Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 436 - файл
.pdf
124 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
Socioeconomic Status
Risk of gastric cancer is associated with socioeconomic status.
Subjects from lower socioeconomic classes had approximately
twice as high a risk of developing intestinal-type gastric cancer
as subjects from higher socioeconomic groups (Barker et al.
1990; Berndt et al. 1968; Haenszel 1958; Wynder et al. 1963).
On the contrary, proximal gastric cancers were associated with
higher socioeconomic class (Powell and McConkey 1990).
Gastric Surgery
There is an increased risk of gastric cancer after gastric surgery,
with the risk being greatest 15–20 years after surgery and then
increasing with time (Neugut et al. 1996; Nomura 1996). The
Bilroth II procedure (gastrojejunostomy) carries a higher risk
than the Bilroth I (gastroduodenostomy). It is thought this is due
to the greater regurgitation of bile and pancreatic juice in the
former procedure, leading to postoperative gastritis. Although
still controversial, in the majority of cases gastric ulcers are not
related to the eventual formation of gastric cancer.
Epstein-Barr Virus
The Epstein-Barr virus (EBV) is associated with a number of
malignancies, especially nasopharyngeal carcinoma. It has
been suggested that it might play a role in the development of
gastric cancer also. In a study conducted in Korea (Shin et al.
1996), evidence of EBV was found in the tumor cells of 12 of 89
(13.5%) gastric carcinoma patients, whereas EBV was found in
none of the gastric tissues of 37 controls with benign ulcer disease, nor in any of the benign tissues of the cases. Some of the
tumor cells had a histologic appearance similar to nasopharyngeal carcinoma. In addition, EBV-associated lymphoepithelioma-like carcinoma constitutes approximately 5% of gastric
cancer cases (Naseem et al. 2018).
Diabetes Mellitus
A meta-analysis of 17 observational studies showed that
diabetes mellitus (DM) is associated with a 19% higher gastric
cancer risk (Yoon et al. 2013). This risk persisted even after H.
pylori eradication particularly in those with HbA1c ≥6.0%
and with a more pronounced effect on cardia cancer (Cheung
et al. 2019). Possible mechanisms include stimulation of cell
proliferation via increased production of insulin and insulingrowth factor (IGF), promotion of angiogenesis by increasing
vascular endothelial growth factor (VEGF), DNA damage by
hyperglycemia and its indirect effect through an increased
production of reactive oxygen species as well as its association
with obesity and gastroesophageal reflux disease (GERD)
(Cheung et al. 2021).
Pharmacological Agents in the Modification
of Gastric Cancer Risk
Emerging evidence has shown that certain medications may
modulate gastric cancer risk, including proton pump inhibitors
(PPIs), aspirin, statins, and metformin. PPIs can worsen atrophic
gastritis via profound acid suppression, (Kuipers et al. 1996) particularly in H. pylori-infected subjects (Cheung and Leung 2019;
Lundell et al. 2015). The resultant increase in gastrin, which has
trophic effect on the gastric mucosa, stimulates enterochromaffin-like cell hyperplasia (Lundell et al. 2015). Acid suppression
also leads to non-H. pylori bacterial overgrowth in the stomach,
which act synergistically on inducing proinflammatory cytokines (interleukin [IL]−1 beta and IL-8) and hence atrophic gastritis (Cheung and Leung 2019). There is also proliferation of
non-gastric micro-organisms (mostly oral flora) that produce
gastric carcinogens (N-nitroso compounds) from food nitrates
via nitrate reductase (Jakszyn et al. 2006). It has been shown that
PPIs are associated with a 2.5-fold higher gastric cancer risk
(Salvo et al. 2021), and the risk persists even after H. pylori eradication (Cheung et al. 2018). However, the causality remains controversial as this is mainly based on observational studies.
Aspirin and statins are inexpensive medications for treating
and preventing cardiovascular diseases. Meta-analyses reported
36% and 32% lower risks of gastric with use of aspirin (Bosetti
et al. 2020) and statins (Singh and Singh 2013) respectively, and
the chemopreventive effects remain even after H. pylori eradication (Cheung et al. 2018; Cheung et al. 2020). As for COX-2
inhibitors, one study revealed that use of rofecoxib for two years
did not regress intestinal metaplasia or its severity in H. pylorieradicated subjects (Leung et al. 2006), while another study
showed that use of celecoxib for two years was only able to regress
advanced gastric lesions in H. pylori-infected but not those with
H. pylori eradication (Wong et al. 2012). Regular nonsteroidal
anti-inflammatory drug (NSAID) use was associated with a 20%
lower gastric cancer in a nationwide cohort study (Wu et al. 2010).
Among patients with DM, metformin was associated with a 24%
lower risk of gastric cancer, (Zhou et al. 2017) with protective
effect even after H. pylori eradication (Cheung et al. 2019).
Imaging and Staging
Imaging
Computed tomography (CT) of the chest, abdomen and pelvis
have been recommended as the minimal required preoperative
tests for gastric cancer by the National Comprehensive Cancer
Network (NCCN) (National Comprehensive Cancer Network
metastatic disease is seen on CT. The major limitations of CT as
a staging study are in the evaluation of small lesions, including
early gastric tumors and peritoneal or liver metastases smaller
7 INTESTINAL-TYPE GASTRIC CANCER 125
https://t.me/medicina_free
than 5 mm (Davies et al. 1997; Kim et al. 2009). Another limitation is its inability to assess the depth of tumor invasion accurately (accuracy ranging from 50–70% (Davies et al. 1997;
Minami et al. 1992), typically for more advanced diseases) and
the presence of lymph node metastasis particularly for nodes
< 0.8 cm (Davies et al. 1997; Düx et al. 1999). Nevertheless, both
over staging due to incorrect estimation of depth of invasion or
false positivity of lymph node involvement attributed to
inflammatory lymphadenopathy may occur. EUS has been
regarded the most reliable nonsurgical modality to evaluate the
depth of gastric invasion; this is particularly relevant when considering endoscopic resection. The sensitivity and specificity for
distinguishing between T1 and T2 cancers with EUS were 85%
and 90%, respectively, while the sensitivity and specificity for distinguishing between T1/2 and T3/4 tumors were 86% and 90%,
respectively (Mocellin and Pasquali 2015). For assessment of
lymph node metastasis, the sensitivity and specificity rate were
83% and 67%, respectively. EUS is better than CT at assessing the
T stage and N stage (Botet et al. 1991), in particular when fineneedle aspiration (FNA) is also performed (Chang et al. 1994).
Nonetheless, newer CT techniques (such as multidetector row
CT [MDCT]) and magnetic resonance imaging (MRI) may have
similar diagnostic performance in terms of T staging (Kwee and
Kwee 2007). The combination of 18-fluorodeoxyglucose (FDG)PET/CT imaging also improves the accuracy of preoperative
staging compared with PDG-PET or CT alone (68% vs 47% vs
53% respectively) (Rosenbaum et al. 2006).
Laparoscopy is also recommended prior to chemoradiation
and/or surgery. The use of laparoscopy may be supported by
the fact that an R0 resection cannot be performed on 30–40%
of patients undergoing surgery. Distant metastasis has been
detected in patients in whom CT did not reveal signs of unresectability (Lowy et al. 1996; O’Brien et al. 1995).
Intraperitoneal disease (including positive peritoneal washings) is found in 20–30% of CT-negative cases upon staging
laparoscopy (Feussner et al. 1999; Lowy et al. 1996).
Laparoscopy identifies CT-occult metastatic disease in
23–37% of patients (Burke et al. 1997; D’Ugo et al. 1997;
Charukhchyan and Lucas 1998; Feussner et al. 1999; Possik
et al. 1986; Stell et al. 1996). Moreover, fewer than 2% of the
patients in these reports required subsequent laparotomy for
palliation. Limitations of laparoscopy in the staging of gastric
cancer include the following: (i) the technique allows for only
two dimensional inspection of the surface of the liver and
peritoneal cavity, (ii) it does not allow palpation, limiting the
identification of small intraparenchymal hepatic metastases
and perigastric lymph nodes; and (iii) laparoscopic inspection
of the peritoneal surfaces does not allow critical tumor-vessel
relationships to be accurately evaluated. Laparoscopic ultrasonography has been proposed as a means of overcoming
some of these limitations and improving the diagnostic yield
(Conlon and Karpeh 1996).
Staging
The two main staging systems for gastric cancer are the TNM
staging system developed jointly by American Joint Committee
on Cancer (AJCC) and International Union Against Cancer
(UICC), and the Japanese Classification of Gastric Carcinoma
by the Japanese Gastric Cancer Association (JGCA). The two
systems are similar in that staging is dependent on the extent of
the primary tumor, the extent of lymph node involvement, and
the presence or absence of distant metastasis. But the difference
between the two systems lies in the classification of regional
lymph node spread. The AJCC/UICC TNM staging system
divides N stage on the basis of the number of metastatic lymph
nodes, while the Japanese classification stresses the location of
involved nodes. The current main classification systems for
gastric cancer are the 8th edition of the AJCC/UICC TNM
classification (2017) (Table 1) (Amin et al. 2017), and the third
English edition of the Japanese classification of gastric carcinoma (Japanese classification of gastric carcinoma 2011). It is
important to note that gastroesophageal junction tumors with
their epicenter located > 2 cm into the proximal stomach are
now staged as stomach cancers in the AJCC/UICC staging.
Based on TNM staging criteria, the depth of invasion (T),
presence of lymph node metastases, and number of lymph
nodes involved (N) predict the risk of relapse. The AJCC/UICC
TNM staging classification includes different prognostic stage
entities for clinical (cTNM; patients newly diagnosed with cancer without treatment) and pathologic (pTNM; patients undergoing resection without preoperative treatment) staging
including post-neoadjuvant therapy (ypTNM; patients
receiving preoperative treatment) (Table 2). It is noteworthy to
mention that the cTNM and ypTNM staging are newly introduced. The clinical staging was based on the National Cancer
Database (NCDB) involving patients treated either surgically
or nonsurgically in the United States, and Shizuoka Cancer
Center dataset involving patients undergoing surgery in Japan
(n=4,091). The performance was externally validated in a
cohort of 4,374 surgically treated patients in Japan (Bando et al.
2019). The pathologic staging was based on International
Gastric Cancer Association (IGCA) database involving >25,000
gastric cancer patients who had surgery with adequate lymph
node dissection from both Asia and the West (84.8% came
from Japan and Korea) (Sano et al. 2017). This was validated in
a large study based on the National Cancer Database in the
United States (In et al. 2017) and cohort with a higher
proportion of advanced disease in Taiwan (Huang et al. 2018).
For the TNM yp staging, it was based on 700 patients only and
therefore only four broad staging categories (stage I–IV) are
presented. By contrast, the JGCA classification is much more
than a staging system. It provides comprehensive and meticulous guidance to surgeons because it describes in detail the anatomical involvement of lymph nodes.
126 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
Category Criteria
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ; intraepithelial tumor without
invasion of the lamina propria, high-grade dysplasia
T1 Tumor invades lamina propria, muscularis mucosae, or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor penetrates subserosa without
T4 Tumor invades serosa (visceral peritoneum) or adjacent structures
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures/organs
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastases in 1–2 lymph nodes
N2 Metastases in 3–6 lymph nodes
N3 Metastases in ≥ 7 lymph nodes
N3 Metastases in 7–15 lymph nodes
N3 Metastases in ≥ 16 lymph nodes
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Table 1 TNM classification of carcinoma
of the stomach. (Adapted from Palis et.al.,
2017).
Treatment
Endoscopic Mucosal Resection (EMR) and
Endoscopic Submucosal Dissection (ESD)
Therapeutic endoscopy in gastric cancer offers minimally
invasive procedures that aim at complete cancer removal in
early gastric cancer (EGC), which is defined as a tumor confined to the mucosa (T1a) or submucosa (T1b), irrespective of
lymph node metastasis. More EGC is detected in the East than
the West as a result of population-based screening programs
(Chan et al. 2019). Patients with Tis or T1a tumors may be
considered for EMR or endoscopic submucosal dissection
(ESD) in experienced centers (National Comprehensive
Cancer Network (NCCN)). For differentiated-type T1
mucosal cancers, endoscopic resection is often successful, as
metastasis does not generally occur (Gotoda et al. 2000).
However, it should be highlighted that lymph node metastasis
may still occur in a small proportion of patients with EGC
(Gotoda 2006).
General criteria of eligibility for endoscopic resection are
2 cm without ulceration, moderately to well differenti-
size ≤
ated adenocarcinoma, confinement to mucosa and absence of
lymphovascular invasion or lymph node involvement
(Japanese gastric cancer treatment guidelines 2014, 2017; Ono
et al. 2016; Smyth et al. 2016). Expansion of criteria have been
proposed for some experienced centers (Japanese gastric cancer treatment guidelines 2014, 2017; Lee et al. 2018). The 5and 10-year survival rates after EMR for early gastric cancer
were 84% and 64% in one study (Uedo et al. 2006). ESD allows
en bloc resection of larger tumors that can be treated with
EMR, resulting in complete resection and lower local recurrence of early gastric cancer (Facciorusso et al. 2014; Zhao and
Wang 2018). The three-year recurrence-free rate was higher in
the ESD versus EMR group (98% vs 93% respectively) in a
multicenter study (Oda et al. 2006). Complications of EMR
and ESD include pain, bleeding, perforation, and stricture
formation. Bleeding is the most common complication and is
typically minor and treatable with endoscopy. The perforation
rate is higher for ESD when compared with EMR, while
7 INTESTINAL-TYPE GASTRIC CANCER 127
https://t.me/medicina_free
Table 2 Clinical, pathological and post-neoadjuvant therapy staging of
carcinoma of the stomach. (Adapted from Palis et.al., 2017).
TNM staging classification
Clinical staging (cTNM)
cT cN M
Stage 0 Tis N0 M0
Stage I T1 N0 M0
T2 N0 M0
Stage IIA T1 N1, N2,, or N3 M0
T2 N1, N2 or N3 M0
Stage IIB T3 N0 M0
T4a N0 M0
Stage III T3 N1, N2, or N3 M0
T4a N1, N2, or N3 M0
Stage IVA T4b Any N M0
Stage IVB Any T Any N M1
Pathological staging (pTNM)
p
T pN M
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T1 N1 M0
T2 N0 M0
Stage IIA T1 N2 M0
T2 N1 M0
T3 N0 M0
Stage IIB T1 N3a M0
T2 N2 M0
T3 N1 M0
T4a N0 M0
Stage IIIA T2 N3a M0
T3 N2 M0
T4a N1 or N2 M0
T4b N0 M0
Stage IIIB T1 N3b M0
T2 N3b M0
T3 N3a M0
T4a N3a M0
T4b N1 or N2 M0
Stage IIIC T3 N3b M0
T4a N3b M0
T4b N3a or N3b M0
Stage IV Any T Any N M1
Post-neoadjuvant therapy
staging (ypTNM)
T ypN M
yp
Stage I T1 N0 M0
T2 N0 M0
T1 N1 M0
Stage II T3 N0 M0
T2 N1 M0
T1 N2 M0
T4a N0 M0
(Continued)
Table 2
Post-neoadjuvant therapy
staging (ypTNM)
ypT ypN M
T3 N1 M0
T2 N2 M0
T1 N3 M0
Stage III T4a N1 M0
T3 N2 M0
T2 N3 M0
T4b N0 M0
T4b N1 M0
T4a N2 M0
T3 N3 M0
T4b N2 M0
T4b N3 M0
T4a N3 M0
Stage IV Any T Any N M1
bleeding risk is not significantly different (Facciorusso et al.
2014; Zhao and Wang 2018).
Laparoscopic Gastrectomy
Laparoscopic gastrectomy is intermediate between EMR and
conventional surgery in terms of invasiveness. With the
advances in instruments and techniques, lymph node dissection becomes possible laparoscopically and thus enables curative resection even when there is lymph node involvement.
Compared with conventional open surgery, laparoscopic gastrectomy is reported to have several benefits for patients,
including less blood loss, less pain, less inflammatory response,
faster recovery including gastrointestinal function, preserved
postoperative immune function, shorter hospital stay, reduced
medical costs, and better QOL, while there is no difference in
operative time, number of lymph nodes harvested, postoperative mortality and five-year overall survival (Adachi et al. 1999;
Adachi et al. 2000; Adachi et al. 2002; Asao et al. 2001; Fujii
et al., 2003; Migoh et al. 2003; Mochiki et al. 2002; Shimizu
et al. 2000; Weber et al. 2003; Wei et al. 2018). Favorable results
have been reported from several RCTs of relatively large sample
size (ranging from 921 to 1416) being conducted in Asia
including China, Japan and Korea (Katai et al. 2020; Kim et al.
2019; Yu et al. 2019). One RCT of much smaller sample size
have been conducted in the West (Facciorusso et al. 2014), and
another one is still ongoing (Straatman et al. 2015).
Robotic Surgery
Robotic gastric surgery has emerged to be an alternative
minimally invasive surgical technique, although it is still not
widely established. It has the merits of three-dimensional
128 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
high-definition visualization, fine articulated movements and
enhanced ergonomics. Compared with laparoscopic surgery,
except for a longer operative time, robotic surgery has been
reported to be associated with less blood loss, greater yield of
lymph nodes, shorter hospital stay, similar postoperative morbidity and mortality (Hu et al. 2016).
Surgery with Intent to Cure: R0 Resection
R0 resection refers to surgery with intent to cure, while R1 resection refers to surgery with microscopic positive resection margin
in the absence of distant metastasis (Hermanek and Wittekind
1994). Partial and total gastrectomy have been compared in two
multicenter RCTs, (Bozzetti et al. 1999; Gouzi et al. 1989) showing no significant difference in surgical outcome but significantly
fewer complications for partial gastrectomy. Therefore, partial
gastrectomy is adequate for patients with gastric cancer located
in the distal half of the stomach, allowing a proximal resection
margin of 6 cm. The margin has to be verified by frozen section.
However, a number of controversies exist over other aspects of
surgical management of gastric cancer. First, the debate continues for proximal gastric cancer. Compared with total gastrectomy, proximal gastrectomy is found to improve nutrition status
without compromising short-term surgical and oncologic outcomes (Tanioka et al. 2020), although larger-size studies with
longer follow-up are still warranted.
The second and more important controversy is the extent of
lymph node dissection. A D1 resection entails a gastrectomy
with the removal of all perigastric nodes and the removal of the
greater and lesser omenta. In addition to these structures, for a
D2 dissection, the surgeon removes the omental bursa portion
of the transverse mesocolon and the nodes along the left gastric,
common hepatic, celiac, and splenic arteries. D2 dissection is
technically more demanding than D1 dissection, requiring a
significant experience and a steep learning curve.
The surgical strategy of the Japanese Research Society for
Gastric Cancer (JRSGC) is based on the gastric lymphatic
drainage. D2 radical gastrectomy has been advocated and has
been practiced as standard surgery in Japan. All the lymph
nodes are retrieved from the resection specimen and examined
for micro-metastasis, which may sometimes be difficult to see
intraoperatively. Japanese series demonstrated a survival
benefit using D2 resection (Maruyama et al. 1987). It is now the
standard treatment for curable gastric cancer in East Asia.
This is in contrast to the West where D1 radical gastrectomy is
more commonly performed due to the lower postoperative morbidity and mortality rate and no significant difference in overall
survival (Cuschieri et al. 1999; Hartgrink et al. 2004). Further,
the difference could also be accounted for partially by understaging in the West where fewer regional lymph nodes were resected
(Bunt et al. 1995). In addition, the Japanese tumors could have
been overstaged as some of the stage I carcinomas were reported
to be dysplasia by pathologists in the West (Schlemper et al.
1997). However, longer follow-up study showed that D2 resection had a lower local and regional recurrence and gastric cancer-related deaths, although overall survival difference remained
statistically insignificant in. Dutch study (Songun et al. 2010). It
was later found that high-volume centers with experience in
operation and postoperative management had lower postoperative complications and a trend toward improved survival (Degiuli
et al. 2010; Degiuli et al. 2014; Enzinger et al. 2007; Mogal et al.
2019). Currently, D2 radical gastrectomy is thus considered a
recommended but not required procedure in the West, and
should only be performed in experienced, high-volume centers
in both NCCN and ESMO guidelines (National Comprehensive
Cancer Network (NCCN); Smyth et al. 2016).
Palliative Treatment
The goal of palliative care is the achievement of the best quality
of life for patients and their families (Cancer pain relief and palliative care 1990). R2 resection refers to macroscopic residual
disease and is therefore considered as non-curative gastrectomy
(Hermanek and Wittekind 1994). Total gastrectomy was not
suggested to be worthwhile as a palliative surgery in the old days
for patients with incurable disease because of the perioperative
morbidity (Lawrence and McNeer 1958; ReMine 1979).
However, the current view is that total palliative gastrectomy
without lymph node dissection is justified in selected patients
due to better symptom relief and low postoperative mortality
rate, for example, perforation, uncontrollable bleeding, or
gastric outlet obstruction (Izuishi and Mori 2016). Palliative
gastrectomy has not been shown to prolong survival in highquality studies. Gastrojejunostomy is preferred to endoluminal
stenting in tumor obstruction, due to lower rates of symptom
recurrence (Upchurch et al. 2018). Therapy for palliation can
also be achieved endoscopically by recanalization or hemostasis
of cancer bleeding. Endoscopic laser ablation technique is very
effective in treating deeper invasive cancers.
Radiotherapy
There is little role for radiotherapy alone in the treatment of
unresectable cancer (Hazard et al. 2006). Early studies showed
that concurrent use with chemotherapy improved survival
compared with radiotherapy alone (Hazard et al. 2006). The
addition of radiotherapy to surgery has been shown to improve
survival in resectable gastric cancer (Valentini et al. 2009).
Chemotherapy
The beneficial effect of perioperative chemotherapy was first
shown in the MAGIC trial (Allum et al. 2003), which randomly
allocated 503 cases of potentially resectable gastric cancer to
7 INTESTINAL-TYPE GASTRIC CANCER 129
https://t.me/medicina_free
either three cycles of pre- and three cycles of postoperative ECF
(epirubicin, cisplatin, and 5-fluorouracil) chemotherapy, or surgery alone. The curative resection rate was increased by neoadjuvant therapy because of a significant downstaging of tumor stage
(surgery only, T3 = 64%; neoadjuvant therapy T3 = 49%; p =
0.011). Perioperative chemotherapy resulted in a significant progression-free survival (PFS) and overall survival (OS).
Subsequently, the FLOT4 trial, which randomly allocated
patients to receive four cycles of pre- and four cycles of postoperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel)
or the MAGIC regimen, showed a higher proportion of patients
achieving pathological complete regression with FLOT (16% vs
6%) (Al-Batran et al. 2016) and an OS benefit for FLOT group
over ECG group (50 months vs 35 months) (Al-Batran et al.
2019). However, due to the toxicity associated with the FLOT
regimen (serious chemotherapy-related adverse events were
27%), it is recommended that fluorouracil and oxaliplatin
(FOLFOX) be used in the majority of patients with good to
moderate performance status (National Comprehensive Cancer
Network (NCCN)). FLOT regimen should be reserved for
selected patients with good performance status. Adding radiotherapy to postoperative chemotherapy does not provide additional survival benefit if preoperative chemotherapy has been
adequately given as shown in the CRITICS trial (Cats et al. 2018).
In patients who have not received preoperative chemotherapy,
postoperative adjuvant chemoradiation therapy (5-fluorouracil/
leucovorin and radiotherapy) has been proven to be beneficial,
in particular for those with less than a D2 lymph node dissection from the INT-0116 trial conducted in the US (Dikken et al.
2010). The beneficial effect on survival remained after a median
follow-up of > 10 years (Smalley et al. 2012). As for those with
D2 lymph node dissection, postoperative chemotherapy with
combination of capecitabine and oxaliplatin or FOLFOX is recommended based on the results of CLASSIC trial, a multi-center
study conducted in South Korea, Taiwan, and China (National
Comprehensive Cancer Network (NCCN); Noh et al. 2014).
However, the Korean ARTIST trial did not reveal an overall
survival benefit for adjuvant chemoradiation (Park et al. 2015),
except for subgroup analysis showing benefit on disease-free
survival in node-positive disease (Kim et al. 2016).
Hyperthermic intraperitoneal chemotherapy (HIPEC) has
been shown to be potentially beneficial in selected cases after
surgery for the treatment of advanced stage gastric cancer with
and without peritoneal carcinomatosis (Desiderio et al. 2017). In
patients without peritoneal carcinomatosis, HIPEC results in a
better overall survival at three or five years when compared with
control group. For those with peritoneal carcinomatosis, there is
a prolonged median survival of four months despite no difference
in the three-year overall survival (Desiderio et al. 2017).
It has been shown that, in RCTs, systemic chemotherapy provides palliation of symptoms, improves survival and quality of
life compared to the best supportive treatment in advanced disease (Ford et al. 2014; Glimelius et al. 1997; Kang et al. 2012).
Two cytotoxic drugs are preferred to three-drug cytotoxic regimen due to lower toxicity. The preferred regimens include a
fluoropyrimidine (fluorouracil or capecitabine) combined with
either oxaliplatin or cisplatin (National Comprehensive Cancer
Network (NCCN)). FOLFOX achieves similar efficacy compared with fluorouracil plus cisplatin but has a lower toxicity
(Al-Batran et al. 2008). Irinotecan and fluorouracil (FOLFIRI)
is an alternative (Guimbaud et al. 2014).
Targeted Therapy
Currently, there are three FDA-approved targeted therapies for
advanced gastric cancer – trastuzumab, ramucirumab, and
pembrolizumab.
Trastuzumab, a monoclonal antibody against human epidermal
growth factor receptor 2 (HER2), was first shown in the ToGA
trial to prolong survival in patients with HER2-positive, locally
advanced, current or metastatic, gastric or esophagogastric
junction adenocarcinoma when being combined with chemotherapy (Bang et al. 2010). Its usefulness in combination with
other chemotherapy regimen was further confirmed in
subsequent studies (Rivera et al. 2019, Soularue et al. 2015).
Ramucirumab, a vascular endothelial growth factor
receptor-2 (VEGF-2) antibody, has been shown to improve
overall survival when being used as monotherapy (Fuchs et al.
2014) or in combination with chemotherapy (Wilke et al. 2014)
in patients with advanced disease progressing on first-line chemotherapy. One of the sides effects is hypertension. However, it
is not useful in prolonging overall survival when being added
to chemotherapy in the first-line setting (Fuchs et al. 2019).
Pembrolizumab, which is a programmed cell death receptor
(PD)−1 antibody, has also demonstrated promising antitumor
activity against unresectable locally advanced or metastatic disease that are microsatellite instability-high (MSI-H)/defective
DNA mismatch repair (dMMR) as a single agent or in
combination with chemotherapy as first-line or rescue therapy
(Muro et al. 2016; Shitara et al. 2020). MSI is due to the presence
of dMMR system in cancers containing thousands of mutations
most commonly found in monomorphic microsatellites
(Luchini et al. 2019).
Therefore, it is recommended that HER2, microsatellite instability by polymerase chain reaction or mismatch repair deficiency by immunohistochemistry, and PD-L1 testing be done in
patients with unresectable locally advanced or metastatic disease (National Comprehensive Cancer Network (NCCN)).
Prognosis and Follow-up
Prognosis
The prognosis of gastric cancer in the West is poorer compared
with that in the East (Chan et al. 2019). There are several reasons for this difference. First, population-based screening
130 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
programs results in detection of more early stage cancers in the
East (e.g. Japan, Korea and the Matsu Island) whereas there are
no widespread screening programs in the West (Chan et al.
2019). A recent meta-analysis showed that endoscopic screening is associated with a 40% lower risk of gastric cancer
mortality (Zhang et al. 2018). Second, proximal cancer, which
is more prevalent in the West, is associated with more advanced
stage at presentation, larger size and poorly differentiated histology (Blot et al 1991; Chan et al. 2019; Crew and Neugut
2006). Third, D2 dissection is the standard of care in the East
compared with the West. The difference in surgical techniques
between the West and the East has been proposed to be a major
reason for discrepancy in survival after gastrectomy – a 4.8fold higher five-year survival probability and 67% lower risk of
cancer recurrence even after adjusting for age, sex, chemotherapy, tumor depth, nodal status, and gastrectomy type
(Markar et al. 2013).
The survival rates in gastric cancer have been shown to be
improving in both Asian and Western countries (Arnold et al.
2019; Chen et al. 2020; Zhang et al. 2011). In a recent population-based study from 21 cancer registries covering 21 jurisdictions in seven countries (Australia, Canada, Denmark,
Ireland, New Zealand, Norway, and United Kingdom), the
age-standardized five-year survival has improved from 14.0–
25.7% to 20.8–32.8% (absolute change ranging from 3.2 to
11.1% between the period of 1995–99 and 2010–2014 (Arnold
et al. 2019). This is attributed to technological advancement
enabling earlier diagnosis, better staging and better and tailored treatment (e.g. precision medicine for targeted therapies
based on molecular markers). This survival improvement is
more pronounced for patients younger than 75 years than
those aged 75 years and older, likely to be related to the wider
access to adjuvant chemotherapy and tolerance to aggressive
treatments.
Nonetheless, overall prognosis of gastric cancer remains
poor despite advancement in the multimodality management
approach. More than half of patients presented with inoperable, advanced-stage disease (Chan et al. 2019). The recurrence
rate could reach 60% even after surgery with curative intent
(Liu et al. 2016). The number of lymph nodes harvested in one
of the most important determining factor, and D2 dissection
can reduce recurrence in this study. Currently, harvesting at
least 16 lymph nodes in either D1 or a modified D2 lymph
node dissection is recommended to stage the nodal status more
accurately (National Comprehensive Cancer Network
(NCCN)). There is a trend for improved overall survival with
increasing number of lymph nodes removed for examination
(Smith et al. 2005). Notably, in a study from Japan, the recurrence rate after laparoscopic gastrectomy was only around 5%
(Nakagawa et al. 2014), with peritoneal metastasis being the
most common (32%), followed by hematogenous spread (25%).
Recurrence mostly occurs within the initial two to three years
after surgery (Liu et al. 2016; Nakagawa et al. 2014).
The pathological stage has consistently been shown to be of
prognostic significance for both five-year survival and local
recurrence rates (Adachi et al. 2000; Roder et al. 1998; Siewert
et al. 1998; Yokota et al. 2000). Siewert et al. has shown that
lymph node ratio and lymph node status are the most important prognostic factors in patients with resected gastric cancer
in a prospective multicenter observation trial. The data confirmed the therapeutic value of D
lymphadenectomy in
2
patients with stage II disease. He also reported that in experienced centers, extended lymph node dissection does not
increase the mortality or morbidity rate of resection for gastric
cancer but markedly improves long-term survival in patients
with stage II tumors. This effect appears to be independent of
the phenomenon of stage migration. Among those with gastric
resection for advanced gastric cancer, dissection of ≥ 15 lymph
nodes is associated with an improved survival (Biondi et al.
2015; Schwarz and Smith 2007). In a large study based on the
National Cancer Database in the United States (In et al. 2017),
the five-year survival rate based on pTNM staging was 81%,
69%, 46–59%, 20–30%, and less than 10% for stage IA, stage IB,
stages IIA-B, stages IIIA-B and stage IIIC-IV, respectively.
Size of the tumor is another important prognostic factor. The
evidence comes from a prospective, randomized trial that demonstrated tumor size to be an independent prognostic factor in a
multivariate analysis (p=0.0002) in patients with tumor-free margins (Siewert et al. 1998). Vascular and lymphatic permeation are
both important potential independent prognostic factors. Studies
have demonstrated that lymph node involvement is a statistically
significant predictor of survival, and the presence of tumor
emboli significantly influences tumor recurrence and death after
curative resection (Yokota et al. 1999, 2000; Maehara et al. 2002).
These findings were supported by other groups (Hyung et al.
2002; Kooby et al. 2003), which reported a poor prognosis associated with advanced T stage and the presence of vascular invasion
(which may be a predictor of biologic aggressiveness).
Diagnostic and Prognostic Markers
The most frequently used tumor markers in gastric cancer are
carcinoembryonic antigen (CEA) and CA19–9, but only a
modest proportion of patients have elevated levels of these
markers (Kim et al. 1995; Ohkura 1999; Pectasides et al. 1997;
Yamao et al. 1999; Ychou et al. 2000). It was found in a large
prospective study that preoperative positive rates for CEA and/
or CA19-9 or both were 28.3% and 45.0%, respectively, among
321 patients with gastric cancer (Takahashi et al. 2003). In
addition, the sensitivities of CEA and either CEA or CA19-9, or
both, for recurrence were 65.8% and 85.0%, respectively, among
the 120 patients who had recurrence (Takahashi et al. 2003).
Soluble E-cadherin has also been reported to have significant
prognostic value (Chan et al. 2003) and to predict recurrence
(Chan et al. 2005). Whether HER2 positivity has prognostic
significance in general remains controversial (National
7 INTESTINAL-TYPE GASTRIC CANCER 131
https://t.me/medicina_free
Comprehensive Cancer Network (NCCN)). However, the
addition of HER2 monoclonal antibodies to chemotherapy
does improve the prognosis in patients with HER2-positive
metastatic disease. MMR status in tumor tissue can be identified by immunohistochemical staining to detect protein
expression levels involved in DNA mismatch repair, while MSI
can be assessed by polymerase chain reactions to detect gene
expression levels of microsatellite makers (Luchini et al. 2019).
The assessment of MSI status predicts treatment response to
PD-1 blockade (i.e. pembrolizumab). The assessment of
PD-L1 protein levels in tumor tissue by IHC assay using
anti-PD-L1 antibodies can also help to predict response to
immunotherapy (U.S. Food and Drug Administration 2017).
A higher level of expression of PD-L1 and PD-1 was associated
with a better survival in a German study (Böger et al. 2016).
The Asian Cancer Research Group (ACRG) used gene expression profiling to define four molecular subtypes of gastric
cancer with different prognosis (Cristescu et al. 2015).
Epithelial to mesenchymal transition (EMT) subtype carries
the worst prognosis with a high recurrence rate, while MSI
subtype has the best prognosis with >50% of patients being
diagnosed at an early stage and low recurrence rate (22%). The
MSS subtypes have an intermediate prognosis and recurrence
rate with TP53-active types showing better prognosis than
TP53-inactive types.
“Liquid biopsy” in terms of evaluating circulating tumor
DNA (ctDNA) in the blood to detect mutations/alterations in
DNA shed from gastric cancers can help in identifying targetable alterations (e.g. MSI) and hence predicting treatment
response (Willis et al. 2019). High ctDNA levels are also associated with peritoneal recurrence and worsened prognosis in
advanced gastric cancer cases (Fang et al. 2016; Okabe et al.
2015).
Gastrointestinal Oncology, 2nd Edition
Intestinal Type Gastric Cancer
Key Take Home Messages
Although gastric cancer incidence has been decreasing, it
•
remains the fifth most common cancer and ranks the fourth for
cancer-related mortality worldwide.
• Although Helicobacter pylori is the most important etiolog-
ical factor of gastric cancer, eradication of this infection does
not eliminate cancer risk in the presence of pre-existing precancerous lesions.
• Endoscopic mucosal resection and endoscopic submucosal
dissection are available endoscopic therapeutic options for
early gastric cancer, sparing the need of gastrectomy.
• D2 radical gastrectomy is the standard treatment for curable
gastric cancer in East Asia with a survival benefit.
• D1 radical gastrectomy is more commonly performed in the
West as it is technically less demanding and carries lower postoperative morbidity and mortality rate without significant difference
in overall survival compared with D2 radical dissection.
• The survival rate of gastric cancer has improved due to tech-
nological advancement enabling earlier diagnosis, better
staging, and tailored treatment.
Knowledge Gaps
The traditional belief of intestinal metaplasia indicating a
•
“point of no return” in the Correa’s cascade has recently been
challenged, although high-quality evidence is still lacking.
• Long-term prospective studies or even randomized clinical
trials are warranted to identify potential chemopreventive
agents against gastric cancer.
• Whether D2 radical gastrectomy provides a better long-term
survival than D1 dissection in the West remains to be determined by further randomized clinical trials with increasing
technological improvement and expertise.
• Precision medicine by integrating multi-level patient data
including clinical, genetic, molecular markers will help to
further predict prognosis and streamline treatment strategies.
Trusted Websites and National Evidence-based
Guideline
•
National Comprehensive Cancer Network (NCCN). NCCN
clinical practice guidelines in oncology. https://www.nccn.org/
professionals/physician_gls/pdf/gastric.pdf
References
Adachi, Y., Shiraishi, N., and Kitano, S. (2002). Modern treatment of early
gastric cancer: review of the Japanese experience. Dig Surg 19: 333–339.
Adachi, Y., Shiraishi, N., Shiromizu, A. et al. (2000). Laparoscopy-assisted
Billroth I gastrectomy compared with conventional open gastrectomy.
Arch Surg 135: 806–810.
Adachi, Y., Shiraishi, N., Suematsu, T. et al. (2000). Most important lymph
node information in gastric cancer: multivariate prognostic study. Ann
Surg Oncol 7: 503–507.
Adachi, Y., Suematsu, T., Shiraishi, N. et al. (1999). Quality of life after
laparoscopy-assisted Billroth I gastrectomy. Ann Surg 229: 49.
Al-Batran, S.E., Hartmann, J.T., Probst, S. et al. (2008). Phase III trial in
metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin
plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft
Internistische Onkologie. J Clin Oncol 26: 1435–1442.
Al-Batran, S.E., Hofheinz, R.D., Pauligk, C. et al. (2016). Histopathological
regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and
leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in
patients with resectable gastric or gastro-oesophageal junction
adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre,
open-label, randomised phase 2/3 trial. Lancet Oncol 17: 1697–1708.
Al-Batran, S.E., Homann, N., Pauligk, C. et al. (2019). Perioperative
chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and
132 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
docetaxel versus fluorouracil or capecitabine plus cisplatin and
epirubicin for locally advanced, resectable gastric or gastro-oesophageal
junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.
Lancet 393: 1948–1957.
Allum, W.H., Cunningham, D., Stenning, S.P. et al. (2003). Perioperative
chemotherapy in operable gastric and lower oesophageal cancer: a
randomised, controlled trial (the MAGIC trial, ISRCTN 9379 (3971)
[Abstract #998]. Proc ASCO 22: 249a.
Amin, M.B., Edge, S.B., Greene, F.L. et al. (2017). AJCC Cancer Staging
Manual. ed vol. 8. New York: Springer.
Arnold, M., Rutherford, M.J., Bardot, A. et al. (2019). Progress in cancer
survival, mortality, and incidence in seven high-income countries 19952014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol
20: 1493–1505.
Asao, T., Hosouchi, Y., Nakabayashi, T. et al. (2001). Laparoscopically
assisted total or distal gastrectomy with lymph node dissection for early
gastric cancer. J Br Surg 88: 128–132.
Bando, E., Makuuchi, R., Irino, T. et al. (2019). Validation of the prognostic
impact of the new tumor-node-metastasis clinical staging in patients
with gastric cancer. Gastric Cancer 22: 123–129.
Bang, Y.J., Van Cutsem, E., Feyereislova, A. et al. (2010). Trastuzumab in
combination with chemotherapy versus chemotherapy alone for
treatment of HER2-positive advanced gastric or gastro-oesophageal
junction cancer (ToGA): a phase 3, open-label, randomised controlled
trial. Lancet 376: 687–697.
Barker, D., Coggon, D., Osmond, C. et al. (1990). Poor housing in childhood
and high rates of stomach cancer in England and Wales. Br J Cancer 61:
575–578.
Barstad, B., Sørensen, T.I., Tjønneland, A. et al. (2005). Intake of wine, beer
and spirits and risk of gastric cancer. Eur J Cancer Prev 14: 239–243.
Bartsch, H., O’Neill, I., and Schulte-Hermann, R. (1987). Relevance of
N-nitroso compounds to human cancer: exposures and mechanisms:
Proceedings of the IXth International Symposium on N-nitroso
Compounds, Held in Baden. Austria: Oxford University Press. 1-5
September 1986.
Berndt, H., Wildner, G., and Klein, K. (1968). Regional and social
differences in cancer incidence of the digestive tract in the German
Democratic Republic. Neoplasma 15: 501–515.
Biondi, A., D’Ugo, D., Cananzi, F.C. et al. (2015). Does a minimum number
of 16 retrieved nodes affect survival in curatively resected gastric cancer?
Eur J Surg Oncol 41: 779–786.
Blaser, M.J. (1992). Helicobacter pylori: its role in disease. Clin Inf Dis 15:
386–391.
Blot, W.J., Devesa, S.S., Kneller, R.W. et al. (1991). Rising incidence of
adenocarcinoma of the esophagus and gastric cardia. JAMA 265: 1287–1289.
Böger, C., Behrens, H.M., Mathiak, M. et al. (2016). PD-L1 is an
independent prognostic predictor in gastric cancer of Western patients.
Oncotarget 7: 24269–24283.
Bonney, G.E., Elston, R.C., Correa, P. et al. (1986). Genetic etiology of
gastric carcinoma: i. Chronic Atrophic Gastritis. Genet Epidemiol 3:
213–224.
Bosetti, C., Santucci, C., Gallus, S. et al. (2020). Aspirin and the risk of
colorectal and other digestive tract cancers: an updated meta-analysis
through 2019. Ann Oncol 31: 558–568.
Botet, J.F., Lightdale, C.J., Zauber, A.G. et al. (1991). Preoperative staging of
gastric cancer: comparison of endoscopic US and dynamic CT. Radiology
181: 426–432.
Bozzetti, F., Marubini, E., Bonfanti, G. et al. (1999). Subtotal versus total
gastrectomy for gastric cancer: five-year survival rates in a multicenter
randomized Italian trial. Ann Surg 230: 170.
Buiatti, E., Palli, D., Decarli, A. et al. (1989). A case‐control study of gastric
cancer and diet in Italy. Int J Cancer 44: 611–616.
Bulay, O., Mlrvish, S.S., Garcia, H. et al. (1979). Carcinogenicity test of six
nitrosamides and a nitrosocyanamide administered orally to rats. J Natl
Cancer Inst 62: 1523–1528.
Bunt, A., Hermans, J., Smit, V. et al. (1995). Surgical/pathologic-stage
migration confounds comparisons of gastric cancer survival rates
between Japan and Western countries. J Clin Oncol 13: 19–25.
Burke, E.C., Karpeh, M., Conlon, K.C. et al. (1997). Laparoscopy in the
management of gastric adenocarcinoma. Ann Surg 225: 262.
Cancer pain relief and palliative care. (1990). Report of a WHO Expert
committee. World Health Organ Tech Rep Ser 804: 1–75.
Capelle, L.G., de Vries, A.C., Haringsma, J. et al. (2010). The staging of
gastritis with the OLGA system by using intestinal metaplasia as an
accurate alternative for atrophic gastritis. Gastrointest Endosc 71:
1150–1158.
Cats, A., Jansen, E.P.M., NCT, V.G. et al. (2018). Chemotherapy versus
chemoradiotherapy after surgery and preoperative chemotherapy for
resectable gastric cancer (CRITICS): an international, open-label,
randomised phase 3 trial. Lancet Oncol 19: 616–628.
Cavaleiro-Pinto, M., Peleteiro, B., Lunet, N. et al. (2011). Helicobacter
pylori infection and gastric cardia cancer: systematic review and metaanalysis. Cancer Causes Control 22: 375–387.
Chan, A.O.O., Chu, K.M., Lam, S.K. et al. (2005). Early prediction of tumor
recurrence after curative resection of gastric carcinoma by measuring
soluble E‐cadherin. Cancer 104: 740–746.
Chan, A.-O.-O., Chu, K.-M., Lam, S.-K. et al. (2003). Soluble E-cadherin is
an independent pretherapeutic factor for long-term survival in gastric
cancer. J Clin Oncol 21: 2288–2293.
Chan, W.L., Lam, K.O., Lee, V.H.F. et al. (2019). Gastric cancer - From
Aetiology to management: differences between the East and the West.
Clin Oncol (R Coll Radiol) 31: 570–577.
Chang, K.J., Katz, K.D., Durbin, T.E. et al. (1994). Endoscopic ultrasound-
guided fine-needle aspiration. Gastrointest Endosc 40: 694–699.
Charukhchyan, S.A. and Lucas, G.W. (1998). Laparoscopy and lesser sac
endoscopy in gastric carcinoma operability assessment. Am Surg 64:
160.
Chen, H.N., Wang, Z., Li, X. et al. (2016). Helicobacter pylori eradication
cannot reduce the risk of gastric cancer in patients with intestinal
metaplasia and dysplasia: evidence from a meta-analysis. Gastric Cancer
19: 166–175.
Chen, Q., Liu, S.Z., Zhang, S.K. et al. (2020). The relative survival and cure
fraction of gastric cancer estimated through flexible parametric models
using data from population-based cancer registration during 2003-2012
in Linzhou, China. Cancer Med 9: 2243–2251.
Cheung, K.S., Chan, E.W., Chen, L. et al. (2019). Diabetes increases risk of
gastric cancer after Helicobacter pylori Eradication: a territory-wide
study with propensity score analysis. Diabetes Care 42: 1769–1775.
Cheung, K.S., Chan, E.W., Wong, A.Y.S. et al. (2018). Long-term proton
pump inhibitors and risk of gastric cancer development after treatment
for Helicobacter pylori: a population-based study. Gut 67: 28–35.
Cheung, K.S., Chan, E.W., Wong, A.Y.S. et al. (2018). Aspirin and risk of
gastric cancer after Helicobacter pylori Eradication: a Territory-Wide
study. J Natl Cancer Inst 110: 743–749.
7 INTESTINAL-TYPE GASTRIC CANCER 133
https://t.me/medicina_free
Cheung, K.S., Chan, E.W., Wong, A.Y.S. et al. (2019). Metformin use and
gastric cancer risk in diabetic patients after Helicobacter pylori
eradication. J Natl Cancer Inst 111: 484–489.
Cheung, K.S., Chan, E.W., Wong, A.Y.S. et al. (2020). Statins were associated
with a reduced gastric cancer risk in patients with eradicated
Helicobacter Pylori infection: a territory-wide propensity score matched
study. Cancer Epidemiol Biomarkers Prev 29: 493–499.
Cheung, K.S., Chung, K.L., and Leung, W.K. (2021). Chemopreventive effect
of Metformin on gastric cancer development. Gut Liver 16: 147–156.
Cheung, K.S. and Leung, W.K. (2019). Long-term use of proton-pump
inhibitors and risk of gastric cancer: a review of the current evidence.
Therap Adv Gastroenterol 12: 1756284819834511.
Coggon, D., Barker, D.J., Cole, R.B. et al. (1989). Stomach cancer and food
storage. JNCI: J Natl Cancer Inst 81: 1178–1182.
Cancer Genome Atlas Research Network. (2014). Comprehensive
molecular characterization of gastric adenocarcinoma. Nature 513:
202–209.
Conlon, K.C. and Karpeh, M.S., Jr. (1996). Laparoscopy and laparoscopic
ultrasound in the staging of gastric cancer. Semin Oncol 23: 347–351.
Correa á (1983). The gastric precancerous process. Cancer Surv 2:
438–450.
Correa, P. (1982a). Precursors of gastric and esophageal cancer. Cancer 50:
2554–2565.
Correa, P. (1988). A human model of gastric carcinogenesis. Cancer Res 48:
3554–3560.
Correa, P., Cuello, C., and Duque, E. (1970). Carcinoma and intestinal
metaplasia of the stomach in Colombian migrants. J Natl Cancer Inst 44:
297–306.
Correa, P., Haenszel, W., Cuello, C. et al. (1975). A model for gastric cancer
epidemiology. Lancet 306: 58–60.
Correa, P., Haenszel, W., and Tannenbaum, S. (1982b). Epidemiology of
gastric carcinoma: review and future prospects. Natl Cancer Inst Monogr
62: 129–134.
Correa, P., Piazuelo, M.B., and Wilson, K.T. (2010). Pathology of gastric
intestinal metaplasia: clinical implications. Am J Gastroenterol 105: 493–498.
Crew, K.D. and Neugut, A.I. (2006). Epidemiology of gastric cancer. Worl d
J Gastroenterol 12: 354–362.
Cristescu, R., Lee, J., Nebozhyn, M. et al. (2015). Molecular analysis of
gastric cancer identifies subtypes associated with distinct clinical
outcomes. Nat Med 21: 449–456.
Cuschieri, A., Weeden, S., Fielding, J. et al. (1999). Patient survival after D1
and D2 resections for gastric cancer: long-term results of the MRC
randomized surgical trial. surgical Co-operative Group. Br J Cancer 79:
1522–1530.
D’Ugo, D., Persiani, R., Caracciolo, F. et al. (1997). Selection of locally
advanced gastric carcinoma by preoperative staging laparoscopy. Surg
Endosc 11: 1159–1162.
Davies, J., Chalmers, A., Sue-Ling, H. et al. (1997). Spiral computed
tomography and operative staging of gastric carcinoma: a comparison
with histopathological staging. Gut 41: 314–319.
Davies, J., Chalmers, A.G., Sue-Ling, H.M. et al. (1997). Spiral computed
tomography and operative staging of gastric carcinoma: a comparison
with histopathological staging. Gut 41: 314–319.
Degiuli, M., Sasako, M., and Ponti, A. (2010). Morbidity and mortality in
the Italian gastric cancer study group randomized clinical trial of D1
versus D2 resection for gastric cancer. Br J Surg 97: 643–649.
Degiuli, M., Sasako, M., Ponti, A. et al. (2014). Randomized clinical trial
comparing survival after D1 or D2 gastrectomy for gastric cancer. Br J
Surg 101: 23–31.
Desiderio, J., Chao, J., Melstrom, L. et al. (2017). The 30-year experience-A
meta-analysis of randomised and high-quality non-randomised studies
of hyperthermic intraperitoneal chemotherapy in the treatment of
gastric cancer. Eur J Cancer 79: 1–14.
Dikken, J.L., Jansen, E.P., Cats, A. et al. (2010). Impact of the extent of
surgery and postoperative chemoradiotherapy on recurrence patterns in
gastric cancer. J Clin Oncol 28: 2430–2436.
Druckrey, H. (1975). Chemical carcinogenesis on N-nitroso derivatives.
Gann Monogr 17: 107–132.
Düx, M., Richter, G.M., Hansmann, J. et al. (1999). Helical hydro-CT for
diagnosis and staging of gastric carcinoma. J Comput Assist Tomogr 23:
913–922.
Soularue, É., Cohen, R., Tournigand, C. et al. (2015). Efficacy and safety of
trastuzumab in combination with oxaliplatin and fluorouracil-based
chemotherapy for patients with HER2-positive metastatic gastric and
gastro-oesophageal junction adenocarcinoma patients: a retrospective
study. Bull Cancer 102: 324–331.
Elder, J. (1995). Carcinoma of the stomach. In: Bockus Gastroenterology,
vol. ume I (ed. W.S.S.F. Haubrich and J.E. Berk), 5e. 805–815.
Philadelphia: WB Saunders Co.
El-Omar, E.M., Carrington, M., Chow, W.-H. et al. (2000). Interleukin-1
polymorphisms associated with increased risk of gastric cancer. Nature
404: 398–402.
Enzinger, P.C., Benedetti, J.K., Meyerhardt, J.A. et al. (2007). Impact of
hospital volume on recurrence and survival after surgery for gastric
cancer. Ann Surg 245: 426–434.
Eurogast Study Group (1993). An international association between
Helicobacter pylori infection and gastric cancer. Lancet 341: 1359–1363.
Facciorusso, A., Antonino, M., Di Maso, M. et al. (2014). Endoscopic
submucosal dissection vs endoscopic mucosal resection for early gastric
cancer: a meta-analysis. World J Gastrointest Endosc 6: 555–563.
Fang, W.L., Lan, Y.T., Huang, K.H. et al. (2016). Clinical significance of
circulating plasma DNA in gastric cancer. Int J Cancer 138: 2974–2983.
Fennerty, M.B. (1994). Helicobacter pylori. Arch Intern Med 154: 721–727.
Feussner, H., Omote, K., Fink, U. et al. (1999). Pretherapeutic laparoscopic
staging in advanced gastric carcinoma. Endoscopy 31: 342–347.
Figueiredo, C., Machado, J.C., Pharoah, P. et al. (2002). Helicobacter pylori
and interleukin 1 genotyping: an opportunity to identify high-risk
individuals for gastric carcinoma. J Natl Cancer Inst 94: 1680–1687.
Ford, A.C., Yuan, Y., and Moayyedi, P. (2020). Helicobacter pylori
eradication therapy to prevent gastric cancer: systematic review and
meta-analysis. Gut 69: 2113–2121.
Ford, H.E., Marshall, A., Bridgewater, J.A. et al. (2014). Docetaxel versus
active symptom control for refractory oesophagogastric adenocarcinoma
(COUGAR-02): an open-label, phase 3 randomised controlled trial.
Lancet Oncol 15: 78–86.
Forman, D. (1991). Helicobacter Pylori Infection: A Novel Risk Factor in the
Etiology of Gastric Cancer. Oxford University Press.
Forman, D., Newell, D., Fullerton, F. et al. (1991). Association between
infection with Helicobacter pylori and risk of gastric cancer: evidence
from a prospective investigation. Br Med J 302: 1302–1305.
Fraser, P., Chilvers, C., Beral, V. et al. (1980). Nitrata and human cancer: a
review of the evidence. Int J Epidemiol 9: 3–12.
Соседние файлы в папке @xirurgi_2025