Meta-ALAlysis: ALA and Prostate Cancer
Meta-ALAlysis: ALA and Prostate Cancer
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: Concerns about the potential increased risk of prostate cancer associated with high intakes of alpha-linolenic acid (ALA; 18:3n-3) were re-assessed by the authors of this systematic review, but the aforementioned concerns could not be completely allayed. Heterogeneity across studies and likely publication bias were identified, as were conflicting conclusions across studies. In the end the researchers agreed there is at least a slight increased risk of prostate cancer associated with high ALA intakes or in the presence of high blood/adipose tissue ALA concentrations. While the risk may previously have been exaggerated, the authors of this review may well have "underblown" the possible association. The study ultimately does little to answer safety questions of high intakes of ALA on prostate cancer development.
Source: Simon JA, et al. The relation of alpha-linolenic acid to the risk of prostate cancer: A systematic review and meta-analysis. Am J Clin Nutr 2009;89(suppl):1558S-1564S.
The authors of this systematic review sought to further investigate the reported relationship between high intakes of ALA, the parent chemical of the n-3 fatty acid line and the single greatest source of n-3 fatty acids in the American diet (found mostly in meat, dairy, nuts, and seeds), and risk of prostate cancer. Part of the impetus for the review was the publication in recent years of additional data, with special note taken of information from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), a large prospective cohort study.
Studies that compared quantiles of ALA intake were identified following a MEDLINE search for articles from 1963 to 2007. No randomized controlled trials (RCTs) were identified. A total of 16 studies were found that permitted pooling of risk results, 8 of which were prospective in design (cohort, case-control, and nested case-control) and 8 of which were retrospective in nature (case-control).
When all studies were considered together, there was an approximately 20% increased risk of prostate cancer (relative risk [RR] = 1.20) among individuals with the highest quantiles of ALA intake, or blood or adipose tissue ALA concentrations. The reviewers identified significant heterogeneity across studies, as well as evidence of publication bias (absence of smaller negative trials). The RR of prostate cancer dropped to 0.94 after adjustment for publication bias.
Subgroup analyses of older vs. newer studies showed a RR of 1.16 for ALA concentration and prostate cancer in older trials, and a RR of 1.24 among newer studies. Among the 8 prospective trials, where bias is far less likely, the pooled RR was 1.02, representing no significant prostate cancer risk, while among the retrospective case-control trials a RR of 1.51 was found with high ALA intake (the authors called this a "nonsignificant 51% increased risk of prostate cancer among men in the highest quantile for ALA" due to a P value of 0.08). Studies that assessed ALA intake with dietary assessment (n = 11) showed a RR of 1.09; studies that directly measured ALA, however, in serum, whole blood, or adipose tissue found that men in the highest ALA quantile had a RR of 1.54, or were at a 54% higher risk of prostate cancer when compared with the lowest quantile of ALA concentration.
The authors focused on the results of the large PLCO trial, which was designed to assess prostate cancer risk based on annual screening (digital rectal examination and PSA testing) and included almost 30,000 subjects. Men in the highest quintile of ALA intake had a RR of 0.94 for prostate cancer compared with men in the lowest quantile of intake. The PLCO trial is ongoing, with plans for a minimum of 13 years of follow-up, but the data referenced by the reviewers reported on 5.1 years of follow-up.
An additional 6 studies were identified that could not be included in a meta-analysis because of the manner in which data were provided, but 5 of the 6 concluded that high ALA intake does not increase the risk of prostate cancer.
The authors conclude that studies of ALA intake and prostate cancer risk have yielded inconsistent results, but that high intakes of ALA may be associated with a small increased risk of prostate cancer.
Commentary
The question of dietary factors and cancer risk has drawn significant necessary research attention, including within the realm of prostate cancer investigation. Concerns have been raised about high intakes of animal protein together with low fruit and vegetable consumption, but data thus far are not conclusive. Animal protein is typically high in ALA. Some nuts and seeds are a source of ALA, and questions of safety have been raised about flaxseed oil and prostate cancer (not so as yet about ground flaxseed, which may be chemopreventive) even in the absence of significant research data. It is in large part due to the current environment of uncertainty about an association between consumption of high-ALA foods and prostate cancer that the authors waded into this mess. While their efforts are worthy, their conclusions do not help clarify matters.
At a time where the RCT is deemed the research gold standard, no RCTs could be found addressing the research question at hand. Methodological differences apparently abound in the existing studies to date, and publication bias can be at least assumed, making firm conclusion-drawing an exercise fraught with problems.
The authors seemingly downplay potential risks, but their analyses yield numbers that should raise concern. Studies that showcased direct measurement of ALA concentrations suggested a significantly increased risk for prostate cancer (54%) when levels were very high. Although retrospective trials are prone to bias, the 51% increased risk for prostate cancer in the highest quantile of ALA intake should at least be considered of potential clinical significance even though the findings were not statistically significant.
The authors rightly point out that a long-term RCT addressing ALA intake and prostate cancer risk is not feasible; however, it seems unreasonable to take relatively short-term data (in the case of PLCO, up to 5.1 years of follow-up) regarding the risk of prostate cancer, an illness that develops over the course of many years, and to minimize the potential risk associated with high intakes of ALA. The authors conclude there may be a small increased risk of prostate cancer at the highest levels of ALA consumption. Some of the numbers presented are not small.
This study is of import because it mandates an uncomfortable statement of truth regarding any association between high levels of ALA intake and prostate cancer development - we're simply not sure yet if there is one.
Concerns about the potential increased risk of prostate cancer associated with high intakes of alpha-linolenic acid (ALA; 18:3n-3) were re-assessed by the authors of this systematic review, but the aforementioned concerns could not be completely allayed.Subscribe Now for Access
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