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CLINICAL AND SYSTEMATIC REVIEWS

The American Journal of GASTROENTEROLOGY VOLUME 112 | AUGUST 2017 www.nature.com/ajg

1234

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INTRODUCTION

Screening for colorectal cancer (CRC) has been proven as an

eff ective prevention strategy to reduce CRC incidence and

mortality ( 1 ). Many international guidelines recommended CRC

screening by fl exible sigmoidoscopy (FS) on a 5-yearly basis, and

colonoscopy were performed 10 yearly ( 2–4 ). FS has been demon-

strated to reduce CRC mortality by randomized controlled

trials and systematic reviews. In relatively resource-deprived

countries where colonoscopic capacity may be limited, FS bears

potential as a primary screening test as it can be performed by

The Association between Distal Findings and Proximal

Colorectal Neoplasia: A Systematic Review and

Meta-Analysis

Jason L.W. Huang , MD 1 , 9 , Y.H. Wang , PhD 2 , 9 , Johnny Y. Jiang , PhD 3 , C.P. Yu , PhD 4 , Y.L. Wu , MD 5 , P. Chen , MD 5 , X.Q. Yuan , MD 5 , Harry H.X. Wang , PhD 6 and Martin C.S. Wong , MD 1 , 7 , 8

OBJECTIVES: Whether screening participants with distal hyperplastic polyps (HPs) detected by fl exible sigmoido-

scopy (FS) should be followed by subsequent colonoscopy is controversial. We evaluated the

association between distal HPs and proximal neoplasia (PN)/advanced proximal neoplasia (APN) in

asymptomatic, average-risk patients.

METHODS: We searched Ovid Medline, EMBASE, and the Cochrane Library from inception to 30 June 2016 and

included all screening studies that examined the relationship between different distal fi ndings and

PN/APN. Data were independently extracted by two reviewers with disagreements resolved by a

third reviewer. We pooled absolute risks and odds ratios (ORs) with a random effects meta-analysis.

Seven subgroup analyses were performed according to study characteristics. Heterogeneity was

characterized with the I 2 statistics.

RESULTS: We analyzed 28 studies (104,961 subjects). When compared with normal distal fi ndings, distal HP

was not associated with PN (OR=1.16, 95% confi dence interval (CI)=0.89–1.51, P =0.14, I 2 =40%)

or APN (OR=1.09, 95% CI=0.87–1.36, P =0.39, I 2 =5%), while subjects with distal non-advanced

or advanced adenoma had higher odds of PN/APN. Higher odds of PN/APN were observed for more

severe distal lesions. Weaker association between distal and proximal fi ndings was noticed in studies

with higher quality, larger sample size, population-based design, and more stringent endoscopy

quality-control measures. The Egger’s regression tests showed all P >0.05.

CONCLUSIONS: Distal HP is not associated with PN/APN in asymptomatic screening population when compared with

normal distal fi ndings. Hence, the presence of distal HP alone detected by FS does not automatically

indicate colonoscopy referral for all screening participants, as other risk factors of PN/APN should be

considered.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Am J Gastroenterol 2017; 112:1234–1245; doi: 10.1038/ajg.2017.130; published online 30 May 2017

1 School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong , Hong Kong , China ; 2 School of Basic Medicine, Peking Union

Medical College and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences , Beijing , China ; 3 Peking Union School of Public Health, Chinese

Academy of Medical Sciences and Peking Union Medical College , Beijing , China ; 4 Li Ping Medical Library, Chinese University of Hong Kong , Hong Kong , China ;

5 North Ruijin Hospital, Shanghai Jiaotong University , Shanghai , China ; 6 School of Public Health, Sun Yat-sen University , Guangzhou , China ; 7 Institute of Digestive

Disease, Faculty of Medicine, Chinese University of Hong Kong , Hong Kong , China ; 8 State Key Laboratory of Digestive Disease, Chinese University of Hong Kong,

Hong Kong, China ; 9 These authors contributed as equal fi rst authors . Correspondence: Martin C.S. Wong, MD, MPH, School of Public Health, Prince of Wales

Hospital , Shatin , Hong Kong SAR, China . E-mail: [email protected] Received 7 November 2016 ; accepted 1 April 2017

CME

Distal Findings and Proximal Neoplasia

© 2017 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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1235

primary care practitioners ( 2 ). FS-based screening could exam-

ine neoplastic lesions in the distal colorectum. Any distal lesions

detected could indicate synchronous risk of proximal neoplasia

(PN) and advanced proximal neoplasia (APN). According to the

latest US Preventive Services Task Force Recommendation State-

ments published in 2016 ( 5,6 ), FS is one of the preferred tests of

choice designed both to detect and prevent CRC if colonoscopy is

not available or acceptable to patients.

Understanding the association between distal and proximal

fi ndings is clinically important, as it guides subsequent follow-

up for subjects with distal lesions found on FS. In four published

meta-analyses ( 7–10 ), the relationship between distal hyperplastic

polyp (HP) and PN/APN in asymptomatic population presented

mixed conclusions. Dave et al. ( 7 ) proposed that, for asymptomatic

subjects, any distal HP detected by FS should be referred for colo-

noscopy workup due to an excessive 20–25% risk of any PN and

4–5% risk of APN. Th is conclusion was later challenged by fi nd-

ings from two meta-analyses ( 8,9 ) that found no excessive risk of

PN or APN conferred by the presence of distal HPs. However, the

latest meta-analysis performed in 2012 that examined the relation-

ship between distal lesions and PN/APN ( 10 ) concluded that all

types of distal lesions, including HPs, were predictive of PN while

all types of distal neoplasia were predictive of APN. Among these

four meta-analyses, nevertheless, three were published more than

a decade ago; and in the latest study published in 2012, approxi-

mately one-third of all the articles (12 in 40) selected were from

symptomatic subjects, and hence its generalizability to guide CRC

screening among asymptomatic subjects was limited. In addition,

since year 2012, several studies with large sample size ( 11–16 ) were

published and many of them were from population-based screen-

ing programs ( 13–15 ). Th ese additional studies allow re-synthesis

of existing data to evaluate the association between distal and

proximal lesions.

Th e purpose of this systematic review and meta-analysis is to

analyze all available data on the risk of PN and APN in asympto-

matic subjects who were detected as having distal lesions with dif-

ferent types of histopathology. In particular, we tested the a priori

hypothesis that distal HP was not associated with PN in asympto-

matic screening populations, aiming to inform necessity of subse-

quent colonoscopy workup for individuals with distal HP detected

by FS.

METHODS

Search strategy and selection criteria

Th e systematic review and meta-analysis adhered to the PRISMA

(Preferred Reporting Items for Systematic reviews and meta-

Analyses) statement ( 17 ), performed according to a predeter-

mined protocol. We searched Ovid Medline (1946 to 30 June

2016), EMBASE (1976 to 30 June 2016), and the Cochrane

Library (1988 to 31 May 2016). Th e search strategy was listed as

below:

1 . Rectal Neoplasms/or Colorectal Neoplasms/or Colonic

Polyps/or Colonic Neoplasms/

2 . (((colon* or rectal or colorectal) adj (cancer* or neoplas* or

tumor* or tumour* or carcinoma* or sarcoma* or adenom*

or adeno?carcinoma* or lesion* or polyp*)) or CRC).ti,ab.

3 . ((proximal or right-side* or “right side*”) adj2 (neoplas* or

lesion* or tumor* or tumour* or polyp*)).mp.

4 . ((distal or left -side* or “left side*”) adj2 (neoplas* or lesion*

or tumor* or tumour* or polyp*)).mp.

5 . case control studies/ or cohort studies/or cross-sectional

studies

6 . ((cohort adj (study or studies)) or “case control” or “cohort

analy*” or (observational adj (study or studies)) or longitudi-

nal or retrospective or “cross sectional” or cross-sectional or

(follow up adj (study or studies))).mp.

7 . 1 or 2

8 . 5 or 6

9 . 3 and 4

10 . 7 and 8

11 . 9 and 10

We restricted our search to cross-sectional studies, case control

studies, and prospective cohort studies on CRC screening that

examined the relationship between distal fi ndings of various

histopathology and PN/APN for average-risk, asymptomatic

subjects. Th e following types of studies were excluded:

1 . Studies that recruited symptomatic patients ( 18,19 );

2 . Studies that did not examine the association between distal

and proximal fi ndings ( 20 );

3 . Studies without data on PN or APN ( 21,22 );

4 . Studies where the screening participants had high risk for

CRC, such as those with positive family history ( 23 );

5 . Studies that consist of data on proximal advanced serrated

lesions only ( 24 ).

We obtained data from summary estimates of all eligible studies

without any language limitations. Reference lists of eligible studies

and related meta-analyses were hand searched to identify further

relevant studies.

Data analysis

Two reviewers (J.L.W.H., Y.H.W.) independently screened all

abstracts identifi ed in the initial search and excluded studies

not fulfi lling the eligible criteria. Th ey extracted data from all

selected full-text articles reviewed in duplicate, and in cases of

disagreement, consensus was made via referral to a third reviewer

(M.C.S.W.). Th e following variables were collected from each

study: sample size, mean age of study participants, proportion

of male subjects, research type (cross-sectional, case control, or

cohort studies), endoscopic strategies (colonoscopy; sigmoido-

scopy followed by colonoscopy, if necessary), and program design

(population-based or opportunistic screening), as well as endo-

scopy quality-control measures (critical or normal).

In these studies, the odds ratio (OR) and absolute risk for PN

or APN conferred by distal HP, distal adenoma (AD), or distal

advanced neoplasia (AN), when compared with subjects with

Huang et al.


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normal distal fi ndings, were retrieved. Th e proportions of individu-

als with PN and APN in all eligible studies were also examined. Th e

proportions of PN and APN were fi rst synthesized and then exam-

ined in four types of subjects with various distal fi ndings: normal,

HP, AD, and AN. AN was defi ned as adenomas measuring ≥10 cm,

adenomas with villous portions, high-grade dysplasia, adenocar-

cinomas, or any combination thereof ( 20 ). If multiple lesions were

reported in one subject, we used the most advanced distal or proxi-

mal lesion as the fi nding. Th e primary outcomes included the ORs

and proportion of PN or APN among the subgroups of HP, AD,

or AN, as well as the respective 95% confi dence interval (CI). Th e

Mantel–Haenszel method based on a random-eff ects model was

used. We tested for heterogeneity by calculating P value and the I 2

statistic in a standard manner, where I 2 >50% or P <0.05 was consid-

ered as a threshold indicating signifi cant heterogeneity.

We used the statistical analysis soft ware (Revman 5.3, Copenhagen,

Denmark: Th e Nordic Cochrane Centre, Th e Cochrane Collabora-

tion, 2014) to synthesize the pooled estimation of OR and perform

subgroup analysis. We explored potential publication bias with an

inverted funnel plot analysis with Eggers’ regression model by Com-

prehensive Meta Analysis (version 2.2, Biostat, 2011, Englewood, NJ).

Subgroup analysis

We conducted a comprehensive quality assessment for all

selected studies during our review process. Because our selected

articles are observational studies, we employed the Newcastle

Ottawa Scale for cross-sectional studies ( 25 ) to evaluate the

selection, comparability, and outcome among the studies. We

renamed the index according to the above identifi ed variables.

Studies that reported compliance with endoscopic quality-con-

trol protocols were scored 2 while studies that did not report

endoscopic quality were scored 1. If there were no descriptions

of the endoscopic tests, a zero score was assigned. For pathol-

ogy reporting of colorectal fi ndings, we assigned a score of 2 for

blind reporting with universal pathological standard; a score of 1

for simple description of the reporting process, and 0 for studies

giving no details. For subject selection, those studies collect-

ing data based on population registries, enrolling subjects from

predefi ned protocols, or GP rosters were given 1 point; while

recruitment of patients from special populations or physician

referral were given zero points, owing to the limited representa-

tiveness of the target population. Because the average sample

size of our selected studies were >3,000, we named studies with

>3,000 subjects as large population (score=1), and studies with

sample size <3,000 as small population (score=0). Regarding sta-

tistical tests, if the tests used to analyze the data were described

clearly and judged appropriately, and the measurement of the

association was presented, including CIs and the probability

level ( P value), 1 point was given; otherwise, a zero point was

assigned. If there was a control variable for APN in the study,

Records identified throughdatabase searching (n=235)121 from Embase, 108 from

Ovid Medline, 6 from Cochrane

Additional records identifiedthrough other sources (n=21)including 1 unpublished study

Records after duplicates were removed (n=74)

Records screened(n=182)

Full-text articles assessedfor eligibility

(n=72)

Studies included inmeta-analysis

(n=28)

Records excluded (n=110):Irrelevant studies (n=72), othercolorectal diseases (n=30), reviewarticles (n=8)

Full-text articles excluded (n=44):Symptomatic subjects/ high-risk individuals(n=22), no data for PN or APN (n=12),studies without relationship between distalfindings and PN (n=7), studies onpolypectomy/serrated lesion (n=3)

Iden

tific

atio

nS

cree

ning

Elig

ibili

tyIn

clud

ed

Figure 1 . Results of the literature search. APN, advanced proximal neoplasia; PN, proximal neoplasia.



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1237

Table

1 .

Chara

cte

rist

ics

of

the s

tudie

s in

clu

ded in t

he m

eta

-analy

sis

S

tudy,

year

N

M

ale

(%)

Mean a

ge

(age r

ange)

Rese

arc

h

site

Rese

arc

h

type

Stu

dy

quality

Endosc

opy

opti

on

Endosc

opy

QC

Endosc

opis

t A

DR

(%

) P

opula

tion-

base

d d

esi

gn

AN

defi ned

Dis

tal

defi ned

1

Rex

et

al.

( 26 )

482

NA

N

A (

50–75

) U

S

1

1

0

0

0

25.7

0

0

1

2

Bra

dy

et

al.

( 27

) 162

75.9

62 (

50–8

1)

US

1

3

0

0

0

48.1

0

0

1

3

Levi

n e

t al.

( 28 )

2,9

72

51.2

61.3

(50–9

5)

US

1

5

1

1

0

NA

0

1

1

4

Ikeda e

t al.

( 29 )

3,1

31

100.0

51.9

(48–5

7)

Jap

an

1

4

0

0

3

25.9

0

1

0

5

Lie

berm

an e

t al.

( 30 )

3,1

21

96.8

62.9

(50–7

5)

US

1

6

0

0

3

37.5

0

1

0

6

Imperiale

et

al.

( 31 )

3,0

25

58.0

59.8

(50–)

US

1

5

0

0

1 a

nd 2

N

A

0

1

0

7

Pin

sky

et

al.

( 32

) 8

,802

61.3

63.2

(55–7

4)

US

(P

LC

O)

1

7

1

1

3

NA

1

1

0

8

Bete

s Ib

anez

et

al.

( 33 )

2,2

10

74.6

57.9

(40–9

0)

Sp

ain

1

4

0

0

1

27.9

0

1

0

9

Chiu

et

al.

( 34 )

1,7

08

59.8

52.5

(N

A)

Taiw

an

1

4

0

0

3

15.4

0

1

0

10

Lin

et

al.

( 35 )

2,3

57

50.0

58.8

(40–)

Taiw

an

1

3

0

0

0

18.1

0

1

0

11

Liu

et

al.

( 36 )

5,9

73

52.3

56.6

(40–)

Taiw

an

1

3

0

0

3

16.3

0

1

0

12

Schoenfe

ld e

t al.

( 37 )

1,4

63

0.0

58.9

(50–7

9)

US

1

6

0

1

1 a

nd 2

20.4

0

1

0

13

Str

ul et

al.

( 38 )

1,1

77

47.5

N

A (

40–80

) Is

rael

1

4

0

0

1

39.6

0

1

0

14

Bye

on e

t al.

( 39

) 8

60

54.8

54.4

(20–)

Asi

a

2

4

0

0

3

19.5

0

1

0

15

Choe e

t al.

( 40 )

5,0

86

70.5

49.3

(20–)

Kore

a

1

3

0

0

1

22.6

0

1

0

16

Lio

u e

t al.

( 41 )

2,1

06

56.6

59.5

(50

–)

Taiw

an

1

1

0

0

0

NA

0

1

0

17

Soon e

t al.

( 42 )

1,3

82

60.0

58.8

(50

–)

Taiw

an

1

2

0

0

1

17.6

0

1

0

18

Era

rsla

n e

t al.

( 4

3 )

1,0

64

38.3

66 (

40–)

Turk

ey

1

1

0

0

0

2.9

0

1

0

19

Park

et

al.

( 44 )

3,9

51

60.1

52.1

(20–)

Kore

a

1

4

0

0

3

33.2

0

1

0

20

Levi

tzky

et

al.

( 45 )

3,4

99

46.8

N

A

US

1

4

0

0

1

NA

0

1

0

21

Imperiale

et

al.

( 11 )

10,1

24

56.0

57.5

(50

–)

US

1

5

0

0

3

22.9

0

1

0

22

Park

et

al.

( 12 )

7,5

89

58.3

50.2

(40

–)

Kore

a

2

3

0

0

1

34.9

0

1

0

23

Lucendo e

t al.

( 46 )

696

39.9

57.7

(50

–)

Sp

an

ish

1

4

0

1

3

22.1

0

1

0

24

Cast

ells

et

al.

( 1

3 )

5,0

59

49.6

5

9 (

50–69

) S

pain

2

5

0

1

3

32.6

1

1

0

25

Kie

dro

wsk

i et

al.

( 14 )

10,1

11

34.1

5

5.5

(50–6

5)

Pola

nd

1

4

0

0

0

19.8

1

2

0

26

Wong e

t al.

( 15 )

5,8

79

47.0

57.7

(50–7

0)

Hon

g K

on

g

1

7

0

1

3

32.5

1

1

0

27

Ruco e

t al.

( 16 )

5,1

39

45.1

58.3

(50–7

4)

Can

ad

a

1

6

0

1

0

NA

0

2

0

28

Huang 2

016 (

47 ) a

5,8

33

46.7

60.0

(50–7

5)

Ch

ina

1

5

0

0

3

28.4

0

1

0

AD

R, adenom

a d

ete

ction r

ate

; A

N, adva

nced n

eopla

sia; N

A, not ava

ilab

le;

QC

, qualit

y contr

ol.

a Stu

dy

from

the a

uth

ors

of th

is s

yste

matic r

evi

ew

(unpublis

hed b

y th

e s

tudy

sele

ction p

eriod):

rese

arc

h t

ype:

1=

cro

ss-s

ectional st

udy,

2=

cohort

stu

dy;

stu

dy

qualit

y: N

ew

cast

le O

ttaw

a S

cale

scale

score

(h

igh

: 4

–7

; lo

w:

1–3);

endosc

opy

option: 0=

colo

nosc

opy,

1=

fl exi

ble

sig

moid

osc

opy

follo

wed b

y colo

nosc

opy,

if necess

ary

; endosc

opy

QC

: 0=

norm

al m

easu

res,

1=

hig

h-leve

l qualit

y contr

ol; e

ndosc

opis

t: 0

=not m

entioned, 1=

gast

roente

rolo

gis

t,

2=

surg

eons,

3=

exp

erienced

endosc

opis

ts; popula

tion-b

ase

d d

esi

gn p

rogra

m:

0=

no,

1=

yes;

adva

nced n

eopla

sia d

efi nitio

n:

0=

NA

, 1=

adenom

as

measu

ring ≥

10

cm

, ad

en

om

as

with

vill

ou

s p

ort

ion

s, h

igh

-gra

de d

ysp

lasi

a,

adenocarc

inom

as,

or

any

com

bin

ation there

of, 2

=1 a

nd a

dva

nced s

err

ate

d lesi

ons;

dis

tal defi ned:

0=

dis

tal-to

-sple

nic

fl e

xure

, 1=

recto

-sig

moid

colo

n.

Huang et al.


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reported that distal HP had higher odds of PN and APN, when

compared with individuals with normal distal fi ndings. Subjects

with distal AD had signifi cantly higher odds of PN (OR=2.36, 95%

CI 1·91–2·92) and APN (OR=2·52, 95% CI 1·84–3·46) compared

with subjects with normal distal fi ndings. Th ese increased odds

could also be observed in subjects with distal AN. It was found

that the more advanced the distal lesions, the higher the odds of

PN/APN. Th ere was no signifi cant heterogeneity when the asso-

ciations between distal HP and PN ( I 2 =40%, P =0.28)/APN ( I 2 =5%,

P =0.39) were examined ( Figure 3a,b ).

Table 4 shows subgroup analyses according to study character-

istics that were regarded as potential moderators of the association

between distal fi ndings and PN/APN. Weaker associations were

noticed in high-quality studies than in low-quality ones (AN-PN);

in studies with large sample size than those with small sample size

(AD-PN); in studies based on population-based design than those

based on opportunistic screening approaches (AN-PN, AD-APN,

AN-APN, HP-APN); in studies with critical endoscopy qual-

ity control than in studies with normal quality-control measures

(AN-PN, AN-APN); in studies where distal lesions were defi ned as

those located in rectosigmoid vs. studies where distal lesions were

defi ned as those distal to the splenic fl exure (AD-APN, AN-APN);

in studies where FS was performed followed by colonoscopy as a

separate procedure than in studies where only colonoscopy was

performed (HP-PN, AD-PN, AD-APN, AN-PN, AN-APN). Sup-

plementary Figure S1 illustrates the Egger’s regression tests for

publication bias. Except for distal AN-APN, all regression tests

had P values >0.05. Th e pooled prevalence of isolated PN (5.6%,

95% CI 3.3–9.1%) and isolated APN (1.0%, 95% CI 0.9–1.2%) are

shown in Supplementary Figure S2 ). Th e proportion of APN was

1.9% (95% CI 1.5–2.5%) among subjects with normal distal fi nd-

ings and 2.4% (95% CI 1.9–3.1%) among subjects with distal HPs

( P =0.390).

DISCUSSION

Th is study found that distal HP was not associated with higher

odds of APN or PN. Th e fi ndings were robust from subgroup

analyses with no publication biases detected. On the contrary, the

presence of distal AN or AD were signifi cantly associated with

APN/PN. Whether to refer subjects with distal HP detected by

FS for colonoscopy workup has been the subject of a long-lasting

debate beginning in the 1980s–1990s, leading to three meta-anal-

yses performed in the early 2000s. Th e study by Lin et al. ( 9 ) was

the only evaluation that performed subgroup analysis stratifying

21 studies into screening and diagnostic cohorts. It was concluded

that there was no increased risk of PN and APN in subjects with

distal HP when compared with those having normal distal fi nd-

ings, based on observations in asymptomatic screening individu-

als. Two meta-analyses ( 7,8 ) reported that in screening studies the

relative risk of distal HP for PN (1.3, 95% CI 0.9–1.8), the OR of

distal HP for PN (1·44, 95% CI 0.79–2.62), and the OR of distal

HP for APN (1.63, 95% CI 0.61–4.33) were not statistically sig-

nifi cant, yet a recent meta-analysis found that HP was a predictor

for PN (OR=1.8, 95% CI 1.3–2.5) ( 10 ). Our study is consistent

one extra mark was given. Th us there was a maximum of eight

points for Newcastle Ottawa Scale assessment in this study.

Again, two authors assessed all the selected studies separately

and sought consensus for any disagreements through referral to

the third reviewer.

Th e data were expected to be heterogeneous. Seven subgroup

analyses on the risk of PN and APN were conducted according to

the study characteristics: (1) study quality: high-quality score (4–8)

vs. low-quality score (1–3); (2) sample size: n >3000 vs. n ≤3000;

(3) program design: population-based vs. opportunistic screening;

(4) endoscopy quality control: normal procedures vs. high-level

quality control; (5) the inclusion of serrated lesion in the defi ni-

tion of AN vs. not; (6) the defi nition of distal lesions: based on

the splenic fl exure as the demarcation point vs. the rectosigmoid;

and (7) the procedure of examination: FS followed by a subsequent

colonoscopy as a separate procedure vs. colonoscopy only. Th ese

subgroup analyses are important as we perceived them as potential

eff ect modifi ers of the present meta-analyses.

RESULTS

A total of 235 titles were obtained from the three databases

( Figure 1 ), in addition to another 21 titles from previous system-

atic reviews and 1 unpublished study performed by our research

group) ( 47 ). Aft er excluding 74 duplicates, 182 abstracts were

reviewed. Among them, 110 articles were excluded based on the

selection criteria. Aft er reviewing 72 full texts, 44 studies were

found ineligible. Twenty-eight studies were fi nally included in the

meta-analysis with a total of 104,961 subjects ( Table 1 ), and the

adenoma detection rate ranged from 2.9% to 48.1%. Th e major-

ity of selected studies that employed a population-based design in

recruiting subjects were of high quality and used large sample size

that were published aft er 2010 ( Table 2 ).

From available data among the selected studies, the proportion

of PN was 13.2% (95% CI, 10.7–16.1%) and that for APN was

2.2% (95% CI, 1.7–2.8%) ( Figure 2a,b ). Table 3 shows the pooled

proportion and OR for the association between distal lesions and

PN/APN. Among asymptomatic subjects, neither PN (OR=1.16,

95% CI 0.89–1.51, P =0.14, I 2 =40%) nor APN (OR=1.09, 95% CI

0.87–1.36, P =0.39, I 2 =5%) was associated with distal HP when

compared with those having normal distal colon. Very few studies

Table 2 . Studies characteristics in different decades

Year range of publication 1990–1999 2000–2009 2010–2016

Studies with large sample

size a (%, n / N )

0 (0/3) 43.8 (7/16) 88.9 (8/9)

High-quality studies b

(%, n / N )

33.3 (1/3) 62.5 (10/16) 88.9 (8/9)

Population-based studies

(%, n / N )

0 (0/3) 6.3 (1/16) 33.3 (3/9)

a Studies with large sample size: n >3000.

b High-quality study: Newcastle Ottawa Scale 4–7.



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1239

with the fi ndings by Lin et al. ( 9 ), demonstrating no increased

risk of PN/APN for distal HP when compared with subjects who

had normal distal fi ndings. Our results imply that subjects with

distal HP detected by FS should not be automatically referred for

subsequent colonoscopy workup. Yet the fi ndings of the present

study should be interpreted with caution, as there is still a risk of

PN/APN in subjects with normal distal colon or distal HPs—and

proximal lesions could only be detected by colonoscopy. Th is is

refl ected by the pooled prevalence of isolated PN (5.6%) and iso-

lated APN (1.0%), which could be regarded by some as signifi cant

and should be taken into account when one considers arrange-

ment of follow-up colonoscopy.

Association studies between distal lesions and PN are impor-

tant, given FS can only visualize the distal colon. Th e meta-analysis

performed by Dodou and De Winter ( 10 ) found that the higher the

histological grade of the distal fi nding, the higher the risk for both

Brady et al. (1993)

a

Byeon et al. (2007)

Castells et al. (2013)

Chiu et al. (2005)

Choe et al. (2007)

Erarslan et al. (2009)

Ikeda et al. (2000)

Ievin et al. (1999)

Lucendo et al. (2013)

Park et al. (2009)

Park et al. (2012)

Pinsky et al. (2003)

Rex et al. (1992)

Soon et al. (2008)

Strul et al. (2006)

Wong et al. (2014)

42/162

92/860

767/5059

112/1708

570/5086

14/1064

405/3131

667/2972

126/696

288/3951

1679/6200

1681/8802

89/482

98/1382

206/1177

1073/5879

7909/48611

0.259

0.107

0.152

0.066

0.112

0.013

0.129

0.224

0.181

0.073

0.271

0.191

0.185

0.071

0.175

0.183

0.132

0.198

0.088

0.142

0.055

0.104

0.008

0.118

0.210

0.154

0.065

0.260

0.183

0.152

0.059

0.154

0.173

0.107

0.332

0.129

0.162

0.078

0.121

0.022

0.142

0.240

0.211

0.081

0.282

0.199

0.222

0.086

0.198

0.193

0.161

5.7

6.2

6.5

6.3

6.3

6.4

6.4

6.5

6.5

6.5

6.5

6.5

6.5

6.2

6.2

4.9

Study name Events/total

TotalEventrate

Lowerlimit

Upperlimit

Relativeweight

Event rate and 95% Cl

–0.40 –0.20 0.00 0.20 0.40

b

Betes Ibanez et al. (2004)Byeon et al. (2007)Castells et al. (2013)Chiu et al. (2005)Choe et al. (2007)Erarslan et al. (2009)Huang et al. (2016)Ikeda et al. (2000)Imperiale et al. (2003)Imperiale et al. (2012)Kiedrowski et al. (2014)levin et al. (1999)Levitzky et al. (2011)Lieberman et al. (2000)Liou et al. (2007)Liu et al. (2005)Lucendo et al. (2013)Park et al. (2009)Park et al. (2012)Pinsky et al. (2003)Ruco et al. (2015)Soon et al. (2008)Wong et al. (2014)

56/221020/860

255/505919/170846/508612/1064151/583329/313183/3025

196/10124133/10111218/297275/3499128/312146/210691/597321/69633/3951109/6200485/8802167/513924/1382140/5879

2537/97931

0.0250.0230.0500.0110.0090.0110.0260.0090.0270.0190.0130.0730.0210.0410.0220.0150.0300.0080.0180.0550.0320.0170.0240.022

0.0200.0150.0450.0070.0070.0060.0220.0060.0220.0170.0110.0650.0170.0350.0160.0120.0200.0060.0150.0510.0280.0120.0200.017

0.0330.0360.0570.0170.0120.0200.0300.0130.0340.0220.0160.0830.0270.0490.0290.0190.0460.0120.0210.0600.0380.0260.0280.028

4.44.0

4.0

4.54.24.44.54.54.5

4.54.34.54.14.24.54.64.54.14.5

4.4

4.33.8

4.5

Study name

TotalEventrate

Lowerlimit

Upperlimit

Relativeweight

Event rate and 95% Cl

–0.10 –0.05 0.00 0.05 0.10

Figure 2 . Proportion of proximal neoplasia (PN) and advanced proximal neoplasia (APN) in All Selected Studies (Random-Effect). ( a ) Proportion of

proximal neoplasia (PN). ( b ) Proportion of advanced proximal neoplasia (APN). CI, confi dence interval.

Huang et al.


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discriminatory than relying on FS result alone to risk-stratify sub-

jects for colonoscopy in current practice protocols, because of

their limited performance to predict APN ( 13,15 ). Th e results of

the present study are applicable to subjects who have undergone

FS screening, where distal fi ndings are available as a predictor for

PN/APN.

For CRC screening, opportunistic testing for individuals is now

shift ing toward organized population screening program with

high quality-control measures and regular surveillance intervals.

Screening based on population-based design could be more repre-

sentative of real-life practices in organized government programs,

and the ORs of diff erent distal fi ndings to APN and PN in asymp-

tomatic individuals retrieved from studies in such programs might

be more generalizable. On the contrary, opportunistic recruitment

of asymptomatic subjects who received colonoscopy might include

subjects with more diverse risk profi le ( 39 ). Th erefore, stronger

associations between distal fi ndings and APN were observed in

opportunistic screening design with higher degrees of heterogene-

ity. Th e OR for AN-APN and AN-PN in studies that adopted pop-

ulation-based designs could be more representative of real clinical

practice. Endoscopy quality, among all quality-control measures to

ensure high-quality CRC screening programs, is another impor-

tant eff ect modifi er. It is noticed that the OR of distal AN for

APN in the studies with less stringent endoscopy quality control

were higher than that in studies with more stringent quality-con-

trol procedures. Th e explanation of these fi ndings remains to be

explored in future studies.

When serrated lesions were included in the defi nition of AN, it

was observed that the magnitude of the OR was higher; the dif-

ference was, however, not statistically signifi cant as there were

only two studies that included serrated lesions. A previous study

that examined a large cohort of Chinese screening participants

found that the presence of large and proximal serrated polyps was

an independent risk factor for synchronous advanced colorectal

PN and APN. Our study presented a similar result, with relatively

lower ORs. Th e major diff erence in the fi ndings between this study

and the meta-analysis by Dodou and De Winter ( 10 ) in 2012 could

be attributed to a number of diff erences in study design. First, we

have included studies that exclusively examined asymptomatic

individuals as CRC screening participants. In addition, our meta-

analysis included a much larger number of individuals, consisting

of seven additional studies that were published aft er 2011–2012

( 11–16,46 ), and one study performed in China with original data

derived from high-quality colonoscopy procedures. Also, this

meta-analysis has focused on the general screening population

and excluded studies that evaluated the association between dis-

tal and proximal lesions among high-risk individuals that could

potentially infl uence the magnitude of associations.

Proximal shift of CRC and increasing isolated PN have been

reported in recent decades ( 10,48,49 ). Nevertheless, identifi cation

of the association between the distal and proximal colon is particu-

larly valuable in countries where colonoscopic capacity might be

limited. Th is is especially the case as FS is increasingly used in some

countries, including several European nations ( 50 ). Th e prediction

for PN and APN is crucial not only for allocation of colonoscopy

resource in population-based screening programs but also for tai-

loring screening option to reduce avoidable procedures, minimize

unnecessary complications, and reducing health-care cost. A few

prediction models for APN have been devised and validated ( 51 );

however, those models usually required many variables, and their

discriminatory capability was fair. Several studies employed distal

fi nding as predictors in their risk algorithms for APN ( 12,31 ). For

instance, Imperiale et al. ( 31 ) included age, gender, and distal fi nd-

ing as predictors—and the model achieved good internal valida-

tion ( c -statistics=0.74) with high discrimination. Park et al. ( 12 )

employed age, gender, smoking status, and distal fi nding detected

by FS as predictive factors in an APN risk model for colonoscopy

referral among low-risk subjects. Th is strategy might be more

Table 3 . Proportion and OR of PN/APN among subjects of different distal fi ndings (random effects)

Proximal fi nding Distal fi nding N a AR (95%CI) b OR (95%CI) b P value c I 2 (%)

PN Normal 10 15.2 (14.8–15.7) —

HP 6 (1) 14.9 (13.6–16.2) 1.16 (0.89–1.51) 0.14 40

AD 10 (10) 26.8 (25.7–27.9) 2.36 (1.91–2.92) <0.001 79

AN 7 (7) 27.2 (25.7–28.7) 2.92 (2.06–4.15) 0.006 67

APN Normal 13 1.9 (1.5–2.5) —

HP 13 (1) 2.4 (1.9–3.1) 1.09 (0.87–1.36) 0.39 5

AD 18 (11) 3.9 (3.5–4.3) 2.52 (1.84–3.46) <0.001 76

AN 19 (17) 10.4 (9.6–11.3) 5.70 (3.93–8.28) <0.001 74

AD, adenoma; AN, advanced neoplasia; APN, advanced neoplasia; AR, absolute risk; CI, confi dential interval; HP, hyperplastic polyp, OR, odds ratio; PN, proximal

neoplasia.

a Numbers in bracket indicate the studies for which the association was statistically different ( P <0.05).

b AR: The absolute risk of PN (or APN) for subjects with a certain distal fi nding (i.e., normal, HP, AD, or AN) was defi ned as the proportion of subjects with PN (or APN)

and this distal fi nding out of the total number of subjects with that distal fi ndings. OR: the odds ratio refers to the number of subjects with PN (or APN) in the group of

subjects with distal lesions compared with the number of subjects with PN (or APN) in the reference group (normal distal fi nding).

c All P values are from comparisons between different distal lesions and PN/APN, compared with normal distal fi ndings.



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1241

neoplasia and multiple non-AN. Hence, the association between

proximal and distal lesions might be diff erent when serrated

lesions were included as they were considered as markers of more

advanced colonic lesions ( 52 ). In addition, the defi nition of “dis-

tal” was also found to modify the association between APN and

distal AN. Lesions detected in the descending colon and splenic

fl exure may represent more advanced serrated lesion and possibly

serrated polyposis syndrome, in which multiple serrated and HPs

were detected in the whole colon. Furthermore, analyses including

studies with FS followed by a subsequent colonoscopy as a sepa-

rate procedure (vs. colonoscopy alone) generated weaker associa-

tions between proximal and distal lesions. Th is observation might

be attributed to the diff erences in bowel preparation, endoscopic

procedural factors, and the possible involvement of two or more

endoscopists for the former group. As these subgroup analyses

included small number of studies and sample size, future evalua-

tion of these associations by larger-scale studies is required.

Our meta-analysis has a number of strengths. First, it included

asymptomatic, average-risk subjects in all selected studies. Hence,

the application of its fi ndings is more generalizable to screening

practices when compared with previous meta-analyses. Also, it is

the most updated meta-analysis with the largest number of screen-

ing participants included from all published studies. In addition,

various moderators of the association between proximal and dis-

tal fi ndings were addressed in subgroup analyses. We performed a

quality assessment based on an internationally recognized New-

castle Ottawa Scale scale for all the selected articles in a systematic

manner. Nevertheless, some limitations should be mentioned. For

instance, publication bias might exist and we could have missed

some gray literature or informal reports. In addition, the bowel

preparation quality and adenoma detection rate, as well as the

qualifi cation and experience of endoscopists involved in the FS

and colonoscopy procedures, might be diff erent, while most of

the studies performed colonoscopy to simulate a procedure where

FS was followed by colonoscopy. Even though patients might

not have a risk of PN detected if the colonoscopy was performed

at around the same time as the FS, there could be a risk of PN

when the patients receive colonoscopy at a signifi cantly later

time period. Also, larger and more numerous distal HPs could

potentially indicate higher risk, such as the presence of serrated

Figure 3 . Forest plots of the association between distal fi ndings (hyperplstic polyp (HP), adenoma (AD), advanced neoplasia (AN)) and PN/APN

comparing with normal distal fi ndings (Random-Effect). ( a ) Odds of proximal neoplasia (PN). ( b ) Odds of advanced proximal neoplasia (APN). CI,

confi dence interval.

Test for overall effect: Z=1.08 (P=0.28)

60

28295

891

4219

2252082

41472

2881428 422

51

8510224

205

42164912626151

13863281

1.8%0.4%4.9%6.0%2.8%5.9%

21.7%

1.23 [0.35, 4.40]2.79 [0.11, 71.00]1.38 [0.88, 2.18]0.85 [0.66, 1.08]1.28 [0.53, 3.11]1.38 [1.05, 1.81]1.16 [0.89, 1.51]

1.1.2 Distal ADChoe et al. (2007)Erarslan et al. (2009)Ikeda et al. (2000)Levin et al. (1999)Lin et al. (2005)Park et al. (2012)Pinsky et al. (2003)Rex et al. (1992)Strul et al. (2006)Wong et al. (2014)Subtotal (95% CI)Total eventsHeterogeneity: Tau2=0.08; Chi2=43.44, df=9 (P<0.00001); I2=79%Test for overall effect: Z=7.97 (P<0.00001)

1.1.3 Distal ANChoe et al. (2007)Ikeda et al. (2000)Levin et al. (1999)Park et al. (2012)Pinsky et al. (2003)Rex et al. (1992)Strul et al. (2006)Subtotal (95% CI)Total eventsHeterogeneity: Tau2=0.13; Chi2=18.24, df=6 (P=0.006); I2=67%

947

Test for overall effect: Z=5.98 (P<0.00001)

Total (95% CI)Total eventsHeterogeneity: Tau2=0.15; Chi2=136.82, df=22 (P<0.00001); I2=84%Test for overall effect: Z=7.78 (P<0.00001)Test for subgroup differences: Chi2=23.19 df=2 (P<0.00001), I2=91.4%

876

9218262

4085452216

280

1700

38490

461763208900

24415690

9546347

2333

2397

2722378

11061213439

414

1680781

2364171843

4736735208483

280114802

5.9%2.1%5.9%4.8%5.3%6.4%6.1%3.9%4.0%6.3%

50.7%

1.77 [1.34, 2.33]7.90 [2.59, 24.05]1.92 [1.48, 2.49]2.02 [1.26, 3.22]4.16 [2.86, 6.08]2.72 [2.35, 3.15]1.46 [1.17, 1.81]3.31 [1.73, 6.34]2.46 [1.31, 4.63]2.40 [2.01, 2.85]2.36 [1.91, 2.92]

307512710 20252 100.0% 2.19 [1.80, 2.67]

0.01 0.1 1 10 100

3112

41354

4250

12

6950

166590

15522

543482

332

432949

111761

232169290

7467474373256302 4.3%

3.4%5.6%4.8%5.9%0.3%3.3%

27.6%

4.91 [2.77, 8.72]2.47 [1.16, 5.26]2.18 [1.58, 3.00]4.91 [3.06, 7.87]1.94 [1.48, 2.54]

0.87 [0.03, 29.20]3.32 [1.54, 7.16]2.92 [2.06, 4.15]

3087

Study or subgroupa

Events Total Events Total WeightOdds ratio

M-H, random, 95% CIOdds ratio

M-H, random, 95% CI

1.1.1 Distal HPBrady et al. (1993)Erarslan et al. (2009)Lin et al. (2005)Pinsky et al. (2003)Rex et al. et al. (1992)Wong et al. et al. (2014)Subtotal (95% CI)Total eventsHeterogeneity: Tau2=0.04; Chi2=8.35, df=5 (P=0.14); I2=40%

Huang et al.


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people of diff erent ethnicities, yet the present studies recruited

subjects from America, Europe, and Asia only. Th e heterogeneity

of the study fi ndings could be partly accounted for by the pooled

ORs from screening participants of diff erent ethnicities.

polyposis syndrome; yet none of the primary studies consisted

of data on the size and number of distal HPs nor the diff erent

subtypes of serrated lesions. Finally, it is well recognized that

the prevalence and distribution of colorectal neoplasia varied in

Figure 3. Continued.

Betes Ibanez et al. (2004)2.1.1 Distal HP

Byeon et al. (2007)Erarslan et al. (2009)Huang et al. (2016)Imperiale et al. (2003)Imperiale et al. (2012)Levitzky et al. (2011)Lieberman et al. (2000)Lin et al. (2005)

Liu et al. (2005)Pinsky et al. (2003)Ruco et al. (2015)

Liou et al. (2007)

Subtotal (95% Cl)

Betes Ibanez et al. (2004)2.1.2 Distal AD

Byeon et al. (2007)Choe et al. (2007)

Ikeda et al. (2000)

Erarslan et al. (2009)Huang et al. (2016)

Imperiale et al. (2003)Imperiale et al. (2012)

Levitzky et al. (2011)Levin et al. (1999)

Lin et al. (2005)

Liu et al. (2005)Park et al. (2009)Park et al. (2012)Pinsky et al. (2003)Ruco et al. (2015)Schoenfeld et al. (2005)

Liou et al. (2007)

Subtotal (95% Cl)

Total events

Heterogeneity: Tau2=0.01; Chi2=12.68, df=12 (P=0.39); I2=5%Test for overall effect: Z=0.76 (P=0.45)

Total events

Betes Ibanez et al. (2004)2.1.3 Distal AN

Byeon et al. (2007)

Choe et al. (2007)

Ikeda et al. (2000)

Chiu et al. (2005)

Huang et al. (2016)

Imperiale et al. (2003)Imperiale et al. (2012)Kiedrowski et al. (2014)

Levitzky et al. (2011)Levin et al. (1999)

Lucendo et al. (2013)Liu et al. (2005)

Park et al. (2012)

Wong et al. (2014)

Pinsky et al. (2003)Ruco et al. (2015)Soon et al. (2008)

Liou et al. (2007)

Subtotal (95% Cl)

Total (95% Cl)

Total events

406 437

Heterogeneity: Tau2=0.33; Chi2=70.77, df=17 (P<0.00001); I2=76%


Test for subgroup differences: Chi2=60.28, df=2 (P<0.00001); I2=96.7%





110

109

206

13436

7318

33180

384100967461229

1019763331208229380

1095900

235153796

782411

1680794

22322364852

3059171

1348843549

292427914736718

15691367

14366

306

183242179

10118

361003325

19399

543

143017

14737

1837

181183

19

119224169

25850

112267353

16658975

1262190

155221051

2055375

22283 65743

21418 36.5%

100.0%

42

324827

121062063

10356

231621

124

281113

1477302595256416801

7606373362180969675474474614

13314119

117

205

311815469

241810311160344047

164 291

741

17205619481913153042

489196151

12421116373410991765

912757

1393636

1645

15135

0.9%0.8%0.5%2.2%2.2%2.5%2.0%2.4%1.8%1.6%1.9%2.6%2.4%

23.7%

2.1%1.5%2.0%1.7%2.5%2.0%2.3%2.5%2.2%2.4%2.1%2.0%2.3%2.0%2.6%2.6%2.5%2.5%

0.33 [0.04, 2.73]1.30 [0.14, 11.94]2.57 [0.10, 65.37]1.36 [0.62, 3.00]1.69 [0.76, 3.76]1.07 [0.64, 1.80]1.29 [0.51, 1.92]1.03 [0.55, 1.92]0.85 [0.29, 2.53]0.55 [0.16, 1.94]3.15 [1.21, 8.22]0.73 [0.48, 1.13]1.26 [0.72, 2.21]

1.09 [0.87, 1.36]

3.10 [1.39, 689]2.25 [0.57, 8.89]1.32 [0.53, 3.30]

10.07 [3.02, 33.64]2.27 [1.37, 3.78]1.72 [0.68, 4.35]4.76 [2.36, 9.60]2.12 [1.34, 3.35]1.05 [0.50, 2.20]2.99 [1.59, 5.63]2.07 [0.92, 4.68]2.46 [1.01, 6.00]2.78 [1.39, 5.58]1.86 [0.75, 4.64]3.25 [2.13, 4.94]0.89 [0.60, 1.33]2.50 [1.56, 4.01]

9.89 [5.76, 16.98]2.52 [1.84, 3.46]

13.16 [4.37, 39.61]8.76 [1.37, 55.97]

12.70 [5.60, 28.79]11.18 [3.33, 37.48]19.42 [9.09, 41.51]8.11 [1.32, 49.83]8.35 [3.28, 21.23]8.32 [4.20, 16.51]3.58 [2.12, 6.04]1.71 [1.06, 2.77]2.07 [0.51, 8.44]

6.07 [1.53, 24.17]15.98 [7.19, 35.51]3.05 [0.86, 10.84]6.58 [2.16, 20.06]2.59 [1.66, 4.05]3.50 [1.75, 7.01]

3.90 [1.12, 13.52]3.29 [1.99, 5.45]5.70 [3.93, 8.28]

2.82 [2.21, 3.60]

2073819

538300

1244270464225316181

2082563

6447

29190 39.8%

1.8%1.1%2.1%1.7%2.2%1.1%2.0%2.3%2.5%2.5%1.4%1.5%2.1%1.6%1.8%2.6%2.3%1.6%2.5%

10461

564 441

Total events 1134 1169

Study or subgroupDistal finding

Events Total Events Total WeightDistal normal Odds ratio

M-H, random, 95% ClOdds ratio

M-H, random, 95% Cl

0.01 0.1 1 10 100

b



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Table 4 . Subgroup analysis according to study characteristics

Study characteristics HP AD AN

N OR (95%CI) P value a N OR (95%CI) P value a N OR (95%CI) P value a

Study quality (NOS scale)

High (4–7) PN 2 1.08 (0.67–1.73) b 0.45 4 1.96 (1.49–2.57) b 0.09 4 2.13 (1.75–2.58) <0.001

Low (1–3) 4 1.36 (0.93–2.00) 6 2.78 (2.05–3.77) b 3 4.82 (3.35–6.93)

High (4–7) APN 9 1.05 (0.83–1.31) 0.68 13 2.47 (1.68–3.63) b 0.86 14 4.80 (3.21–7.18) b 0.09

Low (1–3) 4 1.28 (0.50–3.30) 5 2.63 (1.54–4.48) 5 8.90 (5.29–14.96)

Sample size (in total)

>3,000 PN 2 1.08 (0.67–1.73) b 0.45 5 2.03 (1.60–2.56) b 0 . 05 4 3.24 (1.85–5.69) b 0.29

≤3,000 4 1.36 (0.93–2.00) 5 3.20 (2.17–4.74) 3 2.30 (1.72–3.09)

>3,000 APN 8 1.18 (0.90–1.54) 0.22 11 2.21 (1.62–3.02) b 0.35 13 5.69 (3.37–8.58) b 0.93

≤3,000 5 0.73 (0.36–1.49) 7 3.23 (1.56–6.70) b 6 5.94 (2.33–15.17) b

Population-based study design

Yes PN 2 1.08 (0.67–1.73) b 0.45 2 1.88 (1.15–3.06) b 0.26 1 1.94 (1.48–2.54) 0 . 03

No 4 1.36 (0.93–2.00) 8 2.57 (2.02–3.26) b 6 3.28 (2.22–4.87) b

Yes APN 1 0.73 (0.48–1.13) 0 . 05 1 0.89 (0.60–1.33) <0 . 001 3 3.06 (2.31–4.06) 0 . 005

No 12 1.22 (0.96–1.55) 17 2.74 (2.08–3.61) b 16 6.73 (4.23–10.70) b

Endoscopy quality control

Yes PN 2 1.08 (0.67–1.73) b 0.45 3 1.91 (1.33–2.76) b 0.15 2 2.04 (1.66–2.50) <0 . 001

No 4 1.36 (0.93–2.00) 7 2.66 (2.04–3.47) b 5 4.09 (3.03–5.53)

Yes APN 2 0.93 (0.55–1.58) b 0.39 4 2.20 (0.73–6.61) b 0.75 5 2.59 (1.96–3.41) <0 . 001

No 11 1.21 (0.92–1.58) 15 2.64 (2.18–3.20) 14 8.93 (5.66–11.84) b

Defi nition of AN

No SL PN 4 1.16 (0.82–1.62) NA 9 2.31 (1.86–2.88) b NA 6 2.96 (2.07–4.25) NA

Include SL 0 — 0 — 0 —

No SL APN 12 1.08 (0.83–1.39) 0.61 17 2.53 (1.79–3.56) b 0.97 17 6.17 (4.00–9.53) 0.070

Include SL 1 1.26 (0.72–2.21) 1 2.50 (1.56–4.01) 2 3.55 (2.34–5.39) b

Defi nition of “distal”

Splenic fl exure PN 5 1.16 (0.87–1.56) 0.93 9 2.41 (1.92–3.02) b 0.50 6 3.17 (2.00–5.03) 0.19

Rectosigmoid 1 1.23 (0.35–4.40) 1 2.02 (1.26–3.22) 1 2.18 (1.58–3.00)

Splenic fl exure APN 13 1.09 (0.87–1.36) NA 17 2.66 (1.92–3.66) b 0.02 18 6.22 (4.37–8.86) b <0.001

Rectosigmoid 0 — 1 1.05 (0.50–2.20) 1 2.12 (1.41–3.19)

Procedure

CLN PN 5 1.37 (1.10–1.71) 0.004 8 2.57 (2.10–3.14) b 0.008 5 4.09 (3.03–5.53) <0.001

FS+CLN 1 0.85 (0.66–1.08) 2 1.60 (1.20–2.13) 2 2.04 (1.66–2.50)

CLN APN 12 1.22 (0.96–1.55) 0.05 16 2.92 (2.24–3.80) b <0.001 17 6.73 (4.74–9.55) b <0.001

FS+CLN 1 0.73 (0.48–1.13) 2 0.93 (0.65–1.32) 2 2.12 (1.41–3.19)

AD, adenoma; AN, advanced neoplasia; APN, advanced proximal neoplasia; CI, confi dential interval; CLN, colonoscopy; FS, fl exible sigmoidoscopy; HP, hyperplastic

polyp, NOS, Newcastle Ottawa Scale; OR, odds ratio; PN, proximal neoplasia; SL, serrated lesions. If p < 0.05, the difference between the two subgroups is statistically

signifi cant.

a P values refer to the Cochran tests for differences between subgroups.

b P <0.05 in heterogeneity test.

Huang et al.


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In conclusion, distal HP is neither a marker for PN nor APN

in asymptomatic screening population when compared with nor-

mal distal fi ndings. Th e ORs of AD and distal AN for PN/APN

were signifi cantly increased. Th ese fi ndings did not support rou-

tine referral of all subjects detected having distal HPs. We antici-

pate that this clinical implication has a substantial potential to

reduce unnecessary colonoscopy procedure, complications, and

health-care costs. Future prospective studies employing popula-

tion-based design including screening participants of diff erent

ethnicities screened by good quality-control endoscopies could

shed more light on the relationship between distal and proximal

fi ndings.

ACKNOWLEDGMENTS

We wish to express our gratitude to the statistical advice from the

Division of Biostatistics of the School of Public Health and Primary

Care, Chinese University of Hong Kong.

CONFLICT OF INTEREST

Guarantor of the article: Jason L.W. Huang, MD.

Specifi c author contributions: J.L.W.H., Y.H.W., and M.C.S.W. had

full access to all the data in the study and take responsibility for the

data and the accuracy of the data analysis. M.C.S.W., J.L.W.H., Y.H.W.,

and J.Y.J. contributed to the study concept and design. C.P.Y. off ered

advice on search strategy. All authors analyzed and interpreted the

data. J.L.W.H., H.H.X.W., and J.Y.J. critically revised the manuscript.

All authors read and approved the fi nal manuscript. All authors

included on the paper fulfi ll the criteria of authorship. Th ere is no one

else who fulfi lls the criteria but has not been included as an author.

Financial Support: None.

Potential Competing Interests: None.

Study Highlights

WHAT IS CURRENT KNOWLEDGE

✓ Flexible sigmoidoscopy (FS) becomes more popular as a primary screening test for colorectal cancer (CRC) screen-ing in some European and Asian countries.

✓ FS is a recommended test of choice designed both to detect and prevent CRC if colonoscopy is not available or acceptable to patients.

✓ Whether subjects with distal hyperplastic polyps (HPs) detected should be followed up by colonoscopy workup remains controversial.

WHAT IS NEW HERE

✓ A meta-analysis including 28 studies that included 104,961 average-risk asymptomatic participants for colorectal cancer screening was conducted.

✓ When compared with normal distal fi ndings, distal HP was not associated with proximal neoplasia (PN) or advanced proximal neoplasia (APN).

✓ Subjects with distal non-advanced or advanced adenoma had higher odds of PN/APN, and higher odds of PN/APN were observed for more severe distal lesions.

REFERENCES 1. Brenner H , Kloor M , Pox CP. . Colorectal cancer . Lancet 2014 ; 383 :

1490 – 502 . 2. Sung JJY , Ng SC , Chan FK et al. An updated Asia Pacifi c Consensus

Recommendations on colorectal cancer screening . Gut 2015 ; 64 : 121 – 32 . 3. Leddin DJ. . Canadian Association of Gastroenterology position statement

on screening individuals at average risk for developing colorectal cancer: 2010 . Can J Gastroenterol 2010 ; 24 : 705 – 14 .

4. Qaseem A , Denberg TD , Hopkins RH et al. Screening for colorectal cancer: a guidance statement from the American College of Physicians . Ann Intern Med 2012 ; 156 : 378 – 86 .

5. Bibbins-Domingo K , Grossman DC et al. US Preventive Services Task Force . Screening for colorectal cancer: US Preventive Services Task Force recommendation statement . JAMA 2016 ; 315 : 2564 – 75 .

6. Lin JS , Piper MA , Perdue LA et al. Screening for colorectal cancer: updated evidence report and systematic review for the US Preventive Services Task Force . JAMA 2016 ; 315 : 3576 – 94 .

7. Dave S , Hui S , Kroenke K et al. Is the distal hyperplastic polyp a marker for proximal neoplasia? A systematic review . J Gen Intern Med 2003 ; 18 : 128 – 37 .

8. Lewis JD , Ng K , Hung KE et al. Detection of proximal adenomatous polyps with screening sigmoidoscopy: a systematic review and meta-analysis of screening colonoscopy . Arch Intern Med 2003 ; 163 : 413 – 20 .

9. Lin OS , Gerson LB , Soon MS et al. Risk of proximal colon neoplasia with distal hyperplastic polyps: A meta-analysis . Arch Intern Med 2005 ; 165 : 382 – 90 .

10. Dodou D , De Winter JC . Th e relationship between distal and proximal colonic neoplasia: a meta-analysis . J Gen Intern Med 2012 ; 27 : 361 – 70 .

11. Imperiale TF , Glowinski EA , Lin-Cooper C et al. Tailoring colorectal cancer screening by considering risk of advanced proximal neoplasia . Am J Med 2012 ; 125 : 1181 – 7 .

12. Park HW , Han S , Lee JS et al. Risk stratifi cation for advanced proximal colon neoplasm and individualized endoscopic screening for colorectal cancer by a risk-scoring model . Gastrointest Endosc 2012 ; 76 : 818 – 28 .

13. Castells A , Bessa X , Quintero E et al. Risk of advanced proximal neoplasms according to distal colorectal fi ndings: comparison of sigmoidoscopy-based strategies . J Natl Cancer Inst 2013 ; 105 : 878 – 86 .

14. Kiedrowski M , Mroz A , Kaminski MF et al. Predictive factors of proximal advanced neoplasia in the large bowel . Arch Med Sci 2014 ; 10 : 484 – 9 .

15. Wong MCS , Ching JYL , Ng SC et al. Prediction of proximal advanced neoplasia: A comparison of four existing sigmoidoscopy-based strategies in a Chinese population . Gut 2014 ; 64 : 776 – 83 .

16. Ruco A , Stock D , Hilsden RJ et al. Evaluation of a risk index for advanced proximal neoplasia of the colon . Gastrointest Endosc 2015 ; 81 : 1427 – 32 .

17. Liberati A , Altman DG , Tetzlaff J et al. Th e PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration . Ann Intern Med 2009 ; 151 : W65 – 94 .

18. Gupta S , Balasubramanian BA , Fu T et al. Polyps with advanced neoplasia are smaller in the right than in the left colon: implications for colorectal cancer screening . Clin Gastroenterol Hepatol 2012 ; 10 : 1395 – 401 . e2

19. Parra-Pérez V , Watanabe-Yamamoto J , Nago-Nago A et al. Factors related to advanced colorectal neoplasm at the Policlínico PeruanoJaponés . Rev Gastroenterol Mex 2015 ; 80 : 239 – 47 .

20. Lieberman DA , Prindiville S , Weiss DG et al. VA Cooperative Study Group 380 . Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals . JAMA 2003 ; 290 : 2959 – 67 .

21. Foutch PG , Mai H , Pardy K et al. Flexible sigmoidoscopy may be ineff ective for secondary prevention of colorectal cancer in asymptomatic, average-risk men . Dig Dis Sci 1991 ; 36 : 924 – 8 .

22. Th iis-Evensen E. , Hoff GS , Sauar J et al. Flexible sigmoidoscopy or colonos-copy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of the normal population aged 63– 72 years . Gut 1999 ; 45 : 834 .

23. Gryska P , Cohen A. . Screening asymptomatic patients at high risk for colon cancer with full colonoscopy . Dis Colon Rectum 1987 ; 30 : 18 – 20 .

24. Kahi CJ , Vemulapalli KC , Snover D et al. Distal colorectal fi ndings are not related to the risk of proximal advanced serrated neoplasia. Digestive Diease Week 03-06 May 2014, Vol. 79 ASGE, Chicago, IL, USA, 2014, pp. AB421.

25. Herzog R , Álvarez-Pasquin MJ , Díaz C et al. Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review . BMC Public Health 2013 ; 13 : 154 .



RE

VIE

W

1245

42. Soon M , Soon A , Lin T et al. Distribution of colon neoplasia in Chinese patients: implications for endoscopic screening strategies . Eur J Gastro-enterol Hepatol 2008 ; 20 : 642 – 7 .

43. Erarslan E , Turkay C , Isik A et al. Prevalence of proximal neoplasms among asymptomatic patients according to distal colorectal fi ndings . Dig Dis Sci 2009 ; 54 : 1312 – 6 .

44. Park H- , Byeon J- , Yang S- et al. Colorectal neoplasm in asymptomatic average-Risk Koreans: the KASID prospective multicenter colonoscopy survey . Gut Liver 2009 ; 3 : 35 – 40

45. Levitzky BE , Brown CC , Heeren TC et al. Performance of a risk index for advanced proximal colorectal neoplasia among a racially/ethnically diverse patient population (risk index for advanced proximal neoplasia) . Am J Gastroenterol 2011 ; 106 : 1099 – 106 .

46. Lucendo AJ , Guagnozzi D , Angueira T et al. Th e relationship between proximal and distal colonic adenomas: is screening sigmoidoscopy enough in the presence of a changing epidemiology? Eur J Gastroenterol Hepatol 2013 ; 25 : 973 – 80 .

47. Huang JL , Chen P , Yuan X . An algorithm to predict advanced proximal colorectal neoplasia in Chinese asymptomatic population . Scientifi c Reports 2017 ; 7 ; doi:10.1038/srep46493 .

48. McCallion K , Mitchell RMS , Wilson RH et al. Flexible sigmoidoscopy and the changing distribution of colorectal cancer: Implications for screening . Gut 2001 ; 48 : 522 – 5 .

49. Rozen P , Liphshitz I , Barchana M. . Th e changing epidemiology of colorectal cancer and its relevance for adapting screening guidelines and methods . Eur J Cancer Prev 2011 ; 20 : 46 – 53

50. Schreuders EH , Ruco A , Rabeneck L et al. Colorectal cancer screening: a global overview of existing programmes . Gut 2015 ; 64 : 1637 – 49 .

51. Imperiale TF , Monahan PO , Stump TE et al. Predicting advanced proximal neoplasia in asymptomatic adults without knowing distal colorectal fi nd-ings: a new scoring system with high discrimination. Digestive Disease Week 17-19 May, 2015, Vol. 148, Washington, DC, USA, 2015, pp. S780.

52. Ng SC , Ching JY , Chan VC et al. Association between serrated polyps and the risk of synchronous advanced colorectal neoplasia in average-risk individuals . Aliment PharmacolTh er 2015 ; 41 : 108 – 15 .

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26. Rex DK , Smith JJ , Ulbright TM et al. Distal colonic hyperplastic polyps do not predict proximal adenomas in asymptomatic average-risk subjects . Gastroenterology 1992 ; 102 : 317 – 9 .

27. Brady PG , Straker RJ , McClave SA et al. Are hyperplastic rectosigmoid polyps associated with an increased risk of proximal colonic neoplasms? Gastrointest Endosc 1993 ; 39 : 481 – 5 .

28. Levin TR , Palitz A , Grossman S et al. Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy . J Am Med Assoc 1999 ; 281 : 1611-7 .

29. Ikeda Y , Mori M , Miyazaki M et al. Signifi cance of small distal adenoma for detection of proximal neoplasms in the colorectum . Gastrointest Endosc 2000 ; 52 : 358 – 61 .

30. Lieberman DA , Weiss DG , Bond JH et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer . N Engl J Med 2000 ; 343 : 162 – 8 .

31. Imperiale TF , Wagner DR , Lin CY et al. Using risk for advanced proximal colonic neoplasia to tailor endoscopic screening for colorectal cancer . Ann Intern Med 2003 ; 139 : 959 – 96510 .

32. Pinsky PF , Schoen RE , Weissfeld JL et al. Predictors of advanced proximal neoplasia in persons with abnormal screening fl exible sigmoidoscopy . Clin Gastroenterol Hepatol . 2003 1 : 103 – 10 .

33. Betés Ibáñez M , Munoz-Navas MA , Duque JM et al. Diagnostic value of distal colonic polyps for prediction of advanced proximal neoplasia in an average-risk population undergoing screening colonoscopy . Gastrointest Endosc . 2004 59 : 634 – 41 .

34. Chiu HM , Wang HP , Lee YC et al. A prospective study of the frequency and the topographical distribution of colon neoplasia in asymptomatic average- risk Chinese adults as determined by colonoscopic screening . Gastrointest Endosc 2005 ; 61 : 547 – 53 .

35. Lin OS , Schembre DB , McCormick SE et al. Risk of proximal colorectal neoplasia among asymptomatic patients with distal hyperplastic polyps . Am J Med 2005 ; 118 : 1113 – 9 .

36. Liu HH , Wu MC , Peng Y et al. Prevalence of advanced colonic polyps in asymptomatic Chinese . World J Gastroenterol 2005 ; 11 : 4731 – 4 .

37. Schoenfeld P , Cash B , Flood A et al. Colonoscopic screening of average-risk women for colorectal neoplasia . N Engl J Med 2005 ; 352 : 2061 – 8 .

38. Strul H , Kariv R , Leshno M et al. Th e prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years . Am J Gastroenterol 2006 ; 101 : 255 – 62 .

39. Byeon J , Yang S , Kim TI et al. Colorectal neoplasm in asymptomatic Asians: a prospective multinational multicenter colonoscopy survey . Gastrointest Endosc 2007 ; 65 : 1015 – 22 .

40. Choe JW , Chang H , Yang S et al. Screening colonoscopy in asymptomatic average-risk Koreans: analysis in relation to age and sex . J Gastroenterol Hepatol 2007 ; 22 : 1003 – 8 .

41. Liou JM , Lin JT , Huang SP et al. Screening for colorectal cancer in average-risk Chinese population using a mixed strategy with sigmoidoscopy and colonoscopy . Dis Colon Rectum 2007 ; 50 : 630 – 40 .

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