meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer

Meta-analysis: folic acid in the chemoprevention of colorectaladenomas and colorectal cancerC. CARROLL* , K . COOPER* , D. PAPAIOANNOU*, D. HIND� , P . TAPPENDEN*, H. PILGRIM* &

A. BOOTH*

*Health Economics and Decision

Science, School of Health and Related

Research, University of Sheffield,

Sheffield, UK; �Health Services

Research, School of Health and

Related Research (ScHARR), University

of Sheffield, Sheffield, UK

Correspondence to:

Dr C. Carroll, Health Economics and

Decision Science, School of Health

and Related Research, University of

Sheffield, Regent Court, Regent Street,

Sheffield, UK, S1 4DA.

E-mail: [email protected]

Publication data

Submitted 6 November 2009

First decision 26 November 2009

Resubmitted 3 December 2009

Accepted 12 January 2010

Epub Accepted Article 18 January

2010

SUMMARY

BackgroundFolic acid has been identified as a possible agent for the chemopreven-tion of colorectal cancer.

AimTo assess the effectiveness of folic acid in reducing the recurrence ofadenomas (precursors of colorectal cancer) among populations with ahistory of adenomas and the incidence of colorectal cancer withinaverage-risk populations.

MethodsSystematic review of randomized controlled trials comparing folic acidalone, or with other agents, vs. placebo. Eight databases were searchedfor relevant trials. Meta-analysis was performed.

ResultsThe literature search retrieved 3785 citations. Six studies met the inclu-sion criteria. Meta-analysis of three studies in individuals with a historyof adenomas showed no statistically significant difference in the relativerisk of adenoma recurrence (RR 0.93, P = 0.27). A sensitivity analysis ofthe two higher quality trials changed the direction of effect (RR 1.16,P = 0.11). Meta-analysis of three trials in general populations demon-strated no statistically significant effect on the relative risk of colorectalcancer (RR 1.13, P = 0.54). In all three analyses, outcome event rateswere higher in individuals receiving folic acid.

ConclusionThere is no evidence that folic acid is effective in the chemopreventionof colorectal adenomas or colorectal cancer for any population.

Aliment Pharmacol Ther 31, 708–718

Alimentary Pharmacology & Therapeutics

708 ª 2010 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2010.04238.x

INTRODUCTION

Colorectal cancer is a malignant neoplasm arising

from the lining of the large intestine (colon and rec-

tum) and is the second most common fatal cancer in

western Europe and the United States.1, 2 Incidence of

colorectal cancer increases with age, with the median

age at diagnosis being over 70 years for both colon

and rectal cancer patients.3, 4 Risk factors for the

development of colorectal cancer include genetic syn-

dromes, family or individual history of adenomas and

environmental factors relating to diet and lifestyle.5, 6

Approximately five percent of colorectal cancers are

associated with the genetic syndromes familial adeno-

matous polyposis (FAP) and hereditary nonpolyposis

colorectal cancer (HNPCC or Lynch syndrome)7, 8 and

20% occur in individuals who have a family history of

the disease but for whom no specific disease-causing

mutations can be identified.9, 10 The remaining 75% of

patients have neither a clear family history nor any

known predisposing condition.11

It is thought that most colorectal cancers develop

from adenomatous polyps arising from the lining of

the intestine; indirect evidence suggests that adenomas

may be present for 10 years or more before malig-

nancy develops.12–14 The size and number of adeno-

mas, as well as their histological type and the presence

of epithelial dysplasia, are thought to affect the risk of

colorectal cancer development. Individuals in whom

adenomatous polyps are identified undergo polypecto-

my (removal of polyps) and are invited for endoscopic

surveillance.15 The overall 5-year survival rate for

colorectal cancer in the UK is approximately 50%, but

varies according to the stage of disease at diagnosis.16

The clinical effectiveness of several drug and micronu-

trient interventions for the prevention of colorectal

cancer and ⁄ or the intermediate outcome, adenomatous

polyps, in populations at differing risks for developing

colorectal cancer have been investigated and synthe-

sized by a number of systematic reviews,17 including

non-steroidal anti-inflammatory drugs (NSAIDs);18–20

calcium and vitamin D;21, 22 and antioxidants (includ-

ing vitamin A, vitamin C, vitamin E, selenium and

beta-carotene).23, 24 Only aspirin, celecoxib and, to a

lesser extent, calcium, have been found to have some

chemopreventive effect in populations with a history

of colorectal adenomas.17, 18, 21 Folic acid has also

been proposed as a potential chemopreventive agent

because it may have an effect on DNA damage

and repair25, 26 and because low folate diet has

been associated with an increased risk of colorectal

neoplasia.27–30

The purpose of this work therefore is to systemati-

cally review existing evidence concerning the clinical

effectiveness of folic acid in reducing recurrence of

colorectal adenomas in increased-risk populations and

reducing the occurrence of colorectal cancer in the

general, average-risk population. This is the second

systematic review and meta-analysis of randomized

controlled trials (RCTs) to address this question,31 but

the results of this previous review are discussed in

depth below.

METHODS

A literature search was performed to identify relevant

research using database thesaurus and free text terms

for folate or folic acid and colorectal cancer. A vali-

dated study design filter to identify RCTs was used.32

This search also included other agents of interest, such

as NSAIDs and calcium, as it was part of a larger

assessment of numerous potential chemopreventive

agents for colorectal cancer. (Search strategies are

available from authors). Eight databases were searched

for published and unpublished trials: Cochrane

Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE,

Web of Science, Biological Abstracts (BIOSIS) and

Research Registers. There was no limitation by either

language or date. All searches were conducted in June

2008. The reference lists of relevant studies were also

searched for additional papers.

Studies had to satisfy the following criteria to be

included in the review: RCTs of folic acid or folate,

with or without other agents, in adults with Familial

Adenomatous Polyposis (FAP), Hereditary Non-Polyp-

osis Colorectal Cancer (HNPCC), a history of colorectal

adenomas, or with no increased baseline risk of colo-

rectal cancer. Comparators had to be either placebo or

agents other than folic acid. Outcomes had to include

the recurrence of adenomas or advanced adenomas or

the occurrence of colorectal cancer.

All citations identified by the searching process were

screened by three reviewers (CC, KC, DP) to determine

if they met the inclusion criteria. For quality-control,

a double check for appropriate inclusion and exclusion

was performed on ten percent of the citations by a

fourth reviewer (DH). A kappa of 0.76 was recorded

for inter-rater reliability. Full papers were retrieved for

any citation that appeared to meet the inclusion crite-

ria. In cases where a decision could not be made about

META-ANALYSIS : FOL IC ACID IN THE CHEMOPREVENT ION OF COLORECTAL CANCER 709


ª 2010 Blackwell Publishing Ltd

inclusion on the basis of title or abstract alone, the full

paper was retrieved to make a definitive judgement.

The inclusion and exclusion criteria were then used to

assess full papers. Queries concerning inclusion were

resolved by discussion and consensus between two or

more reviewers. Data from all included trials were

extracted using a form designed specifically for this

review and piloted on a sample paper. One reviewer

(CC) extracted data from the final list of included stud-

ies into pre-designed tables and appraised the quality

of the included studies using a form based on standard

criteria for RCTs.33 Both data extraction and quality

assessment were then checked thoroughly by a second

reviewer (KC). If necessary, authors were contacted by

a letter for relevant data. The aim of the quality

assessment was to evaluate issues relating to the qual-

ity of the reported processes of allocation, randomiza-

tion and blinding, the comparability of the treatment

and control groups, and the appropriateness and qual-

ity of the analysis performed. The quality assessment

process was undertaken to afford an idea of the

respective quality of studies and to inform the internal

validity of the review.

Meta-analysis of trials was performed using REVMAN

5.0.34 For discrete and numerical outcomes, relative

risks (RR) and risk differences (RD) are reported with

95% confidence intervals. The random effects model

was used to account for clinical and methodological

variations between trials. Statistical heterogeneity was

described using the I-squared statistic. Two types of

comparison are analysed and presented: Folic acid

alone vs. placebo alone; and folic acid with or without

other interventions vs. placebo (with or without other

interventions). Only randomized participants for whom

a valid outcome had been evaluated and reported are

included in the analysis.35, 36

RESULTS

The search of electronic databases produced 3785

citations, of which seven papers (four trials) satisfied

the inclusion criteria.37–43 Three additional papers

(two trials) were identified from the references of

these studies.44–46 For full details, see the QUOROM

flowchart (Figure 1). No RCT examining folic acid in

individuals with FAP or HNPCC was identified; three

RCTs examined folic acid in populations with a his-

tory of adenomas37, 38, 44 and three RCTs examined

folic acid in general populations, with no increased

risk of colorectal cancer.39, 40, 46 Two ongoing

studies were identified which assess folic acid for

prevention of adenomas in participants with a history

Unique citations retrieved by search of electronic databases

(n = 3785)

Citations satisfying inclusion criteria (n = 10)

Excluded studies not relevantfor data extraction

(n = 3778)

Populations with a history of adenomas:

3 RCTs (5 papers)

Populations with no history of adenomas or colorectal cancer

3 RCTs (5 papers)

Citations satisfied inclusion criteria (n = 7)

Reference tracking (n = 3)

Figure 1. QUOROM FlowDiagram.

710 C . CARROLL et al.



of adenomas (http://www.clinicaltrials.gov, NCT00512850

and NCT00002650).

Populations with a history of adenomas

Three studies compared folic acid with a control group

(see Table 1). The two largest trials, both multicentre,

were the United States Aspirin ⁄ Folate Polyp Preven-

tion Study (AFPPS) trial38, 41, 42 and the United King-

dom Colorectal Adenoma Prevention trial (ukCAP).37

These trials randomized 1021 and 945 participants

respectively. The Jaszewski et al. trial was a single-

centre study in the United States that randomized 177

participants.44 The mean age reported ranged from 57

to 62 years across all study groups. The ukCAP trial

performed a 2 · 2 factorial comparison with folic

acid at 0.5 mg ⁄ day and aspirin at 300 mg ⁄ day;37 the

AFPPS trial a 3 · 2 factorial comparison with

1 mg ⁄ day folic acid and 81 mg ⁄ day or 325 mg ⁄ day

aspirin.38 In the smaller Jaszewski et al. trial, folic acid

at 5 mg ⁄ day was compared with placebo.44 The dura-

tion of treatment and follow-up in all three trials was

3 years.

The AFPPS and ukCAP trials were both judged to be

of good quality.37, 38 In both studies, allocation con-

cealment was adequate; a central, computer-generated

randomization sequence was used and methods of

blinding were adequate. Power calculations were per-

formed within both studies, but the required sample

size was not achieved for the designated outcome in

the ukCAP trial.37 All three trials reported blinding of

patients and carers; the ukCAP trial also reported

blinding of analysts.37 All studies experienced attri-

tion: attrition rates were 10% or less in the ukCAP and

AFPPS trials.37, 38 The Jaszewski et al. trial was of

generally lower reported quality:44 methods of alloca-

tion and randomization were adequate, but it remains

unclear who was blinded, no power calculation was

performed and the numbers in each arm were not

reported consistently. Attrition rates were also more

than 20% in this trial. However, all within-study

groups appear to be comparable at baseline and inten-

tion-to-treat analyses were performed by all three

studies. Only the results from the first interval (3 years

follow-up) of the AFPPS trial are presented here

because only 607 of 1021 randomized patients (59%)

agreed to be followed-up beyond 3 years, and only

501 patients (49%) agreed to continue taking study

medications beyond 3 years.38 The results from this

second follow-up period are omitted from the analysis

because the rates of attrition render these later data

less robust for the present analysis.

The three included trials were analysed in three dif-

ferent ways: folic acid alone (0.5–5.0 mg ⁄ day) vs. pla-

cebo alone (840 participants in analysis); folic acid

(0.5–1.0 mg ⁄ day) plus aspirin (81–325 mg ⁄ day) vs. pla-

cebo alone (916 participants in analysis) and folic acid

(0.5–1.0 mg ⁄ day) with and without aspirin (81–

325 mg ⁄ day) vs. placebo with or without aspirin (1840

participants in analysis). Meta-analysis showed no sta-

tistically significant effect of folic acid alone vs. pla-

cebo on either the relative or absolute risk of adenoma

or advanced adenoma recurrence, or colorectal cancer

(see Table 2). The analysis did demonstrate a non-statis-

tically significant reduction in the relative risk of ade-

noma recurrence in the folic acid group compared with

placebo [Relative risk (RR) 0.93, 95% CI 0.61–1.41,

P = 0.27; Risk difference (RD) )0.03, 95% CI )0.19–

0.13, P = 0.73) (Figure 2). However, this analysis gener-

ated a large degree of statistical heterogeneity (I2 = 77%

for RR, 81% for RD). Given that there can be a high

degree of bias in lower quality trials,47 a sensitivity

analysis was performed, which excluded the unpub-

lished data from the smaller, lower quality Jaszewski

et al. study (91 participants in analysis). This altered the

findings substantially, changing the direction of effect.

A nonstatistically significant but increased risk of ade-

noma recurrence was observed in the folic acid group

in this sensitivity analysis (RR 1.16, 95% CI 0.97–1.39,

P = 0.11; RD 0.05, 95% CI )0.02–0.12, P = 0.14)

(see Figure 3). A similar, but smaller trend was apparent

comparing folic acid with or without aspirin vs. no folic

acid (RR 1.05, 95% CI 0.93–1.18, P = 0.45; RD 0.02,

95% CI )0.03–0.06, P = 0.43). Similar trends were

apparent for the outcome of advanced adenomas (see

Table 2). Both individual trials also reported this direc-

tion of effect for adenoma and advanced adenoma

recurrence. In contrast, folic acid plus aspirin vs. pla-

cebo indicated a nonstatistically significant reduction

in the relative risk for the folic acid plus aspirin group

(RR 0.90, 95% CI 0.75–1.08, P = 0.27; RD )0.04, 95%

CI )0.10–0.02, P = 0.23), suggesting that it is the aspi-

rin rather than the folic acid having a positive effect

upon adenoma rates.

Average-risk or general population studies (atno increased risk of colorectal cancer)

Three studies were identified which compared a folic

acid intervention with a control group (see Table 1):




Tabl

e1.

Stu

dy

char

acte

rist

ics

Stu

dy

Stu

dy

des

ign

Popula

tion

&ag

eIn

terv

ention

Contr

ol

Tre

atm

ent

dura

tion

Follow

-up

dura

tion

Popula

tions

with

anin

crea

sed

risk

of

colo

rect

alca

nce

r(p

opula

tions

with

ahis

tory

of

aden

om

as)

ukC

AP

37

Phas

eIII,

DB,RCT

His

tory

of

aden

om

as,but

not

FA

Por

HN

PCC

Age

<75

yea

rsel

igib

le(m

ean

58,ra

nge

28–75)

Folic

acid

0.5

mg

⁄day

(N=

234)

Folic

acid

0.5

mg

⁄day

+A

spir

in300

mg

⁄day

(N=

236)

Pla

cebo

only

(N=

233)

Asp

irin

300

mg

⁄day

(N=

236)

3yea

rs3

yea

rs

AF

PPS

38,41,42

Phas

eIII,

DB,RCT

His

tory

of

aden

om

as,but

not

FA

Por

HN

PCC

Age

21–80

yea

rsel

igib

le(m

ean

57

or

58

inal

lgro

ups)

Folic

acid

1m

g⁄d

ayonly

(N=

170)

Folic

acid

1m

g⁄d

ay+

Asp

irin

81

mg

⁄day

(N=

175)

Folic

acid

1m

g⁄d

ay+

Asp

irin

325

mg

⁄day

(N=

171)

Pla

cebo

only

(N=

169)

Asp

irin

81

mg

⁄day

(N=

169)

Asp

irin

325

mg

⁄day

(N=

167)

3yea

rs3

yea

rs

Jasz

ewsk

iet

al.4

4Phas

eIII,

DB,RCT

His

tory

of

aden

om

as,but

not

FA

Por

HN

PCC

Age

18–80

yea

rsel

igib

le(m

ean

60

or

62

ingro

ups)

Folic

acid

5m

g⁄d

ay(N

=80)

Pla

cebo

only

(N=

97)

3yea

rs3

yea

rs

Gen

eral

popula

tions

⁄popula

tions

with

anav

erag

eri

skof

colo

rect

alca

nce

rH

OPE-2

45,46

DB,RCT

His

tory

of

vas

cula

rdis

ease

or

dia

bet

esor

risk

of

ather

osc

lero

sis

Age

55

yea

rsor

old

er(m

ean

69

yea

rs)

Folic

acid

2.5

mg

⁄day

,V

itam

inB6

50

mg

⁄day

,V

itam

inB12

1m

g⁄d

ay(N

=2758)

Som

epar

tici

pan

tsal

sore

ceiv

edan

tioxid

ants

Pla

cebo

(N=

2764)

5yea

rs5

yea

rs

WA

FA

CS

39

DB,RCT

Wom

enw

ith

or

athig

hri

skof

card

iovas

cula

rdis

ease

Age

>40

yea

rs(m

ean

63

yea

rs)

Folic

acid

2.5

mg

⁄day

,V

itam

inB6

50

mg

⁄day

,V

itam

inB12

1m

g⁄d

ay(N

=2721)

Thes

epar

tici

pan

tsw

ere

asu

bse

tof

those

inth

eW

ACS

study,an

dw

ere

also

rece

ivin

gvar

ious

com

bin

atio

ns

of

vitam

inC,vitam

inE

and

bet

a-ca

rote

ne

Pla

cebo

(N=

2721)

7yea

rs7

yea

rs

Zhu

etal

.40,43

DB,RCT

Pat

ients

with

atro

phic

gas

tritis

Age

28–77

yea

rsel

igib

le(m

ean

55–57

yea

rsin

all

gro

ups)

Folic

acid

20

mg

⁄day

for

1yea

rth

en20

mg

twic

ew

eekl

yfo

r1

yea

r;V

itam

inB12

1m

g⁄m

onth

for

1yea

rth

en1

mg

ever

y3

month

sfo

r1

yea

r(N

=44)

Pla

cebo

(N=

54)

Bet

a-ca

rote

ne

(nat

ura

l),

30

mg

⁄day

for

1yea

rth

en30

mg

twic

e⁄w

eek

for

1yea

r)(N

=61)

Bet

a-ca

rote

ne

(synth

etic

),dose

sas

above)

(N=

57)

2yea

rs6

yea

rs

DB,double

-blind;

RCT,ra

ndom

ized

contr

olled

tria

l.




Tabl

e2.

Sum

mar

yof

met

a-an

alyse

s

Incl

uded

studie

sIn

terv

ention

Contr

ol

Follow

-up

(yea

rs)

Even

tra

tes

(Inte

rven

tion

vs.

Contr

ol)

RR

(95%

CI)

I2(%

)RD

(95%

CI)

I2(%

)

Any

aden

om

aukC

AP

37

AFPPS

38,41,42

Jasz

ewsk

i44*

Folic

acid

alone

(0.5

-5m

g⁄d

ay)*

Pla

cebo

alone

3162

⁄429

vs.

148

⁄411*

0.9

3(0

.61,1.4

1)

77

)0.0

3()

0.1

9,0.1

3)

81

ukC

AP

37

AFPPS

38,41,42

Any

folic

acid

(0.5

–1

mg

⁄day

)�

Asp

irin

(81–325

mg

⁄day

)N

ofo

lic

acid

(�A

spir

in)

3336

⁄933

vs.

311

⁄907

1.0

5(0

.93,1.1

8)

00.0

2()

0.0

3,0.0

6)

0

Folic

acid

alone

(0.5

–1

mg

⁄day

)Pla

cebo

alone

3152

⁄383

vs.

126

⁄366

1.1

5(0

.97,1.3

9)

00.0

5()

0.0

2,0.1

2)

0Folic

acid

(0.5

–1

mg

⁄day

)+

Asp

irin

(81–325

mg

⁄day

)Pla

cebo

alone

3184

⁄550

vs.

126

⁄366

0.9

0(0

.75,1.0

8)

0)

0.0

4()

0.1

0,0.0

2)

0

Advan

ced

aden

om

aukC

AP

37

AFPPS

38,41,42

Any

folic

acid

(0.5

–1

mg

⁄day

)�

Asp

irin

(81–325

mg

⁄day

)N

ofo

lic

acid

(�A

spir

in)

3109

⁄933

vs.

94

⁄907

1.1

3(0

.84,1.5

1)

21

0.0

1()

0.0

2,0.0

4)

8

Folic

acid

alone

(0.5

–1

mg

⁄day

)Pla

cebo

alone

360

⁄383

vs.

44

⁄366

1.3

4(0

.77,2.3

6)

55

0.0

4()

0.0

3,0.1

1)

46

Folic

acid

(0.5

–1

mg

⁄day

)+

Asp

irin

(81–325

mg

⁄day

)Pla

cebo

alone

349

⁄550

vs.

44

⁄366

0.7

7(0

.45,1.3

4)

45

)0.0

3()

0.0

9,0.0

4)

58

Colo

rect

alca

nce

rH

isto

ryof

aden

om

asukC

AP

37

AFPPS

38,41,42

Any

folic

acid

(0.5

–1

mg

⁄day

)�

Asp

irin

(81–325

mg

⁄day

)N

ofo

lic

acid

(�A

spir

in)

38

⁄948

vs.

9⁄9

26

0.8

7(0

.34,2.2

5)

00.0

0()

0.0

1,0.0

1)

0

Gen

eral

popula

tion

(no

incr

ease

dbas

elin

eri

skof

colo

rect

alca

nce

r)H

OPE-2

45,46

WA

FA

CS

39

Zhu

etal

.40,43

Any

folic

acid

(2.5

mg

⁄day

to20

mg

⁄day

)(+

Bvits�

Antioxid

ants

)

No

folic

acid

(�A

ntioxid

ants

)5,6,7

68

⁄5523

vs.

60

⁄5539

1.1

3(0

.77,1.6

4)

70.0

0(0

.00,0.0

1)

36

RR,re

lative

risk

;RD

,ab

solu

teri

skdif

fere

nce

;CI,

confi

den

cein

terv

al;

I2,m

easu

reof

het

erogen

eity

.*

Incl

udes

unpublish

eddat

apro

vid

edby

auth

ors

of

Jasz

ewsk

ist

udy.4

4




the international Heart Outcomes Prevention Evalua-

tion (HOPE-2) trial;45, 46 the USA-based Women’s

Antioxidant and Folic Acid Cardiovascular Study

(WAFACS);39 and the Zhu et al. trial based in

China.40, 43 All three were multi-centre trials; the

HOPE-2 and WAFACS trials randomized between 5442

and 5522 participants,39, 46 while the Zhu et al. trial

had a sample of only 216.40 The populations in these

studies had various conditions, including cardiovascu-

lar disease, diabetes and atrophic gastritis, but none

had a history of colorectal cancer nor were they at

any greater risk of colorectal cancer than the general

population. The mean age reported in the three studies

ranged from 55 to 69 years. All three trials included

comparisons against placebo: HOPE-2 and WAFACS

compared folic acid (2.5 mg ⁄ day) plus vitamin B6

(50 mg ⁄ day), and vitamin B12 (1 mg ⁄ day) against pla-

cebo;39, 46 the smaller Zhu et al. trial compared folic

acid (20 mg ⁄ day) for 1 year, then 20 mg twice weekly

for 1 year plus vitamin B12, against placebo.40 The

duration of treatment ranged from 2 to 7 years. The

follow-up ranged from 5 to 7 years.

The HOPE-2 study was assessed as being of

good quality:45, 46 it had adequate allocation conceal-

ment and described methods of blinding. Allocation

concealment, generation of the randomization

sequence and methods of blinding were all unclear in

the two remaining studies. The HOPE-2 trial, however,

only performed a power calculation for the primary

outcome, which was a composite of death from cardio-

vascular causes, myocardial infarction and stroke; no

calculation was performed for secondary outcomes,

which included colorectal cancer. A power calculation

was performed by the WAFACS trial and the required

sample size was achieved for the designated out-

come,39 but no power calculation was performed in

the Zhu et al. trial. In all three studies, fewer than 5%

of those randomized participants were excluded from

the analysis of participants, and all three studies

applied an intention-to-treat analysis.

No adenoma data were reported by these trials, but

colorectal cancer was measured as an outcome. No

study found a statistically significant effect of folic

acid on either the relative or absolute risk of colorectal

cancer. Meta-analysis of all three studies (11 062

participants) comparing folic acid plus B vitamins

(with or without antioxidants) vs. placebo (with or

without antioxidants) demonstrated that the relative

risk of developing colorectal cancer was slightly raised

in the group receiving folic acid plus B vitamins (RR

Study or subgroup

AFPPS 2007Jaszewski et al 2008ukCAP 2008

Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.10; Chi² = 8.65, df = 2 (P = 0.01); I ² = 77%Test for overall effect: Z = 0.35 (P = 0.73)

Events

871065

162

Total

16846

215

429

Events

702256

148

Total

16245

204

411

Weight

40.3%22.6%37.0%

100.0%

M-H, Random, 95% CI

1.20 [0.95, 1.51]0.44 [0.24, 0.83]1.10 [0.81, 1.49]

0.93 [0.61, 1.41]

Folic acid alone Placebo alone Risk ratio Risk ratioM-H, Random, 95% CI

0.01 0.1 1 10 100Favours folic acid Favours placebo

Figure 2. Adenoma recurrence: Folic acid vs. placebo within populations with a history of adenomas.

Study or Subgroup

AFPPS 2007ukCAP 2008

Total (95% CI)


Events

8765

152

Total

168215

383

Events

7056

126

Total

162204

366

Weight

63.4%36.6%

100.0%

M-H, Random, 95% CI

1.20 [0.95, 1.51]1.10 [0.81, 1.49]

1.16 [0.97, 1.39]

Folic acid alone Placebo alone Risk ratio Risk ratioM-H, Random, 95% CI


Figure 3. Adenoma recurrence: Folic acid vs. placebo within populations with a history of adenomas.




1.13, 95% CI 0.77–1.64, P = 0.54; RD 0.00, 95% CI

0.00–0.01, P = 0.76) (see Table 2 and Figure 4).

Adverse events

No studies in any population reported any differences in

serious adverse event rates between the folic acid and

placebo groups. The AFPPS trial reported a higher

occurrence of non-colorectal cancers in the folic acid

group and originally surmised that this was because of a

higher baseline rate of prostate cancer in that group.38

However, it has been concluded subsequently that the

higher rate of prostate cancer in the folic acid group

may be attributable to the potential adverse effect of this

agent as a supplement, in contrast to dietary folate.48

DISCUSSION

Five of the six trials included in this review have been

published since 2006, highlighting the recent interest

in the chemopreventive effects of folic acid. The prin-

cipal analysis of three trials in populations with a his-

tory of adenomas reported a non-statistically

significant reduction in risk of adenoma recurrence. In

contrast, a sensitivity analysis of the two largest, bet-

ter quality trials of folic acid (0.5–1.0 mg ⁄ day) showed

no statistically significant difference in the relative

risk of adenoma recurrence, but changed the direction

of effect: the risk of this outcome appeared to be

higher in the folic acid groups. This trend was also

apparent for advanced adenoma data and also in the

second interval data from the AFPPS trial (from 3 to

5 years after the first 3-year follow-up).38

The smaller, lower quality Jaszewski et al. trial was

the only study to report a positive, statistically signifi-

cant reduction in the mean number of adenomas in

the folic acid arm of the trial (Odds ratio = 2.77) and

its inclusion in the meta-analysis clearly affected the

direction of effect. However, there are good reasons to

consider the sensitivity analysis, which excluded this

trial, to offer the more robust and reliable result. First,

there were missing data and inconsistencies in the

reported numbers in each arm in the Jaszewski et al.

trial. Secondly, this trial used a markedly higher dose

of folic acid (5 mg ⁄ day) than the ukCAP or AFPPS tri-

als (0.5–1 mg ⁄ day) (despite higher doses being poten-

tially associated with accelerated carcinogenesis).49

And, finally, no power calculation was performed and,

with only 91 participants, it may not have been ade-

quately powered to generate a reliable outcome. Inclu-

sion of this trial in the meta-analysis also generated

considerable statistical heterogeneity. Sensitivity anal-

yses based on study quality have also been shown

before to alter the direction of effect significantly in

trials of potential agents for chemoprevention, with

lower quality studies demonstrating effects not mir-

rored by larger, better quality studies.50 The meta-

analysis of the two larger, higher quality trials here

also offers the more reliable evidence on direction of

effect. One of these trials also controlled for alcohol

consumption,38 which may be a potential confounding

variable in any assessment of the chemopreventive

properties of folic acid. 30 Addition of aspirin as an

agent appears to moderate the possible adverse effect

of folic acid, regardless of dose. This is consistent with

the fact that aspirin has been found to be effective in

reducing the risk off adenoma recurrence in popula-

tions with a history of adenomas.17, 18

Three studies of supplemental folic acid in popula-

tions with no increased baseline risk of colorectal can-

cer also failed to demonstrate a statistically significant

beneficial effect of this agent; but again, the relative

risk of the outcome, in this case colorectal cancer,

was slightly higher in individuals receiving folic

acid within these studies. Rather than the intended

beneficial effect anticipated, there therefore appears to

Study or Subgroup

HOPE-2 2006WAFACS 2008Zhu et al 2003

Total (95% CI)


Events

5018

0

68

Total

27582721

44

5523

Events

3722

1

60

Total

27642721

54

5539

Weight

65.3%33.3%

1.4%

100.0%

M-H, Random, 95% CI

1.35 [0.89, 2.06]0.82 [0.44, 1.52]0.41 [0.02, 9.76]

1.13 [0.77, 1.64]

Folic acid+b vit+/–antiox Placebo +/– antioxidants Risk ratio Risk ratioM-H, Random, 95% CI


Figure 4. Colorectal cancer incidence: Folic acid + b vitamins � antioxidants vs. placebo � antioxidants.




be a non-significant trend towards adenoma recur-

rence in populations with a history of colorectal ade-

nomas taking supplemental folic acid, as well as

towards colorectal cancer in general populations.

However, there does not appear to be a linear dose-

response relationship between folic acid and colorectal

cancer across these trials: the same high dose of folic

acid produced very different event rates of colorectal

cancer across two trials.39, 46 The small size of the

third trial and its lack of event data do not permit

conclusions to be drawn on this.40

These results appear to contradict the findings of

observational and animal studies, which indicate that

low folate diet is associated with higher risk of colo-

rectal cancer and that folic acid might suppress cancer

growth.25–30 However, other studies suggest that high

or even ‘normal’ doses of folic acid may accelerate

cancer progression if pre-neoplastic lesions are pres-

ent,49, 51, 52 and only a folate-depleted diet may slow

tumour progression.52 The complexity of the relation-

ship between supplemental folic acid and cancer risk

has understandably generated much recent discussion

and, in some cases, concern, especially in relation to

the policy of fortification of flour with folic acid;53–57

the primary prevention of neural tube defects (NTDs)

in babies being the principal driver behind this pol-

icy.58 These recent commentaries on the role of folic

acid seek to understand why the AFPPS and ukCAP

trials have produced their apparently ‘negative’ results;

explanations include the possible presence of unidenti-

fied lesions with cancer potential in these already at-

risk populations,55 the detrimental effect of synthetic

as opposed to natural, dietary folate48, 54 and the

body’s failure to metabolize higher, supplemental

doses of this B vitamin.51 However, none of these

reviews or commentaries considers the randomized

controlled trials of individuals with no increased base-

line-risk, which are meta-analysed here, but instead

focus only on epidemiological data from the USA and

Canada post-fortification of foods with folic acid.52

The meta-analysis of trials of supplemental folic acid

in general populations presented here mirrors the trend

apparent in the trials of individuals with a history of

colorectal adenomas, albeit at mostly higher doses of

the agent. However, these results must also be treated

with caution for a number of reasons. First, the dura-

tion of follow-up in these general population studies

was only 5–7 years, which may not be long enough to

detect a reliable effect on cancer occurrence: at least

10 years may be required.12, 13 Secondly, none of the

studies included in this second meta-analysis was of

particularly high quality. Thirdly, there may have been

participants in these trials who had adenomas, but this

was not tested for at baseline. Finally, the agents con-

sidered in combination with folic acid in these studies

(antioxidants, including beta-carotene) have also been

associated with increased risk of gastro-intestinal can-

cers in general population studies.23, 49 Consequently,

the hypothesis that folic acid may only have an

adverse effect in the presence of pre-existing lesions

cannot be disproved by the analysis of general popula-

tions reported above. Further limitations are that these

analyses only included 2 or 3 trials in total and that

the age range in all 6 included trials was 55–69 years,

which is somewhat younger than the median age of

individuals at diagnosis of colorectal cancer.3, 4

There remain important questions therefore concern-

ing the chemopreventive or cancer promotion proper-

ties of folic acid. Nevertheless, the UK Food Standards

Agency (FSA) recently reaffirmed its advice that the

addition of folic acid to flour should be mandatory,

judging that the existing research had limited power to

detect an effect on cancer risk.59 However, the agency

also recommended precautionary advice on voluntary

supplementation by individuals at greater than average

risk of developing adenomas, acknowledging the

potential risk to individuals with pre-existing lesions.

Qualitative evidence from the UK also suggests, how-

ever, that people do have concerns regarding the risks

associated with mandatory fortification of flour with

folic acid, and may be unwilling to accept it unless

alternative products are made available, labelling is

explicit and cost is not affected.60 Policy-making based

on current evidence is no easy task.

A recently published review by Fife et al. (2009)31

that evaluated the supplemental effect of folic acid on

colorectal cancer and its precursors also reported a

potential adverse effect of this agent. However, Fife

et al. reported a significant adverse effect of supple-

mental folic acid both on adenoma and advanced ade-

noma recurrence for those who receive the agent for

more than 3 years. This greater adverse effect is in

part because of Fife et al. identifying only three of the

six relevant trials included in the present review. These

three trials also all reported an adverse effect for folic

acid,37, 38, 46 while the three trials missed by that

review either reported no effect or a positive effect for

this agent.39, 40, 44 Publication bias may therefore be

present and the adverse effect of supplemental folic

acid therefore appears to be exaggerated. The assertion




of a statistically significant adverse effect of folic acid

on adenoma recurrence after 3 years is also unfortu-

nately based on colon cancer event data generated

over the full 5-year period from the HOPE-2 trial

being presented and analysed as adenoma event data

from 3 years onwards. Consequently, the findings of

the review and meta-analysis by Fife et al. must be

treated with caution. The findings of the present

review, although more conservative, present a compre-

hensive evaluation of all available data on the impact

of supplemental folic acid on adenomas, advanced

adenomas and colorectal cancer in populations at dif-

ferent levels of risk.

The approach for future research is difficult to deter-

mine. It is clearly important to understand the chemo-

preventive and cancer promotion risk-benefit

relationship of folate and folic acid and its dose,51, 55

and whether certain groups may benefit from any

potential chemopreventive properties of folic acid.54

However, future trials in human subjects must address

the ethical issues raised by the potential for adverse

effects suggested by the evidence.

There is therefore currently no reliable evidence that

folic acid is effective in chemoprevention for either at-

risk or general populations. Supplemental folic acid at

the evaluated doses may even slightly increase the risk

of adenoma recurrence or colorectal cancer in both

populations. Caution must be exercised with these

results, however, as the number of studies is small and

the length of follow-up is potentially too short for

evaluating colorectal cancer as an outcome.

ACKNOWLEDGMENTS

Declaration of personal interests: None. We thank

Professor Richard Logan for his comments on a

version of this paper and Dr Adhip Majumdar for

providing unpublished data at our request. Declara-

tion of funding interests: This study was funded [in

part] by the UK National Co-ordinating Centre for

Health Technology Assessment (NCCHTA 06/70/01).

Writing support was provided by University of Shef-

field. None of the authors has any conflicts of interest

to declare.

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meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer

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