Processed Meat Intake and Bladder Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cohort

This article is featured in Highlights of This Issue, p. 1947

Bladder cancer ranks as the ninth most frequently diagnosed cancer worldwide with around 430,000 new cases diagnosed annually and ranks 13th in terms of deaths' ranks (1). Incidence rate of bladder cancer varies greatly worldwide, with the highest incidence rate observed in men in Southern and Western Europe (1), which gives some indication that some of cancers could be prevented by modifying specific harmful lifestyle or environmental factors. The main risk factors for bladder cancer are cigarette smoking and exposure to certain chemicals in the working and general environments (2). Higher consumption of dairy products (3) and cruciferous vegetable (4), as well as higher physical activity levels (5), may be associated with a reduced risk of bladder cancer.

The association between processed meat intake and the risk of bladder cancer also has been evaluated by several observational studies with inconsistent results (6–10). According to a recent systematic review published in 2018 (2), processed meat and animal protein was considered as a suspected risk factor for bladder cancer. The dose-response meta-analysis performed by Crippa and colleagues (11) found a positive but not significant association between intake of processed meat and bladder cancer risk in a subgroup of five cohort studies with a HR of 1.10 [95% confidence interval (CI), 0.95–1.27] for 50 g per day increment in processed meat consumption.

In this study, we aimed to evaluate the association of processed meat intake with the risk of bladder cancer using the data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort.

The PLCO study is a large population-based cancer screening trial aimed to determine whether selected screening methods are effective in reducing mortality from prostate, lung, colorectal, and ovarian cancer (12). Briefly, individuals were enrolled at 10 screening centers across the United States from 1993 to 2001. A total of 154,897 eligible participants ages 55–74 years were randomly assigned to the intervention arm (n = 77,444) and the control arm (n = 77,453). Subjects included in this study met all the following criteria: (i) had completed the baseline questionnaire; (ii) had completed the diet history questionnaire (DHQ), which was administered to participants starting in 1998; (iii) did not have cancer before completion of DHQ; and (iv) had follow-up time, participants who completed the baseline questionnaire but without follow-up data were excluded. Finally, a total of 101,721 participants were eligible and were followed until December 31, 2009. The PLCO was approved by the Institutional Review Boards of the U.S. NCI as well as the 10 screening centers, and written informed consent was obtained from all participants. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

The baseline questionnaire included self-reported information on age, sex, ethnicity, education, marital status, smoking status, family history of cancer, medical history, and other factors. Dietary data were collected using the DHQ, which included the portion size and frequency of intake of 124 food items and supplement use during the past year.

The amount of meat intake was calculated using the detailed analysis file output by DietCalc (available at: http://riskfactor.cancer.gov/DHQ/dietcalc/index.html), which lists the daily gram amounts for each food and question, as estimated by DietCalc from the coded responses to frequency of consumption and serving size question. DietCalc determines the gram amounts by sex and serving size (small, medium, large, or overall) using a nutrient database based on national dietary data [USDA's 1994–96 Continuing Survey of Food Intakes by Individuals (CSFII), available from the USDA Food Surveys Research Group, or the Nutrition Data Systems for Research (NDS-R) from the University of Minnesota]. The products included for various meat group definitions are listed in Supplementary Table S1.

Study participants were mailed a questionnaire annually to ascertain cancer cases. Participants were asked whether they were diagnosed with any cancer, the type of cancer, and the date of diagnosis in the previous year. Cancer diagnoses were ascertained through medical record abstraction. Vital status was obtained by the administration of the annual study update questionnaires, reports from relatives, friends, or physicians, and National Death Index searches.

Cox proportional hazards regression was used to estimate hazard ratios and 95% CIs. Follow-up started at cohort entry and ended at the earliest of the following events: diagnosis of bladder cancer, death, or study closure (December 31, 2009). Models were adjusted for potential confounders including randomization arm (intervention vs. control), age (categorical), sex (male vs. female), race (non-Hispanic White vs. Other), body mass index (BMI) at the time of enrollment (<25 kg/m² vs. ≥25 kg/m²), education (≤high school vs. ≥some college), marital status (married vs. not married), smoking status (never vs. former ≤ 15 years since quit vs. former > 15 years since quit vs. former year since quit unknown vs. current smoker ≤ 1 pack per day vs. current smoker >1 pack per day vs. current smoker intensity unknown), alcohol drinking status (never vs. former vs. current), total energy intake (continuous), and family history of any cancer (yes vs. no). Missing values for covariates were treated as dummy variables in the models. To test interactions, we performed likelihood-ratio tests, which compared models with and without the interaction term. The meat intake was firstly examined as quintiles. We also examined the association between intake of processed red meat and bladder cancer risk using restricted cubic spline models with three knots (i.e., 10th, 50th, and 90th percentiles; ref. 13). All statistical analyses were performed using the software STATA version 15 (Stata Corp). All tests were two-sided.

Among the 101,721 individuals included in our study, the median energy intake was 1,608 kcal/day. After a median of 12.5 years of follow-up, 776 new cases of bladder cancer were identified. The incidence rate of bladder cancer was 6.65 (95% CI, 6.20–7.13) per 10,000 person-years. Table 1 shows the main characteristics of 101,721 subjects in the PLCO Cancer Screening Trial by processed red meat intake. Participants who consumed higher amounts of processed red meat were heavier, less educated, more likely to be male, have a history of smoking, and have a higher total energy intake.

In the multivariate analysis model, no significant association with bladder cancer risk was observed for intake of red meat (HR Q5 vs. Q1 = 1.04; 95% CI, 0.79–1.38; P_trend = 0.699) or white meat (HR Q5 vs. Q1 = 0.98; 95% CI, 0.77–1.25; P_trend = 0.377) when comparing the highest versus lowest intake quintile after adjusting for potential confounders (Table 2).

When analyzed for processed meat intake, a significant increased risk of bladder cancer was noted in the multi-adjusted model for intake of processed red meat (HR Q5 vs. Q1 = 1.47; 95% CI, 1.12–1.93; P_trend = 0.008). In contrast, there was only a suggestive but not significant association between intake of total processed meat and bladder cancer risk after multivariable adjustment (HR Q5 vs. Q1 = 1.16; 95% CI, 0.89–1.50; P_trend = 0.073). Given that confounding by smoking was a key issue, we further performed analyses among nonsmokers at baseline (never plus former). As a result, intake of processed red meat was significantly associated with an increased risk of bladder cancer among nonsmokers (HR Q5 vs. Q1 = 1.49; 95% CI, 1.10–2.02; P_trend = 0.021; Supplementary Table S2).

No significant interactions were observed with sex, BMI, and smoking status in all analyses (all P > 0.05). A spline regression plot of bladder cancer risk in relation to intake of processed red meat is shown in Fig. 1. There was no statistical evidence for nonlinearity (P_nonlinearity > 0.05).

In this large prospective study, higher intake of processed red meat was significantly related to a higher bladder cancer risk after adjusting for confounders. In contrast, there was only a suggestive but not significant association between intake of total processed meat and bladder cancer risk.

Processed meat mainly referred to processed red meat, but may contain small amounts of processed white meat (poultry and fish) also. Enhanced intake of white meat or poultry appears to be favorable diet indicators and has been found to be negatively associated with some types of cancers (14, 15). The involvement of white meat into processed meat may attenuate the link between total processed meat and bladder cancer risk, which could partly explain the suggestive but not significant association observed in this study, as well as in previous cohort studies (7, 16).

The biological mechanisms underlying the association between intake of processed red meat and bladder cancer risk remains unclear. The most established mechanism involves the formation of endogenous nitrosamines from nitrites that are particularly abundant in processed meats (17). Experimental studies have confirmed that some nitrosamine metabolites induced bladder tumors in animal models (18). In addition, tobacco smoke, a well-established risk factor for bladder cancer, is a main source of exogenous exposure to nitrosamines. A recent large cohort of British rubber workers with 49 years follow-up revealed that N-nitrosamines exposure was also associated with mortality from bladder cancer (19). Finally, heterocyclic amines and polycyclic aromatic hydrocarbons, which are formed by high temperature cooking, may also mediate the association between consumption of processed red meat and bladder cancer risk (20, 21).

The findings of this study suggested that there were null associations between red meat or white meat intake and bladder cancer risk. Larsson and colleagues (16) also observed no association between the intake of red meat or white meat and the risk of bladder cancer in a Swedish prospective cohort. Holick and colleagues (22) reported that fish intake was not likely to be associated with the risk of bladder cancer in the Health Professionals Follow-up Study and the Nurses' Health Study. In contrast, Lin and colleagues (20) found that high red meat intake was associated with an increased risk of bladder cancer in a large case–control study comprising of 884 bladder cancer cases and 878 healthy controls.

Strengths of the large-scale PLCO include the prospective design and high completeness of follow-up (23), which makes information and selection bias unlikely. The availability of smoking status data and many other potential confounders made the adjustment possible. The limitations of PCLO include no updated information on meat intake during follow-up, misclassification with DHQ, and possible residual confounding or confounding by unmeasured factors.

In conclusion, this large prospective study suggests that consumption of processed red meat is related to an increased risk of bladder cancer.

No potential conflicts of interest were disclosed.

The statements contained herein are solely those of the author and do not represent or imply concurrence or endorsement by NCI.

The author thanks the NCI for access to NCI's data collected by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. This study was supported by a grant from the National Natural Science Foundation of China (81702500).

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