Explaining the Obesity Paradox: The Association between Body Composition and Colorectal Cancer Survival (C-SCANS Study)
01 Jul 2017-Cancer Epidemiology, Biomarkers & Prevention (Cancer Epidemiol Biomarkers Prev)-Vol. 26, Iss: 7, pp 1008-1015
TL;DR: Sarcopenia is prevalent among patients with non-metastatic colorectal cancer, and should, along with adiposity, be a standard oncological marker, according to optimal stratification and sex- and BMI-specific cut points.
Abstract: Background: Body composition may partially explain the U-shaped association between body mass index (BMI) and colorectal cancer survivalMethods: Muscle and adiposity at colorectal cancer diagnosis and survival were examined in a retrospective cohort using Kaplan-Meier curves, multivariable Cox regression, and restricted cubic splines in 3,262 early-stage (I-III) male (50%) and female (50%) patients Sarcopenia was defined using optimal stratification and sex- and BMI-specific cut points High adiposity was defined as the highest tertile of sex-specific total adipose tissue (TAT) Primary outcomes were overall mortality and colorectal cancer-specific mortality (CRCsM)Results: Slightly over 42% patients were sarcopenic During 58 years of follow-up, 788 deaths occurred, including 433 from colorectal cancer Sarcopenic patients had a 27% [HR, 127; 95% confidence interval (CI), 109-148] higher risk of overall mortality than those who were not sarcopenic Females with both low muscle and high adiposity had a 64% higher risk of overall mortality (HR, 164; 95% CI, 105-257) than females with adequate muscle and lower adiposity The lowest risk of overall mortality was seen in patients with a BMI between 25 and <30 kg/m2, a range associated with the greatest number of patients (586%) who were not at increased risk of overall mortality due to either low muscle or high adiposityConclusions: Sarcopenia is prevalent among patients with non-metastatic colorectal cancer, and should, along with adiposity be a standard oncological markerImpact: Our findings suggest a biologic explanation for the obesity paradox in colorectal cancer and refute the notion that the association between overweight and lower mortality is due solely to methodologic biases Cancer Epidemiol Biomarkers Prev; 26(7); 1008-15 ©2017 AACR
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TL;DR: Pediagnosis inflammation was associated with at-diagnosis sarcopenia, suggesting that these commonly collected biomarkers could enhance prognostication and open new therapeutic avenues to improve cancer outcomes.
Abstract: Importance Systemic inflammation and sarcopenia are easily evaluated, predict mortality in many cancers, and are potentially modifiable. The combination of inflammation and sarcopenia may be able to identify patients with early-stage colorectal cancer (CRC) with poor prognosis. Objective To examine associations of prediagnostic systemic inflammation with at-diagnosis sarcopenia, and determine whether these factors interact to predict CRC survival, adjusting for age, ethnicity, sex, body mass index, stage, and cancer site. Design, Setting, and Participants A prospective cohort of 2470 Kaiser Permanente patients with stage I to III CRC diagnosed from 2006 through 2011. Exposures Our primary measure of inflammation was the neutrophil to lymphocyte ratio (NLR). We averaged NLR in the 24 months before diagnosis (mean count = 3 measures; mean time before diagnosis = 7 mo). The reference group was NLR of less than 3, indicating low or no inflammation. Main Outcomes and Measures Using computed tomography scans, we calculated skeletal muscle index (muscle area at the third lumbar vertebra divided by squared height). Sarcopenia was defined as less than 52 cm2/m2and less than 38 cm2/m2for normal or overweight men and women, respectively, and less than 54 cm2/m2and less than 47 cm2/m2for obese men and women, respectively. The main outcome was death (overall or CRC related). Results Among 2470 patients, 1219 (49%) were female; mean (SD) age was 63 (12) years. An NLR of 3 or greater and sarcopenia were common (1133 [46%] and 1078 [44%], respectively). Over a median of 6 years of follow-up, we observed 656 deaths, 357 from CRC. Increasing NLR was associated with sarcopenia in a dose-response manner (compared with NLR Conclusions and Relevance Prediagnosis inflammation was associated with at-diagnosis sarcopenia. Sarcopenia combined with inflammation nearly doubled risk of death, suggesting that these commonly collected biomarkers could enhance prognostication. A better understanding of how the host inflammatory/immune response influences changes in skeletal muscle may open new therapeutic avenues to improve cancer outcomes.
304 citations
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...Body mass index, mean (SD) 28 (6) 28 (6) 28 (7)...
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TL;DR: Understanding patients' nutritional requirements could lead to targeted prescriptions to prevent or attenuate low MM in cancer, with the overall aim of minimizing muscle loss during anti‐cancer therapy and maximizing muscle anabolism during recovery.
Abstract: Many patients with cancer experience poor nutritional status, which detrimentally impacts clinical outcomes. Poor nutritional status in cancer is primarily manifested by severe muscle mass (MM) depletion, which may occur at any stage (from curative to palliative) and often co-exists with obesity. The objective of this article was to discuss gaps and opportunities related to the role of nutrition in preventing and reversing low MM in cancer. It also provides a narrative review of relevant nutritional interventions for patients capable of oral intake. The impact of nutrition interventions to prevent/treat low MM in cancer is not well understood, potentially due to the limited number of studies and of clinically viable, accurate body composition assessment tools. Additionally, the type of study designs, inclusion criteria, length of intervention, and choice of nutritional strategies have not been optimal, likely underestimating the anabolic potential of nutrition interventions. Nutrition studies are also often of short duration, and interventions that adapt to the metabolic and behavioural changes during the clinical journey are needed. We discuss energy requirements (25-30 kcal/kg/day) and interventions of protein (1.0-1.5 g/kg/day), branched-chain amino acids (leucine: 2-4 g/day), β-hydroxy β-methylbutyrate (3 g/day), glutamine (0.3 g/kg/day), carnitine (4-6 g/day), creatine (5 g/day), fish oil/eicosapentanoic acid (2.0-2.2 g/day EPA and 1.5 g/day DHA), vitamin/minerals (e.g. vitamin D: 600-800 international units per day), and multimodal approaches (nutrition, exercise, and pharmaceutical) to countermeasure low MM in cancer. Although the evidence is variable by modality type, interventions were generally not specifically studied in the context of cancer. Understanding patients' nutritional requirements could lead to targeted prescriptions to prevent or attenuate low MM in cancer, with the overall aim of minimizing muscle loss during anti-cancer therapy and maximizing muscle anabolism during recovery. It is anticipated that this will, in turn, improve overall health and prognostication including tolerance to treatment and survival. However, oncology-specific interventions with more robust study designs are needed to facilitate these goals.
168 citations
Cites background from "Explaining the Obesity Paradox: The..."
...LowMM in cancer also occurs at any disease stage.(14,15) Many believe that nutrition is not a priority once cancer is diagnosed or even that it can increase tumour growth,(16) which is not founded on scientific evidence....
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...at the time of cancer diagnosis and continue to lose muscle throughout the disease trajectory, even in the context of curative disease.(4,9,12,14) Therefore, a nutrition interven-...
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...overweight or obesity leading to favourable outcomes) in cancer may be due to the lack of body composition data and the use of body mass index, which confounds the association of low MM with shorter survival.(14,42) As such, interventions leading to disproportional gains in adipose tissue versus MM might have limited impact on clinical out-...
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TL;DR: Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival.
Abstract: Importance The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. Objective To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. Design, Setting, and Participants This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. Exposures We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. Main Outcomes and Measures Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free, recurrence-free, and overall survival. Results Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99;P = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06;P = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76;P = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84;P = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94;P = .05 for trend). Conclusions and Relevance Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. Trial Registration clinicaltrials.gov Identifier: NCT00003835
129 citations
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...Total grains that are whole, median (IQR), % 30 (14-50) 46 (22-65) 50 (31-65) 56 (37-69) 62 (51-78) <....
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...BMI, median (IQR) 33 (30-36) 29 (26-32) 26 (23-29) 25 (23-28) 23 (22-25) <....
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...of unique fruits and vegetables consumed per month, median (IQR) 27 (22-30) 27 (24-31) 29 (24-33) 30 (26-32) 31 (27-34) <....
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...Physical activity, median (IQR), MET-h/wk 2 (1-5) 6 (2-10) 9 (3-18) 22 (12-37) 31 (21-46) <....
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TL;DR: A large body of epidemiological evidence supports a causal relationship between excess adiposity and elevated risk of developing gastrointestinal cancers and emerging evidence suggests that the gut microbiome, gut hormones, and non alcoholic fatty liver disease might also have important roles in mediating the obesity-gastrointestinal cancer relationship.
Abstract: Excess adiposity is a risk factor for several cancers of the gastrointestinal system, specifically oesophageal adenocarcinoma and colorectal, small intestine, pancreatic, liver, gallbladder and stomach cancers. With the increasing prevalence of obesity in nearly all regions of the world, this relationship could represent a growing source of cancers of the digestive system. Experimental and molecular epidemiological studies indicate important roles for alterations in insulin signalling, adipose tissue-derived inflammation and sex hormone pathways in mediating the association between adiposity and gastrointestinal cancer. The intestinal microbiome, gut hormones and non alcoholic fatty liver disease (NAFLD) also have possible roles. However, important gaps remain in our knowledge. For instance, our understanding of how adiposity throughout the life course is related to the risk of gastrointestinal cancer development and of how obesity influences gastrointestinal cancer prognosis and survival is limited. Nonetheless, the increasing use of state-of-the-art analytical methods (such as omics technologies, Mendelian randomization and MRI) in large-scale epidemiological studies offers exciting opportunities to advance our understanding of the complex relationship between adiposity and gastrointestinal cancers. Here, we examine the epidemiology of associations between obesity and gastrointestinal cancer, explore potential mechanisms underlying these relationships and highlight important unanswered research questions.
121 citations
TL;DR: There is growing evidence that body composition may in part explain the "obesity paradox", and more research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality.
Abstract: Despite a greater risk of cancer associated with higher BMI, overweight (BMI 25-<30 kg/m2) and class I obese (BMI 30-<35 kg/m2) patients often have a paradoxically lower risk of overall mortality after a cancer diagnosis, a phenomenon called the "obesity paradox." Only when patients exceed a BMI ≥35 kg/m2 are elevations in mortality risk consistently noted. This paradox has been dismissed as the result of methodologic bias, which we will describe and debate here. However, even if such bias influences associations, there is growing evidence that body composition may in part explain the paradox. This phenomenon may more accurately be described as a BMI paradox. That is, BMI is a poor proxy for adiposity and does not distinguish muscle from adipose tissue, nor describe adipose tissue distribution. Low muscle mass is associated with higher risk of recurrence, overall and cancer-specific mortality, surgical complications, and treatment-related toxicities. Patients with who are overweight or obese have on average higher levels of muscle than their normal-weight counterparts. Also, there is some evidence that patients with moderate levels of subcutaneous adipose tissue may have lower mortality. More research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality. Cancer Res; 78(8); 1906-12. ©2018 AACR.
120 citations
Cites background from "Explaining the Obesity Paradox: The..."
...Furthermore, in the C-SCANS cohort, we note that overweight versus normal-weight patients have a lower mortality risk regardless of stage, including a protective association in stage I patients who we would not expect to die from their cancer (33)....
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References
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TL;DR: Evidence is provided of the great variability of body composition in patients with cancer and links body composition, especially sarcopenic obesity, to clinical implications such as functional status, survival, and potentially, chemotherapy toxicity.
Abstract: Summary Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer. Methods Between Jan 13, 2004, and Jan 19, 2007, 2115 patients with solid tumours of the respiratory or gastrointestinal tract from a cancer treatment centre serving northern Alberta, Canada, were identified. Available lumbar CT images of the obese patients were analysed for total skeletal muscle cross-sectional area; these values were also used to estimate total body fat-free mass (FFM). Findings Of the 2115 patients initially identified, 325 (15%) were classified as obese (body-mass index [BMI] ≥30). Of these obese patients, 250 had CT images that met the criteria for analysis. The remaining 75 patients were recorded as without assessable scans. Obese patients had a wide range of muscle mass. Sex-specific cut-offs that defined a significant association between low muscle mass with mortality were ascertained by optimum stratification analysis: 38 (15%) of 250 patients who had assessable CT images that met the criteria for analysis were below these cut-offs and were classified as having sarcopenia. Sarcopenic obesity was associated with poorer functional status compared with obese patients who did not have sarcopenia (p=0·009), and was an independent predictor of survival (hazard ratio [HR] 4·2 [95% CI 2·4–7·2], p r 2 =0·37). Assuming that FFM represents the volume of distribution of many cytotoxic chemotherapy drugs, we estimated that individual variation in FFM could account for up to three-times variation in effective volume of distribution for chemotherapy administered per unit body-surface area, in this population. Interpretation This study provides evidence of the great variability of body composition in patients with cancer and links body composition, especially sarcopenic obesity, to clinical implications such as functional status, survival, and potentially, chemotherapy toxicity. Funding Canadian Institutes of Health Research (Ottawa, ON, Canada), Alberta Cancer Board (Edmonton, AB, Canada), and Translational Research Training in Cancer (Edmonton, AB, Canada).
2,165 citations
TL;DR: Patients with cancer who are cachexic by the conventional criterion and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.
Abstract: Purpose Emerging evidence suggests muscle depletion predicts survival of patients with cancer. Patients and Methods At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models. Results Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P .001).
1,813 citations
"Explaining the Obesity Paradox: The..." refers background in this paper
...This approach is common for defining low muscle mass in cancer (28, 29)....
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TL;DR: Investigation of the relationships between abdominal SM and AT areas from single images and total body component volumes in a large and diverse sample of healthy adult subjects found that measurement of a single abdominal image can provide estimates of total bodySM and AT for group studies of healthy adults.
Abstract: A single abdominal cross-sectional computerized axial tomography and magnetic resonance image is often obtained in studies examining adipose tissue (AT) distribution. An abdominal image might also provide additional useful information on total body skeletal muscle (SM) and AT volumes with related physiological insights. We therefore investigated the relationships between abdominal SM and AT areas from single images and total body component volumes in a large and diverse sample of healthy adult subjects. Total body SM and AT volumes were derived by whole body multislice magnetic resonance imaging in 123 men [age (mean ± SD) of 41.6 ± 15.8 yr; body mass index of 25.9 ± 3.4 kg/m2] and 205 women (age of 47.8 ± 18.7 yr; body mass index of 26.7 ± 5.6 kg/m2). Single abdominal SM and AT slice areas were highly correlated with total body SM (r = 0.71–0.92; r = 0.90 at L4–L5 intervertebral space) and AT (r = 0.84–0.96; r = 0.94 at L4–L5 intervertebral space) volumes, respectively. R2 increased by only 5.7–6.1% for ...
1,278 citations
"Explaining the Obesity Paradox: The..." refers background in this paper
...Single-slice abdominal cross-sectional areas at the L3 vertebra are strongly correlated withwhole body volumes ofmusclemass andadipose tissue (26)....
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TL;DR: It is demonstrated that low SMI at cancer diagnosis is associated with worse survival in patients with solid tumours and further research into understanding and mitigating the negative effects of sarcopenia in adults with cancer is needed.
674 citations
TL;DR: Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors.
Abstract: Human muscle undergoes constant changes. After about age 50, muscle mass decreases at an annual rate of 1–2%. Muscle strength declines by 1.5% between ages 50 and 60 and by 3% thereafter. The reasons for these changes include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living. In addition, lipids are deposited in the muscle, but these changes do not usually lead to a loss in body weight. Once muscle mass in elderly subjects falls below 2 standard deviations of the mean of a young control cohort and the gait speed falls below 0.8 m/s, a clinical diagnosis of sarcopenia can be reached. Assessment of muscle strength using tests such as the short physical performance battery test, the timed get-up-and-go test, or the stair climb power test may also be helpful in establishing the diagnosis. Sarcopenia is one of the four main reasons for loss of muscle mass. On average, it is estimated that 5–13% of elderly people aged 60–70 years are affected by sarcopenia. The numbers increase to 11–50% for those aged 80 or above. Sarcopenia may lead to frailty, but not all patients with sarcopenia are frail—sarcopenia is about twice as common as frailty. Several studies have shown that the risk of falls is significantly elevated in subjects with reduced muscle strength. Treatment of sarcopenia remains challenging, but promising results have been obtained using progressive resistance training, testosterone, estrogens, growth hormone, vitamin D, and angiotensin-converting enzyme inhibitors. Interesting nutritional interventions include high-caloric nutritional supplements and essential amino acids that support muscle fiber synthesis.
638 citations