Submitted to: Lancet
Publication Type: Other
Publication Acceptance Date: 3/15/2008
Publication Date: 4/19/2008
Citation: Mason, J.B., Cole, B.F., Baron, J.A., Kim, Y., Refsum, H., Selhub, J., Smith, A. 2008. Folic acid fortification and cancer risk: plea for objective evaluation of the evidence. Lancet. 371: 1335-1336. Interpretive Summary:
Technical Abstract: The letter from Bayston and colleagues,1 representing the Association for Spina Bifida and Hydrocephalus, dismisses concerns raised by two recent studies2, 3 of a possible increase in colorectal cancer (CRC) risk following a high intake of folic acid. In relation to the postulated link between fortification and incidence of CRC2, Bayston and colleagues state ‘The rise in CRC incidence.…started before the introduction of fortification on any large scale and so could not have been caused by fortification’. The facts indicate otherwise. Legislation allowed for the initiation of voluntary fortification in the USA and in Canada in March and December of 1996, respectively, and this began almost immediately. For instance, data from Canada show that serum folate levels began to rise appreciably within 60 days after the introduction of voluntary fortification and that >95% of the total increase had occurred before the date at which fortification became mandatory in November 1998.4 Thus, the rise in CRC rates that occurred in the USA and Canada in 1996 and 1997, respectively, coincided with the rise in folate status. Bayston and colleagues then imply that the rise in CRC rates in North America was due to an increasing use of endoscopic screening of the colon. In fact, the data shown by Mason and colleagues2 indicate that the increase in screening occurred gradually through 1999, and so could not explain the marked change in CRC rates that began in 1996-1997. Bayston and colleagues also dismiss concerns raised by Cole and colleagues3 first by stating that ‘The paper…. relates to colorectal adenomas, not carcinomas’. This statement ignores the fact that colorectal adenomas are an established surrogate biomarker for the subsequent risk of developing CRC.5 Bayston and colleagues correctly state that the primary endpoint of the study—total adenoma recurrence—was not significantly modified. But the observation that in pre-specified secondary analyses the two subcategories of adenomas (three or more adenomas and ‘advanced’ adenomas) that are most closely linked to CRC risk occurred significantly more frequently amongst those receiving folic acid supplements3 was dismissed as ‘the effects of chance’.1 Bayston and colleagues also ignore a difference in serious adverse events in the trial reported by Cole and colleagues: the higher incidence of non-colorectal cancers (mainly prostate) in patients taking folic acid.3 Contrary to the statement by Bayston, there is no contradiction in the report by Logan and colleagues.6 That study ended after only 3 years follow-up; the adverse effects seen by Cole emerged during longer-term follow-up. We believe that there are thus reasons to delay any decisions regarding folic acid fortification in the UK, until a more complete understanding of the likely benefits and risks can be established. HR and ADS are members of the committee supervising a trial of B vitamins (including folic acid) in the elderly with memory impairment. The other authors declare no conflict of interest.