2013

Int. J. Hyperthermia, March 2013; 29(2): 156–167

RESEARCH ARTICLE

Surgery combined with intraoperative hyperthermic intraperitonealchemotherapy (IHIC) for gastric cancer: A systematic review andmeta-analysis of randomised controlled trials

DENG-HAI MI1,2,3, ZHENG LI1,2,3, KE-HU YANG1,2, NONG CAO1,2,

ANNE LETHABY1,4, JIN-HUI TIAN1, NANCY SANTESSO1,5, BIN MA1,

YAO-LONG CHEN1, & YA-LI LIU1

1Evidence-Based Medicine Centre of Lanzhou University, Lanzhou, Gansu Province, China, 2Department of General

Surgery, First Clinical Medicine College of Lanzhou University, Lanzhou, Gansu Province, China, 3Department of

Oncology, Second People’s Hospital of Gansu Province, Lanzhou, Gansu Province, China, 4Department of Obstetrics

and Gynecology, Auckland City Hospital, Auckland, New Zealand, and 5McMaster University Health Sciences Centre,

Hamilton, Ontario, Canada

(Received 27 May 2012; Revised 9 January 2013; Accepted 15 January 2013)

AbstractBackground: Adjuvant intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) is a therapy which combinesthermotherapy and intraperitoneal chemotherapy. It is theoretically powerful for patients with advanced gastric cancer(AGC), but is there evident advantage in clinical practice? We need evidence to guide our decision-making.Objectives: Meta-analysis was performed to assess the effectiveness and safety of adjuvant intraoperative hyperthermicintraperitoneal chemotherapy (IHIC) for patients with resectable locally advanced gastric cancer, and to provide thereference for clinical practice and study.Methods: We searched the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases (ChineseBioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang) electronicallyand also retrieved papers from other sources (tracing related references and communication with other authors). All relevantrandomised controlled trials (RCTs) were collected to compare surgery combined with IHIC to surgery without IHIC forAGC. There were no language restrictions. After independent quality assessment and data extraction by two reviewers,meta-analysis was conducted by RevMan 5.1 software.Results: 16 RCTs involving 1,906 patients were included. Compared with surgery alone, combination therapy (surgery plusIHIC) was associated with a signiEcant improvement in survival rate at 1 year (hazard ratio (HR)¼ 2.99; 95% confidenceinterval (CI)¼ 2.21 to 4.05; p< 0.00001), 2 years (HR¼ 2.43; 95%CI¼ 1.81 to 3.26; p< 0.00001), 3 years (HR¼ 2.63;95%CI¼ 2.17 to 3.20; p< 0.00001), 5 years (HR¼ 2.49; 95%CI¼ 1.97 to 3.14; p< 0.00001), and 9 years (HR¼ 2.14;95%CI¼ 1.38 to 3.32; p¼ 0.0007). Compared with surgery alone, combination therapy was associated with a signiEcantreduction in recurrence rate at 2 years (RR¼ 0.42; 95%CI¼ 0.29 to 0.61; p< 0.00001), 3 years (RR¼ 0.35; 95%CI¼ 0.24to 0.51; p< 0.00001) and 5 years (RR¼ 0.47; 95%CI¼ 0.39 to 0.56; p< 0.00001). IHIC was not found to be associatedwith higher risks of anastomotic leakage, ileus, bowel perforation, myelosuppression, gastrointestinal reaction andhypohepatia, but it increased the incidence of abdominal pain (RR¼ 21.46; 95%CI¼ 5.24 to 87.78; p< 0.00001).Conclusions: Compared with surgery alone, surgery combined with IHIC can improve survival rate and reduce the recurrencerate, with acceptable safety. However, safety outcomes should be further evaluated by larger samples and high qualitystudies. Additionally, hyperthermia for the intraperitoneal chemotherapy needs more clinical research.

Keywords: gastric cancer, radical surgery, hyperthermia, intraperitoneal chemotherapy, meta-analysis

Correspondence: Ke-Hu Yang, Professor of Oncology, Evidence Based Medicine Center of Lanzhou University, 199 Donggang West Road, Chengguan

District, Lanzhou City, Gansu Province, 730000, China. Tel: þ86-931-8912767. Fax: þ86-931-8915076. E-mail: kehuyangebm2006@126.com &

caonong2012@163.com

ISSN 0265–6736 print/ISSN 1464–5157 online � 2013 Informa UK Ltd.

DOI: 10.3109/02656736.2013.768359

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Introduction

A total of 989 600 new stomach cancer cases and

738 000 deaths are estimated to have occurred in

2008, accounting for 8% of the total cases and 10%

of total deaths worldwide. Over 70% of new cases

and deaths occur in developing countries. Generally,

stomach cancer rates are about twice as high in men

as in women [1]. Currently, surgical resection is

the mainstay of treatment for gastric cancer, but the

therapeutic effect after operation is reduced immen-

sely because of recurrence and metastasis. Despite

the use of radiotherapy or adjuvant or neoadjuvant

systemic chemotherapy, the long-term survival in

patients with locally advanced gastric cancer remains

limited. We need to search for more effective

adjuvant treatment regimens to change the current

situation.

There are many adjuvant treatments being inves-

tigated to reduce the recurrence rate and metastasis

rate. Intraoperative hyperthermic intraperitoneal

chemotherapy (IHIC) is the synthesis of thermo-

therapy, chemotherapy and peritoneal perfusion,

which as a targeted adjuvant treatment after surgery

may be considered a rational prophylactic and

therapeutic approach. Although the theoretical ratio-

nale is very appealing, the real situation in clinical

practice is unclear. Is there any signiEcant impact of

adjuvant IHIC on the outcomes of patients with

AGC? A systematic review [2] has proved that IHIC

has a positive effect on gastric cancer with peritoneal

metastasis, but what about the effect on patients

without peritoneal metastasis who have undergone

radical surgery? The current randomised controlled

trials (RCTs) have mostly small sample sizes and

have shown inconclusive results. So we performed

this meta-analysis of RCTs to reliably assess the

effectiveness and safety of adjuvant IHIC in the

treatment of resectable AGC without peritoneal

metastasis, and to provide the reference for further

clinical practice and study.

Methods

Study selection criteria

The studies were selected for review if they fulElled

the following inclusion criteria:

1. Study type: RCTs regardless of use of blinding.

2. Participants: Patients with histologically diag-

nosed primary cancer of the stomach having

radical resection. Studies of patients having non-

radical resection were excluded. Locally advanced

gastric cancer was defined as macroscopic serosal

invasion, excluding peritoneal or distant

metastases.

3. Intervention and comparison: Trials testing the

efEcacy and safety of radical surgery (RS)

combined with IHIC versus RS without IHIC,

no matter whether to implement post-operative

chemotherapy.

4. Outcomes: The primary end point of this meta-

analysis was overall survival, deEned as the time

from random assignment to the last follow-up or

death.

There were no language restrictions. When multi-

ple publications from the same institution were

identified as duplicates, only the most recent

update with the largest number of patients or

longer follow-up group was included.

Literature search strategy

We performed literature searches of the Cochrane

Library, PubMed, Embase, Web of Science, the

Chinese Biomedical Literature Database, Chinese

Journal Full Text Database and the Chinese

Wanfang Literature Database. The search terms

contained the target disease group and intervention

group, and all searches used a topic search combined

with a non-topic search. The search had no language

restrictions and the period of searching was from the

inception of databases to October, 2012. All relevant

RCTs were collected to evaluate the effectiveness

and safety of adjuvant IHIC for patients with

resectable locally advanced gastric cancer. The

reference lists of articles identified were reviewed

for further identiEcation of potentially relevant

studies. We also used Google Scholar and Medical

Matrix to search for relevant papers. Both published

and unpublished trials were sought to limit publica-

tion bias. We also communicated with some experts

to ask whether they knew about any unpublished

trials.

Literature screening

Studies were selected according to the inclusion and

exclusion criteria. The title and abstract were

assessed and if potentially relevant the publication

was retrieved to assess the full text. If necessary, we

contacted authors for missing data. All steps were

completed by two investigators (Zheng Li and Deng-

hai Mi) independently, and all steps were cross-

checked. We address discrepancies in the discussion.

Problems with discrepancies were judged by the

senior investigator (Ke-hu Yang) if they could not be

resolved by the two investigators. The Enal results

were reviewed by all three senior investigators.

Data extraction and critical appraisal

Two investigators (Zheng Li and Deng-hai

Mi) independently read each article included.

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Data extracted included the study design, year of

publication, number of patients, methodology, qual-

ity criteria, completeness of cytoreduction, criteria

used to define IHIC, IHIC protocol, treatment

outcomes, and prognostic factors associated with

outcomes. All data were extracted from texts, tables,

and figures of the articles and then tabulated.

The quality of studies was appraised indepen-

dently using the following criteria: (1) whether the

method of allocation was truly random; (2) whether

there was proper concealment of allocation;

(3) whether the groups were similar at baseline in

terms of prognostic features; (4) whether loss to

follow-up in each treatment group was speciEed and

(5) whether intention-to-treat (ITT) analysis was

conducted. When studies did not report adequate

information to determine the above-mentioned

assessment criteria, we tried to obtain additional

data direct from the investigators.

Discrepancies between the two investigators

were resolved by discussion and consensus with a

senior investigator (Nong Cao). The Enal results

were reviewed by all three senior investigators to

avoid bias.

Statistical analysis

Data were synthesised using RevMan 5.1 provided

by the Cochrane organisation. The heterogeneity

between the results of the research included was

examined by the chi-square test. Chi-square tests

were used to study heterogeneity between trials. The

I-squared value was used to estimate the percentage

of total variation across studies.

When the homogeneity of statistics between

studies was considered adequate (P40.1,

I2< 50%), we used the fixed effects model; if there

was obvious heterogeneity between the studies

(P< 0.1, I2450%), we analysed the sources of

heterogeneity, and then performed subgroup analysis

according to factors accounting for the heterogeneity.

When there was enough similarity between the

studies within the group or between the groups

(P40.1, I2< 50%) we used the fixed effects model to

perform meta-analysis. If there was statistical hetero-

geneity but no clinical and methodological hetero-

geneity between the subgroups we used the random

effects model. If the heterogeneity was substantial

between the studies included we used descriptive

analysis. We performed sensitivity analysis to exam-

ine the stability of the results where necessary.

The primary end point of this meta-analysis was

overall survival, deEned as the time from random

assignment to the last follow-up or death. Secondary

end points were the incidence of recurrence and

quality of life. Safety was also assessed, although the

frequency of important long-term adverse events may

not be adequately captured by the information

provided in RCTs. Results regarding the overall

survival were expressed as hazard ratios (HR) with

95% conEdence intervals (CI). Other indicators

used relative risk (RR) with 95%CI. All p-values

were two-sided. All statistical analysis was conducted

by Cochrane Review Manager 5.1.

Results

Results of the search and identified studies

There were 491 references identified through elec-

tronic database and other searches. A total of 113

articles were excluded as duplicates by Endnote and

seven articles were excluded as duplicates by

reviewers. The titles and abstracts of 371 potentially

appropriate articles were read by the reviewers, and

326 were excluded because they did not meet the

inclusion criteria. A total of 45 articles were

appraised by full text to confirm the studies included.

Articles were also excluded where patients had

peritoneal metastasis or had palliative surgery.

Finally, 16 RCTs [3–18] were included for appraisal

and data extraction for meta-analysis. The 16 RCTs

had a total sample of 1906 patients. The full details

are listed in Figure 1).

Characteristics of studies included

In these 16 studies [3–18], 1906 patients were

randomly assigned, of whom 935 patients were to

receive radical resection with adjuvant IHIC and 909

patients were to receive radical resection without

IHIC. A total of 62 patients with intraoperative

normothermic intraperitoneal chemotherapy (INIC)

were randomly assigned in two studies [7, 15]. Two

trials were reported in one article [5], and we used

the one in which the patients underwent radical

resection, with the exclusion of the other trial where

patients had palliative surgery. All of the 16 studies

[3–18] had RS with IHIC and RS alone, but

only some of them implemented post-operative

chemotherapy. Although there was a difference,

it was irrelevant to our analysis because the post-

operative treatment was balanced in the two com-

parative groups of every study. The full details are

listed in Table I.

Quality of trials

There was good agreement between the reviewers on

the eligibility and quality of the studies. Table II

demonstrates the quality of all 16 RCTs included in

the systematic review [3–18]. An attempt was made

to contact the corresponding authors of RCTs, where

necessary, to obtain missing details relating to

methodological quality.

158 D.-H. Mi et al.

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Eight RCTs [3, 6–8, 14–17] used an adequate

approach to sequence generation using computer-

generated random numbers or random-number

tables. The adequacy of randomisation was unclear

in the remaining eight RCTs. In the same eight

RCTs [3, 6–8, 14–17], the method of allocation

concealment was adequate; randomisation was

performed on a central site and transmitted to

treatment providers by telephone, fax or sealed

opaque envelopes. In the remaining eight RCTs

[4, 5, 9–13, 18], the information regarding

approaches to allocation concealment could not be

determined. The baseline features were similar

between treatment groups in all 16 RCTs. Four

RCTs [3, 10, 13, 16] had no loss to follow-up, two

RCTs [4, 17] speciEed numbers lost to follow-up in

each treatment group, and this was unclear in the

remaining 10 RCTs. Six [6–8,14,15,17] RCTs

analysed the data on an intention-to-treat (ITT)

basis, whereby participants were analysed in the

groups to which they were initially randomised; and

10 RCTs [3–5, 9–13, 16, 18] did not perform ITT

analysis. Blinding after allocation was impossible

because of the nature of the trials. The full details

are listed in Table II.

Assessment of overall survival

Subgroup analysis was used to evaluate total survival

of different follow-up years. A signiEcant survival

improvement was found in favour of IHIC: 1 year

(HR¼ 2.99; 95%CI¼ 2.21 to 4.05; p< 0.00001), 2

years (HR¼ 2.43; 95%CI¼ 1.81 to 3.26;

p< 0.00001), 3 years (HR¼ 2.63; 95%CI¼ 2.17 to

3.20; p< 0.00001), 5 years (HR¼ 2.49;

95%CI¼ 1.97 to 3.14; p< 0.00001), 9 years

(HR¼ 2.14; 95%CI¼ 1.38 to 3.32; p¼ 0.0007).

There was no substantial statistical heterogeneity

among the trials, and the meta-analysis was per-

formed using the fixed effects model in all sub-

groups. We did not synthesise the subgroups of

different years because it was inapposite. All the

details are shown in Figure 2.

Assessment of disease recurrence

Two RCTs [6, 17], three [6, 9, 16], five [3, 6, 7, 12,

17], and eight RCTs [3, 6, 8, 10–13, 15] documen-

ted the incidence of 1-year, 2-year, 3-year and 5-year

recurrence respectively; we performed the subgroup

meta-analysis for these different follow-up years.

There was no substantial statistical heterogeneity

Potential studies evaluating IHIC for gastric cancer (N = 491) in: The Cochrane Library (n = 50) PubMed (n = 89) Embase (n = 78) Web of Science (n = 61) The Chinese Biomedical Literature Database (n = 103) The Chinese Journal Full Text Database (n = 63) The Chinese WanFang Literature Database (n = 47)

Duplicated studies (n = 113) were excluded by Endnote software

Potential appropriate studies to be included in the systematic review (n = 371)

Studies excluded (n = 154) because: Review (n = 33) Editorial (n = 6) Cohort study (n = 13) Case controlled study (n = 45) Animal experiment (n = 31) Case report (n = 26)

Studies excluded (n = 172) because: Not gastric cancer (n = 71) Not radical surgery (n = 18) Not IHIC intervention (n = 83)

Potential appropriate studies selected for full text evaluation (n = 45)

Studies excluded (n = 8) because: Duplicate publications (n = 3) No outcomes of interest (n = 2) The loss to follow-up is greater than 20% (n = 3)

Potential appropriate studies for final analysis (16 studies with 1,906 patients)

Duplicated studies (n = 7) were excluded by investigators

Studies excluded (n = 21) because: Not random trial (n = 2) Not the befitting patients (n = 6) Not real IHIC (n = 8) Not radical surgery (n = 5)

Figure 1. Selection process for RCTs of RS combined with IHIC for resectable AGC.

Meta-analysis of IHIC for AGC 159

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Tab

leI.

Tri

ald

esig

nan

db

asel

ine

char

acte

rist

ics

of

stu

die

sin

clu

ded

.

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dy

and

year

NS

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pe

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can

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arac

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stic

s

of

pat

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urg

ery

Tre

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ent

of

exp

erim

enta

lgro

up

Tre

atm

ent

of

con

tro

l

Ch

enet

al.,

20

06

[3]

14

0R

CT

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mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

d5

-Fu

RS

alo

ne

Ch

enet

al.,

20

05

[4]

60

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

CD

DP

and

5-F

uR

Sal

on

e

Ch

enet

al.,

20

01

[5]

60

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

CD

DP

RS

alo

ne

Fu

jim

oto

etal

.,1

99

9[6

]1

41

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

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tasi

sR

adic

alIH

ICw

ith

MM

CR

Sal

on

e

Fu

jim

ura

etal

.,1

99

4[7

]5

8R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

dM

MC

RS

alo

ne

Ham

azo

eet

al.,

19

94

[8]

82

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

MM

CR

Sal

on

e

Jin

,2

00

7[9

]1

16

RC

TP

rim

ary

AG

CW

ith

sero

sal

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sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

CD

DP

and

MM

CR

Sal

on

e

Wan

get

al.,

20

06

[10

]6

8R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

PR

Sal

on

e

Wan

get

al.,

20

02

[11

]2

28

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

MM

Can

d5

-Fu

RS

alo

ne

Wan

g,

20

10

[12

]1

16

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

CD

DP

and

5-F

uR

Sal

on

e

Ye

etal

.,2

00

7[1

3]

20

3R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

d5

-Fu

RS

alo

ne

Yo

nem

ura

etal

.,1

99

5[1

4]

16

0R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

dM

MC

RS

alo

ne

Yo

nem

ura

etal

.,2

00

1[1

5]

13

9R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

dM

MC

RS

alo

ne

Zh

ang

etal

.,2

00

7[1

6]

21

2R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

Pan

dM

MC

RS

alo

ne

Zh

anet

al.,

20

10

[17

]6

0R

CT

Pri

mar

yA

GC

Wit

hse

rosa

lin

vasi

on

bu

tw

ith

ou

tp

erit

on

eal

met

asta

sis

Rad

ical

IHIC

wit

hC

DD

PR

Sal

on

e

Zh

ang

etal

.,1

99

8[1

8]

63

RC

TP

rim

ary

AG

CW

ith

sero

sal

inva

sio

nb

ut

wit

ho

ut

per

ito

nea

lm

etas

tasi

sR

adic

alIH

ICw

ith

5-F

uan

dD

DW

RS

alo

ne

AG

C,

Ad

van

ced

gas

tric

can

cer;

CD

DP

,C

isp

lati

n;

DD

W,

Do

ub

led

isti

lled

wat

er;

IHIC

,In

trao

per

ativ

eh

yper

ther

mic

intr

aper

ito

nea

lch

emo

ther

apy;

MM

C,

Mit

om

ycin

;N

,N

um

ber

of

pat

ien

ts;

RC

T,

Ran

do

mis

edco

ntr

olled

tria

l;R

S,

Rad

ical

surg

ery;

5-F

u,

Flu

oro

ura

cil.

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among these RCTs and we performed the meta-

analysis using the fixed effects model in all sub-

groups. It was found that IHIC could reduce

recurrence rate signiEcantly: 2 years (RR¼ 0.42;

95%CI¼ 0.29 to 0.61; p< 0.00001), 3 years

(RR¼ 0.35; 95%CI¼ 0.24 to 0.51; p< 0.00001), 5

years (RR¼ 0.47; 95%CI¼ 0.39 to 0.56;

p< 0.00001). However, there was no signiEcant

difference in the 1-year recurrence rate (RR¼ 0.66;

95%CI¼ 0.25 to 1.78; p¼ 0.41) because of the

limited sample size. We did not combine the

subgroups of different years because it was inappo-

site. The full details are listed in Table III.

Assessment of safety

Four studies [3, 4, 9, 12] reported the incidence of

abdominal pain, comparing 212 patients in the IHIC

groups with 218 patients in the control groups. There

was statistical difference in the meta-analysis of the

incidence of abdominal pain between the two groups

and no substantial heterogeneity was identiEed

(RR¼ 21.46; 95%CI¼ 5.24 to 87.78; p< 0.00001).

But all the reports explained that pain naturally

resolved. There was no statistical heterogeneity in the

meta-analysis of anastomotic leakage, ileus, bowel

perforation, myelosuppression, gastrointestinal reac-

tion and hypohepatia between the two groups. We

used the fixed effects model, and the results of meta-

analysis showed no statistical differences in these

morbidity rates between the IHIC and without IHIC

groups. The full details are listed in Table III.

Analysis of publication bias

We used the funnel plot to examine the publication

bias in the outcome of meta-analysis with the most

RCTs contributing data. The horizontal axis of the

plot was the HR effect estimate and the vertical axis

of the plot was the standard error (SE) of the log

(HR). The funnel plot of 3-year survival rate suggests

that the quantity distribution of the RCTs is

generally balanced, so the influence of publication

bias is limited to the meta-analysis of the 3-year

survival rate. All the details are shown in Figure 3.

Discussion

Surgical treatment is still the main treatment for

stomach cancer, but 5-year survival rate after surgery

alone is very low. The main reason for death is post-

operative loco-regional (peritoneal) recurrence and

distant metastases. One of the long-term goals of

treatment is to reduce the recurrence rate of stomach

cancer, which is critical to improve overall survival.

IHIC is the organic combination of hyperthermia,

chemotherapy and intraperitoneal perfusion, which

can improve the sensitisation and antipersonnel force

for cancer. So theoretically, IHIC has a very obvious

advantage compared with conventional systemic

chemotherapy.

Effectiveness evaluation

The existing systematic review [2] has suggested that

IHIC has a positive effect on gastric cancer with

peritoneal metastasis, but what about the effect of

this treatment on patients without peritoneal metas-

tasis and undergoing radical surgery? There are only

a few available trials with small sample sizes for the

comparison of RS combined with IHIC and RS

alone, but the meta-analysis was still able to

demonstrate statistically signiEcant and clinically

Table II. Quality assessment of RCTs included for meta-analysis.

Study and year

Truly

random

Allocation

concealment

Baseline

features

Loss to

follow-up

ITT

analysis

Eligibility

criteria

Chen et al., 2006 [3] Yes Yes Adequate No No Adequate

Chen et al., 2005 [4] Unclear Unclear Adequate Yes (N¼ 4) No Adequate

Chen et al., 2001 [5] Unclear Unclear Adequate Unclear No Adequate

Fujimoto et al., 1999 [6] Yes Yes Adequate Unclear Yes Adequate

Fujimura et al., 1994 [7] Yes Yes Adequate Unclear Yes Adequate

Hamazoe et al., 1994 [8] Yes Yes Adequate Unclear Yes Adequate

Jin, 2007 [9] Unclear Unclear Adequate Unclear No Adequate

Wang et al., 2006 [10] Unclear Unclear Adequate No No Adequate

Wang et al., 2002 [11] Unclear Unclear Adequate Unclear No Adequate

Wang, 2010 [12] Unclear Unclear Adequate Unclear No Adequate

Ye et al., 2007 [13] Unclear Unclear Adequate No No Adequate

Yonemura et al., 1995 [14] Yes Yes Adequate Unclear Yes Adequate

Yonemura et al., 2001 [15] Yes Yes Adequate Unclear Yes Adequate

Zhang et al., 2007 [16] Yes Yes Adequate No No Adequate

Zhan et al., 2010 [17] Yes Yes Adequate Yes (N¼ 1) Yes Adequate

Zhang et al., 1998 [18] Unclear Unclear Adequate Unclear No Adequate

Meta-analysis of IHIC for AGC 161

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relevant differences. The results of this meta-analysis

indicate that compared with RS alone, RS combined

with IHIC is more beneficial and superior for

primary AGC without peritoneal metastasis, and is

associated with improving overall survival and redu-

cing recurrence.

To further clarify the effects of adjuvant IHIC and

explore variation among trials, we categorised the

trials according to the post-operative treatment with

or without chemotherapy. We performed both

subgroup analysis and sensitivity analysis. The results

of meta-analysis did not change, suggesting that

Figure 2. Meta-analysis of overall survival rate for patients in the two groups.

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these findings are robust. The data show that the

post-operative treatment is irrelevant to compare

effectiveness of RS combined with IHIC and RS

alone, which is because the post-operative treatments

are balanced between the two groups in each RCT.

There is no consistent method in the reports of

loco-regional peritoneal recurrence and distant

metastases, so we performed the meta-analysis

using the disease recurrence rate which contains

loco-regional peritoneal recurrence and distant

metastases. Although there is some clinical hetero-

geneity in the recurrence rate of different RCTs, it is

appropriate to combine studies and we can get the

general trend to evaluate IHIC.

Historical analyses of treatment failure after

curative resection for gastric cancer showed that

approximately half of patients had a Erst site of

recurrence in their peritoneal cavity and the devel-

opment of local-regional recurrence had a negative

impact on overall survival [19–21]. We searched for

the best combination treatment for the eradication of

carcinomatosis. IHIC can effectively prevent the

recurrence of cancer, especially for patients with

serosal invasion but without peritoneal metastasis,

who have undergone radical surgery [6, 8, 14]. It is

one of the reasons why IHIC can improve overall

survival. IHIC can improve survival rates mainly

through eradicating residual disease in the peritoneal

Figure 3. Funnel plot analysis.

Table III. Meta-analysis of recurrence rate and safety for patients in the two arms.

IHIC Control Heterogeneity

Statistical

Result of meta-analysis

Outcome Included studies n N n N I2 % P method RR (95%CI) P

1-year recurrence rate 2 [6, 17] 6 101 9 100 0 0.81 M-H, fixed 0.66 (0.25, 1.78) 0.41

2-year recurrence rate 3 [6, 9, 16] 31 221 84 248 0 0.78 M-H, fixed 0.42 (0.29, 0.61) <0.00001

3-year recurrence rate 5 [3, 6, 7, 12, 17] 30 249 84 248 0 0.45 M-H, fixed 0.35 (0.24, 0.51) <0.00001

5-year recurrence rate 8 [3, 6, 8, 10–13, 15] 111 555 228 518 0 0.45 M-H, fixed 0.47 (0.39, 0.56) <0.00001

Abdominal pain 4 [3, 4, 9, 12] 40 212 0 218 0 0.78 M-H, fixed 21.46 (5.24, 87.78) <0.00001

Anastomotic leakage 6 [6–8, 10, 14, 15] 10 299 11 287 0 0.98 M-H, fixed 0.86 (0.38, 1.95) 0.72

Ileus 2 [10, 15] 3 85 1 78 0 0.78 M-H, fixed 2.08 (0.32, 13.55) 0.45

Bowel perforation 2 [7, 15] 2 70 0 65 0 0.94 M-H, fixed 2.70 (0.29, 25.15) 0.38

Myelosuppression 3 [3, 12, 14] 13 205 12 211 0 0.79 M-H, fixed 1.10 (0.53, 2.29) 0.80

Gastrointestinal reaction 2 [3, 12] 26 126 22 130 0 0.94 M-H, fixed 1.23 (0.73, 2.05) 0.44

Hypohepatia 2 [3, 12] 4 126 1 130 0 0.57 M-H, fixed 3.09 (0.50, 18.87) 0.22

CI, Confidence interval; IHIC, Intraoperative hyperthermic intraperitoneal chemotherapy; M-H, Mantel-Haenszel; RR, Relative risk.

Meta-analysis of IHIC for AGC 163

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cavity, but the recurrence also occurred through

lymphatic and haematogenous dissemination, so

IHIC should be combined with post-operative

intravenous chemotherapy.

We should also pay attention to intraoperative

normothermic intraperitoneal chemotherapy (INIC)

versus IHIC. Hyperthermia is an effective treatment

modality to augment chemotherapy-based anti-

cancer treatments by various forms, which has been

demonstrated by experiments [22–23].

Hyperthermia also has been proven to modulate

directly or indirectly the cells of the innate and

adaptive immune system, thereby improving effec-

tiveness [24–26]. The data of two meta-analyses

[27–28] demonstrated a positive effect of INIC, and

the authors also emphasise that IHIC is superior

because hyperthermia has a synergistic and addi-

tional anti-tumour activity. Two [7, 15] included

RCTs of the present meta-analysis and Tan et al.’s

RCT [29] performed the comparison of IHIC and

INIC. The results indicate that IHIC is superior in

terms of signiEcantly improving overall survival and

reducing recurrence. The control group underwent

post-gastric resection lavage with saline only in every

RCT included, but the effectiveness was limited

compared to those with INIC or IHIC, as demon-

strated by the trials and this review.

Berardi et al.’s systematic review [30] indicates

that neoadjuvant chemotherapy (NAC) could

improve the global outcome of patients with locally

advanced gastric cancer allowing a radical resection.

Li et al.’s meta-analysis [31] suggests that NAC

could improve tumour stage and survival rate of

patients with AGC with reasonable safety. Three

meta-analyses [32–34] suggest that adjuvant che-

motherapy (AC) may produce a small survival

benefit in patients with curatively resected gastric

carcinoma. Chen et al.’s meta-analysis [35] recom-

mends that combined NAC and AC should be used

to improve the overall survival of AGC patients.

Comprehensive tumour treatment to improve

the curative effect is very important, so that in

the future there might also be the possibility of

NACþ surgeryþ IHICþAC as a potential therapy,

which suggests that gastric cancer would be treated

by an interdisciplinary approach in general.

Safety evaluation

There are two kinds of post-operative treatment in

the RCTs: with or without chemotherapy. Post-

operative factors were balanced in the two treatment

groups of every RCT, so the contrasts of overall

survival and recurrence rate were independent of

the post-operative chemotherapy (PC). And it is

appropriate to synthesise the data of all RCTs for

meta-analysis of overall survival and recurrence rate.

But the PC is relevant to the safety evaluation

because many complications and adverse effects were

caused by chemotherapy. For example, it is not

appropriate to compare myelosuppression between

the two groups of the RCTs without PC because only

the IHIC group had chemotherapy while the other

group had no chemotherapy. So the data from the

RCTs without PC could not be pooled together for

the meta-analysis of myelosuppression, gastrointest-

inal reaction, hypohepatia and renal dysfunction,

which were the side effects of chemotherapy.

The reports of safety evaluation are not consistent,

so we performed the meta-analysis using the data

discussed by the investigators. Although there is

some clinical heterogeneity in the safety evaluation

of different RCTs, it is appropriate to combine

studies and we can get the general trend to evaluate

the IHIC.

The meta-analysis showed that IHIC does not

increase the incidence of anastomotic leakage, ileus,

bowel perforation, myelosuppression, gastrointest-

inal reaction and hypohepatia. Abdominal pain was

increased by IHIC but all the reports explained that it

disappears naturally. So we suggest that surgery

combined with IHIC for advanced gastric cancer is a

feasible treatment.

Study limitations

Only acceptable RCTs were included in order to

ensure the quality of the meta-analysis, but the data

in some types of trials have also investigated this

issue. One study [36] of 174 patients was excluded

because it was a retrospective study. Three RCTs

[37–39] were excluded because the rate of loss to

follow-up was more than 20%, which might cause

bias. All of these studies indicated that IHIC has

superior curative effects and is feasible.

The quality of some of the RCTs included was not

adequate in this meta-analysis as they did not report

the detailed method of random sequence generation

and concealment of allocation. Recurrence and

safety were not reported in a unified standard

throughout the trials, thus there may be lack of

precision in the meta-analysis; however, the sensitiv-

ity analysis indicated that findings were not markedly

changed. The data were insufficient to evaluate the

safety of IHIC adequately. In addition, economic

outcomes and quality of life were not reported in any

of the RCTs included. Although the surgical

methods in some RCTs are not currently acceptable

anymore, they are irrelevant to the results of this

meta-analysis because the surgical factors were

balanced in the two groups of every RCT.

Because of the reasons above, we suggest that

prospective trials should be well-designed, well-

executed and well-reported, in order to adequately

164 D.-H. Mi et al.

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evaluate the role of IHIC. We also need to collect the

data of non-randomised studies to adequately assess

the safety of IHIC.

The conclusion and the prospect of thermatology

Compared with RS alone, RS combined with IHIC

for AGC without peritoneal metastasis can reduce

post-operative recurrence rates and improve overall

survival without increasing the risk of anastomotic

leakage, ileus, bowel perforation, myelosuppression,

gastrointestinal reaction and hypohepatia. Although

IHIC increased the incidence of abdominal pain, this

disappeared naturally. The safety of IHIC can be

generally accepted. There are also some problems

with IHIC, which should be improved by clinical

practice and study. Some of these include the best

temperature for perfusion, the dosage and compat-

ibility of medicines for perfusion, and other issues.

In addition, we should pay attention to try to prevent

and reduce adverse reactions and complications.

Hyperthermia therapy has positive clinical value

for the tumour. There have been many evidence-

based studies for hyperthermia therapy. Two reviews

[40–41], from Lancet Oncology and the International

Journal of Hyperthermia, have introduced various

clinical applications of hyperthermia, and have

summarised the clinical trials comprehensively

regarding hyperthermia combined with radiotherapy

and chemotherapy for various tumours.

Chua et al.’s study [42] demonstrated a superior

effect in patients with advanced ovarian cancer who

received cytoreductive surgery and IHIC, when

compared with the traditional standard of care.

Two Cochrane systematic reviews [43–44] investi-

gated hyperthermia treatment for cervical cancer and

rectal cancer respectively, and suggested there were

positive effects of hyperthermia therapy. Two trials

[45–46] indicated that radiotherapy combined with

hyperthermia had significant benefits compared to

radiotherapy alone for the lung or nasopharyngeal

cancer. Two trials [47–48] suggested that che-

motherapy combined with hyperthermia had signifi-

cant benefits for lung or pancreatic cancer. Bergs

et al.’s review [49] suggested that trimodality therapy

consisting of hyperthermia, cisplatin and radiation is

effective and feasible in patients and seems to be

promising. Mi et al.’s meta-analysis [50] indicated

that chemoradiotherapy combined with hyperther-

mia for non-small-cell lung cancer had superior

effects. Three trials [51–53] indicated that neo-

adjuvant chemoradiation combined with regional

hyperthermia followed by oesophageal resection for

patients with oesophageal cancer resulted in good

loco-regional control and overall survival. Kang

et al.’s trial [54] indicated that hyperthermia

seemed to increase the response of both primary

tumour and lymph nodes to preoperative radio-

chemotherapy in patients with locally advanced rectal

cancer. All these studies have demonstrated the value

of hyperthermia therapy for cancer, and provided the

reference for clinical practice and research of

hyperthermia at the same time.

Non-invasive temperature measurement, targeted

therapy and control of thermal dose are the crux of

hyperthermia treatment. Two studies [55–56] sug-

gested that targeted hyperthermia by nanoparticles

has great value and is promising. Three studies

[57–59] researching the method of non-invasive

temperature measurement are valuable for the

improvement of the efficacy of hyperthermia treat-

ment. We hope that there will be more high quality

experiments and clinical trials researching hyperther-

mia therapy for tumours, and breaking through the

technical bottleneck of hyperthermia treatment,

which is critical to popularise this treatment.

We hope that hyperthermia therapy for tumours

can play an increasing role in clinical practice.

Acknowledgements

We wish to thank Qi Zhou, of the Department of

Clinical Epidemiology and Biostatistics, McMaster

University, for her valuable guidance in data analysis.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the paper.

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