Explaining the Obesity Paradox: The Association between Body Composition and Colorectal Cancer Survival (C-SCANS Study)

Abstract

Background Body composition may partially explain the U-shaped association between BMI and colorectal cancer (CRC) survival. Methods Muscle and adiposity at CRC 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 (OM) and CRC specific mortality (CRCsM). Results Forty-two percent of patients were sarcopenic. During 6.0 years of follow-up, 788 deaths occurred, including 433 from CRC. Sarcopenic patients had a 27% (HR 1.27; 95% CI 1.09, 1.48) higher risk of OM, than those who were not sarcopenic. Females with both low muscle and high adiposity had a 64% higher risk of OM (HR 1.64; 95% CI 1.05, 2.57) when compared to females with adequate muscle and lower adiposity. The lowest risk of OM was seen in patients with a BMI between 25-<30-kg/m2, a range associated with the greatest number of patients (58.6%) who were not at increased risk of OM due to either low muscle or high adiposity. Conclusions Sarcopenia is prevalent among non-metastatic CRC patients, and should, along with adiposity be a standard oncological marker. Impact Our findings suggest a biological explanation for the obesity paradox in CRC and refute the notion that the association between overweight and lower mortality is due solely to methodological biases.

Screening for low muscularity in colorectal cancer patients: a valid, clinic‐friendly approach that predicts mortality

“…These cut‐points were sensitive (0.75; 95% CI: 0.70, 0.80) and specific (0.77; 95% CI: 0.73, 0.80) relative to previously published cut‐points15 for low muscle mass derived from the total cross‐sectional area (Table 7). As shown in the Kaplan–Meier curves, patients with low muscle identified by these cut‐points had worse overall survival, with a median survival time of 6.3 years for patients below the cut‐point compared with 7.4 years for patients above the cut‐point (Figure 2, log‐rank P ‐value <0.001).…”

“…Thus, to compare the magnitude of the associations of muscle assessed using each of the methods with overall mortality after colorectal cancer diagnosis, we standardized the linear and total cross‐sectional areas to the normal distribution and report mortality associations per standard deviation (SD). To derive sex‐specific cut‐points for low muscle from the linear area that identified patients with increased risk of death, we used optimal stratification, a method commonly employed in the oncology literature to derive cut‐points for continuous exposures 15, 17, 32. For each candidate cut‐point, the log‐rank statistic testing the between group difference in overall survival was computed, and the cut‐point with the maximum absolute value of the log‐rank statistic was chosen 32.…”

“…For each candidate cut‐point, the log‐rank statistic testing the between group difference in overall survival was computed, and the cut‐point with the maximum absolute value of the log‐rank statistic was chosen 32. We then calculated the sensitivity and specificity of these linear area cut‐points for identifying low muscle relative to previously published cut‐points based on total cross‐sectional area from the C‐SCANS cohort (<52 cm 2 /m 2 and <38 cm 2 /m 2 for normal or overweight men and women, respectively, and <54 cm 2 /m 2 and <47 cm 2 /m 2 for obese men and women, respectively) 15. As there are no universally accepted cut‐points for low muscle mass from CT and the appropriate binary cut‐points are debated in the oncology literature,33 we also presented results with the linear measures as continuous and categorical in tertiles to represent the dose–response relationship with mortality and enable comparison with other studies which selected different cut‐points.…”

“…Low skeletal muscle mass is common among cancer patients1, 2 and predicts surgical complications,3, 4, 5, 6, 7, 8, 9 treatment toxicity,10, 11, 12, 13, 14 poor quality of life, and reduced survival 9, 15, 16, 17. This accumulating evidence has prompted oncologists to identify skeletal muscle mass as an important biomarker for numerous adverse outcomes in cancer patients 18.…”

“…In the present study, we applied the linear measures method among an ethnically and racially diverse group of 807 non‐metastatic colorectal cancer patients. The muscle area of these patients was previously quantified using standard analysis of total L3 cross‐sectional area and found to be associated with surgical complications, treatment‐related toxicities,28 and premature mortality 15. If shown to be valid, the linear measures method has high potential for integration into existing clinical workflows as a tool to screen cancer patients for low muscle, improve prognostication, and target supportive interventions like nutrition and physiotherapy.…”