2 Q1 Body Size Indicators and Risk of Gallbladder 3 Cancer: Pooled Analysis of Individual-Level Data 4 Q2 from 19 Prospective Cohort Studies
5 Peter T. Campbell1, Christina C. Newton1, Cari M. Kitahara2, Alpa V. Patel1, Patricia Hartge2, 6 Jill Koshiol2, Katherine McGlynn2, Hans-Olov Adami3,4, Amy Berrington2,
7 Laura E. Beane Freeman2, Leslie Bernstein5, Julie E. Buring3,6, Neal D. Freedman2, 8 Yu-Tang Gao7, Graham G. Giles8, Marc J. Gunter9, Mazda Jenab9, Linda M. Liao2,
9 Roger L. Milne8, Kim Robien10, Dale P. Sandler11, Catherine Schairer2, Howard D. Sesso3,6, 10 Xiao-Ou Shu12, Elisabete Weiderpass4,13,14,15, Alicja Wolk16, Yong-Bing Xiang7,
11 Anne Zeleniuch-Jacquotte17, Wei Zheng12, and Susan M. Gapstur1
12 Abstract
13 Background:There are few established risk factors for gallblad- 14 der cancer beyond gallstones. Recent studies suggest a higher risk 15 with high body mass index (BMI), an indicator of general heavi- 16 ness, but evidence from other body size measures is lacking.
17 Methods:Associations of adult BMI, young adult BMI, height, 18 adult weight gain, waist circumference (WC), waist–height ratio 19 (WHtR), hip circumference (HC), and waist–hip ratio (WHR) 20 with gallbladder cancer risk were evaluated. Individual-level data 21 from 1,878,801 participants in 19 prospective cohort studies (14 22 studies had circumference measures) were harmonized and 23 included in this analysis. Multivariable Cox proportional hazards 24 regression estimated HRs and 95% confidence intervals (CI).
25 Results:After enrollment, 567 gallbladder cancer cases were 26 identified during 20.1 million person-years of observation, 27 including 361 cases with WC measures. Higher adult BMI (per
29 5 kg/m2, HR: 1.24; 95% CI, 1.13–1.35), young adult BMI (per
30 5 kg/m2, HR: 1.12; 95% CI, 1.00–1.26), adult weight gain (per
31 5 kg, HR: 1.07; 95% CI, 1.02–1.12), height (per 5 cm, HR: 1.10;
32 95% CI, 1.03–1.17), WC (per 5 cm, HR: 1.09; 95% CI, 1.02–1.17),
33 WHtR (per 0.1 unit, HR: 1.24; 95% CI, 1.00–1.54), and HC (per
34 5 cm, HR: 1.13; 95% CI, 1.04–1.22), but not WHR (per 0.1 unit,
35 HR: 1.03; 95% CI, 0.87–1.22), were associated with higher risks of
36 gallbladder cancer, and results did not differ meaningfully by sex
37 or other demographic/lifestyle factors.
38 Conclusions:Thesefindings indicate that measures of overall
39 and central excess body weight are associated with higher gall-
40 bladder cancer risks.
41 Impact:Excess body weight is an important, and potentially
42 preventable, gallbladder cancer risk factor.Cancer Epidemiol Biomar-
43 kers Prev; 1–10.2016 AACR.
44
45 Introduction
46 Gallbladder cancer etiology is poorly understood with only a 47 few, mostly nonmodifiable, established risk factors, including 48 older age, female sex, abnormal pancreatic-biliary junction, and 49 history of cholesterol gallstones (1). Identifying modifiable risk 50 factors for gallbladder cancer is hindered by its rarity and poor
52 prognosis. In more-developed areas, such as the United States,
53 Australia, and Western Europe, incidence rates are 1 to 2 cases per
54 100,000 persons each year, whereas in certain high-risk popula-
55 tions, such as Mapuche Indians in South America, incidence rates
56 exceed 20 per 100,000 (2). Overall 5-year relative survival is
57 approximately 18% for U.S. adults diagnosed with gallbladder
1Epidemiology
Q3 Research Program, American Cancer Society, Atlanta, Georgia.
2Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.3Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts.4Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden.5Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute of the City of Hope, Los Angeles, California.6Divisions of Preventive Medicine and Aging, Brigham and Women's Hospital, Boston, Massachusetts.7Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.8Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia; and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.9Section of Nutrition and Metabolism, International Association for Cancer Research, Lyons, France.
10Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC.11Epidemiology Branch, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, North Carolina.12Division of Epidemiology, Department
of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.13Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.14Department of Research, Cancer Registry of Norway, Oslo, Norway.
15Samfundet Folkh€alsan, Helsinki, Finland.16Department of Environmental Med- icine, Karolinska Institutet, Stockholm, Sweden.17Department of Population Health, New York UniversitySchool of Medicine, New York City, New York. Q4
Note:Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).
Corresponding Author:Peter T. Campbell, American Cancer Society, 250 Williams Street NW, Atlanta, GA30303. Phone: 404-327-6460; Fax: 404- Q5 327-6450; E-mail: [email protected]
doi:10.1158/1055-9965.EPI-16-0796
2016 American Association for Cancer Research.
AU
Biomarkers
& Prevention
www.aacrjournals.org 1
60 cancer, and the overall median survival time is 3 to 7 months (3).
61 The poor prognosis is due, in part, to the lack of specific symptoms 62 for the disease. Early-staged gallbladder cancers are uncommon 63 and are typically only detected incidentally during cholecystec- 64 tomy for gallstones, but only 1% to 3% of patients with gallstones 65 will ever develop gallbladder cancer (4).
66 Because excess body weight is a risk factor for gallstones and 67 several other digestive system cancers (e.g., colorectum, liver, and 68 pancreas; refs. 5–9), it is a plausible risk factor for gallbladder 69 cancer. The 2015 World Cancer Research Fund's Continuous 70 Update Project (CUP) on gallbladder cancer concluded that body 71 fatness, as defined by high body mass index (BMI), is a "probable"
72 risk factor for gallbladder cancer (10). The CUP identified eight 73 prospective cohort studies (11–18) that contributed to dose– 74 response meta-analyses and reported that each 5 kg/m2increase 75 in BMI was associated with a 25% higher risk of gallbladder 76 cancer. Of those eight studies, four provided relative risks (RR) 77 for BMI that were not statistically significant (11, 12, 14, 15), and 78 two included biliary system cancer mortality as the main outcome 79 (14, 18). Waist circumference, an indicator of central adiposity 80 that might be more etiologically relevant to cancers of the diges- 81 tive system, has been evaluated by only one relatively small study 82 (76 cases) that reported higher risks with increasing waist circum- 83 ference (11).
84 Because the evidence base for overall body fatness (based on 85 BMI) and gallbladder cancer risk is considered probable and not 86 convincing, and because risk estimates for indicators of central 87 adiposity and other non-BMI measures of body size are especially 88 rare, we conducted a pooled analysis of data from 19 prospective 89 cohort studies based in the United States, Europe, Australia, and 90 Asia to investigate associations of BMI (at enrollment during 91 adulthood and recalled from young-adulthood), height, adult 92 weight gain, waist circumference, waist–height ratio, hip circum- 93 ference, and waist–hip ratio with gallbladder cancer risk.
94 Materials and Methods
95 Study population
96 All member studies of the NCI Cohort Consortium (http://epi.
97 grants.cancer.gov/Consortia/cohort.html) with body size data 98 were invited to participate, and 19 prospective cohort studies 99 were included in this analysis: Physicians' Health Study (PHS);
100 NIH-AARP Diet and Health Study (NIH-AARP); Agricultural 101 Health Study (AHS); Breast Cancer Detection Demonstration 102 Project Follow-Up Study (BCDDP); Prostate, Lung, Colorectal 103 and Ovarian Cancer Screening Trial (PLCO); Women's Health 104 Study (WHS); New York University Women's Health Study 105 (NYUWHS); Cancer Prevention Study-II Nutrition Cohort 106 (CPS-II); Iowa Women's Health Study (IWHS); California 107 Teachers' Study (CTS); European Prospective Investigation into 108 Cancer and Nutrition (EPIC); Melbourne Collaborative Cohort 109 Study (MCCS); Cohort of Swedish Men (COSM); Swedish Mam- 110 mography Cohort (SMC); The Sister Study (SISTER); Shanghai 111 Men's Health Study (SMHS); Shanghai Women's Health Study 112 (SWHS); Vitamins and Lifestyle Study (VITAL); and Women's 113 Lifestyle and Health Study (WLH). Participants gave written, 114 informed consent at enrollment or consent was implied from 115 the return of questionnaires. All studies were approved by the 116 Institutional Review Boards of their host centers.
117 All studies submitted de-identified, participant-level data 118 from their entire cohort study to the data coordinating center.
120 Data were centrally harmonized and pooled for analyses. Prior
121 to exclusions, participant-level data were provided for
122 2,213,174 men and women. The following exclusions were
123 applied: missing age at study entry, or baseline age less than 18
124 years, or older than 85 years (n¼5,501); less than 1 year of
125 follow-up time (n¼51,399); missing BMI (n¼147.552); BMI
126 less than 15 kg/m2 or greater than 60 kg/m2 (n ¼ 2,110);
127 missing height (n¼26,698); height less than 122 cm or greater
128 than 244 cm (n¼137); and prevalent cancer at baseline (n¼
129 100,976). Data from 1,878,801 participants comprised the
130 analytic cohort.
131 Gallbladder cancer diagnoses [International Classification of
132 Diseases, 10thversion (ICD-10): C23.9; ref. 19] were verified after
133 enrollment by linking to state/provincial/federal cancer or death
134 registries and/or medical record abstraction.
135 Exposures
136 Height and weight were self-reported in most cohorts and
137 directly measured in others (MCCS, SMHS, SWHS, EPIC, SIS-
138 TER); BMI was calculated as weight (kg) divided by height-
139 squared (m2) and categorized according to World Health
140 Organization criteria (20): underweight (15 < 18.5 kg/m2),
141 normal weight (18.5<25 kg/m2), overweight (25<30 kg/m2),
142 and obese (30 kg/m2). Obesity was additionally stratified as
143 classes I (30–34.9 kg/m2), II (35–39.9 kg/m2), and III (40 kg/
144 m2). Young-adult BMI was available from 10 of the cohort
145 studies (NIH-AARP, AHS, COSM, CPS-II, IWHS, MCCS, PLCO,
146 SMC, VITAL, and WLH), derived from recalled weight at ages
147 18 to 21 years, and categorized as above for adult BMI. Height,
148 in cm, was categorized into four groups for women (<160, 160
149
<165, 165<170, and170) and men (<170, 170<175, 175<
150 180, and180). Adult weight gain was estimated by subtract-
151 ing young adult weight from baseline weight, both in kg, and
152 categorized as: any weight loss, weight stable (0 kg change) or
153 weight gain of5, weight gain of 6 to 10, weight gain of 11 to
154 15, weight gain of 16 to 20, and weight gain of21.
155 Waist circumference and hip circumference were measured by
156 trained staff (EPIC, MCCS, NYUWHS, SISTER, SMHS, SWHS) or
157 self-measured by participants who were given instructions on the
158 protocol [NIH-AARP, BCDDP, COSM, CTS, IWHS, CPS-II (waist
159 circumference only), WLH, and SMC]. The remainingfive cohort
160 studies did not collect waist circumference or hip circumference
161 data. Waist circumference and hip circumference were available at
162 baseline enrollment for COSM, IWHS, MCCS, SISTER, SMC,
163 SMHS, SWHS, and WLH, whereas NIH-AARP, BCDDP, CPS-II
164 (waist circumference only), CTS, EPIC, and NYUWHS collected
165 these data 1 to 8 years after baseline. Participants with waist or hip
166 circumference measures below 50 cm or above 190 cm were
167 excluded from the relevant analysis (n¼1,329 andn¼345 were
168 excluded from waist and hip circumference analyses, respective-
169 ly). Waist circumference, in cm, was categorized in four predefined
170 groups (women: 50–<70, 70–<80, 80–<90, and 90–<191; men:
171 50–<90, 90–<100, 100–<110, and 110–<191). Hip circumfer-
172 ence, in cm, was also categorized in four pre-defined groups
173 (women: 50–<90, 90–<100, 100–<110, and 110–<191; men:
174 50–<95, 95–<105, 105–<115, and 115–<191). Waist–height
175 ratio was calculated by dividing waist by height, both in cm, and
176 categorized as <0.45, 0.45–<0.50, 0.50–<0.55, and 0.55 for
177 women and<0.50, 0.50–<0.55, 0.55–<0.60, and0.60 for men.
178 Waist–hip ratio was calculated by dividing waist circumference by
179 hip circumference, both in cm, and categorized into four groups
182 for women (<0.75, 0.75–<0.80, 0.80–<0.85, and0.85) and men 183 (<0.90, 0.90–<0.95, 0.95–<1.00, and1.00).
184 Smoking was defined according to baseline cigarette smoking 185 status and categorized as never, former, current, or missing.
186 Alcohol consumption was defined as non-drinker and, among 187 persons who consumed alcohol, in categories of grams per day 188 (grams/day:<10, 10–<20, 20–<30, and 30þ), or missing. Race 189 was self-identified and categorized as white, black/African Amer- 190 ican, and all other races including those who did not report race.
191 Physical activity was categorized into study-specific quintiles or 192 missing. Education was categorized as less than high school, high 193 school graduate, some college, college graduate or more, or 194 missing. Sex (men, women) and history of gallstones (yes, no) 195 were defined as binary variables. Missing data were treated with an 196 indicator variable.
197 Statistical analysis
198 Cox proportional hazards regression models estimated HRs 199 and 95% confidence intervals (CI) for the associations of body 200 size variables with gallbladder cancer risk. Follow-up time for 201 both BMI measures and height began on the date of enrollment 202 when height and weight werefirst reported, whereas follow-up 203 time for waist circumference, hip circumference, waist–height 204 circumference, and waist–hip ratio analyses began on the date 205 waist/hip circumference was evaluated. Cases that were diagnosed 206 after baseline but before the time of waist/hip circumference 207 assessment were excluded from those analyses. Studies that did 208 not collect waist/hip circumference data were omitted from the 209 respective analyses. All statistical models were analyzed from a 210 pooled cohort of the combined studies with individual-level data.
211 Initially, Cox models included only baseline age, study, and sex as 212 covariates. Subsequently, more comprehensive models included 213 age, study, sex, alcohol consumption, race, education, physical 214 activity, and smoking status. An additional more comprehen- 215 sively adjusted model also included personal history of gallstones.
216 Waist circumference, waist–height ratio, hip circumference, and 217 waist–hip ratio are presented with and without adjustment for 218 BMI. Adult weight gain statistical models included young adult 219 BMI. Linear models estimated associations of continuous body 220 size measures (per unit increase and per 1 SD) with gallbladder 221 cancer risk. Wald tests assessed linear trends.
222 Sensitivity analyses excluded gallbladder cancers that were 223 diagnosed in thefirst 2 and 5 years after baseline to evaluate 224 potential bias from prediagnosis weight loss due to disease 225 progression. Sensitivity analyses also evaluated the impact of 226 excluding participants who were diagnosed with gallstones at 227 baseline. Two-stage individual participant meta-analyses 228 explored potential heterogeneity of HRs across studies for con- 229 tinuous body size measures. Meta-analysis methods also evalu- 230 ated potential heterogeneity according to region of study origin 231 [i.e., North America (NIH-AARP, AHS, BCDDP, CPS-II, CTS, 232 NYUWHS, PHS, PLCO, SISTER, VITAL, and WHS), Europe (i.e., 233 COSM, EPIC, SMC, and WLH), Asia (i.e., SMHS and SWHS), and 234 Australia (i.e., MCCS)] and BMI-assessment method (i.e., self- 235 reported vs. directly measured weight and height) for the associ- 236 ation between adult BMI and gallbladder cancer risk.
237 Interaction terms with the main exposures (continuous terms) 238 and time tested the proportional hazards assumption of the Cox 239 models. No interactions were observed. Restricted cubic splines 240 evaluated potential nonlinearity of the associations for body size 241 measures with gallbladder cancer risk. AllPvalues were two-sided;
243 Pvalues less than 0.05 were considered statistically significant.
244 SAS software was used for all statistical analyses (SAS Institute,
245 Inc., version 9.4).
246 Results
247 In this analysis of 1.88 million adults enrolled in 19 pro-
248 spective cohort studies, 567 gallbladder cancers occurred dur-
249 ing 20.1 million person-years of observation. For analyses of
250 waist circumference/waist–height ratio and hip circumference,
251 361 and 318 cases were identified, respectively. Table 1 shows
252 baseline characteristics of participants: mean age was 56.7
253 years, mean BMI at baseline was 26.1 kg/m2, mean waist
254 circumference was 86.5 cm, 71% reported any alcohol intake,
255 and 15.6% were current smokers.
256 The overall and sex-specific associations between adult BMI
257 and gallbladder cancer risk are shown in Table 2. Compared
258 with a normal adult BMI at baseline, overweight, class I obesity,
259 class II obesity, and class III obesity were associated with 27%,
260 53%, 86%, and 131% higher risks of gallbladder cancer,
261 respectively, after adjusting for age, sex, study, race, physical
262 activity, education, smoking, alcohol, and gallstones. There was
263 no indication that risks differed meaningfully by sex (Pinter-
264 action, 0.89). There was no statistically significant evidence of
265 between-study heterogeneity for adult BMI (I2: 0%; P value,
266 0.49; Supplementary Fig. S1). HRs for continuous adult BMI
267 from both the pooled cohort approach (Table 2) and from the
268 two-stage individual participant meta-analysis (Supplementary
269 Fig. S1) yielded similar results. Restricted cubic spline analyses
270 supported a linear association (Fig. 1; P value for linearity:
271
<0.0001;Pvalue for nonlinearity: 0.95).
272 There was evidence supporting a positive association between
273 young adult BMI (modeled as a continuous measure) and gall-
274 bladder cancer risk (HR, 1.12, per 5 kg/m2), although the prev-
275 alence of obesity was lower than at baseline enrollment, as
276 expected, and the sex-specific obese categories contained few
277 cases (Table 2). Adult weight gain also was positively associated
278 with risk (HR, 1.07, per 5 kg). The continuous model for height
279 showed a 10% increased risk with each 5 cm increase. There was
280 no evidence of statistically significant interactions for sex and
281 young adult BMI, height or adult weight gain (allPvalues for
282 interaction0.23) or of between-study heterogeneity for young
283 adult BMI (I2: 0%;Pvalue: 0.72; Supplementary Fig. S2), height
284 (I2: 28%;Pvalue: 0.13; Supplementary Fig. S3), or adult weight
285 gain (I2: 6%;Pvalue: 0.39; Supplementary Fig. S4). Restricted
286 cubic spline analyses confirmed linear associations of young adult
287 BMI, adult weight gain, and height with gallbladder cancer risk
288 and demonstrated no evidence of nonlinearity (allPvalues for
289 linearity:<0.0001; allPvalues for nonlinearity:0.30).
290 Associations of waist circumference, waist–height ratio, hip
291 circumference, and waist–hip ratio overall and by sex with gall-
292 bladder cancer risk are shown in Table 3. Although sample sizes
293 were smaller for the waist- and hip-circumference–related mea-
294 sures than for the weight- and height-related measures, statisti-
295 cally significant positive associations were identified for contin-
296 uous measures of waist circumference (HR, 1.09, per 5 cm), waist–
297 height ratio (HR, 1.24, per 0.1), and hip circumference (HR, 1.13,
298 per 5 cm). Waist–hip ratio was not statistically significantly
299 associated with risk. Associations were similar when stratified by
300 sex (allPvalues for interaction:0.34). There was no statistically
301 significant evidence of between-study heterogeneity for waist
www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 2017 3
Table1.SummaryofcohortstudiesincludedintheRareCancerCollaboration(gallbladdercancer) Baseline cohort sample size Gallbladder cancer case Baseline age Baseline BMI (kg/m2) Baseline BMI 30kg/m2WC(cm)a
BaselineWC men:110cm women:90cma
Current cigarette smokera
Alcoholintake (g/day) amongdrinkersaAnyalcohol intakeaHistoryof gallstones Studyname(acronym)GenderNNMean(SD)Mean(SD)%Mean(SD)%%Mean(SD)%% NIH-AARPDietandHealthStudy (NIH-AARP)
Women191,3065761.3(5.4)26.9(5.6)23.384.6(13.4)30.714.58.5(20.9)70.613.7 Men296,1835361.5(5.4)27.3(4.2)21.497.9(11.0)13.011.022.9(51.1)78.96.5 AgriculturalHealthStudy(AHS)Women21,643446.7(12.0)25.9(4.9)18.6––10.12.9(6.1)55.6– Men20,464447.4(13.0)27.5(4.1)23.4––14.38.3(14.6)67.5– TheBreastCancerDetection DemonstrationProject(BCDDP)
Women37,793861.2(8.0)25.1(4.6)13.281.9(11.8)21.212.88.0(14.2)48.912.4 CohortofSwedishMen(COSM)Men42,790960.0(9.6)25.8(3.4)10.196.0(10.1)9.024.715.4(23.5)91.311.3 CancerPreventionStudy-II(CPS-II)Women80,3544362.1(6.6)25.6(4.7)15.786.3(13.0)35.18.69.0(13.1)52.417.1 Men71,3042163.9(6.1)26.4(3.7)14.498.8(10.1)12.79.117.1(21.6)65.79.0 CaliforniaTeachers'Study(CTS)Women103,8112151.4(13.5)24.8(5.0)13.981.7(13.0)23.65.011.3(9.7)66.76.4 EuropeanProspectiveWomen254,1696150.4(10.7)25.5(4.6)15.281.2(11.5)21.420.29.6(12.0)83.69.2 InvestigationintoCancerandCancer andNutrition(EPIC) Men143,3572451.7(10.1)26.5(3.7)15.595.1(10.3)8.129.921.8(23.7)93.44.2 IowaWomen'sHealthStudy (IWHS)
Women37,5065461.5(4.2)26.1(4.9)18.569.4(10.9)4.914.78.9(13.1)43.6– MelbourneCollaborativeCohortWomen22,1971754.3(8.6)26.8(4.9)22.380.1(11.8)20.09.012.4(14.2)57.612.2 Study(MCCS)Men15,537454.9(8.8)27.2(3.6)19.193.5(10.0)6.214.824.7(25.3)81.34.7 NewYorkUniversityWomen's HealthStudy(NYUWHS) Women13,211450.2(8.7)24.9(4.6)12.775.1(11.7)10.818.013.3(14.4)42.05.0 Physicians'HealthStudy(PHS)Men28,108754.7(9.7)25.1(3.0)6.2––9.2––3.7 Prostate,Lung,Colorectal,andWomen68,9052262.5(5.4)27.1(5.5)24.9––9.55.6(14.0)99.916.7 OvarianCancerScreeningTrial (PLCO)
Men68,9641562.7(5.3)27.6(4.2)23.4––11.516.5(33.1)99.97.5 TheSisterStudy(SISTERS)Women47,551355.0(9.0)27.8(6.2)29.686.3(14.7)36.08.36.8(10.0)95.414.5 SwedishMammographyCohort (SMC) Women33,7183261.3(9.1)25.0(4.0)10.683.6(10.7)26.423.66.9(10.2)83.519.7 ShanghaiMen'sHealthStudy (SMHS)
Men60,8851954.8(9.7)23.7(3.1)2.685.1(8.7)0.558.735.4(32.3)33.47.5 ShanghaiWomen'sHealthStudy (SWHS)
Women74,4605752.1(9.1)24.0(3.4)5.277.9(8.8)10.42.410.4(13.9)1.911.3 VitaminsandLifestyleStudyWomen30,842760.7(7.4)27.2(5.8)25.3––7.69.4(13.1)57.9– (VITAL)Men30,866460.6(7.3)27.6(4.4)23.9––8.917.4(21.8)70.1– Women'sHealthStudy(WHS)Women38,6861054.2(7.0)26.0(5.1)18.2––13.18.6(11.1)56.69.9 Women'sLifestyleandHealthStudy (WLH)
Women44,191740.2(5.8)23.5(3.6)5.877.0(9.3)9.620.94.1(4.5)86.2– AllwomenWomen1,100,34340755.4(10.7)25.8(5.0)17.181.3(12.5)22.313.28.6(14.0)66.512.1 N(%)missing–––––36.236.21.65.95.920.4 AllmenMen778,45816058.6(9.0)26.7(4.0)17.395.1(11.2)9.219.021.3(38.6)77.76.7 N(%)missing–––––44.844.82.110.010.014.0 AllcombinedAll1,878,80156756.7(10.1)26.1(4.7)17.286.5(13.8)17.415.614.2(28.4)71.09.8 N(%)missing–––––39.739.71.87.67.617.8 aAmongnonmissingresponders.
Table2.AssociationsofBMI,adultweightgain,andheightwithgallbladdercancer AllWomenMen MinimallyadjustedMultivariable-adjustedMultivariable-adjustedMinimallyadjustedMultivariable-adjustedMultivariable-adjustedMinimallyadjustedMultivariable-adjustedMultivariable-adjusted BMI(kg/m2)CaseaRR(95%CI)bRR1(95%CI)cRR2(95%CI)dCaseaRR(95%CI)bRR1(95%CI)cRR2(95%CI)dCaseaRR(95%CI)bRR1(95%CI)cRR2(95%CI)d BaselineBMI <18.581.20(0.59–2.43)1.19(0.59–2.43)1.21(0.60–2.47)61.04(0.46–2.36)1.06(0.47–2.39)1.07(0.47–2.43)22.13(0.51–8.89)2.00(0.48–8.36)2.03(0.49–8.50) 18.5–<252001.00(ref)1.00(ref)1.00(ref)1591.00(ref)1.00(ref)1.00(ref)411.00(ref)1.00(ref)1.00(ref) 25–<302261.36(1.12–1.64)1.29(1.07–1.57)1.27(1.04–1.54)1471.31(1.05–1.65)1.24(0.99–1.56)1.21(0.97–1.52)791.53(1.04–2.24)1.49(1.01–2.19)1.46(0.99–2.16) 30–<35911.76(1.37–2.26)1.60(1.24–2.06)1.53(1.18–1.98)591.56(1.16–2.12)1.41(1.04–1.92)1.35(0.99–1.83)322.37(1.47–3.83)2.16(1.33–3.52)2.11(1.30–3.44) 35-<40292.26(1.52–3.35)1.99(1.33–2.96)1.86(1.25–2.78)252.38(1.56–3.65)2.11(1.37–3.26)1.97(1.28–3.05)41.68(0.60–4.75)1.45(0.51–4.11)1.39(0.49–3.96) 40132.94(1.67–5.18)2.50(1.41–4.43)2.31(1.30–4.09)112.84(1.53–5.25)2.47(1.32–4.62)2.28(1.22–4.26)23.48(0.83–14.5)2.74(0.65–11.6)2.61(0.62–11.0) <18.581.20(0.59–2.43)1.19(0.59–2.43)1.21(0.60–2.47)61.05(0.46–2.36)1.06(0.47–2.40)1.08(0.48–2.43)22.13(0.51–8.89)2.00(0.48–8.36)2.03(0.49–8.50) 18.5–<252001.00(ref)1.00(ref)1.00(ref)1591.00(ref)1.00(ref)1.00(ref)411.00(ref)1.00(ref)1.00(ref) 25–<302261.36(1.12–1.65)1.29(1.07–1.57)1.27(1.04–1.54)1471.31(1.05–1.65)1.24(0.99–1.56)1.21(0.96–1.52)791.53(1.04–2.24)1.49(1.01–2.19)1.46(0.99–2.16) 301331.92(1.54–2.41)1.72(1.37–2.17)1.64(1.30–2.07)951.82(1.40–2.36)1.62(1.24–2.12)1.54(1.17–2.01)382.31(1.46–3.66)2.08(1.30–3.33)2.02(1.26–3.24) Per5kg/m2e1.31(1.21–1.43)1.26(1.16–1.37)1.24(1.13–1.35)1.31(1.20–1.44)1.27(1.15–1.40)1.24(1.13–1.37)1.31(1.09–1.59)1.24(1.02–1.50)1.22(1.01–1.49) Pvaluefortrend<0.0001<0.0001<0.0001<0.0001<0.0001<0.00010.0050.03120.0431 Pinteractionwithsex0.990.980.89 PerStdDeve1.28(1.19–1.39)1.24(1.14–1.34)1.21(1.12–1.31)1.29(1.18–1.40)1.24(1.14–1.36)1.22(1.12–1.34)1.28(1.08–1.53)1.22(1.02–1.45)1.20(1.01–1.44) Young-adultBMI <18.5380.85(0.60–1.19)0.83(0.59–1.17)0.83(0.59–1.18)280.75(0.50–1.13)0.74(0.49–1.10)0.74(0.49–1.11)101.24(0.63–2.44)1.20(0.61–2.35)1.20(0.61–2.36) 18.5–<252221.00(ref)1.00(ref)1.00(ref)1631.00(ref)1.00(ref)1.00(ref)591.00(ref)1.00(ref)1.00(ref) 25–<30291.29(0.87–1.90)1.25(0.84–1.84)1.24(0.84–1.83)151.24(0.73–2.11)1.18(0.70–2.02)1.18(0.69–2.00)141.36(0.76–2.45)1.35(0.75–2.43)1.34(0.75–2.42) 3071.92(0.90–4.08)1.77(0.83–3.77)1.75(0.82–3.73)41.59(0.59–4.29)1.45(0.54–3.93)1.44(0.53–3.90)32.74(0.86–8.79)2.60(0.81–8.36)2.57(0.80–8.26) Per5kg/m2e1.13(1.02–1.25)1.12(1.00–1.26)1.12(1.00–1.26)1.18(0.95–1.47)1.15(0.91–1.45)1.15(0.91–1.45)1.12(0.97–1.29)1.12(0.97–1.30)1.12(0.96–1.30) Pvaluefortrend0.01750.04450.05310.13850.23490.25020.13750.12850.1399 Pinteractionwithsex0.670.850.86 PerStdDeve1.07(1.01–1.14)1.07(1.00–1.14)1.07(1.00–1.14)1.10(0.97–1.25)1.08(0.95–1.24)1.08(0.95–1.23)1.06(0.98–1.16)1.07(0.98–1.16)1.07(0.98–1.16) Adultweightchange(kg)f Lostweight261.12(0.66–1.91)1.11(0.65–1.90)1.12(0.66–1.90)170.81(0.44–1.49)0.82(0.44–1.53)0.82(0.44–1.53)93.44(1.05–11.3)3.18(0.95–10.6)3.18(0.95–10.6) Gained0to5311.00(ref)1.00(ref)1.00(ref)271.00(ref)1.00(ref)1.00(ref)41.00(ref)1.00(ref)1.00(ref) Gained6to10501.23(0.78–1.92)1.19(0.76–1.87)1.19(0.76–1.87)371.06(0.65–1.74)1.03(0.63–1.70)1.03(0.63–1.70)132.38(0.78–7.30)2.33(0.76–7.17)2.33(0.76–7.17) Gained10to15431.09(0.69–1.73)1.04(0.65–1.65)1.03(0.65–1.65)320.98(0.58–1.63)0.93(0.56–1.56)0.93(0.55–1.56)111.92(0.61–6.06)1.84(0.58–5.82)1.83(0.58–5.78) Gained16to20441.29(0.82–2.06)1.20(0.76–1.91)1.19(0.75–1.90)321.16(0.70–1.95)1.09(0.65–1.82)1.08(0.64–1.82)122.28(0.73–7.11)2.08(0.67–6.51)2.06(0.66–6.45) Gained21961.68(1.12–2.54)1.50(0.99–2.27)1.48(0.97–2.25)611.35(0.86–2.14)1.22(0.76–1.95)1.20(0.75–1.93)353.76(1.32–10.7)3.17(1.10–9.14)3.13(1.08–9.03) Per5kg1.07(1.02–1.12)1.07(1.02–1.12)1.07(1.02–1.12)1.07(1.02–1.13)1.07(1.01–1.13)1.07(1.01–1.13)1.06(0.98–1.15)1.05(0.97–1.15)1.05(0.96–1.14) Pvaluefortrend0.00320.00540.00720.0090.01490.01820.16750.24540.2667 Pinteractionwithsex0.960.940.93 PerStdDeve1.19(1.06–1.34)1.18(1.05–1.33)1.18(1.05–1.33)1.20(1.05–1.38)1.19(1.03–1.37)1.19(1.03–1.37)1.16(0.94–1.44)1.14(0.91–1.43)1.13(0.91–1.42) Height(cm) M<170,W<1601671.00(ref)1.00(ref)1.00(ref)1371.00(ref)1.00(ref)1.00(ref)301.00(ref)1.00(ref)1.00(ref) M170–<175,W160–<1651371.00(0.79–1.27)1.06(0.83–1.34)1.06(0.83–1.34)1101.04(0.80–1.35)1.11(0.86–1.45)1.12(0.86–1.45)270.84(0.49–1.45)0.87(0.51–1.49)0.86(0.50–1.48) M175–<180,W165–<1701431.21(0.95–1.54)1.31(1.03–1.68)1.31(1.03–1.68)1021.24(0.94–1.64)1.37(1.04–1.82)1.38(1.04–1.82)411.09(0.65–1.83)1.15(0.68–1.95)1.14(0.67–1.93) M180þ,W170þ1201.23(0.94–1.61)1.37(1.05–1.80)1.37(1.05–1.79)581.16(0.83–1.61)1.32(0.94–1.83)1.32(0.94–1.84)621.27(0.76–2.10)1.36(0.81–2.27)1.34(0.80–2.24) Per5cm1.07(1.00–1.13)1.10(1.03–1.17)1.10(1.03–1.17)1.04(0.96–1.12)1.07(0.99–1.16)1.07(0.99–1.16)1.13(1.01–1.25)1.14(1.03–1.27)1.14(1.02–1.27) Pvaluefortrend0.0490.00430.00460.37550.07180.07010.03180.01550.0179 Pinteractionwithsex0.240.230.23 PerStdDeve1.13(1.00–1.28)1.20(1.06–1.36)1.20(1.06–1.36)1.07(0.92–1.25)1.15(0.99–1.34)1.15(0.99–1.35)1.26(1.02–1.56)1.30(1.05–1.61)1.30(1.05–1.61) Abbreviation:RR,relativerisk. aSomecountsdonotaddtototalsbecauseofmissingdata. bAdjustedforage,sex,andstudy. cAdjustedforage,sex,study,race,physicalactivity,education,smoking,andalcohol. dAdjustedforage,sex,study,race,physicalactivity,education,smoking,alcohol,andgallstones. eContinuousBMImodelsexcludethose<18.5kg/m2. fAlladultweightchangemodelsadditionallyadjustforyoungadultBMI.
www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 2017 5
304 circumference (I2: 9%; Pvalue: 0.36; Supplementary Fig. S5), 305 waist–height ratio (I2: 35%;Pvalue: 0.11; Supplementary Fig. S6), 306 hip circumference (I2: 16%;Pvalue: 0.29; Supplementary Fig. S7), 307 or waist–hip ratio (I2: 0%;Pvalue: 0.88; Supplementary Fig. S8).
308 Restricted cubic spline analyses supported linear associations of 309 waist circumference (Fig. 2;Pvalue for linearity:<0.0001;Pvalue 310 for nonlinearity: 0.62), waist–height ratio (Pvalue for linearity:
311 <0.0001; P value for nonlinearity: 0.76), hip circumference 312 (Pvalue for linearity:<0.0001;Pvalue for nonlinearity: 0.97), 313 and waist–hip ratio (Pvalue for linearity:<0.0001;Pvalue for 314 nonlinearity: 0.13) with gallbladder cancer risk.
315 When analyses were restricted to studies and participants that 316 had both BMI and waist circumference in the individual-level data 317 that included all participants, gallbladder cancer risks were sim- 318 ilarly elevated for each 1 SD unit increase in waist circumference 319 (HR, 1.28; 95% CI, 1.13–1.46) and BMI (HR, 1.21; 95% CI, 1.09– 320 1.34), when modeled separately. When BMI and waist circum- 321 ference were included in the same model, both HRs were atten- 322 uated and no longer statistically significant (waist circumference 323 HR, 1.21; 95% CI, 0.99–1.50; BMI HR, 1.06; 95% CI, 0.89–1.27).
324 In sensitivity analyses, the main studyfindings were not mate- 325 rially different after excluding gallbladder cancers that occurred in 326 thefirst 2 and 5 years after baseline and after excluding partici- 327 pants who reported history of gallstones (data not shown). No 328 strong evidence for geographic heterogeneity was detected for 329 continuous adult BMI and gallbladder cancer risk (i.e., North 330 America: HR, 1.25; 95% CI, 1.12–1.38; Europe: HR, 1.12; 95% CI, 331 0.91–1.37; Asia: HR, 1.18; 95% CI, 0.84–1.67; Australia: HR, 1.85;
332 95% CI, 1.32–2.59;Pvalue for heterogeneity: 0.09). Studies with 333 self-reported versus directly measured height and weight yielded 334 relatively similar results (i.e., self-reported BMI, per 5 kg/m2, HR, 335 1.22; 95% CI, 1.10–1.35; directly measured BMI, per 5 kg/m2, HR, 336 1.30; 95% CI, 1.10–1.54;Pvalue for heterogeneity: 0.53).
337 Discussion
338 In this large prospective analysis of 1.88 million adults enrolled 339 in 19 cohort studies, greater BMI (both at middle age and during
341 young adulthood), adult weight gain, height, waist circumference,
342 waist–height ratio, and hip circumference were all consistently
343 associated with higher risks of gallbladder cancer. Results for
344 waist–hip ratio generally suggested an increased risk, consistent
345 with the other anthropometric measures, but the results were not
346 statistically significant. Restricted cubic spline analyses supported
347 linear associations for all anthropometric measures with gallblad-
348 der cancer risk, indicating dose–response associations throughout
349 the ranges of body size measures observed in this study. The main
350 study results were consistent when stratified by sex, and they were
351 not materially different in statistical models that included many
352 confirmed and potential risk factors for gallbladder cancer, includ-
353 ing sex, smoking, alcohol, race, education, and history of choles-
354 terol gallstones. The main study results were robust after a series of
355 sensitivity analyses, including individual participant meta-anal-
356 yses and when excluding cases that occurred in thefirst 5 years of
357 follow-up.
358 Studies regarding BMI and gallbladder cancer risk have been
359 generally hampered by small numbers of outcomes and the
360 related issues of limited statistical power and imprecise risk
361 estimates: of the 12 prospective cohort studies on this topic
362 in the literature (11–13, 15–17, 21–26), six identified fewer than
363 100 cases (11, 12, 17, 22, 23, 25), and while most studies reported
364 HRs above one, many studies were not statistically significant (11,
365 12, 15, 23, 25). With data from 567 gallbladder cancer cases, this
366 study makes an important contribution toward confirming the
367 association between high BMI and this rare and highly fatal
368 cancer. The HR identified in this study for obese BMI and gall-
369 bladder cancer risk (HR, 1.64) is similar in magnitude to results
370 from individual large, prospective cohort studies (13, 16, 21, 26),
371 and to results from a recent meta-analysis (HR, 1.62; ref. 27). In
372 addition, this study identified similar HRs for linear BMI and
373 gallbladder cancer risk when stratified by sex, similar to the
374 conclusion reached by the recent CUP (10), but somewhat in
375 contrast to earlier reports that suggested the association was
376 higher for women than men (27–29). Because gallbladder cancer
377 is more common in women than in men (by approximately
378 2-fold, typically), it is plausible that the earlier studies compared
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00
65 60 55 50 45 40 35 30 25 20 15
Rate rao
Body mass index (kg/m2)
Figure 1.
Restricted cubic spline analysis of BMI and risk of gallbladder cancer in the Rare Cancer Collaboration. The solid line indicates the HR, whereas the dashed line indicates 95% CIs
Q7 .
