INTRODUCTION
Background
Gastric cancer is the most common cancer and the fourth most common cause of cancer
death in South Korea [1]. Despite the large number of gastric cancer patients newly
diagnosed and treated annually in South Korea, there has been no appropriate practice
guideline for domestic medical situations. Although Korean guidelines for gastric
cancer were published through interdisciplinary collaborations in 2004 and 2014 [2
3], they were not widely used in South Korea. Therefore, we have produced the present
clinical practice guideline to create guidelines that can provide the standard of
gastric cancer treatment in accordance with the medical reality in South Korea.
Scope
The present clinical practice guideline is intended for physicians to treat patients
with gastric cancer. This guideline is specific and comprehensive for gastric cancer
treatment and pathological evaluations; however, it does not address issues related
to prevention, screening, diagnosis, and postoperative follow-up. It is based on domestic
and overseas evidence and has been developed to be applied to Korean gastric cancer
patients under the current medical situation and to ensure their widespread adoption
in clinical practice.
This guideline is intended to help medical staffs and educate training physicians
at secondary and tertiary care medical institutions, including endoscopists, surgeons,
medical oncologists, radiology oncologists, and pathologists. Additionally, the guideline
was designed to allow patients and populations to receive optimum care by providing
adequate medical information. Furthermore, it is intended for widespread adoption
to increase the standard of gastric cancer treatment, thereby contributing to improving
patient quality of life as well as national health care.
Chronology
The present guideline was initiated by the Korean Gastric Cancer Association (KGCA)
based on the consensus for national need with the associated academic societies. This
guideline was prepared in an integrated and comprehensive manner through an interdisciplinary
approach that included the KGCA, the Korean Society of Medical Oncology (KSMO), the
Korean Society of Gastroenterology (KSG), the Korean Society for Radiation Oncology
(KOSRO), and the Korean Society of Pathologists (KSP), along with the participation
of experts in the methodology of guideline development (National Evidence-based Healthcare
Collaborating Agency). To complete this guideline, the Guideline Committee of the
KGCA established the Development Working Group and Review Panel for Korean Practice
Guidelines for Gastric Cancer 2018. The members were nominated by each participant
association and society. This guideline will be revised every 3 to 5 years when there
is solid evidence that can affect the outcomes of patients with gastric cancer.
Method
We systematically searched published literature using databases including MEDLINE,
EMBASE, and the Cochrane Library through January 2018. Manual searches were also performed
to complement the results. The selection of relevant studies was performed by panels
composed of pairs of clinical experts. The selection and exclusion criteria were predefined
and tailored to key questions. The articles were screened by title and abstract and
full texts were then retrieved for selection. In each step, 2 panels were independently
selected and reached agreements.
We critically appraised the quality of the selected studies using risk-of-bias tools.
We used Cochrane Risk of Bias (ROB) for randomized controlled trials (RCTs), ROB for
Nonrandomized Studies for non-RCTs, Quality Assessment of Diagnostic Accuracy Studies-2
for diagnostic studies, and A Measurement Tool to Assess Systematic Reviews for systematic
reviews/meta-analysis [4
5
6
7]. The panels independently assessed and reached a consensus. Disagreements were
resolved by discussion and the opinion of a third member. We extracted data using
a predefined format and synthesized these data qualitatively. Evidence tables were
summarized according to key questions.
The levels of evidence and grading of the recommendations were modified based on the
Scottish Intercollegiate Guidelines Network and Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) methodology reviews [8
9].
The evidence was classified into 4 levels. The main factors were study design and
quality (Table 1). Additionally, we considered outcome consistency. The grading of
the recommendations was performed according to a modified GRADE methodology into 5
levels including strong for, weak for, weak against, strong against, and inconclusive
(Table 2). The recommendation factors considered evidence level, clinical applicability,
and benefit and harm. The Development Working Group simultaneously reviewed the draft
and discussed for consensus.
Table 1
Levels of evidence
Class
Explanation
High
At least 1 RCT or SR/meta-analysis with no concern regarding study quality
Moderate
At least 1 RCT or SR/meta-analysis with minor concern regarding study quality or at
least 1 cohort/case-control/diagnostic test design study with no concern regarding
study quality
Low
At least 1 cohort/case-control/diagnostic test study with minor concern regarding
study quality or at least 1 single arm before-after study, cross-sectional study with
no concern regarding study quality
Very low
At least 1 cohort/case-control/diagnostic test design study with serious concern regarding
study quality or at least 1 single arm before-after study, cross-sectional study with
minor/severe concern regarding study quality
Table 2
Grading of recommendations
Grade classification
Explanation
Strong for
The benefit of the intervention is greater than the harm, with high or moderate levels
of evidence. The intervention can be strongly recommended in most clinical practice.
Weak for
The benefit and harm of the intervention may vary depending on the clinical situation
or patient/social value. The intervention is recommended conditionally according to
the clinical situation.
Weak against
The benefit and harm of the intervention may vary depending on the clinical situation
or patient/social values. The intervention may not be recommended in clinical practice.
Strong against
The harm of the intervention is greater than the benefit, with high or moderate levels
of evidence. The intervention should not be recommended in clinical practice.
Inconclusive
It is not possible to determine the recommendation direction owing to a lack of evidence
or a discrepancy in results. Thus, further evidence is needed.
Review and approval process
The Review Panel examined the final version of the draft by careful expert review.
Revisions were made reflecting the Review Panel's opinions. The guideline was then
approved by the KSMO, the KSP, the KSG, the KOSRO, and the KGCA at a Korean Gastric
Cancer Guideline Presentation Symposium held on 30th November 2018.
OVERALL TREATMENT ALGORITHM
All statements in this guideline are summarized in Table 3. The tumor description
was confined to adenocarcinoma and the tumor status (TNM and stage) was based on the
American Joint Committee on Cancer (AJCC)/Union for International Cancer Control 8th
edition [10].
Table 3
Summary of statements
No.
Recommendations
Level of evidence
Grade of recommendation
Statement 1
Endoscopic resection is recommended for well or moderately differentiated tubular
or papillary early gastric cancers meeting the following endoscopic findings: endoscopically
estimated tumor size ≤2 cm, endoscopically mucosal cancer, and no ulcer in the tumor.
Moderate
Strong for
Statement 2
Endoscopic resection could be performed for well or moderately differentiated tubular
early gastric cancer or papillary early gastric cancers with the following endoscopic
findings: endoscopically estimated tumor size >2 cm, endoscopically mucosal cancer,
and no ulcer in the tumor or endoscopically estimated tumor size ≤3 cm, endoscopically
mucosal cancer, and ulcer in the tumor.
Moderate
Weak for
Statement 3
Endoscopic resection could be considered for poorly differentiated tubular or poorly
cohesive (including signet-ring cell) early gastric cancers meeting the following
endoscopic findings: endoscopically estimated tumor size ≤2 cm, endoscopically mucosal
cancer, and no ulcer in the tumor.
Low
Weak for
Statement 4
After endoscopic resection, additional curative surgery is recommended if the pathologic
result is beyond the criteria of the curative endoscopic resection or if lymphovascular
or vertical margin invasion is present.
Moderate
Strong for
Statement 5
Proximal as well as total gastrectomy could be performed for early gastric cancer
in terms of survival rate, nutrition, and quality of life. Esophagogastrostomy after
proximal gastrectomy can result in more anastomosis-related complications including
stenosis and reflux; caution is needed in the selection of reconstruction method.
Moderate
Weak for
Statement 6
PPG could be performed for early gastric cancer as well as DG in terms of survival
rate, nutrition, and quality of life.
Moderate
Weak for
Statement 7
Gastroduodenostomy and gastrojejunostomy (Roux-en-Y and loop) are recommended after
DG in middle and lower gastric cancers. There are no differences in terms of survival,
function, and nutrition between the different types of reconstruction.
High
Strong for
Statement 8
D1+ is recommended during the surgery for early gastric cancer (cT1N0) patients in
terms of survival.
Low
Strong for
Statement 9
Prophylactic splenectomy for splenic hilar LND is not recommended during curative
resection for advanced gastric cancer in the proximal third stomach.
High
Strong against
Statement 10
Lower mediastinal LND could be performed to improve oncologic outcome without increasing
postoperative complications for adenocarcinoma of the EGJ.
Low
Weak for
Statement 11
Laparoscopic surgery is recommended in early gastric cancer for postoperative recovery,
complications, quality of life, and long-term survival.
High
Strong for
Statement 12
Laparoscopic gastrectomy could be performed for advanced gastric cancer in terms of
short-term surgical outcomes and long-term prognosis.
Moderate
Weak for
Statement 13
Adjuvant chemotherapy (S-1 or capecitabine plus oxaliplatin) is recommended in patients
with pathological stage II or III gastric cancer after curative surgery with D2 LND.
High
Strong for
Statement 14
Adjuvant chemoradiation could be added in gastric cancer patients after curative resection
with D2 lymphadenectomy to reduce recurrence and improve survival.
High
Weak for
Statement 15
Neoadjuvant chemotherapy for potentially resectable gastric cancer is not conclusive
if D2 LND is considered.
High
Inconclusive
Statement 16
The evidence for the effectiveness of neoadjuvant chemoradiation in locally advanced
gastric cancer is not conclusive if D2 LND is considered.
High
Inconclusive
Statement 17
Palliative gastrectomy is not recommended for metastatic gastric cancer except for
palliation of symptoms.
High
Strong against
Statement 18-1
Palliative first-line combination platinum/fluoropyrimidine is recommended in patients
with locally advanced unresectable or metastatic gastric cancer if the patient's performance
status and major organ functions are preserved.
High
Strong for
Statement 18-2
Palliative trastuzumab combined with capecitabine or fluorouracil plus cisplatin is
recommended in patients with HER2 IHC 3+ or IHC 2+ and ISH-positive advanced gastric
cancer.
High
Strong for
Statement 19
Palliative second-line systemic therapy is recommended in patients with locally advanced
unresectable or metastatic gastric cancer if the patient's performance status and
major organ functions are preserved. Ramucirumab plus paclitaxel is preferably recommended
and monotherapy with irinotecan, docetaxel, paclitaxel, or ramucirumab could also
be considered.
High
Strong for
Statement 20
Palliative third-line systemic therapy is recommended in patients with locally advanced
unresectable or metastatic gastric cancer if the patient's performance status and
major organ functions are preserved.
High
Strong for
Statement 21
Palliative RT could be offered to alleviate symptoms and/or improve survival in recurrent
or metastatic gastric cancer.
Moderate
Weak for
Statement 22
Peritoneal washing cytology is recommended for staging. Advanced gastric cancer patients
with positive cancer cells in the peritoneal washing cytology are associated with
frequent cancer recurrence and a poor prognosis.
Moderate
Strong for
PPG = preserving gastrectomy; DG = distal gastrectomy; LND = lymph node dissection;
EGJ = esophagogastric junction; IHC = immunohistochemistry; ISH = in situ hybridization;
RT = radiotherapy.
Gastric adenocarcinoma was divided into localized (non-metastatic [M0]) and metastatic-1
(M1) disease according to the status of distant metastasis (Fig. 1).
Fig. 1
Overall treatment algorithm.
Diff. = differentiated; Undiff. = undifferentiated.
In cases of M0 gastric cancer, clinical (c) T- and N-stages can be determined based
on preoperative esophagogastroduodenoscopy or endoscopic ultrasound examination findings
and computed tomography. Endoscopic resection can be indicated for selected cT1aN0
gastric cancer with minimal risk of lymph node (LN) metastasis (statements 1–3). The
necessity of additional curative gastrectomy after endoscopic treatment is determined
based on the pathologic review of the endoscopic resection specimen (statement 4).
Surgical resection is recommended if the tumor is outside of endoscopic resection
indications in cT1a and ≥cT1b or cN+. The extent of gastrectomy (statements 5 and
6) and lymphadenectomy (statements 8, 9, and 10), reconstruction methods (statement
7), and approach methods (statements 11 and 12) should be considered when deciding
surgical procedures.
Adjuvant chemotherapy is recommended in patients with pathological stage II or III
gastric cancer after curative R0 resection with D2 LN dissection (LND) (statement
13). Adjuvant chemoradiation can be considered in patients with incomplete resection,
including R1 resection and/or less than D2 LND, and after curative R0 resection with
D2 LND, especially with LN metastasis (statement 14). When the result of primary gastrectomy
is R1 resection, 3 treatment options can be considered, according to the location
of microscopic residual tumor: re-resection, adjuvant chemoradiotherapy, or palliative
therapy, depending on the clinical situation.
Although neoadjuvant chemo (radio) therapy has high levels of evidence, we did not
reach a conclusion on whether to recommend it in Asian populations because the backgrounds
of almost all clinical trials on preoperative therapy were not consistent with Asian
situations (statements 15 and 16).
Palliative systemic therapy is the primary treatment to be considered in patients
with locally advanced unresectable or those after non-curative resection or metastatic
disease (M1) (statements 18–20). Palliative radiotherapy (RT) can be considered for
the alleviation of tumor-related symptoms or to improve survival (statement 21); however,
palliative gastrectomy not intended to alleviate tumor-related symptoms or complications
(i.e., obstruction, bleeding, perforation, etc.) is not recommended for the purpose
of improving overall survival (OS) (statement 17).
ENDOSCOPIC RESECTION
Statement 1. Endoscopic resection is recommended for well or moderately differentiated
tubular or papillary early gastric cancers meeting the following endoscopic findings:
endoscopically estimated tumor size ≤2 cm, endoscopically mucosal cancer, and no ulcer
in the tumor (evidence: moderate, recommendation: strong for).
Endoscopic submucosal dissection (ESD) has been used as a minimally invasive treatment
modality for early gastric cancer since the early 2000s in Korea [11
12]. A total of 7,734 early gastric cancer patients underwent ESD in 2014 [12]. Many
studies have indicated that ESD should be considered as the first-line treatment modality
for the early gastric cancer with well or moderately differentiated tubular adenocarcinoma
or papillary adenocarcinoma with tumor size ≤2 cm, confined to the mucosal layer,
and without ulcer in the tumor as these findings definitely indicated that the lesions
had a very low-risk of LN metastasis [13
14] and ESD allows high rates of en bloc curative resection with low adverse event
rates [11
14
15
16
17
18] (Fig. 2).
Fig. 2
Treatment algorithm for endoscopic resection.
Diff. = differentiated; Undiff. = undifferentiated; ESD = endoscopic submucosal dissection.
The 5-year OS rates of patients meeting this definite indication for ESD did not differ
significantly from those of patients who received endoscopic resection (93.6%–96.4%)
and surgery (94.2%–97.2%) in large retrospective cohort studies in Korea [16
17
18]. The 10-year OS rates were comparable between endoscopic resection (81.9%) and
surgery (84.9%) (P=0.14) [17].
However, the 5-year cumulative metachronous recurrence rates were significantly higher
after endoscopic resection (5.8%–10.9%) than those after surgery (0.9%–1.1%) [16
17
18]. Therefore, close surveillance should be performed after ESD to detect early-stage
metachronous gastric cancer that can be treated with endoscopic resection. Nevertheless,
endoscopic treatment for early gastric cancer can provide a better quality of life,
though stomach preservation might provoke worries of metachronous cancer recurrence
[19]. Moreover, ESD had lower treatment-related complication rates [17
18], shorter hospital stay, and lower costs than those of surgery [16].
In the aspect of patient preference, ESD can provide better health-related quality
of life for early gastric cancer patients, especially in terms of physical function,
eating limits, dyslexia, diarrhea, and body image [20].
Statement 2. Endoscopic resection could be performed for well or moderately differentiated
tubular early gastric cancer or papillary early gastric cancers meeting the following
endoscopic findings: endoscopically estimated tumor size >2 cm, endoscopically mucosal
cancer, and no ulcer in the tumor or endoscopically estimated tumor size ≤3 cm, endoscopically
mucosal cancer, and ulcer in the tumor (evidence: moderate, recommendation: weak for).
Endoscopic resection for early gastric cancer is limited in that LND cannot be performed
during the procedure. Therefore, to achieve curative resection and comparable survival
to that of surgery with endoscopic resection, early gastric cancers with very low-risk
of LN metastasis should be carefully selected. The clinically acceptable rate of LN
metastasis might be determined in the context of perioperative mortality associated
with radical gastrectomy (0.1%–0.3% in a high-volume center in Korea and Japan) [21
22
23]. In addition, it is required that en bloc resection is technically feasible with
endoscopic resection to avoid the possibility of remnant tumor or local recurrence
after the procedure. When the following criteria 1 or 2 were met, the extragastric
recurrence (LN or distant metastasis) rate after endoscopic resection was between
0 and 0.21%, which is comparable to that of perioperative mortality associated with
radical gastrectomy [24
25
26
27].
Although standard gastrectomy with LND is recommended when submucosal invasion of
the tumor (T1b) is suspected in preoperative evaluation, the extragastric recurrence
rate after ESD ranged from 0.9% to 1.5% in large retrospective cohort studies when
the pathologic specimen of ESD fulfilled criteria 3 [24
25
26]. Because the diagnosis of minute submucosal invasion (≤500 µm) of the tumor before
ESD is very difficult, criteria 3 applies to post-ESD pathologic specimens.
When criteria 1, 2, or 3 were met, the OS was comparable between patients undergoing
endoscopic resection and those treated with radical surgery [18
28
29
30
31
32
33
34
35
36
37
38].
Criteria 1, 2, and 3: well or moderately differentiated tubular adenocarcinoma or
papillary adenocarcinoma, en bloc resection, negative lateral resection margins, negative
vertical resection margin, no lymphovascular invasion (LVI), and 1) tumor size >2
cm, mucosal cancer, no ulcer in the tumor, or 2) tumor size ≤3 cm, mucosal cancer,
ulcer in the tumor, or 3) tumor size ≤3 cm, submucosal invasion depth ≤500 μm from
the muscularis mucosa layer.
Because many the factors of these criteria can be confirmed after ESD (i.e., en bloc
resection, resection margin, LVI, and minute submucosal invasion), ESD can be considered
if the early gastric cancer meets the following endoscopic findings: 1) Well or moderately
differentiated tubular adenocarcinoma or papillary adenocarcinoma on forceps biopsy
specimen, endoscopically estimated tumor size >2 cm, endoscopically mucosal cancer,
and no ulcer in the tumor, or 2) Well or moderately differentiated tubular adenocarcinoma
or papillary adenocarcinoma on forceps biopsy specimen, endoscopically estimated tumor
size ≤3 cm, endoscopically mucosal cancer, and ulcer in tumor (Fig. 2).
Until now, the standard treatment for these criteria has been gastrectomy with LND.
Although a number of retrospective cohort studies support these criteria, no prospective
trial has compared the outcomes of endoscopic resection with those of standard operation
based on these criteria. A significant portion of these criteria estimated by pre-ESD
workup is confirmed to be out of criteria by the pathologic examination of ESD specimens
[39
40
41
42
43]. Thus, standard operation (gastrectomy with LND) may also be considered for cases
meeting these criteria.
Statement 3. Endoscopic resection could be considered for poorly differentiated tubular
or poorly cohesive (including signet-ring cell) early gastric cancers meeting the
following endoscopic findings: endoscopically estimated tumor size ≤2 cm, endoscopically
mucosal cancer, and no ulcer in the tumor (evidence: low, recommendation: weak for).
Poorly-differentiated tubular and poorly cohesive (including signet-ring cell) early
gastric cancers are associated with a higher risk of LN metastasis than those of well
and moderately differentiated tubular early gastric cancer. Thus, endoscopic resection
can be considered very cautiously within strict criteria. When the following criteria
were fulfilled, a few retrospective cohort studies reported extragastric recurrence
after endoscopic resection [24
26
44
45
46
47
48
49] and a comparable OS between patients undergoing endoscopic resection and those
treated with radical gastrectomy [18
29
35
36
49].
Poorly differentiated tubular adenocarcinoma or poorly cohesive carcinoma (including
signet-ring cell carcinoma), en bloc resection, negative lateral resection margins,
negative vertical resection margin, no LVI, and tumor size ≤ 2 cm, mucosal cancer,
and no ulcer in the tumor.
Because many factors of these criteria can be confirmed after ESD (i.e., en bloc resection,
resection margin, and LVI), ESD can be considered for poorly-differentiated tubular
and poorly cohesive (including signet-ring cell) early gastric cancers meeting the
following endoscopic findings (Fig. 2).
Poorly differentiated tubular adenocarcinoma or poorly cohesive carcinoma (including
signet-ring cell carcinoma) on forceps biopsy specimen, endoscopically estimated tumor
size ≤2 cm, endoscopically mucosal cancer, and no ulcer in the tumor.
Until now, the standard treatment for these criteria has been gastrectomy with LND.
A few retrospective cohort studies support these criteria for ESD and the results
of prospective trials are lacking (level of evidence is low, and the level of recommendation
is weak). A significant portion of these criteria estimated by pre-ESD workup is confirmed
to be out of criteria by the pathologic examination of ESD specimens [39
40
41
42
43]. Thus, standard operation (gastrectomy with LND) can also be considered for cases
meeting these criteria.
Statement 4. After endoscopic resection, additional curative surgery is recommended
if the pathologic result is beyond the criteria of the curative endoscopic resection
or if lymphovascular or vertical margin invasion is present (evidence: moderate, recommendation:
strong for).
Early gastric cancer patients who received endoscopic resection could be considered
as being beyond the criteria of endoscopic resection by pathologic specimen evaluation.
Resected tumor characteristics beyond the following criteria are also considered for
non-curative resection: 1) Differentiated (well or moderately differentiated tubular
or papillary) intramucosal cancer measuring >2 cm in the long diameter without ulcer
(active or scar), 2) differentiated mucosal cancer measuring <3 cm with ulcer (active
or scar), 3) undifferentiated (poorly differentiated tubular or poorly cohesive) mucosal
cancer measuring <2 cm without ulcer (active or scar), and 4) differentiated mucosal
cancer measuring <3 cm with subtle submucosal invasion (<500 µm). LVI and positive
vertical margin, which are confirmed after endoscopic resection, are also important
reasons for the recommendation of rescue surgery (Fig. 2).
Many studies have investigated the long-term outcomes with or without additional surgery
in patients who did not meet the curative criteria for endoscopic resection in early
gastric cancer [39
40
41
42
50
51
52
53
54
55
56
57]. All studies were retrospective cohort designs and only 2 used propensity score
matching analysis, which is used to minimize potential selection bias and mimic randomization
in observational studies [39
50]. Although several small studies showed no difference in OS between rescue surgery
and follow-up [51
52
53], most studies, including the 2 studies that used propensity score matching, showed
a significant survival benefit (OS or disease-specific survival [DSS]) for additional
curative surgery compared to that for follow-up [39
40
41
42
50
54
55
56
57]. Patients with LVI or deep vertical margins showed a particularly evident survival
benefit for additional curative surgery [40
54
55
57].
The Japanese multicenter retrospective cohort study that used propensity score matching
analysis reported 5-year DSS rates after ESD of 99.0% in the additional curative surgery
group and 96.8% in the no additional curative surgery group (P=0.013). The 5-year
OS rates were 91.0% and 75.5%, respectively (P<0.001) [50]. In the Korean single-center
retrospective cohort study using propensity score matching analysis, the 5-year overall
mortality in no additional curative surgery group (26.0%; 95% confidence interval
[CI], 13.5%–49.9%) was higher than that of the matched initial standard surgery patients
(14.5%; 95% CI, 6.3%–33.6%; P=0.04). The overall mortality did not differ significantly
between the initial ESD with additional curative surgery group and the corresponding
initial standard surgery group [39]. Thus, additional curative surgery is strongly
recommended in patients undergoing non-curative endoscopic resection (exceeding the
criteria of endoscopic resection) for early gastric cancer.
The survival benefit of additional curative surgery in older patients (>75 years)
is controversial. Two studies showed a significant survival benefit but another study
showed no difference in long-term outcomes [42
54
56]. Selection bias is inevitable in retrospective cohort designs. For example, all
studies showed a younger age in the additional curative surgery group compared to
that in the follow-up group, although the age difference disappeared after propensity
score matching in 2 studies. Patients undergoing noncurative resection without additional
curative surgery also tended to have a higher incidence of comorbidity [41
42]. Although 2 of 12 studies used propensity score matching analysis, selection and
measurement biases are still possible. Additional curative surgery may be not feasible
in some patients because of very old age, poorly-controlled underlying diseases, or
poor general condition. In these patients, follow-up observation could be a feasible
option after they are provided an explanation of the risk of recurrence.
SURGICAL THERAPY
Standard surgery is recommended in cases of cT1a, which are outside of the indication
for endoscopic resection, and ≥cT1b or cN+ and M0 gastric cancer (Fig. 3A).
Fig. 3
(A) Treatment algorithm for resectable gastric adenocarcinoma. (B) Treatment algorithm
for resectable esophagogastric junction adenocarcinoma.
ESD = endoscopic submucosal dissection; LND = lymph node dissection.
Standard surgery is defined as total or subtotal gastrectomy with D2 LND. Subtotal
gastrectomy in distal gastric cancer has been recognized as a standard surgery based
on the results of 2 RCTs in which the subtotal gastrectomy group showed similar long-term
oncologic results and lower morbidity and mortality rates compared to those in the
total gastrectomy group [58
59
60]. Although the standard extent of LND has been debated for decades among Eastern
and Western countries, there has been an international trend to accept D2 LND as a
standard surgery [2
61
62
63], which was supported by results of prospective trials and meta-analyses [64
65
66]. The extent of LND in each gastrectomy was defined according to Japanese guidelines
[63].
Palliative systemic therapy is the primary treatment in cases of locally advanced
unresectable or cM1 gastric cancer (Fig. 1). However, conversion surgery could be
considered if R0 resection is possible after palliative systemic therapy, which is
currently under investigation. Surgery with curative intent could also be considered
in cases of locally advanced unresectable or cM1 gastric cancer not detected in preoperative
evaluation but incidentally identified during surgery and if R0 resection is possible,
which should be investigated in future studies. Intraperitoneal chemotherapy with
or without hyperthermia could be applied to patients with peritoneal metastasis in
a clinical trial setting; however, this requires additional evidence.
Gastric resection and reconstruction
Statement 5. Both proximal and total gastrectomy could be performed for early gastric
cancer in terms of survival rate, nutrition, and quality of life. Esophagogastrostomy
after proximal gastrectomy can result in more anastomosis-related complications including
stenosis and reflux, and caution is needed in the selection of reconstruction method
(evidence: moderate, recommendation: weak for).
A prospective randomized controlled study comparing proximal and total gastrectomy
with sufficient numbers of cases and power to evaluate the survival rate as the primary
endpoint has not been conducted. However, several retrospective studies reported non-inferior
long-term survival rates after proximal gastrectomy as compared to that of total gastrectomy
[67
68
69
70
71
72
73
74]. In addition, the incidences of early postoperative complications after proximal
gastrectomy were similar to those after total gastrectomy in most studies [68
70
71
73
75
76
77]; however, they have also been reported to be more [72] and less [69] frequent.
Although various reconstructions after proximal gastrectomy have been tried in order
to reduce short- or long-term complications, they remain controversial. Esophagogastrostomy
after proximal gastrectomy is the simplest procedure but resulted in significantly
more frequent reflux esophagitis (16.2%–42.0% vs. 0.5%–3.7%) and symptoms of reflux
[67
69
72
74
76
77], as well as stenosis at the anastomosis site (3.1%–38.2% vs. 0%–8.1%) [67
69
71
72
74
76
77]. An et al. [69] and Ahn et al. [70] concluded that proximal gastrectomy with esophagogastrostomy
is an inferior surgical method to total gastrectomy due to the significantly higher
incidence of anastomosis-related and/or postoperative complications and no nutritional
benefit. However, other studies have reported that proximal gastrectomy with esophagogastrostomy
can be still beneficial compared to total gastrectomy in terms of serum albumin level
[71
72
77], maintenance of body weight [74
76
77
78], prevention of anemia [72
74
77], and serum vitamin B12 level [72].
Jejunal interposition could be another option after proximal gastrectomy. Anastomosis
with jejunal interposition has been shown to be beneficial in the context of nutritional
parameters and anemia [71
74
75
76]. Postgastrectomy syndrome including dumping syndrome occurred less frequently
in patients who underwent proximal gastrectomy with jejunal interposition compared
to that in patients who underwent total gastrectomy [75
76]. A study including 115 cases that received esophagogastrostomy and 78 that received
jejunal interposition also reported less frequent diarrhea and dumping syndrome for
proximal gastrectomy (2.0 vs. 2.3 points on a 7-point scale) [78].
Recently, double-tract reconstruction after proximal gastrectomy has been proposed
as an option that did not increase the incidence of complications or reflux and showed
superiority to total gastrectomy in terms of body weight, anemia, and serum vitamin
B12 level [73]. A multicenter prospective randomized clinical trial was launched in
2016 in Korea based on this result (NCT02892643).
The incidence of metachronous cancer in the remnant stomach after proximal gastrectomy
was 33.1% (6/192) and 6.2% (4/65) in reports by Huh et al. [72] and Ohashi et al.,
[76] respectively.
In conclusion, proximal gastrectomy is a surgical option with possible benefits in
aspects of shorter operative time, less blood loss, better maintenance of postoperative
nutrition, lower incidence of anemia, better maintenance of vitamin B12 level, and
lower incidence of post-gastrectomy syndrome (Fig. 3A). However, proximal gastrectomy
requires caution in the choice of reconstruction technique because of the significantly
increased incidence of anastomosis-related complications and reflux to the esophagus
after esophagogastrostomy.
Statement 6. Pylorus-preserving and distal gastrectomy (DG) could be performed for
early gastric cancer in terms of survival rate, nutrition, and quality of life (evidence:
moderate, recommendation: weak for).
Conventional DG and pylorus-preserving gastrectomy (PPG) can be performed for middle-third
early gastric cancer. PPG preserves the pre-pyloric antrum and the pylorus to prevent
the rapid transit of food into the duodenum and reflux of the duodenal contents. Consequently,
the postoperative incidence of dumping syndrome and reflux gastritis is decreased,
and a nutritional benefit is expected.
Most of the literature on PPG is retrospective studies. All studies that assessed
the long-term survival concluded that there was no difference in long-term survival
between conventional DG and PPG (5-year survival rates: 95% for PPG vs. 87% for DG,
P=0.087 [79]; 3-year survival rates: 98.2% for PPG vs. 98.8% for DG, P=0.702 [80];
odds ratio [OR] of PPG, 0.83, 95% CI, 0.10–6.66, P=0.86 [81]; hazard ratio [HR] for
recurrence in PPG, 0.393, 95% CI, 0.116–1.331, P=0.12 [82]). In addition, except for
1 report from Japan [79], most of the reports concluded that there was no difference
in the incidence of postoperative complications [80
81]. As expected, after PPG, patients showed a significantly low incidence of postoperative
dumping syndrome and reflux (reflux: 4% for PPG vs. 40% for DG; reflux gastritis:
8% for PPG vs. 68% for DG [83]; dumping syndrome: OR, 0.02, 95% CI, 0.10–0.41, P<0.001;
bile reflux: OR, 0.16, 95% CI, 0.06–0.45, P<0.01; remnant gastritis: OR, 0.2, 95%
CI, 0.08–0.50, P<0.001; reflux esophagitis: OR, 0.78, 95% CI, 0.43–1.40, P=0.41 [81]).
Some studies reported significantly reduced development of gallstones after PPG [80
81]. However, significantly more patients complained of delayed gastric emptying after
PPG (symptoms of delayed gastric emptying at 1 postoperative year: 15.8% for PPG vs.
0% for DG; 7.8% for PPG vs. 1.7% for DG [80]; and OR for delayed gastric emptying,
2.12, 95% CI, 1.43–3.15, P<0.001 [81]).
PPG for middle-third early gastric cancer can be performed with relatively similar
incidences of surgical complications and long-term survival (Fig. 3A). Although it
is evident that PPG significantly reduces the incidence of post-gastrectomy syndromes
such as dumping syndrome, reflux and gallstone formation, postoperative delayed gastric
emptying is not uncommon. Thus, we are awaiting the results of a large-scale, prospective
randomized trial. Therefore, PPG can be performed at the surgeon's discretion with
caution regarding postoperative delayed emptying.
Statement 7. Gastroduodenostomy and gastrojejunostomy (Roux-en-Y and loop) are recommended
after DG in middle and lower gastric cancer. There are no differences in terms of
survival, function, and nutrition between the different types of reconstruction (evidence:
high, recommendation: strong for).
A variety of reconstructions after subtotal gastrectomy have been proposed, including
Billroth I, Billroth II, and Roux-en-Y; however, there is still no consensus regarding
a standard reconstruction method. Complications after subtotal gastrectomy, such as
reflux gastritis and esophagitis, dumping syndrome, and delayed gastric emptying,
could depend on the reconstruction method [84]. A recent meta-analysis of the types
of reconstruction method and endoscopic findings showed no difference in the incidence
of dumping syndrome. Roux-en-Y reconstruction is superior to Billroth I and Billroth
II reconstruction in terms of preventing bile reflux (OR, 0.095; 95% CI, 0.010–0.63
and OR, 0.064; 95% CI, 0.0037–0.84, respectively) and remnant gastritis (OR, 0.33;
95% CI, 0.16–0.58 and OR, 0.40; 95% CI, 0.17–0.92, respectively). Meanwhile, Roux-en-Y
gastric anastomosis resulted in more frequent delayed gastric emptying than did Billroth
I (OR, 3.4; 95% CI, 1.1–13) [85]. However, there was no difference in patient quality
of life according to the type of reconstruction (P=0.290–0.994) [86]. In addition,
there were no differences in nutritional aspects among those methods [86
87]. Although no prospective study has assessed the incidence of remnant gastric cancer
according to the anastomotic method, a nationwide survey in Japan reported no difference
in terms of remnant gastric cancer [88].
In conclusion, there are no significant differences in the functional, nutritional,
and long-term prognosis of each reconstruction method.
Lymphadenectomy
Statement 8. D1+ is recommended during surgery for early gastric cancer (cT1N0) patients
in terms of survival (evidence: low, recommendation: strong for).
In gastric cancer surgery, adequate resection of regional LNs is essential along with
resection of the primary lesion. It is recommended to perform modified D2, D1, or
D1+ if early gastric cancer is not clinically suspected to have LN metastasis. Standard
D2 is recommended for early gastric cancer with suspected LN metastasis. However,
no prospective clinical trials have compared the survival of patients after modified
D2 or standard D2.
The results of a retrospective study published in Italy indicated that LN metastasis
was a poor prognostic factor for early gastric cancer patients, suggesting that standard
D2 should be performed even for early gastric cancer [89]. Other Italian researchers
have reported 10-year survival rates of 95% and 87.5% after standard D2 and D1, respectively,
in early gastric cancer patients. There were no statistically significant differences
in 10-year survival between groups (P=0.80) [90]. In a report from Japan, the 5- and
10-year survival rates were 97% and 91% in patients after standard D2 and 98% and
91% after modified D2 (D1+). There were no cases with metastasis to second-tier LNs
in patients with cT1N0 or cT1N1 disease [91].
In conclusion, D1+ is recommended for the treatment of T1N0 gastric cancer patients,
with relatively comparable oncological safety (Fig. 3A).
Statement 9. Prophylactic splenectomy for splenic hilar LND is not recommended during
curative resection for advanced gastric cancer in the proximal-third stomach (evidence:
high, recommendation: strong against).
The standard surgical procedure for proximal-third gastric carcinoma is total gastrectomy
with proper lymphadenectomy. Therapeutic splenectomy is necessary if the tumor directly
invades the spleen or if LN metastasis around the splenic hilum is suspected. However,
there is debate regarding whether the spleen should be preserved or resected during
total gastrectomy in patients diagnosed with proximal-third gastric cancer without
a definite indication for splenectomy.
Three prospective randomized clinical trials have evaluated the survival advantage
of prophylactic splenectomy in proximal-third gastric carcinoma [92
93
94]. However, no studies recommend prophylactic splenectomy to dissect macroscopically-negative
LNs around the splenic hilum for proximal-third gastric cancer. The only study in
Korean patients showed a slightly better 5-year OS in the splenectomy group but the
difference was not statistically significant (P=0.50) [93]. A recent large-scale study
showed that postoperative complications were more common for splenectomy than for
spleen preservation (30.3% and 16.7%, P<0.010), without a survival advantage [94].
However, prophylactic splenectomy for patients with Borrmann type IV or tumors located
in the greater curvature remains inconclusive because they were not included in the
enrollment criteria of the largest randomized controlled clinical trial [94].
A systemic review of splenectomy for proximal-third gastric cancer concluded that
spleen-preserving total gastrectomy decreased postoperative complications without
negatively affecting the OS [95]. In addition, a meta-analysis indicated that splenectomy
did not show a beneficial effect on survival rate compared to splenic preservation
[96].
Therefore, prophylactic splenectomy for LND is not recommended in the curative resection
for proximal-third gastric cancer without macroscopically LN metastasis near the spleen
or direct invasion of the spleen or distal pancreas (Fig. 3A). This statement addresses
the need for prophylactic splenectomy and does not address the need for prophylactic
LN #10 dissection, which should be investigated in the future and is not conclusive
in the present guideline.
Statement 10. Lower mediastinal LND could be performed to improve oncologic outcome
without increasing postoperative complications for adenocarcinoma of the esophagogastric
junction (EGJ) (evidence: low, recommendation: weak for).
Dissection of the lower mediastinal LN as a part of the treatment for Siewert type
II or III EGJ adenocarcinoma is controversial. High level of evidence is lacking regarding
the necessity for lower mediastinal LND. Although LN metastasis in the lower mediastinal
LNs is frequently found in Siewert type II or III EGJ cancer, it usually indicates
a poor prognosis. In a retrospective analysis conducted in Korea, the 5-year disease-free
survival (DFS) rates were 62.6% and 82.5% for Siewert type II and III cancers, respectively
[97]. In this study, when these cancers were early gastric cancer, survival was good
and comparable (93.2% vs. 96.7% vs. 98.7% for Siewert type II, III, and upper-third
gastric cancer, P=0.158); however, for advanced cancer, the survival was worse in
Siewert type II than that in Siewert type III cancer (47.9% vs. 75.4% vs. 71.8% in
Siewert type II, III, and upper-third gastric cancer, P<0.001).
Most randomized clinical trials on this issue have compared the surgical outcomes
of transabdominal and transthoracic approaches [98
99
100
101]. However, no study has demonstrated a survival benefit of transthoracic approaches
by thorough dissection of the lower mediastinal LNs and negative surgical margins
over transabdominal approaches for Siewert type II and III EGJ cancer. In a Japanese
phase III randomized clinical trial comparing outcomes between the left thoracoabdominal
and transhiatal approaches for EGJ cancer, the 5-year OS were 37.9% and 52.3%, respectively.
The HR of death for the left thoracoabdominal approach compared to the transhiatal
approach was 1.36 (0.89–2.08, P=0.92).
A cohort study was also performed in the UK of Siewert type I and II EGJ cancer with
data from 2 institutions [102]. In this study, the in-hospital mortality rates were
1.1% and 3.2% (P=0.110) and there were no differences in OS (HR, 1.07; 95% CI, 0.84–1.36)
or time to tumor recurrence (HR, 0.99; 95% CI, 0.76–1.29) between the transhiatal
and transthoracic approaches. A meta-analysis reported the transthoracic approach
to be associated with higher incidences of systemic complications such as respiratory
and cardiovascular problems, longer hospital stay, and early postoperative mortality
compared to those in the transabdominal approach [103]. Survival did not differ between
the 2 approaches.
Based on the results from these studies, lower mediastinal LND for EGJ adenocarcinoma,
especially by means of transthoracic approaches, to obtain more LNs and a negative
surgical margin may not be recommended (Fig. 3B).
Surgical approach
Statement 11. Laparoscopic surgery is recommended in early gastric cancer for improved
postoperative recovery, complications, quality of life, and long-term survival (evidence:
high, recommendation: strong for).
Laparoscopic gastrectomy is currently widely performed in the treatment of early gastric
cancer. Since the first clinical trial was reported in the early 2000s [104], studies
comparing laparoscopic and open surgery for early gastric cancer have proven the oncologic
safety and excellence of laparoscopic gastrectomy [23
105
106
107
108
109
110
111].
The 5-year survival rates of laparoscopic gastrectomy did not significantly differ
from those of open gastrectomy for early gastric cancer in a Korean single-center
RCT with a large number of enrolled patients (DFS, 98.8% vs. 97.6%; P=0.514 and OS,
97.6% vs. 96.3%; P=0.721) [107]. In addition, the complication rate was significantly
lower for laparoscopic than that for open gastrectomy (23.2% vs. 41.5%; P=0.012).
A multicenter RCT conducted in Korea (KLASS-01) recently demonstrated better short-term
outcomes of laparoscopic gastrectomy than those of open gastrectomy. In this study,
the overall complication rate was significantly lower for laparoscopic than for open
gastrectomy (13.0% vs. 19.9%, P=0.001) and the mortality rates did not differ between
the 2 groups (0.6% vs. 0.3%, P=0.687) [23].
Therefore, laparoscopic surgery comprised of gastrectomy and adequate LND demonstrated
a more beneficial effect for patients with early gastric cancer in terms of all oncologic
aspects compared to those for open surgery. In early gastric cancer, laparoscopic
surgery should be the first option for treatment (Fig. 3A).
Statement 12. Laparoscopic gastrectomy could be performed for advanced gastric cancer
in terms of short-term surgical outcomes and long-term prognosis (evidence level:
moderate, recommendation: weak for).
Most previous studies suggesting the feasibility of laparoscopic gastrectomy for locally
advanced gastric cancer were small retrospective studies. Meta-analyses of those retrospective
studies have demonstrated that laparoscopic gastrectomy required longer operating
times but led to less operative blood loss, faster postoperative bowel recovery, and
reduced hospital stay compared to those for open surgery [112
113
114
115
116
117
118]. The postoperative morbidity and mortality rates of laparoscopic gastrectomy
were also lower or similar compared to those for open surgery. As for the quality
of LND, most studies have reported that the number of harvested LNs during laparoscopic
surgery does not differ significantly from that of open surgery. Furthermore, the
long-term outcomes including OS and DFS were comparable between laparoscopic and open
surgery.
Despite reports from a number of retrospective studies, the long-term outcomes of
laparoscopic gastrectomy for advanced gastric cancer have rarely been investigated
in prospective studies. Park et al. [119] performed a randomized phase II trial comparing
non-compliance of D2 LND, short-term surgical outcomes, and 3-year DFS between laparoscopy-assisted
DG (LADG) and open DG (ODG) for cT2-4/cN0-2 gastric cancer. In their study, there
were no significant differences between groups in postoperative morbidity (17% in
LADG vs. 18.8% in ODG, P=0.749) and hospital stay (9.8 days in LADG vs. 9.1 days in
ODG, P=0.495). The non-compliance rates of D2 LND, defined as the proportion of patients
with more than 1 empty LN station, were also similar between the 2 groups (47.0% in
LADG vs. 43.2% in ODG, P=0.648). There was no significant difference in 3-year DFS
between the 2 groups (80.1% in LADG vs. 81.9% in ODG, P=0.648). In addition, other
small RCTs from Western countries have also reported that laparoscopic gastrectomy
showed no significant differences in disease recurrence and OS of advanced gastric
cancer compared to open surgery [120
121]. However, these studies are limited by their small sample sizes and inappropriate
study designs; the final results of ongoing large multicenter randomized trials are
awaited to determine the long-term outcomes of laparoscopic gastrectomy for locally
advanced gastric cancer [122
123].
The short-term outcomes of laparoscopic gastrectomy with D2 LND for locally advanced
gastric cancer have relatively been well demonstrated in clinical trials. Interim
analysis of a large multicenter RCT in China (CLASS-01) reported no significant difference
in postoperative complications between LADG and ODG (15.2% in LADG vs. 12.9% in ODG,
P=0.285) [123]. In their study, patients with LADG also showed better postoperative
recovery, such as faster bowel recovery and reduced hospital stay, than those with
ODG (10.8 days in LADG vs. 11.3 days in ODG, P<0.001). Another small RCT reported
similar numbers of harvested LNs and postoperative morbidity between open and laparoscopic
gastrectomy with D2 LND [124]. More recently, a Japanese multicenter randomized trial
(JLSSG 0901) reported interim results on the short-term outcomes of laparoscopic gastrectomy
with D2 LND [125]. In their study, the incidence of anastomosis leakage or pancreatic
fistula was 4.7%, which was within their expected target range and the study is ongoing.
In conclusion, with advances in laparoscopic surgery, short-term surgical outcomes
and technical adequacy of laparoscopic gastrectomy with D2 LND have been well demonstrated
both in retrospective studies and large RCTs. However, the long-term outcomes of laparoscopic
gastrectomy for locally advanced gastric cancer require further investigation in large
multicenter RCTs (Fig. 3A).
Robot gastrectomy
The current robotic surgical systems provide advantages such as 3-dimensional views,
wristed instruments with 7 degrees of freedom, and tremor filtration, which enable
surgeons to perform more accurate and thorough operations compared to that for conventional
laparoscopic surgery [97
126
127
128]. Although it remains unclear whether the benefits of robotic gastrectomy outweigh
the cost, the use of robotic gastrectomy has expanded gradually since the first clinical
application of robotic surgery for the treatment of gastric cancer [97
129]. Robotic gastrectomy has shown several clinical benefits, including reduced blood
loss and a possibly larger number of retrieved LN than those for conventional laparoscopic
gastrectomy [126
130
131
132]. However, these advantages did not seem to significantly improve the short-term
outcomes of patients [97
126
129]. These negative results were also demonstrated in a prospective multicenter study
in Korea, although it was a non-randomized trial comparing the relatively early experience
of robotic gastrectomy to well-established laparoscopic surgery [129]. The long-term
oncologic outcomes of robotic gastrectomy reported by a few retrospective analyses
are similar to those for laparoscopic surgery, but evidence is still lacking [126
130
131]. Overall, robotic gastrectomy seems to be feasible, safe, and easy to learn,
but its advantages over laparoscopic gastrectomy are not obvious from the patient's
standpoint.
ADJUVANT THERAPY
Statement 13. Adjuvant chemotherapy (S-1 or capecitabine plus oxaliplatin) is recommended
in patients with pathological stage II or III gastric cancer after curative surgery
with D2 LND (evidence: high, recommendation: strong for).
Surgical resection with D2 LND is the standard of care in gastric cancer. However,
high rates of locoregional and distant recurrences have been reported in these cases,
for which the prognosis is usually very poor [133].
European phase III studies demonstrated that perioperative chemotherapy including
adjuvant chemotherapy was superior to surgery alone for patients with resectable gastroesophageal
cancer [134
135]. As only 30%–50% of these European cases involved D2 LND, perioperative chemotherapy
was not accepted as a treatment for such cases in East Asia.
Recently, 2 large randomized phase III trials conducted in Asian patients showed a
significant survival benefit for adjuvant chemotherapy over observation after curative
surgery with D2 LND in patients with resectable gastric cancer [136
137]. In the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) in Japan,
1,059 patients with stage II (excluding T1) or III gastric cancer (by Japanese classification,
2nd English edition [138]) following D2 gastrectomy received observation or S-1 for
1 year after surgery [136]. The rates of relapse-free survival at 3 years were 72.2%
in the S-1 group and 59.6% in the surgery-only group (HR, 0.62; 95% CI, 0.50–0.77;
P<0.001) and the 3-year OS rates were 80.1% and 70.1%, respectively (HR, 0.68; 95%
CI, 0.52–0.87; P=0.003). In the capecitabine and oxaliplatin adjuvant study in stomach
cancer (CLASSIC) conducted in South Korea, China, and Taiwan, 1,035 patients with
stage II–IIIB gastric cancer (by AJCC 6th edition [139]) following D2 gastrectomy
received either observation or capecitabine and oxaliplatin for 6 months [137]. The
3-year DFS rates were 74% in the chemotherapy and surgery group and 59% in the surgery-only
group (HR, 0.56; 95% CI, 0.44–0.72; P<0.001). The 5-year follow-up data in these 2
studies confirmed these findings [140
141].
Based on the results of these studies, both chemotherapy regimens (S-1 or capecitabine
plus oxaliplatin) are currently accepted as standard treatment in pathological stage
II or III gastric cancer after D2 gastrectomy in East Asia (Fig. 1).
Statement 14. Adjuvant chemoradiation could be added for gastric cancer patients after
curative resection with D2 lymphadenectomy to reduce recurrence and improve survival
(evidence: high, recommendation: weak for).
High rates of loco-regional recurrence (LRR) have been reported in gastric cancer
even after complete resection, especially in locally advanced stages of gastric cancer
[142]. There have been attempts to minimize recurrences and improve outcomes through
adjuvant RT, usually combined with chemotherapy, and several prospective or retrospective
studies have shown promising outcomes of improved survival by reducing LRR [143
144
145]. In this context, a randomized phase III trial comparing surgery followed by
adjuvant chemoradiation therapy (CRT) versus surgery alone in stage IB through IV
(M0) gastric cancer (by AJCC 6th edition [139]) was performed (South Western Oncology
Group-Directed Intergroup Study 0116 [INT-0116]) [146
147]. There was a clear advantage when adding adjuvant CRT, with a significant prolongation
of survival as well as reduction of recurrences. Despite the positive outcomes of
the INT-0116 study, however, several limitations were revealed. First, D2 lymphadenectomy,
highly recommended as a standard surgical procedure in locally advanced gastric cancer,
was performed in only 10% of the enrolled patients [65]. Second, this study was mainly
conducted in gastric cancer patients from a Western population with different characteristics
from those of Asian populations including Korean [148]. Because of these limitations,
the necessity of adjuvant RT in completely resected stomach cancer remains controversial.
Meanwhile, a retrospective pooled analysis of Dutch Gastric Cancer Group Trial reported
that adjuvant CRT improved survival as well as local control in the D1 but not D2
resected subgroup [149].
However, adjuvant chemotherapy without RT showed a survival benefit over surgery alone
in following randomized phase III trials and has become a standard of care [136
137
140
141]. Thus, the role of RT in addition to chemotherapy has been further questioned.
Several RCTs have compared adjuvant CRT versus chemotherapy alone in gastric cancer
after complete resection with D2 lymphadenectomy [150
151
152
153
154]. Among them, one trial performed by a single Korean institution (Lee et al.,
[153] Adjuvant Chemoradiation Therapy in Stomach Cancer [ARTIST] trial) completed
the preplanned patient accrual but 3 other trials (2 Korean and 1 Greek trial) failed
to complete the planned registration and were terminated prematurely [150
151
152]. There was no mention of the planned number of patients or completion of registration
in the 1 remaining multicenter Chinese trial [154].
A meta-analysis of the aforementioned trials found that adjuvant CRT can improve not
only LRR-free survival (LRRFS) but also DFS compared to chemotherapy alone [155
156
157
158
159
160]. However, improved OS in adjuvant CRT was not demonstrated. Furthermore, the
ARTIST trial failed to confirm the superiority of adjuvant CRT over chemotherapy alone
in terms of DFS as well as OS for all patients even after long-term follow-up, although
it showed a significant benefit in LRRFS [153
161
162]. The beneficial effect of DFS on adjuvant CRT was limited to patients with nodal
involvement. This trial is considered to be the most reliable study in terms of adjuvant
RT in gastric cancer for Korean patients because it is a well-designed prospective
study that was conducted and completed in Korea.
Based on the results of these studies, adjuvant CRT can be considered in gastric cancer
patients with incomplete resection and/or less than D2 lymphadenectomy (Fig. 1). Adjuvant
CRT could also be considered in patients with gastric cancer after complete resection
with D2 lymphadenectomy, especially for those with LN metastasis.
NEOADJUVANT THERAPY
Statement 15. Neoadjuvant chemotherapy for potentially resectable gastric cancer is
not conclusive if D2 LND is considered (evidence: high, recommendation: inconclusive).
European phase III studies demonstrated that perioperative chemotherapy including
neoadjuvant chemotherapy was superior to surgery alone in potentially resectable gastric
cancer. The outcomes of patients treated with surgery alone were compared to those
of patients treated with perioperative epirubicin, cisplatin, and infusional 5-fluorouracil
(5-FU) in the MAGIC trial or with perioperative cisplatin and infusional 5-FU in the
FNCLCC/FFCD trial [135
163]. In these studies, perioperative chemotherapy significantly prolonged both OS
and progression-free survival (PFS) or DFS. The FLOT-4 study showed that a perioperative
regimen comprising 5-FU, leucovorin, oxaliplatin, and docetaxel was superior to perioperative
epirubicin, cisplatin, and 5-FU or capecitabine [134]. However, as D2 LND was performed
in only 30%–50% of patients in these European studies, these perioperative chemotherapeutic
regimens might not be applicable to patients in Korea, where D2 LND is the standard
of care. Recently, the Japanese phase III JCOG 0501 study compared 2 cycles of neoadjuvant
S-1 plus cisplatin followed by D2 surgery and adjuvant S-1 to D2 surgery followed
by adjuvant S-1 in far-advanced localized gastric cancer. This trial observed no statistically
significant difference in OS and PFS between the 2 arms [164].
Therefore, neoadjuvant chemotherapy for potentially resectable gastric cancer is not
conclusive at present in Korea except in clinical trials (Fig. 1).
Statement 16. The evidence for the effectiveness of neoadjuvant chemoradiation in
locally advanced gastric cancer is not conclusive if D2 LND is considered (evidence:
high, recommendation: inconclusive).
Neoadjuvant CRT is mainly studied for cancer of the esophagus, EGJ, and/or gastric
cardia, where obtaining a complete R0 resection is challenging and thus, there is
a higher probability of locoregional relapse. Two RCTs have been conducted and 1 trial
is ongoing to compare the outcomes of neoadjuvant CRT versus neoadjuvant chemotherapy
alone in resectable cancer of the EGJ or stomach [165
166
167
168].
The PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET) showed a higher
probability of pathologic complete response (15.6% vs. 2.0%) and pathologic N0 (64.4%
vs. 37.7%) after neoadjuvant CRT compared to those for neoadjuvant chemotherapy alone
[168]. Additionally, improved OS was also noticed after neoadjuvant CRT (47.4% vs.
27.7% at 3 years), although the difference failed to reach statistical significance
(P=0.07). The improved OS remained in long-term analysis (39.5% vs. 24.4% at 5 years,
P=0.06) with a significant benefit of LRRFS (P=0.01; HR, 0.37) [167]. Similar benefits
of neoadjuvant CRT were also reported in another RCT from Sweden and Norway [165].
Neoadjuvant CRT showed higher probabilities of complete pathologic response (28% vs.
9%, P=0.002), pathologic N0 (62% vs. 35%, P=0.001), and R0 resection rate (87% vs.
74%, P=0.04) in this study. The Trial Of Preoperative therapy for Gastric and Esophagogastric
junction AdenocaRcinoma (TOPGEAR) also demonstrated that neoadjuvant CRT can be safely
delivered to the majority (85%) of patients without a significant increase in treatment-related
toxicities or surgical morbidity [166]. Those findings have been confirmed in several
meta-analyses of randomized trials [159
169
170
171].
Despite their promising outcomes, the aforementioned studies were performed mainly
in patients with esophageal and/or EGJ cancer. EGJ cancer is common in Western countries
[148] and most studies evaluating the efficacy of neoadjuvant CRT for gastric cancer
(mainly EGJ cancer) were also performed in Western populations. Thus, it might be
inappropriate to simply apply these results to Asian populations, especially to Koreans,
where gastric cancer occurs mainly in the antral area [148] (Fig. 1). To evaluate
the effect of neoadjuvant CRT in gastric cancer, further prospective studies targeting
Asian populations with non-junction cancer are mandatory.
PALLIATIVE THERAPY
The prognosis for locally advanced unresectable or metastatic gastric cancers is dismal,
and these patients have a median OS of 6–13 months. The goals of therapy for these
patients are to palliate disease-related symptoms and to prolong survival. Such palliative
systemic therapy also provides a greater quality of life than best supportive care.
Thus, systemic therapy is the primary treatment to be considered in patients with
locally advanced unresectable (unresectable T4b or extensive nodal disease) or metastatic
disease or those after non-curative resection. Palliative systemic therapy for advanced
gastric cancer should be determined based on patient performance status, medical comorbidities,
and organ function. Furthermore, systemic therapy regimens can be individualized for
each patient, with the regimen determined by the clinician according to various patient
or gastric cancer-related conditions and participation in clinical trials can be actively
considered. A recent study conducted in Germany reported that patients' preferences
impacted the specific responses, including low toxicity of chemotherapy, self-care
ability, and additional survival benefits [172]. Therefore, patient preferences should
also be considered in making decisions regarding palliative therapy
Surgery
Statement 17. Palliative gastrectomy is not recommended for metastatic gastric cancer
except for palliation of symptoms (evidence level: high, recommendation: strong against).
Palliative surgery is usually indicated for metastatic gastric cancer for the control
of urgent symptoms such as obstruction, bleeding, or perforation. However, the effect
of palliative gastrectomy on the survival of patients with metastatic gastric carcinoma
has long been debated. Several retrospective studies have reported inconsistent results
depending on patient population and analytic methods. Some studies have reported significantly
improved patient survival for gastrectomy plus chemotherapy compared to chemotherapy
alone in carefully selected patients [173
174
175
176
177
178
179]. Some reports have suggested that patients with hepatic metastasis might benefit
from gastrectomy plus partial hepatectomy when no other distant metastasis existed
[180
181
182
183]. In contrast, other studies have reported that gastrectomy neither prolonged
patient survival nor improved the quality of life in patients with metastatic gastric
carcinoma [184
185
186
187
188
189
190
191]. Meanwhile, a meta-analysis of 14 retrospective studies showed that gastrectomy
followed by chemotherapy could significantly improve patient survival (median survival,
14.96 vs. 7.07 months; HR, 0.56; 95% CI, 0.39–0.80), compared to that for chemotherapy
alone [192]. Another meta-analysis of 19 non-randomized studies reported that gastrectomy
could improve patient survival (1-year survival: OR, 2.6; 95% CI, 1.7–4.3; P<0.001)
in metastatic gastric carcinoma [193]. However, these studies are mostly biased by
patient selection, in which surgery was usually indicated for patients with relatively
better performance status and less advanced disease.
To investigate the survival benefit of gastrectomy for metastatic gastric carcinoma,
a large international phase III trial was performed in Korea, Japan, and Singapore
(REGATTA trial) [194]. In this trial, 175 advanced gastric cancers with a single non-curable
factor (liver, peritoneum, or distant nodal metastasis) were randomly assigned to
receive gastrectomy plus chemotherapy or chemotherapy alone. The results of an interim
analysis revealed that gastrectomy prior to chemotherapy had no effect on OS (HR,
1.08; 95% CI, 0.74–1.58; P=0.66) or PFS (HR, 1.01; 95% CI, 0.74–1.37; P=0.96). Based
on these findings, this trial was interrupted in 2013, concluding that gastrectomy
did not show any survival benefit compared to that for chemotherapy alone in advanced
gastric carcinoma with a single non-curable factor.
In conclusion, although some retrospective studies have reported a possible survival
benefit of palliative gastrectomy for metastatic gastric carcinoma, a well-designed
multi-institutional randomized trial proved that gastrectomy does not improve patient
survival in metastatic gastric carcinoma. Therefore, gastrectomy should only be performed
with a palliative intent to relieve patient symptoms (Fig. 1).
First-line systemic therapy
Statement 18-1. Palliative first-line platinum/fluoropyrimidine combination is recommended
in patients with locally advanced unresectable or metastatic gastric cancer if the
patient's performance status and major organ functions are preserved (evidence: high,
recommendation: strong for).
The effective cytotoxic agents for advanced gastric cancer include infusional 5-FU,
oral fluoropyrimidines, platinum agents, taxanes, irinotecan, and anthracyclines.
Randomized studies have evaluated various 5-FU-based regimens for the treatment of
locally advanced unresectable or metastatic gastric cancer [195
196
197]. In a meta-analysis, significant OS benefits were shown for chemotherapy versus
best supportive care, with increased survival of approximately 6 months. In addition,
combination chemotherapy showed a statistically significant survival benefit over
single-agent chemotherapy, with a difference in weighted mean average survival of
approximately 1 month [198] (Fig. 4).
Fig. 4
Treatment algorithm for palliative systemic therapy.
HER2 = human epidermal growth factor receptor 2; XP = capecitabine and cisplatin;
FP = fluorouracil and cisplatin; IHC = immunohistochemistry.
*HER2 IHC 3+ or IHC 2+ and in situ hybridization-positive; †Evaluation of patient
performance status, comorbidities, and organ function.
Although infusional 5-FU is one of the most commonly used cytotoxic agents for advanced
gastric cancer, continuous intravenous infusions can prolong hospital stays and result
in thrombosis and infection. Randomized phase III studies have demonstrated that the
oral fluoropyrimidines capecitabine [199
200
201] and S-1 [202
203] are as effective as infusional 5-FU. Therefore, oral fluoropyrimidines (capecitabine
or S-1) are safe and convenient alternatives to 5-FU for combinations with platinum
compounds in patients with advanced gastric cancer. For many years, cisplatin was
the leading compound used for the treatment of patients with advanced gastric cancer.
To avoid some of the associated side effects such as nausea, vomiting, nephrotoxicity,
and ototoxicity, other platinum compounds were investigated. The results of the REAL-2
study suggested that pooled oxaliplatin-based regimens are not inferior to pooled
cisplatin-based regimens in terms of OS [199]. A randomized trial in Germany showed
that oxaliplatin had better efficacy than that of cisplatin in older adult patients
and a more favorable overall toxicity profile [204]. The G-SOX study in Japan and
the SOPP study in Korea showed that S-1 plus oxaliplatin is as effective as S-1 plus
cisplatin for the treatment of advanced gastric cancer, with a favorable safety profile
[205
206]. Therefore, oxaliplatin is at least as effective as cisplatin for prolonging
survival and is generally better tolerated.
Regarding combination therapies, it remains unclear if there is a benefit from combining
3 rather than 2 cytotoxic agents. The phase III V325 study showed an increased overall
response rate, PFS, and OS for docetaxel, cisplatin, 5-FU (DCF) compared to those
of cisplatin/5-FU [207]. However, the implementation of DCF is difficult in clinical
practice because the DCF regimen showed only a modest OS benefit (9.2 [DCF] vs. 8.6
months [CF]) but caused markedly increased hematological and gastrointestinal toxicity
in this highly selected study population, with a median age of 55 years. In various
clinical trials, modifications of this DCF regimen have demonstrated efficacy with
improved safety profiles in patients with advanced gastric cancer. Therefore, selected
patients can benefit from docetaxel-containing triplet combinations but increased
side effects should be considered (high, weak for).
Statement 18-2. Palliative trastuzumab combined with capecitabine or fluorouracil
plus cisplatin is recommended in patients with human epidermal growth factor receptor
2 (HER2) immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization (ISH)-positive
advanced gastric cancer (evidence: high, recommendation: strong for).
Trastuzumab is a humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody
and the first successful biologic agent, with documented clinical activity as a first-line
treatment in advanced gastric cancer (Fig. 4). The Trastuzumab for Gastric Cancer
(ToGA) trial demonstrated clinically and statistically significant improvements in
OS with the addition of trastuzumab to a cisplatin/fluoropyrimidine doublet (13.8
vs. 11.1 months; HR, 0.74; 95% CI, 0.60–0.91; P<0.01) [208]. A post hoc subgroup analysis
revealed that the addition of trastuzumab to chemotherapy substantially improved the
OS of patients whose tumors were IHC 3+ or ICH 2+ and ISH-positive (16.0 vs. 11.8
months; HR, 0.65; 95% CI, 0.51–0.83). Therefore, a trastuzumab-containing regimen
is recommended in patients with HER2-positive gastric cancer and a combination of
trastuzumab, cisplatin, and either capecitabine or infusional 5-FU is recommended
in clinical practice based on the results of this trial.
Various agents targeting epidermal growth factor receptor, hepatocyte growth factor
receptor, and vascular endothelial growth factor receptor (VEGFR) have been evaluated
as first-line treatments for advanced gastric cancer; however, except for trastuzumab,
none of these agents demonstrated a significant OS benefit in global phase III trials.
Second-line systemic therapy
Statement 19. Palliative second-line systemic therapy is recommended in patients with
locally advanced unresectable or metastatic gastric cancer if the patient's performance
status and major organ functions are preserved. Ramucirumab plus paclitaxel is preferably
recommended and monotherapy with irinotecan, docetaxel, paclitaxel, or ramucirumab
could also be considered (evidence: high, recommendation, strong for).
Randomized trials and a meta-analysis have demonstrated the survival benefit of second-line
palliative chemotherapy (with irinotecan or taxanes) compared to best supportive care
alone for patients with locally advanced unresectable or metastatic gastric cancer
(HR, 0.64; 95% CI, 0.52–0.79; P<0.001) [209
210
211
212] (Fig. 4). Weekly paclitaxel resulted in a similar OS to that achieved with irinotecan
in phase III trials [213
214]. In addition, ramucirumab, a monoclonal antibody targeting VEGFR-2, was shown
to significantly improve survival in 2 phase III double-blind placebo-controlled trials.
In the REGARD trial, patients receiving ramucirumab had improvements in both OS and
PFS compared to those in patients receiving placebo [215]. Similarly, in the RAINBOW
trial, the addition of ramucirumab to weekly paclitaxel significantly prolonged the
median OS (9.6 vs. 7.4 months; HR, 0.807; 95% CI, 0.678–0.962; P=0.017) compared to
that for paclitaxel plus placebo [216].
Based on the available data, ramucirumab in combination with paclitaxel is recommended
as the most preferred second-line treatment. Irinotecan, docetaxel, paclitaxel, or
ramucirumab as single agents can also be considered as a second-line option if not
previously administered in the first-line treatment.
Pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody, was recently approved
by the Food and Drug Administration (FDA) for the treatment of unresectable or metastatic
microsatellite instability-high (MSI-H) or deficient mismatch repair (MMR) solid tumors
that have progressed after initial treatments, thus representing a second-line or
later option for such gastric cancer cases [217].
Third-line systemic therapy
Statement 20. Palliative third-line systemic therapy is recommended in patients with
locally advanced unresectable or metastatic gastric cancer if the patient's performance
status and major organ functions are preserved (evidence: high, recommendation: strong
for).
Despite the lack of clear evidence for third-line cytotoxic chemotherapy, data from
several phase II and retrospective studies indicate a 15%–20% response rate with third-line
taxane- or irinotecan-based chemotherapy [218
219
220] (Fig. 4). In a randomized phase III trial in Korea, second- or third-line salvage
chemotherapy significantly prolonged patient survival compared to that for best supportive
care [210]. Therefore, palliative third-line chemotherapy with cytotoxic agents (e.g.,
irinotecan, paclitaxel, or docetaxel) not used in second-line therapy can be recommended
(moderate, strong for). Recently, a phase III study of patients with metastatic gastric
cancer refractory to standard therapies showed a benefit in terms of OS with TAS-102
(trifluridine/tipiracil) compared to that for best supportive care [221]. TAS -102
can be considered if it is approved for use in gastric cancer (high, weak for).
In a randomized phase III trial, apatinib mesylate, a small-molecule inhibitor of
VEGFR-2, significantly prolonged the survival of patients who experienced disease
progression after 2 or more lines of systemic therapy [222]. However, with an increasing
number of patients receiving ramucirumab in the second-line setting, the efficacy
of apatinib mesylate in overcoming resistance to ramucirumab is unclear. Moreover,
the only results with apatinib mesylate have been reported among Chinese patients;
therefore, additional studies are needed to confirm these results (high, weak for).
Recently, immune checkpoint inhibitors have been shown to enhance antitumor T-cell
activity via inhibition of the PD-1 receptor. Nivolumab is a humanized IgG4 anti-PD-1
monoclonal antibody. ATTRACTION-2 (ONO-4538-12), the first phase III trial of third-line
or later nivolumab versus placebo, showed the efficacy and safety of nivolumab in
heavily pretreated patients with advanced gastric cancer (median OS, 5.26 vs. 4.14
months; HR, 0.63; 95% CI, 0.51–0.78; P<0.001) [223]. Another such antibody, pembrolizumab,
also showed promising activity and manageable safety in advanced gastric cancer patients
who had received at least 2 lines of treatment in a phase Ib trial (KEYNOTE-012) (8)
as well as a phase II trial (KEYNOTE-059; cohort 1), in which the overall response
rates trended higher in PD-L1-positive versus PD-L1-negative tumors [224
225]. Nivolumab improves OS as third-line treatment irrespective of PD-L1 status in
Asian patients with gastric cancer and is registered in Korea, Japan, and Taiwan (high,
strong for). Pembrolizumab shows significant efficacy as a third-line treatment, especially
in PD-L1-positive patients in whom its use is approved by the US FDA (moderate, weak
for).
Radiotherapy (RT)
Statement 21. Palliative RT could be offered to alleviate symptoms and/or improve
survival in recurrent or metastatic gastric cancer (evidence: moderate, recommendation:
weak for).
Systemic chemotherapy is the mainstay treatment for the management of recurrent or
metastatic gastric cancer, even for isolated LRR [50]. However, the addition of local
modalities including RT may add a benefit over chemotherapy alone in certain situations
[226
227
228
229
230
231].
Unfortunately, no prospective randomized phase III trial has evaluated the efficacy
of adding RT in recurrent or metastatic gastric cancer. However, successful symptom
alleviation has been reported with the addition of RT in symptomatic advanced gastric
cancer [228
229
230] and prolongation of survival is suggested according to the results of several
prospective and retrospective reports [226
227
228
231]. Tey et al. [230] reported improvement of symptoms such as tumor bleeding (83/103,
80.6%), obstruction (9/17, 52.9%), and pain (5/11, 45.5%) after RT, with an acceptable
rate (2.6%) of grade 3 gastrointestinal toxicities [230]. Sun et al. [228] reported
that clinical symptoms were relieved after RT in 19 of 21 patients (90.5%) with recurrent
gastric cancer with abdominal LN metastasis. Hingorani et al. [227] reported the outcomes
of a retrospective study comparing chemotherapy followed by RT to primary tumor and
chemotherapy alone in metastatic EGJ cancer patients with responding or stable disease
after 3 months of chemotherapy. Both OS and time to local progression were significantly
improved in irradiated patients, at 23.3 vs. 14.0 months (P<0.001) and 17.3 vs. 8.3
months (P=0.006), respectively.
Despite a lack of evidence from randomized phase III trials on the efficacy of RT
in recurrent or metastatic stomach cancer, RT could be used for palliation of symptoms
in localized primary and/or metastatic disease and could possibly improve survival
by maximizing local control in patients with responding or stable disease after chemotherapy
(Fig. 1). The efficacy and necessity of RT in recurrent or metastatic stomach cancer
should be evaluated in larger studies.
PATHOLOGY
This guideline only describes in detail several pathological topics important to gastric
cancer treatment. For topics not described here, please refer to the existing guidelines
[2
232].
Histologic classification
World Health Organization (WHO) classification is used for the pathologic classification
of gastric carcinoma [233]. Lauren classification is added in resected specimens,
including ESD specimens [234].
WHO classifications
1) Papillary adenocarcinoma
Although the diagnostic criteria for papillary carcinoma are not clearly defined in
the 2010 WHO Blue Book, many publications define papillary carcinoma as more than
50% of the tumor present in the papillary [235]. Papillary adenocarcinoma is graded
as well, moderately, or poorly differentiated [233]. Most papillary adenocarcinomas
are well-differentiated. However, the prognosis is poor if the nuclear atypia is severe
[236]. Therefore, such cases should be classified as poorly differentiated.
2) Tubular adenocarcinoma
Tubular adenocarcinoma, the most common histologic type of gastric carcinoma, is graded
as well, moderately, or poorly differentiated. Well-differentiated tubular adenocarcinoma
is composed of well-formed tubular structures. Poorly differentiated adenocarcinoma
shows irregular glands with indistinct lumens. Moderately differentiated adenocarcinomas
are intermediate between well- and poorly differentiated [233].
3) Mucinous adenocarcinoma
This variant of adenocarcinoma is defined by the presence of >50% of tumor lesions
with an extracellular mucin pool regardless of the tumor cell type, signet ring cell
or not [233].
4) Poorly cohesive carcinoma
This tumor is composed of poorly cohesive neoplastic cells that are isolated or form
small aggregates [233]. This type includes signet ring cell carcinoma and other cellular
variants composed of poorly cohesive neoplastic cells [233]. However, signet ring
cell carcinoma is usually diagnosed separately if the signet ring cell component exceeds
50% rather than diagnosed as poorly cohesive carcinoma.
5) Mixed carcinoma
This type of carcinoma has a discrete mixture of both glandular (tubular or papillary)
and signet ring/poorly cohesive components [233]. The latter component is associated
with a poor prognosis [233].
Addendum: In Japan, gastric carcinomas are commonly divided into 2 major categories,
differentiated and undifferentiated types, especially with respect to the indications
for endoscopic resection [237
238]. Although the WHO classifications do not completely match to this classification,
the differentiated type generally includes well and moderately differentiated tubular
adenocarcinomas and papillary adenocarcinoma, while the undifferentiated type includes
poorly differentiated tubular adenocarcinoma and poorly cohesive carcinoma. Mucinous
adenocarcinoma is classified as differentiated (with tubules) or undifferentiated
(with signet ring cells) according to the type of tumor cell and is sometimes also
categorized as undifferentiated type.
Lauren classifications
The Lauren classification divides tumors into intestinal, diffuse, and mixed types
[234]. Intestinal carcinomas form glands with various degrees of differentiation and
are almost invariably associated with intestinal metaplasia and variable degrees of
atrophic gastritis. Diffuse carcinoma consists of poorly cohesive cells with little
or no gland formation. Tumors containing approximately equal quantities of intestinal
and diffuse components are termed “mixed.”
Pathologic diagnosis of mixed histology
In early gastric cancer, the histologic type and grade of the biopsy tissue are important
for determining the treatment modality. Tumor heterogeneity and inter- and intra-observer
discrepancies may lead to differences in histological types before and after ESD [239
240
241]. Submucosal and even intramucosal cancer with heterogeneity have recently been
reported to have a higher incidence of LN metastasis than that of homogeneously differentiated
types of tumor [242
243]. Thus, there is a view that the minor component of undifferentiated histology
should be reported in cases of biopsy and ESD specimens. However, this requires more
discussion and consensus of clinical and pathologic departments.
Biomarkers
HER2
IHC tests should first be performed for evaluation of HER2 status. IHC results are
scored as 0, 1+, 2+, or 3+ (Table 4). IHC 3+ is considered positive for HER2 overexpression,
while IHC 0-1+ is considered negative. IHC 2+ is regarded as an equivocal finding
and should be followed by ISH tests. The area with the strongest IHC intensity should
be selected and stained for HER2 and chromosome enumeration probe (CEP) 17. The criteria
for HER2 amplification is a HER2:CEP17 ratio of ≥2. If CEP17 polysomy is present and
the ratio is <2, an average HER2 signal of >6 is interpreted as a positive finding.
IHC 3+ or IHC 2+ and ISH-positivity are considered HER2-positive [244
245]. HER2-positivity is an indication for anti-HER2 targeted therapy in the palliative
setting [208].
Table 4
Interpretation of IHC findings [244
245]
HER2 status
Intensity
IHC staining
Negative
0
Reactivity in <10%* of tumor cells
Negative
1+
Faint membranous† reactivity in ≥10% of tumor cells; reactive only in part of their
membrane
Equivocal
2+
Weak to moderate complete or basolateral membranous reactivity in ≥10% of tumor cells
Positive
3+
Strong complete or basolateral membranous reactivity in ≥10% of tumor cells
IHC = immunohistochemistry; HER2 = human epidermal growth factor receptor 2.
*For biopsy samples, measure scores when stained tumor cell clusters (≥5 cells) are
present, irrespective of the percentage of tumor cells; †Only membranous staining
should be considered true reactivity.
Microsatellite instability (MSI)
MSI is assessed by polymerase chain reaction (PCR)-based tests, which can be replaced
by IHC tests for the 4 MMR proteins (MMR deficient [dMMR]) [246
247]. Instability is examined by PCR of a representative panel of microsatellites.
The grade of the instability is determined by the numbers of unstable microsatellites:
MSI-H, MSI-low (MSI-L), or microsatellite stable (MSS) [248
249]. MSI-H is considered MSI-positive. In the IHC method, the IHC staining is done
for the 4 MMR proteins: MLH1, MSH2, PMS2, and MSH6. When the expression of any one
of the MMR proteins is lost, the case is considered to be dMMR. MSI positivity is
the criteria for MSI-subtype gastric cancer. MSI-positive gastric cancer is classified
as a separate subtype in the molecular classifications of gastric cancer and shows
elevated mutation rates and distinctive patterns of methylation [250
251]. This subtype has unique clinical characteristics, including distal location,
high frequency of intestinal-type histology, lower stage, and good prognosis [252].
In the palliative setting, MSI positivity is an indication for immune checkpoint inhibitor
therapy (pembrolizumab) [253].
Epstein-Barr virus (EBV)
The presence of the EBV genome can be examined by several methods. The most widely
used method for tissue sections, performed in almost all hospitals, is ISH to EBV-encoded
RNA (EBER) [254]. When signals in the tumor cell nuclei are observed, the case is
considered to be EBV-positive gastric cancer. EBV positivity is the criteria for EBV-positive
gastric cancer. EBV-positive gastric cancer is classified as a separate subtype in
the molecular classification of gastric cancer and shows hypermethylation different
from that of the MSI subtype [250]. This subtype is distinct in its proximal location,
relation to poorly differentiated histology, lower stage, and good prognosis [255
256].
PD-L1
Several systems can be used for the interpretation of IHC staining of PD-L1. The combined
positive score (CPS) [224] is the number of PD-L1-stained viable tumor cells, lymphocytes,
and macrophages divided by the number of viable tumor cells, multiplied by 100. Lymphocytes
or macrophages are scorable when they are contiguous: intercalated within a confluent
area of neoplastic cells or a part of a confluent area adjacent to neoplastic cells
(within a 20× field) [257]. The tumor proportion score (TPS) is the percentage of
viable tumor cells showing partial or complete membrane staining at any intensity
[258]. The criteria for PD-L1 positivity differs depending on the therapeutic agent.
For pembrolizumab, PD-L1 positivity is defined as CPS ≥1. In a clinical trial that
enrolled 259 patients, the objective response rates were 15.5% and 6.4% in patients
with CPS ≥1 and <1, respectively [225]. For nivolumab, the cut-off for PD-L1 expression
has not been established. In a clinical trial, an exploratory subgroup analysis was
performed with a TPS of >1% vs. ≤1% but the median survival increased regardless of
PD-L1 level [223].
Peritoneal washing cytology
Statement 22. Peritoneal washing cytology is recommended for staging. Advanced gastric
cancer patients with positive cancer cells in the peritoneal washing cytology are
associated with frequent cancer recurrence and poor prognosis (evidence: moderate,
recommendation: strong for).
The association between peritoneal washing cytology results and prognosis in patients
with advanced gastric cancer has been reported in prospective [259
260] and retrospective [261
262
263
264] studies but not in any randomized case-control studies. The exact prognostication
of advanced gastric cancer patients with positive peritoneal washing cytology result
is difficult due to variability in enrolled patients, peritoneal washing methods,
and treatment of cancer patients in these studies. Recent systemic reviews and meta-analyses
have shown that peritoneal washing cytology is useful for determining the prognosis
of advanced gastric cancer patients [265
266
267
268].
Although some studies have reported that peritoneal washing cytology results are not
related to prognosis, most studies and meta-analyses have observed a high recurrence
rate and short survival time in advanced gastric cancer patients with positive washing
cytology. In 2 meta-analyses, the HRs for survival among cytology-positive patients
were 3.27 (95% CI, 2.82–3.78) [267] and 3.46 (95% CI, 2.77–4.31) [265], respectively,
which was significantly higher than those for cytology-negative patients. The HR of
cancer recurrence (4.15; 95% CI, 3.10–5.57) was also higher in cytology-positive patients
[267].
The positivity rate of peritoneal washing cytology varies from 7% to 58% [259
260
261
263
264
265
267]; this range may be due to differences in the study populations, including early
gastric cancer patients. The diverse pathologic criteria of positive cancer cells
could also contribute to the wide range of positivity. Although most of the studies
did not address the pathologic criteria for ‘positive’ cancer cells in peritoneal
washing cytology, there is a need for further studies to establish these pathologic
criteria for the clinical application of peritoneal washing cytology in advanced gastric
cancer patients.
In conclusion, peritoneal washing cytology is recommended for accurate staging and
prognosis for advanced gastric cancer even though there remain several controversies.
MULTIDISCIPLINARY TEAM (MDT)APPROACH
The effectiveness of MDTs in cancer treatment has been controversial because there
was no strong evidence and MDT also requires significant time and resources [269
270]. However, MDT has been important for the treatment of cancer because treatment
methods are diverse, complex, and specialized. The advantages of MDT include correct
diagnosis, changing to a better treatment plan, and survival benefit. For these reasons,
health services in several countries have produced guidelines citing MDTs as the preferred
system for cancer treatment [271].
Several studies have shown the advantages of MDT in gastrointestinal malignancy. After
MDT meetings, changes in diagnosis occurred in 18.4%–26.9% of evaluated patients [272
273], and the treatment plan was changed in 23.0%–76.8% of cancer patients [273
274
275]. Furthermore, the National Comprehensive Cancer Network guideline emphasizes
the recommendation for MDT and the European Society for Medical Oncology and European
Cancer Organization guidelines indicate that MDT before determining cancer treatment
is mandatory [61
62
276].
The many types of MDT include conferences the without patient present, face-to-face
with the patient, and telemedicine. There is no strong evidence regarding which type
is better, although Kunkler et al. [277] reported no difference between telemedicine
and face-to-face medicine. In addition, Allum et al. [61] recommended that MDTs should
discuss treatment decisions with patients. The MDT members for gastric cancer treatment
are recommended to include surgeons, gastroenterologist, medical and radiation oncologists,
radiologists and pathologists, and other members such as those from nutritional services,
social workers, nurses, and palliative care specialists [62
276
278
279].
In conclusion, MDT treatment has a benefit in the treatment of gastric cancer patients
regarding patient satisfaction, change to better treatment plans, and more correct
diagnosis; however, stronger evidence is required.
ACKNOWLEDGMENTS
Members of the Guideline Committee
Development Working Group
Korean Gastric Cancer Association: Keun Won Ryu (National Cancer Center), Young Suk
Park (Seoul National University Bundang Hospital), Oh Kyoung Kwon (Kyungpook National
University Chilgok Hospital), Jeong Oh (Chonnam National University Hwasun Hospital),
Han Hong Lee (The Catholic University of Korea Seoul St. Mary's Hospital), Seong Ho
Kong (Seoul National University Hospital), Taeil Son (Severance Hospital), Hoon Hur
(Ajou University Hospital), Ye Seob Jee (Dankook University Hospital), Hong Man Yoon
(National Cancer Center); Korean Society of Gastroenterology: Changyoo Kim (National
Cancer Center), Byung-Hoon Min (Samsung Medical Center), Ho-june Song (Asan Medical
Center), Woon Geon Shin (Kangdong Sacred Heart Hospital), Sang Kil Lee (Severance
Hospital), Jae-Young Jang (Kyung Hee University Hospital), Hye-kyung Jung (Ewha Womans
University Mokdong Hospital); Korean Society of Medical Oncology: Min-Hee Ryu (Asan
Medical Center), Sun Jin Sym (Gachon University Gil Medical Center), Sangcheul Oh
(Korea University Guro Hospital), Byoung Yong Shim (Catholic University of Korea St.
Vincent's Hospital), Dae Young Zang (Hallym University Sacred Heart Hospital), Hye
Sook Han (Chungbuk National University Hospital), Dong-Hoe Koo (Kangbuk Samsung Hospital),
Hyeong Su Kim (Hallym University Kangnam Sacred Heart Hospital), Chi Hoon Maeng (Kyung
Hee University Hospital), In Gyu Hwang (Chung-Ang University Hospital); Korean Society
for Radiation Oncology: Jeong Il Yu (Samsung Medical Center), Eui Kyu Chie (Seoul
National University Hospital); Korean Society of Pathologists: Joon Mee Kim (Inha
University Hospital), Baek-Hui Kim (Korea University Guro Hospital), Myeong-Cherl
Kook (National Cancer Center), Hye Seung Lee (Seoul National University Bundang Hospital);
National Evidence-Based Healthcare Collaboration Agency: Miyoung Choi.
Review Panel
Korean Gastric Cancer Association: Chan-Young Kim (Chonbuk National University Hospital),
Sungho Jin (Korea Institute of Radiological and Medical Sciences); Korean Society
of Gastroenterology: Jae Myung Park (Seoul St. Mary's Hospital), Cheol Min Shin (Seoul
National University Bundang Hospital); Korean Society of Medical Oncology: Do-Youn
Oh (Seoul National University Hospital), Keun-Wook Lee (Seoul National University
Bundang Hospital); Korean Society for Radiation Oncology: Tae-Hyun Kim (National Cancer
Center); Korean Society of Pathologists: Kyoung-Mee Kim (Samsung Medical Center).