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reviews Annals of Oncology

Annals of Oncology 23: 2536–2546, 2012
Published online 26 April 2012

Dietary fructose, carbohydrates, glycemic indices
and pancreatic cancer risk: a systematic review
and meta-analysis of cohort studies
D. Aune1*, D. S. M. Chan1, A. R. Vieira1, D. A. Navarro Rosenblatt1, R. Vieira1, D. C. Greenwood2,
J. E. Cade3, V. J. Burley3 & T. Norat1
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London; 2Biostatistics Unit, Centre for Epidemiology and Biostatistics;
School of Food Science and Nutrition, University of Leeds, Leeds, UK

Received 30 December 2011; revised 2 March 2012; accepted 6 March 2012

Downloaded from by guest on November 20, 2016
Background: Dietary carbohydrates, glycemic load and glycemic index have been hypothesized to influence
pancreatic cancer risk, but epidemiological studies have been inconsistent. We conducted a systematic review and
meta-analysis of prospective studies to clarify these results.
Methods: PubMed and several other databases were searched for prospective studies of intake of carbohydrates,
glycemic index and glycemic load and pancreatic cancer up to September 2011. Summary relative risks were
estimated using a random effects model.
Results: Ten cohort studies (13 publications) were included in the meta-analysis. The summary relative risk (RR) per
10 glycemic index units was 1.02 [95% confidence interval (CI): 0.93–1.12, I 2 = 0%], per 50 glycemic load units was
1.03 (95% CI: 0.93–1.14, I 2 = 10%), per 100 g/day of total carbohydrates was 0.97 (95% CI: 0.81–1.16, I 2 = 35%), and
per 25 g/day of sucrose intake was 1.05 (95% CI: 0.85–1.23, I 2 = 53%). A positive association was observed with
fructose intake, summary RR = 1.22 (95% CI: 1.08–1.37, I 2 = 0%) per 25 g/day.
Conclusions: This meta-analysis does not support an association between diets high in glycemic index, glycemic
load, total carbohydrates or sucrose and pancreatic cancer risk. The finding of an increased risk with fructose intake
warrants further investigation in studies with better adjustment for confounding and in non-American populations.
Key words: carbohydrates, glycemic index, glycemic load, fructose, pancreatic cancer, sucrose

introduction hypothesized to be involved in the etiology of pancreatic
cancer, but to date no convincing dietary risk factors for
Pancreatic cancer is the ninth most common cause of cancer pancreatic cancer have been established [8].
with 277 000 new cases diagnosed in 2008 worldwide, Several lines of evidence indicate that insulin resistance may
accounting for ∼2.2% of all cancer cases [1]. The survival of play a role in the etiology of pancreatic cancer. Some
pancreatic cancer patients is very poor and 5-year survival rates established or possible risk factors for pancreatic cancer
are 2%–8% [2]. Currently, there are no established methods for including overweight and obesity, low physical activity and
screening or early detection; thus, primary prevention by type 2 diabetes are linked to insulin resistance [6, 8, 9].
altering modifiable risk factors will probably be the most Epidemiological studies have reported increased pancreatic
effective way of reducing the pancreatic cancer burden at cancer risk with elevated blood glucose or C-peptide [10–12]
present. Ecological studies have suggested that modifiable risk and dietary carbohydrates are the main dietary component
factors are likely to be important in pancreatic cancer etiology affecting an individual’s insulin secretion and glycemic
[3]. However, with the exception of tobacco smoking, which response [13]. Several studies have investigated the association
explains ∼20%–25% of pancreatic cancer cases [4, 5], and between diets high in carbohydrates, glycemic index (GI) or
diabetes [relative risk (RR) = 1.8] [6] and body fatness (RR = glycemic load (GL) and pancreatic cancer risk; however, the
1.10 per 5 kg/m2) [7], relatively few modifiable risk factors results have been inconsistent [14–26]. Also, it is not known
have been firmly established. Dietary factors have been whether specific types of carbohydrates (e.g. fructose, glucose
or sucrose) are associated with pancreatic cancer risk. Some
*Correspondence to: Dr D. Aune, Department of Epidemiology and Biostatistics, School experimental and epidemiological studies have suggested that
of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place,
high fructose intake may increase risk of insulin resistance,
Paddington, London W2 1PG, UK. Tel: +44 (0)-20-7594-8478; Fax: +44-(0)-20-7594-
0768; E-mail: type 2 diabetes and obesity [27–29]; however, data regarding

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email:

The search and data extraction up to December 2005 were conducted by JEC. Cochrane Library. that were included in and was checked for accuracy by TN.1093/annonc/mds076 |  . we assumed the open- Downloaded from http://annonc. ISI each quintile. we used the method by Greenland and and pancreatic cancer risk. Embase. case-cohort or fractional polynomial regression model was determined. the total number of person-years was divided by 5 when data conducted by several reviewers at University of Leeds. Small study effects. 25 g/day increment for sucrose/fructose intake (the approximate mean difference between the highest and lowest intake across studies). 20. CINAHL. and for a 100 g/day increment for total carbohydrates and published systematic reviews and meta-analyses [31. 15. If the intakes for the review (http://www. The search and data We identified 10 cohort studies (13 publications) [14–26].g.pdf ). A two-tailed P < 0. Estimates of the relative risk (hazard ratio. available with the 95% confidence intervals in the publication. The dose–response results in the forest plots are meta-analyses were followed [30]. We National Research Register and In Process Medline. carbohydrate and GI/GL intake. for The literature search and data extraction up to December 2005 were example. publication year. we conducted a systematic review Longnecker [34] to compute study-specific slopes (linear trends) and 95% CIs from the natural logs of the RRs and CIs across categories of and dose–response meta-analysis of prospective studies. For one study [17] that reported results risk have also been inconsistent with inverse [25]. VJB and several other reviewers at the University of Leeds. were reported in densities (e. RRs and 95% CIs for the highest versus the lowest level of intake and variables adjusted for in the analysis. quantity of intake. Results from these sensitivity name. a change in the lower and upper bound for studies that reported intakes by ranges. and the results were considered to indicate small data extraction and quality assessment study effects when P < 0. dietary analyses are reported for the two studies that had the most positive and assessment method (type. One to heterogeneity) [37]. validated). 23] and positive [21] associations reported.05 was 17. Volume 23 | No. results These data were checked for accuracy by DA. weighted by the inverse of its variance. but reported the total number of cases/person-years. To effects model to obtain an overall combined estimate for both genders. defined as the nested case-control study design and to investigate the association between one with the lowest deviance. A likelihood ratio test was used to assess dietary carbohydrates (excluding fiber). gram per 1000 kcal). the analysis of carbohydrate. was reported [17]. assessed by inspection of the funnel plots and with Egger’s test [38] and with Beggapos. number of cases.10. smoking. age. 15. we combined the results using a fixed- 17. gender. follow-up period. Initially. 10 | October 2012 doi:10. country where the study was conducted. alcohol. GI. 32].and 50-unit increment per day for GI and GL. 2016 from January 2006 to September 2011.oxfordjournals. the studies that were included in our analysis as well as those listed in the respectively. 21. number of cases. Studies on sucrose intake and pancreatic cancer considered statistically significant. DSMC. 22. geographic location and results were included in analyses stratified by gender as the publication adjustment for potential confounding factors such as body mass index used for the main analysis [19] did not report sex-specific results and one (BMI). we recalculated the cancer_resource_center/downloads/SLR_Manual. Standard criteria for conducting and reporting intake [19. publication was excluded from the dose–response analysis of sucrose and energy and red and processed meat were conducted to investigate potential fructose intake because only the highest versus the lowest intake was sources of heterogeneity. BIOSIS. AMED. For the Heterogeneity between studies was assessed by the Q test and I 2 (a dose–response analysis. sample size. We examined a potential nonlinear dose–response relationship by using study selection fractional polynomial models [35]. We also searched the reference lists of all presented for a 10. such as publication bias. One of these publications was We used random effects models to calculate summary RRs and 95% CIs only included in subgroup analyses by sex [26] as it was for the highest versus the lowest level of carbohydrate and GI/GL intake superseded by another publication from the same study [19]. The average of the natural Eight studies were from North America and two were from logarithm of the RRs was estimated and the RR from each study was Europe. GI or GL and pancreatic cancer the difference between the nonlinear and linear models to test for risk. The best fitting second-order To be included. exposure. Because all the relevant estimated the midpoint in each category by calculating the average of the studies were identified through searches in PubMed.Annals of Oncology reviews fructose intake and pancreatic cancer are inconsistent [14. 22]. null [14. duplicate publication [26] was excluded from the main analysis. and for the dose-response analyses [33]. so no dose–response could be estimated for this publication. separately for men and women. GL For the dose–response analyses. supplementary Figure S1 (available at data synthesis and analysis Annals of Oncology online)]. 19–22]. the study large study or a study with an extreme result. intake was assigned to the corresponding relative risk for each study. CAB Abstracts. number of food items and whether it had been negative influence on the summary estimate. physical activity. We conducted sensitivity analyses excluding The following data were extracted from each study: The first author’s last one study at a time to clarify whether the results were simply due to one name. one extraction from January 2006 to September 2011 was conducted by DA of which was a case-cohort study [18]. We followed a predefined protocol ended interval length to be the same as the adjacent interval. We estimated the distribution of cases or person-years in studies that did not data sources and searches report these. When protocol was made and only PubMed was used for the updated searches the highest or lowest category was open ended. The median or mean level of intake in each category of Web of Science. LILACS. We identified 13 relevant publications in the search [14–26]. the study had to have a prospective cohort. The method requires that the distribution of cases and person-years or noncases and the RRs with the variance methods estimates for at least three quantitative exposure categories are known. but its duration of follow-up. clarify the association between intake of carbohydrates. intake of fruit and by guest on November 20. which includes reported intakes to absolute intakes using the mean or median energy details of the search terms. GI and GL intake and pancreatic cancer risk [Table 1.s test [39]. Subgroup and meta-regression analyses by sex. risk ratio) had to be nonlinearity [36]. several were analyzed by quintiles in order to derive the number of person-years in databases were searched including Pubmed.dietandcancerreport. a quantitative measure of intake had to be measure of the proportion of total variation in study estimates that is due provided.

30 (0.0 0.10 1.00 (0.34 versus 0 1.12 (0.46) carbohydrate Glycemic load ≥74.22) Starch ≥59.. red cases carbohydrate meat.5 versus 9.20 (0. 79 years: 287 Dietary total 285 versus 203 g/day 0.88–1.95 (0.74–1. Prospective cohort studies of intake of carbohydrates.2 versus 0 0.89–1.6 versus 24. 2010.16) Volume 23 | No.71 versus ≤17.30) carbohydrates g/1000 kcal/day Starch ≥56.65) g/1000 kcal/day Sucrose ≥29.7 1. USA [19] NIH-AARP Diet 1995/1996–2003. 2009.97–2. sex.oxfordjournals.10 (0.56 (1..89 1.75–1. age 55– 124 food items g/1000 kcal/day BMI. Glycemic load ≥73.09) Maltose ≥2.75) g/1000 kcal/day Jiao et al.89) energy intake Dietary fructose 33 versus 13 g/day 0. Dietary Exposure Quantity RR (95% CI) Adjustment for age. SFA.17) Meinhold et al.91 (0.18 versus 0 0.50) alcohol. BMI Available ≥138.9 versus 8. physical women. [21] Colorectal and years follow-up women. age 50– Glycemic index 56 versus 48 units/day 1.84–1. cigarette Ovarian Cancer 74 years: 266 Glycemic index ≥56.8 versus 2.55 0.73–1.80 (0. income.35 (1.10–1.80 (0.63) activity.06–2.15) Age.78–1.90–1..5–46. 8 139 503 Validated FFQ. glycemic index and glycemic load and pancreatic cancer risk reviews  | Aune et al.4 versus 0.11 (0.28 1.04–1.79 (0.78–1.12 (0.45 0. 2010. total energy. DM.13 (0. 1998–2006.55–1. age 50– 124 food items units/day intake. 482 362 men and Validated FFQ.83–1.07) Age. year. number of assessment confounders cases Simon et al.2 by guest on November 20.32) Age. 10 | October 2012 Lactose ≥12.47) smoking status Screening Trial cases units/day Available ≥137. Dietary sucrose 60 versus 32 g/day 1.38) Annals of Oncology Downloaded from http://annonc. 6.57 versus ≤54.04 1. race.06–2. Author.55 (1.4 versus 0.88–1.16) Sucrose ≥30.0 versus 0.0 versus 0.27) g/1000 kcal/day Fructose ≥17.07 (0. Study follow-up 71 years: 1151 Total ≥151. total energy and Health 7.15) alcohol use.11) Total sugar ≥75.9 versus 4.89 (0. sex. USA [20] Women’s Health 1993/1998–.29) Free fructose ≥18. USA Prostate.59 1.0 1. Glycemic index ≥52.17 versus ≤50.5 109 175 men and Validated FFQ.78–1.29 (1.48 versus ≤7.54–1.59) Free glucose ≥17. Initiative years follow-up postmenopausal 122 food items day BMI. smoking.76–1. Table 1.02 1.2 years women. cases carbohydrates smoking status.16 1. 2016 . gender.95 (0.41 (0.95 (0.45 1.27 versus ≤38.09 (0.68 1. Lung.69–1.84–1.67) Galactose ≥0.00 versus ≤102. country Study name Follow-up period Study size.56–1. Glycemic load 150 versus 105 units/ 0.

Per 50 g/day 1.1 versus < 13.9 g/day 0.98 (0.0 1.24) Age.80 energy intake. [22] Cohort Study 8 years follow. years of Cancer follow-up years: 305 cases Sucrose 84.3 versus 24.10 (0. smoking 69 years: 408 Glycemic index 64 versus 55 units/day 0.26 1.1093/annonc/mds076 |  Added sugars ≥6.3 3980 men and Validated FFQ.02–1.49 (0. race/ethnicity.95–1.23 (0.44 versus ≤83. family 71 years: 601/ history of any 348 cases cancer. Glycemic load ≥82. Available 312 versus 221 g/day 0. units/day alcohol. fruit. cigarettes Finland [25] Beta-Carotene 16.08 (0.58–1.94) (women) units/day Meinhold et al. carbohydrate DM.27) BMI. vegetables. Netherlands 1986–1999.40) energy.55) Age.81–1.52) smoking.67 (0. 2008. 162 150 men and Validated FFQ. George et al. total Glycemic index. age 45– 180 food items g/1000 kcal/day smoking status.03 (0.43 1.02 versus ≤ by guest on November 20.7 1.2 years 183–535 124 food items men units/day education.56 versus ≤50. BMI. USA NIH-AARP Diet 1995/1996–2003.7 versus < 46.04 (0. 13. smoking.93) Age. age 50– status. BMI g/1000 kcal/day doi:10. 10 | October 2012 [26] and Health 7. Fructose ≥15.00 (0. USA Multiethnic 1993/1996–2002.3 1.08) activity. 262 642 men and Validated FFQ. total Prevention energy.7 1.5 versus < 3.91 0..1 years men. hypertension.80–1.3 versus < 63.75-1.6 versus < 40. fiber Nothlings et al.92–1. women. family Sucrose ≥22. 2009. Alpha-Tocopherol 1985/1988–2004.28 (0.77–1.19 (0. 2007.87 (0. ≥56.46–0.4 versus < 7..98) smoking.2 g/ 1. marital Study follow-up women.85–1.31 versus ≤66.73) meat.59–1.47–0. Glycemic load 156 versus 88 units/day 0. ≥57.65) history of g/1000 kcal/day pancreatic cancer.52) Age. physical Glycemic load ≥164. red g/1000 kcal/day and processed Total sugar ≥62.85 (0.68 (0. alcohol.3 1. up 75 years: 434 Carbohydrates ≥58. 27 035 smoking Validated FFQ. 2009.35 (1.26–0. age 50–69 276 food items carbohydrates per day. energy The Netherlands [18] Cohort Study years follow-up women.04 (0. Glycemic index. BMI. menopausal women units/day hormone therapy Glycemic load ≥135..46) pack-yrs of cases g/1000 kcal/day smoking.91–1.69–1. DM Study Heinen et al. 2016 .20 0.oxfordjournals.42–1.19) per day.03 (0.44) 1000 kcal/day Continued reviews Downloaded from http://annonc.. years of Total 256 versus 155 g/day 1.71–1.81–1.39) intake.29) status.65 (0. age 55– 150 items Per 50 g/day 1. cigarettes cases Per 5 units 0. race-ethnicity. Annals of Oncology Volume 23 | No. sex.

diabetes mellitus..74–1. 2005. smoking status. Alpha-Tocopherol 1985/1988–1997. age.36) women Johnson et al. [14] Study years follow-up age 34–59 food items Glycemic index 81 versus 65 1.30 (0. 27 111male Validated FFQ. relative risk.66) group Sucrose >34 versus < 17 g/day 0.17) cholecystectomy..59–1. BMI.80 (0.96 versus ≤68.98 0. Fructose 45 versus 11 g/day 1.17) Fructose >25 versus < 13 g/day 1.34 (0.61 0. Downloaded from http://annonc. Canada Canadian 1980/1985–2000.56–1. DM.96) pancreatic cancer. 86 Glycemic index >92 versus < 63 units/ 1.73–1.41 energy intake. carbohydrate randomization Total sugar >96 versus < 64 g/day 0.13) Stolzenberg-Solomon 2002.50–1.14) women Fructose.89 (0. DM.45) gain.83 versus ≤69.83–1.75) pack-years years: 66 cases BMI.99 (0. physical activity Harnack et al.08 (0. Carbohydrate >238 versus ≤178 g/day 1.2 years smokers. USA Nurses’ Health 1980–1998.80 (0. BMI.82–2.37–1.5 years 112 cases food items day smoking.53–1. smoking.American Association of Retired Persons. food frequency questionnaire.58) Age.45–1. [23] Health Study years follow-up age 55–69 126 food items Sucrose >47 versus ≤30 g/day 0.97) pack-years of years: 180 cases Carbohydrates 202 versus 110 g/day 1.oxfordjournals.62 (0.20) Age. age 50– food items men units/day gallstones.22 (0. FFQ. >169.7 0..81–2.69–1. Carbohydrate >330.67–2. 49 613 women: Validated FFQ.28 (0. smoking. Screening Study follow-up Glycemic load >169 versus < 125 0.. height.15 versus ≤129.2 versus ≤260.03) Energy.94 (0.96–2. 68 Glycemic load.56–1. parity.. NIH-AARP.18 (0. CI. [15] National Breast 16. SFA.37 versus ≤95. Cohort cases units/day family history of Carbohydrate >218.87 (0. Study 2 9 years follow. 2016 .53 (0. Author. gender. Validated FFQ. Dietary Exposure Quantity RR (95% CI) Adjustment for age. years of Volume 23 | No.57 (0. race.11 (0. alcohol. 33 551 women. 2002. number of assessment confounders cases Patel et al. 124 907 men and Validated FFQ. sex. USA Iowa Women’s 1986–2002. saturated fatty acids.45) Age.90 (0.56–1. Nutrition up 74 years: 401 Glycemic index >81.95–2. USA [17] Cancer Prevention 1992/1997–2001..31–1.65– by guest on November 20. Validated FFQ. BMI. Glycemic index >89 versus < 82 units/ 1.56 1. women.88 versus ≤119. follow-up years: 181 cases Glycemic load >188 versus < 151 0. confidence interval. body mass index. intake g/day location of weight Glycemic load.45) intake g/day Sucrose. 61 Glycemic load 167 versus 80 g/day 1.35–1. sedentary women units/day behavior Glycemic index >79.62–1. study Total >236 versus < 152 g/day 0. 2007.00 (0. men and Quintile 5 versus 1 1. 8 33 976 women.20) total energy intake.10 (0.34) multivitamin use Silvera et al.65) Age. 2005. >132.71–1.84 (0.43 (0. 10 | October 2012 Finland [24] Beta-Carotene 10.64 (0.73–1.02 1. 1997. Continued reviews  | Aune et al.74) units/day Carbohydrate >177.64) Age. USA Iowa Women’s 1986–1994. Validated FFQ. 18 88 802 women. year. men and Quintile 5 versus 1 0. age 276 food items g/day smoking Cancer follow-up 50–69 years: Prevention 163 cases Study Michaud et al. National Institutes of Health .26) center. Table 1.93 versus ≤162. RR.13 0.42 1.57) calorie intake.09) smoking.56–3.16 (0. Annals of Oncology Sucrose 55 versus 17 g/day 1. country Study name Follow-up period Study size. pack- [16] Health Study 16 years age 55–69 126 food items day years. DM.63 (0.

glycemic load. available at available at Annals of Oncology online). The summary RR for total of 3420 cases among 1 194 043 participants.17.s test. Pnonlinearity = 1.16) when excluding the National Study was excluded to 1. There was no evidence for a evidence for a nonlinear association between GI and pancreatic nonlinear association between GL and pancreatic cancer risk.12. P = 0.00 (supplementary Figure S3a. dose-response analysis dose–response analysis Nine cohort studies [14–22] were included in the dose– Eight cohort studies [14–21] were included in the dose– response analysis. I 2 = 10%. The summary RR per 50 units/day was 1.Annals of Oncology reviews glycemic index glycemic load high versus low analysis high versus low analysis Eight cohort studies [14–21] were included in the high versus Nine cohort studies [14–22] were included in the analysis of low analysis of GI and pancreatic cancer risk and included high versus low GL and pancreatic cancer risk and included a 2986 cases among 1 031 893 participants. Glycemic index.American Association of Retired Persons Cancer Prevention Study 2 Nutrition Cohort was excluded.60.01 (95% CI: 0.03 response analysis. available at available at Annals of Oncology online).94–1. Pheterogeneity = 0. Figure 1. summary RR was 1.1093/annonc/mds076 |  .68.02 (95% CI: 0. Annals of Oncology online).s of small study effects with Eggerapos. There was no indication Downloaded from http://annonc.12) when excluding the Nurses’ Health Study 1.15.04 [95% confidence interval (CI): 0. 2016 There was no indication of small study effects with Eggerapos..91– by guest on November 20.35) (Figure 1b).88–1.s test. or with test. Pnonlinearity = 0.26.oxfordjournals. total carbohydrates and sucrose intake and pancreatic cancer. I 2 = 19%.91– (95% CI: 0. The all studies was 1.92] (supplementary Figure S2a. Volume 23 | No. Pheterogeneity = 0. P = 0.05 (95% CI: 0.54 or with Beggapos.97) (Figure 1a) In a sensitivity analysis. I 2 = 0%.51 (supplementary Figure S3b. dose–response analysis.93–1. Annals of Oncology online).11) when the Canadian National Breast Cancer Screening to 1. P = 0.95–1.93–1.s test. I 2 = 0%.14.01 (95% CI: 0.27) (supplementary Figure S2b.93–1.01 [14–21]. cancer risk. (95% CI: 0. There was no Beggapos. the summary RR ranged from 1.17) when the Institutes of Health . 10 | October 2012 doi:10. P = 0. The summary RR ranged from 1.05 (95% CI: 0. Pheterogeneity = 0. The summary RR per 10 units/day was 1. Pheterogeneity = 0. (NIH-AARP) Diet and Health Study.

12–1. The summary RR per 100 g/day and pancreatic cancer.37. Pheterogeneity = 0.92 (95% CI: Annals of Oncology total carbohydrates The summary RR for a 25 g/day increment was 1. Beta-Carotene Cancer with and without adjustment for these factors.90–1. response analysis of fructose intake and pancreatic cancer risk.97–1. 19–22]. to our knowledge.14) (Figure 1c). The summary RR ranged from 0. dose–response analysis 19–22].14 (95% CI: 0.23. by guest on November 20. 15. There was no evidence of a nonlinear and S2. 17–20. 19–22].93– high versus low analysis of fructose intake and pancreatic 1. Pheterogeneity = 0. total carbohydrates or The summary RR was 1.46. Cancer Screening Trial study was excluded to 1.62. sucrose and fructose [14.42) when excluding the Women’s Health Initiative.004. 20.22.05 (95% CI: 0. 19. 20]. Pheterogeneity = 0. I 2 = 37%. available at Annals of Oncology online). There was a Annals of Oncology online).10 (95% CI: however. available at Annals of Oncology online). 15. 19.25. There was no evidence of fructose analysis (Table 2) nor in the analysis of total small study effects with Eggerapos.22.32 (supplementary and 0. When excluding one study [20] from the analysis. available at discussion Annals of Oncology online). the high versus low analysis summary RR was 1. 17–20.s test. The Nine cohort studies [14.02 (95% CI: 0.89–1.75– other carbohydrates 1. 17. 15. available at further sensitivity analyses using the same dataset to clarify if Annals of Oncology online). 1. Volume 23 | No. 22–24] were included in evidence for a nonlinear association between fructose intake the dose–response analysis. or Beggapos. I 2 = 35%.21 (95% cancer and included 2831 cases among 1 156 512 participants. I 2 = 25%. 15. Pheterogeneity = 0. 21. 1.36) when the high versus low analysis of total carbohydrate intake and excluding the NIH-AARP Diet and Health study to 1.13) when excluding the NIH-AARP Diet and Health Study Few studies investigated the association between intake of other to 1. However. but there was no association in the dose–response analysis.05–1. glucose.40. GI.65–1.s test.s test.12–1. I 2 = 0%. 10 | October 2012 . When the analyses were restricted to the studies that were common for the analyses of total fructose carbohydrates.00 (Figure 2b). = 0. 17. We found no statistically significant association between intake dose–response analysis of total carbohydrates. Pnonlinearity = 1.92–1. GI or GL and pancreatic cancer Six cohort studies [14. There was no evidence CI: 0.85–1. I 2 = 38%.47. 2016 = 0. high versus low analysis Nine cohort studies [14. P available at Annals of Oncology online). 21]. n = 3) for total sugar [15. neither in the Prevention Study was excluded. 404 participants. red and processed meat intake [19. this is the first meta-analysis to report an  | Aune et al. 1. I 2 = 82%. available at and S2. or with Beggapos.82–1. Pheterogeneity = 0.26 (95% CI: 1. 1. I 2 = 0%. Pheterogeneity = 0.81–1. P Pheterogeneity = 0.97 (95% CI: 0.42. Pheterogeneity = 0.04) 20]. was no evidence of small study effects with Eggerapos. 15. was 0. Pheterogeneity = 0. Lung. or sucrose galactose. P = 0. There high versus low intake was 1. 25] were included in the intake [14. Because not all association between sucrose and pancreatic cancer risk. association between intake of GI.14 (supplementary Figure S3d. I 2 = 0%.19. Pheterogeneity = 0. sucrose and pancreatic cancer risk (supplementary Tables S1 Pheterogeneity = 0.00 (95% CI: 0. In meta-regression analyses. The summary RR was 1. 22–24] were included in summary RR ranged from 1. n = 2) Figure S3c.s test showed P = 0.15.43) (Figure 2a). 25] were included in Subgroup. GL or sucrose (supplementary Tables S1 s test. The summary RR was 1. 22].14) (supplementary Figure S2c. The summary RR ranged from 1.96–1.86– There was no evidence of small study effects with Eggerapos.17) for sucrose and 1.71. P = 0. 20] or physical activity [14. studies reported on all types of carbohydrates. available at Annals of Oncology online). test.06. there was.18 (95% CI: 1.78–1. we conducted Pnonlinearity = 0.s 1. Seven cohort studies [14.08–1. 15. 25] pancreatic cancer risk.02 (95% CI: although the number of studies was low in some of these 0.04 (95% CI: 0. I 2 = 35%. 19–23.oxfordjournals. although some evidence with Beggapos.21) when excluding the Alpha- carbohydrates and pancreatic cancer risk. 19. 22]. 22] and energy Eight cohort studies [14.98 (95% CI: 0.99–1. significant association for fructose intake in the subgroups of studies that adjusted for smoking [14.00 (95% CI: 0. no evidence of heterogeneity between the subgroups 0.08 (95% CI: 0. Pnonlinearity = 0. P = 0.71.16) when the Prostate. The summary RR per 25 g/day was subgroups of studies that adjusted for intake of alcohol [15. for starch (results not shown) [19. n = 3) for available for a nonlinear association between carbohydrates and carbohydrates (total carbohydrates minus fiber) [19. 15. (Figure 1d). GL.26 (95% pancreatic cancer risk and included 3202 cases among 1 112 CI: 1.02) (supplementary Figure S2d.24) (supplementary Figure S4. 15.s test. P = 0.16.24) when the Alpha-Tocopherol.42). BMI [14. meta-regression and sensitivity analyses the high versus low analysis of sucrose intake and pancreatic In subgroup analyses. The summary RR for Tocopherol and Beta-Carotene Cancer Prevention Study. Beggapos.16 (95% CI: 0.01–1. 19–22] were included in the dose– risk in categorical and dose–response meta-analyses. carbohydrates.35. but the summary RR dose–response analysis remained similar. 19–22] were included in the Pheterogeneity = 0. I 2 = 53%. 15. sucrose. CI: 1.32) for fructose.22 (95% CI: high versus low analysis 1.64.29. the results were consistent in showing no cancer and included 3202 cases among 1 217 523 participants.17.04 (95% Downloaded from http://annonc. There was no Nine cohort studies [14. Colorectal and Ovarian subgroups (Table 2). there was a ‘study effect’. diabetes status [14. maltose. I 2 = 56%. 19–23.37. I 2 = 16%. There were not enough studies to conduct analyses of lactose.17) for total carbohydrates.

. measurement errors. however. 20]. Fructose and pancreatic cancer. BMI [14. there was no association in the few studies that most likely result in bias toward the null and. Because of the few studies in some of these carbohydrate intake and pancreatic cancer risk. the results were cancer risk. of small study effects in this analysis and in the one analysis carbohydrates. none of the studies smoking [14. 19–22]. 15. not change the results. 20]. GI or GL may be particularly challenging because these There was no evidence of heterogeneity between these measures are based on their postprandial blood glucose subgroups with and without adjustment for these potentially response and are not concentration values of nutrients in the Volume 23 | No. thus.oxfordjournals. Assessment of subgroup analyses interpretation of these analyses is difficult. 19–22]. 2016 Figure 2. Intake of diets high in fructose. 10 | October 2012 doi:10.1093/annonc/mds076 |  . 19–22]. however. GI and GL may be associated with other where there was some indication of small study effects this was behaviors including physical activity. For the other exposures. 22] and energy intake [14. 19. 15. association between intake of fructose and increased pancreatic confounding factors. however. diabetes [14. similar across subgroups and there was no evidence of Our meta-analysis may have several limitations which must heterogeneity between the subgroups. The Measurement errors in the assessment of dietary intake are results for fructose intake persisted in studies that adjusted for known to bias effect estimates. adjusted for alcohol [ by guest on November 20. We found little evidence be taken into consideration. dose–response analysis. 20] and physical underestimate the association between fructose and activity [14. 15. which possibly could confound associations we observed. overweight and obesity. caused by only one study [20] and exclusion of that study did smoking and intake of alcohol and red and processed meat. intake of red included in this meta-analysis made any corrections for and processed meat [19.Annals of Oncology reviews Downloaded from http://annonc. Any measurement errors would.

a P for heterogeneity within each subgroup. ‘n’.22 (1.37) 0 0.44) 0 0.98–1.98 Geographic location Europe 0 NC America 6 1.22 (1.30 ( Annals of Oncology Table 2. studies using similar uric acid [42]. Because we transketolase-like protein 1 reduces cancer cell proliferation based our analyses on prospective studies.44) 0 0.6 by guest on November 20. In addition.00 (0. vegetables Yes 0 NC No 6 1. which may not have been specifically selected and nucleic acids is further illustrated by increased production of validated for dietary GI or GL.08–1.08–1.92–1.77 No 3 1.36) 9.87–1.09–1. both the contribution of fructose to nucleic acid synthesis through of which are established risk factors for pancreatic cancer.6 0.37) 0 0. Volume 23 | No.oxfordjournals.87–1.26 (1. Synthesis of nucleic acids and pancreatic cancer risk adjusted for BMI.93 Red.05 (0.89 ≥10 years follow-up 2 1. 2016 Alcohol Yes 3 1. foods consumed.36) 9. dose–response analysis Fructose n RR (95% CI) I2 (%) Ph a Ph b All studies 6 1.11–1.03–1. obscured due to measurement errors. experimental studies have shown that chronic fructose feeding The specific mechanism that may explain an association in animals leads to insulin resistance and obesity [27].22 (1.08 0.64) 67.37) 0 0.28 No 4 1. processed meat Yes 2 1.11–1.11–1. all the studies included in the analysis of fructose and greater than glucose [42].22 (1. although no weak association with pancreatic cancer may have been association was observed in women [47].43 NC No 0 RR.37) 0 0. confidence interval.58) 57.10 0.08–1.74–1.00 (0.9 0. Several between fructose intake and pancreatic cancer remains [28. denotes the number of studies. 44] while activation of transketolase stimulates tumor usual GI or GL values based on a limited number of food growth [45].09 (0.17 (0. we have effectively  | Aune et al.9 0.61) Cases ≥500 1 1. not calculable because no studies were present in one of the subgroups.93 Body mass index Yes 6 1.28 (1.29 Cases 300 to < 499 1 1. the pentose phosphate pathway (catalyzed by transketolase) is however.43 Number of cases Cases < 300 4 1.37) 0 0.35 0.37) 0 0.25 (0. but the metabolism of fructose differs from other studies have reported positive associations between fructose carbohydrates such as glucose. CI.22 (1. Most dietary questionnaires have estimated [43.85 0.89 Smoking Yes 6 1.08 (0.48) 0 0. particular.31 No 4 1.73–1. GI or GL and risk of type 2 diabetes [40] and cardiovascular Interestingly.46) 0 0.08 0. Subgroup analyses of fructose intake and pancreatic cancer. 10 | October 2012 . Recently.18 0. NC.64) 67. it has been shown that intake and type 2 diabetes and obesity in humans as well. and questionnaires have been able to detect associations between increased risk of gout among high fructose consumers [46].69) 0 0.08–1.09 (0.5 0.22 (1.60–1.26 (0.5 0. It has been shown that suppression of Our meta-analysis also has several strengths.2 0. However.43 NC No 0 Diabetes Yes 2 1. but not all [51] epidemiological and experimental speculative.08–1.43 NC No 0 Physical activity Yes 2 1.20 Duration of follow-up < 10 years follow-up 4 1.43 Sex Men 0 NC Women 3 1. one study reported an elevated pancreatic cancer disease [41]. 48–50].98–1.43 Energy intake Yes 6 1.49) 38. cancer cells.40) 38.26 (1. b P for heterogeneity between subgroups with meta-regression analysis.35 Fruits.60–1. a by-product of purine metabolism. suggesting an nucleotides is necessary for proliferating tissues and in association independent of BMI. relative risk.54) Adjustment for confounding factors Downloaded from http://annonc. although we cannot exclude the possibility that a risk among men with high serum uric acid levels.23 (1. The contribution of fructose to the generation of items.08–1.31 No 4 1.

DCG naturally in fruits and vegetables. although the data are disclosure not completely consistent [22. It is possible study selection.dietandcancerreport. 92: 2076–2083. sources of fructose and pancreatic cancer risk are warranted 3. Zhang J. of which the World Cancer Research Fund (2007/SP01) as part of the largest part came from sugar-sweetened beverages (30%). Given the few established dietary risk factors and the risk of pancreatic cancerArch Intern Med 1996. Food. summary RR of 1.63) for heavy soft drink consumers among five cohort studies [57]. DC: AICR 2007. Fructose has also largely replaced sucrose as a approval of the manuscript. populations. Washington.06 (95% CI: 1. nutrition. data extraction. Hu FB. GI or GL. de Vries E. which reached significance on a gLOBOCAN 2008Int J Cancer 2010. carbohydrates may increase pancreatic cancer risk. Shin HR. Further studies of fructose intake and specific sites since the 1990sEur J Cancer 2008. World Cancer Research Fund/American Institute for Cancer Research. 23: 843–852. We thank the systematic literature review team at the 9. and ∼3000 cases. 156: 2255–2260. They may not represent the views of 10. In addition. All authors had full access to all of the data in the World Cancer Research Fund/American Institute for Cancer the study. collection. our meta. statistical analyses. Continuous Update Project (http://www.oxfordjournals. for Cancer Research and may differ from those in future Our meta-analysis is consistent with two previous meta. These estimates are of similar size as our results for Europe: a combined approach of incidence. However. physical analyses that found no association between GI and GL and activity and cancer risk. we had managing the database for the Continuous Update Project. statistical analyses and wrote the first draft of that the association may reflect certain foods or drinks with a the original manuscript and takes responsibility for the high fructose content. The third National Health and Nutrition Examination Survey reported that over 10% of funding Americanapos. Iodice S. van Dam RM. TN statistical power to detect moderate associations. Berkel HJ. Role of the funding source: The sponsor of this Research report from 2007. 56. Stampfer MJ et al. although not in Europe. A meta-analysis found a The authors have declared no conflict of interest. RV was responsible for developing and depending on the exposure. Some studies have reported elevated risk of pancreatic cancer with high intake of sugar-sweetened beverages [53–55] which can be high in high-fructose corn syrup. Jeon CY. while data on vegetable intake were study had no role in the decisions about the design and Downloaded from http://annonc.Annals of Oncology reviews avoided recall bias and reduced the possibility of selection bias. our results indicate that intake of fructose. Physical Activity and the Prevention of Cancer: a Global Perspective. Zhao Z. Bray F et al. but pancreatic cancer: a review and meta-analysisLangenbecks Arch Surg 2008. Huxley R. 15: and it is not known whether these findings apply to other 500–508. Chan DS et al.s daily calories come from fructose. A prospective study of cigarette smoking pancreatic cancer. sucrose. December 2005. 2016 even more limited or conflicting [8]. survival and mortality for 17 cancer fructose intake. Animal fat consumption and pancreatic cancer since all the studies reporting on fructose intake were American incidence: evidence of interaction with cigarette smokingAnn Epidemiol 2005. Soerjomataram I et al. 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Fuchs CS.2 million participants. abdominal fatness and drinks. Maisonneuve P. DA did the updated literature search. for pancreatic cancer.12) per 175 g/day 2.1093/annonc/mds076 |  . 8. not total carbohydrates. Ferlay J. updates of the evidence related to food. prospective conduct of the study. Lokken RP. Berrington de Gonzalez A. Estimates of worldwide burden of cancer in 2008: = 1. Aune D. DSMC and pancreatic cancer risk based on five to six cohort studies the systematic literature review team at the University of Leeds [31. further studies of fructose intake and 6. conducted the search. Greenwood DC. Woodward M. clarify whether the results reflect the effect of specific foods or 7. 10 | October 2012 doi:10. 44: 1345–1389. All authors contributed to the revision of although the evidence was considered only limited suggestive in the manuscript. 4. 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