Grain Intake and Clinical Outcome in Stage III Colon Cancer: Results From CALGB 89803 (Alliance)

Grain Intake and Clinical Outcome in Stage III Colon Cancer: Results From CALGB 89803 (Alliance) Background: Energy balance–related risk factors for colon cancer recurrence and mortality—type II diabetes, hyperinsuline- mia, inflammation, and visceral obesity—are positively correlated with consumption of refined grains and negatively corre- lated with consumption of whole grains. We examined the relationship between the consumption of refined and whole grains with cancer recurrence and mortality in a cohort of patients with colon cancer. Methods: We conducted a prospective observational study of 1024 patients with stage III colon cancer who participated in a randomized trial of postoperative chemotherapy. Patients reported consumption of refined and whole grains using a food frequency questionnaire during and six months after chemotherapy. The primary outcome was disease-free survival (DFS). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. All P values are two-sided. Results: During a median follow-up of 7.3 years, 394 patients experienced a DFS event. The hazard ratio for DFS was 1.56 (95% CI ¼ 1.09 to 2.24) for patients consuming three or more servings per day of refined grains compared with patients consuming less than one serving per day (P ¼ .005). The hazard ratio for DFS was 0.89 (95% CI ¼ 0.66 to 1.20) for patients consuming trend three or more servings per day of whole grains compared with patients consuming less than one serving per day (P ¼ .54). trend The hazard ratio for DFS of substituting one serving per day of refined grain with one serving per day of whole grain was 0.87 (95% CI ¼ 0.79 to 0.96, P ¼ .007). Conclusions: The choice of grain consumed may be associated with cancer recurrence and mortality. Future studies are necessary to confirm our findings and to inform the design of randomized trials. Each year, 83 000 people are diagnosed with stage I–III colon lifestyle behaviors, such as their dietary choices, may influence cancer in the United States (1). Despite surgical resection, either cancer recurrence and mortality (3). Consumption of a Western- alone or in combination with adjuvant chemotherapy, style diet (4), high-glycemic carbohydrates (5), red and proc- 25%30% of patents will experience recurrent and metastatic essed meats (6), and sugar-sweetened beverages are associated disease within three years of diagnosis, and 91% of those who with a higher risk of recurrence and mortality (7,8). Conversely, recur within three years die by five years (2). Consequently, coffee (9), milk (10), and modest alcohol consumption are asso- patients with colon cancer are motivated to understand how ciated with a lower risk of recurrence and mortality (8). Received: February 22, 2018; Revised: March 16, 2018; Accepted: March 29, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 1of 8 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Evidence describing other dietary constituents will inform clini- because of declining health, patients were excluded if they ex- cal recommendations for patients and guide the design of ran- perienced cancer recurrence or death within 90 days of com- domized trials of dietary modification (11). pleting the questionnaire (Q1). Figure 1 describes the derivation Whole grains contain endosperm, germ, and bran, whereas of the final sample size of 1024 patients included in this study. refined grains have the germ and bran removed during the mill- There were no substantive differences in the baseline character- ing process. The consumption of refined grains is associated istics of patients included in the dietary analysis, and the with an increased risk of developing type II diabetes (12–14). remaining patients enrolled in CALGB 89803 (5). The consumption of refined grains is positively correlated with All patients signed informed consent, which was approved hyperinsulinemia (15), inflammation (16), and visceral obesity by the National Cancer Institute Cancer Treatment Evaluation (17). This is relevant to patients with colon cancer because type Program and each participating site’s institutional review II diabetes (18,19), hyperinsulinemia (20), inflammation (21), board. and visceral obesity are risk factors for cancer recurrence and mortality (22). Conversely, the consumption of whole grains is associated with a lower risk of developing type II diabetes (23). Dietary Assessment The consumption of whole grains is negatively correlated with The consumption of refined and whole grain foods was quanti- hyperinsulinemia (24), inflammation (25), and visceral obesity fied using semiquantitative food frequency questionnaires (17). Randomized trials in healthy men and women demon- (FFQ) that included 131 food items, vitamin and mineral supple- strate that substituting refined grains with whole grains reduces ments, and open-ended sections for other supplements and insulin resistance (26,27), inflammation (28,29), and body fat foods not specifically listed (32). For each food, a common unit (29,30). or portion size (eg, slice of bread) was specified, and the patient We prospectively examined the relationship between the was asked to report how often, on average over the previous consumption of refined grains and whole grains with cancer re- three months, they consumed that portion size. Up to nine fre- currence and mortality in a cohort of patients with stage III co- quency responses were possible, which ranged from never to lon cancer enrolled in a National Cancer Institute–sponsored six or more times per day. Type and brand of cereal were also randomized clinical trial of postoperative chemotherapy. We assessed. We computed nutrient intakes by multiplying the fre- hypothesized that 1) higher consumption of refined grains quency of consumption of each food by the nutrient content of would be associated with an increased risk of cancer recurrence the specified portions using composition values from the and mortality; 2) higher consumption of whole grains would be Department of Agriculture. All nutrient values were energy- associated with a decreased risk of cancer recurrence and mor- adjusted using the residuals method (33). tality, and 3) substitution of refined grains with whole grains Foods were classified as refined or whole grains using the would be associated with a decreased risk of cancer recurrence technique developed by Jacobs and colleagues (34). Refined and mortality. grains included sweet rolls, cake deserts, white bread, pasta, English muffins, muffins, biscuits, refined grain cereals, white rice, pancakes, waffles, and pizza. Whole grains included dark Methods bread, whole grain ready-to-eat cereals (25% whole grain con- tent by weight), popcorn, cooked oatmeal, wheat germ, brown Study Population rice, bran, and other grains. A full description of the FFQ, repro- ducibility, and validity statistics has been reported previously Patients in this prospective cohort study participated in the (32,35). The performance of the FFQ to quantify individual grain National Cancer Institute (NCI)–sponsored Cancer and products is high; the correlation between the FFQ and detailed Leukemia Group B (CALGB; now Alliance for Clinical Trials in diet records is 0.75 for cereal, 0.71 for white bread, and 0.77 for Oncology) 89803 postoperative chemotherapy trial for stage III dark bread (36). Variables including prudent and Western die- colon cancer (31). Patients were recruited from the United States tary patterns, the healthy eating index, and glycemic load were and Canada. The primary aim of CALGB 89803 was to compare calculated using the dietary assessment following techniques weekly 5-fluorouracil and leucovorin with weekly irinotecan, 5- described previously (8). fluorouracil, and leucovorin (ClinicalTrials.gov NCT000038350). Patients who completed Q1 and whose cancer had not re- Between May 1999 and May 2001, the trial enrolled 1264 curred prior to Q1 completion were included in these analyses. patients. After the enrollment of 87 patients, an amendment re- The median time from study entry to Q1 (range) was 3.5 (0.2–9.9) quired patients to complete a self-administered questionnaire months. We updated dietary exposures based on the results of that quantified diet and lifestyle behaviors midway through Q2 using cumulative averaging, with weighting that is propor- chemotherapy (approximately four months after surgical tional to times between Q1 and Q2 and then between Q2 and resection, questionnaire 1 [Q1], and again six months after the event (or censoring) time (4). This technique accounts for completion of chemotherapy [14 months after surgical changes in diet that may occur over time, thereby maximizing resection; Q2]). the information obtained from the available data. Eligible patients underwent a complete surgical resection of the primary tumor within 56 days of trial enrollment, had re- gional lymph node metastases but no evidence of distant me- Study End Points tastases, had a baseline Eastern Cooperative Oncology Group performance status of 0 to 2, and had adequate bone marrow, The primary end point of this study was disease-free survival renal, and hepatic function. Patients were excluded from this (DFS), and secondary end points included recurrence-free sur- analysis if they reported unreasonable energy intake (<600 or vival (RFS) and overall survival (OS). DFS was defined as the >4200 calories per day for men; <500 or >3500 calories per day time from completion of Q1 to cancer recurrence, occurrence of for women) or left 70 or more food items blank (see Dietary a new primary colon cancer, or death from any cause, which- Assessment below). To avoid bias in dietary assessment ever occurred first. RFS was defined as the time from Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 3 of 8 Figure 1. Derivation of cohort. Caloric intake exclusion: <600 calories or >4200 calories per day for men and <500 calories and >3500 calories per day for women. Q1 ¼ questionnaire 1 (midway through adjuvant therapy); Q2 ¼ questionnaire 2 (six months after completion of adjuvant therapy). completion of Q1 to cancer recurrence or occurrence of a new and refined grain intake (for whole grain models). We used primary colon cancer; patients who died without known disease time-varying covariates to adjust for body mass index (BMI), recurrence were censored at the last documented physician physical activity, total energy intake, whole grain intake, and re- evaluation. OS was defined as the time from completion of Q1 fined grain intake. Other covariates, including age at Q1, sex, to death from any cause. race, performance status (physician estimate of patient ability for self-care, daily activity, and physical ability), depth of inva- sion through bowel wall (T stage), number of positive lymph nodes (N stage), location of the primary tumor, and chemother- Statistical Analysis apy treatment arm, were entered into the model as fixed covariates. In the clinical trial, there were no statistical differences in DFS, RFS, or OS between treatment arms (31). Therefore, data for We tested for linear trends across frequency categories of consumption by assigning each patient the median value for patients in both arms were combined and analyzed according to frequency categories of dietary intake. For the primary analy- each category and modeling the value as a continuous variable. We graphically examined the frequency of grain consumption sis, consumption of refined and whole grain foods was catego- rized into three groups (<1, 1–2, and 3 servings per day). Cox as a continuous variable using nonlinear restricted cubic splines. The proportionality of hazards assumption was exam- proportional hazards regression was used to determine the si- multaneous influence of other potential confounding variables. ined by including time-dependent covariates in the regression models and visually inspecting log-log plots. To evaluate the ef- Three models were built to incrementally examine the associa- tion between grain intake and the study end points. Model 1 fect of substituting refined grains with whole grains, we built substitution models by simultaneously entering whole and re- was adjusted for age and energy intake; model 2 was adjusted for demographic, clinical, and behavioral variables; model 3 was fined grain intakes into a model as continuous variables, then exponentiating the difference in coefficients to obtain an esti- adjusted for the covariates in model 2, plus the complementary grain measure: whole grain intake (for refined grain models) mate that is on the hazard ratio scale (37). The hazard ratios Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 4of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. Baseline characteristics of 1024 patients by servings of refined and whole grains Refined grain intake, servings/d Whole grain intake, servings/d <1 1–2 3 <1 1–2 3 (n ¼ 160) (n ¼ 565) (n ¼ 299) P (n ¼ 294) (n ¼ 481) (n ¼ 249) P Age, median (IQR), y 61 (54–69) 59 (51–68) 62 (51–70) .11 59 (50–68) 60 (52–68) 61 (52–70) .20 Sex, No. (%) <.001 <.001 Male 79 (49.4) 284 (50.3) 213 (71.2) 177 (60.2) 241 (50.1) 158 (63.5) Female 81 (50.6) 281 (49.7) 86 (28.8) 117 (39.8) 240 (49.9) 91 (36.5) Race, No. (%) .18 .04 White 136 (85.0) 503 (89.0) 270 (90.3) 247 (84.0) 436 (90.7) 226 (90.8) Black 16 (10.0) 39 (6.9) 13 (4.4) 27 (9.2) 29 (6.0) 12 (4.8) Other 8 (5.0) 23 (4.1) 16 (5.3) 20 (6.8) 16 (3.3) 11 (4.4) Baseline performance .72 .002 status, No. (%)* 0 121 (75.6) 419 (74.2) 210 (70.2) 199 (67.7) 367 (76.3) 184 (73.9) 1 2 36 (22.5) 135 (23.9) 82 (27.4) 90 (30.6) 109 (22.7) 54 (21.7) Missing/unknown 3 (1.9) 11 (1.9) 7 (2.4) 5 (1.7) 5 (1.0) 11 (4.4) Invasion through bowel .18 .21 wall by T stage, No. (%) T1 2 19 (11.9) 88 (15.6) 30 (10.0) 33 (11.2) 69 (14.3) 35 (14.1) T3 4 138 (86.2) 465 (82.3) 260 (87.0) 256 (87.1) 403 (83.8) 204 (81.9) Missing/unknown 3 (1.9) 12 (2.1) 9 (3.0) 5 (1.7) 9 (1.9) 10 (4.0) Positive lymph nodes, No. (%) .22 .04 1 3 110 (68.7) 361 (63.9) 174 (58.2) 180 (61.2) 314 (65.3) 151 (60.7) 4 47 (29.4) 195 (34.5) 118 (39.5) 110 (37.4) 162 (33.7) 88 (35.3) Missing/unknown 3 (1.9) 9 (1.6) 7 (2.3) 4 (1.4) 5 (1.0) 10 (4.0) Location of primary .78 .12 tumor, No. (%) Right 4 (2.5) 23 (4.1) 9 (3.0) 12 (4.1) 13 (2.7) 11 (4.4) Left 59 (36.9) 222 (39.3) 105 (35.1) 123 (41.8) 182 (37.8) 81 (32.5) Transverse 61 (38.1) 207 (36.6) 115 (38.5) 99 (33.7) 186 (38.7) 98 (39.4) Multiple 33 (20.6) 104 (18.4) 61 (20.4) 56 (19.0) 93 (19.3) 49 (19.7) Missing 3 (1.9) 9 (1.6) 9 (3.0) 4 (1.4) 7 (1.5) 10 (4.0) Treatment arm, No. (%) .24 .24 FU/LV 88 (55.0) 272 (48.1) 156 (52.2) 157 (53.4) 229 (47.6) 130 (52.2) IFL 72 (45.0) 293 (51.9) 143 (47.8) 137 (46.6) 252 (52.4) 119 (47.8) BMI, median (IQR), kg/m 27.5 (23.8–32.2) 27.2 (23.8–30.9) 27.5 (24.2–31.3) .54 27.6 (23.5–32.3) 27.4 (24.4–31.1) 26.6 (23.6–30.7) .29 Physical activity, 5.0 (1.7–14.8) 4.6 (0.9–15.4) 5.1 (1.1–17.8) .47 3.7 (0.6–9.6) 5.1 (1.3–15.1) 7.1 (1.6–22.5) <.001 median (IQR), MET-h/w Current use of aspirin, No. (%) 38 (23.8) 156 (27.6) 87 (29.1) .47 82 (27.9) 131 (27.2) 68 (27.3) .98 Dietary intake, median (IQR) Alcohol consumption, g/d 0.1 (0.0–1.8) 0.4 (0.0–2.0) 0.2 (0.0–3.5) .70 0.2 (0.0–3.5) 0.2 (0.0–2.0) 0.4 (0.00–2.0) .77 Coffee intake, cups/wk 3.0 (0.0–17.5) 7.0 (0.5–17.5) 7.0 (0.5–17.5) .001 7.0 (0.4–17.5) 6.5 (0.5–17.5) 7.0 (0.2–17.0) .85 Sugar sweetened 1.0 (0.4–3.8) 2.4 (0.5–6.0) 3.0 (0.7–7.0) <.001 3.1 (0.6–7.0) 1.7 (0.5–5.7) 1.6 (0.5–5.5) .02 beverages, s/wk Cereal fiber, g/d 5.6 (3.6–8.1) 5.7 (4.3–7.3) 5.4 (4.3–7.0) .48 4.1 (3.1–4.9) 5.8 (4.7–7.2) 7.8 (6.2–9.9) <.001 Western diet pattern, 124 (77.5) 329 (58.2) 59 (19.7) <.001 147 (50.0) 252 (52.4) 113 (45.4) .20 No. < median (%) Prudent diet pattern, 97 (60.6) 266 (47.1) 149 (49.8) .01 197 (67.0) 228 (47.4) 87 (34.9) <.001 No. < median (%) AHEI dietary pattern, 63 (39.4) 254 (45.0) 195 (65.2) <.001 189 (64.3) 221 (45.9) 102 (41.0) <.001 No. < median (%) Glycemic load, No. < median (%) 96 (60.0) 278 (49.2) 138 (46.2) .02 168 (57.1) 246 (51.1) 98 (39.4) <.001 *Baseline performance status: 0 indicates fully active; 1 indicates restricted in physically strenuous activity but ambulatory and able to perform light work; 2 indicates ambulatory and capable of all self-care but unable to perform any work activities, up to approximately 50% of waking hours. AHEI ¼ Alternate Healthy Eating Index 2010; BMI ¼ body mass index; FU/LV ¼ fluorouracil and leucovorin; IFL ¼ irinotecan, fluorouracil, and leucovorin; IQR ¼ interquartile range; MET-h/w ¼ metabolic equivalent task hours per week; s ¼ servings. derived from these models are interpreted as the estimated ef- All analyses were performed with SAS, version 9.4 (SAS fect of substituting one daily serving of refined grain with one Institute, Cary, NC). A P value of less than .05 was considered daily serving of whole grain. statistically significant. All P values are two-sided. Data Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 5 of 8 collection and statistical analyses were conducted by the Alliance Statistics and Data Center at Duke University Medical Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairperson following Alliance policies. All analyses were based on the study database frozen on November 9, 2009. Results Baseline Characteristics Baseline characteristics of the 1024 patients by frequency of consumption of refined and whole grains are displayed in Table 1. Those in the highest category of refined grain intake were more likely to be male and report a higher consumption of coffee, sugar-sweetened beverages, and poorer overall die- tary patterns, compared with patients in the lowest category of refined grain intake. Those in the highest category of whole grain intake were more likely to be male and of white race, to have fewer positive lymph nodes and better performance sta- tus, and to report higher physical activity, higher consumption of cereal fiber, and more favorable overall dietary patterns, compared with patients in the lowest category of whole grain intake. Associations Between Cancer Recurrence and Mortality With Grain Intake Figure 2. Adjusted cubic spline model for intake of refined grains and associa- The median follow-up time from completion of Q1 was 7.3 tion with colon cancer recurrence and mortality (disease-free survival). Models years. During follow-up, we observed 394 DFS events, 350 RFS are adjusted for age, sex, race, performance status, T stage, positive lymph events, and 311 OS events. nodes, location of primary tumor, treatment arm, body mass index, physical ac- In the adjusted cubic spline model, higher intake of refined tivity, total energy, and whole grain intake. grains was associated with an increased risk of cancer recur- rence and mortality (P ¼ .03) (Figure 2). The associations be- CI ¼ 0.77 to 0.96, P ¼ .006) and OS (HR ¼ 0.87, 95% CI ¼ 0.78 to tween cancer recurrence and mortality with refined and whole 0.97, P ¼ .01). grain intake are displayed in Table 2. The multivariable- adjusted hazard ratio for DFS was 1.56 (95% CI ¼ 1.09 to 2.24) for those consuming three or more servings per day of refined Discussion grains compared with those consuming less than one serving per day (P ¼ .005). Results were similar for RFS and OS. trend In this prospective cohort of patients with stage III colon cancer Exclusion of patients who experienced a DFS event in the first who participated in an NCI-sponsored randomized trial of post- 90 to 365 days after Q1 did not substantively alter the above- operative chemotherapy, higher consumption of refined grains described results. was associated with an increased risk of cancer recurrence and In the adjusted cubic spline model, higher intake of whole mortality, and the substitution of refined grains with whole grains was associated with a reduced risk of cancer recurrence grains was associated with a decreased risk of cancer recur- and mortality (P ¼ .05) (Figure 3). The multivariable-adjusted rence and mortality. These data add to an evidence base that hazard ratio for DFS was 0.89 (95% CI ¼ 0.66 to 1.20) for those has documented the importance that dietary choices may have consuming three or more servings per day of whole grains com- on clinical outcomes in this population. pared with those consuming less than one serving per day Type II diabetes (18,19), hyperinsulinemia (20), inflamma- (P ¼ .54). Results were similar for RFS and OS. Exclusion of trend tion (21), and visceral obesity are risk factors for cancer recur- patients who experienced a DFS event in the first 90 to 365 days rence and mortality (22). Many of these risk factors have been after Q1 did not substantively alter the above-described results. proposed as biological mediators of the relationship between energy balance–related lifestyle factors (diet, physical activ- ity, obesity) and clinical outcome in patients with cancer Substitution Analysis (38,39). The consumption of refined grains is associated with The consumption of refined grains was negatively correlated an increased risk of developing type II diabetes (12–14)and with the consumption of whole grains (r ¼ –.19, P < .001). We positively correlated with hyperinsulinemia (15), inflamma- therefore sought to estimate the influence of substituting one tion (16), and visceral obesity (17). Conversely, the consump- daily serving of refined grain with one daily serving of whole tion of whole grains is associated with a lower risk of grain. In substitution analysis, the multivariable-adjusted haz- developing type II diabetes (23) and negatively correlated with ard ratio for DFS by substituting one daily serving of refined hyperinsulinemia (24), inflammation (25), and visceral obesity grain with one daily serving of whole grain was 0.87 (95% CI ¼ 0. (17). The observed relationship between the consumption of 79 to 0.96, P ¼ .007). Results were similar for RFS (HR ¼ 0.86, 95% refined grains with cancer recurrence and mortality is Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 6of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 2. Associations between colon cancer recurrence and mortality with refined and whole grain intake* Grain intake, servings/d Outcome and exposure <1 1–2 3 P trend Disease-free survival Refined grain intake No. of events/No. at risk 53/160 204/565 137/299 Model 1† 1.00 (referent) 1.18 (0.87 to 1.61) 1.75 (1.24 to 2.46) <.001 Model 2‡ 1.00 (referent) 1.16 (0.85 to 1.58) 1.58 (1.12 to 2.24) .003 Model 3§ 1.00 (referent) 1.15 (0.84 to 1.58) 1.56 (1.09 to 2.24) .005 Whole grain intake No. of events/No. at risk 129/294 173/481 92/249 Model 1† 1.00 (referent) 0.77 (0.61 to 0.97) 0.81 (0.62 to 1.07) .19 Model 2‡ 1.00 (referent) 0.81 (0.64 to 1.03) 0.85 (0.64 to 1.13) .32 Model 3§ 1.00 (referent) 0.84 (0.66 to 1.07) 0.89 (0.66 to 1.20) .54 Recurrence-free survival Refined grain intake No. of events/No. at risk 48/160 177/565 125/299 Model 1† 1.00 (referent) 1.11 (0.80 to 1.54) 1.73 (1.21 to 2.49) <.001 Model 2‡ 1.00 (referent) 1.08 (0.78 to 1.50) 1.59 (1.10 to 2.29) .001 Model 3§ 1.00 (referent) 1.08 (0.77 to 1.50) 1.57 (1.08 to 2.30) .003 Whole grain intake No. of events/No. at risk 111/294 155/481 84/249 Model 1† 1.00 (referent) 0.81 (0.64 to 1.04) 0.89 (0.67 to 1.20) .53 Model 2‡ 1.00 (referent) 0.82 (0.64 to 1.06) 0.90 (0.67 to 1.21) .58 Model 3§ 1.00 (referent) 0.86 (0.67 to 1.12) 0.97 (0.71 to 1.33) .98 Overall survival Refined grain intake No. of events/No. at risk 38/160 158/565 115/299 Model 1† 1.00 (referent) 1.33 (0.92 to 1.90) 2.09 (1.40 to 3.10) <.001 Model 2‡ 1.00 (referent) 1.32 (0.92 to 1.90) 1.89 (1.27 to 2.81) <.001 Model 3§ 1.00 (referent) 1.32 (0.91 to 1.90) 1.88 (1.25 to 2.85) .001 Whole grain intake No. of events/No. at risk 108/294 130/481 73/249 Model 1† 1.00 (referent) 0.69 (0.54 to 0.89) 0.74 (0.55 to 1.01) .09 Model 2‡ 1.00 (referent) 0.78 (0.60 to 1.02) 0.81 (0.59 to 1.11) .24 Model 3§ 1.00 (referent) 0.81 (0.62 to 1.06) 0.86 (0.62 to 1.20) .46 *Two-sided P values. Trend across quintiles. CI ¼ confidence interval; HR ¼ hazard ratio. †Model 1: adjusted for age and time-varying total energy. ‡Model 2: adjusted for age, sex, race, performance status, T stage, positive lymph nodes, location of primary tumor, treatment arm, time-varying body mass index, physical activity, and total energy. §Model 3: adjusted for age, sex, race, performance status, T stage, positive lymph nodes, location of primary tumor, treatment arm, time-varying body mass index, physical activity, total energy, and whole grain intake (for refined grain models) or refined grain intake (for whole grain models). therefore biologically possible. This mechanistic hypothesis with clinical outcome. A decade ago, the initial observation was in oncology parallels that of cardiology, where the consump- made that a Western-style diet was associated with cancer re- tion of refined grains is associated with an increased risk of currence and mortality in patients with colon cancer (4). Since incident cardiovascular disease and cardiovascular-specific that time, the specificity of our understanding regarding what mortality (40). dietary constituents may influence clinical outcome has A novel aspect of our study was the observation that evolved, and now includes high-glycemic carbohydrates (5), red substituting one daily serving of refined grains with one daily and processed meats (6), and sugar-sweetened beverages (7,8), serving of whole grains was associated with a 13% lower risk of as well as coffee (9), milk (10), and modest alcohol consumption cancer recurrence or mortality during the follow-up period. (8). These observational data will be useful to inform and tailor Clinical trials in healthy men and women demonstrate that the design of a dietary modification intervention trial in substituting refined grains with whole grains reduces insulin patients with colon cancer, a trial that will eventually need to resistance (27), inflammation (28), and body fat (30). For exam- be tested with a disease end point to provide persuasive evi- ple, in a randomized crossover trial, six weeks of a whole grain dence to inform clinical practice. diet reduced concentrations of fasting insulin compared with a The principal strength of this study was embedding the FFQ refined grain diet (15.065.5 pmol/L, P ¼ .03) (27). Similarly, in a in a randomized clinical trial. Consequently, this study had a 12-week randomized trial, a whole grain diet reduced body fat large sample size with a well-defined study population. Follow- compared with a refined grain diet (1.9%, P ¼ .04) (30). These up in this study was standardized, such that all patients under- data suggest that randomized trials of dietary modification are went quarterly medical examinations to identify recurrent dis- feasible and induce physiologic changes that may be associated ease. Although the FFQ was self-reported, it was collected Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 7 of 8 that a higher consumption of refined grains was associated with an increased risk of cancer recurrence and mortality, and the substitution of refined grains with whole grains was associated with a decreased risk of cancer recurrence and mortality. Although this observational study does not provide definitive evidence for causality, these data may inform clini- cal recommendations for patients and inform hypotheses to guide the design of future observational studies and random- ized trials of dietary modification in patients with colon cancer. Funding Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology and U10CA180820 to the ECOG-ACRIN (CA60138, U10CA180857, U10CA180836, U10CA180867). Additional sup- port was provided by Pharmacia & Upjohn Company, now Pfizer Oncology. Dr. Brown is supported by a grant from the National Cancer Institute (K99CA218603). Dr. Ogino is sup- ported by a grant from the National Cancer Institute (R35CA197735). Drs. Fuchs and Meyerhardt are supported in part by grants from the National Cancer Institute (R01CA118553, R01CA149222, R01CA169141, and P50CA127003). The sponsors did not participate in the de- sign or conduct of the study; collection, management, anal- Figure 3. Adjusted cubic spline model for intake of whole grains and association with colon cancer recurrence and mortality (disease-free survival). Models are ysis, or interpretation of the data; or the preparation, adjusted for age, sex, race, performance status, T stage, positive lymph nodes, review, or approval of the manuscript. location of primary tumor, treatment arm, body mass index, physical activity, total energy, and refined grain intake. Notes prospectively, such that any ascertainment bias in the FFQ Affiliations of authors: Dana-Farber/Partners CancerCare, would be nondifferential and shift our effect size estimates Boston, MA (JCB, SZ, RJM, SO, KN, JAM); Duke Cancer Institute, toward the null. We excluded patients who experienced recur- Duke University Medical Center, Durham, NC (DN); Memorial rent disease or mortality within 90 days of completing the FFQ Sloan Kettering Cancer Center, New York, NY (LBS); Toledo to minimize the potential of occult disease inducing changes Community Hospital Oncology Program, Toledo, OH (RBM); in dietary intake. We adjusted for variables that may confound Ho ˆpital du Sacre-Coeur de Montreal Montreal, Canada (RW); the relationship between the consumption of refined and Edward-Elmhurst Heatlhcare, Naperville, IL (AH); Robert H. whole grains with cancer recurrence and mortality; several of Lurie Comprehensive Cancer Center, Northwestern these variables were time-varying, allowing us to account for University, Chicago, IL (AB); Virginia Oncology Associates, changes in BMI, physical activity, and other aspects of dietary Norfolk, VA (DA); Southeast Clinical Oncology Research intake that may have occurred after completing (SCOR) Consortium, Mission Hospitals, Inc., Asheville, NC chemotherapy. (MM); University of Chicago Comprehensive Cancer, Chicago, The principal limitation of this study is the observational de- IL (HK); University of California at San Francisco sign, such that we cannot rule out the possibility of residual Comprehensive Cancer Center, San Francisco, CA (AV); confounding. Although the FFQ used in the study was self- Harvard T.H. Chan School of Public Health, Boston, MA (SO, reported, it is correlated with plasma concentrations of carote- YL, WCW, ELG); Brigham and Women’s Hospital, Boston, MA noids, tocopherols, and fatty acids in patients with colon cancer (SO, XZ, ELG); Yale Cancer Center, Yale School of Medicine, (32). Future studies should consider the potential utility of pre- New Haven, CT (CSF). dicting prognosis with objective measures of dietary intake, ClincalTrials.gov registration: NCT000038350. such as metabolites in urine or plasma samples (41,42). The The views expressed in the article are those of the authors patients in the current study elected to enroll in a clinical trial and not an official position of their affiliated institutions or and may not be representative of colon cancer patients in the funders. US population with respect to demographic and lifestyle behav- iors. 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Am J Clin Nutr. 2016;104(3): consumption and the risk of type 2 diabetes: A systematic review and dose- 776–789. response meta-analysis of cohort studies. Eur J Epidemiol. 2013;28(11):845–858. Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Cancer Spectrum Oxford University Press

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Abstract

Background: Energy balance–related risk factors for colon cancer recurrence and mortality—type II diabetes, hyperinsuline- mia, inflammation, and visceral obesity—are positively correlated with consumption of refined grains and negatively corre- lated with consumption of whole grains. We examined the relationship between the consumption of refined and whole grains with cancer recurrence and mortality in a cohort of patients with colon cancer. Methods: We conducted a prospective observational study of 1024 patients with stage III colon cancer who participated in a randomized trial of postoperative chemotherapy. Patients reported consumption of refined and whole grains using a food frequency questionnaire during and six months after chemotherapy. The primary outcome was disease-free survival (DFS). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. All P values are two-sided. Results: During a median follow-up of 7.3 years, 394 patients experienced a DFS event. The hazard ratio for DFS was 1.56 (95% CI ¼ 1.09 to 2.24) for patients consuming three or more servings per day of refined grains compared with patients consuming less than one serving per day (P ¼ .005). The hazard ratio for DFS was 0.89 (95% CI ¼ 0.66 to 1.20) for patients consuming trend three or more servings per day of whole grains compared with patients consuming less than one serving per day (P ¼ .54). trend The hazard ratio for DFS of substituting one serving per day of refined grain with one serving per day of whole grain was 0.87 (95% CI ¼ 0.79 to 0.96, P ¼ .007). Conclusions: The choice of grain consumed may be associated with cancer recurrence and mortality. Future studies are necessary to confirm our findings and to inform the design of randomized trials. Each year, 83 000 people are diagnosed with stage I–III colon lifestyle behaviors, such as their dietary choices, may influence cancer in the United States (1). Despite surgical resection, either cancer recurrence and mortality (3). Consumption of a Western- alone or in combination with adjuvant chemotherapy, style diet (4), high-glycemic carbohydrates (5), red and proc- 25%30% of patents will experience recurrent and metastatic essed meats (6), and sugar-sweetened beverages are associated disease within three years of diagnosis, and 91% of those who with a higher risk of recurrence and mortality (7,8). Conversely, recur within three years die by five years (2). Consequently, coffee (9), milk (10), and modest alcohol consumption are asso- patients with colon cancer are motivated to understand how ciated with a lower risk of recurrence and mortality (8). Received: February 22, 2018; Revised: March 16, 2018; Accepted: March 29, 2018 © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 1of 8 by Ed 'DeepDyve' Gillespie user on 21 June 2018 2of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Evidence describing other dietary constituents will inform clini- because of declining health, patients were excluded if they ex- cal recommendations for patients and guide the design of ran- perienced cancer recurrence or death within 90 days of com- domized trials of dietary modification (11). pleting the questionnaire (Q1). Figure 1 describes the derivation Whole grains contain endosperm, germ, and bran, whereas of the final sample size of 1024 patients included in this study. refined grains have the germ and bran removed during the mill- There were no substantive differences in the baseline character- ing process. The consumption of refined grains is associated istics of patients included in the dietary analysis, and the with an increased risk of developing type II diabetes (12–14). remaining patients enrolled in CALGB 89803 (5). The consumption of refined grains is positively correlated with All patients signed informed consent, which was approved hyperinsulinemia (15), inflammation (16), and visceral obesity by the National Cancer Institute Cancer Treatment Evaluation (17). This is relevant to patients with colon cancer because type Program and each participating site’s institutional review II diabetes (18,19), hyperinsulinemia (20), inflammation (21), board. and visceral obesity are risk factors for cancer recurrence and mortality (22). Conversely, the consumption of whole grains is associated with a lower risk of developing type II diabetes (23). Dietary Assessment The consumption of whole grains is negatively correlated with The consumption of refined and whole grain foods was quanti- hyperinsulinemia (24), inflammation (25), and visceral obesity fied using semiquantitative food frequency questionnaires (17). Randomized trials in healthy men and women demon- (FFQ) that included 131 food items, vitamin and mineral supple- strate that substituting refined grains with whole grains reduces ments, and open-ended sections for other supplements and insulin resistance (26,27), inflammation (28,29), and body fat foods not specifically listed (32). For each food, a common unit (29,30). or portion size (eg, slice of bread) was specified, and the patient We prospectively examined the relationship between the was asked to report how often, on average over the previous consumption of refined grains and whole grains with cancer re- three months, they consumed that portion size. Up to nine fre- currence and mortality in a cohort of patients with stage III co- quency responses were possible, which ranged from never to lon cancer enrolled in a National Cancer Institute–sponsored six or more times per day. Type and brand of cereal were also randomized clinical trial of postoperative chemotherapy. We assessed. We computed nutrient intakes by multiplying the fre- hypothesized that 1) higher consumption of refined grains quency of consumption of each food by the nutrient content of would be associated with an increased risk of cancer recurrence the specified portions using composition values from the and mortality; 2) higher consumption of whole grains would be Department of Agriculture. All nutrient values were energy- associated with a decreased risk of cancer recurrence and mor- adjusted using the residuals method (33). tality, and 3) substitution of refined grains with whole grains Foods were classified as refined or whole grains using the would be associated with a decreased risk of cancer recurrence technique developed by Jacobs and colleagues (34). Refined and mortality. grains included sweet rolls, cake deserts, white bread, pasta, English muffins, muffins, biscuits, refined grain cereals, white rice, pancakes, waffles, and pizza. Whole grains included dark Methods bread, whole grain ready-to-eat cereals (25% whole grain con- tent by weight), popcorn, cooked oatmeal, wheat germ, brown Study Population rice, bran, and other grains. A full description of the FFQ, repro- ducibility, and validity statistics has been reported previously Patients in this prospective cohort study participated in the (32,35). The performance of the FFQ to quantify individual grain National Cancer Institute (NCI)–sponsored Cancer and products is high; the correlation between the FFQ and detailed Leukemia Group B (CALGB; now Alliance for Clinical Trials in diet records is 0.75 for cereal, 0.71 for white bread, and 0.77 for Oncology) 89803 postoperative chemotherapy trial for stage III dark bread (36). Variables including prudent and Western die- colon cancer (31). Patients were recruited from the United States tary patterns, the healthy eating index, and glycemic load were and Canada. The primary aim of CALGB 89803 was to compare calculated using the dietary assessment following techniques weekly 5-fluorouracil and leucovorin with weekly irinotecan, 5- described previously (8). fluorouracil, and leucovorin (ClinicalTrials.gov NCT000038350). Patients who completed Q1 and whose cancer had not re- Between May 1999 and May 2001, the trial enrolled 1264 curred prior to Q1 completion were included in these analyses. patients. After the enrollment of 87 patients, an amendment re- The median time from study entry to Q1 (range) was 3.5 (0.2–9.9) quired patients to complete a self-administered questionnaire months. We updated dietary exposures based on the results of that quantified diet and lifestyle behaviors midway through Q2 using cumulative averaging, with weighting that is propor- chemotherapy (approximately four months after surgical tional to times between Q1 and Q2 and then between Q2 and resection, questionnaire 1 [Q1], and again six months after the event (or censoring) time (4). This technique accounts for completion of chemotherapy [14 months after surgical changes in diet that may occur over time, thereby maximizing resection; Q2]). the information obtained from the available data. Eligible patients underwent a complete surgical resection of the primary tumor within 56 days of trial enrollment, had re- gional lymph node metastases but no evidence of distant me- Study End Points tastases, had a baseline Eastern Cooperative Oncology Group performance status of 0 to 2, and had adequate bone marrow, The primary end point of this study was disease-free survival renal, and hepatic function. Patients were excluded from this (DFS), and secondary end points included recurrence-free sur- analysis if they reported unreasonable energy intake (<600 or vival (RFS) and overall survival (OS). DFS was defined as the >4200 calories per day for men; <500 or >3500 calories per day time from completion of Q1 to cancer recurrence, occurrence of for women) or left 70 or more food items blank (see Dietary a new primary colon cancer, or death from any cause, which- Assessment below). To avoid bias in dietary assessment ever occurred first. RFS was defined as the time from Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 3 of 8 Figure 1. Derivation of cohort. Caloric intake exclusion: <600 calories or >4200 calories per day for men and <500 calories and >3500 calories per day for women. Q1 ¼ questionnaire 1 (midway through adjuvant therapy); Q2 ¼ questionnaire 2 (six months after completion of adjuvant therapy). completion of Q1 to cancer recurrence or occurrence of a new and refined grain intake (for whole grain models). We used primary colon cancer; patients who died without known disease time-varying covariates to adjust for body mass index (BMI), recurrence were censored at the last documented physician physical activity, total energy intake, whole grain intake, and re- evaluation. OS was defined as the time from completion of Q1 fined grain intake. Other covariates, including age at Q1, sex, to death from any cause. race, performance status (physician estimate of patient ability for self-care, daily activity, and physical ability), depth of inva- sion through bowel wall (T stage), number of positive lymph nodes (N stage), location of the primary tumor, and chemother- Statistical Analysis apy treatment arm, were entered into the model as fixed covariates. In the clinical trial, there were no statistical differences in DFS, RFS, or OS between treatment arms (31). Therefore, data for We tested for linear trends across frequency categories of consumption by assigning each patient the median value for patients in both arms were combined and analyzed according to frequency categories of dietary intake. For the primary analy- each category and modeling the value as a continuous variable. We graphically examined the frequency of grain consumption sis, consumption of refined and whole grain foods was catego- rized into three groups (<1, 1–2, and 3 servings per day). Cox as a continuous variable using nonlinear restricted cubic splines. The proportionality of hazards assumption was exam- proportional hazards regression was used to determine the si- multaneous influence of other potential confounding variables. ined by including time-dependent covariates in the regression models and visually inspecting log-log plots. To evaluate the ef- Three models were built to incrementally examine the associa- tion between grain intake and the study end points. Model 1 fect of substituting refined grains with whole grains, we built substitution models by simultaneously entering whole and re- was adjusted for age and energy intake; model 2 was adjusted for demographic, clinical, and behavioral variables; model 3 was fined grain intakes into a model as continuous variables, then exponentiating the difference in coefficients to obtain an esti- adjusted for the covariates in model 2, plus the complementary grain measure: whole grain intake (for refined grain models) mate that is on the hazard ratio scale (37). The hazard ratios Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 4of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 1. Baseline characteristics of 1024 patients by servings of refined and whole grains Refined grain intake, servings/d Whole grain intake, servings/d <1 1–2 3 <1 1–2 3 (n ¼ 160) (n ¼ 565) (n ¼ 299) P (n ¼ 294) (n ¼ 481) (n ¼ 249) P Age, median (IQR), y 61 (54–69) 59 (51–68) 62 (51–70) .11 59 (50–68) 60 (52–68) 61 (52–70) .20 Sex, No. (%) <.001 <.001 Male 79 (49.4) 284 (50.3) 213 (71.2) 177 (60.2) 241 (50.1) 158 (63.5) Female 81 (50.6) 281 (49.7) 86 (28.8) 117 (39.8) 240 (49.9) 91 (36.5) Race, No. (%) .18 .04 White 136 (85.0) 503 (89.0) 270 (90.3) 247 (84.0) 436 (90.7) 226 (90.8) Black 16 (10.0) 39 (6.9) 13 (4.4) 27 (9.2) 29 (6.0) 12 (4.8) Other 8 (5.0) 23 (4.1) 16 (5.3) 20 (6.8) 16 (3.3) 11 (4.4) Baseline performance .72 .002 status, No. (%)* 0 121 (75.6) 419 (74.2) 210 (70.2) 199 (67.7) 367 (76.3) 184 (73.9) 1 2 36 (22.5) 135 (23.9) 82 (27.4) 90 (30.6) 109 (22.7) 54 (21.7) Missing/unknown 3 (1.9) 11 (1.9) 7 (2.4) 5 (1.7) 5 (1.0) 11 (4.4) Invasion through bowel .18 .21 wall by T stage, No. (%) T1 2 19 (11.9) 88 (15.6) 30 (10.0) 33 (11.2) 69 (14.3) 35 (14.1) T3 4 138 (86.2) 465 (82.3) 260 (87.0) 256 (87.1) 403 (83.8) 204 (81.9) Missing/unknown 3 (1.9) 12 (2.1) 9 (3.0) 5 (1.7) 9 (1.9) 10 (4.0) Positive lymph nodes, No. (%) .22 .04 1 3 110 (68.7) 361 (63.9) 174 (58.2) 180 (61.2) 314 (65.3) 151 (60.7) 4 47 (29.4) 195 (34.5) 118 (39.5) 110 (37.4) 162 (33.7) 88 (35.3) Missing/unknown 3 (1.9) 9 (1.6) 7 (2.3) 4 (1.4) 5 (1.0) 10 (4.0) Location of primary .78 .12 tumor, No. (%) Right 4 (2.5) 23 (4.1) 9 (3.0) 12 (4.1) 13 (2.7) 11 (4.4) Left 59 (36.9) 222 (39.3) 105 (35.1) 123 (41.8) 182 (37.8) 81 (32.5) Transverse 61 (38.1) 207 (36.6) 115 (38.5) 99 (33.7) 186 (38.7) 98 (39.4) Multiple 33 (20.6) 104 (18.4) 61 (20.4) 56 (19.0) 93 (19.3) 49 (19.7) Missing 3 (1.9) 9 (1.6) 9 (3.0) 4 (1.4) 7 (1.5) 10 (4.0) Treatment arm, No. (%) .24 .24 FU/LV 88 (55.0) 272 (48.1) 156 (52.2) 157 (53.4) 229 (47.6) 130 (52.2) IFL 72 (45.0) 293 (51.9) 143 (47.8) 137 (46.6) 252 (52.4) 119 (47.8) BMI, median (IQR), kg/m 27.5 (23.8–32.2) 27.2 (23.8–30.9) 27.5 (24.2–31.3) .54 27.6 (23.5–32.3) 27.4 (24.4–31.1) 26.6 (23.6–30.7) .29 Physical activity, 5.0 (1.7–14.8) 4.6 (0.9–15.4) 5.1 (1.1–17.8) .47 3.7 (0.6–9.6) 5.1 (1.3–15.1) 7.1 (1.6–22.5) <.001 median (IQR), MET-h/w Current use of aspirin, No. (%) 38 (23.8) 156 (27.6) 87 (29.1) .47 82 (27.9) 131 (27.2) 68 (27.3) .98 Dietary intake, median (IQR) Alcohol consumption, g/d 0.1 (0.0–1.8) 0.4 (0.0–2.0) 0.2 (0.0–3.5) .70 0.2 (0.0–3.5) 0.2 (0.0–2.0) 0.4 (0.00–2.0) .77 Coffee intake, cups/wk 3.0 (0.0–17.5) 7.0 (0.5–17.5) 7.0 (0.5–17.5) .001 7.0 (0.4–17.5) 6.5 (0.5–17.5) 7.0 (0.2–17.0) .85 Sugar sweetened 1.0 (0.4–3.8) 2.4 (0.5–6.0) 3.0 (0.7–7.0) <.001 3.1 (0.6–7.0) 1.7 (0.5–5.7) 1.6 (0.5–5.5) .02 beverages, s/wk Cereal fiber, g/d 5.6 (3.6–8.1) 5.7 (4.3–7.3) 5.4 (4.3–7.0) .48 4.1 (3.1–4.9) 5.8 (4.7–7.2) 7.8 (6.2–9.9) <.001 Western diet pattern, 124 (77.5) 329 (58.2) 59 (19.7) <.001 147 (50.0) 252 (52.4) 113 (45.4) .20 No. < median (%) Prudent diet pattern, 97 (60.6) 266 (47.1) 149 (49.8) .01 197 (67.0) 228 (47.4) 87 (34.9) <.001 No. < median (%) AHEI dietary pattern, 63 (39.4) 254 (45.0) 195 (65.2) <.001 189 (64.3) 221 (45.9) 102 (41.0) <.001 No. < median (%) Glycemic load, No. < median (%) 96 (60.0) 278 (49.2) 138 (46.2) .02 168 (57.1) 246 (51.1) 98 (39.4) <.001 *Baseline performance status: 0 indicates fully active; 1 indicates restricted in physically strenuous activity but ambulatory and able to perform light work; 2 indicates ambulatory and capable of all self-care but unable to perform any work activities, up to approximately 50% of waking hours. AHEI ¼ Alternate Healthy Eating Index 2010; BMI ¼ body mass index; FU/LV ¼ fluorouracil and leucovorin; IFL ¼ irinotecan, fluorouracil, and leucovorin; IQR ¼ interquartile range; MET-h/w ¼ metabolic equivalent task hours per week; s ¼ servings. derived from these models are interpreted as the estimated ef- All analyses were performed with SAS, version 9.4 (SAS fect of substituting one daily serving of refined grain with one Institute, Cary, NC). A P value of less than .05 was considered daily serving of whole grain. statistically significant. All P values are two-sided. Data Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 5 of 8 collection and statistical analyses were conducted by the Alliance Statistics and Data Center at Duke University Medical Center. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairperson following Alliance policies. All analyses were based on the study database frozen on November 9, 2009. Results Baseline Characteristics Baseline characteristics of the 1024 patients by frequency of consumption of refined and whole grains are displayed in Table 1. Those in the highest category of refined grain intake were more likely to be male and report a higher consumption of coffee, sugar-sweetened beverages, and poorer overall die- tary patterns, compared with patients in the lowest category of refined grain intake. Those in the highest category of whole grain intake were more likely to be male and of white race, to have fewer positive lymph nodes and better performance sta- tus, and to report higher physical activity, higher consumption of cereal fiber, and more favorable overall dietary patterns, compared with patients in the lowest category of whole grain intake. Associations Between Cancer Recurrence and Mortality With Grain Intake Figure 2. Adjusted cubic spline model for intake of refined grains and associa- The median follow-up time from completion of Q1 was 7.3 tion with colon cancer recurrence and mortality (disease-free survival). Models years. During follow-up, we observed 394 DFS events, 350 RFS are adjusted for age, sex, race, performance status, T stage, positive lymph events, and 311 OS events. nodes, location of primary tumor, treatment arm, body mass index, physical ac- In the adjusted cubic spline model, higher intake of refined tivity, total energy, and whole grain intake. grains was associated with an increased risk of cancer recur- rence and mortality (P ¼ .03) (Figure 2). The associations be- CI ¼ 0.77 to 0.96, P ¼ .006) and OS (HR ¼ 0.87, 95% CI ¼ 0.78 to tween cancer recurrence and mortality with refined and whole 0.97, P ¼ .01). grain intake are displayed in Table 2. The multivariable- adjusted hazard ratio for DFS was 1.56 (95% CI ¼ 1.09 to 2.24) for those consuming three or more servings per day of refined Discussion grains compared with those consuming less than one serving per day (P ¼ .005). Results were similar for RFS and OS. trend In this prospective cohort of patients with stage III colon cancer Exclusion of patients who experienced a DFS event in the first who participated in an NCI-sponsored randomized trial of post- 90 to 365 days after Q1 did not substantively alter the above- operative chemotherapy, higher consumption of refined grains described results. was associated with an increased risk of cancer recurrence and In the adjusted cubic spline model, higher intake of whole mortality, and the substitution of refined grains with whole grains was associated with a reduced risk of cancer recurrence grains was associated with a decreased risk of cancer recur- and mortality (P ¼ .05) (Figure 3). The multivariable-adjusted rence and mortality. These data add to an evidence base that hazard ratio for DFS was 0.89 (95% CI ¼ 0.66 to 1.20) for those has documented the importance that dietary choices may have consuming three or more servings per day of whole grains com- on clinical outcomes in this population. pared with those consuming less than one serving per day Type II diabetes (18,19), hyperinsulinemia (20), inflamma- (P ¼ .54). Results were similar for RFS and OS. Exclusion of trend tion (21), and visceral obesity are risk factors for cancer recur- patients who experienced a DFS event in the first 90 to 365 days rence and mortality (22). Many of these risk factors have been after Q1 did not substantively alter the above-described results. proposed as biological mediators of the relationship between energy balance–related lifestyle factors (diet, physical activ- ity, obesity) and clinical outcome in patients with cancer Substitution Analysis (38,39). The consumption of refined grains is associated with The consumption of refined grains was negatively correlated an increased risk of developing type II diabetes (12–14)and with the consumption of whole grains (r ¼ –.19, P < .001). We positively correlated with hyperinsulinemia (15), inflamma- therefore sought to estimate the influence of substituting one tion (16), and visceral obesity (17). Conversely, the consump- daily serving of refined grain with one daily serving of whole tion of whole grains is associated with a lower risk of grain. In substitution analysis, the multivariable-adjusted haz- developing type II diabetes (23) and negatively correlated with ard ratio for DFS by substituting one daily serving of refined hyperinsulinemia (24), inflammation (25), and visceral obesity grain with one daily serving of whole grain was 0.87 (95% CI ¼ 0. (17). The observed relationship between the consumption of 79 to 0.96, P ¼ .007). Results were similar for RFS (HR ¼ 0.86, 95% refined grains with cancer recurrence and mortality is Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 6of 8 | JNCI J Natl Cancer Inst, 2018, Vol. 0, No. 0 Table 2. Associations between colon cancer recurrence and mortality with refined and whole grain intake* Grain intake, servings/d Outcome and exposure <1 1–2 3 P trend Disease-free survival Refined grain intake No. of events/No. at risk 53/160 204/565 137/299 Model 1† 1.00 (referent) 1.18 (0.87 to 1.61) 1.75 (1.24 to 2.46) <.001 Model 2‡ 1.00 (referent) 1.16 (0.85 to 1.58) 1.58 (1.12 to 2.24) .003 Model 3§ 1.00 (referent) 1.15 (0.84 to 1.58) 1.56 (1.09 to 2.24) .005 Whole grain intake No. of events/No. at risk 129/294 173/481 92/249 Model 1† 1.00 (referent) 0.77 (0.61 to 0.97) 0.81 (0.62 to 1.07) .19 Model 2‡ 1.00 (referent) 0.81 (0.64 to 1.03) 0.85 (0.64 to 1.13) .32 Model 3§ 1.00 (referent) 0.84 (0.66 to 1.07) 0.89 (0.66 to 1.20) .54 Recurrence-free survival Refined grain intake No. of events/No. at risk 48/160 177/565 125/299 Model 1† 1.00 (referent) 1.11 (0.80 to 1.54) 1.73 (1.21 to 2.49) <.001 Model 2‡ 1.00 (referent) 1.08 (0.78 to 1.50) 1.59 (1.10 to 2.29) .001 Model 3§ 1.00 (referent) 1.08 (0.77 to 1.50) 1.57 (1.08 to 2.30) .003 Whole grain intake No. of events/No. at risk 111/294 155/481 84/249 Model 1† 1.00 (referent) 0.81 (0.64 to 1.04) 0.89 (0.67 to 1.20) .53 Model 2‡ 1.00 (referent) 0.82 (0.64 to 1.06) 0.90 (0.67 to 1.21) .58 Model 3§ 1.00 (referent) 0.86 (0.67 to 1.12) 0.97 (0.71 to 1.33) .98 Overall survival Refined grain intake No. of events/No. at risk 38/160 158/565 115/299 Model 1† 1.00 (referent) 1.33 (0.92 to 1.90) 2.09 (1.40 to 3.10) <.001 Model 2‡ 1.00 (referent) 1.32 (0.92 to 1.90) 1.89 (1.27 to 2.81) <.001 Model 3§ 1.00 (referent) 1.32 (0.91 to 1.90) 1.88 (1.25 to 2.85) .001 Whole grain intake No. of events/No. at risk 108/294 130/481 73/249 Model 1† 1.00 (referent) 0.69 (0.54 to 0.89) 0.74 (0.55 to 1.01) .09 Model 2‡ 1.00 (referent) 0.78 (0.60 to 1.02) 0.81 (0.59 to 1.11) .24 Model 3§ 1.00 (referent) 0.81 (0.62 to 1.06) 0.86 (0.62 to 1.20) .46 *Two-sided P values. Trend across quintiles. CI ¼ confidence interval; HR ¼ hazard ratio. †Model 1: adjusted for age and time-varying total energy. ‡Model 2: adjusted for age, sex, race, performance status, T stage, positive lymph nodes, location of primary tumor, treatment arm, time-varying body mass index, physical activity, and total energy. §Model 3: adjusted for age, sex, race, performance status, T stage, positive lymph nodes, location of primary tumor, treatment arm, time-varying body mass index, physical activity, total energy, and whole grain intake (for refined grain models) or refined grain intake (for whole grain models). therefore biologically possible. This mechanistic hypothesis with clinical outcome. A decade ago, the initial observation was in oncology parallels that of cardiology, where the consump- made that a Western-style diet was associated with cancer re- tion of refined grains is associated with an increased risk of currence and mortality in patients with colon cancer (4). Since incident cardiovascular disease and cardiovascular-specific that time, the specificity of our understanding regarding what mortality (40). dietary constituents may influence clinical outcome has A novel aspect of our study was the observation that evolved, and now includes high-glycemic carbohydrates (5), red substituting one daily serving of refined grains with one daily and processed meats (6), and sugar-sweetened beverages (7,8), serving of whole grains was associated with a 13% lower risk of as well as coffee (9), milk (10), and modest alcohol consumption cancer recurrence or mortality during the follow-up period. (8). These observational data will be useful to inform and tailor Clinical trials in healthy men and women demonstrate that the design of a dietary modification intervention trial in substituting refined grains with whole grains reduces insulin patients with colon cancer, a trial that will eventually need to resistance (27), inflammation (28), and body fat (30). For exam- be tested with a disease end point to provide persuasive evi- ple, in a randomized crossover trial, six weeks of a whole grain dence to inform clinical practice. diet reduced concentrations of fasting insulin compared with a The principal strength of this study was embedding the FFQ refined grain diet (15.065.5 pmol/L, P ¼ .03) (27). Similarly, in a in a randomized clinical trial. Consequently, this study had a 12-week randomized trial, a whole grain diet reduced body fat large sample size with a well-defined study population. Follow- compared with a refined grain diet (1.9%, P ¼ .04) (30). These up in this study was standardized, such that all patients under- data suggest that randomized trials of dietary modification are went quarterly medical examinations to identify recurrent dis- feasible and induce physiologic changes that may be associated ease. Although the FFQ was self-reported, it was collected Downloaded from https://academic.oup.com/jncics/article-abstract/2/2/pky017/5025854 by Ed 'DeepDyve' Gillespie user on 21 June 2018 J. C. Brown et al. | 7 of 8 that a higher consumption of refined grains was associated with an increased risk of cancer recurrence and mortality, and the substitution of refined grains with whole grains was associated with a decreased risk of cancer recurrence and mortality. Although this observational study does not provide definitive evidence for causality, these data may inform clini- cal recommendations for patients and inform hypotheses to guide the design of future observational studies and random- ized trials of dietary modification in patients with colon cancer. Funding Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821 and U10CA180882 to the Alliance for Clinical Trials in Oncology and U10CA180820 to the ECOG-ACRIN (CA60138, U10CA180857, U10CA180836, U10CA180867). Additional sup- port was provided by Pharmacia & Upjohn Company, now Pfizer Oncology. Dr. Brown is supported by a grant from the National Cancer Institute (K99CA218603). Dr. Ogino is sup- ported by a grant from the National Cancer Institute (R35CA197735). Drs. Fuchs and Meyerhardt are supported in part by grants from the National Cancer Institute (R01CA118553, R01CA149222, R01CA169141, and P50CA127003). The sponsors did not participate in the de- sign or conduct of the study; collection, management, anal- Figure 3. Adjusted cubic spline model for intake of whole grains and association with colon cancer recurrence and mortality (disease-free survival). Models are ysis, or interpretation of the data; or the preparation, adjusted for age, sex, race, performance status, T stage, positive lymph nodes, review, or approval of the manuscript. location of primary tumor, treatment arm, body mass index, physical activity, total energy, and refined grain intake. Notes prospectively, such that any ascertainment bias in the FFQ Affiliations of authors: Dana-Farber/Partners CancerCare, would be nondifferential and shift our effect size estimates Boston, MA (JCB, SZ, RJM, SO, KN, JAM); Duke Cancer Institute, toward the null. We excluded patients who experienced recur- Duke University Medical Center, Durham, NC (DN); Memorial rent disease or mortality within 90 days of completing the FFQ Sloan Kettering Cancer Center, New York, NY (LBS); Toledo to minimize the potential of occult disease inducing changes Community Hospital Oncology Program, Toledo, OH (RBM); in dietary intake. We adjusted for variables that may confound Ho ˆpital du Sacre-Coeur de Montreal Montreal, Canada (RW); the relationship between the consumption of refined and Edward-Elmhurst Heatlhcare, Naperville, IL (AH); Robert H. whole grains with cancer recurrence and mortality; several of Lurie Comprehensive Cancer Center, Northwestern these variables were time-varying, allowing us to account for University, Chicago, IL (AB); Virginia Oncology Associates, changes in BMI, physical activity, and other aspects of dietary Norfolk, VA (DA); Southeast Clinical Oncology Research intake that may have occurred after completing (SCOR) Consortium, Mission Hospitals, Inc., Asheville, NC chemotherapy. (MM); University of Chicago Comprehensive Cancer, Chicago, The principal limitation of this study is the observational de- IL (HK); University of California at San Francisco sign, such that we cannot rule out the possibility of residual Comprehensive Cancer Center, San Francisco, CA (AV); confounding. Although the FFQ used in the study was self- Harvard T.H. Chan School of Public Health, Boston, MA (SO, reported, it is correlated with plasma concentrations of carote- YL, WCW, ELG); Brigham and Women’s Hospital, Boston, MA noids, tocopherols, and fatty acids in patients with colon cancer (SO, XZ, ELG); Yale Cancer Center, Yale School of Medicine, (32). Future studies should consider the potential utility of pre- New Haven, CT (CSF). dicting prognosis with objective measures of dietary intake, ClincalTrials.gov registration: NCT000038350. such as metabolites in urine or plasma samples (41,42). The The views expressed in the article are those of the authors patients in the current study elected to enroll in a clinical trial and not an official position of their affiliated institutions or and may not be representative of colon cancer patients in the funders. US population with respect to demographic and lifestyle behav- iors. 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JNCI Cancer SpectrumOxford University Press

Published: May 30, 2018

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