Physical
Activity, Biomarkers, and Disease Outcomes in Cancer Survivors
A Systematic Review
Rachel
Ballard-Barbash, Christine M. Friedenreich, Kerry S. Courneya, Sameer M.
Siddiqi, Anne McTiernan, Catherine M. Alfano
J Natl Cancer Inst. 2012;104(11):815-840.
Abstract and Introduction
Abstract
Background
Cancer survivors often seek information about how lifestyle factors, such as
physical activity, may influence their prognosis. We systematically reviewed
studies that examined relationships between physical activity and mortality
(cancer-specific and all-cause) and/or cancer biomarkers.
Methods We identified 45 articles published from January 1950 to August
2011 through MEDLINE database searches that were related to physical activity,
cancer survival, and biomarkers potentially relevant to cancer survival. We
used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Statement to guide this review. Study characteristics, mortality outcomes, and
biomarker-relevant and subgroup results were abstracted for each article that
met the inclusion criteria (ie, research articles that included participants
with a cancer diagnosis, mortality outcomes, and an assessment of physical
activity).
Results There was consistent evidence from 27 observational studies that
physical activity is associated with reduced all-cause, breast cancer–specific,
and colon cancer–specific mortality. There is currently insufficient evidence
regarding the association between physical activity and mortality for survivors
of other cancers. Randomized controlled trials of exercise that included
biomarker endpoints suggest that exercise may result in beneficial changes in
the circulating level of insulin, insulin-related pathways, inflammation, and,
possibly, immunity; however, the evidence is still preliminary.
Conclusions Future research directions identified include the need for
more observational studies on additional types of cancer with larger sample
sizes; the need to examine whether the association between physical activity
and mortality varies by tumor, clinical, or risk factor characteristics; and
the need for research on the biological mechanisms involved in the association
between physical activity and survival after a cancer diagnosis. Future
randomized controlled trials of exercise with biomarker and cancer-specific
disease endpoints, such as recurrence, new primary cancers, and cancer-specific
mortality in cancer survivors, are warranted.
Introduction
An estimated 13.8 million cancer survivors were living in
the United States as of 2010, and this number is projected to grow to 18.1
million by 2020.[1] With advances in cancer screening and treatment, cancer
survivors are living longer and are seeking information about how lifestyle factors,
such as physical activity, may influence their prognosis.[2] Evidence of
the influence of physical activity on health-related fitness, quality of life,
and other patient-reported outcomes among cancer survivors during and after
treatment has been reviewed previously.[3–12] In 2010, the American College of Sports Medicine (ACSM)
reviewed the research on the safety and efficacy of exercise training during
and after adjuvant cancer therapy.[13] That review focused on randomized controlled trial (RCT) evidence,
where available, which was extensive for breast and prostate cancers and more
limited for colon, hematological, and gynecological cancers, and also included
a limited number of prospective cohort studies. Overall, the RCT evidence
indicates that exercise training is safe during and after cancer treatment,
although the ACSM review did identify some areas of concern for survivor safety
with particular types and intensities of exercise for certain survivor groups.
The ACSM review found that exercise training resulted in improvements in
physical functioning, quality of life, and cancer-related fatigue for a number
of cancer survivor groups.[13] In 2008, the US Department of Health and Human Services
published physical activity guidelines based primarily on a review of research
on physical activity and cancer prevention; that publication included a short
review on cancer survivorship based on three studies published before 2007 that
focused on late and long-term effects of physical activity.[4] Since the
publication of these two reviews, there have been many more studies examining
the effects of physical activity in cancer survivors, warranting a more
detailed assessment of this evidence.
In addition to the observational research on the effects of
physical activity in cancer survivors, several RCTs of exercise interventions
and mortality outcomes in cancer survivors have begun or been published. In
2009, the first RCT to investigate the effect of a specific physical activity
intervention on overall and disease-free survival among colon cancer survivors
was launched in Canada and Australia.[14] In addition, several smaller RCTs have examined the effect
of physical activity interventions on a number of biomarkers and mechanistic
pathways that may be relevant to cancer prognosis. The purpose of this review
was to systematically examine results of in two areas of research involving
cancer survivors: physical activity and cancer-specific and all-cause
mortality, and physical activity and relevant cancer biomarkers. This
systematic review differs from previous reviews, which were broad or focused on
health-related fitness outcomes and/or patient-reported outcomes, such as
quality of life, fatigue, and cancer-related symptoms,[4,5,8–11,13]
examined only one cancer,[6,9,12] addressed cancer prevention in addition to cancer survival,[4,11] or included
combined dietary and physical activity interventions.[7] We also
summarize the limited number of RCTs that assessed effects of physical activity
interventions on biomarkers in cancer patients or survivors to evaluate the
extent of evidence on biological mechanisms that may underlie associations
between physical activity and cancer prognosis. Finally, we propose priorities
for future research in this field.
Methods
Search Strategy
We followed the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statement guidelines[15] to identify,
screen, and describe the protocols used in this systematic review. We conducted
two unique searches in January 2011 of titles and abstracts in the MEDLINE
database that were published since January 1950. Additional studies suggested
by the authors of this review and those listed as references in related reviews
were also included. We reran these searches in August 2011 to ensure that we
had captured any additional articles that had been published in the interim.
Both search strategies were limited to English language articles that described
studies in humans. The first set of search terms, which describe physical
activity and cancer survival, were cross-searched using the following
algorithm: (((((((((((((("physical activity"[Title]) OR "weight
training"[Title]) OR "resistance training"[Title]) OR
"physically active"[Title]) OR exercise[Title]) OR fitness[Title]) OR
aerobic[Title]) OR "motor activity"[Title])) AND
((((cancer[Title/Abstract]) OR neoplasm[Title/Abstract]) OR
tumor[Title/Abstract]) OR carcinoma[Title/Abstract])) AND
(((((((((patient[Title/Abstract]) OR survivor[Title/Abstract]) OR
survival[Title/Abstract]) OR survivorship[Title/Abstract]) OR
prognosis[Title/Abstract]) OR recurrence[Title/Abstract]) OR
progression[Title/Abstract]) OR disease-free[Title/Abstract]) OR
mortality[Title/Abstract]) AND (Humans[Mesh] AND English[lang]))) NOT
review[Publication Type]) NOT comment[Publication Type]) NOT
editorial[Publication Type].
The second set of search terms, which describe physical
activity and biomarkers that are potentially relevant to cancer survival,
included the above terms and the following cancer-relevant biomarkers:
estrogen, androgen, sex hormone, leptin, adipokines, tumor necrosis factor,
interleukin, C-reactive protein, prostate-specific antigen, insulinlike growth
factor, inflammatory markers, insulin, glucose, hormone, oxidative stress, DNA
damage, and prostaglandin. These biomarkers were chosen because previous
studies have shown that they may be affected by physical activity in persons
without cancer[4,16] and because they are involved in hypothesized biological
mechanisms that may be associated with cancer prognosis.[17–19] These terms
were cross-searched using the following algorithm: ((((((((((("physical
activity"[Title/Abstract]) OR "weight training"[Title/Abstract])
OR "resistance training"[Title/Abstract]) OR "physically
active"[Title/Abstract]) OR exercise[Title/Abstract]) OR
fitness[Title/Abstract]) OR aerobic[Title/Abstract]) OR "motor
activity"[Title/Abstract])) AND
(((((((((((((((((((((((biomarker[Title/Abstract]) OR marker[Title/Abstract]) OR
estrogen[Title/Abstract]) OR androgen[Title/Abstract]) OR "sex
hormone"[Title/Abstract]) OR leptin[Title/Abstract]) OR "insulin
resistance"[Title/Abstract]) OR adipokine[Title/Abstract]) OR
TNF[Title/Abstract]) OR interleukin[Title/Abstract]) OR
"c-reactive"[Title/Abstract]) OR PSA[Title/Abstract]) OR IGF[Title/Abstract])
OR "inflammatory marker"[Title/Abstract]) OR
inflammation[Title/Abstract]) OR insulin[Title/Abstract]) OR
glucose[Title/Abstract]) OR hyperglycemia[Title/Abstract]) OR
hormone[Title/Abstract]) OR "oxidative stress"[Title/Abstract]) OR
"dna damage"[Title/Abstract]) OR prostaglandin[Title/Abstract]) OR
"immune function"[Title/Abstract])) AND
(((((((((patient[Title/Abstract]) OR survivor[Title/Abstract]) OR
survival[Title/Abstract]) OR survivorship[Title/Abstract]) OR prognosis[Title/Abstract])
OR recurrence[Title/Abstract]) OR progression[Title/Abstract]) OR
"disease-free"[Title/Abstract]) OR mortality[Title/Abstract])) AND
((((cancer[Title/Abstract]) OR tumor[Title/Abstract]) OR
carcinoma[Title/Abstract]) OR neoplasm[Title/Abstract]) NOT review[Publication
Type] NOT comment[Publication Type] NOT editorial[Publication Type] AND
(Humans[Mesh] AND English[lang]).
For the purpose of this review, cancer survivor was defined
according to the National Cancer Institute Office of Cancer Survivorship as a
person who is diagnosed with cancer from the onset of their diagnosis through
the balance of his or her life.[20]
Selection Criteria
The titles and abstracts of the results of both search
strategies were screened by two of the authors (R. B.-Barbash and S. M.
Siddiqi) to determine their eligibility. Studies were eligible for inclusion in
this review if they were research articles published in peer-reviewed journals
and described results from an RCT or an observational study that investigated
physical activity and cancer-specific outcomes, recurrence, new primary cancer
or cancer-specific deaths, or deaths from any cause or biomarkers in cancer
survivors. Studies were required to include an assessment of physical activity.
Articles that reported associations between physical activity and biomarkers in
cancer survivors were also abstracted for review. Studies that focused solely
on quality-of-life outcomes were excluded, as were studies that were classified
as commentaries, reviews, or editorials.
For inclusion in this review, observational studies were
required to be based on follow-up of cancer survivors and contain data on
cancer-specific or all-cause mortality. Studies that examined cancer mortality
in samples that were not limited to cancer survivors and instead focused on
healthy individuals or patients without cancer were excluded. We included all
studies that met the inclusion criteria regardless of the sample size except
for one study[21] that was an early report of the association between
physical activity and breast cancer survival and was followed by a later
analysis with longer follow-up and more case subjects,[22] which was
included in this review.
For inclusion in this review, RCTs of physical activity
interventions were required to include cancer survivors as participants and
report results on biomarkers. Articles that reported only pilot data (rather
than outcomes of a full-scale study) or descriptions of the design of a RCT
were excluded. In addition, RCTs were not included if the intervention was
physical activity combined with another intervention. Also excluded were trials
that were not randomized, did not include a control group, or that tested acute
biomarker effects from a single bout of exercise.
We included RCTs in which physical activity was defined as
aerobic, endurance, or strength training exercise performed for recreational,
household, commuting, or work-related purposes. We excluded RCTs that examined
other types of conditioning or stretching exercise, such as yoga, Pilates, or
Tai Chi, and nonpurposive movement. These restrictions were not applied to
physical activity reported in observational studies.
Data Synthesis
We abstracted relevant study characteristics, including
disease outcome and biomarker-relevant results, from each study into tables,
each of which was independently reviewed and verified by at least two authors (
[R. B.-Barbash and C. M. Friedenreich]; [R. B.-Barbash, C. M. Friedenreich, and
K. S. Courneya]; [R. B.-Barbash and A. McTiernan]; [K. S. Courneya and C. M.
Alfano]). For observational studies, study characteristics included study
design, sample size and description, length of follow-up, type of disease,
disease stage, treatment, type of physical activity assessment, and the timing
of that assessment relative to diagnosis. For RCTs, study characteristics
included sample size and description, description of the intervention and
control arms, type of physical activity assessment and the timing of that
assessment relative to diagnosis, and the rates of attrition and adherence. We
evaluated the studies by considering their study design, data collection and
analytic methods, and adjustment for confounding factors, such as cancer stage,
tumor subtypes, comorbidity, other clinical characteristics, and related health
and lifestyle characteristics, including body mass index (BMI) and dietary
intake. We summarized the results for specific population subgroups for studies
that reported them.
Table 1. Observational
studies of physical activity and disease and mortality events in breast cancer
survivors*
First | Sample | Study | Disease | Physical | Overall | Subgroup |
Studies that assessed physical | ||||||
Rohan (23), 1995, Australia | 451 women with breast cancer, 112 | Follow-up of a population-based | Tumor diameter, ER and PR status; | Interviewer-administered | HR of breast cancer–specific death | No statistically significant |
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