Abstract
Background: Folate and other one-carbon metabolism nutrients may influence prostate cancer pathogenesis. Prior studies of these nutrients in relation to prostate cancer incidence have been inconclusive, and none have explored prostate cancer survival.
Objective: The objective was to assess whether dietary intakes of folate, riboflavin, vitamin B-6, vitamin B-12, and methionine measured around the time of prostate cancer diagnosis are associated with prostate cancer survival.
Design: This population-based prospective study comprised 525 men from Örebro, Sweden, who received a diagnosis of incident prostate cancer between 1989 and 1994 and completed a self-administered food-frequency questionnaire. Record linkages to the Swedish Death Registry enabled all cases to be followed for up to 20 y after diagnosis, and the cause of death was assigned via medical record review. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% CIs. During a median of 6.4 y of follow-up, 218 men (42%) died of prostate cancer and 257 (49%) of other causes.
Results: A comparison of the highest with the lowest quartile showed that vitamin B-6 intake was inversely associated with prostate cancer–specific death (HR: 0.71; 95% CI: 0.46, 1.10; P for trend = 0.08), especially in men with a diagnosis of localized-stage disease (HR; 0.05; 95% CI: 0.01, 0.26; P for trend = 0.0003). However, vitamin B-6 intake was not associated with improved prostate cancer survival among advanced-stage cases (HR: 1.04; 95% CI: 0.64, 1.72; P for trend = 0.87). Folate, riboflavin, vitamin B-12, and methionine intakes were not associated with prostate cancer survival.
Conclusion: A high vitamin B-6 intake may improve prostate cancer survival among men with a diagnosis of localized-stage disease.
INTRODUCTION
Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer deaths in European men, accounting for >87,000 deaths in 2006 (1). In Sweden, the incidence:mortality ratio is ≈3:1, which indicates that a significant proportion of men with prostate cancer live with the disease and eventually die of other causes (2). This proportion is even larger in populations in whom opportunistic screening by prostate-specific antigen (PSA) occurs; in the United States, the incidence:mortality ratio is >6:1 (3). However, it is largely unknown whether the prostate carcinogenic process can be altered by modifications in dietary or lifestyle habits (4, 5).
Dramatic differences in prostate cancer mortality rates globally and in changes in disease patterns associated with immigrant populations hint that nutrition could influence prostate cancer incidence (6, 7). Epidemiologic studies of diet and prostate cancer that have suggested stronger associations with advanced stage disease provide further support (8), although data on postdiagnostic diet and lifestyle as predictors of survival are limited (9–11).
Folate and related nutrients may influence prostate cancer initiation and progression through their role in the one-carbon metabolism pathway, which is necessary for DNA synthesis, repair, and methylation (12). Folate and methionine directly enter the pathway and act as a methyl donor for DNA synthesis and methylation, whereas riboflavin, vitamin B-6 (pyridoxine, pyridoxal, and pyridoxamine), and vitamin B-12 (cobalamin) serve as enzymatic cofactors (13). Aberrations in DNA methylation can lead to chromosomal instability and transcriptional gene silencing, and these epigenetic events have been observed throughout the natural history of prostate carcinogenesis (14, 15).
Studies examining the link between one-carbon metabolism–related nutrients and prostate cancer incidence are limited and largely inconclusive (16–28). To our knowledge, no studies have explored these nutrients in relation to prostate cancer survival. In the current population-based cohort study, we prospectively followed 525 prostate cancer cases to examine the association of dietary intake of folate, riboflavin, vitamin B-6, vitamin B-12, and methionine with prostate cancer survival. Because nutrient intakes may have a greater opportunity to intervene on survival among cases with organ-confined disease, we also evaluated the association between these nutrients and prostate cancer survival by localized- or advanced-stage disease status at diagnosis.
SUBJECTS AND METHODS
Study population
In this population-based study of men with incident prostate cancer, cases were recruited as part of a population-based case-control study that was published previously (29–31). The study base encompassed Örebro County, Sweden, with a 1990 population of ≈270,000 men and women (32). In this population, all men suspected of having prostate cancer were referred to 1 of 3 area hospitals (Örebro, Karlskoga, or Lindesberg) for diagnostic confirmation and treatment. The current study was approved by the ethical review board in Uppsala, Sweden.
Eligible cases were men aged <80 y, born in Sweden, and with a new diagnosis of prostate cancer at 1 of the 3 Örebro County hospitals from January 1989 to September 1991 or May 1992 to July 1994. Because private care is rare in Sweden, the series is essentially population-based. All cases were cytologically and/or histologically confirmed. Most of the cases were diagnosed as a result of prostate-related symptoms, because screening for prostate cancer was not performed in this area of Sweden at the time of the study. Tumor stage and grade were assigned according to the World Health Organization (WHO; 1980) and TNM (UICC; 1978) classifications, respectively (33, 34). Skeletal scintigraphy and radiography (if needed) were used to evaluate the presence of skeletal metastases. We categorized cases as having localized-stage disease if the tumor was confined to the prostate gland at the time of diagnosis (clinical stage T0–2, M0) or advanced disease if the tumor had extended through the prostatic capsule or had metastasized (clinical stages T3–4, M0 or T0–4, M1). Of the 525 cases (81% of all eligible cases) that completed the baseline questionnaire, 230 (44%) had localized-stage and 295 (56%) had advanced-stage disease.
Assessment of diet and other covariates
A self-administered, semiquantitative food-frequency questionnaire (FFQ) was used to collect information on diet in the previous year (30). The 68 items on the FFQ, which represented major foods in the Swedish diet, were used to calculate daily nonalcohol energy intake and specific nutrient values. The frequency of consumption of a food item was multiplied by the age-specific standard portion size (Swedish National Food Administration handbook on average weights of foods and dishes, 1988) and by the nutrient composition of the food item. To account for the correlation of nutrient intake with energy, folate, riboflavin, vitamin B-6, vitamin B-12, and methionine intakes were adjusted for nonalcohol energy intake by using the residuals method (35). On average, the men completed the questionnaire within 3 mo after diagnosis.
In the original case-control study, a validation study was performed by administering 1-wk diet records, 4 times over the span of 1 y, to 87 of the control subjects. Pearson correlation coefficients between energy-adjusted nutrients estimated from the FFQ and the diet records were moderate: r = 0.6 for folate, r = 0.7 for vitamin B-6, and r = 0.6 for vitamin B-12 intake (30). Estimated riboflavin and methionine intakes from the diet records were unavailable.
Information on family history of cancer, smoking habits, alcohol intake, and anthropometric measures were assessed via in-home interviews for the cases diagnosed in the first time period (January 1989 to September 1991) and via self-administered supplemental questions included in the FFQ mailing for those diagnosed in the second time period (May 1992 to July 1994). Information on primary treatment of prostate cancer was obtained through medical record review.
Ascertainment of outcome
All residents in Sweden have a national registration number that permits linkage across nationwide health registries. Deaths among the cases were identified through linkage to the Swedish Cause of Death Registry, with >99% coverage of the Swedish population. The cause of death was determined according to medical record review by a committee of study urologists (Ove Andrén, Swen-Olof Andersson, and Jan-Erik Johansson).
Statistical analysis
The 525 cases were followed from the date of diagnosis until the date of death from prostate cancer or censored on date of death from another cause or end of the follow-up period (1 February 2009). No cases were lost to follow-up. Cox proportional hazards regression was used to calculate multivariate hazard ratios (HRs) and 95% CIs. All models included stratification by age at diagnosis (41–64, 65–69, 70–74, and 75–79 y) and calendar year of diagnosis (1989–1991 and 1992–1994). Folate, riboflavin, vitamin B-6, vitamin B-12, and methionine intakes were categorized into quartiles based on the distribution among the cases and modeled as indicator variables, with the lowest quartile assigned as the referent group. Tests for trend were conducted by modeling the median value for each quartile as a continuous variable and were evaluated by using the Wald test.
The assumption of proportional hazards was tested separately for each nutrient (folate, riboflavin, vitamin B-6, vitamin B-12, and methionine) by adding an interaction term between nutrient intake (median value for each quartile) and follow-up time (continuous) to the model of the nutrient main effect (quartiles), with age at diagnosis and calendar year of diagnosis as stratification variables. The interaction terms were not statistically significant by the Wald test, thus satisfying the assumption.
The following covariates were considered potential confounders in the multivariate models: nonalcohol energy intake (continuous), clinical stage (T0–1, T2, T3, and T4/M1), tumor grade (well, moderately, or poorly differentiated), family history of prostate cancer in father or brother (yes or no), primary treatment (watchful waiting, hormones, prostatectomy, or other), height (continuous), body mass index (BMI; in kg/m2) at diagnosis (continuous), smoking status (cigarettes: never, former, current, or missing), and alcohol use (nondrinker, <55 g/wk, or ≥55 g/wk). The alcohol use cutoff of 55 g/wk was chosen because it was the median value among the drinkers. Four men missing information on height and BMI were assigned the mean values, because this number was too small to create a separate category for missing data.
All categorical covariates were modeled as indicator variables. To individually assess the linearity of energy intake, height, and BMI, we used likelihood ratio tests to compare the models with indicator variables of covariate categories (energy intake: <1725, 1725–2016, 2017–2430, and ≥2431 kcal/d; height: <170, 170–174, 175–179, and ≥180 cm; BMI: <20, 20–24, 25–29, and ≥30) to the models with a continuous variable of the median values for each category. Because the indicator variable and corresponding linear models were not significantly different, these 3 covariates were modeled as their original continuous values.
We examined whether the associations of nutrient intake with prostate cancer survival varied by clinical stage (localized-stage or advanced-stage disease), tumor grade (well differentiated or moderately/poorly differentiated), alcohol use (nondrinker, <55 g/wk, or ≥55 g/wk), and smoking status (never, former, or current) by constructing an interaction term between nutrient intake (median value for each quartile) and the stratification variable. We used a likelihood ratio test to evaluate the null hypothesis of no effect modification for the association between nutrient intake and prostate cancer–specific mortality by clinical stage, tumor grade, alcohol use, and smoking status. In a sensitivity analysis, we excluded cases that died <2 y after diagnosis and reanalyzed the association between nutrient intake and prostate cancer survival among localized- and advanced-stage cases.
Analyses were conducted by using SAS software (version 9.1; SAS Institute Inc, Cary, NC). All statistical tests were 2-sided, and P values <0.05 were considered to be statistically significant.
RESULTS
In our prospective study of 525 prostate cancer cases, the mean (± SD) age at diagnosis was 70.7 ± 5.9 y, with a median follow-up time of 6.4 y (range: 1 mo to 20 y). During 3986 person-years of follow-up, 218 (42%) men died of prostate cancer, and 257 (49%) died of other causes. Compared with men with localized-stage disease at diagnosis, those with advanced-stage cancers were more likely to die of prostate cancer, have shorter follow-up time, and be diagnosed with a less-differentiated tumor (Table 1). Mean intakes of folate, riboflavin, vitamin B-6, vitamin B-12, and methionine were comparable with those in other Swedish population-based cohort studies (36–39), and mean dietary intakes of the B vitamins exceeded the Recommended Dietary Allowance (RDA), except for folate (40).
TABLE 1.
Characteristics of 525 men with prostate cancer in Örebro County, Sweden, from 1989 to 19941
| All cases (n = 525) | Localized stage2 (n = 230) | Advanced stage3 (n = 295) | |
| Vital status (%) | |||
| Alive at end of follow-up | 9 (50) | 17 (38) | 4 (12) |
| Prostate cancer death | 42 (218) | 19 (44) | 59 (174) |
| Other cause of death | 49 (257) | 64 (148) | 37 (109) |
| Person-years of follow-up | 7.6 ± 5.54 (525) | 9.8 ± 5.6 (230) | 5.9 ± 4.7 (295) |
| Age at diagnosis (%) | |||
| <65 y | 16 (82) | 18 (41) | 14 (41) |
| 65–69 y | 21 (113) | 21 (48) | 22 (65) |
| 70–74 y | 33 (172) | 33 (76) | 32 (96) |
| ≥75 y | 30 (158) | 28 (65) | 32 (93) |
| Year of diagnosis (%) | |||
| 1989–1991 | 49 (256) | 53 (121) | 46 (135) |
| 1992–1994 | 51 (269) | 47 (109) | 54 (160) |
| Clinical stage (%) | |||
| T0 localized | 17 (87) | — | — |
| T0 diffuse | 8 (43) | — | — |
| T1 | 1 (4) | — | — |
| T2 | 18 (96) | — | — |
| T3 | 33 (72) | — | — |
| T4 or M1 | 23 (123) | — | — |
| Tumor grade (%) | |||
| Well differentiated | 52 (273) | 74 (171) | 35 (102) |
| Moderately differentiated | 37 (192) | 23 (52) | 47 (140) |
| Poorly differentiated | 11 (60) | 3 (7) | 18 (53) |
| Family history of prostate cancer, father or brother (%) | 12 (61) | 13 (31) | 10 (30) |
| Primary treatment (%) | — | — | — |
| Watchful waiting | 67 (350) | 80 (184) | 56 (166) |
| Hormone therapy | 24 (128) | 6 (13) | 39 (115) |
| Prostatectomy | 4 (22) | 9 (21) | <1 (1) |
| Other | 5 (25) | 5 (12) | 4 (13) |
| Height (cm) | 175 ± 6 (521) | 175 ± 6 (229) | 175 ± 6 (292) |
| BMI at diagnosis (kg/m2) | 25.9 ± 3.5 (521) | 26.3 ± 4.8 (229) | 25.7 ± 3.2 (292) |
| Smoking status, cigarettes (%) | |||
| Never smoker | 29 (154) | 26 (59) | 32 (95) |
| Former smoker | 38 (199) | 40 (92) | 36 (107) |
| Current smoker | 23 (118) | 25 (57) | 21 (61) |
| Missing | 10 (54) | 9 (22) | 11 (32) |
| Alcohol use (%) | |||
| Nondrinker | 48 (251) | 49 (113) | 47 (138) |
| 3 to <55 g/wk | 26 (138) | 28 (65) | 25 (73) |
| ≥55 g/wk | 26 (136) | 23 (52) | 28 (84) |
| Dietary intake | |||
| Nonalcohol energy (kcal/d) | 2101 ± 567 (525) | 2055 ± 523 (230) | 2137 ± 597 (295) |
| Folate (μg/d) | 244 ± 47 (525) | 243 ± 45 (230) | 244 ± 48 (295) |
| Riboflavin (mg/d) | 2.1 ± 0.4 (525) | 2.1 ± 0.4 (230) | 2.2 ± 0.4 (295) |
| Vitamin B-6 (mg/d) | 2.1 ± 0.3 (525) | 2.1 ± 0.3 (230) | 2.1 ± 0.3 (295) |
| Vitamin B-12 (μg/d) | 8.2 ± 3.6 (525) | 8.1 ± 3.7 (230) | 8.2 ± 3.4 (295) |
| Methionine (g/d) | 2.0 ± 0.3 (525) | 2.0 ± 0.3 (230) | 2.0 ± 0.3 (295) |
n in parentheses.
Stage T0–2, M0.
Stage T3–T4, M0, or T0–4, M1.
Mean ± SD (all such values).
Vitamin B-6 intake was marginally inversely associated with prostate cancer–specific mortality (HRQ4 vs Q1: 0.70; 95% CI: 0.46, 1.05; P for trend = 0.04) and overall mortality (HRQ4 vs Q1: 0.83; 95% CI: 0.63, 1.09; P for trend = 0.06) in the model adjusted for age at diagnosis, calendar year, energy intake, height, BMI, smoking status, and alcohol use (Table 2). After further adjustment for clinical characteristics (clinical stage, tumor grade, family history of prostate cancer, and primary treatment), these associations became nonsignificant for both prostate cancer–specific (P for trend = 0.08) and overall (P for trend = 0.11) mortality although the estimates were qualitatively similar. Folate, riboflavin, vitamin B-12, methionine, and alcohol intake were not associated with prostate cancer–specific or overall survival.
TABLE 2.
Multivariate hazard ratios (and 95% CIs) for the association of nutrient intake, by quartile (Q), with prostate cancer–specific and overall mortality in a prospective cohort study of 525 prostate cancer cases, Örebro County, Sweden
| Prostate cancer–specific mortality |
Overall mortality |
|||||||
| No. of prostate cancer deaths | Hazard ratio (95% CI) |
No. of all-cause deaths | Hazard ratio (95% CI) |
|||||
| Nutrient intake | Nutrient range1 | Person-years of follow-up | Model 12 | Model 23 | Model 12 | Model 23 | ||
| Folate (μg/d) | ||||||||
| Q1 | 148–210 | 969 | 52 | 1.00 (referent) | 1.00 (referent) | 120 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 210–238 | 907 | 63 | 1.29 (0.88, 1.89) | 1.49 (0.99, 2.23) | 124 | 1.27 (0.98, 1.65) | 1.41 (1.08, 1.84) |
| Q3 | 238–271 | 976 | 49 | 0.89 (0.60, 1.33) | 1.10 (0.72, 1.68) | 120 | 1.12 (0.86, 1.46) | 1.26 (0.96, 1.65) |
| Q4 | 271–449 | 1134 | 54 | 0.81 (0.54, 1.21) | 0.88 (0.57, 1.36) | 111 | 0.92 (0.70, 1.21) | 1.02 (0.77, 1.34) |
| P for trend | 0.12 | 0.26 | 0.32 | 0.83 | ||||
| Riboflavin (mg/d) | ||||||||
| Q1 | 1.1–1.9 | 977 | 53 | 1.00 (referent) | 1.00 (referent) | 116 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.9–2.1 | 998 | 60 | 1.03 (0.71, 1.51) | 1.11 (0.74, 1.65) | 122 | 1.03 (0.79, 1.34) | 1.13 (0.86, 1.48) |
| Q3 | 2.1–2.4 | 1026 | 49 | 0.82 (0.55, 1.23) | 0.73 (0.48, 1.12) | 117 | 0.96 (0.74, 1.25) | 0.91 (0.69, 1.19) |
| Q4 | 2.4–3.4 | 985 | 56 | 1.02 (0.69, 1.50) | 1.00 (0.66, 1.51) | 120 | 1.12 (0.86, 1.46) | 1.18 (0.91, 1.54) |
| P for trend | 0.85 | 0.63 | 0.47 | 0.46 | ||||
| Vitamin B-6 (mg/d) | ||||||||
| Q1 | 1.3–1.9 | 896 | 53 | 1.00 (referent) | 1.00 (referent) | 123 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.9–2.1 | 892 | 57 | 1.05 (0.72, 1.55) | 1.29 (0.86, 1.93) | 117 | 1.07 (0.82, 1.39) | 1.11 (0.85, 1.45) |
| Q3 | 2.1–2.2 | 1096 | 58 | 0.83 (0.56, 1.22) | 1.03 (0.69, 1.54) | 121 | 0.81 (0.62, 1.05) | 0.87 (0.67, 1.13) |
| Q4 | 2.2–2.9 | 1102 | 50 | 0.70 (0.46, 1.05) | 0.71 (0.46, 1.10) | 114 | 0.83 (0.63, 1.09) | 0.85 (0.64, 1.13) |
| P for trend | 0.04 | 0.08 | 0.06 | 0.11 | ||||
| Vitamin B-12 (μg/d) | ||||||||
| Q1 | 0.7–5.4 | 1048 | 56 | 1.00 (referent) | 1.00 (referent) | 116 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 5.4–7.3 | 1015 | 58 | 1.06 (0.73, 1.55) | 1.02 (0.69, 1.52) | 122 | 1.05 (0.81, 1.38) | 1.06 (0.81, 1.39) |
| Q3 | 7.3–10.7 | 948 | 57 | 1.05 (0.71, 1.54) | 1.00 (0.67, 1.50) | 119 | 1.07 (0.82, 1.41) | 1.09 (0.82, 1.44) |
| Q4 | 10.7–26.2 | 975 | 47 | 0.90 (0.60, 1.36) | 0.79 (0.51, 1.21) | 118 | 1.31 (1.00, 1.72) | 1.28 (0.97, 1.69) |
| P for trend | 0.57 | 0.23 | 0.05 | 0.08 | ||||
| Methionine (g/d) | ||||||||
| Q1 | 1.2–1.8 | 1017 | 48 | 1.00 (referent) | 1.00 (referent) | 112 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.8–1.9 | 988 | 64 | 1.36 (0.92, 2.01) | 1.31 (0.87, 1.96) | 123 | 1.09 (0.83, 1.42) | 1.06 (0.81, 1.39) |
| Q3 | 1.9–2.1 | 1015 | 54 | 1.21 (0.81, 1.81) | 1.20 (0.78, 1.83) | 118 | 1.06 (0.81, 1.39) | 1.08 (0.82, 1.42) |
| Q4 | 2.1–3.5 | 966 | 52 | 1.07 (0.71, 1.60) | 1.14 (0.75, 1.74) | 122 | 1.17 (0.89, 1.52) | 1.20 (0.91, 1.57) |
| P for trend | 0.98 | 0.68 | 0.30 | 0.19 | ||||
| Alcohol | ||||||||
| Nondrinker | 1966 | 101 | 1.00 (referent) | 1.00 (referent) | 224 | 1.00 (referent) | 1.00 (referent) | |
| <55 g/wk | 1077 | 53 | 0.92 (0.65, 1.31) | 1.09 (0.75, 1.58) | 126 | 0.96 (0.76, 1.21) | 1.04 (0.82, 1.33) | |
| ≥55 g/wk | 943 | 64 | 1.30 (0.92, 1.84) | 1.31 (0.90, 1.90) | 125 | 1.10 (0.86, 1.40) | 1.06 (0.83, 1.36) | |
| P for trend | 0.08 | 0.15 | 0.36 | 0.68 | ||||
Ranges may overlap because of rounding.
Cox proportional hazards regression model adjusted for age at diagnosis (41–64, 65–69, 70–74, and 75–79 y), calendar year of diagnosis (1989–1991 and 1992–1994), nonalcohol energy intake (continuous), height (continuous), BMI at diagnosis (continuous), and smoking status (never, former, current, or missing). Models for folate, riboflavin, vitamin B-6, vitamin B-12, and methionine were additionally adjusted for alcohol use (nondrinker, <55 g/wk, and ≥55 g/wk).
Cox proportional hazards regression model additionally adjusted for clinical stage (T0–1, T2, T3, or T4/M1), tumor grade (well, moderately, or poorly differentiated), family history of prostate cancer in father or brother (yes or no), and primary treatment (watchful waiting, hormones, prostatectomy, or other).
High vitamin B-6 intake was associated with a significant reduction in prostate cancer–specific mortality (HRQ4 vs Q1 = 0.05; 95% CI: 0.01, 0.26; P for trend = 0.0003) among cases with a diagnosis of localized-stage disease, but not among those with advanced-stage disease (HRQ4 vs Q1: 1.04; 95% CI: 0.64, 1.72; P for trend = 0.87) (Table 3). The association between vitamin B-6 and prostate cancer–specific mortality remained similar after further adjustment of the multivariate model for folate, riboflavin, vitamin B-12, and methionine intakes among localized-stage cases (HRQ4 vs Q1: 0.02; 95% CI: 0.002, 0.12; P for trend = 0.0001) and among advanced-stage cases (HRQ4 vs Q1 = 0.97; 95% CI: 0.50, 1.91; P for trend = 0.79). In contrast, we found no association between folate, riboflavin, vitamin B-12, methionine, or alcohol intake and prostate cancer survival across clinical stage subgroups. Furthermore, none of the associations between nutrient intake and prostate cancer survival differed by tumor grade, alcohol use (not tested in the alcohol intake model), or smoking status (data not shown).
TABLE 3.
Multivariate hazard ratios (and 95% CIs) across clinical stage subgroups for the association of nutrient intake, by quartile (Q), with prostate cancer–specific mortality in a prospective cohort study of 525 prostate cancer cases, Örebro County, Sweden
| Localized stage at diagnosis (n = 230)1 |
Advanced stage at diagnosis (n = 295)2 |
||||||||
| Nutrient range3 | Person-years of follow-up | No. of prostate cancer deaths | Hazard ratio (95% CI) |
Person-years of follow-up | No. of prostate cancer deaths | Hazard ratio (95% CI) |
|||
| Nutrient intake | Model 14 | Model 25 | Model 14 | Model 25 | |||||
| Folate (μg/d) | |||||||||
| Q1 | 148–210 | 553 | 13 | 1.00 (referent) | 1.00 (referent) | 416 | 39 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 210–238 | 491 | 13 | 1.22 (0.54, 2.78) | 1.23 (0.53, 2.88) | 416 | 50 | 1.35 (0.85, 2.16) | 1.58 (0.97, 2.58) |
| Q3 | 238–271 | 556 | 8 | 0.75 (0.29, 1.90) | 0.63 (0.23, 1.76) | 420 | 41 | 0.97 (0.61, 1.54) | 1.24 (0.76, 2.02) |
| Q4 | 271–449 | 653 | 10 | 0.58 (0.22, 1.51) | 0.50 (0.17, 1.48) | 481 | 44 | 0.92 (0.57, 1.48) | 1.04 (0.63, 1.72) |
| P for trend | 0.19 | 0.16 | 0.34 | 0.71 | |||||
| P for heterogeneity6 | 0.10 | ||||||||
| Riboflavin (mg/d) | |||||||||
| Q1 | 1.1–1.9 | 571 | 11 | 1.00 (referent) | 1.00 (referent) | 406 | 42 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.9–2.1 | 583 | 11 | 1.11 (0.45, 2.70) | 1.34 (0.49, 3.67) | 415 | 49 | 1.06 (0.68, 1.66) | 1.09 (0.69, 1.73) |
| Q3 | 2.1–2.4 | 601 | 13 | 1.02 (0.44, 2.40) | 1.11 (0.45, 2.75) | 425 | 36 | 0.88 (0.54, 1.41) | 0.67 (0.41, 1.11) |
| Q4 | 2.4–3.4 | 496 | 9 | 0.91 (0.35, 2.37) | 1.02 (0.34, 3.02) | 489 | 47 | 0.95 (0.61, 1.47) | 0.96 (0.60, 1.52) |
| P for trend | 0.82 | 0.97 | 0.66 | 0.58 | |||||
| P for heterogeneity6 | 0.82 | ||||||||
| Vitamin B-6 (mg/d) | |||||||||
| Q1 | 1.3–1.9 | 417 | 14 | 1.00 (referent) | 1.00 (referent) | 479 | 39 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.9–2.1 | 558 | 12 | 0.54 (0.23, 1.24) | 0.39 (0.15, 1.04) | 333 | 45 | 1.65 (1.05, 2.57) | 1.59 (1.00, 2.52) |
| Q3 | 2.1–2.2 | 670 | 15 | 0.60 (0.27, 1.36) | 0.47 (0.19, 1.18) | 427 | 43 | 1.13 (0.71, 1.79) | 1.12 (0.69, 1.80) |
| Q4 | 2.2–2.9 | 606 | 3 | 0.08 (0.02, 0.36) | 0.05 (0.01, 0.26) | 496 | 47 | 0.97 (0.60, 1.56) | 1.04 (0.64, 1.72) |
| P for trend | 0.0007 | 0.0003 | 0.58 | 0.87 | |||||
| P for heterogeneity6 | 0.0005 | ||||||||
| Vitamin B-12 (μg/d) | |||||||||
| Q1 | 0.7–5.4 | 664 | 12 | 1.00 (referent) | 1.00 (referent) | 384 | 44 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 5.4–7.3 | 592 | 11 | 1.11 (0.46, 2.67) | 1.22 (0.47, 3.16) | 423 | 47 | 0.87 (0.56, 1.35) | 0.91 (0.58, 1.44) |
| Q3 | 7.3–10.7 | 490 | 12 | 1.75 (0.72, 4.27) | 1.37 (0.53, 3.57) | 458 | 45 | 0.80 (0.52, 1.25) | 0.92 (0.58, 1.45) |
| Q4 | 10.7–26.2 | 506 | 9 | 1.20 (0.47, 3.04) | 0.85 (0.30, 2.42) | 469 | 38 | 0.69 (0.43, 1.09) | 0.74 (0.45, 1.22) |
| P for trend | 0.52 | 0.79 | 0.10 | 0.26 | |||||
| P for heterogeneity6 | 0.63 | ||||||||
| Methionine (g/d) | |||||||||
| Q1 | 1.2–1.8 | 587 | 8 | 1.00 (referent) | 1.00 (referent) | 430 | 40 | 1.00 (referent) | 1.00 (referent) |
| Q2 | 1.8–1.9 | 564 | 16 | 2.01 (0.78, 5.18) | 1.97 (0.73, 5.31) | 424 | 48 | 1.33 (0.85, 2.09) | 1.20 (0.76, 1.89) |
| Q3 | 1.9–2.1 | 583 | 11 | 1.26 (0.45, 3.50) | 1.49 (0.51, 4.36) | 432 | 43 | 1.27 (0.79, 2.04) | 1.20 (0.73, 1.97) |
| Q4 | 2.1–3.5 | 518 | 9 | 1.28 (0.45, 3.64) | 1.38 (0.45, 4.19) | 448 | 43 | 0.97 (0.61, 1.54) | 1.07 (0.67, 1.73) |
| P for trend | 1.00 | 0.81 | 0.72 | 0.82 | |||||
| P for heterogeneity6 | 0.85 | ||||||||
| Alcohol | |||||||||
| Nondrinker | 1105 | 22 | 1.00 (referent) | 1.00 (referent) | 861 | 79 | 1.00 (referent) | 1.00 (referent) | |
| <55 g/wk | 647 | 12 | 0.83 (0.39, 1.76) | 0.83 (0.36, 1.94) | 430 | 41 | 0.96 (0.64, 1.44) | 1.07 (0.69, 1.66) | |
| ≥55 g/wk | 500 | 10 | 0.90 (0.40, 2.02) | 1.03 (0.44, 2.42) | 443 | 54 | 1.28 (0.87, 1.88) | 1.33 (0.87, 2.01) | |
| P for trend | 0.85 | 0.88 | 0.17 | 0.17 | |||||
| P for heterogeneity6 | 0.83 | ||||||||
Stage T0–2, M0.
Stage T3–T4, M0, or T0–4, M1.
Ranges may overlap because of rounding.
Cox proportional hazards regression model adjusted for age at diagnosis (41–64, 65–69, 70–74, and 75–79 y), calendar year of diagnosis (1989–1991 and 1992–1994), nonalcohol energy intake (continuous), height (continuous), BMI at diagnosis (continuous), and smoking status (never, former, current, or missing). Models for folate, riboflavin, vitamin B-6, vitamin B-12, and methionine were additionally adjusted for alcohol use (nondrinker, <55 g/wk, or ≥55 g/wk).
Cox proportional hazards regression model additionally adjusted for clinical stage (T0–1, T2, T3, or T4/M1), tumor grade (well, moderately, or poorly differentiated), family history of prostate cancer in father or brother (yes or no), and primary treatment (watchful waiting, hormones, prostatectomy, or other).
Likelihood ratio test comparing the association (model 2) between nutrient intake and prostate cancer–specific mortality by clinical stage.
In a sensitivity analysis that excluded men who died within the first 2 y of follow-up, the results were equivalent to the original analysis among cases with a diagnosis of localized-stage disease because none died of prostate cancer in this time frame. Forty-nine prostate cancer deaths were excluded among the advanced-stage cases, and the results for the association of nutrient intake with prostate cancer–specific mortality remained nonsignificant: HRQ4 vs Q1 = 1.04 (95% CI: 0.57, 1.89; P for trend = 0.68) for folate, HRQ4 vs Q1 = 1.03 (95% CI: 0.59, 1.80; P for trend = 0.82) for riboflavin, HRQ4 vs Q1 = 0.91 (95% CI: 0.51, 1.63; P for trend = 0.61) for vitamin B-6, HRQ4 vs Q1 = 0.56 (95% CI: 0.30, 1.04; P for trend = 0.09) for vitamin B-12, HRQ4 vs Q1 = 1.04 (95% CI: 0.58, 1.86; P for trend = 0.92) for methionine, and HR≥55 g/wk vs 0 g/wk = 1.24 (95% CI: 0.74, 2.07; P for trend = 0.37) for alcohol.
DISCUSSION
In this first population-based, prospective study of nutrients involved in the one-carbon metabolism pathway and prostate cancer survival, we report a strong inverse association between vitamin B-6 intake and prostate cancer–specific mortality among men with localized-stage disease. No association was observed between vitamin B-6 intake and prostate cancer survival among advanced-stage cases, which suggests that the benefit of vitamin B-6 intake in slowing disease progression may be limited to men with organ-confined tumors. We also observed a modest reduction in overall mortality with increasing vitamin B-6 intake among the entire cohort; thus, we cannot conclude that vitamin B-6 acts specifically to reduce prostate cancer mortality. We found no association of folate, riboflavin, vitamin B-12, or methionine intake with prostate cancer survival in the current study, nor did these results differ by clinical stage.
Our findings of a beneficial link between high vitamin B-6 intake and prostate cancer survival are more striking than earlier studies of disease risk. Three retrospective studies of dietary habits and prostate cancer risk have shown null or nonsignificant inverse associations with increasing vitamin B-6 intake (18, 19, 21). A prospective cohort study in Finnish male smokers observed that increasing vitamin B-6 intake significantly reduced the risk of prostate cancer (P for trend = 0.045), and this inverse association was even stronger among the heavier smokers (23). Our results did not differ by current, former, or never smoking status, but we were not able to explore finer subgroups of current smokers. A subsequent study nested within the Finnish cohort (22) and a Swedish nested case-control study (26) failed to detect associations between serum concentrations of vitamin B-6 and prostate cancer risk.
Vitamin B-6 is known to play a role in several cellular processes in addition to its function as an enzymatic cofactor in the one-carbon metabolism pathway. In particular, in vitro studies have shown that intracellular pyridoxal phosphate, the active form of vitamin B-6, interacts with the steroid hormone–receptor complex, thereby decreasing transcription of hormone-responsive genes (41, 42). Also, an in vivo study of vitamin B-6 deficiency showed an increased uptake and nuclear retention of testosterone in the rat prostate (43). Given that an androgen (eg, testosterone) blockade slows the disease progression of clinically localized prostate cancer (44, 45), a high vitamin B-6 intake may improve prostate cancer survival by reducing the responsiveness of the prostate to testosterone. Consistent with our findings among localized-stage cases, it is plausible that vitamin B-6 has the greatest effect in early-stage, androgen-dependent disease.
Although we did not find a link between folate and prostate cancer survival, prior observational studies have reported positive (16, 21), null (17, 20, 22, 23, 27, 28), or inverse (19, 24) associations between folate intake or circulating concentrations and risk of prostate cancer. Additionally, a US-based randomized clinical trial that evaluated the secondary prevention of colorectal adenomas observed an excess of incident prostate cancers among men randomly assigned to 1 mg folic acid/d compared with the placebo group (46). Our findings, however, may not be directly comparable with findings in populations with higher folate intakes. The average folate intake in our study population was 244 μg/d, which is comparable with other intake estimates among Swedish adults (36, 38), but well below the RDA of 400 μg/d in the United States. After folic acid fortification of the food supply was implemented in 1998, most individuals in the United States met the RDA (47).
The lack of an association between riboflavin intake and prostate cancer survival in our study is consistent with 2 retrospective studies that found no association between riboflavin intake and prostate cancer risk (21, 25), whereas one prospective study found a positive association with elevated plasma riboflavin (26). Our null findings concerning vitamin B-12 intake and prostate cancer survival are less consistent with the literature: 1 retrospective (21) and 3 prospective studies (16, 17, 23) have shown a significantly elevated risk of overall or advanced prostate cancer with increasing intake or plasma concentrations of vitamin B-12, whereas one study reported a null association (22). Our results do not support an elevated rate of prostate cancer–specific mortality with increasing vitamin B-12 intake, which suggests that vitamin B-12 may play a role in prostate cancer initiation but not progression. The lack of association between methionine intake and prostate cancer survival in our study is consistent with 2 prior studies of diet and prostate cancer risk (19, 23).
We did not find an association between alcohol intake and prostate cancer survival, in general agreement with the literature on risk (48, 49). Although evidence shows that alcohol may modify the association between folate and risk of colorectal and breast cancers (50, 51), our results for nutrient intake and prostate cancer survival did not differ across subgroups of alcohol use. Furthermore, smoking has been inversely associated with plasma folate and vitamin B-12 concentrations (52, 53), although our results also did not differ by smoking status.
Because men with a more aggressive tumor may have altered their eating habits at the time of dietary assessment because of imminent disease, we conducted a sensitivity analysis in which we excluded cases that died within 2 y of diagnosis. Our results for the sensitivity analysis were similar to the full analysis.
A limitation of the current study was the single assessment of diet, which eliminated the possibility to examine dietary changes during follow-up. Because regular use of any type of supplement was rare in our cohort (<10%), we were only able to assess food sources of nutrients. Extrapolations to higher intakes of folate and B vitamins can therefore not be made based on these results. It should further be noted that the analyses of vitamin B-6 intake and prostate cancer–specific mortality among cases with a diagnosis of localized-stage disease was based on relatively few outcomes, with only 3 deaths occurring in the highest quartile of B-6 intake.
The strengths of our study included its prospective population-based design, long follow-up period, and complete follow-up of all cases. Because >40% of the cases died of prostate cancer, we had ample power to assess the effect of nutrient intake on survival in the entire cohort and among subgroups. Also, the collection of numerous clinical and lifestyle covariates related to prostate cancer survival allowed for statistical adjustment of these factors to limit potential confounding. However, residual and unmeasured confounding, by physical activity, for example, remains a concern. The study cohort offers a unique setting specifically for studies of the effects of nutrients involved in the one-carbon metabolism on prostate cancer survival. Sweden has no folate fortification program and screening for PSA was not in practice at the time the study subjects were recruited. Whereas these practices may differ from other countries, the biologic mechanisms underlying the observed associations should act similarly in other populations; thus, our results should be generalizable to other settings.
In summary, we found a strong inverse association between vitamin B-6 intake and prostate cancer–specific mortality limited to cases with localized-stage disease at diagnosis. Our results potentially have greater relevance in the era of PSA screening, which results in a greater proportion of prostate cancers being diagnosed at an earlier stage. If confirmed by other studies, these novel findings may introduce new opportunities for the secondary prevention of prostate cancer.
Acknowledgments
The authors' responsibilities were as follows—JLK: statistical analysis and writing of the manuscript; KF and LAM: manuscript revision and significant consultation; NH and AW: data collection; and J-EJ, S-OA, and OA: study design, data collection, and significant consultation. None of the authors reported a conflict of interest.
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