise training in enhancing quality of life in early stage breast

cancer survivors receiving chemotherapy: A multicentre randomized trial

Methods

Participants 210 post-surgical breast cancer survivors scheduled for adjuvant chemotherapy



Courneya 2005 (Continued)

Interventions Intervention: Aerobic training,

Resistance training, 12 - 24 weeks,

Control: no intervention (waiting list).

Outcomes Psychosocial well-being (e.g. fatigue, depression, anxiety, self-esteem), QOL (physical, functional, emotional,

social, and spiritual well-being), and physical fitness (i.e., cardiovascular endurance, muscular endurance,

body composition)

Starting date

Contact information Courneya, Kerry

1Faculty of Physical Education, University of Alberta

Notes six months follow-up!

Kleine-Tebbe 2006

Trial name or title Influence of aerobic exercise compared to relaxation training for women with breast cancer during adjuvant

chemotherapy

Methods

Participants 33 breast cancer patients receiving chemotherapy

Interventions Intervention: Aerobic training (walking), supervised, 24 weeks; 3/week, 20 - 25 min.

Control: Relaxation training

Outcomes Cardiorespiratory fitness, fatigue, body composition, quality of life, anxiety, depression, immune functioning

Starting date December 2003

Contact information Anke Kleine-Tebbe, Ph.D, Brustzentrum Charite, Campus Virchow Klinikum, Augustenburger Platz 1,

13353 Berlin

Notes

Mutrie 2005

Trial name or title A randomised controlled trial of a supervised exercise programme as a rehabilitation treatment for women

receiving early stage breast cancer treatment

Methods

Participants 182 breast cancer patients, receiving chemotherapy or radiotherapy



Mutrie 2005 (Continued)

Interventions Intervention: 12 week supervised exercise programme,

50 - 75% age-adjusted HRmax,

10 - 20 min plus warm-up, cool-down and relaxation,

2/week .

Control: usual care and monitoring.

Outcomes General quality of life (FACT-G), breast-specific quality of life (FACT-B), fatigue (FACT-F), endocrine

symptoms (FACT-ES), depression (BDI), mood (PANAS), physical performance (12 minute walking test),

physical activity (SPAQ), body composition (BMI), perceived expectations and benefits

Starting date

Contact information Anna Campbell Ph.D

Cancer Research UK Physical Activity Study

Strathclyde University (Jordanhill Campus)

Pesoe Building,

76 Southbrae Drive,

Glasgow G13 1PP

Phone:44-141-950-3137

[email protected]

Anna Campbell Ph.D

Cancer Research UK Physical Activity Study

Strathclyde University (Jordanhill Campus)

Pesoe Building,

76 Southbrae Drive,

Glasgow G13 1PP

Phone:44-141-950-3137

[email protected]

Notes six months follow-up!



D A T A A N D A N A L Y S E S

Comparison 1. Exercise versus control

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Cardiorespiratory fitness 5 207 Std. Mean Difference (IV, Random, 95% CI) 0.66 [0.20, 1.12]

2 Strength 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

3 Fatigue 6 317 Std. Mean Difference (IV, Random, 95% CI) -0.12 [-0.37, 0.13]

4 Weight change 3 147 Mean Difference (IV, Random, 95% CI) -1.11 [-2.44, 0.22]

5 Cancer specific quality of life 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

6 Cancer site-specific quality of life 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

7 Anxiety 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

8 Mood disturbance 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

9 Depression 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

10 Natural killer cells 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

11 T-cells 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

12 Oxidative stress 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

13 Nausea relief 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

14 Sleep disturbances 1 Std. Mean Difference (IV, Random, 95% CI) Totals not selected

Analysis 1.1. Comparison 1 Exercise versus control, Outcome 1 Cardiorespiratory fitness.

Review: Exercise for women receiving adjuvant therapy for breast cancer

Comparison: 1 Exercise versus control

Outcome: 1 Cardiorespiratory fitness

Study or subgroup Exercise Control

Std.Mean

Difference Weight

Std.Mean

Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Campbell 2005 10 1423 (261) 9 1083 (176) 12.9 % 1.44 [ 0.41, 2.48 ]

Drouin 2002 13 22.6 (6.2) 8 16.6 (2.2) 14.3 % 1.13 [ 0.17, 2.09 ]

Mock 1997 22 3371 (300.46) 22 3089 (300.46) 22.3 % 0.92 [ 0.30, 1.55 ]

Segal 2001 SD 40 26.3 (5.3) 20 25.1 (6.1) 25.0 % 0.21 [ -0.33, 0.75 ]

Segal 2001SU 42 26.2 (5.1) 21 25.1 (6.1) 25.4 % 0.20 [ -0.33, 0.72 ]

Total (95% CI) 127 80 100.0 % 0.66 [ 0.20, 1.12 ]

Heterogeneity: Tau2 = 0.14; Chi2 = 8.83, df = 4 (P = 0.07); I2 =55%

Test for overall effect: Z = 2.81 (P = 0.0049)

-4 -2 0 2 4

Favours Control Favours exercise



Analysis 1.2. Comparison 1 Exercise versus control, Outcome 2 Strength.



Outcome: 2 Strength


Std.Mean

Difference

Std.Mean

Difference


Drouin 2002 13 31.3 (6.5) 8 32 (6.4) -0.10 [ -0.99, 0.78 ]

-4 -2 0 2 4

Favours control Favours exercise

Analysis 1.3. Comparison 1 Exercise versus control, Outcome 3 Fatigue.



Outcome: 3 Fatigue


Std.Mean

Difference Weight

Std.Mean

Difference


Campbell 2005 10 2.43 (1.94) 9 4.35 (3.48) 6.9 % -0.66 [ -1.59, 0.27 ]

Drouin 2002 13 3.4 (1.9) 8 3.9 (2.4) 7.6 % -0.23 [ -1.11, 0.66 ]

Mock 1997 22 26.12 (20.27) 24 43.05 (36.37) 15.7 % -0.56 [ -1.15, 0.03 ]

Mock 2004 54 3.5 (2.4) 54 3.7 (2.6) 32.1 % -0.08 [ -0.46, 0.30 ]

Segal 2001 SD 40 -60.8 (23.5) 20 -61.6 (17.7) 18.5 % 0.04 [ -0.50, 0.57 ]

Segal 2001SU 42 -55.8 (24) 21 -61.6 (17.7) 19.1 % 0.26 [ -0.27, 0.78 ]

Total (95% CI) 181 136 100.0 % -0.12 [ -0.37, 0.13 ]

Heterogeneity: Tau2 = 0.01; Chi2 = 5.83, df = 5 (P = 0.32); I2 =14%


-4 -2 0 2 4

Favours exercise Favours control



Analysis 1.4. Comparison 1 Exercise versus control, Outcome 4 Weight change.



Outcome: 4 Weight change

Study or subgroup Exercise ControlMean

Difference WeightMean

Difference


MacVicar 1989 12 0.82 (2.1) 12 1.99 (2.1) 63.0 % -1.17 [ -2.85, 0.51 ]

Segal 2001 SD 40 0.4 (3.71) 20 0.6 (6.21) 20.4 % -0.20 [ -3.15, 2.75 ]

Segal 2001SU 42 -1.4 (6.28) 21 0.6 (6.21) 16.7 % -2.00 [ -5.27, 1.27 ]

Total (95% CI) 94 53 100.0 % -1.11 [ -2.44, 0.22 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.65, df = 2 (P = 0.72); I2 =0.0%


-10 -5 0 5 10


Analysis 1.5. Comparison 1 Exercise versus control, Outcome 5 Cancer specific quality of life.



Outcome: 5 Cancer specific quality of life


Std.Mean

Difference

Std.Mean

Difference


Campbell 2005 10 11.9 (13.8) 9 -2.9 (16.1) 0.95 [ -0.01, 1.91 ]

-4 -2 0 2 4




Analysis 1.6. Comparison 1 Exercise versus control, Outcome 6 Cancer site-specific quality of life.



Outcome: 6 Cancer site-specific quality of life


Std.Mean

Difference

Std.Mean

Difference


Campbell 2005 10 14.3 (19.8) 9 -1.7 (19.4) 0.78 [ -0.16, 1.72 ]

-4 -2 0 2 4


Analysis 1.7. Comparison 1 Exercise versus control, Outcome 7 Anxiety.



Outcome: 7 Anxiety


Std.Mean

Difference

Std.Mean

Difference


Mock 1997 22 10.44 (24.7) 24 26.93 (24.7) -0.66 [ -1.25, -0.06 ]

-4 -2 0 2 4




Analysis 1.8. Comparison 1 Exercise versus control, Outcome 8 Mood disturbance.



Outcome: 8 Mood disturbance


Std.Mean

Difference

Std.Mean

Difference


Drouin 2002 13 5.1 (22.1) 8 23.9 (32) -0.69 [ -1.60, 0.22 ]

-4 -2 0 2 4


Analysis 1.9. Comparison 1 Exercise versus control, Outcome 9 Depression.



Outcome: 9 Depression


Std.Mean

Difference

Std.Mean

Difference


Mock 1997 22 9.51 (23.5) 24 21.05 (23.5) -0.48 [ -1.07, 0.10 ]

-4 -2 0 2 4




Analysis 1.10. Comparison 1 Exercise versus control, Outcome 10 Natural killer cells.



Outcome: 10 Natural killer cells


Std.Mean

Difference

Std.Mean

Difference


Drouin 2002 13 8.5 (9.2) 8 6.6 (4.2) 0.24 [ -0.65, 1.12 ]

-4 -2 0 2 4


Analysis 1.11. Comparison 1 Exercise versus control, Outcome 11 T-cells.



Outcome: 11 T-cells


Std.Mean

Difference

Std.Mean

Difference


Drouin 2002 13 2.5 (1.1) 8 1.8 (1) 0.63 [ -0.27, 1.54 ]

-4 -2 0 2 4




Analysis 1.12. Comparison 1 Exercise versus control, Outcome 12 Oxidative stress.



Outcome: 12 Oxidative stress


Std.Mean

Difference

Std.Mean

Difference


Drouin 2002 10 244 (132.6) 5 316.4 (118.3) -0.53 [ -1.63, 0.57 ]

-4 -2 0 2 4


Analysis 1.13. Comparison 1 Exercise versus control, Outcome 13 Nausea relief.



Outcome: 13 Nausea relief

Study or subgroup Exercise Control Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Winningham 1988 8/16 3/26 4.33 [ 1.34, 13.99 ]

0.01 0.1 1 10 100




Analysis 1.14. Comparison 1 Exercise versus control, Outcome 14 Sleep disturbances.



Outcome: 14 Sleep disturbances


Std.Mean

Difference

Std.Mean

Difference


Mock 1997 22 12.38 (29.5) 24 32.58 (29.5) -0.67 [ -1.27, -0.08 ]

-4 -2 0 2 4


A D D I T I O N A L T A B L E S

Table 1. Eligibility assessment

Eligibility criteria

1. Number of groups involved in the trial (at least two groups required);

2. Proportion of patients with breast cancer (> 80% breast cancer patients required);

3. Intervention examined (exercise training);

4. Time of exercise training (concurrent with adjuvant treatment);

5. Duration of exercise intervention (at least six weeks) and

6. Type of outcomes as specified.

Table 2. Methodological quality assessment tool

Quality criteria

1.Were the eligibility criteria specified?

2.Was a method of randomisation performed?

3.Was the treatment allocation concealed?

4.Were groups similar at baseline?

5.Were interventions explicitly described?

6.Were co-interventions either avoided or comparable?

7.Was adherence acceptable in all groups?

8.Was the outcome assessor blinded to the intervention?

9.Were outcome measures relevant?

10.Were adverse effects described?

11.Was the withdrawal/ drop-out rate acceptable and were reasons described?

12.Was short-term follow-up measurement performed?

13.Was long-term follow-up measurement performed?

14.Was timing of outcome assessment comparable in both groups?



Table 2. Methodological quality assessment tool (Continued)

15.Was the sample size described for each group at randomisation?

16.Did the analysis include intention-to-treat analysis?

17.Were point estimates and measures of variability presented for the primary outcome measures?

Table 3. Analysis of training stimulus

Aerobic exercise Resistive exercise

1. Intensity: 55 - 85% of maximum heart rate or 40 - 75% of

maximum heart rate reserve or 40 - 75% of maximum oxygen

uptake reserve;

2. Duration of sessions: 20 - 60 min (minimum of 10 min. con-

tinuous bouts throughout the day) or exercise to tolerance;

3. Frequency: at least three days per week; 4. Total exercise period:

at least six weeks

1. Intensity: 10-15 repetitions to near fatigue or at least 60% of

one Repetition Maximum;

2. Number of sets completed (duration): at least 1set;

3. Frequency: two or three days per week;

4. Total exercise period: at least six weeks.

Table 4. SMD/WMD calculation

Outcome Study-ID Instruments, units Calculation base

Cardiorespiratory Fitness Campbell 2005;

Drouin 2002;

Mock 1997;

Segal 2001 SD;

Segal 2001 SU

metres (12-minute walk);

peak VO2;

feet (12-minute walk);

peak VO2;

peak VO2

final values

Strength Drouin 2002 kg final values

Fatigue Campbell 2005;

Drouin 2002;

Mock 1997;

Mock 2004;

Segal 2001 SD;

Segal 2001 SU

Piper Fatigue Scale;


Symptom Assessment Scale;


SF-36 vitality reversed;

SF-36 vitality reversed;

final values

Weight change Mac Vicar 1989;

Segal 2001 SD;

Segal 2001 SU

kg change scores

Cancer specific quality of life Campbell 2005 Functional Assessment of Can-

cer Therapy - general (FACT-

G)

change scores

Cancer -site specific quality of

life

Campbell 2005 Functional Assessment of Can-

cer Therapy-Breast (FACT-B)

change scores

Anxiety Mock 1997 Symptom Assessment Scale final values



Table 4. SMD/WMD calculation (Continued)

Mood Disturbance Drouin 2002 Profile of Mood States (POMS) final values

Depression Mock 1997 Symptom Assessment Scale final values

T-Cells Drouin 2002 CD4+/CD8+ final values

Natural Killer Cells Drouin 2002 Natural killer cytotoxic activity,

lytic units

final values

Oxidative Stress Drouin 2002 8-Isoprostane final values

Sleep disturbances Mock 1997 Symptom Assessment Scale final values

Table 5. Methodological Scores

Study Internal Validity Descriptive Validity Statistical Validity Total Score

Items Items Items

2, 3, 6, 7, 8, 9, 11, 14,

16; Score

1, 4, 5, 10, 12, 13; Score 15, 17; Score

Campbell 2005 +, ?, +, +, ?, +, +, +, -, 6 +, +, +, +, +, -, 5 +, +, 2 13

Crowley 2003 +, +, +, +, +, +, +, +, +, 9 +, -, -, +, +, -, 3 +, -, 1 13

Drouin 2002 +, +, ?, +, ?, +, +, +, -, 6 +, +, -, +, +, -, 4 +, +, 2 12

MacVicar 1986 -, ?, ?, ?, ?, +, +, +, ?, 3 +, ?, +, -, +, -, 3 +, -, 1 7

MacVicar/ Winningham

1989

?, ?, +, +, ?, +, -, +, -, 4 +, +, -, -, +, -, 3 +, -, 1 8

Mock 1997 -, -, +, +, ?, +, +, +, -, 5 +, +, +, +, +, -, 5 -, -, 0 10

Mock 2004 +, +, +, -, -, +, +, +, +, 7 +, +, +, +, +, -, 5 +, +, 2 14

Segal 2001 +, +, ?, +, ?, +, -, +, +, 6 +, +, +, +, +, -, 5 +, +, 2 13

Winningham 1988 ?, ?, +, ?, ?, +, +, +, +, 5 +, +, +, -, +, - , 4 +, -, 1 10



A P P E N D I C E S

Appendix 1. Medline search strategy (1966-2004) (OVID)

1.RANDOMIZED-CONTROLLED-TRIAL in PT

2.CONTROLLED-CLINICAL-TRIAL in PT

3.RANDOMIZED-CONTROLLED-TRIALS

4.RANDOM-ALLOCATION

5.DOUBLE-BLIND-METHOD

6.SINGLE-BLIND-METHOD

7.#1 or #2 or #3 or #4 or #5 or #6

8.(TG=ANIMALS) not ((TG=HUMAN) and (TG=ANIMALS))

9.#7 not #8

10.CLINICAL-TRIAL in PT

11.explode CLINICAL-TRIALS/ all subheadings

12.(clin* near trial*) in TI

13.(clin* near trial*) in AB

14.(singl* or doubl* or trebl* or tripl*) near (blind* or mask*)

15.(#14 in TI) or (#14 in AB)

16.PLACEBOS

17.placebo* in TI

18.placebo* in AB

19.random* in TI

20.random* in AB

21.RESEARCH-DESIGN

22.#10 or #11 or #12 or 13 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21

23.((TG=ANIMALS) not (TG=HUMAN)) and (TG=ANIMALS)

24.#22 not #23

25.#24 not #9

26.TG=COMPARATIVE-STUDY

27.explode EVALUATION-STUDIES/ all subheadings

28.FOLLOW-UP-STUDIES

29.PROSPECTIVE-STUDIES

30.control* or prospectiv* or volunteer*

31.(#30 in TI) or (#30 in AB)

32.#26 or #27 or #28 or #29 or #31

33.(TG=ANIMALS) not ((TG=HUMAN) and (TG=ANIMALS))

34.#32 not #33

35.#34 not (#9 or #25)

36.#9 or #25 or #35

37.explode “Breast-Neoplasms”/ all subheadings

38.Cancer*

39.Carcinom*

40.Neoplas*

41.Malignan*

42.#38 or #39 or #40 or #41

43.Breast*

44.#42 and #43

45.#37 or #44

46.explode “Exercise”/ all subheadings

47.explode “Exercise-Movement-Techniques”/ all subheadings

48.explode “Exercise-Therapy”/ all subheadings

49.explode “Physical-Education-and-Training”/ all subheadings



50.explode “Physical-Fitness”/ all subheadings

51.explode “Exertion”/ all subheadings

52.explode “Sports”/ all subheadings

53.(sport or sports) in ti, ab

54.physical activit* in ti,ab

55.kinesi?therap* in ti,ab

56.exercise* in ti, ab

57.walking in ti, ab

58.jogging in ti, ab

59.swimming in ti, ab

60.cycling in ti, ab

61.bicycling in ti, ab

62.weight in ti, ab

63.training in ti, ab

64.muscle in ti, ab

65.strengthening in ti, ab

66. endurance in ti, ab

67.#46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or 57# or #58 or #59 or #60 or #61 or #62 or #63 or

#64 or #65 or #66

68.#36 and #45 and #67

W H A T ’ S N E W

Last assessed as up-to-date: 15 July 2004.

Date Event Description

9 September 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 4, 2004

Review first published: Issue 4, 2006

C O N T R I B U T I O N S O F A U T H O R S

MM: electronic searching and handsearching, study selection, data extraction, methodological assessments, quantitative and qualitative

synthesis of included studies, reporting.

TB: study selection, data extraction, methodological assessments, quantitative and qualitative synthesis of included studies, manuscript

review.

KLR: contacted experts for identifying additional trials, contributed to consensus finding when disagreement in data extraction and

methodological assessments persisted between the other two authors (MM, TB), contacted trial investigators for additional data,

contributed to planning of quantitative synthesis of studies; reviewed manuscript.



D E C L A R A T I O N S O F I N T E R E S T

None known

I N D E X T E R M SMedical Subject Headings (MeSH)

∗Exercise Therapy; Breast Neoplasms [∗therapy]; Chemotherapy, Adjuvant [adverse effects]; Fatigue [rehabilitation]; Physical Fitness;

Radiotherapy, Adjuvant [adverse effects]; Randomized Controlled Trials as Topic; Weight Gain

MeSH check words

Female; Humans



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