Obesity and Cancer: The Risks, Science, and Potential Management Strategies
Obesity and Cancer: The Risks, Science, and Potential Management Strategies
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. 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. 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. 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: 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). 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. 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. 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. 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 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. 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. 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. 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. 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). 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. 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. 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. 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. In a prospective cohort of 535 newly diagnosed breast cancer patients, adjuvant chemotherapy and onset of menopause were the strongest predictors of weight gain. The causes of this weight gain have not been identified but could be from a mixture of reduced physical activity after diagnosis, changes in dietary intake,[26,28] and reduced rates of metabolism. 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). 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. 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]). 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). In breast cancer survivors, return to prediagnosis weight is rare. Four studies have investigated the relationship between weight gain after diagnosis and prognosis. 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. 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. 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; 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. 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. 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. Interventions that may reduce weight, conversely, such as increasing physical activity, have been shown to improve quality of life in cancer survivors.