Prevention of cervical intraepithelial neoplasia and ...

Prevention cancer”

of cervical

intraepithelial

neoplasia

and cervical

-

Frank

L Meyskens

Jr and

ABSTRACT in the management cervical

We review of cervical

cancer.

shown

Two

that folic

CIN.

A large

acid

with

CIN

indicate

that

large,

was

effective

from

a pilot

dysplasia)

/3-carotene

acid,

applied

suppress

CIN:

a large

more

cancer,

retinoic

retinoic

moderate

but

30 patients dysplasia) ongoing

ran-

definitively.

Am

chemoprevention

trial,

acid

Folic

(CIN) acid

amount natural

the

and

of data history

cervical

is critical

to DNA

in folic

acid

suggests that of cervical

carcinoma

nutrients may intraepithelial

(1-10)

synthesis

and

or abnormalities

(Table

1).

methylation,

and

in its metabolism

lead

nutrient was shown to be effective CIN and cervical cancer (4, 13).

effect

occurs

through

anism

is unknown

but

affect

its response

directly

subsequently

/3-trans

to represent

the end

general, (retinoids)

reasonable.

retinoic

acid,

virus

infection

CLINICAL Two

CIN

II,

These

at least

over

authors

also

the noted

cell folate concentration with nonusers, which CIN.

Epidemiologic

CIN role,

short

term

(3 mo)

a statistically

lower

in oral contraceptive was particularly marked investigations

of the

were were

sufficiently launched.

The seems cervical

status

encouraging of

vitamins

that A

and

trial

(12).

mean

red

blood

of folic

acid

in

support a protective preliminary studies

definitive C and

of the

users compared in patients with

role

and cervical cancer also consistently although not a strong one (6). These

I and

phase

III

/3-carotene

trials

nutriture

strongest

for

ascorbic

acid

and

serum concentrations are at increased risk; /3-carotene

ciation of CIN with cigarette smoking has observations, because /3-carotene is known ber

of

Am

J C/in

studies Nutr

to

be

protective

l995:62(suppl):I4l7S-9S.

against Printed

(1

of these the data are The

asso-

also extended from a large

these num-

lung

,

3, 9).

cancer.

in USA.

Subse-

© 1995

American

( 14).

In

large,

placebo-controlled,

in the

treatment

deficiency

corrected would

enrolled

randomized

before

alter

subjects

the

who

Over

already

15 y, we

II trials phase

response

rate

(2 1 ), which

I

From

to the

cervix

II trial

the Department

Gynecology,

might

resulted was

phase III trial are summarized

period folic

indoes acid

acid-deficient normal Papa-

disease a series /3-trans

reverse

sufficiently

Irvine,

might

of pilot retinoic

and acid CIN

complete

clinical

encouraging

that

and the Department

of California,

clinic

or suppress

in a 50%

was undertaken; the key in Table 2 (23).

of Medicine

University

folic with

transmitted

whether

The

randomized that study

enlist women

conducted

topically

folic

that

development of histologic outcome because both trials had CIN. To answer this critical

have

(20-22).

using

shown

II over a 3-6-mo addressed whether

to determine

applied

and

of

the

eventual

in a sexually population.

the past I and

trials

convincingly

future trials will need to without CIN; for example,

nicolaou smears be a good study phase

to the evolution

TRIALS

changes

to have a substantial role in the development of CIN and cancer as determined by various epidemiologic stud-

ies. Persons who have low nutrients or low dietary intake

thought

change

evidence suggests and human pap-

to contribute

issue, women

CIN

acid

combine

women

improve

is generally

cellular

of cervical cancer. The amassing vitamin nutriture, cigarette smoking,

I and trial

could

may A and

growth and enhancing maturation (15. 16). Retinoic acid was also shown to influence the maturation state of keratinocytes infected with human papilloma virus (17), an important observation because these viruses appear to be important in the

creased regression of CIN not occur (18, 19). Neither

contraceptives

mech-

carotenoid

and its natural and synthetic derivatives the growth of epithelial cells-slowing

to megaloblastic changes in numerous tissues, including the cervix. Megaloblastic features observed by Papanicolaou smears and related to oral contraceptive use can be reversed by folic acid supplementation ( 1 1 ). Additional studies by Butterworth et al (12) showed that folic acid supplementation in oral

smokthis

to vitamin

which

in affecting

have

used

The

or by conversion

arm

who

against Whether

an antioxidant-mediated

seems

ligand

vitamin A modulate

illoma CIN.

A considerable play a role in

deficiency

this

etiology that low

BACKGROUND

neoplasia

quently, ing-related protective

have

grade

/3-trans

in reversing

the question 14175-95.

Cervix

folic

trials

low to moderate

trial involving CIN II (moderate

and

can

WORDS

/3-carotene,

controlled

in reversing of locally

domized trial will answer J C/in Nutr 1995:62(suppl): KEY

randomized

trial

agent

Results

I (mild that

the current status of prevention trials intraepithelial neoplasia (CIN) and

is inactive

the

CIN.

Manetta

Clinical

results

a

from

of Obstetrics Cancer

Center,

Orange. 2

Supported

a grant 3

from

Address

in part

by National

Hoffmann-La reprint

requests

Center,

101 City Drive,

Society

for Clinical

Institutes

Roche. to

Orange.

Nutrition

Nutley, FL

of Health

grant

CA-62203

and

NI.

Meyskens,

lr,

UCI

Clinical

Cancer

CA 92668. 14175

Downloaded from www.ajcn.org by guest on July 13, 2011

severe

acid

randomized

showed

not

Alberto

14185

MEYSKENS

TABLE Strength

I of evidence

that candidate

chemopreventives

prevent

AND

cervical

cancer’

MANETFA

TABLE

3

Number

of patients

of /3-carotene neoplasia Type

Folic

acid

Epidemiologic

+ +

A

Clinical Phase

+ +

+

/3-Carotene Vitamin

C

1

not

,

trial

,

III trial negative

Phase Phase

3

+ +

Phase

11,2 and

+

+ + +

Phase

III

II trial completed: III trials in cervical

at two different

This

institutions,

randomized

whether

, strong

+ + +

and/or

Phase

CIN.

III trial

was

retinoic

Analyses

(15 1 women

NA,

on

in 1994

to the

301

women

and

(60%)

were

6 mo,

those

associated

have

sions these

150

with

shown

that

in some cases epidemiologic

completed

a phase

II trial

of oral

measurable

residual

lesions

docervical

curettage,

and

and and

with

or in utero exposure treated and received

birth biopsy

of involvement compared

control methods, and koilocytotic

of the using

cervix

Fisher’s

treatment the two

group. patients versible.

at study.

exact

Retinoic acid increased rate of CIN II from 27% retinoic between

entered

for 2 d at months 3 and 6. Patients receiving those receiving placebo were similar with respect

to age, ethnicity, the endocervical

histologic atypia, and Treatment

group arms

(P was

present

effects

of

). No

in

to diethylstilbestrol. 30 mg /3-carotene

of management also provided

chemoprevention

treatment the severe

point. These

might be useful in some patients. further support to the notion that

of human

In addition

cancer

to the substantial

a protective

role

of /3-carotene

and

0.70) between the not produce serum

More vaginal and vulvar side effects were seen in the receiving retinoic acid, but these were mild and reThese results were encouraging and suggested that

this modality The study

of /3-carotene that a plateau

histologic regression group to 43% in the difference dysplasia

phase

results

of endpoint

intraepithelial

to entry

neoplasia

markers

and

data

against

cancers

many

(particu-

biopsy

in participant

with

2.

intervention

Regression2

acid

acid

from reference

biopsy P

=

not 0.041

Other

is complete available)

at

biopsy 15, 9,

en-

malignancy were up to and

CIN

with

extent P

a

I or II

(one to two quadrants 0.002 at 6 mo) did. shed cervicovaginal after 3 mo of oral

an excellent

correlation

Interestingly, of either vitamin and

therefore Various

(R

=

/3-carotene did E or A at any a randomized

biologic

interme-

U

measured.

the participation

I, Palan

Batieha

PR,

of a large

University

number

of California

cervical

Other

32 (43%)

43

18(27%)

48

10 (25%)

30

16(31%)

35

12, 21,

(or endocervical

or 27 mo

for moderate

dysplasia

and

P

is no response

or CIN

upstaged.

=

0.33

as defined for severe

curettage in the dysplasia.

SH, Goldberg

of colleagues Irvine

Cancer

at the Centers.

GL,

Burk

RD.

Romney

SL.

levels in women evaluated for dysplasia. Cancer Detect Prey

de Vet tions

Berry

and

Inst

HC, PR,

6. Butterwoi-th cervical

7. Romney

Romney I NatI

SL, Basu

Morris

the

nested

IS,

Spate

subsequent

case-control

VE,

risk

study.

of

Can-

1993:2:335-9.

PA,

F. Risk Am SL,

McLennan

R, Truswell

AS,

and risk of in situ cervical

Cancer IAMA

factors

I Public Mikhail

levels

CE Ir, Hatch

dysplasia.

EP,

and

Brinton

cancer.

I

1988:80:580-5.

Sturmans

beta-carotene

cancer.

Prey

G. Mock

in diet and plasma

for prevention.

5. Palan if

text.

Biomarkers

KE,

Norkus

micronutrients

in a population-based

Epidemiol

Cancer

HK,

Serum

cancer

Brock NatI

4.

Armenian

GW.

LA. Nutrients

22. response

Vermund

acid and beta-carotene smoking, and cervix

AM,

plasma Regression

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a colposcopy

patients

undertaken.

and

Strict

1991:15:165-70.

cervical

(CIN)’

Placebo Severe

2

be extensively

of Arizona

1 . Basu

cer

Placebo ‘ Reproduced

of

encouraging

will

CIN.

lesions cornCIN I and II,

Thirty patients orally per day for

to have findings.

was

been

for

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