Jingjie Xiao

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

Background: Body composition may partially explain the U-shaped association between body mass index (BMI) and colorectal cancer survival. Methods: 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 5.8 years of follow-up, 788 deaths occurred, including 433 from colorectal cancer. Sarcopenic patients had a 27% [HR, 1.27; 95% confidence interval (CI), 1.09–1.48] 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, 1.64; 95% CI, 1.05–2.57) 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 (58.6%) who were not at increased risk of overall mortality due to either low muscle or high adiposity. Conclusions: Sarcopenia is prevalent among patients with non-metastatic colorectal cancer, and should, along with adiposity be a standard oncological marker. Impact: 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.

Analysis of Body Mass Index and Mortality in Patients With Colorectal Cancer Using Causal Diagrams.

IMPORTANCE Physicians and investigators have sought to determine the relationship between body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and colorectal cancer (CRC) outcomes, but methodologic limitations including sampling selection bias, reverse causality, and collider bias have prevented the ability to draw definitive conclusions. OBJECTIVE To evaluate the association of BMI at the time of, and following, colorectal cancer (CRC) diagnosis with mortality in a complete population using causal diagrams. DESIGN, SETTING, AND PARTICIPANTS This retrospective observational study with prospectively collected data included a cohort of 3408 men and women, ages 18 to 80 years, from the Kaiser Permanente Northern California population, who were diagnosed with stage I to III CRC between 2006 and 2011 and who also had surgery. EXPOSURES Body mass index at diagnosis and 15 months following diagnosis. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for all-cause mortality and CRC-specific mortality compared with normal-weight patients, adjusted for sociodemographics, disease severity, treatment, and prediagnosis BMI. RESULTS This study investigated a cohort of 3408 men and women ages 18 to 80 years diagnosed with stage I to III CRC between 2006 and 2011 who also had surgery. At-diagnosis BMI was associated with all-cause mortality in a nonlinear fashion, with patients who were underweight (BMI <18.5; HR, 2.65; 95% CI, 1.63-4.31) and patients who were class II or III obese (BMI ≥35; HR, 1.33; 95% CI, 0.89-1.98) exhibiting elevated mortality risks, compared with patients who were low-normal weight (BMI 18.5 to <23). In contrast, patients who were high-normal weight (BMI 23 to <25; HR, 0.77; 95% CI, 0.56-1.06), low-overweight (BMI 25 to <28; HR, 0.75; 95% CI, 0.55-1.04), and high-overweight (BMI 28 to <30; HR, 0.52; 95% CI, 0.35-0.77) had lower mortality risks, and patients who were class I obese (BMI 30 to <35) showed no difference in risk. Spline analysis confirmed a U-shaped relationship in participants with lowest mortality at a BMI of 28. Associations with CRC-specific mortality were similar. Associations of postdiagnosis BMI and mortality were also similar, but patients who were class I obese had significantly lower all-cause and cancer-specific mortality risks. CONCLUSIONS AND RELEVANCE In this study, body mass index at the time of diagnosis and following diagnosis of CRC was associated with mortality risk. Though evidence shows that exercise in patients with cancer should be encouraged, findings suggest that recommendations for weight loss in the immediate postdiagnosis period among patients with CRC who are overweight may be unwarranted.

Association of Weight Change after Colorectal Cancer Diagnosis and Outcomes in the Kaiser Permanente Northern California Population

Background: Higher body mass index (BMI) is associated with incident colorectal cancer but not consistently with colorectal cancer survival. Whether weight gain or loss is associated with colorectal cancer survival is largely unknown. Methods: We identified 2,781 patients from Kaiser Permanente Northern California diagnosed with stages I–III colorectal cancer between 2006 and 2011 with weight and height measurements within 3 months of diagnosis and approximately 18 months after diagnosis. We evaluated associations between weight change and colorectal cancer–specific and overall mortality, adjusted for sociodemographics, disease severity, and treatment. Results: After completion of treatment and recovery from stage I–III colorectal cancer, loss of at least 10% of baseline weight was associated with significantly worse colorectal cancer–specific mortality (HR 3.20; 95% confidence interval [CI], 2.33–4.39; Ptrend < 0.0001) and overall mortality (HR 3.27; 95% CI, 2.56–4.18; Ptrend < 0.0001). For every 5% loss of baseline weight, there was a 41% increased risk of colorectal cancer–specific mortality (95% CI, 29%–56%). Weight gain was not significantly associated with colorectal cancer–specific mortality (Ptrend = 0.54) or overall mortality (Ptrend = 0.27). The associations were largely unchanged after restricting analyses to exclude patients who died within 6 months and 12 months of the second weight measurement. No significant interactions were demonstrated for weight loss or gain by gender, stage, primary tumor location, or baseline BMI. Conclusions: Weight loss after diagnosis was associated with worse colorectal cancer–specific mortality and overall mortality. Reverse causation does not appear to explain our findings. Impact: Understanding mechanistic underpinnings for the association of weight to worse mortality is important to improving patient outcomes. Cancer Epidemiol Biomarkers Prev; 26(1); 30–37. ©2016 AACR. See all the articles in this CEBP Focus section, “The Obesity Paradox in Cancer: Evidence and New Directions.”

The association between body composition and toxicities from the combination of Doxil and trabectedin in patients with advanced relapsed ovarian cancer.

Emerging research suggests that body composition can predict toxicity of certain chemotherapeutic agents. We used data from a clinical study to investigate associations between body composition and combined DOXIL (pegylated liposomal doxorubicin; PLD) and trabectedin (Yondelis) treatment, an effective treatment for ovarian cancer that shows high interpatient variation in toxicity profile. Patients (n = 74) participating in a phase III randomized trial of relapsed advanced ovarian cancer receiving PLD (30 mg/m(2)) and trabectedin (1.1 mg/m(2)) were included. Muscle tissue was measured by analysis of computerized tomography images, and an extrapolation of muscle and adipose tissue to lean body mass (LBM) and fat mass (FM) were employed. Toxicity profile after cycle 1 was used and graded according to the National Cancer Institute Common Toxicity Criteria (version 3). Patients presented with a wide range of body composition. In overweight and obese patients (body mass index (BMI) ≥ 25 kg/m(2), n = 48) toxicity was more prevalent in those with lower BMI (p = 0.028) and a lower FM (n = 43, p = 0.034). Although LBM alone was not predictive of toxicity, a lower FM/LBM ratio was the most powerful variable associated with toxicity (p = 0.006). A different pattern emerged among normal weight patients (n = 26) where toxicity was rare among patients with smaller BMI (<21 kg/m(2)). A clear association between both FM and LBM (primarily driven by FM) in explaining PLD plus trabectedin toxicity emerged, but only in individuals with excess body weight, with a lower ratio predicting higher exposure and risk for toxicity.

Association of Systemic Inflammation and Sarcopenia With Survival in Nonmetastatic Colorectal Cancer: Results From the C SCANS Study

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/m2 and less than 38 cm2/m2 for normal or overweight men and women, respectively, and less than 54 cm2/m2 and less than 47 cm2/m2 for 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 < 3, odds ratio, 1.35; 95% CI, 1.10-1.67 for NLR 3 to <5; 1.47; 95% CI, 1.16-1.85 for NLR ≥ 5; P for trend < .001). An NLR of 3 or greater and sarcopenia independently predicted overall (hazard ratio [HR], 1.64; 95% CI, 1.40-1.91 and HR, 1.28; 95% CI, 1.10-1.53, respectively) and CRC-related death (HR, 1.71; 95% CI, 1.39-2.12 and HR, 1.42; 95% CI, 1.13-1.78, respectively). Patients with both sarcopenia and NLR of 3 or greater (vs neither) had double the risk of death, overall (HR, 2.12; 95% CI, 1.70-2.65) and CRC related (HR, 2.43; 95% CI, 1.79-3.29). 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.

Metabolic Dysfunction, Obesity, and Survival Among Patients With Early-Stage Colorectal Cancer.

PURPOSE The effects of obesity and metabolic dysregulation on cancer survival are inconsistent. To identify high-risk subgroups of obese patients and to examine the joint association of metabolic syndrome (MetSyn) in combination with obesity, we categorized patients with early-stage (I to III) colorectal cancer (CRC) into four metabolic categories defined by the presence of MetSyn and/or obesity and examined associations with survival. METHODS We studied 2,446 patients diagnosed from 2006 to 2011 at Kaiser Permanente. We assumed MetSyn if patients had three or more of five components present at diagnosis: fasting glucose > 100 mg/dL or diabetes; elevated blood pressure (systolic ≥ 130 mm Hg, diastolic ≥ 85 mm Hg, or antihypertensives); HDL cholesterol < 40 mg/dL (men) or < 50 mg/dL (women); triglycerides ≥ 150 mg/dL or antilipids; and/or highest sex-specific quartile of visceral fat by computed tomography scan (in lieu of waist circumference). We then classified participants according to the presence (or absence) of MetSyn and obesity (BMI < 30 or ≥ 30 kg/m2) and assessed associations with overall and CRC-related survival using Cox proportional hazards models adjusted for demographic, tumor, and treatment factors and muscle mass at diagnosis. RESULTS Over a median follow-up of 6 years, 601 patients died, 325 as a result of CRC. Mean (SD) age was 64 (11) years. Compared with the reference of nonobese patients without MetSyn (n = 1,225), for overall survival the hazard ratios (HR) and 95% CIs were 1.45 (1.12 to 1.82) for obese patients with MetSyn (n = 480); 1.09 (0.83 to 1.44) for the nonobese with MetSyn (n = 417), and 1.00 (0.80 to 1.26) for obese patients without MetSyn (n = 324). Obesity with MetSyn also predicted CRC-related survival: 1.49 (1.09 to 2.02). The hazard of death increased with the number of MetSyn components present, independent of obesity. CONCLUSION Patients with early-stage CRC with obesity and MetSyn have worse survival, overall and CRC related.

Computed tomography-derived skeletal muscle index: A novel predictor of frailty and hospital length of stay after transcatheter aortic valve replacement.

To determine the prevalence of low skeletal muscle mass in patients undergoing transcatheter aortic valve replacement (TAVR) and whether skeletal muscle mass measured from preoperative computed tomography (CT) images provides value in predicting postoperative length of stay (LOS). BACKGROUND There are limited data on the use of body composition as a frailty measure in TAVR patients and no studies have determined if this measure predicts LOS. METHODS We studied 104 consecutive patients who underwent TAVR at Tallahassee Memorial Hospital from 2012 to 2016. Patient demographics, standard frailty measures (hand grip, albumin, and 5-m walk test), clinical comorbidities, echocardiographic data, and Valve Academic Research Consortium II major complications were recorded prospectively. Skeletal muscle index (SMI) [skeletal muscle mass cross-sectional area at L3/height2] was measured from CT images using Slice-O-Matic software (Tomovision, Montreal, Quebec, Canada). Clinical outcomes were assessed and multivariate methods used to determine predictors of LOS. RESULTS Sarcopenia was prevalent in men (83%) and women (56%). Patients who suffered from a major complication had significantly longer length of stay (13 vs 4.6days, P<.0001). Skeletal muscle index correlated with age, sex, body mass index, handgrip strength, and previous coronary artery bypass graft surgery, but not major complications. A multivariate model including all univariate predictors of LOS showed SMI, major complications, transapical access, atrial fibrillation, and chronic obstructive pulmonary syndrome as independent predictors of LOS. For every 14-cm2/m2 increase in SMI, there was a 1-day reduction in LOS. None of the standard measures of frailty predicted LOS. CONCLUSIONS Skeletal muscle index, a measure of sarcopenia readily determined from pre-TAVR CT scans, independently predicts TAVR LOS better than standard frailty testing. Further evaluation of SMI as a frailty measure after TAVR and other cardiovascular procedures is warranted.

Visceral adiposity and cancer survival: a review of imaging studies.

Although obesity is a well-known risk factor for cancer, the association between obesity and cancer survival remains controversial. This is partially due to the inability of conventional obesity measures to directly assess adiposity or adipose tissue distribution. As a metabolic organ, visceral adipose tissue (VAT) secrets a variety of cytokines and cytokine-like factors, potentially affecting cancer survival. The objective of this review was to investigate the influence of imaging-assessed VAT on cancer survival. A total of 22 studies assessing the impact of visceral adiposity on survival were included. Negative associations between VAT and survival were more frequently observed among patients with colorectal (four of six studies) and pancreatic (three of five studies) cancers, compared to higher VAT predicting longer survival in most studies of renal cell carcinoma patients (four of five studies). Methodological limitations, including unstandardised VAT measurement methods, lack of other body composition measurement (i.e. muscle mass), small sample size and heterogeneous cohort characteristics, may explain controversial findings related to the impact of VAT on cancer survival.

Associations of pre-existing co-morbidities with skeletal muscle mass and radiodensity in patients with non-metastatic colorectal cancer: Co-morbidities and Muscle Abnormalities in Colorectal Cancer

Co‐morbidities and computerized tomography‐measured muscle abnormalities are both common in cancer patients and independently adversely influence clinical outcomes. Muscle abnormalities are also evident in other diseases, such as diabetes and obesity. This study examined for the first time the association between co‐morbidities and muscle abnormalities in patients diagnosed with colorectal cancer (CRC).

Muscle radiodensity and mortality in patients with colorectal cancer: Muscle Radiodensity and Prognosis in CRC

Low skeletal muscle radiodensity (SMD) is related to higher mortality in several cancers, but the association with colorectal cancer (CRC) prognosis is unclear.