International Journal of Surgery 51 (2018) 120–127

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International Journal of Surgery

journal homepage: www.elsevier.com/locate/ijsu

Review

Neoadjuvant chemotherapy in advanced gastric and esophago-gastric T

cancer. Meta-analysis of randomized trials
Federico Coccolinih,∗, Matteo Nardib, Giulia Montoria, Marco Ceresolia, Andrea Celottic,
Stefano Cascinud, Paola Fugazzolaa, Matteo Tomasonia, Olivier Glehene, Fausto Catenaf,
Yutaka Yonemurag, Luca Ansalonih
a
General Surgery Dept., Papa Giovanni XXIII Hospital, Bergamo, Italy
b
General Surgery Dept., La Sapienza University Hospital, Roma, Italy
c
Second Surgical Dept., Civili Hospital, Brescia, Italy
d
Medical Oncology Dept., University Hospital, Modena, Italy
e
General Surgery Dept., Centre Hospitalier Lyon Sud, Hospices Civils de Lyon and EMR 3738, Université Lyon 1, France
f
General Surgery Dept., Ospedale Maggiore, Parma, Italy
g
General Surgery Dept., Kusatsu General Hospital, Yabase 1660, Japan
h
General, Emergency and Trauma Surgery Dept., Bufalini Hospital, Cesena, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Introduction: Even in after curative surgery and adequate linfoadenectomy the survival of advanced gastric
Gastric cancer cancer (AGC) remains poor. At present some data have been published on the effects of NACT and perioperative
Esophago-gastric cancer chemotherapy on AGC and Esophago-gastric cancer (EGC) but not definitive ones. The present meta-analysis
Perioperative aims to evaluate the effects of neoadjuvant chemotherapy (NACT) on the AGC and EGC.
Neoadjuvant chemotherapy
Material and methods: A systematic review with meta-analysis of randomized controlled trials (RCTs) of
Survival
Management
NACT + surgery vs. Surgery in patients with AGC and EGC was performed.
Treatment Results: 15 RCTs have been included (2001 patients: 977 into NACT + surgery arm and 1024 into control arm).
Recurrence NACT + Surgery reduces the overall mortality at 1, 3 and 5-year in cumulative analysis (RR = 0.78; 0.81; 0.88
Post-operative respectively), at 1, 2, 3 and 5-years in EGC (RR = 0.79; 0.83; 0.84; 0.91 respectively) and at 3 and 5-years in
Mortality AGC (RR = 0.74; 0.82 respectively). Morbidity and perioperative mortality rate are not influenced by NACT.
Morbidity Recurrence rate is reduced by NACT + surgery in EGC (RR = 0.80).
Conclusions: NACT reduces the mortality in gastric and esophago-gastric cancer. Morbidity and perioperative
mortality are not influenced by NACT. The overall recurrence rate is reduced by NACT in esophago-gastric
cancer.

1. Introduction
Gastric cancer (GC) represents the fourth form of cancer in term of
diffusion and formally the second cause of cancer death [1,2]. Recently,
has been observed as the esophago-gastric cancer (EGC) incidence has
increased in North America and western European countries; as a
counterpart, the GC incidence has decreased [3,4]. Even after curative
surgery and adequate linfoadenectomy the survival of advanced gastric
cancer (AGC) remains poor. Various therapeutical approaches have
been studied and applied to improve survival. Neoadjuvant che-
motherapy (NACT) has been defined as any preoperative chemotherapy
scheme aiming to convert unresectable into resectable tumors and/or to
increase microscopic complete tumor resection rates [5]. NACT could
potentially increase the curative resection rate, improve the tumor
downstaging possiblities and reduce the tumor-related symptoms if the
choosen drugs have effect on the specific tumor biology [6]. Hoever has
been reported as NACT could potentially increase the surgical related
complications and as a consequence the perioperative mortality, if it
doesn't delay surgical resection. At present some data have been pub-
lished on the effects of NACT on AGC and EGC but not definitive ones.
Moreover the new TNM 8th stadiation modified the division of the GC
and EGC formally including these last among the GC [7].
The present meta-analysis aims to evaluate the effects of NACT on
the AGC and EGC.

∗
Corresponding author. General, Emergency and Trauma Surgery Dept., Bufalini Hospital, Viale Giovanni Ghirotti, 286, 47521 Cesena, Italy. Tel.: +39 05473522132.
E-mail address: federico.coccolini@gmail.com (F. Coccolini).

https://doi.org/10.1016/j.ijsu.2018.01.008
Received 18 December 2017; Accepted 7 January 2018
Available online 20 February 2018
1743-9191/ © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
F. Coccolini et al.
2. Material and method
2.1. Literature search strategy
Electronic searches were performed using Medline, Embase
(1988–March 2017), PubMed (January 1980–March 2017), Cochrane
Central Register of Controlled Trials (CCTR), Cochrane Database of
Systematic Reviews (CDSR) and CINAHL from (1966–March 2017). The
search terms were: ‘neoadjuvant chemotherapy’, ‘stomach’, ‘gastric
cancer’, ‘advanced’, ‘randomized trial’, ‘meta-analysis’ combined with
AND/OR. Research included also all the MeshTerms. No search re-
strictions 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.
2.2. Selection criteria
Studies which have been judged eligible for this systematic review
and consequent meta-analysis are those in which patients with AGC or
EGC both without peritoneal carcinosis were randomly assigned to re-
ceive either NACT + surgery or surgery without NACT. All included
patients must have histologically-proven gastric or gastro-oesophageal-
junction adenocarcinoma and underwent potentially curative resection.
All forms of NACT in addition to surgery were included. No language
restrictions have been applied. Eligibility for study inclusion into the
meta-analysis and study quality assessment were performed in-
dependently by two authors (MN, FeCo). Study data were extracted
onto standard forms independently by two authors (MN, FeCo).
Discrepancies between the two investigators were resolved by discus-
sion and evaluation of the question with the other investigators.
The primary outcome measures for the meta-analysis were the im-
pact of NACT on 1, 2, 3 and 5-year mortality and the effect of NACT on
perioperative mortality, morbidity and recurrence in AGC and EGC.
2.3. Assessment of risk of bias
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
Collaboration [8] 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 all 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.
2.4. Statistical analysis
Data from the individual eligible studies were entered into a spread
sheet for further analysis. Review Manager (RevMan) (Version 5.3.
Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2011) was used to perform the statistical analysis. Risk
Ratio (RR) was calculated for discrete variables. The fixed-effects and
random-effects models were used to calculate the outcomes [8,9].
Heterogeneity amongst the trials was determined by means of the Co-
chrane Q value and quantified using the I2 inconsistency test.
121
International Journal of Surgery 51 (2018) 120–127
3. Results
Fifteen RCTs fulfilled the inclusion criteria and were included in the
meta-analysis (publication dates 1987–2014). There were a total of
2001 patients (977 randomized to receive NACT + radical resection
and 1024 randomized to receive radical resection without NACT)
(Table 2).
3.1. Quality of trials
There was good agreement between the reviewers (FeCo, MN) about
the eligibility and quality of the studies. Table 1 demonstrates the
quality of the 15 included RCTs [6,10–23].
In eight RCTs [6,11–13,17,19,20], the method of allocation con-
cealment was adequate; randomisation was performed on a central site
and transmitted to treatment providers by telephone, fax or sealed
opaque envelopes. In the remaining 7 RCTs [10,14–16,18,21–23] the
information regarding approaches to allocation concealment could not
be determined. The baseline features were similar between treatment
groups in all 15 RCTs thus reducing the clinical heterogeneity. All RCTs
specified the eligibility criteria for patients to be enrolled. All RCTs
specified numbers lost to follow-up in each treatment group. All RCTs
analysed the data on an intention-to-treat (ITT) basis, whereby parti-
cipants were analysed in the groups to which they were initially ran-
domised. Blinding after allocation was impossible because of the nature
of the trials. All fifteen RCTs were considered to be at acceptable risk of
bias in the important domains (Table 1).
3.2. 1-year mortality
Eight studies reported 1-year mortality in AGC and three in EGC
[6,10,12,13,17–19] 291 and 436 patients received the surgical treat-
ment alone and 236 and 435 NACT + surgery in the two groups re-
spectively (Fig. 1). There was no statistical heterogeneity between
studies. In the fixed-effects model, the 1-year mortality rate was sig-
nificantly favourable to the NACT + surgery arm in the cumulative
analysis (RR = 0.78, 95%CI = 0.67–0.94) in the EGC (RR = 0.79,
95%CI = 0.64–0.97) and was not significantly favourable to the
NACT + surgery arm in AGC (RR = 0.81, 95%CI = 0.61–1.09).
3.3. 2-years mortality
Three studies reported 2-years mortality in EGC [6,11,13] 436 pa-
tients received the surgical treatment alone and 435 NACT + surgery
(Fig. 1). There was no statistical heterogeneity between studies. In the
fixed-effects model, the 2-years mortality rate was significantly fa-
vourable to the NACT + surgery arm (RR = 0.83,
95%CI = 0.73–0.93).
3.4. 3-years mortality
Five studies reported 3-year mortality in AGC and three in EGC
[6,10–13,17,18,22] 315 and 436 patients received the surgical treat-
ment alone and 254 and 435 NACT + surgery in the two groups re-
spectively (Fig. 1). There was statistical heterogeneity between studies.
In the fixed-effects model, the 3-year mortality rate was significantly
favourable to the NACT + surgery arm in the cumulative analysis
(RR = 0.81, 95%CI = 0.74–0.89), in the EGC (RR = 0.84,
95%CI = 0.76–0.92) and in AGC (RR = 0.74, 95%CI = 0.60–0.91).
3.5. 5-year mortality
Eight studies reported 5-year mortality in AGC and three in EGC
[6,10–13,15,18,20–23] 472 and 436 patients received the surgical
treatment alone and 422 and 435 NACT + surgery in the two groups
respectively (Fig. 1). There was statistical heterogeneity between
F. Coccolini et al. International Journal of Surgery 51 (2018) 120–127

Table 1
Included trials risk of bias and quality assessment.

Study (Ref.) Randomization Allocation Homogeneous Baseline Eligibility criteria Loss to follow-up and drop-out Intention-to-treat
Year concealment characteristic described analysis

Imano (10) YES Unclear YES YES YES YES

2010
Cunningham(6) YES YES NO YES YES YES
2006
Schumacher (11) YES YES YES YES YES YES
2010
Hartgrink (12) YES YES YES YES YES YES
2004
Ychou (13) YES YES YES YES YES YES
2011
Hashemzadeh (14) YES Unclear YES YES YES YES
2014
Zhang (15) YES Unclear YES YES YES YES
2004
Biffi (16) YES Unclear YES YES YES YES
2010
Yonemura (17) YES YES YES YES YES YES
1993
Nio (18) YES Unclear YES YES YES YES
2004
Sun (19) YES YES YES YES YES YES
2011
Kobayashi (20) YES YES YES YES YES YES
2000
Lygidakis (21) YES Unclear YES YES YES YES
1999
Shchepotin (22) YES Unclear YES YES YES YES
1999
Wang (23) YES Unclear YES YES YES YES
2000

studies. In the fixed-effects model, the 5-year mortality rate was fa-
vourable to the NACT + surgery arm in the cumulative analysis
(RR = 0.88, 95%CI = 0.83–0.93), in the EGC (RR = 0.91,
95%CI = 0.86–0.96) and in AGC (RR = 0.82, 95%CI = 0.71–0.95).
3.6. Morbidity
Six studies reported the morbidity in AGC and three in EGC
[6,10,11,13–16,18,23] 380 and 436 patients received the surgical
treatment alone and 272 and 435 NACT + surgery in the two groups
respectively (Fig. 2). There was acceptable statistical heterogeneity
between studies. In the fixed-effects model, the morbidity rate was not
influenced by the different treatment in AGC (RR = 0.99,
95%CI = 0.65–1.51) in the EGC (RR = 1.12, 95%CI = 0.94–1.33) and
in the cumulative analysis (RR = 1.09, 95%CI = 0.93–1.28).
3.7. Perioperative mortality
Six studies reported the post-operative mortality in AGC and three
in EGC [6,11–17,23] 227 and 436 patients received the surgical treat-
ment alone and 179 and 435 NACT + surgery in the two groups re-
spectively (Fig. 3). There was acceptable statistical heterogeneity be-
tween studies. In the fixed-effects model, the post-operative mortality
rate was not influenced by the different treatment in AGC (RR = 1.26,
95%CI = 0.36–4.40) in the EGC (RR = 1.30, 95%CI = 0.70–2.42) and
in the cumulative analysis (RR = 1.29, 95%CI = 0.74–2.25).
3.8. Overall recurrence
Two studies reported recurrence rate in EGC [6,13] 364 patients
received the surgical treatment alone 364 NACT + surgery (Fig. 4).
There was low statistical heterogeneity between studies. In the fixed-
effects model, the recurrence rate was significantly favourable to the
NACT + surgery arm in the EGC (RR = 0.80, 95%CI = 0.65–0.98).
4. Discussion
The real effect of NACT on AGC and EGC is still greatly unknown.
Encouraging results have been published in term of survival. Definitive
results on survival and effect on short-term complications are needed.
In fact the occurrence of short-term complications could potentially
delay the surgical intervention and definitively reduce the survival and
disease free outcomes. The present paper aims to investigate the effect
of NACT on survival and post-operative morbidity and short-term
mortality in both EGC and AGC. A few papers have been published
about the effect of NACT but no conclusive data exist [5,24–26].
Moreover the comparison between NACT and perioperative che-
motherapy in term of efficacy haven't yet given definitive results. An
active matter of debate is the different NACT regimens utilized by the
different groups [6,27]. In fact several chemotherapy regimens have
been published with good results. Few data are available to evaluate the
best NACT regimen. A previously published meta-analysis showed that
combination regimen and IV route of NACT had a high efficiency on
AGC [24]. In present study the different regimens have not been dis-
tinguished and they have all been considered as part of NACT, re-
producing the daily clinical practice of the different realities.
The present analysis shows as the NACT doesn't give any adverse
effect during the perioperative period. In fact it doesn't increase the
complications and post-operative mortality rate. The effect on EGC and
AGC are positive and prolonged at all time-points in term of survival.
The cumulative analysis demonstrated that all survival results are sig-
nificant confirming the effective role of NACT especially in considera-
tion of the new anathomo-pathological TNM division of esophageal and
gastric cancer.
The post-operative morbidity is of fundamental importance because
of its occurrence could potentially delay the adjuvant chemotherapy or
some times preclude the possibility to prosecute the chemotherapy after
the surgical procedures. This brings detrimental effects on the short and
long-term prognosis. Moreover the reduction of tumor load for many

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 Table 2
F. Coccolini et al.

Summary of the 15 included trials. (Preop: preoperative, Postop: postoperative, FU: Fluoruracil, CDDP: Cisplatin, Cht: Chemotherapy, nd: not defined).

Study (Ref.) Number of Study period Neoadjuvant Chemotherapy + Surgery arm Surgery arm Kind of tumor Lynphadenectomy
Year patients N = 977 N = 1024
N = 2001

1 Imano (10) 63 1992–2002 N = 47 N = 16 Gastric cancer D2

2010 PREOP: 72 h before surgery
Group F = 16 pz single cycle 5-FU
(330 mg/m2/24 h) for 72 h - 80 h before surgery
Group C = 15 pz single cycle CDDP
3cycles (6 mg/m2/each time) for 30 min at 68 h 44 h and 20 h before surgery
Group FC = 16 pz single cycle 5-FU + CDDP
2 Hartgrink (12) 56 1993–1996 N = 27 N = 29 Gastric cancer D1
2004 PREOP: FAMTX (Methotrexate 1500 mg/m2 + 5-FU 1500 mg/m2 + 30 mg Leucovorin every 6 h)
3 Hashemzadeh (14) 60 2011–2014 N = 30 N = 30 Gastric cancer D1 59%
2014 PREOP: Docetaxel 75 mg/m Cisplatin 75 mg/m2, 5-Fluoruracil 750 mg/m/day every 3 weeks for D2 8,1%
6 courses.
4 Zhang (15) 91 nd N = 37 N = 54 Gastric cancer
2004 PREOP: Intrarterial infusion FAP (5-FU 1.0 g + Adriamicin 30–50 mg + Cysplatin 40–60 mg) or
FMP (5-FU 1.0 g + Mytomicin 8–10 mg + Cysplatin 40–60 mg
POSTOP: FAP or FMP
5 Biffi (16) 69 1999–2005 N = 34 N = 35 Gastric cancer D2
2010 PREOP: 21days cycle TCF (docetaxel 75 mg/m2 1 h IVday 1, cisplatin 75 mg/m 4 h IV day 1 5-Fu
300 mg/m per day continuous IV infusion day 1–14)

123
6 Yonemura (17) 55 1988–1991 N = 29 N = 26 Gastric cancer
1993 PREOP: Cisplatin 75 mg/m + Mytomicin 10 mg/m2 + Etoposide 150 mg/body + UFT
(Tegafur + Uracil) 400 mg/d every 3 weeks
7 Nio (18) 295 1991–1999 N = 102 N = 193 Gastric cancer D2
2004 PPREOP and POSTOP: UFT (tegafur 8 mg/kg/d + uracil 6 mg/kg/d) over 2 weeks
8 Sun (19) 55 2008–2010 N = 29 N = 26 Gastric cancer NR
2011 3 cycles PREOP and 3 Cycles POSTOP
Docetaxel 75 mg/m2 + 5 fluoruracil 500 mg/m2 + Leucovirin 200 mg/m2
9 Kobayashi (20) 171 1990–1993 N = 91 N = 80 Gastric cancer D2
2000 PREOP and POSTOP
5-FU 610 mg/m2 day > 10 d
10 Lygidakis (21) 58 1995–1999 N = 39 N = 19 Gastric cancer D3 76%
1999 Neo Abdominal stop flow hypoxic perfusion CHT: Mytomicin C 5 Fluoruracil Leucovorin D2 24%
Farmorubicin + systemic chemiotherapy Group A N = 20;
Without CHT Group B N = 19
11 Shchepotin (22) 97 NR N = 47 N = 50 Gastric cancer
1995
12 Wang (23) 60 1987–1988 N = 30 N = 30 Gastric cancer
2000 FPLC oral
13 Cunningham (6) 503 1994–2002 N = 250 N = 253 Gastric cancer + Oesophagogastric D2 mainly
2006 PERIOP: 3 cycles preoperatively + 3 cycles postoperatively junction
Each cycle ECF (Epirubicin 50 mg/m2 + Cisplatin 60 mg/m2 + Fluoruracil 200 mg/m2
14 Schumacher (11) 144 1994–2004 N = 72 N = 72 Gastric cancer + Oesophagogastric D2
2010 PREOP: Two −48-day cycles of Cisplatin 50 mg/m2 + L-Folinic Acid 500 mg/m2 junction
IV + Fluoruracil 2000 mg/m2
15 Ychou (13) 224 1995–2003 N = 113 N = 111 Gastric cancer + Oesophagogastric D2
2011 PREOP: 3 cycles of Cisplatin 100 mg/m2 + 5-FU 800 mg/m2 for five days every 28 days and 3 or junction
4 postoperative same cycles
International Journal of Surgery 51 (2018) 120–127
F. Coccolini et al. International Journal of Surgery 51 (2018) 120–127

Fig. 1. Mortality (A: 1-year, B: 2-years, C: 3-years,

D: 5-years).

aspects may reduce the risk of complications by reducing the surgical the NACT; for this reason it should be considered a re-staging of the
effort. As a counterpart, however, if the NACT is not effective on the disease during the NACT.
specific tumor biology the risk is to have a disease progression during Recently the new TNM 8th classification of neoplastic diseases

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F. Coccolini et al. International Journal of Surgery 51 (2018) 120–127

Fig. 2. Morbidity.

redefined the classification of the gastric and gastro-esophageal junc-
tion tumors and formally included the EGC among the gastric cancers
[7]. This meta-analysis confirms the same behavior of the EGC and the
AGC according to the clinical answer to NACT in the long-term results.
The AGC and EGC considering the adenocarcinoma histology could be
considered very similar according to the biological behavior. The main
difference is the anatomical diffusion due to the localization, to the
different anatomy of the two regions and the consequent lymphatic
drainage. This issue remains a matter of great interest but from the
chemotherapy point of view the unification of these previously differ-
entiated anatomical and hysto-pathological entities could facilitate the
therapeutic algorithms without detrimental effects on the long-term
survival.
In order to further improve the outcomes of such hard disease to
treat with curative intent, several studies and meta-analysis have been
published to demonstrate the efficacy of intra-peritoneal chemotherapy
(IPC) [28]. The association of IPC and NACT is potentially very effective
as showed by the studies of the Peritoneal Surface Oncology Group
International (PSOGI) [29] that promotes the bidirectional approach to
the AGC with peritoneal carcinosis combining novel comprehensive
treatment consisting of cytoreductive surgery and perioperative che-
motherapy for the treatment of peritoneal metastases from gastric
cancer with curative intent. The NACT could potentially have a role
also in the prevention and treatment of peritoneal carcinosis (PC) but
more effective could be the associated use with the neoadjuvant IPC to
prevent the PC occurrence. In fact where serosal invasion exists the PC
is practically unavoidable. A recent study showed promising results
with the association of NACT and prophylactic hyperthermic in-
traperitoneal chemotherapy [30]. Lastly it could be considered the
positive effect of the IPC in all those patients who cannot complete the

Fig. 3. Perioperative mortality.

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F. Coccolini et al.
Fig. 4. Recurrence rate in Esophago-Gastric Cancer.
postoperative chemotherapy. In fact almost the 50% of operated pa-
tients are not able to be undergone or to complete the adjuvant che-
motherapy. Two randomized studies by Chunningham and Ychou re-
ported a percentage of 65.6% and 41.6% and of 50% and 44% of
patients who respectively started and completed the postoperative
chemo-therapy in the first and in the second study [6,13]. In this per-
spective, to warrant the best chemotherapeutical coverage to all these
patients, the use of IPC could be a hypothesis to be taken into con-
sideration. In fact the eventual adjunct of adjuvant chemotherapy after
the IPC would be the optimum in advanced tumors even in absence of
PC [28–30].
The main criticism of the present study is the incomplete patients
selection and staging (advanced and early GC) with lack of considera-
tion for the intraperitoneal cytological status. In fact the presence of a
positive cytology in intraperitoneal lavage brings different overall and
disease free survival outcomes [31,32]. If the different studies would
had been homogeneously considered the staging and the cytological
status, results could have been potentially different, with a hypothetical
improvement in efficacy of NACT in patients with negative cytology
and with different subgroup analysis for the AGC patients. Moreover it
isn't possible to perform subgroup analysis according to the histology of
the included patients. These factors could contribute to explain the
different short-term outcomes in AGC and EGC. It could be hypothe-
sized that the patients affected by AGC that deceased in the short-term,
could have been those with the more advanced stages, the positive
cytology or those with more aggressive histology. As a consequence the
NACT could potentially have good survival results in AGC even in the
short-term with a complete patients selection and staging, meaning
with the use of intra-peritoneal cytology, explorative laparoscopy and
eco-endoscopy.
5. Conclusion
NACT reduces the mortality in gastric and esophago-gastric cancer.
Morbidity and perioperative mortality are not influenced by NACT. The
overall recurrence rate is reduced by NACT in esophago-gastric cancer.
Conflicts of interest
All authors declare to have no conflict of interest.
Sources of funding
All authors declare to have no sources of funding for this research.
Ethical approval
Not required.
Research registration unique identifying number (UIN)
Reviewregistry412.
126
International Journal of Surgery 51 (2018) 120–127
Author contribution
Federico Coccolini, Matteo Nardi, Giulia Montori, Marco Ceresoli,
Andrea Celotti, Stefano Cascinu, Paola Fugazzola, Matteo Tomasoni,
Olivier Glehen, Fausto Catena, Yutaka Yonemura, Luca Ansaloni con-
tributed to the design and implementation of the research, to the ana-
lysis of the results and to the writing of the manuscript.
Guarantor
Federico Coccolini.
Acknowledgment
None.
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