Hi Paul, I'd like to bring this to your attention. Full Text
of Paper and Comment of The Lancet attached.

[Hendrik was reminded by private email that Yahoo strips off all attachments
since Paul and I have the settings on MoreLife Yahoo for no html. He sent the
full text of the paper and editorial commentary to Paul directly as requested.
**Kitty]


The Lancet: Volume 364, Number 9441 02 October 2004

Antioxidant supplements for prevention of gastrointestinal
cancers: a systematic review and meta-analysis

Goran Bjelakovic, Dimitrinka Nikolova, Rosa G Simonetti,
Christian Gluud

Summary

Background Oxidative stress can cause cancer. Our aim was to
establish whether antioxidant supplements reduce the
incidence of gastrointestinal cancer and mortality.

Methods With the Cochrane Collaboration methodology, we
reviewed all randomised trials comparing antioxidant
supplements with placebo for prevention of gastrointestinal
cancers. We searched electronic databases and reference
lists (February, 2003). Outcome measures were incidence of
gastrointestinal cancers, overall mortality, and adverse
effects. Outcomes were analysed with fixed-effect and
random-effects model meta-analyses and were reported as
relative risk with 95% CIs.

Findings We identified 14 randomised trials (n=170 525).
Trial quality was generally high. Heterogeneity of results
was low to moderate. Neither the fixed-effect (relative risk
0·96, 95% CI 0·88-1·04) nor random-effects meta-analyses
(0·90, 0·77-1·05) showed significant effects of
supplementation with ß-carotene, vitamins A, C, E, and
selenium (alone or in combination) versus placebo on
oesophageal, gastric, colorectal, pancreatic, and liver
cancer incidences. In seven high-quality trials (n=131727),
the fixed-effect model showed that antioxidant significantly
increased mortality (1·06, 1·02-1·10), unlike the
random-effects meta-analysis (1·06, 0·98-1·15). Low-quality
trials showed no significant effect of antioxidant
supplementation on mortality. The difference between the
mortality estimates in high-quality and low-quality trials
was significant (Z=2·10, p=0·04 by test of
interaction).ß-carotene and vitamin A (1·29, 1·14-1·45) and
ß-carotene and vitamin E (1·10, 1·01-1·20) significantly
increased mortality, whereas ß-carotene alone only tended to
increase mortality (1·05, 0·99-1·11). In four trials (three
with unclear or inadequate methodology), selenium showed
significant beneficial effect on the incidence of
gastrointestinal cancer.

Interpretation We could not find evidence that antioxidant
supplements can prevent gastrointestinal cancers; on the
contrary, they seem to increase overall mortality. The
potential preventive effect of selenium should be studied in
adequate randomised trials.

[To quote from the comment to the above publication, the findings of this
meta-analysis present evidence for "a schism between the evidence from
randomised trials and that from large observational studies, with the latter
backed up by persuasive arguments about biological mechanisms."

Some potential reasons for this contradictory finding are:

1) "the effect on diseases with long latency periods of pharmacological doses of
specific micronutrients over a few years in middle-aged adults is a
different scenario from physiological doses of the same micronutrients provided
as part of a balanced diet on a lifelong basis."
2) The antioxidants used in the studies analysed were too narrow in scope. Eg
the vitamin E was all alpha-tocopherol, there were no bioflavonoids with the
vitamin C, the beta carotene was not accompanied by other carotenoids and other
important antioxidants that help recycle those given were not included.
3) Gastrointestinal cancers were the only end-point looked for. All other
mortality effects were ignored.
4) Since the studies examined were only short term trials it is possible that
those selected for such trials were already sickly and that the antioxidants
were simply too little, too late.

In addition, again in the words of the commenter, "the heterogeneity of the
trials is a key issue. Heterogeneity arose almost wholly from the outlying
result from one trial in an anomalous population of smokers, ex-smokers, and
occupationally exposed asbestos workers. The other high quality trials show
little heterogeneity, and do not suggest increased mortality". IOW, one trial
with particularly susceptible participants which contained a lot of variability
of results skewed the overall probability into the "significant" region.

As the commenter concluded: "The mortality analysis in Bjelakovic and
colleagues’ review is work in progress, and does not offer convincing proof of
hazard." -- Paul]