Pre-diagnostic body mass index and colorectal cancer survival

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1 Pre-diagnostic body mass index and colorectal cancer survival Jonathan Kocarnik, PhD MPH WHI Cancer SIG call 16 November 2015

2 2 BACKGROUND Body mass index (BMI) is a modifiable risk factor for colorectal cancer (CRC) incidence Higher BMI associated with higher CRC risk BMI appears associated with CRC survival as well, but evidence is mixed Higher BMI generally associated with higher CRC mortality A few studies observe higher BMI associated with lower CRC mortality (an obesity paradox) Observed sex differences in both CRC incidence (higher in males) and survival (better in females)

3 3 AIMS Evaluate whether BMI is associated with overall survival following CRC diagnosis Evaluate whether BMI is associated with CRC-specific survival following CRC diagnosis Evaluate whether associations between BMI and survival vary by cancer site, cancer stage, or sex.

4 4 STUDIES INCLUDED 6 studies collaborating with the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) HPFS - Health Professionals Follow-up study NHS - Nurses Health Study PHS - Physicians Health study PLCO - Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial VITAL - VITamins And Lifestyle study WHI - Women s Health Initiative Total 2,900 CRC cases followed for median 4.2 years 998 deaths, 700 from CRC-related causes

5 5 METHODS Cox regression, using a pooled GECCO dataset Primary variable of interest: BMI (kg/m 2 ) Normal ( ), Overweight ( ), Obese ( 30.0) Excluded Underweight (<18.5), BMI 1 year before dx Adjust/stratify by cancer stage (I-IV) Adjustment variables Age at diagnosis (continuous) Sex (Male vs. Female) Study (categorical) Smoking status (current, former, or never smoker)

6 6 STUDY DEMOGRAPHICS Total cases * 2900 No. deaths (%) 998 (34) No. CRC deaths (%) 700 (24) Median years follow-up 4.2 Sex (% female) 65 Mean age at reference (SD) 64.3 (7.1) Mean age at diagnosis (SD) 71.2 (7.3) Smoking status (%) Current 260 (09) Former 1331 (46) Never 1286 (45) BMI category (%) Normal ( ) 1009 (35) Overweight ( ) 1151 (40) Obese ( 30.0) 698 (24) Stage at diagnosis (%) I 847 (31) II 766 (28) III 694 (26) IV 397 (15) Tumor site (%) Distal 759 (27) Proximal 1524 (53) Rectal 527 (18) * After exclusions (n = 594)

7 7 OVERALL SURVIVAL Stage-adjusted n (events) 2644 (879) HR 95% CI p-value Normal (Ref.) Overweight Obese CRC-specific Stage I Stage II Stage III survival Stage-adjusted Stage IV n (events) 823 (126) n (events) 750 (172) 680 (250) 2644 (625) 391 (331) HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value Normal (Ref.) Normal (Ref.) Overweight Overweight Obese Obese

8 8 CRC-SPECIFIC SURVIVAL Stage-adjusted n (events) 2644 (625) HR 95% CI p-value Normal (Ref.) Overweight Obese Stage I Stage II Stage III Stage IV n (events) 823 (39) 750 (76) 680 (197) 391 (313) HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value Normal (Ref.) Overweight Obese

9 9 RESULTS For overweight patients, observe a trend of increased survival, except for those with stage I disease For obese patients, observe a trend of decreased survival, except for those with stage IV disease Overweight vs. Normal BMI (HR) Obese vs. Normal BMI (HR) Stage Overall CRC-specific Stage Overall CRC-specific I I II II III III IV IV Compared to normal BMI, observed a statistically significant increase in CRC-specific survival in the overweight group 18% stage-adjusted decreased risk of mortality 48% decreased risk of mortality for stage 2 cancers

10 10 SENSITIVITY ANALYSES Sex-stratified results remained significant for females, but not males Appears that the lower end of normal BMI ( ) is particularly vulnerable, especially for stage IV disease Saw differences by tumor location, with higher BMI significantly increasing survival in stage IV rectal cancer Tighter restrictions on time from BMI measurement to diagnosis led to stronger findings (unlikely that these findings are due to reverse causality or misclassification)

11 11 DISCUSSION The relationship between BMI and survival after CRC diagnosis appears to vary according to degree of body weight and stage at diagnosis Higher levels of BMI generally appear to be associated with decreased survival for early-stage disease, and increased survival for later-stage disease Some of the observed obesity paradox for CRC survival may be due to differences in the relationship with BMI by cancer stage at diagnosis While maintaining a healthy weight is important for lowering CRC risk, some degree of adiposity may be advantageous for survival once CRC has manifested

12 12 DISCUSSION Treatment, toxicity, and metabolic requirements vary by stage of disease. In early stages, perhaps no benefit from additional stores of energy (due to curative resection) In later stages, higher adiposity may provide an increased ability to cope with the physiological stressors of cancer treatment (chemotherapy, etc.) Might be an upper limit to the benefit of excess metabolic capacity (e.g. overweight vs. obese) May point to importance of adequate adiposity for disease survival (possible U/J shaped mortality curve) Other measures of body adiposity may be useful to explore effects of body fat distribution and composition

13 13 INTERNATIONAL SURVIVAL ANALYSIS IN COLORECTAL CANCER CONSORTIUM (ISACC) Cohort / Longitudinal studies Acronym Study name Country Years of recruitment Number of cases ColoCare ColoCare Consortium USA COLON Colorectal cancer: Longitudinal Observational study on Nutritional and lifestyle Netherlands factors that influence colorectal tumour recurrence, survival and quality of life CORSA Colorectal cancer study of Austria Austria ,250 CPS-2 Cancer Prevention Study - 2 USA ,019 EPIC European Prospective Investigation into Cancer and Nutrition Europe ( ,000 ESTHER-VERDI Epidemiologische Studie zu Chancen der Verhütung, Früherkennung und optimierten THerapie chronischer ERkrankungen in der älteren Bevölkerung countries) Germany (VERDI); (ESTHER I); (ESTHER II) HPFS Health Professionals Follow-up Study USA NHS Nurses' Health Study USA PHS Physician's Health Study USA PLCO Prostate, Lung, Colorectal, and Ovarian Cancer Screening USA VITAL VITamins And Lifestyle USA WHI Women's Health Initiative USA ,500 Case-control studies Acronym Study name Country Years of recruitment Number of cases CCFR-Seattle Colorectal Cancer Family Registry - Seattle USA ,700 CCFR-Ontario Colorectal Cancer Family Registry - Ontario Canada DACHS* Darmkrebs: Chancen der Verhütung durch Screening Germany ,249 DALS Diet, Activity, and Lifestyle Study USA ,116 NFCCR Newfoundland Colorectal Cancer Registry Canada ; Clinical trials Acronym Study name Country Years of recruitment Number of cases N0147 N0147 (NCCTG) USA ,098 N9741 N9741 (NCCTG) USA QUASAR* QUick And Simple And Reliable Trial Europe ,436 Spain CTs Mosaic Trial; CPT.ES1.604; 03-TTD-01; 04-TTD-02 Spain (varied) 768 VICTOR* Vioxx in Colorectal Therapy: Definition of Optimal Regime UK ,400 * Project analyses to be performed by the study (not the coordinating center) 600

14 Expected study data availability Study Survival Genetic Epidemiologic Treatment Tumor Characteristics CCFR Y Y Y Y N ColoCare Y Y Y Y Y COLON Y Y Y Y N CORSA Y Y Y Y Y CPS-2 Y Y Y Y Y DACHS * Y Y Y Y Y DALS Y Y Y N Y EPIC Y Y Y Y Y ESTHER-VERDI Y N Y N N HPFS Y Y Y N Y N0147 Y Y N Y Y N9741 Y Y N Y N NFCCR Y Y Y Y Y NHS Y Y Y N Y PHS Y Y Y N N PLCO Y Y Y Y Y QUASAR * Y Y N Y N Spain CTs Y Y N Y Y VICTOR * Y N N Y Y VITAL Y Y Y Y N WHI Y Y Y Y Y TOTAL * Several studies performing analyses separately. Tumor data likely not available until later. 14

15 15 ISACC INFORMATION Collaborative opportunities open to all (submit project proposal) Analysis support for projects conducted at the coordinating center (or study) Project leads in charge of manuscript Open monthly conference calls Third Thursday, alternates 9am / 2pm Pacific For more information, or to join the listserve, contact Jonathan Kocarnik jkocarni@fredhutch.org Kendra Blalock kblalock@fredhutc.org

16 16 THANK YOU Fred Hutch Barbara Banbury Kendra Blalock Jian Gong Tabitha Harrison Xinwei Hua Jonathan Kocarnik Polly Newcomb Ulrike Peters Amanda Phipps Jamaica Robinson Harvard Andrew Chan Dawn Chong Many others!