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Obesity and Cancer: The Risks, Science, and Potential Management Strategies

Obesity and Cancer: The Risks, Science, and Potential Management Strategies

ABSTRACT: Overweight and obesity increase the risk of developing several cancers. Once cancer develops, individuals may be at increased risk of recurrence and poorer survival if they are overweight or obese. A statistically significant association between overweight or obesity and breast cancer recurrence or survival has been observed in the majority of populationbased case series; however, adiposity has been shown to have less of an effect on prognosis in the clinical trial setting. Weight gain after breast cancer diagnosis may also be associated with decreased prognosis. New evidence suggests that overweight/obesity vs normal weight may increase the risk of poor prognosis among resected colon cancer patients and the risk of chemical recurrence in prostate cancer patients. Furthermore, obese cancer patients are at increased risk for developing problems following surgery, including wound complication, lymphedema, second cancers, and the chronic diseases affecting obese individuals without cancer such as cardiovascular disease and diabetes. Mechanisms proposed to explain the association between obesity and reduced prognosis include adipose tissue-induced increased concentrations of estrogens and testosterone, insulin, bioavailable insulin-like growth factors, leptin, and cytokines. Additional proposed mechanisms include reduced immune functioning, chemotherapy dosing, and differences in diet and physical activity in obese and nonobese patients. There have been no randomized clinical trials testing the effect of weight loss on recurrence or survival in overweight or obese cancer patients, however. In the absence of clinical trial data, normal weight, overweight, and obese patients should be advised to avoid weight gain through the cancer treatment process. In addition, weight loss is probably safe, and perhaps helpful, for overweight and obese cancer survivors who are otherwise healthy.

Overweight and obesity increase
the risk of developing several
types of cancer.[1] Depending
on the disease site, individuals
who develop cancer may be at increased
risk of recurrence and poorer
survival if they are overweight or
obese. The vast preponderance of information
on the effect of adiposity
on prognosis is limited to breast cancer,
although data are emerging on
additional cancer sites (particularly the
colon and prostate). However, the
mechanisms that might explain the
association between adiposity and
prognosis may pertain to sites other
than the breast.

The effects of obesity on cancer
outcome are substantial, where observed,
and of potentially great clinical
importance. The prevalence of
overweight and obesity is higher in
patients with some forms of cancer,
compared with individuals from the
general population.[1] Compounding
this is the fact that weight gain after
diagnosis is common in some cancer
patients; this is especially true among
breast cancer patients receiving systemic
adjuvant therapy.[2,3] Weight
gain during the period after breast cancer
diagnosis has also been associated
with an adverse effect on recurrence
risk and survival.[2] In addition to
adversely affecting prognosis, overweight
and obesity also increase both
the risk of several complications from
cancer treatment and the risk of several
comorbidities. There are several
potential mechanisms that might explain
the link between increased adiposity
and reduced prognosis,
including hormonal, inflammatory,
and immune system effects. Although
definitive clinical trials testing the effect
of weight loss on prognosis in
cancer patients have not been conducted,
strategies for weight control
may be helpful for some cancer patients
and survivors.

There are several ways to measure
body composition and adiposity.
Simple, inexpensive, and noninvasive
techniques include measuring height,
weight, body mass index (BMI,
kg/m2), and waist and hip circumferences;
employing bioelectric impedance
analysis (which estimates percent
body fat); and using fat calipers (which
can be used to estimate overall and
regional body fat). Other body composition
measures give more reliable
and valid measures of body composition,
but are more invasive and expensive.
The latter category includes
underwater weighing (considered the
"gold standard" for body composition),
dual-energy x-ray absortiometry
(DEXA) scan (which measures
lean mass, bone mass, and fat mass),
computed tomography (CT) scan, and
magnetic resonance imaging (MRI)
scan (used to estimate intra-abdominal
and subcutaneous abdominal fat,
typically measured with one crosssectional
slice in order to reduce radiation
exposure and costs).

Body mass index is the measure of
adiposity most commonly used in
studies of obesity and breast cancer.
For comparison purposes, it is the one
used throughout this article. Obesity
experts have developed the following
categories of adiposity based on
BMI[4]: underweight (< 18.5), normal
weight (18.5-24.9), overweight
(25.0-29.9), and obese (≥ 30.0)
(Table 1). Obesity is further subclassified;
the most important subclassification
is ≥ 40.0, or extreme obesity,
as individuals often have serious
metabolic complications at this level
of obesity.

Overweight, Obesity,
and Breast Cancer
Nonpatient Populations
In the American Cancer Society
Prevention Study II, a prospective cohort
study of 900,000 American
adults, 57,145 cancer deaths were
identified during 16 years of followup.[
5] Cancer mortality was determined
through personal inquiries and
linkage with the National Death Index.
The relative risk (RR) for breast
cancer associated with categories of
increasing BMI, compared with women
with BMI < 25.0, were as follows:
1.34 (BMI 25.0-29.9), 1.63 (BMI
30.0-34.9), 1.70 (BMI 35.0-39.9),
and 2.12 (BMI ≥ 40.0). The test for
trend was highly significant (P < .001).

For men, the relative risk of death
from any cancer was 1.52 (95% confidence
interval [CI] = 1.13-2.05); for
women, the relative risk was 1.62
(95% CI = 1.40-1.87).[5] In both men
and women, BMI was also significantly
associated with higher rates of
death due to cancer of the esophagus,
colon and rectum, liver, gallbladder,
pancreas, and kidney, as well as non-
Hodgkin's lymphoma and multiple
myeloma. Significant trends of increasing
risk of death with higher
BMIs were observed for cancers of
the stomach and prostate in men and
cancers of the breast, uterus, cervix,
and ovary in women. In the Iowa
Women's Health Study, with a cohort
of 21,707 women, a positive association
of waist-hip ratio with breast cancer
mortality was also observed after
follow-up of up to 7 years.[6]

Because these studies did not focus
on a patient population, but rather
on risk in an originally cancer-free
population, it is not clear how much
of the effect of BMI on mortality was
due to increased cancer incidence with
obesity, and how much was due to
decreased survival among obese cancer
patients. Indeed, increased adiposity
has been found to be associated
with increased incidence of cancers
of the breast (postmenopausal), colon,
endometrium, lower esophagus,
kidney, and pancreas,[1,7-9] poor
prognosis among breast, colon, and
prostate cancer patients,[2,10-12] and
stage at diagnosis.[11-15]

Patient Populations
Nearly 40 studies have examined
the association of obesity with breast
cancer outcomes in patient populations.[
2,3] A statistically significant
association between overweight or
obesity and recurrence or survival was
seen in 26 reports that included a total
of 29,460 women with breast cancer,
while several studies including over
5,000 women did not yield such associations.[
2] Negative effects of body
weight on breast cancer recurrence
and survival have been observed in
both pre- and postmenopausal women.[
2] Interestingly, the association between
increased adiposity and reduced
prognosis has largely been observed in
hospital-based case series and population-
based studies. Some cooperative
groups have published data on the effect
of overweight or obesity on prognosis,
with varying results.[16,17]

Goodwin et al conducted a metaanalysis
of studies published prior to
1992 and estimated that overweight
or obesity was associated with a statistically
significantly increased risk
of recurrence (78% to 91%) and a
36% to 56% increased risk of
death.[18] In another study, obesity
was strongly and statistically significantly
associated (P = .005) with disease-
free survival and overall survival
in a cohort of 535 women (median
age: 50 years) with newly diagnosed
breast cancer. In addition, obesity at
diagnosis was related (hazard ratio
[HR] = 1.86, 95% CI = 1.02-3.40) to
a significant decrease in survival in
postmenopausal women with inflammatory
breast cancer.[19] These
associations between obesity and adverse
breast cancer outcome are substantial,
with differences comparable
in magnitude to those associated with
adjuvant hormonal therapy and chemotherapy,
and of potentially great
clinical importance.

A recent review of published prospective
studies of adiposity and breast
cancer prognosis[2] concluded that the
majority of studies identified a significant
adverse association of obesity with
either recurrence or death. Despite these
numerous studies, it is still not clear
whether there are interactions with adjuvant
therapy. A recent National Surgical
Adjuvant Breast and Bowel
Project (NSABP) analysis of 3,385 patients
from a randomized, placebo-controlled
trial evaluating tamoxifen for
lymph node-negative, estrogen receptor
(ER)-positive breast cancer found
that obese women benefited from
tamoxifen therapy as much as lighterweight
women did.[16] Futhermore, in
that population, BMI was not adversely
associated with breast cancer mortality.
Compared with normal weight
women, obese women had greater allcause
mortality (HR = 1.31, 95% CI =
1.12-1.54) and greater risk of death
due to causes unrelated to breast cancer
(HR = 1.49, 95% CI = 1.15-1.92).

Goodwin et al recently reported a
prospective cohort study that was
designed to examine the prognostic
effect of obesity in early-stage breast
cancer.[20] Height and weight were
measured in a fasting state prior to
initiation of adjuvant treatment in 535
women with T1-3, N0/1, M0 breast
cancer. After a median follow-up
of 50 months, obesity predicted distant
disease-free and overall survival
(P < .001). Women with BMI 20-25
had the lowest risk of recurrence and
death; those with BMI < 20 or BMI
> 25 had an increased risk of recurrence
(RR = 1.18 and 1.72, respectively)
and death (RR = 1.21 and 1.78,
respectively). The adverse effect of
obesity persisted after adjustment for
tumor stage, nodal stage, tumor grade,
estrogen and progesterone receptor
status, and adjuvant treatment (chemotherapy
and/or hormone therapy).
All but two of the deaths were due to
breast cancer.

Body fat distribution may be relevant
to breast cancer prognosis. Researchers
in British Columbia, Canada,
identified 603 patients with incident
breast cancer and collected self-reported
anthropometric data prior to treatment.[
21] After up to 10 years of
follow-up, the relative risk for breast
cancer mortality for highest vs lowest
quartile of waist-to-hip ratio in postmenopausal
cases was 3.3 (95% CI =
1.1-10.4). The increased mortality risk
was limited to those with ER-positive
tumors. A small study found that increased
truncal obesity significantly
predicted breast cancer survival.[22]
In that study, 83 of 166 breast carcinoma
patients (50%) with up to 10
years of follow-up died of their breast
cancer. Android body fat distribution,
as indicated by a higher suprailiacthigh
ratio, was a statistically significant
(P < .0001) prognostic indicator
for survival after controlling for stage
of disease, with a hazard ratio of 2.6
(95% CI = 1.63-4.17).

Risk of future second primary
breast cancer may also be increased
with increased adiposity. Results from
a population-based cohort of 1,285
breast cancer survivors suggest an increased
risk for contralateral breast
cancer among overweight or obese
breast cancer survivors.[23] In the
NSABP analysis of 3,385 tamoxifen
patients, contralateral breast cancer
hazard was higher in obese women
than in underweight/normal weight
women (HR = 1.58, 95% CI = 1.10-
2.25), as was the risk of additional
primary breast cancers (HR = 1.62,
95% CI = 1.16-2.24).[16]

Overweight, Obesity,
and Other Cancers

In a series of 1,106 prostate cancer
cases from several institutions, obese
patients were found to have highergrade
tumors and higher rates of
positive surgical margins.[11] In a
multivariate analysis of these patients,
BMI > 35.0 was a significant predictor
of biochemical failure. In another
multi-institutional pooled analysis of
3,162 men, BMI was an independent
predictor of higher Gleason grade cancer,
and was associated with a higher
risk of biochemical recurrence.[12]

In a cohort of 3,759 colon cancer
patients in a randomized adjuvant chemotherapy
trial, obese women had a
statistically significant (34%) increased
risk of overall mortality and a
nonsignificant (24%) increased risk
of disease recurrence after a mean 9.4
years follow-up.[10] However, obesity
was not associated with prognosis
in men in the same cohort.

In two single-hospital case series,
increased BMI was associated with
improved prognosis in over 1,000 renal
cancer patients.[24,25]

Effect of Weight Gain
After Diagnosis and
Risk of Cancer Mortality

Weight gain after diagnosis has
been frequently reported for breast
cancer patients, especially among
women receiving systemic adjuvant
chemotherapy.[2] In a prospective
cohort of 535 newly diagnosed breast
cancer patients, adjuvant chemotherapy
and onset of menopause were
the strongest predictors of weight
gain.[26] The causes of this weight
gain have not been identified but could
be from a mixture of reduced physical
activity after diagnosis,[27] changes
in dietary intake,[26,28] and reduced
rates of metabolism.[3]

In the Health, Eating, Activity, Lifestyle
(HEAL) study, a population-based
cohort of 1,185 women with stage 0 to
IIIA breast cancer, levels of recreational
physical activity significantly decreased
between diagnosis and 1 year
after diagnosis regardless of age at diagnosis
(Figure 1).[27] This decrease
was seen in women at all stages, although
it was most pronounced in the
higher stages (Figure 2). Women who
had been treated with chemotherapy
were more likely to decrease their
activity levels, although women with
any treatment were likely to have reduced
activity levels (Figure 3). Obese
women reduced their activity levels
more than did lighter-weight women
(Figure 4). The amount of decrease in
physical activity could explain the degree
of weight gain in those who gained
weight after diagnosis, even without
changes in dietary composition.

One report suggested associations
between obesity, depressive symptomatology,
and abnormal eating attitudes
in women at risk for breast cancer
recurrence, which could compound
patients' attempts to maintain or lose
excess weight.[28]

Tamoxifen treatment does not appear
to influence body weight.[26,29]
Although anthracycline chemotherapy
may have less of an effect on weight
than other chemotherapy regimens,
weight gains of between 2 and 4 kg
have commonly been reported following
some chemotherapy regimens such
as CMF (cyclophosphamide, methotrexate,
fluorouracil [5-FU]).[30] This
weight gain consists primarily of body
fat. In a report of the National Cancer
Institute of Canada Clinical Trials
Group, adjuvant CMF and CEF (cyclophosphamide,
epirubicin, 5-FU) was
associated with average weight increases
of 4.36 and 2.93 kg, respectively
(P < .001 compared to baseline).[31]
In breast cancer survivors, return to
prediagnosis weight is rare.[2]

Four studies have investigated the
relationship between weight gain after
diagnosis and prognosis.[2] Three
of these studies in early-stage resected
breast cancer found that weight
gain after diagnosis increased recurrence
risk or deceased survival.

Obesity and Development of Comorbidities
Obese cancer patients are at increased
risk for developing problems
following surgery, including wound
complications, lymphedema, and perhaps
congestive heart failure in women
who had received doxorubicin.[2]
Obesity is also a risk factor for endometrial
cancer development; this
may place women who take tamoxifen
at further increased risk of developing
this disease.[32]

In a study of 1,800 postmenopausal
breast cancer patients identified
through the National Cancer Institute's
Surveillance, Epidemiology, and End
Results (SEER) program and followed
for 30 months after diagnosis, only
51% of deaths were attributed to breast
cancer[33]; the percentage of deaths
ascribed to breast cancer decreased
with age. Most prostate cancer patients
die of causes other than their
cancer, which underscores the need
for healthy lifestyle recommendations
for this patient population.[34]

Attention to obesity as a risk factor
for potentially fatal comorbid conditions
such as cardiovascular disease,
venous thromboembolic disease, and
stroke, is of potential major importance
in optimizing cancer patient outcome.
This is especially true in older
patient populations. Furthermore, obesity
increases risk of several other cancers,
including endometrial, renal,
esophageal, and colon cancer.[1] Patients
who have had a diagnosis of
cancer are at increased risk for some
of these cancers, and obese patients
have a further increased risk.

Obesity and Quality of
Life in Cancer Patients

For some cancer patients and survivors,
quality of life may be adversely
affected by obesity.[35] Interventions
that may reduce weight, conversely,
such as increasing physical activity,
have been shown to improve quality
of life in cancer survivors.[36]

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