Download Surgical management of advanced gastric cancer: An evolving issue

Available online at www.sciencedirect.com
ScienceDirect
EJSO xx (2015) 1e10
www.ejso.com
Review
Surgical management of advanced gastric cancer: An
evolving issue
L. Marano a,*, K. Polom b, A. Patriti a, G. Roviello c, G. Falco d,
A. Stracqualursi e, R. De Luca f, R. Petrioli g, M. Martinotti h,
D. Generali i, D. Marrelli b, N. Di Martino j, F. Roviello b
a
General, Minimally Invasive and Robotic Surgery, Department of Surgery, “San Matteo degli Infermi”
Hospital, ASL Umbria 2, Via Loreto 3, 06049, Spoleto PG, Italy
b
Department of Medical, Surgical and Neuroscience; Unit of General and Minimally Invasive Surgery,
University of Siena, Viale Bracci 11, 53100, Italy
c
Section of Pharmacology and University Center DIFF e Drug Innovation Forward Future, Department of
Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25124 Brescia, Italy
d
Surgery Unit IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
e
General Surgery, Department of Surgery, “Santa Marta e Santa Venera” Hospital, ASL Catania 3, 95124,
Acireale CT, Italy
f
Department of Surgical Oncology, National Cancer Research Centre e Istituto Tumori “G. Paolo II”,
Bari, Italy
g
Medical Oncology Unit, University of Siena, Viale Bracci 11, 53100, Siena, Italy
h
Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1,
34129 Trieste, Italy
i
Department of Surgery, AO Istituti Ospitalieri di Cremona, Cremona, 26100, Italy
j
8th General and Gastrointestinal Surgery, Department of Internal Medicine, Surgical, Neurological Metabolic
Disease and Geriatric Medicine, Second University of Naples, Piazza Miraglia 2, 80138 Naples, Italy
Accepted 30 October 2015
Available online - - -
Abstract
Worldwide, gastric cancer represents the fifth most common cancer and the third leading cause of cancer deaths. Although the overall 5year survival for resectable disease was more than 70% in Japan due to the implementation of screening programs resulting in detection of
disease at earlier stages, in Western countries more than two thirds of gastric cancers are usually diagnosed in advanced stages reporting a 5year survival rate of only 25.7%. Anyway surgical resection with extended lymph node dissection remains the only curative therapy for
non-metastatic advanced gastric cancer, while neoadjuvant and adjuvant chemotherapies can improve the outcomes aimed at the reduction
of recurrence and extension of survival. High-quality research and advances in technologies have contributed to well define the oncological
outcomes and have stimulated many clinical studies testing multimodality managements in the advanced disease setting.
This review article aims to outline and discuss open issues in current surgical management of advanced gastric cancer.
Ó 2015 Published by Elsevier Ltd.
Keywords: Advanced gastric cancer; Lymphadenectomy; HIPEC; Laparoscopic surgery; Robotic surgery
Introduction
* Corresponding author. General, Minimally Invasive and Robotic Surgery, Department of Surgery, “San Matteo degli Infermi” Hospital e
ASL Umbria 2, Via Loreto 3, 06049, Spoleto (PG), Italy. Tel.: þ39
3341839626.
E-mail address: [email protected] (L. Marano).
Although the incidence of gastric cancer has decreased
worldwide, it is still the third most common cause of
cancer-related and one of the most common malignancies
http://dx.doi.org/10.1016/j.ejso.2015.10.016
0748-7983/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
2
L. Marano et al. / EJSO xx (2015) 1e10
in the world, ranking fifth after lung, breast, colorectal and
prostate cancer.1 These discouraging results are explained
mainly by a late diagnosis. However, focusing the global
incidence and outcomes of gastric cancer with relation to
geography, a significant discrepancy in the data between
the Asian and Western Countries was found. While in the
United States the incidence is estimated at 21.600 new
cases a year, in the South Korea it accounts for 33.000
new cases per year, followed by Mongolia, Japan and
China.2 Nevertheless, Asian gastric cancer patients have a
better prognosis than Western patients, probably due to
active screening programs resulting in detection of disease
at earlier stages, with an overall survival rate more than
70% in Japan for resectable disease.3 On the contrary, in
Europe and the United States, more than two thirds of
gastric cancers are usually diagnosed in advanced stages
with a locally advanced resectable disease as routine
screening for gastric cancer is not recommended owing to
cost ineffectiveness.4 As a result, a 5-year survival rate of
only about 25% in locally advanced disease is registered
in these countries.5
Surgical resection with extended lymph node dissection
remains the only curative therapy for non-metastatic gastric
cancer, while neoadjuvant and adjuvant chemotherapies, as
well as chemoradiation, can improve the outcomes aimed at
the reduction of recurrence and extension of survival.
This review article aims to outline and discuss open issues in current surgical management of advanced gastric
cancer.
“Advanced gastric cancer” for a surgeon
An accurate categorization of the tumor stage, including
the invasive depth and lymph node status, is crucial for
prognostic assessment and decision making of the stagespecific therapeutic strategy.6 The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system
has been used widely for clinical practice and research in
determining tumor stage in gastric cancer, representing
the most important independent prognostic factor.7 Several
versions of this classification system have been used over
the past 30 years and in 2010, the 7th edition of the
AJCC/UICC gastric cancer staging manual was introduced,
resulting in several changes from the 6th edition, renewing
T categories, reducing cutoffs of N status (with a new minimum number of 16 nodes to be removed for an accurate
staging), and including a positive peritoneal cytological
lavage as M1.8 In the medical literature there are a large
number of studies that examine the difference between
the 6th and the 7th AJCC/UICC TNM for GC, however
the superiority of the latest edition is still debated worldwide. To this address some Authors support 7th edition as
more accurate in overall survival prediction while other
did not evidence a better survival discrimination and risk
stratification compared with 6th edition,9e12 suggesting
an hybrid TNM staging system combining T categories
from 7th edition and N categories from 6th edition. Further
nationwide studies are necessary to evaluate the validity
and effectiveness of the new classification from various angles. Finally, the modified staging of gastric cancer to
include cancers of the esophagogastric junction (EGJ)
arising more than 5 cm distally of the EGJ or within
5 cm of the EGJ but without extension to the esophagus
or EGJ13 generated controversies regarding biological and
prognostic considerations, suggesting the Siewert classification14 would be more adequate in staging these tumors.
Interestingly, in the literature, the definition of early
gastric cancer (EGC) is well codified,15 even there is
considerable heterogeneity in the definition of advanced
gastric cancer (AGC). De Sol et al.16 individually analyzed
all parameters of the 6th TNM classification for AGC reported in each previous selected study providing a summary
of babel-like definitions. Only few Authors considered as
AGC the T3 or T4 neoplasms,17,18 whereas the remaining
studies accounted as AGC all neoplasms with parietal invasion initiating from stage T2.19e21 As regard the N parameter, most of Authors defined gastric cancers as “advanced”
even in the absence of regional lymph nodes involvement
(N0),17,19,20,22,23 others18 required at least one metastatic
lymph node (N1 or more) and only few21,24 did not
consider the N parameter. Furthermore gastric cancers
were defined advanced irrespective of the presence or
absence of distant metastasis (M1 or M0).
Currently the tendency of surgeons is to consider as
AGC a non-early/non-metastatic gastric cancer infiltrating
deeper than submucosal layer with or without nodal
involvement (T2-4b/N0-3b/M0, 7th AJCC/UICC TNM),
for which the surgical therapy alone, while not always
providing any advantage, still remains the central curative
modality at present.
Optimal surgery
Extension of gastric resection
Although a surgical R0 resection and a retrieval of a
minimum of 16 lymph nodes25 represent the well ascertained mandatory surgical principles, there is still some
controversies and opinions about the extent of surgical
resection and lymphadenectomy. The primary tumor excision is based on the location, extension and histologic subtype of gastric cancer. Proximal gastric cancers are
generally treated with total gastrectomy since the anastomosis between the esophagus and distal stomach is
burdened with a significant rate of postoperative complications as well as intractable postoperative reflux esophagitis.26 Total gastrectomy is also required for large tumors
or tumors of the lesser curve/gastric body. Conversely,
antral cancers may be adequately resected with a distal gastrectomy if a 5 cm margin can be achieved. As regard the
importance of histologic subtype (intestinal or diffuse
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
L. Marano et al. / EJSO xx (2015) 1e10
subtype according to the Lauren’s classification)27 on the
extension of tumor resection, only in the recent past it
has been clarified. Several years ago, total gastrectomy
was hypothesized to offer oncological advantages over subtotal distal resection (for cancers of the antrum) entailing a
wider lymphadenectomy and effective removal of multicenter neoplastic foci for diffuse subtype carcinomas.28
Nevertheless, two European trials reported no differences
in overall survival rates between total and subtotal distal
gastrectomy to this address.28,29 Currently, there is general
agreement that “a proximal margin of at least 3 cm is recommended for T2 or deeper tumors with an expansive
growth pattern and 5 cm is recommended for those with
infiltrative growth pattern”, thus finally ending a longterm debate.30
In T4 cases, however, a multivisceral resection (MVR),
or gastrectomy with resection of adjacent organs, may be
required to provide patients with advanced gastric cancer
the best chance at survival with a curative R0 resection,
but the price to pay seems to be very high in terms of postoperative morbidity and the prognostic benefit of MVR in
patients with locally advanced disease is still debated.23,31
Furthermore, the true microscopic invasion into adjacent
organ is hard to identify with pre-operative imaging or
even during an operation, making the decision to proceed
with MVR a surgical challenge.32 Kasakura et al.31 reported a higher complication rate in multivisceral resection
group compared to gastrectomy alone group, with no survival difference, while Pacelli et al.,33 in an Italian multicenter observational study, found no significant
differences in postoperative morbidity and mortality rates.
Other retrospective studies investigating this issue evidenced a survival disadvantage for gastrectomy with additional organ resection.34,35 Contrarily, most studies
registered an overall 5-year survival improvement
(19.9%e38%) for patients who underwent gastrectomy
with multivisceral resections when compared with patients
who underwent gastrectomy alone or palliative surgery.33
More interestingly many prognostic factors for T4 gastric
cancers after multiorgan resection were largely investigated
and R0 resection, number and type of resected organs,
lymph node metastasis, depth of invasion and peritoneal
spreading were believed to be independent prognostic factors with a state of uncertainty still.33 Almost all published
studies confirm that R0 resection represent the most powerful prognostic factor.31e36 The 5-year survival rate in patients with T4 gastric cancer undergoing curative R0
resection ranges from 23% to 46%, and this rate decreases
in cases of Rþ resection, ranging from 17.5% to 0%.36 As
regard the number of resected organs, it has been found a
negative prognostic index by several authors while other
studies reported no statistically significant difference in
the survival of patients who underwent en bloc resection
of 1 organ when compared with those who had 2 or more
resected organs, showing that the involvement of several organs should not be a contraindication for surgery.36,37
3
Splenectomy, pancreaticosplenectomy, colectomy, or any
other organ resection did not result as predictors of poor
survival,34 while positive peritoneal washing cytology as
well as the depth of invasion and the presence and extent
of lymph node metastasis were reported as the most powerful independent poor prognostic factor for patients with T4
gastric cancer treated with potentially curative resection.33
On the basis of these results, actually, the gastrectomy
with multivisceral resection should be the therapeutic
choice in locally advanced gastric cancer patients where a
complete resection could be realistically obtained and
when lymph node metastatic involvement is not evident,
with an acceptable postoperative morbidity and mortality
rates.
Lymphadenectomy
Controversy over the extent of lymph node dissection in
the gastric cancer treatment has been a topic of debate for
decades. In D1 dissections, only the perigastric nodes
directly attached along the lesser curvature and greater curvatures of the stomach are removed (stations 1e6: right and
left pericardial, lesser curvature, greater curvature, supra
and infrapyloric). D2 dissections add the removal of nodes
along the left gastric artery (station 7), common hepatic artery (antero-superior group, station 8a), celiac trunk (station
9), splenic hilus and splenic artery (station 10 and 11), hepatoduodenal ligament (along the proper hepatic artery, station 12a).30
Even though the D2 lymphadenectomy has been traditionally recommended in Japan as standard practice since
the 1960s on the basis of long-term results and overall survival rates improvement,30 in Western countries the majority of surgeons still perform a D1 dissection. This
incongruity was based on the results of two large European
randomized clinical trials23,38 that failed to prove a survival
benefit of D2 lymphadenectomy compared to D1. Furthermore these studies were harshly criticized mainly for the
lack of experience of many participating surgeons as well
as the inclusion of splenectomy and/or pancreatectomy as
part of a D2 resection, with subsequently confounding results of post-operative morbidity and mortality rates. By
contrast, a randomized trial in Taiwan proved a significant
benefit in overall survival (OS) and recurrence free survival
(RFS) for a D2 dissection as compared with D1 lymphadenectomy, with no increase in operative mortality, which
also indicate that adequate local control is essential for
the treatment of gastric cancer.19 Recently, in Dutch trial,
a 15-year follow-up showed a lower rate of local recurrence
and gastric cancer-related mortality in the D2 lymphadenectomy group compared to the D1 group.39
A recent meta-analysis40 including eight Eastern and
Western randomized controlled trials over 2000 patients,
showed no significant differences in overall survival between D1 and D2. Subgroup analysis of patients without
spleen and pancreas resection had a clear trend for OS
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
4
L. Marano et al. / EJSO xx (2015) 1e10
and RFS much more benefiting D2 compared to D1 patients, highlighting the spleen and pancreas-sparing D2
lymphadenectomy as the standard surgical approach to
resectable gastric cancer. Indeed, using a RAND Corporation/University of California Los Angeles (UCLA) Appropriateness Methodology (RAM), an expert panel
considered D2 lymphadenectomy in all patients with
tumors > T1N0.41 The panel also found the use of total
gastrectomy for all patients and distal gastrectomies for patients with distal gastric cancers, in expert hands, as the
optimal surgical standard.
Another debated issue concerns the clinical value of systematic para-aortic nodal dissection (PAND) in addition to
D2 gastrectomy in resectable advanced gastric cancer. In
2008 the Japan Clinical Oncology Group (JCOG), in a randomized controlled trial comparing D2 lymphadenectomy
alone with D2 lymphadenectomy plus PAND in patients
undergoing gastrectomy for curable advanced gastric cancer, did not found improvement in overall or recurrence
free survival with the super-extended lymphadenectomy.42
There were no significant differences between the two
groups in the surgery-related complication rates, even if
the D2 lymphadenectomy plus PAND was associated with
a longer intervention time, greater blood loss, and a significant increase in minor complications.42 After these results
the prophylactic D2 lymphadenectomy plus PAND is no
longer recommended in patients undergoing gastrectomy
for curable gastric cancer.30
Recently the Italian Research Group for Gastric Cancer
(GIRCG), in a retrospective study on 568 patients undergoing curative gastrectomy for advanced gastric cancer found
that D2 lymphadenectomy plus PAND reverses the negative
impact of diffuse histotype on relapses, especially on locoregional recurrences.43 Therefore the super-extended
nodal dissection could be considered a valid therapeutic option in histotype-oriented tailored treatment of advanced
GC.
Obviously, many factors as patient comorbidities, tumor
extension and surgical expertise can affect the choice of
surgical decision since the more aggressive surgical strategy can affect the outcomes as regard survival, treatmentrelated mortality and morbidity, and postoperative quality
of life.
An accurate preoperative prognostic assessment as well
as remarkable clinical experience are essential to establish
the best tailored approach for individual patients.
Multimodality management
Neoadjuvant chemotherapy
Neoadjuvant chemotherapy (CHT) for AGC aims at disease downstaging, increasing the rate of curative resection,
and reducing the incidence of systemic metastases by
means of undetectable micrometastasis eradication. Overall, pre-surgical patients usually can tolerate treatments
better due to a higher performance, with no postoperative morbidity and mortality increased rates. On this
basis, all guidelines actually recommend this treatment
for patients with locally advanced gastric cancer.
The first randomized controlled trial of pre-operative
chemotherapy (FAMTX - 5-Fluorouracil, doxorubicin and
methotrexate) versus surgery alone on 56 patients with
apparently operable gastric cancer, did not show a beneficial effect of neoadjuvant treatment.44 Two years later the
MAGIC trial45 evaluated the efficacy of a preoperative
and postoperative cisplatin, epirubicin and 5-FU (ECF)
CHT versus surgery alone on 503 potentially resectable
gastric, esophagogastric junction or lower esophagus cancer patients. As compared with the surgery group, the
perioperative-chemotherapy group had a higher likelihood
of overall survival (HR for death ¼ 0.75; 95% CI:
0.60e0.93, P ¼ 0.009; 5-year survival rate: 36% vs 23%)
and progression-free survival (HR for progression ¼ 0.66;
95% CI: 0.53e0.81, P < 0.001). Of note there was a greater
proportion of T1 and T2 tumors and less advanced nodal
disease in the perioperative group. Similar benefit emerged
from the French FFCD 9703 trial, in which 224 patients
with resectable adenocarcinoma of the EGJ or lower esophagus (75% of all patients), and of the stomach (25% of all
patients), were randomly assigned to either perioperative
chemotherapy with infusional 5-fluorouracil plus cisplatin
(CF) followed by surgery and adjuvant CF chemotherapy,
or surgery alone.46 The neoadjuvant treatment significantly
increased the curative resection (84% vs 74%; P ¼ 0.04), 5year disease-free survival (34% vs 19%; P ¼ 0.003) and 5year overall survival (38% vs 24%; P ¼ 0.02) rates.
Recently, the European EORTC 40954 phase III trial47
examined the efficacy of preoperative cisplatin, 5fluorouracil, and leucovorin chemotherapy in gastric and
EGJ cancer patients compared to surgery alone. This trial
was stopped for poor accrual after 144 patients were
randomly assigned (72:72). The curative resection rate
was 81.9% after neoadjuvant chemotherapy as compared
with 66.7% with surgery alone (P ¼ 0.036). The surgeryonly group had more lymph node metastases than the neoadjuvant group (76.5% vs 61.4%; P ¼ 0.018). Postoperative
complications were more frequent in the neoadjuvant arm
(27.1% vs 16.2%; P ¼ 0.09). After a median follow-up of
4.4 years and 67 deaths, a survival benefit could not be
shown (hazard ratio, 0.84; 95% CI, 0.52 to 1.35;
P ¼ 0.466).
This trial showed a significantly increased R0 resection
rate but failed to demonstrate a survival benefit. Possible
explanations are low statistical power, a high rate of proximal gastric cancer including EGJ cancer and/or a better
outcome than expected after radical surgery alone due to
the high quality of surgery with resections of regional
lymph nodes outside the perigastric area (D2 dissection).
It seems clear that tumor downstaging and R0 resection
rates increase after neoadjuvant chemotherapy. However,
there are still debates about survival after preoperative
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
L. Marano et al. / EJSO xx (2015) 1e10
treatment, since that the MAGIC and the French FFCD
9703 trials are affected by a lot of staging and surgical
drawbacks. Similarly, the EORTC trial failed to confirm
this advantage.
The optimal patient selection in the clinical trials setting,
by means of appropriate pretreatment staging as well as
prediction of response to therapy, could be the cornerstone
for correctly evaluating the survival benefit of neoadjuvant
therapy in advance gastric cancer. Further data will be provided by expected results from the ongoing MAGIC B,
CRITICS and JCOG 0501 prospective trials based on the
neoadjuvant modality approach.
Cytoreductive surgery and heated intraperitoneal
chemotherapy (HIPEC)
Gastrectomy for gastric cancer with positive peritoneal
cytological lavage or peritoneal carcinosis (PC), classified
as metastatic disease according to current TNM,8 has no
benefit role except as a palliative surgery to reduce symptoms such as bleeding and stricture, resulting in extremely
poor prognosis after surgery.48 However, recent data suggests that in selected patients the surgical resection may
have a role. According to the recent recommendations,
cytoreductive surgery (CRS) and heated intraperitoneal
chemotherapy are highly suggested for the treatment of
peritoneal pseudomyxoma, peritoneal mesothelioma, and
peritoneal carcinosis from colorectal and ovarian cancer.49
Treatment of peritoneal malignancies from gastric cancer
represents a new attracting topic in the management of
GC but it is still to be validated.
Yang et al.,50 in a randomized phase III study evaluating
the efficacy and safety of CRS and HIPEC (Cisplatin and
Mitomycin C) versus CRS alone for the treatment of peritoneal carcinosis from gastric cancer, reported a survival
improvement with acceptable morbidity in CRS and HIPEC group (median survival rate: 6.5 months; 95% CI,
4.8e8.2 months in CRS vs 11 months; 95% CI, 10e11.9
months in CRS and HIPEC, p ¼ 0.046). Similarly, Magge
et al.51 prospectively analyzed 23 patients with peritoneal
carcinosis from gastric cancer undergoing CRS and HIPEC,
reporting a median overall survival (OS) of 9.5 months
(95% CI: 4.7e17.3), with 1- and 3-year OS rates of 50
and 18% respectively. A multivariate Cox regression model
showed that male gender, lymph node involvement, residual tumor nodules and >2 anastomoses were joint significant predictors of poor OS, while signet ring cells
histological subtype, male gender and >2 anastomoses
were joint significant predictors of poor progression, suggesting that CRS with HIPEC may offer survival benefit
in a carefully selected population.
In 2006, the combination of bidirectional chemotherapy
[intraperitoneal and intravenous or bidirectional intraperitoneal and systemic induction chemotherapy (BIPSC)] prior
to CRS and HIPEC was described as a new therapeutic
strategy for patients with peritoneal carcinosis from gastric
5
cancer.52 Canbay et al.53 recently published results from a
single Japanese specialized center in peritoneal malignancy
evaluating the outcome of bidirectional induction chemotherapy (intraperitoneal docetaxel and cisplatin followed
by four cycles of oral S-1) in patients with PC arising
from GC. After BIPSC, 152 of 194 (78.3%) patients who
showed negative results on peritoneal cytology underwent
CRS plus HIPEC. Major complications occurred in
23.6% of patients, with treatment-related mortality of
3.9%. The median survival rate was 15.8 months, with 1-,
2-, and 5-year survival rates of 66, 32 and 10.7%, respectively. Furthermore, a meta-analysis of 20 randomized
controlled trials including a total of 2145 patients (1152
randomized to receive radical resection and HIPEC and
993 randomized to receive radical resection alone) also reported an improvement in 1-, 2- and 3-year overall survival
in CRS and HIPEC treatment.54
In light of such evidences, while CRS and HIPEC is not
commonly recommended in peritoneal carcinosis from GC,
selected patients may benefit of this more aggressive treatment for a long-term survival but it should be performed in
clinical trial in specialized high volume centers only.
Surgery of liver metastasis
The new challenge in the treatment of gastric cancer is represented by liver metastases, considered as a systemic disease
with no indication for surgery with curative intent. Synchronous or metachronous liver metastases are found in 3.5%e
9.9% of patients diagnosed as gastric cancer55 and only
4%e20% of these metastatic patients underwent hepatectomy for cure, since such metastases are found as clinically
resectable disease, and can represent exceptions to either
palliative chemotherapy or supportive care. Mortality is reported to be 1.1% and morbidity ranged from 19% to 47%.
Mainly, a 5-year survival rate ranged from 0% to 37%and a
median survival time ranged from 9 to 38.8 months.56,57
Although the Japanese Gastric Cancer Treatment Guidelines30 recommend only chemotherapy, radiation, palliative
surgery, and best supportive care for treatment of Stage IV
or metastatic gastric cancer, recently the guidelines committee of the Japan Gastric Cancer Association decided to
revisit the treatment of potentially resectable metastatic disease. Patients diagnosed to have single liver metastasis or a
small number of metastatic nodules (<3), less than 5 cm in
size, could be indicated for surgery.58
Radiofrequency ablation (RFA), conducted either percutaneously under ultrasonic imaging guidance, laparoscopically, or by the open surgery approach, may represent a
valid alternative to surgical resection to treat selected patients with liver metastasis, including metastasis with less
than 3 cm in diameter or patients unfit for major hepatic
surgery.59 Unfortunately reports on RFA applied to liver
metastases from gastric cancer remain scarce and further
prospective studies are needed to establish its real efficacy
compared to surgical resection alone.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
6
L. Marano et al. / EJSO xx (2015) 1e10
Technical issues
Staging laparoscopy
The efficacy of staging laparoscopy (SL) in detecting
occult intra-abdominal metastasis, also by means of cytological examination of peritoneal aspirate or washing, has
been assessed only in prospective and retrospective observational studies over the last 20 years.60,61 Although it represents a recommended tool able to identify patients who
may benefit from chemotherapeutic approaches, its
employment in the gastric cancer patients setting is still
modest.62,63 Coburn et al.62 reported staging laparoscopy
in only 8.8% of 3666 gastric cancer patients. Similarly, in
a large cohort of 11,759 patients who underwent surgery
for gastric cancer by Karanicolas et al.63 only 8% had staging laparoscopy. Recently the application of SL is
becoming more used routinely. Tourani et al.64 performed
SL in 74.3% of patients, while Convie et al.65 reported a
routinely use of SL in all gastric cancer patients. Interestingly, unsuspected metastatic distant disease was detected
in 18e40% of cases65e67 while unexpected peritoneal
metastasis in 22e40%,67e69 leading to a high rate of unnecessary laparotomies or gastrectomies with change in the
treatment intent.70
On the other hand, in the multimodal therapeutic setting
the laparoscopy also represents an accurate “second staging” tool in patients receiving intensive chemotherapy for
carcinosis GC in all cases in which the lesions cannot be
detected by CT or US helping make decisions regarding
R0 gastrectomy.71 Yano et al.71 showed that a second staging laparoscopy accurately assessed the response to neoadjuvant chemotherapy, improving make decisions regarding
R0 gastrectomy. Furthermore, Ajani et al.63 highlighted
that clinical staging by laparoscopy and endoscopic ultrasonography improved R0 resection rates after chemotherapy
in patients with potentially resectable gastric cancer.
The ultrasonographic tool added to SL (laparoscopic ultrasonography) represents a new fascinating challenge that
showed further improvement in diagnostic accuracy for detecting small liver metastases, lymph node metastases and
for the assessment of the local extension of gastric cancer.72
It is clearer now that the role of staging laparoscopy in
the treatment decision and multidisciplinary therapy of
gastric cancers is emerging; due to major advantage in preventing unnecessary laparotomies associated with an unobtrusive morbidity rate as well as the effectiveness in
response assessment after neoadjuvant chemotherapy, staging laparoscopy should be routinely performed in the staging of gastric cancer.
Laparoscopic gastrectomy
The first laparoscopic distal gastrectomy (LDG) for
early gastric cancer was described by Kitano et al.73 in
1994 while the first laparoscopic total gastrectomy with a
D2 lymphadenectomy for advanced gastric cancer was reported in 2000 by Uyama et al.74 To date, laparoscopic
approach is considered effective and feasible for the treatment of EGC due to low postoperative pain, earlier return
to normal bowel function and resumption of oral intake,
faster recovery, shorter hospital stay, better cosmetic
outcome and lower financial costs, compared with the
open approach.75e77 Moreover controversies about the
lower lymph node sampling following laparoscopic resection compared with the open one have also been clarified
since no significant differences have been found when
less than D2 lymphadenectomy was performed.
As regard to the AGC, however, only a few surgeons
worldwide have performed laparoscopic gastric resections.78e83 However, the role of minimally invasive
treatment in this setting still remains unclear due to its technical difficulty and the lack of long-term results. Furthermore some issues are debated so far: dissection of lymphnode stations 12a or 10 is considered technically challenging due to the serious risks of organ injury, bleeding,
and/or bile and pancreatic leakage from a major vessel80,84;
lymphadenectomy results in morbidity and mortality rates
similar to those of open resections23,38; a peritoneal seeding
of malignant cells as well as port-site recurrence have been
proposed as potential complications of the serosal infiltrated tumors by the laparoscopic approach; long-term
oncological outcomes are still poor.81,84
Recently Zou et al.85 conducted an interesting metaanalysis of 14 trials (1 RCT, 13 non-RCTs) comparing laparoscopic and open D2 gastrectomies for the treatment of
advanced gastric cancer. Laparoscopic and open approach
resulted in comparable numbers of sampled lymph nodes,
tumor recurrence and metastasis rates as well as diseasefree and overall survival rates. Laparoscopic approach provides better short-term prognoses with lower postoperative
pain, faster recovery, and shorter hospital stays, without differences in morbidity and mortality were found. A longer
operative time was registered for the minimally invasive
technique only.
Despite these encouraging results indicating that the
laparoscopic technique represents an acceptable alternative
to open surgery for AGC, additional clinical trials are
needed for further evaluation of this procedure. Seven
RCTs comparing the laparoscopic gastrectomy and open
gastrectomy to treat AGC in East Asia (three in China,
three in South Korea, and one in Japan)86e92 are currently
ongoing and the results will help researchers to further
clarify this matter.
Robotic surgery
The da Vinci Surgical System (Intuitive Surgical, Inc.,
Sunnyvale, CA, USA) is characterized by a threedimensional, ten-fold magnified vivid view of the operating
field, instruments with articulating end-effectors and 7 degrees of freedom, tremor filtering, and motion scaling.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
L. Marano et al. / EJSO xx (2015) 1e10
Application of the da Vinci robotic surgical system has
opened up a new era of minimally invasive approaches in
gastric cancer overcoming intrinsic limitations of a traditional laparoscopy experienced during the D2 lymph node
dissection and reconstruction of bowel continuity.93 The
first series of robot-assisted gastrectomy (RAG) were published by Giulianotti et al.94 and Hashizume et al.95 in
2003. Since then, many available reports highlight how robotic gastrectomy is a safe and feasible option for the treatment of gastric cancer93e97; unfortunately these published
studies are small and limited to perioperative outcomes,
with no oncological long-term results. Similarly, a published meta-analysis evaluated eight retrospective studies
comparing RAG with laparoscopic gastrectomy98 reporting
RAG is as acceptable as laparoscopic gastrectomy in terms
of safety and oncological effectiveness, highlighting a lack
of oncological long-term outcomes. Recently, Coratti
et al.99 reported an unique retrospective study providing
long-term survival data following 98 robot-assisted gastrectomies for cancer, suggesting that the robotic platform can
produce oncological outcomes similar to open or conventional laparoscopic surgery.
Currently, although there is a lack of specific studies
investigating the role of robotic surgery in the AGC settings, the accepted indications for RAG are similar to those
in laparoscopic surgery. However, the robotic approach for
treatment of AGC should be performed only in the context
of controlled studies and in dedicated centers.
Conclusion
In 2015, several controversial issues and open questions
as regard the optimal surgical treatment of advanced GC
surgical treatment still exist. Depending on the site and
extent of cancer, surgery remains the only potentially curative treatment for AGC, and a spleen and pancreas-sparing
D2 lymphadenectomy should be recommended as standard
of care in resectable neoplasms. Anyway, a multimodal
approach is mandatory to achieve better survival results.
Perioperative and adjuvant chemotherapy can improve
outcome of resectable advanced gastric cancer treated
with standard of care surgical approach. Nevertheless results of neoadjuvant therapy trials are controversial, and
further data related to the open problems will be provided
by expected results of the ongoing randomized studies.
Furthermore, more aggressive approaches to surgical resection including cytoreductive surgery plus HIPEC for peritoneal carcinosis as well as surgical treatment of liver-limited
metastases, may also be considered for the treatment of
selected patients. In the same way, minimally invasive gastrectomy, either laparoscopic or robotic, is currently under
extensive consideration as possible approached that should
be offered by experienced surgeons in dedicated centers.
Although more studies are needed to adequately assess
the indications and oncological effectiveness of minimally
invasive techniques in advanced gastric cancer treatment,
7
their surgical potentiality in continuous quality improvement of gastric cancer treatment cannot be overlooked.
Conflict of interest statement
The Authors have no conflict of interest or financial ties
to disclose.
References
1. Fock KM. Review article: the epidemiology and prevention of gastric
cancer. Aliment Pharmacol Ther 2014;40:250–60.
2. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee JS. Prediction of
cancer incidence and mortality in Korea, 2013. Cancer Res Treat
2013;45:15–21.
3. World Health Organization. GLOBOCAN 2012: estimated cancer
incidence, mortality and prevalence worldwide 2012.
4. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F.
Gastric cancer: descriptive epidemiology, risk factors, screening, and
prevention. Cancer Epidemiol Biomark Prev 2014;23:700–13.
5. Kunz PL, Gubens M, Fisher GA, Ford JM, Lichtensztajn DY,
Clarke CA. Long-term survivors of gastric cancer: a California
population-based study. J Clin Oncol 2012;30:3507–15.
6. Kim JP, Lee JH, Kim SJ, Yu HJ, Yang HK. Clinicopathologic characteristics and prognostic factors in 10,783 patients with gastric cancer. Gastric Cancer 1998;1:125–33.
7. Zen WJ, Hu WQ, Wang LW, et al. Lymph node ratio is a better prognosticator than lymph node status for gastric cancer: a retrospective
study of 138 cases. Oncol Lett 2013;6:1693–700.
8. Sobin LH, Gospodarowicz MK, Wittekind C. International union
against cancer (UICC) TNM classification of malignant tumors. 7th
ed. New York: Wiley-Liss; 2010.
9. Qiu MZ, Wang ZQ, Zhang DS, et al. Comparison of 6th and 7th
AJCC TNM staging classification for carcinoma of the stomach in
China. Ann Surg Oncol 2011;18:1869–76.
10. Kikuchi S, Futawatari N, Sakuramoto S, et al. Comparison of staging
system between the old (6th edition) and new (7th edition) TNM
classifications in advanced gastric cancer. Anticancer Res 2011;31:
2361–5.
11. Jung H, Lee HH, Song KY, Jeon HM, Park CH. Validation of the seventh edition of the American Joint committee on cancer TNM staging
system for gastric cancer. Cancer 2011;117:2371–8.
12. Marano L, Boccardi V, Braccio B, et al. Comparison of the 6th and
7th editions of the AJCC/UICC TNM staging system for gastric cancer focusing on the “N” parameter-related survival: the monoinstitutional NodUs Italian study. World J Surg Oncol 2015;13:215.
13. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer staging manual. 7th ed. New York: Springer New
York; 2009.
14. R€udiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma of
the esophagogastric junction: results of surgical therapy based on
anatomical/topographic classification in 1,002 consecutive patients.
Ann Surg 2000;232:353–61.
15. Murakami T. Early cancer of the stomach. World J Surg 1979;3:685–
92.
16. De Sol A, Trastulli S, Grassi V, et al. Requirement for a standardised
definition of advanced gastric cancer. Oncol Lett 2014;7:164–70.
17. Zhang CH, Zhan WH, He YL, Chen CQ, Huang MJ, Cai SR. Spleen
preservation in radical surgery for gastric cardia cancer. Ann Surg
Oncol 2007;14:1312–9.
18. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent
in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007;
14:317–28.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
8
L. Marano et al. / EJSO xx (2015) 1e10
19. Wu CW, Hsiung CA, Lo SS, et al. Nodal dissection for patients with
gastric cancer: a randomised controlled trial. Lancet Oncol 2006;7:
309–15.
20. Degiuli M, Sasako M, Ponti A, et al. Italian Gastric Cancer Study
Group. Randomized clinical trial comparing survival after D1 or
D2 gastrectomy for gastric cancer. Br J Surg 2014;101:23–31.
21. Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons TSouthwest
Oncology Group and the Gastric Intergroup. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in
gastric cancer: the effect of undertreatment. Ann Surg Oncol 2002;
9:278–86.
22. Cuschieri A, Weeden S, Fielding J, et al. Patient survival after D1 and
D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer
1999;79:1522–30.
23. Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and
mortality after D1 and D2 resections for gastric cancer: preliminary
results of the MRC randomised controlled surgical trial. The Surgical
Cooperative Group. Lancet 1996;347:995–9.
24. Kampsch€
oer GH, Maruyama K, van de Velde CJ, Sasako M,
Kinoshita T, Okabayashi K. Computer analysis in making preoperative decisions: a rational approach to lymph node dissection in gastric
cancer patients. Br J Surg 1989;76:905–8.
25. Seevaratnam R, Bocicariu A, Cardoso R, et al. How many lymph nodes should be assessed in patients with gastric cancer? A systematic
review. Gastric Cancer 2012;15:S70–88.
26. Someya S, Shibata C, Tanaka N, et al. Duodenal switch for intractable reflux gastroesophagitis after proximal gastrectomy. Tohoku J
Exp Med 2013;230:129–32.
27. Lauren P. The two histological main types of gastric carcinoma: diffuse
and so-called intestinal-type carcinoma. An attempt at a histo-clinical
classification. Acta Pathol Microbiol Scand 1965;64:31–49.
28. Gouzi JL, Huguier M, Fagniez PL, et al. Total versus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A French prospective controlled study. Ann Surg 1989;209:162–6.
29. Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L.
Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 1999;230:170–8.
30. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14:113–23.
31. Kasakura Y, Fujii M, Mochizuki F, Kochi M, Kaiga T. Is there a
benefit of pancreaticosplenectomy with gastrectomy for advanced
gastric cancer? Am J Surg 2000;179:237–42.
32. Coburn NG. Lymph nodes and gastric cancer. J Surg Oncol 2009;99:
199–206.
33. Pacelli F, Cusumano G, Rosa F, et al. Italian Research Group for
Gastric Cancer. Multivisceral resection for locally advanced gastric
cancer: an Italian multicenter observational study. JAMA Surg
2013;148:353–60.
34. Brady MS, Rogatko A, Dent LL, Shiu MH. Effect of splenectomy on
morbidity and survival following curative gastrectomy for carcinoma.
Arch Surg 1991;126:359–64.
35. Otsuji E, Yamaguchi T, Sawai K, Okamoto K, Takahashi T. Total
gastrectomy with simultaneous pancreaticosplenectomy or splenectomy in patients with advanced gastric carcinoma. Br J Cancer
1999;79:1789–93.
36. Kodama I, Takamiya H, Mizutani K, et al. Gastrectomy with combined resection of other organs for carcinoma of the stomach with invasion to adjacent organs: clinical efficacy in a retrospective study.
J Am Coll Surg 1997;184:16–22.
37. Ozer I, Bostanci EB, Orug T, et al. Surgical outcomes and survival
after multiorgan resection for locally advanced gastric cancer. Am J
Surg 2009;198:25–30.
38. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison
of morbidity after D1 and D2 dissection for gastric cancer in 996
Dutch patients. Lancet 1995;345:745–8.
39. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ.
Surgical treatment of gastric cancer: 15-year follow-up results of
the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;
11:439–49.
40. Jiang L, Yang KH, Chen Y, et al. Systematic review and metaanalysis of the effectiveness and safety of extended lymphadenectomy in patients with resectable gastric cancer. Br J Surg 2014;
101:595–604.
41. Brar S, Law C, McLeod R, et al. International multidisciplinary
expert panel. Defining surgical quality in gastric cancer: a RAND/
UCLA appropriateness study. J Am Coll Surg 2013;217:347–57.
42. Sasako M, Sano T, Yamamoto S, et al. Japan Clinical Oncology
Group. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 2008;359:453–62.
43. de Manzoni G, Verlato G, Bencivenga M, et al. Impact of superextended lymphadenectomy on relapse in advanced gastric cancer.
Eur J Surg Oncol 2015;41:534–40.
44. Hartgrink HH, van de Velde CJ, Putter H, et al. Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch
randomized FAMTX trial. Eur J Surg Oncol 2004;30:643–9.
45. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.
N Engl J Med 2006;355:11–20.
46. Boige V, Pignon J, Saint-Aubert B, et al. Final results of a randomized trial comparing preoperative 5-fluorouracil (f) cisplatin (P) to
surgery alone in adeno-carcinoma of stomach and lower esophagus
(aSlE): FNLCC ACCORD 07-FFCD 9703 Trial. J Clin Oncol
2007;25. Abstract 4510.
47. Schuhmacher C, Gretschel S, Lordick F, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer
of the stomach and cardia: European Organisation for Research
and Treatment of Cancer randomized trial 40954. J Clin Oncol
2010;28:5210–8.
48. Kokkola A, Louhimo J, Puolakkainen P. Does non-curative gastrectomy improve survival in patients with metastatic gastric cancer?
J Surg Oncol 2012;106:193–6.
49. Yan TD, Black D, Savady R, Sugarbaker PH. A systematic review on
the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei. Ann Surg Oncol
2007;14:484–92.
50. 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;18:1575–81.
51. Magge D, Zenati M, Mavanur A, et al. Aggressive locoregional surgical therapy for gastric peritoneal carcinomatosis. Ann Surg Oncol
2014;21:1448–55.
52. Yonemura Y, Bandou E, Sawa T, et al. Neoadjuvant treatment of
gastric cancer with peritoneal dissemination. Eur J Surg Oncol
2006;32:661–5.
53. Canbay E, Mizumoto A, Ichinose M, et al. Outcome data of patients
with peritoneal carcinomatosis from gastric origin treated by a strategy of bidirectional chemotherapy prior to cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy in a single specialized
center in Japan. Ann Surg Oncol 2014;21:1147–52.
54. Coccolini F, Cotte E, Glehen O, et al. Intraperitoneal chemotherapy
in advanced gastric cancer. Meta-analysis of randomized trials. Eur J
Surg Oncol 2014;40:12–26.
55. Takemura N, Saiura A, Koga R, et al. Long-term outcomes after surgical resection for gastric cancer liver metastasis: an analysis of 64
macroscopically complete resections. Langenbecks Arch Surg 2012;
397:951–7.
56. Makino H, Kunisaki C, Izumisawa Y, et al. Indication for hepatic
resection in the treatment of liver metastasis from gastric cancer.
Anticancer Res 2010;30:2367–76.
57. Thelen A, Jonas S, Benckert C, et al. Liver resection for metastatic
gastric cancer. Eur J Surg Oncol 2008;34:1328–34.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
L. Marano et al. / EJSO xx (2015) 1e10
58. Kodera Y, Fujitani K, Fukushima N, et al. Surgical resection of hepatic metastasis from gastric cancer: a review and new recommendation in the Japanese gastric cancer treatment guidelines. Gastric
Cancer 2014;17:206–12.
59. Chen J, Tang Z, Dong X, et al. Radiofrequency ablation for liver
metastasis from gastric cancer. Eur J Surg Oncol 2013;39:701–6.
60. D’Ugo DM, Pende V, Persiani R, Rausei S, Picciocchi A. Laparoscopic staging of gastric cancer: an overview. J Am Coll Surg
2003;196:965–74.
61. Ajani JA, Mansfield PF, Lynch PM, et al. Enhanced staging and all
chemotherapy preoperatively in patients with potentially resectable
gastric carcinoma. J Clin Oncol 1999;17:2403–11.
62. Coburn NG, Lourenco LG, Rossi SE, et al. Management of gastric
cancer in Ontario. J Surg Oncol 2010;102:54–63.
63. Karanicolas PJ, Elkin EB, Jacks LM, et al. Staging laparoscopy in the
management of gastric cancer: a population-based analysis. J Am
Coll Surg 2011;213:644–51.
64. Tourani SS, Cabalag C, Link E, Chan ST, Duong CP. Laparoscopy
and peritoneal cytology: important prognostic tools to guide treatment selection in gastric adenocarcinoma. ANZ J Surg 2015;85:69–
73.
65. Convie L, Thompson RJ, Kennedy R, Clements WD, Carey PD,
Kennedy JA. The current role of staging laparoscopy in oesophagogastric cancer. Ann R Coll Surg Engl 2015;97:146–50.
66. Blackshaw GR, Barry JD, Edwards P, Allison MC, Thomas GV,
Lewis WG. Laparoscopy significantly improves the perceived preoperative stage of gastric cancer. Gastric Cancer 2003;6:225–9.
67. Muntean V, Mihailov A, Iancu C, et al. Staging laparoscopy in gastric
cancer. Accuracy and impact on therapy. J Gastrointestin Liver Dis
2009;18:189–95.
68. Nakagawa S, Nashimoto A, Yabusaki H. Role of staging laparoscopy
with peritoneal lavage cytology in the treatment of locally advanced
gastric cancer. Gastric Cancer 2007;10:29–34.
69. Yano M, Tsujinaka T, Shiozaki H, et al. Appraisal of treatment strategy by staging laparoscopy for locally advanced gastric cancer.
World J Surg 2000;24:1130–5.
70. Bonenkamp JJ, Sasako M, Hermans J, van de Velde CJ. Tumor load
and surgical palliation in gastric cancer. Hepatogastroenterology
2001;48:1219–21.
71. Yano M, Shiozaki H, Inoue M, et al. Neoadjuvant chemotherapy followed by salvage surgery: effect on survival of patients with primary
noncurative gastric cancer. World J Surg 2002;26:1155–9.
72. van Delden OM, de Wit LT, Nieveen van Dijkum EJ, Reeders JW,
Gouma DJ. Laparoscopic ultrasonography for abdominal tumor staging. Eur Radiol 1998;8:1405.
73. Kitano S, Shimoda K, Miyahara M, et al. Laparoscopic approaches in
the management of patients with early gastric carcinomas. Surg Laparosc Endosc 1995;5:359–62.
74. Uyama I, Sugioka A, Matsui H, Fujita J, Komori Y, Hasumi A. Laparoscopic D2 lymph node dissection for advanced gastric cancer
located in the middle or lower third portion of the stomach. Gastric
Cancer 2000;3:50–5.
75. Kitano S, Shiraishi N, Fujii K, Yasuda K, Inomata M, Adachi Y.
A randomized controlled trial comparing open vs laparoscopyassisted distal gastrectomy for the treatment of early gastric cancer:
an interim report. Surgery 2002;131:S306–11.
76. Lee JH, Han HS, Lee JH. A prospective randomized study comparing
open vs laparoscopy-assisted distal gastrectomy in early gastric cancer: early results. Surg Endosc 2005;19:168–73.
77. Kim HH, Hyung WJ, Cho GS, et al. Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an
interim reportea phase III multicenter, prospective, randomized Trial
(KLASS Trial). Ann Surg 2010;251:417–20.
78. Chen QY, Huang CM, Lin JX, et al. Laparoscopy-assisted versus
open D2 radical gastrectomy for advanced gastric cancer without
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
9
serosal invasion: a case control study. World J Surg Oncol 2012;
10:248.
Hamabe A, Omori T, Tanaka K, Nishida T. Comparison of long-term
results between laparoscopy-assisted gastrectomy and open gastrectomy with D2 lymph node dissection for advanced gastric cancer.
Surg Endosc 2012;26:1702–9.
Sato H, Shimada M, Kurita N, et al. Comparison of long-term prognosis of laparoscopy assisted gastrectomy and conventional open gastrectomy with special reference to D2 lymph node dissection. Surg
Endosc 2012;26:2240–6.
Kim KH, Kim MC, Jung GJ, Choi HJ, Jang JS, Kwon HC. Comparative analysis of five-year survival results of laparoscopy-assisted gastrectomy versus open gastrectomy for advanced gastric cancer: a casecontrol study using a propensity score method. Dig Surg 2012;29:
165–71. http://dx.doi.org/10.1159/000338088 PMID: 22614362.
Zhao Y, Yu P, Hao Y, et al. Comparison of outcomes for laparoscopically assisted and open radical distal gastrectomy with lymphadenectomy for advanced gastric cancer. Surg Endosc 2011;25:2960–6.
Huang JL, Wei HB, Zheng ZH, et al. Laparoscopy-assisted D2
radical distal gastrectomy for advanced gastric cancer. Dig Surg
2010;27:291–6.
Shinohara T, Satoh S, Kanaya S, et al. Laparoscopic versus open D2
gastrectomy for advanced gastric cancer: a retrospective cohort study.
Surg Endosc 2013;27:286–94.
Zou ZH, Zhao LY, Mou TY, et al. Laparoscopic vs open D2 gastrectomy for locally advanced gastric cancer: a meta-analysis. World J
Gastroenterol 2014;20:16750–64.
Li G. Multicenter study on laparoscopic distal subtotal gastrectomy
for advanced gastric cancer (CLASS-01). NLM identifier
NCT01609309. Available from: URL: http://clinicaltrials.gov/ct2/
show/NCT01609309.
Shi Y. Comparison of laparoscopic vs open gastrectomy for advanced
gastric cancer: a prospective randomized trial. NLM identifier
NCT01043835. Available from: URL: http://clinicaltrials.gov/ct2/
show/NCT01043835.
Huang CM. Prospective randomized controlled trial of laparoscopic
D2 radical gastrectomy and open surgery for advanced gastric cancer. ChiCTR identifier ChiCTRTRC-11001340. Available from:
URL: http://www.chictr.org/en/proj/show.aspx?proj¼66.
Han SU. Efficacy of laparoscopic subtotal gastrectomy with D2
lymph node dissection for locally advanced gastric cancer
(KLASS-02-RCT). NLM identifier NCT01456598. Available from:
URL: http://clinicaltrials.gov/ct2/show/NCT01456598.
Kim YW. Feasibility study of laparoscopy-assisted d2 distal gastrectomy to treat advanced gastric cancer (COACT_1001). NLM identifier NCT01088204. Available from: URL: http://clinicaltrials.gov/
ct2/show/NCT01088204.
Kim W. Comparison of the laparoscopy-assisted distal gastrectomy
and open distal gastrectomy for advanced gastric cancer. NLM identifier NCT00741676. Available from: URL:http://clinicaltrials.gov/
ct2/show/NCT00741676.
Tsuyoshi E. Randomized controlled trial to evaluate laparoscopic vs
open surgery for advanced gastric Cancer (JLSSG0901: Adv.GCLAP/OPEN, PII/III). JPRN identifier JPRN-UMIN000003420. Available
from:
URL:
http://apps.who.int/trialsearch/trial.aspx?
TrialID¼JPRNUMIN000003420.
Patriti A, Ceccarelli G, Bellochi R, et al. Robot-assisted laparoscopic
total and partial gastric resection with D2 lymph node dissection for
adenocarcinoma. Surg Endosc 2008;22:2753–60.
Giulianotti PC, Coratti A, Angelini M, et al. Robotics in general surgery: personal experience in a large community hospital. Arch Surg
2003;138:777–84.
Woo Y, Hyung WJ, Pak KH, et al. Robotic gastrectomy as an oncologically sound alternative to laparoscopic resections for the treatment of early-stage gastric cancers. Arch Surg 2011;146:1086–92.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016
10
L. Marano et al. / EJSO xx (2015) 1e10
96. Hyun MH, Lee CH, Kwon YJ, et al. Robot versus laparoscopic gastrectomy for cancer by an experienced surgeon: comparison of surgery, complications, and surgical stress. Ann Surg Oncol 2013;20:
1258–65.
97. Huang KH, Lan YT, Fang WL, et al. Initial experience of robotic
gastrectomy and comparison with open and laparoscopic gastrectomy
for gastric cancer. J Gastrointest Surg 2012;16:1303–10.
98. Shen WS, Xi HQ, Chen L, Wei B. A meta-analysis of robotic versus
laparoscopic gastrectomy for gastric cancer. Surg Endosc 2014;28:
2795–802.
99. Coratti A, Fernandes E, Lombardi A, et al. Robot-assisted surgery for
gastric carcinoma: five years follow-up and beyond: a single western
center experience and long-term oncological outcomes. Eur J Surg
Oncol 2015;15:00026–8. pii: S0748-7983.
Please cite this article in press as: Marano L, et al., Surgical management of advanced gastric cancer: An evolving issue, Eur J Surg Oncol (2015), http://
dx.doi.org/10.1016/j.ejso.2015.10.016