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Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy
Version of Record online: 10 JAN 2013
Copyright © 2013 American Cancer Society
Volume 119, Issue 8, pages 1528–1536, 15 April 2013
How to Cite
Sinicrope, F. A., Foster, N. R., Yothers, G., Benson, A., Seitz, J. F., Labianca, R., Goldberg, R. M., DeGramont, A., O'Connell, M. J., Sargent, D. J. and for the Adjuvant Colon Cancer Endpoints (ACCENT) Group (2013), Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy. Cancer, 119: 1528–1536. doi: 10.1002/cncr.27938
- Issue online: 8 APR 2013
- Version of Record online: 10 JAN 2013
- Manuscript Accepted: 14 NOV 2012
- Manuscript Revised: 7 NOV 2012
- Manuscript Received: 13 SEP 2012
- body mass index;
- colon cancer;
- adjuvant therapy;
Although obesity is an established risk factor for developing colon cancer, its prognostic impact and relation to patient sex in colon cancer survivors remains unclear.
The authors examined the prognostic and predictive impact of the body mass index (BMI) in patients with stage II and III colon carcinoma (N = 25,291) within the Adjuvant Colon Cancer Endpoints (ACCENT) database. BMI was measured at enrollment in randomized trials of 5-fluorouracil–based adjuvant chemotherapy. Association of BMI with the time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were determined using Cox regression models. Statistical tests were 2-sided.
During a median follow-up of 7.8 years, obese and underweight patients had significantly poorer survival compared with overweight and normal-weight patients. In a multivariable analysis, the adverse prognostic impact of BMI was observed among men but not among women (Pinteraction = .0129). Men with class 2 and 3 obesity (BMI ≥35.0 kg/m2) had a statistically significant reduction in DFS (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.01-1.33; P = .0297) compared with normal-weight patients. Underweight patients had a significantly shorter TTR and reduced DFS (HR, 1.18; 95% CI, 1.09-1.28; P < .0001) that was more significant among men (HR, 1.31; 95% CI, 1.15-1.50; P < .0001) than among women (HR, 1.11; 95% CI, 1.01-1.23; P = .0362; Pinteraction = .0340). BMI was not predictive of a benefit from adjuvant treatment.
Obesity and underweight status were associated independently with inferior outcomes in patients with colon cancer who received treatment in adjuvant chemotherapy trials. Cancer 2013. © 2013 American Cancer Society.
The increasing prevalence of obesity and its association with both cancer risk and prognosis have major importance in public health. Approximately 34% of adults in the United States are obese, which is defined as having a body mass index (BMI)1, 2 ≥30 kg/m2. Rates of obesity have increased 2-fold among adults and 3-fold among children in the past 30 years in the United States.3 Although obesity is an established risk factor for colorectal cancer (CRC) incidence and death,4-8 its association with mortality in survivors of CRC is less clear, and inconsistent results have been reported.9-12 Within clinical trials of adjuvant chemotherapy in patients with colon cancer, the obese subgroup has represented 17% to 35% of the study cohorts, which has limited the statistical power for comparison with survival outcomes. Evidence indicates that the time frame during which BMI is estimated or determined (ie, prediagnosis vs postdiagnosis) may also influence its prognostic impact.13 To date, there are inconsistent data as to whether the association of BMI with CRC survival may differ by patient sex.9, 11
In the current study, we determined the association of BMI with colon cancer prognosis and examined its potential predictive impact for the outcome of 5-fluorouracil (5-FU)–based adjuvant chemotherapy. We tested the hypothesis that obese patients have an increased risk of colon cancer recurrence and death compared with normal-weight patients that may be more evident in men compared with women. We used the Adjuvant Colon Cancer Endpoints (ACCENT) database, a pooled resource of >20,000 participants in national and international colon cancer adjuvant chemotherapy trials.14 This database provides a unique opportunity to definitively address the impact of BMI on clinical outcomes in patients with colon cancer. Clarification of the role of BMI in prognosis can influence patient education and management, because body weight represents a modifiable factor that may influence patient outcomes.
MATERIALS AND METHODS
We used the ACCENT Group14 database, which contains data on TNM stage II and III colon cancers (N = 25,291) from patients who participated in 21 randomized trials of 5-FU–based adjuvant chemotherapy conducted in North America and Europe (Table 1). We included all trials that had the following data: BMI, age, tumor stage, sex, and censoring variables for clinical outcome. The database does not include data on toxicity or comorbid conditions. All studies were approved by institutional review boards at the respective study sites, and all participants provided written informed consent. This study was conducted under an institutional review board-approved protocol.
|Variable||No. of Patients (%)|
|NSABP C-01||664 (2.6)|
|NSABP C-02||678 (2.7)|
|NSABP C-03||1042 (4.1)|
|NSABP C-04||2083 (8.2)|
|NSABP C-05||2136 (8.4)|
|NSABP C-06||1556 (6.2)|
|NSABP C-07||2434 (9.6)|
|CALGB 89803||1236 (4.9)|
|SWOG 9415||912 (3.6)|
|NCCTG 78-48-52||240 (0.9)|
|NCCTG 87-46-51||106 (0.4)|
|NCCTG 89-46-51||907 (3.6)|
|NCCTG 91-46-53||871 (3.4)|
|Surgery vs 5-FU||3872 (15.3)|
|5-FU vs 5-FU variations||8820 (34.9)|
|5-FU vs oxaliplatin||4671 (18.5)|
|5-FU vs irinotecan||4410 (17.4)|
|5-FU vs oral 5-FU||3518 (13.9)|
|Underweight <20 kg/m2||1853 (7.3)|
|Normal, 20-24.9 kg/m2||9887 (39.1)|
|Overweight, 25-29.9 kg/m2||9088 (35.9)|
|Obese, ≥30 kg/m2||4463 (17.6)|
|Class 1, 30-34.9 kg/m2||3203 (12.7)|
|Class 2-3, ≥35 kg/m2||1260 (5)|
Measurement and Categorization of Body Mass Index
Body weight and height were measured and recorded at study enrollment by trained staff and were used to calculate the BMI (in kg/m2). BMI categories were created on the basis of World Health Organization classifications and previous reports1 as follows: underweight, BMI <20 kg/m2; normal weight, 20 to 24.9 kg/m2; overweight, 25 to 29.9 kg/m2; and obese, ≥30 kg/m2 (class 1 obese, 30-34.9 kg/m2; class 2 and 3 obese, ≥35.0 kg/m2).
The association of the categorical BMI with clinicopathologic variables was analyzed using the Kruskal-Wallis test (continuous) or the chi-square test (≥3 categories). The Cochran-Armitage test for trend was used across the ordered BMI categories (2-level variables). The association of BMI with clinicopathologic variables was determined using chi-square tests and Wilcoxon rank-sum tests. The time to recurrence (TTR) was calculated as the number of years from random assignment to colon cancer recurrence. Disease-free survival (DFS) was measured from the date of randomization to the first date of local, regional, or distant relapse or death. Overall survival (OS) was calculated with date of death as the outcome. Outcome variables were censored at 8 years, and their distributions were estimated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazard models15 were used to explore associations of BMI with outcome variables. Score (univariate) and likelihood-ratio (multivariate) test P values were used to test the significance of each covariate after stratifying by treatment group. Interaction effects were tested in Cox models with the use of the likelihood-ratio test. The prognostic impact of BMI also was modeled using restricted cubic splines.16 All statistical tests were 2-sided. Analyses were performed using SAS software (SAS Institute, Cary, NC).
The study included 25,291 patients with curatively resected, TNM stages II and III colon cancer who participated in 21 randomized trials of 5-FU–based adjuvant chemotherapy (Table 1). BMI was measured at study entry and was categorized as indicated in Table 1: the median BMI was 25.4 kg/m2 (range, 10.0-70.3 kg/m2). After a median follow-up of 7.8 years in living patients, 32% had cancer recurrence, and 32% (N = 7973) had died.
Across BMI categories, we observed statistically significant but clinically modest associations between BMI and tumor stage, the number of metastatic lymph nodes, age, sex, Eastern Cooperative Oncology Group performance status, and T-classification (all P < .0001) (Table 2). Tumors from obese patients versus normal-weight patients were more likely to be, stage III versus II, distal, and T1/T2 versus T3/T4 tumors (all P < .01) (Table 2). Compared with normal-weight patients, obese patients were more likely to have >3 metastatic regional lymph nodes (N2 disease; P = .0001) (Table 2). Similar numbers of surgically removed lymph nodes were examined from obese patients compared with patients in other BMI categories. Compared with normal-weight patients, underweight patients were significantly more likely to be younger (median, 58 years vs 61 years; P < .0001), to be women (69% vs 48%; P < .0001), and to have a performance status of 1 or 2 versus 0 (24% vs 19%; P < .0001) (Table 2).
|BMI Category: No. of Patients (%)||P|
|Variable||Underweight, N = 1853||Normal, N = 9887||Overweight, N = 9088||Obese, N = 4463||Total, N = 25,291||Overalla||Obese vs Normalb||Underweight vs Normalb|
|TNM Stage||< .0001||.0013||.0783|
|II||648 (35||3250 (32.9)||2801 (30.8)||1346 (30.2)||8045 (31.8)|
|III||1205 (65)||6637 (67.1)||6287 (69.2)||3117 (69.8)||17,46 (68.2)|
|1-2||921 (80.3)||5149 (80.7)||4821 (82.3)||2198 (81.4)||13,089 (81.4)|
|3-4||226 (19.7)||1233 (19.3)||1036 (17.7)||502 (18.6)||2997 (18.6)|
|Distal||913 (55.3)||4804 (54.7)||4497 (55.5)||2352 (57.2)||12,566 (55.5)|
|Proximal||739 (44.7)||3979 (45.3)||3609 (44.5)||1757 (42.8)||10,084 (44.5)|
|Sex||< .0001||0.0190||< .0001|
|Women||1284 (69.3)||4709 (47.6)||3342 (36.8)||2220 (49.7)||11,555 (45.7)|
|Men||569 (30.7)||5178 (52.4)||5746 (63.2)||2243 (50.3)||13,736 (54.3)|
|Performance statusd||<.0001||.0138||< .0001|
|0||1289 (76)||7580 (81.4)||7067 (82.2)||3352 (79.4)||19,288 (81)|
|1||381 (22.5)||1657 (17.8)||1470 (17.1)||840 (19.9)||4348 (18.3)|
|2||25 (1.5)||70 (0.8)||58 (0.7)||29 (0.7)||182 (0.8)|
|T1-T2||190 (11.4)||1207 (13.3)||1258 (14.6)||687 (15.9)||3342 (14.1)|
|T3-T4||1478 (88.6)||7896 (86.7)||7345 (85.4)||3647 (84.1)||20,366 (85.9)|
|Age: Median, y||58.0||61.0||62.0||60.0||61.0||< .0001||.0007||< .0001|
|No. of positive lymph nodesd||< .0001||<.0001||.2708|
|0||641 (37.9)||3232 (35.9)||2785 (33.5)||1342 (32.2)||8000 (34.5)|
|1-3||693 (41)||3831 (42.5)||3679 (44.3)||1819 (43.7)||10,022 (43.2)|
|>3||357 (21.1)||1950 (21.6)||1840 (22.2)||1006 (24.1)||5153 (22.2)|
In univariate analysis, the BMI category was associated significantly with TTR, DFS, and OS across all adjuvant studies (Table 3). Overweight patients were not at increased risk of recurrence or mortality compared with normal-weight patients. Obese patients had shorter TTR and worse DFS and OS (OS: hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.04-1.18; P = .0014) versus normal-weight patients (Table 3). Underweight patients also had shorter TTR and worse DFS rates (HR, 1.11; 95% CI, 1.03-1.20; P = .0093) and OS rates (Table 3). Patients who had stage III tumors versus stage II tumors, poor differentiation, and increased numbers of metastatic lymph nodes all had shorter TTR, DFS, and OS (all P < .0001) (Table 3). Higher T-classification, but not primary tumor site, and worse Eastern Cooperative Oncology Group performance status were associated similarly with worse outcome (data not shown). Analysis by patient sex revealed that the BMI category was significantly prognostic in men for TTR (P = .0015), DFS (P < .0001), and OS (P < .0001), but not in women (all P > .20) (Table 3, Fig. 1A-D).
|Time-to Recurrence||Disease-Free Survival||Overall Survival|
|Variable||HR (95% CI)||Pa||HR (95% CI)||Pa||HR (95% CI)||Pa|
|Underweight||1.11 (1.02-1.21)||.0169b||1.11 (1.03-1.20)||.0093b||1.12 (1.02-1.22)||.0132b|
|Overweight||1.01 (0.96-1.06)||.7992b||1.00 (0.96-1.05)||.9373b||1.03 (0.97-1.08)||.3283b|
|Obese||1.07 (1.01-1.14)||.0290b||1.07 (1.01-1.13)||.0174b||1.11 (1.04-1.18)||.0014b|
|Class 1||1.06 (0.99-1.13)||.1140b||1.06 (1.00-1.13)||.0681b||1.11 (1.04-1.19)||.0024b|
|Class 2-3||1.11 (1.00-1.22)||.0500b||1.10 (1.00-1.20)||.0503b||1.09 (0.98-1.21)||.1018|
|BMI category, overall||.0015b||< .0001||< .0001|
|Underweight||1.17 (1.01-1.35)||.0401b||1.23 (1.08-1.40)||.0019b||1.29 (1.12-1.48)||.0004b|
|Overweight||0.99 (0.93-1.06)||.8171b||0.97 (0.91-1.03)||.2641b||0.98 (0.92-1.05)||.5213b|
|Obese||1.14 (1.05-1.24)||.0023b||1.11 (1.03-1.20)||.0073b||1.14 (1.04-1.24)||.0033b|
|Class 1||1.12 (1.02-1.23)||.0167b||1.09 (1.00-1.18)||.0558b||1.12 (1.02-1.23)||.0170b|
|Class 2-3||1.21 (1.04-1.40)||.0127b||1.20 (1.04-1.37)||.0096b||1.19 (1.02-1.38)||.0242b|
|BMI category, overall||.4660||.3969||.2064|
|Underweight||1.09 (0.98-1.21)||.1276b||1.09 (0.98-1.20)||.1005b||1.08 (0.96-1.20)||.2028b|
|Overweight||1.03 (0.95-1.11)||.5088b||1.04 (0.96-1.12)||.3390b||1.07 (0.99-1.16)||.0862b|
|Obese||1.00 (0.92-1.10)||.9441b||1.03 (0.95-1.12)||.4342b||1.08 (0.99-1.19)||.0955b|
|Class 1||0.98 (0.89-1.09)||.7759b||1.03 (0.93-1.13)||.6004b||1.10 (0.99-1.22)||.0767b|
|Class 2-3||1.04 (0.91-1.19)||.5738b||1.05 (0.92-1.19)||.4578b||1.05 (0.91-1.20)||.5327b|
|Histologic gradec||< .0001||< .0001||< .0001|
|3-4||1.40 (1.31-1.49)||1.37 (1.29-1.46)||1.54 (1.44-1.65)|
|Stage||< .0001||< .0001||< .0001|
|III||2.76 (2.60-2.92)||2.34 (2.22-2.46)||2.43 (2.29-2.57)|
|Sex||.3966||< .0001||< .0001|
|Men||1.02 (0.98-1.06)||1.09 (1.04-1.13)||1.10 (1.06-1.15)|
|No. of metastatic lymph nodes||< .0001||< .0001||< .0001|
|1-3||2.09 (1.97-2.23)||1.83 (1.73-1.94)||1.87 (1.76-1.99)|
|>3||4.17 (3.91-4.46)||3.46 (3.26-3.66)||3.75 (3.52-4.00)|
|Treatment arm||< .0001||< .0001||< .0001|
|Experimental||0.88 (0.84-0.92)||0.89 (0.85-0.92)||0.91 (0.87-0.96)|
A significant interaction between obesity and patient sex was observed in which obese men (HR, 1.14; 95% CI, 1.05-1.24; P = .0023), but not obese women (HR, 1.00; P = .9441), had significantly shorter TTR (Pinteraction = .0345) (Table 3). Furthermore, underweight and obese men had significantly poorer DFS and OS compared with women (Table 3, Fig. 1A-D). Men with class 2 and 3 obesity had significantly inferior outcomes for TTR (P = .0127), DFS (P = .0096), and OS (P = .0242) compared with women (all P > .45) (Table 3). The correlation between BMI and survival outcomes did not differ significantly according to patient age or tumor stage (data not shown).
In a multivariable analysis, the BMI category was associated significantly with TTR, DFS, and OS after adjusting for covariates (see Table 4). Compared with normal-weight patients, obese patients had poorer DFS and OS (HR, 1.10; 95% CI, 1.04-1.17; P = .0023), even after adjusting for age, stage, treatment, and sex. Overweight and normal-weight patients had similar outcomes, whereas underweight patients had significantly worse TTR (P = .0044), DFS (HR, 1.18; 95% CI, 1.09-1.28; P < .0001), and OS (HR, 1.21; 95% CI, 1.11-1.32; P < .0001) after adjusting for covariates (see Table 4).
|Time to Recurrence||Disease-Free Survival||Overall Survival|
|Variable||HR (95% CI)||Pa||HR (95% CI)||Pa||HR (95% CI)||Pa|
|All patients, N = 25,291|
|BMI category, overall||.0073||< .0001||< .0001|
|Underweight vs normal||1.13 (1.04-1.24)||.0044b||1.18 (1.09-1.28)||< .0001b||1.21 (1.11-1.32)||< .0001b|
|Overweight vs normal||0.99 (0.94-1.04)||.7258b||0.97 (0.92-1.02)||.1912b||0.99 (0.94-1.04)||.6074b|
|Obese vs normal||1.06 (1.00-1.13)||.0707b||1.06 (1.00-1.13)||.0337b||1.10 (1.04-1.17)||.0023b|
|Class 1 vs normal||1.05 (0.98-1.12)||.1797b||1.05 (0.98-1.12)||.1526b||1.10 (1.02-1.18)||.0084b|
|Class 2-3 vs normal||1.08 (0.98-1.20)||.1194b||1.10 (1.01-1.21)||.0362b||1.11 (1.00-1.23)||.0450b|
|Age, 1-y increase||1.00 (1.00-1.00)||.5483||1.01 (1.01-1.01)||< .0001||1.01 (1.01-1.02)||< .0001|
|Stage, III vs II||2.77 (2.61-2.93)||< .0001||2.34 (2.23-2.47)||< .0001||2.43 (2.30-2.57)||< .0001|
|Treatment, experimental vs control||0.87 (0.83-0.91)||< .0001||0.88 (0.85-0.92)||< .0001||0.91 (0.87-0.95)||< .0001|
|Sex, men vs women||1.05 (1.01-1.10)||.0190||1.13 (1.08-1.18)||< .0001||1.14 (1.09-1.19)||< .0001|
|Men, N = 13,736|
|BMI category, overall||.0009||< .0001||< .0001|
|Underweight vs normal||1.22 (1.05-1.42)||.0078b||1.31 (1.15-1.50)||< .0001b||1.39 (1.21-1.60)||< .0001b|
|Overweight vs normal||0.97 (0.90-1.03)||.3314b||0.94 (0.88-1.00)||.0430b||0.95 (0.89-1.02)||.1339b|
|Obese vs normal||1.10 (1.01-1.20)||.0228b||1.09 (1.01-1.17)||.0360b||1.11 (1.02-1.21)||.0137b|
|Class 1 vs normal||1.09 (0.99-1.20)||.0659b||1.06 (0.98-1.16)||.1562b||1.10 (1.00-1.20)||.0517b|
|Class 2-3 vs normal||1.14 (0.98-1.33)||.0792b||1.16 (1.01-1.33)||.0297b||1.16 (1.00-1.35)||.0452b|
|Age, 1-y increase||1.00 (1.00-1.00)||.1847||1.01 (1.01-1.02)||< .0001||1.02 (1.01-1.02)||< .0001|
|Stage, III vs II||2.78 (2.57-3.00)||< .0001||2.28 (2.13-2.44)||< .0001||2.35 (2.18-2.53)||< .0001|
|Treatment, experimental vs control||0.86 (0.81-0.91)||< .0001||.88 (0.83-0.92)||< .0001||0.91 (0.86-0.97)||.0017|
|Women, N = 11,555|
|BMI category, overall||.4597||.2117||.1070|
|Underweight vs normal||1.09 (0.98-1.21)||.1255b||1.11 (1.01-1.23)||.0362b||1.12 (1.00-1.25)||.0455b|
|Overweight vs normal||1.04 (0.96-1.12)||.3776b||1.03 (0.96-1.11)||.4506b||1.05 (0.97-1.14)||.1970b|
|Obese vs normal||1.01 (0.93-1.11)||.7637b||1.04 (0.96-1.13)||.3268b||1.09 (1.00-1.20)||.0553b|
|Class 1 vs normal||1.00 (0.90-1.11)||.9828b||1.03 (0.94-1.14)||.5091b||1.10 (0.99-1.23)||.0655b|
|Class 2-3 vs normal||1.04 (0.91-1.19)||.5827b||1.06 (0.93-1.21)||.3548b||1.07 (0.93-1.24)||.3258b|
|Age, 1-y increase||1.00 (0.99-1.00)||.0191||1.00 (1.00-1.01)||.0051||1.01 (1.01-1.01)||< .0001|
|Stage, III vs II||2.76 (2.52-3.01)||< .0001||2.45 (2.26-2.65)||< .0001||2.55 (2.34-2.79)||< .0001|
|Treatment, experimental vs control||0.89 (0.83-0.95)||.0004||0.89 (0.84-0.95)||.0003||0.91 (0.85-0.97)||.0064|
The BMI category was significantly prognostic in men (Table 4, Fig. 1A,C) for TTR (P = .0009), DFS (P < .0001), and OS (P < .0001) but not in women (all P > .10; OS, Pinteraction = .0129) (Table 4, Fig. 1B,D). Obese and underweight men had significantly poorer clinical outcomes versus normal-weight men (Table 4). A greater impact of class 2 and 3 obesity versus class 1 obesity on DFS and OS rates was observed among men (Table 4). The significant interaction between BMI and clinical outcome variables was primarily because underweight men, but not women, had inferior TTR (HR, 1.22; 95% CI, 1.05-1.42; P = .0078), DFS (HR, 1.31; 95% CI, 1.15-1.50; P < .0001), and OS (HR, 1.39; 95% CI, 1.21-1.60; P < .0001; Pinteraction = .0340) compared with normal-weight men.
We explored whether a curvilinear or quadratic relation could describe the observed results for BMI. By using restricted cubic splines, we observed that the continuous BMI (using 4 knots) displayed a significant curvilinear relation with OS both overall (P < .025) (Fig. 2A) and according to patient sex (Pinteraction = 0.05) (Fig. 2B). Underweight men had worse OS compared with underweight women, and obesity played a comparatively lesser role in predicting poor OS (Fig. 2B). The relation between continuous BMI and DFS and TTR was more quadratic in nature, in which only 3 knots were significant using restricted cubic splines. Given this finding, we modeled BMI as a quadratic variable in multivariate Cox models and observed that the quadratic BMI was associated significantly with DFS (P < .0001) and TTR (P = .0008) after adjusting for age, stage, treatment, and sex.
We assessed whether BMI was predictive of benefit from 5-FU–based adjuvant chemotherapy among patients with stage II and III disease. We examined 8 adjuvant studies in which a treatment benefit was observed. Among those 8 trials, 6 evaluated 5-FU versus observation, and 2 evaluated 5-FU plus oxaliplatin versus 5-FU. There was no statistically significant interaction for BMI and treatment for TTR, DFS, or OS in either univariate or multivariable analysis. The multivariate interaction models revealed a continued treatment benefit across all BMI categories after adjusting for age, stage, and sex. Furthermore, there was no evidence for a differential treatment effect by adjuvant chemotherapy regimen.
In this study, we used BMI measured by trained personnel at the time patients entered an adjuvant study. We observed that obese patients, but not overweight patients, had significantly poorer survival compared with normal-weight patients after adjustment for covariates, and this effect was most evident among patients who had severe (class 2 and 3) obesity. An important finding of our study is that an adverse impact of obesity on colon cancer outcomes was limited to men. Severely obese men had a 16% increase in mortality relative to normal-weight patients. Another important finding is that underweight patients had increased cancer recurrence and inferior outcomes. A statistically significant interaction was observed between underweight status and patient sex, whereby underweight men had a 39% increase in all-cause mortality compared with normal-weight men or women. In previous studies, the inferior outcome among underweight patients with cancer was attributed to noncancer–related deaths.17, 18 However, we observed a shorter TTR and DFS for underweight patients, suggesting that the impact on prognosis is cancer-related.
Inconsistent data exist for the impact of patient sex on outcome in obese patients with colon cancer. In patients with stage II and III colon cancers, the association between obesity and mortality was reported to be stronger among women than among men.9 In contrast, no differences according to sex were observed in another study that also examined data from colon cancer adjuvant trials.12 Our finding of a stronger association of obesity with adverse outcome among men versus women is consistent with the reported higher rate of incident colon cancers among obese men versus women.4, 6, 9, 20 Mechanisms underlying this observation may be related to body fat distribution, because BMI is related more closely to abdominal or central adiposity in men.21, 22 Abdominal adiposity is associated with hyperinsulinemia, insulin resistance, and the insulin-like growth factor-I axis as potential mediators of increased CRC risk and mortality.23-25 The attenuated impact of obesity on colon cancer outcomes observed among women versus men in our study may be because of an effect modification by estrogen. Estrogen levels correlate with BMI in postmenopausal women, because their major source is conversion from androgens in adipose tissue.26 The association of obesity with CRC risk is reduced after menopause,27 and hormone-replacement therapy is consistently associated with reduced colon cancer mortality.28-30
Excess mortality among underweight patients with colon cancer has been attributed to noncancer causes, and mainly to chronic respiratory conditions.18 In our study, differences in performance status based on BMI were not clinically meaningful, and strict eligibility criteria for the adjuvant studies excluded patients who had significant comorbidities. Because BMI was recorded at adjuvant trial enrollment, it will be important to distinguish between patients who are underweight but have stable weight over time versus those who experienced significant cancer-related weight loss before trial enrollment. Significant cancer-related weight loss may identify a poor prognostic subgroup, because cancer cachexia is associated with inferior outcomes.31-33 Loss of adipose tissue accounts for the majority of the cancer-related weight loss, yet the preferential loss of skeletal muscle adversely impacts mortality.34-36 Although it was not included in the ACCENT database, cigarette smoking is associated with a lower BMI, and current smokers who are underweight or obese have high mortality rates,37 especially among men.38, 39
Evidence suggests that the time frame during which BMI is determined can influence its association with clinical outcome. A prospective cohort study found that self-reported BMI prediagnosis (mean, 7 years before CRC diagnosis) was associated independently with a statistically significant increase in the risk of all-cause and cancer-specific mortality, whereas postdiagnosis BMI (mean interval, 1.5 years after diagnosis) was not.13 Prediagnosis BMI measurements have also demonstrated a higher risk of all-cause mortality in obese women versus normal-weight women.17, 40
We also determined whether BMI was predictive of a clinical benefit in patients who received 5-FU–based adjuvant chemotherapy versus observation or no 5-FU. Our data indicate that adjuvant chemotherapy is beneficial for patients in high-risk and low-risk BMI categories, and outcomes were similar among those who received older versus more modern adjuvant regimens as well as among North American and European patients.
Strengths of our study include BMI measurements performed by trained staff and the rigorous collection of data on recurrence and survival within clinical trials over an extended follow-up period. Limitations include the retrospective study design and lack of data on smoking, diet, physical activity, menopausal status, or receipt of hormone replacement therapy, which may have independent associations with outcomes and may inform the interpretation of sex-related differences. It is noteworthy that neither lifestyle factors nor demographic factors had an impact on the association of prediagnosis BMI with survival among patients who had colon cancer in a large cohort study.13 Although the large sample size within the ACCENT database indicates that modest absolute differences in clinical outcomes may be statistically significant, our results must be interpreted in that context.
In summary, obese and underweight BMI are associated with increased mortality in colon cancer survivors, especially among men. In underweight patients, shorter TTR and reduced DFS rates suggest increased tumor aggressiveness. Together, these data suggest that interventions to modify patient BMI after a colon cancer diagnosis have the potential to improve patient outcomes.
This work was supported by a National Cancer Institute Senior Scientist Award (K05CA-142885 to Dr. Sinicrope) and by a North Central Cooperative Treatment Group Biospecimen Resource National Institutes of Health grant (CA-114740).
CONFLICT OF INTEREST DISCLOSURE
The authors made no disclosures.
- 1World Health Organization. Report of a WHO Consultation to Obesity. Obesity: Preventing and Managing the Global Epidemic. Geneva, Switzerland: World Health Organization; 1998.
- 15Regression models and life tables. J R Stat Soc B. 1972; 34: 187-200..
- 16Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York: Springer-Verlag; 2001..