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EJSO 40 (2014) 12e26
www.ejso.com
Review
Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of
randomized trials
F. Coccolini a,b,*, E. Cotte b, O. Glehen b, M. Lotti a, E. Poiasina a, F. Catena c, Y. Yonemura d,
L. Ansaloni a
a
b
General Surgery Dept., Papa Giovanni XXIII Hospital, Bergamo, Italy
General Surgery Dept., Centre Hospitalier Lyon Sud, Hospices Civils de Lyon and EMR 3738, Universite Lyon 1, France
c
General Surgery Dept., Ospedale Maggiore, Parma, Italy
d
General Surgery Dept., Kusatsu General Hospital, Yabase 1660, Japan
Accepted 23 October 2013
Available online 5 November 2013
Abstract
Introduction: An important component of treatment failure in gastric cancer (GC) is cancer dissemination within the peritoneal cavity and
nodal metastasis. Intraperitoneal chemotherapy (IPC) is considered to give a fundamental contribute in treating advanced GC. The purpose
of the study is to investigate the effects of IPC in patients with advanced GC.
Material and methods: A systematic review with meta-analysis of randomized controlled trials (RCTs) of IPC þ surgery vs. control in
patients with advanced GC was performed.
Results: Twenty prospective RCTs have been included (2145 patients: 1152 into surgery þ IPC arm and 993 into control arm).
Surgery þ IPC improves: 1, 2 and 3-year mortality (OR ¼ 0.31, 0.27, 0.29 respectively), 2 and 3-year mortality in patients with locoregional nodal metastasis (OR ¼ 0.28, 0.16 respectively), 1 and 2-year mortality rate in patients with serosal infiltration (OR ¼ 0.33,
0.27 respectively). Morbidity rate was increased by surgery þ IPC (OR ¼ 1.82). The overall recurrence and the peritoneal recurrence rates
were improved by surgery þ IPC (OR ¼ 0.46 and 0.47 respectively). There was no statistically significant difference in lymph-nodal recurrence rate. The rate of haematogenous metastasis was improved by surgery þ IPC (OR ¼ 0.63).
Conclusions: 1, 2 and 3-year overall survival is incremented by the IPC. No differences have been found at 5-year in overall survival rate. 2
and 3-year mortality rates in patients with nodal invasion and 1 and 2-year mortality rates in patients with serosal infiltration are improved
by the use of IPC. IPC has positive effect on peritoneal recurrence and distant metastasis. Morbidity rate is incremented by IPC. Locoregional lymph-nodes invasion in patients affected by advanced gastric cancer is not a contraindication to IPC.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Gastric cancer; Intraperitoneal chemotherapy; HIPEC; Carcinosis; Nodal infiltration; Meta-analysis
Introduction
Gastric cancer (GC) is the second leading cause of cancer death and the fourth most common cancer in the
world.1,2 GC disseminates principally through the haematic
torrent or through the peritoneal fluids. It has been
* Corresponding author. General Surgery Dept., Papa Giovanni XXIII
Hospital, Piazza OMS 1, 24127 Bergamo, Italy. Tel.: þ39 (0)
352673486; fax: þ39 (0)352674963.
E-mail addresses: federico.coccolini@gmail.com, fedecocco@iol.it (F.
Coccolini).
0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejso.2013.10.019
demonstrated as peritoneal dissemination is more frequent
than haematogenous metastases. The 40% of patients died
for GC have hepatic metastases, while the 53e60% showed
a disease progression and died with peritoneal carcinosis
(PC). The two most important factors affecting prognosis
in GC are the serosal invasion and the lymphatic spread.3e5
When gastric serosa is infiltrated, PC could be considered
practically unavoidable.6 As a consequence, up to half of
the patients with advanced GC will develop PC in spite
even radical surgery.8e11 PC is already present in 5e20%
of patients explored for potentially curative resection also
F. Coccolini et al. / EJSO 40 (2014) 12e26
in early gastric cancer.6,7 Surgical resection associated to
systemic chemotherapy is the mainstay of treatment. Systemic chemotherapy improves median survival in advanced
and/or metastatic GC to not more than 12 months.12e15 The
same gain in term of survival has not been described with
macroscopic PC16e19 due to the inadequate diffusion of
systemic chemotherapy into the abdominal cavity.20
As many patients present with advanced-stage-disease,
the research for more effective treatments is mandatory.
An important component of treatment failure is cancer
dissemination within the peritoneal cavity and nodal metastasis. In contrast to lymphatic and haematogenous dissemination, peritoneal spread should be regarded as a locoregional disease extension rather than systemic metastasis.21 Taking the natural history of GC into account, the
use of intraperitoneal chemotherapy (IPC) as a targeted
adjuvant treatment after surgery may be considered a
rational prophylactic/therapeutic approach. Actually IPC
has been progressively more used in advanced GC due to
the appealing theoretical rationales. Although many
different regimens of IPC exist, they all could be considered as the different applications of the same treatment
method. IPC allows to reach an high intraperitoneal drug
concentration and allows the drugs to directly act on the
free-tumour-cells and peritoneal nodules. Drugs absorbed
through the peritoneum enter the portal vein, and also
have a chemotherapeutic effect on the liver.22 It remains
controversial if the IPC has a positive effect on the
lymph-node metastasis. The purpose of the present metaanalysis of randomized controlled trials (RCT) investigating the effects of IPC in patients with advanced GC.
13
Material and method
which patients with advanced GC (with or without PC)
were randomly assigned to receive either surgery combined
with IPC or surgery without IPC. All included patients must
have histologically-proven gastric or gastro-oesophagealjunction adenocarcinoma and underwent potentially curative resection. Included studies consider both patients
with locally advanced GC with macroscopic serosal invasion, and patients with peritoneal carcinomatosis but
without distant metastasis. All forms of IPC in addition
to surgery were included. No language restrictions have
been applied. Eligibility for study inclusion into the metaanalysis and study quality assessment were performed independently by two authors (EC, FeCo). Study data were extracted onto standard forms independently by two authors
(EC, FeCo). Discrepancies between the two investigators
were resolved by discussion and evaluation of the question
with a senior investigator. The final results were reviewed
by three senior investigators (YY, LA, OG).
The primary outcome measures for the meta-analysis
were the impact of IPC on 1, 2, 3 and 5-year mortality
and the effect of IPC on the mortality of patients with
loco-regional nodal metastasis. For this last outcome were
included data from studies in which at least the 80% of patients had loco-regional nodal metastasis at the time of
intervention. The same criteria has been adopted to evaluate
the impact of IPC on survival in patients with serosal invasion (secondary outcome) (including studies with at least
the 80% of patients with serosal infiltration at the time of
diagnosis). To evaluate the mortality rates studies were
divided into two sub-groups: studies that included patients
with and without PC. Moreover the impact of IPC on recurrence (overall, peritoneal, lymph-nodal) and haematogenous metastasis and morbidity, has been evaluated.
Literature search strategy
Assessment of risk of bias
Electronic searches were performed using Medline, Embase (1988eDecember 2012), PubMed (January
1980eDecember 2012), Cochrane Central Register of
Controlled Trials (CCTR), Cochrane Database of Systematic
Reviews (CDSR) and CINAHL from (1966e2012). The
search terms were: ‘intraperitoneal chemotherapy’, ‘stomach’, ‘gastric cancer’, ‘carcinosis’, ‘randomized trial’,
‘meta-analysis’ combined with AND/OR. Research included
also all the MeshTerms. No search restrictions were imposed.
The reference lists of all retrieved articles were reviewed for
further identification of potentially relevant studies. Review
articles were also obtained to determine other possible studies.
Duplicate published trials with accumulating numbers of patients or increased lengths of follow-up, were considered
only in the last or at least in the more complete version.
There is a potential risk of overestimating the beneficial
treatment effects of RCT with a resultant risk of bias. The
risk of bias was assessed comprehensively according to
guidelines of the Cochrane Collaboration23,24 and six items
have been considered relevant (Table 1): 1) whether the
method of allocation was truly random; 2) whether there
was proper allocation concealment; 3) whether the groups
were similar at baseline; 4) whether the eligibility criteria
were documented; 5) whether loss to follow-up in each
treatment arm was specified; 6) whether intention-to-treat
analysis was conducted. Therefore the evaluation of the
quality level of the study was conducted as follows: Positive answer to at least six questions was required for a trial
to be rated as high quality. With a positive answer to five or
four questions the study was considered of fair quality.
With a positive answer to three or fewer questions the study
was registered as low quality. When studies did not report
adequate information to determine the above-mentioned
assessment criteria, an attempt to obtain direct additional
data from the investigators was made. Studies reported in
Selection criteria
Studies which have been judged eligible for this systematic review and consequent meta-analysis are those in
14
F. Coccolini et al. / EJSO 40 (2014) 12e26
Table 1
Bias risk and quality assessment.
Study (ref.) year
Randomization
Allocation
concealment
Homogeneous
baseline
characteristic
Eligibility
criteria
Loss to follow-up
and drop-out
described
Intention-to-treat analysis
Study quality
Koga11 1987
Hagiwara26 1992
Hamazoe9 1993
Fujimura28 1994
Sautner27 1994
Ikeguchi10 1995
Takahashi29 1995
Fujimoto30 1999
Rosen31 1998
Yu32 1998
Shimoyama33 1999
Tan41 2000
Yonemura34 2001
Wei35 2004
Zuo40 2004
Ding38 2007
Kuramoto7 2009
Deng39 2009
Yang36 2011
Miyashiro37 2011
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
Unclear
YES
Unclear
Unclear
Unclear
Unclear
YES
Unclear
YES
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
YES
Unclear
Unclear
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
Unclear
Unclear
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
YES
Unclear
YES
YES
Unclear
YES
YES
NO
NO
Unclear
Unclear
YES
NO
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
NO
YES
YES
YES
Unclear
YES
YES
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Fair
Low
Fair
High
Low
High
High
Chinese and Japanese languages were translated with the
assistance of native speakers.
Statistical analysis
Data from the individual eligible studies were entered into a
spread sheet for further analysis. Review Manager (RevMan)
(Version 5.1. Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2011) was used to perform the statistical analysis. Pooled odds ratios (OR) were calculated for
discrete variables. The fixed-effects and random-effects
models were used to calculate the outcomes.25,26 In case of
significant statistical heterogeneity, only the results of the
random-effects model were reported. Heterogeneity amongst
the trials was determined by means of the Cochran Q value and
quantified using the I2 inconsistency test.
on a central site and transmitted to treatment providers by
telephone, fax or sealed opaque envelopes. In the remaining
fifteen RCTs9e11,27,28,30,32e36,38e41 the information
regarding approaches to allocation concealment could not
be determined. The baseline features were similar between
treatment groups in all 20 RCTs thus reducing the clinical
heterogeneity. All RCTs but two38,40 specified the eligibility criteria for patients to be enrolled. All RCTs but
two39,40 specified numbers lost to follow-up in each treatment group. Six RCTs7,27,40,36e38 analysed the data on an
intention-to-treat (ITT) basis, whereby participants were
analysed in the groups to which they were initially randomised. Four RCTs did not perform ITT analysis10,11,26,35
and in the remnant ten RCTs it was unclear.9,28e34,39,41
Blinding after allocation was impossible because of the nature of the trials. All twenty RCTs were considered to be at
acceptable risk of bias in the important domains (Table 1).
Results
Overall 1-year mortality
Twenty RCTs, fulfilled the inclusion criteria and were
included in the meta-analysis (publication dates
1987e2011). There were a total of 2145 patients (1152 randomized to receive radical resection þ IPC and 993 randomized to receive radical resection without IPC) (Table 2).
Quality of trials
There was good agreement between the reviewers (EC
and FeCo) about the eligibility and quality of the studies.
Table 1 demonstrates the quality of the 20 included
RCTs.7,9e11,26e41
In five RCTs,7,26,29,31,37 the method of allocation
concealment was adequate; randomisation was performed
Nine studies reported 1-year mortality,7,26e28,36,38e41
two randomized patients with PC.27,36 343 patients received
the standard treatment and 283 surgery þ IPC (Fig. 1).
There was no statistical heterogeneity between studies. In
the random-effects model, the 1-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.31, 95%CI ¼ 0.19e0.48).
Overall 2-year mortality
Seven studies reported 2-year mortality,26,28e30,33,36,41
three included patients with PC.29,30,36 249 patients
received the standard treatment and 277 surgery þ IPC
F. Coccolini et al. / EJSO 40 (2014) 12e26
15
Table 2
Summary of the 20 included studies.
Study (Ref.)
year
Number of
patients
Study
period
Stage
I/II
III
IV
Intraperitoneal chemotherapy arm n ¼ 1152
Surgery arm
n ¼ 993
n ¼ 32
HIPEC: MMC 64e100 mg in 8e12 lt.
solution
Temp: 40e45 C
Time: 50e60 min.
Technique: close
Lost F-Up: 0/60 (both arms)
n ¼ 25
Perfusion: MMC 500 mg þ 375 mg CH
Technique: close
Lost F-Up: 1/50 (both arms)
n ¼ 42
HIPEC: MMC (10 mg/ml)
Temp: 40e45 C
Time: 50e60 min
Technique: close
Lost F-Up: 0/82(both arms)
n ¼ 40
Perfusion: MMC 30 mg/kg þ CDDP 300 mg/kg
in 10 lt. saline solution
Time: 60 min.
Hyperthermic: 41e42 C (n ¼ 22)
Normothermic: 37e38 C (n ¼ 18)
Technique: open
Lost F-Up: 0/58 (both arms)
n ¼ 33
EPIC (started between 10 and 28 POD) CDDP
90 mg/m2 in 2 lt. saline
solution
Time perfusion: 4 h.
Treatment repeated monthly
Technique: close
Lost-F-Up: 3/67 (both arms)
n ¼ 56
Perfusion: MMC 50 mg þ CH in 100 ml
saline solution
Temperature: room temperature
Technique: close
Lost-F-Up: 2/113 (both arms)
n ¼ 78
HIPEC: MMC 80e100 mg/m2 in 8e10 lt.
solution
Temperature: 40e45 C
Time: 50e60 min.
Technique: open
Lost-F-Up: 0/174 (both arms)
n ¼ 46
Perfusion: MMC 50 mg þ 375 CH
Technique: open
Lost-F-Up: 0/91 (both arms)
n ¼ 125
EPIC: MMC 10 mg/m2 in 1 lt. dextrose
solution for 23 h (POD 1), 5-FU
700 mg/m2 in 1 lt.
dextrose sol. (POD 2, 3, 4, 5)
Temperature: 37 C
Technique: close
Lost-F-Up: 3/248 (both arms)
(continued
n ¼ 27
1
Koga11 1987
60
1983e1985
ND
ND
ND
2
Hagiwara26 1992
50
1987e1991
ND
ND
0
3
Hamazoe9 1993
82
1983e1986
14
57
11
4
Fujimura28 1994
58
1988e1992
20
20
18
5
Sautner27 1994
67
1985e1989
0
42
25
6
Takahashi29 1995
113
1987e1992
0
76
37
7
Ikeguchi10 1995
174
1980e1989
ND
ND
ND
8
Rosen31 1998
91
1994e1997
0
79
12
9
Yu32 1998
248
1990e1995
93
84
71
n ¼ 25
n ¼ 40
n ¼ 18
n ¼ 34
n ¼ 57
n ¼ 96
n ¼ 45
n ¼ 123
on next page)
16
F. Coccolini et al. / EJSO 40 (2014) 12e26
Table 2 (continued)
Study (Ref.)
year
Number of
patients
Study
period
Stage
I/II
10
Fujimoto30 1999
141
1987e1996
24
11
Shimoyama33 1999
46
1991e1993
12
Tan41 2000
51
13
Yonemura34 2001
14
IV
Intraperitoneal chemotherapy arm n ¼ 1152
58
59
21
24
1
1995e1998
ND
ND
ND
139
1988e1993
0
102
37
Zuo40 2004
82
1998e2000
18
54
10
15
Wei35 2004
156
1999e2001
41
93
22
16
Ding38 2007
78
2001e2003
20
33
25
17
Deng39 2009
85
2002e2004
25
37
24
18
Kuramoto7 2009
88
1995e2005
ND
ND
ND
n ¼ 71
HIPEC: MMC 10 mg/ml in 3e4 lt. solution
Temperature: 43e45 C
Time: 120 min.
Technique: close
Lost F-Up: 0/141 (both arms)
n ¼ 30
Perfusion: MMC 10 mg in 0.5 lt. solution þ
systemic chemother as in
surgery arm
Temperature: room temperature
Technique: open
Lost-F-Up: 0/46 (both arms)
n ¼ 22
HIPEC: MMC 64 mg in 10 lt. solution
Temperature: 45 C
Time: 60 min.
Lost-F-Up: 0/51 (both arms)
n ¼ 48 HIPEC
n ¼ 44 NIC
Perfusion: MMC 30 mg þ CDDP 300 mg in
8e10 lt. saline solution.
Temperature: 42 C and 37 C
Time: 60 min
Technique: open
Lost-F-Up: 0/139 (both arms)
n ¼ 46
EPIC (3 cycles between POD 21 and 28)
CDDP-80e100 mg þ 5-FU 1 g in 2 lt solution
Temperature: 41e43 C
Time: 60 min.
Technique: close
n ¼ 101
HIPEC (n ¼ 52): 1 g/m2 5-FU in 1 lt. solutions
Temperature: 43e45 C
Time: 60 min.
HIPEC þ EPIC (n ¼ 49): HIPEC þ 60 mg/m2
CDDP in 1 lt. solution for
24 h (POD 1)
Lost-F-Up: 0/156 (both arms)
n ¼ 41
EPIC: 60mg/m2 CDDP in 2.5e3.5 lt. solution
Temperature: 42e44 C
Time: 30 min (4 cycles)
Technique: close
Lost-F-Up: 0/78 (both arms)
n ¼ 44
HIPEC: 1000e1500 mg 5-FU þ MMC20 mg
in 3 lt. solution
Temperature: 42e43 C
Time: 60e90 min.
EPIC: 5-FU 1000e1500 mg in 3 lt. solution
Temperature: 42e43 C
Time: 60 min.
n ¼ 30 intraperitoneal lavage þ NIC
n ¼ 29 NIC
NIC: CDDP 100 mg in 1.5 lt. solution
Time: 1 h.
Technique: close
Lost-F-Up: 0/88 (both arms)
III
Surgery arm
n ¼ 993
n ¼ 70
n ¼ 16
n ¼ 29
n ¼ 47
n ¼ 36
n ¼ 55
n ¼ 37
n ¼ 41
n ¼ 30
F. Coccolini et al. / EJSO 40 (2014) 12e26
17
Table 2 (continued )
Study (Ref.)
year
19
Yang36 2011
20
Miyashiro37 2011
Number of
patients
Study
period
Stage
I/II
68
2007e2009
0
268
1993e1998
ND
III
0
ND
IV
Intraperitoneal chemotherapy arm n ¼ 1152
68
n ¼ 34
HIPEC: CDDP 120 mg þ MMC 30 mg in 6 lt. solution
Temperature: 43 0.5 C
Time: 60e90 min.
Technique: open
Lost-F-Up: 0/68 (both arms)
n ¼ 135
Perfusion: CDDP 70mg/m2 for 2 h
in 1 lt. solution.
Chemotherapy: i.v. CDDP 70mg/m2
(POD 14), i.v. 5-FU 700 mg/m2 (POD 14, 16),
Oral FU 267 mg/m2 daily, for 12 months
starting in the 4th Post-Op week
Lost-F-Up: 1/268 (both arms)
ND
Surgery arm
n ¼ 993
n ¼ 34
n ¼ 133
Abbreviations: HIPEC ¼ hyperthermic intraperitoneal chemotherapy, EPIC ¼ early postoperative intraperitoneal chemotherapy, NIC ¼ normothermic intraperitoneal chemotherapy MMC ¼ Mytomicin C, CDDP ¼ cisplatin, CH ¼ activated carbon, POD ¼ post-operative day, 5-FU ¼ 5-fluoruracil, ND ¼ not
declared.
(Fig. 1). There was acceptable statistical heterogeneity between studies. In the random-effects model, the 2-year mortality rate was significantly favourable to the surgery þ IPC
arm (OR ¼ 0.27, 95%CI ¼ 0.16e0.47).
Overall 3-year mortality
Nine studies reported 3-year mortality,26e29,36,38e41three
enrolled patients with PC.27,29,36 311 patients received the
standard treatment and 340 surgery þ IPC (Fig. 2). There
was acceptable statistical heterogeneity between studies.
In the fixed-effects model, the 3-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.29, 95%CI ¼ 0.20e0.41).
Overall 5-year mortality
Six studies reported 5-year mortality,7,9,10,27,34,37 two
included patients with PC.27,37 379 patients received the
standard treatment and 439 surgery þ IPC (Fig. 2). There
was acceptable statistical heterogeneity between studies.
In the random-effects model, there was no statistically significant difference in the 5-year mortality rate (OR ¼ 0.99,
95%CI ¼ 0.71e1.37).
1-Year mortality in patients with peritoneal
carcinomatosis
Two studies randomized patients with PC (68 patients:
standard treatment and 67: surgery þ IPC)27,36 (Fig. 1).
There was no statistical heterogeneity between studies. In
the random-effects model, the 1-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.25, 95%CI ¼ 0.12e0.51).
2-Year mortality in patients with peritoneal
carcinomatosis
Three studies included patients with PC (161 patients:
standard treatment and 161 surgery þ IPC)29,30,36
(Fig. 1). There was no statistical heterogeneity between
studies. In the random-effects model, the 2-year mortality
rate was favourable to the surgery þ IPC arm
(OR ¼ 0.29, 95%CI ¼ 0.17e0.51).
3-Year mortality in patients with peritoneal
carcinomatosis
Three RCTs enrolled patients with PC (125 patients:
standard treatment and 123 surgery þ IPC)27,29,36 (Fig.
2). There was statistical heterogeneity between studies. In
the fixed-effects model, the 3-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.25, 95%CI ¼ 0.14e0.47).
5-Year mortality in patients with peritoneal
carcinomatosis
Two RCTs included patients with PC (167 patients: standard treatment and 168 surgery þ IPC)27,37 (Fig. 2). There
was no statistical heterogeneity between studies. In the
random-effects model, there was no statistically significant
difference in the 5-year mortality rate (OR ¼ 1.05, 95%
CI ¼ 0.67e1.55).
1-Year mortality in patients without peritoneal
carcinomatosis
Seven trials evaluated the 1-year mortality (276 patients:
standard
treatment
and
215
18
F. Coccolini et al. / EJSO 40 (2014) 12e26
Figure 1. Overall mortality at 1 year (A) and at 2 years (B).
surgery þ IPC)7,26,28,38e41 (Fig. 1). There was no statistical heterogeneity between studies. In the randomeffects model, the 1-year mortality rate was significantly
favourable to the surgery þ IPC arm (OR ¼ 0.34, 95%
CI ¼ 0.18e0.62).
2-Year mortality in patients without peritoneal
carcinomatosis
Four trials evaluated the 2-year mortality (88 patients:
standard treatment and 116 surgery þ IPC)26,28,33,41
(Fig. 1). There was statistical heterogeneity between
studies. In the random-effects model, the 2-year mortality
rate was significantly favourable to the surgery þ IPC
arm (OR ¼ 0.24, 95%CI ¼ 0.08e0.76).
3-Year mortality in patients without peritoneal
carcinomatosis
Six trials evaluated the 3-year mortality (186 patients:
standard treatment and 217 surgery þ IPC)26,28,38e41
(Fig. 2). There was no statistical heterogeneity between
studies. In the fixed-effects model, the 3-year mortality
rate was significantly favourable to the surgery þ IPC
arm (OR ¼ 0.31, 95%CI ¼ 0.20e0.47).
5-Year mortality in patients without peritoneal
carcinomatosis
Four studies evaluated the 5-year mortality (212 patients: standard treatment and 271 surgery þ IPC)7,9,10,34
F. Coccolini et al. / EJSO 40 (2014) 12e26
19
Figure 2. Overall mortality at 3 years (C) and at 5 years (D).
(Fig. 2). There was statistical heterogeneity between
studies. In the random-effects model, there was no statistically significant difference in the 5-year mortality rate
(OR ¼ 0.89, 95%CI ¼ 0.49e1.63).
Overall recurrence
Eight RCTs were included7,9,28,30e32,34,39 (Fig. 2), one
included patients with PC (31). 413 patients received the
standard treatment and 519 surgery þ IPC. There was no
statistical heterogeneity between studies. In the randomeffects model, the overall recurrence rate was significantly
favourable to the surgery þ IPC arm (OR ¼ 0.46, 95%
CI ¼ 0.35e0.62).
Peritoneal recurrence
Eleven RCTs reported the peritoneal recurrence
rate,9,10,28,30e32,34,36,38,41 two included patients with PC
(30, 36). 568 patients received the standard treatment and
650 surgery þ IPC (Fig. 3). There was statistical heterogeneity between studies. In the random-effects model, the
peritoneal recurrence rate was significantly favourable to
the surgery þ IPC arm (OR ¼ 0.47, 95%CI ¼ 0.35e0.63).
Dividing RCTs into those who treated patients with and
without PC: 104 patients received the standard treatment
and 105 patients were treated with surgery þ IPC for PC.
There was great statistical heterogeneity between studies.
In the random-effects model, the peritoneal recurrence
20
F. Coccolini et al. / EJSO 40 (2014) 12e26
Figure 3. Recurrence rate: overall (A) and peritoneal (B).
rate was significantly favourable to the surgery plus IPC
arm (OR ¼ 0.29, 95%CI ¼ 0.12e0.70). In the PCprophylaxis trials 464 patients received the standard treatment and 545 surgery þ IPC. There was acceptable statistical heterogeneity between studies. In the random-effects
model, the peritoneal recurrence rate was significantly favourable to the surgery þ IPC arm (OR ¼ 0.50, 95%
CI ¼ 0.37e0.68).
Lymph-nodal recurrence
Six RCts reported the lymph-nodal recurrence
rate,7,9,28,30,32,34 two included 100% of patients with positive lymph-nodes at the intervention.30,7 327 patients
received the standard treatment and 429 surgery þ IPC
(Fig. 4). There was no statistical heterogeneity between
studies. In the random-effects model, there were no statistically significant difference in lymph-nodal recurrence rate between the two groups (OR ¼ 0.47, 95%
CI ¼ 0.35e0.63). Dividing studies into those who
included 100% of patients with lymph-nodal metastasis
and the other four studies: 99 patients with 100% of
lymph-nodal metastasis received the standard treatment
and 130 surgery þ IPC. There was no statistical heterogeneity between studies. In the random-effects model,
there was no statistically significant difference in
lymph-nodal recurrence rate between the two groups
(OR ¼ 0.95, 95%CI ¼ 0.40e2.27). In the remnant four
studies, 228 patients received standard treatment and
299 surgery þ IPC. There was statistical heterogeneity
between studies. In the random-effects model there was
no statistically significant difference in lymph-nodal
recurrence rate between the two groups (OR ¼ 0.94,
95%CI ¼ 0.38e2.30).
Haematogenous metastasis
Eight studies were included (387 patients: standard treatment and 514 surgery þ IPC)7,9,28,30,32,34,38,39 (Fig. 4).
There was acceptable statistical heterogeneity between
F. Coccolini et al. / EJSO 40 (2014) 12e26
21
Figure 4. Recurrence rate: lymph-nodal (C) and haematogenous metastasis (D).
studies. In the random-effects model, the rate of haematogenous metastasis was significantly favourable to the
surgery þ IPC arm (OR ¼ 0.63, 95%CI ¼ 0.40e0.98).
1-Year mortality in patients with nodal metastasis
Three RCTs were included (83 patients standard treatment and 105 surgery þ IPC)7,26,41 (Fig. 5). There was
no statistical heterogeneity between studies. In the
random-effects model, there was no statistically significant
difference (OR ¼ 0.51, 95% CI ¼ 0.22e1.17).
2-Year mortality in patients with nodal metastasis
Four RCTs were included26,29,30,41 (Fig. 5). 181 patients
received the standard treatment and 173 surgery þ IPC.
There was no statistical heterogeneity between studies. In
the random-effects model, the 2-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.28, 95%CI ¼ 0.17e0.45).
3-Year mortality in patients with nodal metastasis
Three RCTs were included26,29,41 (Fig. 5). 111 patients
received the standard treatment and 102 surgery þ IPC.
There was no statistical heterogeneity between studies. In
the random-effects model, the 2-year mortality rate was
significantly favourable to the surgery þ IPC arm
(OR ¼ 0.16, 95%CI ¼ 0.08e0.29).
1-Year mortality in patients with serosal infiltration
Three RCTs were included26,27,41 (Fig. 6). One study
included patients with PC.27 88 patients received the standard
treatment and 79 surgery þ IPC. There was no statistical heterogeneity between studies. In the random-effects model, the
1-year mortality rate was significantly favourable to the
surgery þ IPC arm (OR ¼ 0.33, 95%CI ¼ 0.15e0.72).
2-year mortality in patients with serosal infiltration
Three RCTs were included26,29,41 (Fig. 6). One study
included patients with PC.29 111 patients received the
22
F. Coccolini et al. / EJSO 40 (2014) 12e26
Figure 5. Mortality in patients with loco-regional lymph-nodal metastasis at 1 year (A), at 2 years (B) and at 3 years (C).
standard treatment and 102 surgery þ IPC. There was no
statistical heterogeneity between studies. In the randomeffects model, the 2-years mortality rate was significantly
favourable to the surgery þ IPC arm (OR ¼ 0.27, 95%
CI ¼ 0.15e0.48).
Morbidity
Ten RCTs were included9e11,28e32,34,36 (Fig. 7). 558 patients
received the standard treatment and 616 surgery þ IPC. There
was statistical heterogeneity between studies. In the fixedeffects model, the morbidity rate was significantly favourable
to the surgery arm (OR ¼ 1.82, 95%CI ¼ 1.29e2.57).
Discussion
PC is the most common form of evolution and recurrence in patients suffering from GC,Although PC has
been for long considered as incurable and associated with
extremely poor prognosis, in the last 20 years was established the concept of multimodal treatment which combines
systemic chemotherapy, radical surgery and IPC. The principal aim of the multimodal treatment in GC is to prevent
and/or to treat efficiently PC. Some cohort studies demonstrated its efficacy in advanced GC with or without PC.42
Many RCT confirmed its efficacy in treating advanced
GC with or without PC and in preventing the locoregional recurrence.7,9e12,26e41 The published RCT applied
different forms of IPC. All demonstrated advantages
compared to the standard treatment considered as radical
surgery and systemic chemotherapy. In our opinion the
different forms of IPC can be considered as a unique treatment. The different way to apply it, gives slightly different
results, but the inclusion in the multimodal treatment
approach gives to all of them the same attribute: the direct
application of a chemotherapeutic agents on the macro/
microscopic tumour seeding or residual. This gives the
advantage to treat directly, with limited systemic chemotherapy diffusion, the microscopic component of tumour
which spilled during the surgical manipulation or which
diffuses through the peritoneal fluid circulations. The possibility to apply IPC also in neoadjuvant setting has been
recently investigated with promising results.43,44 The
main differences between the different forms of IPC are
principally due to the pharmacokinetic and pharmacodynamic of the different drugs in the different situations.
F. Coccolini et al. / EJSO 40 (2014) 12e26
23
Figure 6. Mortality in patients with serosal invasion at 1 year (A) and at 2 years (B).
The survival and recurrence rate of patients affected by
advanced GC depends strongly on the presence of PC and
on loco-regional nodal infiltration. Nodal invasion could
be theoretically considered as extra-peritoneal disease
demonstrating the cancer systemic diffusion beyond the
peritoneal cavity. With this assumption, theoretically IPC
would have limited or no efficacy due to its presumed
only loco-regional effect. The effect of IPC on nodal metastasis has never been clearly demonstrated. Two previous
RCT analysed the effect of IPC on survival relatively to
the positivity of lymph-nodes at pathological examination.10,34 Yonemura et al. found on one hand no statistically
significant differences in negative-nodes patient group. On
the other hand they found an increase in survival with the
application of IPC in positive-node patients group. The survival was moreover increased by the application of hyperthermic IPC.34 Ikeguchi et al. demonstrated the limited
positive effect on survival of IPC in patients with positive
lymph-nodes. They divided patients into three subgroups:
no lymph-nodes metastases, 1e9 positive lymph-nodes
and more than 10 positive lymph-nodes.10 Authors demonstrated the appreciable but not statistically significant (66%
in surgery þ IPC group vs. 44% in control group) difference in 5-year survival in 1e9 positive lymph-nodes patients subgroup.10 The present meta-analysis demonstrated
positive effect on mortality in patients with loco-regional
lymph-nodal invasion: 2 and 3-year mortality rates are positively affected by the use of IPC. As a counterpart, the rate
of nodal recurrence is not so positively affected by the IPC
either in patients with 100% of positive loco-regional
lymph-nodes either in remnant patients group. The positive
effect on nodal metastasis is absolutely in agreement with
the haematogenous metastasis rate reduction. It remains
hard to explain the absence of significant effect of IPC on
1-year mortality.
Serosal infiltration could be considered as a strong indicator of tumour cells diffusion to the peritoneal cavity. This
cell diffusion can be classified as “on-going peritoneal
carcinomatosis”. Many studies included patient case-mix
that comprehends many patients with no evident PC but
with serosal infiltration. Also in ours daily practice we
face doubt cases with no evident PC but with evident and
“high-suspicion” serosal infiltration. These patients group
represent a challenge because of the impossibility to definitively include them into either the PC-prophylaxis or into
the PC-treatment group. They could be considered as an intermediate undefined group. The use of IPC in these cases
could be controversial as no definitive evaluation of the effect of IPC in preventing and treating PC have been published. The previously published meta-analysis45e48
suggested the efficacy in treating/preventing PC of IPC
but they did not analyse the different groups separately.
For this reason the analysis of IPC effect on prevention/
treatment of PC has been conducted either separating
studies that consider the prevention and the treatment of
PC either considering them together. In 1, 2 and 3-year
mortality analysis, IPC demonstrated to offer good chance
to patients affected by advanced GC. The gain in terms
of survival is confirmed considering the two groups either
separately either together. The 5-year mortality analysis
demonstrated to be not statistically significant. This data
differs from the last published meta-analysis which found
5 and 9-year survival benefit.48 The last published metaanalysis and the previous published ones analysed different
primary outcomes. However all confirmed the efficacy of
IPC in increasing the survival rates at different time points.
24
F. Coccolini et al. / EJSO 40 (2014) 12e26
Figure 7. Morbidity.
The present study included a higher number of studies than
the previous ones. Contemporarily it didn’t differentiate between the different form of IPC administration; as stated
before we considered all the IPC administrations as declinations of the same treatment included in a multimodal
diagnostic-therapeutic pathway. Reduced 1 and 2-year mortality have been also demonstrated by analysing only
studies including patients with serosal invasion. Overall
and peritoneal recurrence rate and haematogenous metastasis rate are positively influenced by IPC. These data agree
with those about the efficacy on nodal metastasis. None of
the previous meta-analysis analysed the different pattern of
recurrence. These results suggest the possibility to enlarge
the selection criteria for surgery þ IPC in advanced GC
either with either without PC. In fact the high rate of
loco-regional and systemic recurrence contributes to maintain the indications to surgery þ IPC as a kind of
“desperate” alternative in many centers.
As demonstrated by the present and previous metaanalysis as well as randomized trials, IPC plays a positive
and fundamental role in treating GC and in preventing
PC. Survival rates are increased by IPC even if morbidity
has been demonstrated to be at risk of increasing with
IPC after surgery.21,46 Four published meta-analysis found
different results.21,46e48 In the present study the morbidity
analysis showed as surgery þ IPC increased the rate of
post-operative complications. Data about morbidity however are not definitive because of the impossibility to
completely analyse the real impact of IPC on postoperative complications.
As many randomized trials and meta-analysis about the
effect of IPC as in GC have never been published for other
diseases. The majority of them give positive results in terms
of mortality and recurrence rate in patients who generally
experiment a poor prognosis with relatively scarce chance
of cure. IPC offers evidence-based good possibilities to
improve the limited weapons we have to face with a such
aggressive disease. However, no definitive indications on
its use have been still given by expert panels. The present
paper will contribute to solve the controversies about the
efficacy of IPC on nodal metastasis. In our opinion, in
agreement with the results of the present study, IPC should
start to be considered as part of common clinical practice in
the treatment of advanced GC with or without PC. A big
effort should be done to investigate more the physiopathology of this form of treatment.
Conclusion
1, 2 and 3-year overall survival is incremented by the
IPC. No differences have been found at five years in overall
survival. 2 and 3-year mortality in patients with nodal invasion and 1 and 2-year mortality in patients with serosal invasion are improved by IPC. A positive effect of IPC has
been found on overall and peritoneal recurrence and on
distant metastasis. Morbidity rate is incremented by IPC.
Loco-regional lymph-nodes invasion in patients affected
by advanced gastric cancer is not a contraindication to IPC.
Acknowledgement
We would like to thank Dr. He Ping, from the Chengdu
Hospital (Sichuan province, China) for the precious
collaboration.
Conflict of interest
All authors declare to have no conflict of interest.
References
1. Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors.
J Clin Epidemiol 2003;56(1):1–9.
2. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J
Clin 1999;49(1):33–64.
3. Nakamura K, Ueyama T, Yao T, et al. Pathology and prognosis of
gastric carcinoma. Findings in 10,000 patients who underwent primary
gastrectomy. Cancer 1992;70:1030–7.
F. Coccolini et al. / EJSO 40 (2014) 12e26
4. Takahashi T, Hagiwara A, Sawai K, Kondo S, Yamaguchi T. Intensive
intraoperative local chemotherapy for lymph node and peritoneal metastases in gastric cancer. Onkologie 1991;14:152–7.
5. Yu CC, Levison DA, Dunn JA, et al. Pathological prognostic factors in
the second British Stomach Cancer Group trial of adjuvant therapy in
resectable gastric cancer. Br J Cancer 1995;71:1106–10.
6. Ikeguchi M, Oka A, Tsujitani S, Maeta M, Kaibara N. Relationship
between area of serosal invasion and intraperitoneal free cancer cells
in patients with gastric cancer. Anticancer Res 1994;14:2131–4.
7. Kuramoto M, Shimada S, Ikeshima S, et al. Extensive intraoperative
peritoneal lavage as a standard prophylactic strategy for peritoneal
recurrence in patients with gastric carcinoma. Ann Surg 2009;250:
242–6.
8. Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of
failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8:1–11.
9. Hamazoe R, Maeta M, Kaibara N. Intraperitoneal thermochemotherapy for prevention of peritoneal recurrence of gastric cancer. Final results of a randomized controlled study. Cancer 1994;73:2048–52.
10. Ikeguchi M, Kondou A, Oka A, Tsujitani S, Maeta M, Kaibara N. Effects of continuous hyperthermic peritoneal perfusion on prognosis of
gastric cancer with serosal invasion. Eur J Surg 1995;161:581–6.
11. Koga S, Hamazoe R, Maeta M, Shimizu N, Murakami A, Wakatsuki T.
Prophylactic therapy for peritoneal recurrence of gastric cancer by
continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer 1988;61:232–7.
12. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for
advanced gastric cancer. Cochrane Database Syst Rev 2010 Mar 17;
(3):CD004064.
13. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. V325 study group.
Phase III study of docetaxel and cisplatin plus fluorouracil compared
with cisplatin and fluorouracil as first-line therapy for advanced gastric
cancer: a report of the V325 study group. J Clin Oncol 2006;24:4991–7.
14. Cunningham D, Starling N, Rao S, et al. Upper gastrointestinal clinical studies group of the national cancer research institute of the
United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36–46.
15. Roth AD, Fazio N, Stupp R, et al. Swiss group for clinical cancer
research. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin;
and epirubicin, cisplatin, and fluorouracil as systemic treatment for
advanced gastric carcinoma: a randomized phase II trial of the Swiss
group for clinical cancer research. J Clin Oncol 2007;25:3217–23.
16. Ross P, Nicolson M, Cunningham D, et al. Prospective randomized
trial comparing mitomycin, cisplatin, and protracted venous-infusion
fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in
advanced esophagogastric cancer. J Clin Oncol 2002;20:1996–2004.
17. Baba H, Yamamoto M, Endo K, et al. Clinical efficacy of S-1 combined with cisplatin for advanced gastric cancer. Gastric Cancer
2003;6(Suppl. 1):45–9.
18. Yabusaki H, Nashimoto A, Tanaka O. Evaluation of TS-1 combined
with cisplatin for neoadjuvant chemotherapy in patients with advanced
gastric cancer. Gan To Kagaku Ryoho 2003;30:1933–40.
19. Preusser P, Wilke H, Achterrath W, et al. Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable
gastric cancer. J Clin Oncol 1989;7:1310–7.
20. Al-Shammaa HA, Li Y, Yonemura Y. Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic
chemotherapy for peritoneal carcinomatosis. World J Gastroenterol
2008;14:11.
21. Yan TD, Black D, Sugarbaker PH, et al. A systematic review and
meta-analysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol
2007;14:2702–13.
22. Speyer JL, Sugarbaker PH, Collins JM, et al. Portal levels and hepatic
clearance of 5-fluorouracil after intraperitoneal administration in humans. Cancer Res 1981;41:1916–22.
25
23. Higgins JPT, Green S. Cochrane handbook for systematic reviews of
interventions: the cochrane collaboration. Chirchester (UK): John Wiley & Sons; 2008.
24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials 1986;7(3):177–88.
25. Demets DL. Methods for combining randomized clinical trials:
strengths and limitations. Stat Med 1987;6(3):341–50.
26. Hagiwara A, Takahashi T, Kojima O, et al. Prophylaxis with carbonadsorbed mitomycin against peritoneal recurrence of gastric cancer.
Lancet 1992;339:629–31.
27. Sautner T, Hofbauer F, Depisch D, Schiessel R, Jakesz R. Adjuvant
intraperitoneal cisplatin chemotherapy does not improve long-term
survival after surgery for advanced gastric cancer. J Clin Oncol
1994;12(5):970–4.
28. Fujimura T, Yonemura Y, Muraoka K, et al. Continuous hyperthermic
peritoneal perfusion for the prevention of peritoneal recurrence of
gastric cancer: randomized controlled study. World J Surg 1994;
18(1):150–5.
29. Takahashi T, Hagiwara A, Shimotsuma M, Sawai K, Yamaguchi T.
Prophylaxis and treatment of peritoneal carcinomatosis: intraperitoneal chemotherapy with mitomycin C bound to activated carbon particles. World J Surg 1995;19(4):565–9.
30. Fujimoto S, Takahashi M, Mutou T, Kobayashi K, Toyosawa T. Successful intraperitoneal hyperthermic chemoperfusion for the prevention of postoperative peritoneal recurrence in patients with advanced
gastric carcinoma. Cancer 1999;85(3):529–34.
31. Rosen HR, Jatzko G, Repse S, et al. Adjuvant intraperitoneal chemotherapy with carbon-adsorbed mitomycin in patients with gastric cancer: results of a randomized multicenter trial of the Austrian
Working Group for Surgical Oncology. J Clin Oncol 1998;16(8):
2733–8.
32. Yu W, Whang I, Chung HY, Averbach A, Sugarbaker PH. Indications
for early postoperative intraperitoneal chemotherapy of advanced
gastric cancer: results of a prospective randomized trial. World J
Surg 2001;25(8):985–90.
33. Shimoyama S, Shimizu N, Kaminishi M. Type-oriented intraoperative
and adjuvant chemotherapy and survival after curative resection of
advanced gastric cancer. World J Surg 1999;23(3):284–91.
34. Yonemura Y, de Aretxabala X, Fujimura T, et al. Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer:
final results of a randomized controlled study. Hepatogastroenterology
2001;48(42):1776–82.
35. Wei G, Fang GE, Bi JW, et al. Efficacy of intraoperative hypothonic
peritoneal chemo-hyperthermia combined with early postoperative
intraperitoneal chemotherapy on gastric cancer. Chinese J Cancer
2005;24(4):478–82.
36. Yang XJ, Huang CQ, Suo T, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients
with peritoneal carcinomatosis from gastric cancer: final results of a
phase III randomized clinical trial. Ann Surg Oncol 2011;18(6):
1575–81.
37. Miyashiro I, Furukawa H, Sasako M, et al. Gastric Cancer Surgical
Study Group in the Japan Clinical Oncology Group. Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive
gastric cancer versus curative resection alone: final results of the Japan
Clinical Oncology Group trial JCOG9206-2. Gastric Cancer 2011;
14(3):212–8.
38. Ding WT, Duan DM, Sun GS, Gu C. Clinical observation on early
intraperitoneal hypothermic perfusion chemotherapy in the treatment
of stomach carcinoma after operation. Tumor 2007;27(7):585–7.
39. Deng HJ, Wei ZG, Zhen L, Li GX, Huang XC, Quing SH. Clinical
application of perioperative continuous hyperthermic peritoneal perfusion chemotherapy for gastric cancer. J South Med Univ 2009;29(2):
295–7.
40. Zuo Y, Xu M, Shen D, Lu WD, Lu JF. Postoperative intraperitoneal
hyperthermic
chemoperfusion
combined
with
intravenous
26
41.
42.
43.
44.
F. Coccolini et al. / EJSO 40 (2014) 12e26
chemotherapy for 82 advanced gastric cancer patients. Chin J Oncol
2004;26(4):247–9.
Tan CQ, Wang XJ, Xu YK. Clinical studies on prevention of postoperational intraperitoneal neoplasm seeding of advanced gastric cancer by surgery combined with intraperitoneal perfusion of hyperthermic mitomycin C. J Pract Oncol 2000;15(3):165–7.
Glehen O, Gilly FN, Arvieux C, et al. Association Française de Chirurgie. Peritoneal carcinomatosis from gastric cancer: a multiinstitutional study of 159 patients treated by cytoreductive surgery
combined with perioperative intraperitoneal chemotherapy. Ann Surg
Oncol 2010;17(9):2370–7.
Yonemura Y, Elnemr A, Endou Y, et al. Multidisciplinary therapy for
treatment of patients with peritoneal carcinomatosis from gastric cancer. World J Gastrointest Oncol 2010 Feb 15;2(2):85–97.
European Union Network of Excellence (EUNE) for Gastric Cancer
Steering Group. Gastric cancer in Europe. Br J Surg 2008;95:406–8.
45. Xu DZ, Zhan YQ, Sun XW, Cao SM, Geng QR. Meta-analysis of
intraperitoneal chemotherapy for gastric cancer. World J Gastroenterol
2004;10(18):2727–30.
46. Huang JY, Xu YY, Sun Z, et al. Comparison different methods of intraoperative and intraperitoneal chemotherapy for patients with gastric
cancer: a meta-analysis. Asian Pac J Cancer Prev 2012;13(9):4379–
85.
47. Sun J, Song Y, Wang Z, et al. Benefits of hyperthermic intraperitoneal
chemotherapy for patients with serosal invasion in gastric cancer: a
meta-analysis of the randomized controlled trials. BMC Cancer
2012;12:526.
48. Mi DH, Li Z, Yang KH, et al. Surgery combined with intraoperative
hyperthermic intraperitoneal chemotherapy (IHIC) for gastric cancer:
a systematic review and meta-analysis of randomised controlled trials.
Int J Hyperthermia 2013;29(2):156–67.