Research JAMA Oncology | Original Investigation Analysis of Body Mass Index and Mortality in Patients With Colorectal Cancer Using Causal Diagrams Candyce H. Kroenke, ScD; Romain Neugebauer, PhD; Jeffrey Meyerhardt, MD; Carla M. Prado, PhD; Erin Weltzien, BA; Marilyn L. Kwan, PhD; Jingjie Xiao, MS; Bette J. Caan, DrPH Editorial page 1127 IMPORTANCE Physicians and investigators have sought to determine the relationship Supplemental content 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 Ն35; 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 Author Affiliations: Division of recommendations for weight loss in the immediate postdiagnosis period among patients Research, Kaiser Permanente Oakland, California (Kroenke, with CRC who are overweight may be unwarranted. Neugebauer, Weltzien, Kwan, Caan); Dana Farber Cancer Institute, Boston, Massachusetts (Meyerhardt); Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada (Prado, Xiao). Corresponding Author: Candyce H. Kroenke, ScD, Division of Research, Kaiser Permanente, 2000 Broadway, JAMA Oncol. 2016;2(9):1137-1145. doi:10.1001/jamaoncol.2016.0732 Fifth Floor, Oakland, CA 94612 Published online May 19, 2016. ([email protected]). (Reprinted) 1137 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Research Original Investigation Body Mass Index and Colorectal Cancer Prognosis ody mass index (BMI [calculated as weight in kilo- grams divided by height in meters squared]) is posi- Key Points tively associated with the risk of colorectal cancer B Question What is the effect of body mass index (BMI) on 1-9 (CRC). For that reason, investigators have hypothesized colorectal cancer (CRC) mortality? that being overweight or obese leads to worse CRC progno- Findings In a complete population of patients with CRC with sis. However, though previous studies have shown an prospectively collected data, BMI at (and following) diagnosis of apparently elevated mortality risk in patients who are class CRC was associated with all-cause and disease-specific mortality in 10-12 II or III obese (BMI ≥35), associations of class I obesity a nonlinear fashion with the highest risks occurring in patients who (BMI 30 to <35) and survival are mixed; some studies show a were underweight, low-normal weight, and class II or III obese. By higher mortality risk6,10,13-16 and others show no higher17 contrast, patients who were overweight consistently had the mortality risk or a possible lower18 mortality risk, depending lowest mortality risk. in part on when BMI is measured relative to diagnosis. Meaning Despite scientific evidence showing that exercise in Patients who have CRC and are overweight or obese have patients with cancer should be encouraged, findings suggest that shown lower mortality risks11,18 compared with patients recommendations for weight loss in the immediate postdiagnosis who are normal weight or underweight when BMI is mea- period in patients with CRC who are overweight may be sured following diagnosis, but concerns are that the obesity unwarranted. paradox could reflect sample selection bias, reverse causal- ity, and/or collider bias.19-21 We sought to employ methods to overcome these concerns in our evaluation of the effect We hypothesized higher mortality risks in patients with of BMI on postdiagnosis mortality. CRC who were underweight or were class II or III obese and a First, many studies of weight and CRC survival are con- lower mortality risk in patients who were overweight, ducted in samples recruited after diagnosis, causing con- compared with patients of normal weight. cerns that only the healthiest may enroll. Such sampling se- lection bias could produce an obesity paradox if the sickest patients who are overweight are less likely to enroll than the Methods sickest patients who are normal weight or if those patients die prior to enrollment. Second, patients who are underweight or Study Population normal weight may have higher mortality compared with pa- The study population consisted of all patients ages 18 to 80 tients who are overweight because they may include patients years from KPNC diagnosed between 2006 to 2011 with stage who are cachectic nearing death (ie, reverse causality).22 A third I to III invasive CRC whose cancer was confirmed by com- concern is collider bias20; in the presence of an unmeasured puted tomography, who received surgery, and for whom an risk factor for CRC diagnosis (eFigure 1 in the Supplement), se- electronic weight and height were available at diagnosis. lecting a population based on a CRC diagnosis could intro- Case ascertainment began in 2006, 1 year after weights rou- duce a spurious association between an exposure (eg, postdi- tinely became available in the EMR, to enable inclusion of pre- agnosis BMI) and an outcome (eg, death) that could reverse the diagnosis weight in analyses. Approximately one-third of the direction of association, making a harmful exposure appear California population are Kaiser Permanente members; mem- protective.21 In other words, collider bias may occur if being bers represent the underlying population except at socioeco- overweight or obese leads to higher disease incidence, but un- nomic extremes.24 Approximately 5% of patients were miss- measured risk factors occurring disproportionately in pa- ing at-diagnosis BMI data in a year. Overall, 33 patients (1.0%) tients who are normal-weight are more strongly related to mor- were lost to follow-up; 1693 (49.7%) of study participants were tality than being overweight or obese. In this case, spuriousness women and 1715 (50.3%) were men. A waiver of written in- can be avoided with adjustment for prediagnosis BMI formed consent was obtained and the study was approved by (eFigure 1 in the Supplement). the KPNC institutional review board. Using electronic medical record (EMR) data collected as a part of routine clinical care within the Kaiser Permanente Data Collection Northern California (KPNC) population, we examined the Body Mass Index effect of BMI at diagnosis, and following diagnosis, on all- Height and weight were measured by a medical assistant at each cause mortality and CRC-specific mortality in KPNC patients medical visit. Body mass index was computed as weight in diagnosed with CRC between 2006 and 2011 using several kilograms divided by height in meters squared. Patients were strategies to overcome bias. These included the use of data included in analyses if they had a BMI recorded less than 6 from a complete population of patients with CRC with longi- months from a CRC diagnosis and prior to surgery. Body mass tudinally collected data, examination of associations in index closest to the diagnosis date (median [range], 0.0 patients with stage I disease not expected to be at imminent [−5.3 to 6.0] months) was used in analyses of at-diagnosis risk of death, stratification by weight loss status, and the BMI; BMI measured 9 or more months before CRC diagnosis use of causal diagrams to identify sufficient adjustment (median [range], −12.5 [−9.0 to −68.9]) was used to assess pre- sets23 of covariates. Related to this, we were able to adjust diagnosis BMI; and BMI measured approximately 15 months for prospectively collected data on prediagnosis BMI, a following diagnosis (median [range], 14.7 [9.0-27.0] months), unique feature of our data. posttreatment, was used to assess postdiagnosis BMI. 1138 JAMA Oncology September 2016 Volume 2, Number 9 (Reprinted) jamaoncology.com Copyright 2016 American Medical Association.