2011
Hellenic Society of
Medical Oncology
Consensus Meeting
on Gastric Cancer
Androulakis N, Boutis A, Golfinopoulos V, Katopodi O,
Liakakos T, Vini L, Makatsoris T, Nasioulas G,
Pentheroudakis G, Sgouros J, Spiliotis J, Triantopoulou
C,Tzardi M, Vasileiadis K, Xynos E.
Suggestions, Opinions &
Recommendations
for the Diagnosis, Management,
Treatment and Surveillance of Gastric
Cancer
Suggestions, Opinions & Recommendations for the
Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer
December 7-9, 2011
LEGAL DISCLAIMER
HeSMO considers adherence to these guidelines to be voluntary. The ultimate
determination regarding their application is to be made by the physician in light of
each patient’s individual circumstances. In view of the consultory and non-binding
nature, these guidelines cannot form the basis for legal action or litigation for
compliance or absence of compliance in the clinical practice setting but can only be
considered as general guidelines based on best available evidence for assistance in
decision-making.
Any person seeking to apply or consult the evidence-based series is expected to use
independent medical judgment in the context of individual clinical circumstances or
seek out the supervision of a qualified clinician. HESMO makes no representation or
guarantees of any kind whatsoever regarding their content or use or application and
disclaims any responsibility for their application or use in any way.
In addition, these guidelines describe evaluations and administration of therapies in
clinical practice; they cannot be assumed to apply to interventions performed in the
context of clinical trials, given that such clinical studies are designed to test innovative
management strategies in a disease for which better treatment is sorely needed.
However, by reviewing and synthesizing the latest literature, this practice guideline
serves to identify questions for further research and the settings in which
investigational therapy should be considered.
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December 7-9, 2011
Evidence Level and Recommendation Grade
Level of Evidence
I
Evidence from at least one large randomized control trial of good methodological quality (low
potential for bias) or meta-analyses of well-conducted RCTs without heterogeneity
II
Small RCTs or large RCTs with a suspicion of bias (lower methodological quality) or metaanalyses of such trials or of trials with demonstrated heterogeneity
III
Prospective cohort studies
IV
Retrospective cohort studies or case-control studies
V
Studies without control group, case reports, experts opinions
Strength of Recommendation
A
Strong evidence for efficacy with a substantial clinical benefit, strongly recommended
B
Strong or moderate evidence for efficacy but with a limited clinical benefit, generally
recommended
C
Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages
(adverse events, costs,..) optional
D
Moderate evidence against efficacy or for adverse outcome, generally not recommended
E
Strong evidence against efficacy or for adverse outcome, never recommended
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December 7-9, 2011
Contents
LEGAL DISCLAIMER ................................................................................................. 2
EVIDENCE LEVEL AND RECOMMENDATION GRADE ........................................... 3
1. GENERAL CONSIDERATIONS .............................................................................. 6
1.1 MOLECULAR BASIS .......................................................................................... 7
1.2 PROGNOSTIC AND PREDICTIVE FACTORS ................................................... 7
2. DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS ............................................. 9
2.1 CLINICAL PRESENTATION, DIAGNOSIS AND STAGING ................................ 9
2.1.1 Clinical features ........................................................................................ 9
2.1.2 Diagnosis ............................................................................................... 10
2.1.3 Endoscopic Staging................................................................................ 11
2.1.4 Endoscopic Surveillance ........................................................................ 12
2.2 GASTRIC POLYPS ........................................................................................... 13
2.2.1 Fundic gland polyps ............................................................................... 13
2.2.2 Hyperplastic polyps ................................................................................ 14
2.2.3 Adenomatous polyps .............................................................................. 14
2.2.4 Hamartomatous polyps .......................................................................... 14
2.2.5 Familial adenomatous polyposis ............................................................ 15
3. HEREDITARY GASTRIC CANCER ...................................................................... 16
3.1 INTRODUCTION AND DIAGNOSIS ................................................................. 16
3.2 MANAGEMENT ................................................................................................ 17
3.3 SURVEILLANCE............................................................................................... 17
4. IMAGING WORK UP AT STAGING ...................................................................... 20
4.1 CROSS SECTIONAL IMAGING MODALITIES ................................................. 20
4.2 HISTOPATHOLOGICAL FEATURES ............................................................... 21
4.2.1 Specimen Preparation ............................................................................ 21
4.2.2 Gross Description ................................................................................... 21
4.2.3 Microscopic Description ......................................................................... 22
4.2.4 Gastric endoscopic mucosal resection specimen ................................... 25
5. NEO-ADJUVANT, PERI-OPERATIVE AND ADJUVANT CHEMOTHERAPY ...... 26
5.1 NEO-ADJUVANT CHEMORADIOTHERAPY .................................................... 26
5.2 ADJUVANT CHEMORADIOTHERAPY ............................................................. 28
5.3 PERIOPERATIVE AND ADJUVANT CHEMOTHERAPY .................................. 30
6. SURGICAL TREATMENT ..................................................................................... 35
7. LOCALLY ADVANCED DISEASE ........................................................................ 40
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7.1 DEFINITION SELECTION CRITERIA ............................................................... 40
7.2 MANAGEMENT OF LOCALLY ADVANCED GASTRIC CANCER .................... 42
7.2.1 Radiotherapy .......................................................................................... 42
7.2.2 Chemotherapy ........................................................................................ 43
7.2.3 Management of Peritoneal Disease ....................................................... 44
................................................................................................................................... 45
8. TREATMENT OF METASTATIC DISEASE AND PALLIATIVE CARE ................ 46
8.1 IMAGING .......................................................................................................... 46
8.2 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE .................. 47
8.2.1 First-line therapy..................................................................................... 48
8.2.2 Second-line therapy ............................................................................... 51
8.2.3 Targeted Therapies ................................................................................ 51
8.3 PALLIATIVE AND SUPPORTIVE CARE ........................................................... 54
8.3.1 Chemoradiotherapy ................................................................................ 55
8.3.2 Surgery................................................................................................... 55
8.4 TUMOR-RELATED SYMPTOMS ...................................................................... 56
9. REFERENCES ...................................................................................................... 59
POSITION STATEMENT ........................................................................................... 71
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1. GENERAL CONSIDERATIONS
The worldwide incidence of gastric cancer has declined rapidly over the recent few
decades, the reasons for which are incompletely understood. Part of the decline may
be due to the recognition of certain risk factors such as H. pylori and other dietary and
environmental risks. Refrigerators also improved the storage of food, thereby
reducing salt-based preservation, preventing bacterial and fungal contamination,
whilst they also allowed for fresh food and vegetables to be more readily available,
which may be a valuable source of antioxidants important for cancer prevention.
However, the rate of decline has been variable in different regions. In the United
States, the incidence rate for non-cardia gastric cancer declined among all race and
age groups except for whites aged 29 to 39 years for whom it increased [Anderson et
al, 2010]. Despite the general decline, the absolute number of new cases per year is
increasing, mainly due to aging in the world population. Thus, gastric cancer will
continue to represent an important cause of cancer and cancer-related mortality for
the foreseeable future.
Despite the decline in gastric cancer overall, there has been an explosive increase in
incidence of cancer of the gastric cardia [Powell and McConkey, 1990]. The shift from
distal to proximal stomach may in part be due to the decrease in the distal cancers.
However, it has also been proposed that carcinoma at the cardia is a different entity
from that of the rest of the gastric carcinoma. The histologic pattern of gastric cancer
is also changing with a decline in the intestinal-type compared with the diffuse type
[Henson et al., 2004].
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1.1 MOLECULAR BASIS
Gastric cancer is the second cause of cancer-related death worldwide. The etiology of
it is likely to be multifactorial. Factors that predispose patients to develop gastric
cancer are among others, obesity, gastroesophageal reflux disease and helicobacter
pylori infection. Some of these factors are more important for the development of
tumors of the proximal stomach while others for the development of tumors of the
body and antrum of the stomach.
The above mentioned factors are related to the development of gastric cancer by
causing mutation in tumor suppressor genes or by activating oncogenes. Despite the
fact that many studies are underway trying to identify these genes, so far we have
important data only for a few genes. Two of them are E-cadherin, in diffuse type of
gastric adenocarcinoma, and the tumor suppressor gene p-53 [Tamura et al., 2006].
1.2 PROGNOSTIC AND PREDICTIVE FACTORS
Prognostic factors
Advanced stage by the 7th edition of the staging system developed jointly by the
AJCC and the IUCC confers a worse prognosis. In patients presenting with resectable
early gastric cancer, the prognosis depends on the surgical staging. The more the
number of lymph nodes are involved the worse the prognosis. Also, both poor
performance status and alkaline phosphatase’s level 100IU, or more, are poor
prognostic factors. Kattan et al. developed a nomogram that uses various
clinicopathologic factors in patients who had R0 tumor resection, to predict the risk of
recurrence. These factors are age and gender of the patient, primary tumor site,
Lauren classification, tumor size and depth, and number of positive lymph nodes
[Kattan et al., 2003]
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Also, in patients with localized disease and receiving pre-operative chemotherapy, the
type of response to chemotherapy is correlated to survival. Residual tumor less than
10% was related to better overall survival in one study [Becker et al, 2003] while in
another the number of positive lymph nodes and the presence of perineural or
perivascular invasion were related to worse prognosis.
There are no conclusive data regarding the prognostic significance of HER2 protein
expression.
Predictive factors
Many predictive factors have been proposed but none of them has been adequately
validated. Overexpression of the receptor HER2 in patients with locally advanced,
recurrent or metastatic gastric cancer is related to response to treatment with
Trastuzumab [Bang et al, 2010].
Recommendations

HER2 overexpression should be tested in all patients with locally advanced
or metastatic gastric cancer as it is a predictive factor for response to
chemotherapy combined with trastuzumab. (LOE I, SOR A)
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2. DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS
2.1 CLINICAL PRESENTATION, DIAGNOSIS AND STAGING
2.1.1 Clinical features
Weight loss and persistent abdominal pain are the most common symptoms at initial
diagnosis. Weight loss usually results from insufficient caloric intake rather than
increased catabolism, and may be attributable to anorexia, nausea, abdominal pain,
early satiety, and/or dysphagia. When present, abdominal pain tends to be epigastric,
vague and mild early in the disease but more severe and constant as the disease
progresses. Cancers arising from the proximal stomach may present with dysphagia,
and advanced distal tumors may cause gastric outlet obstruction. A pseudoachalasia
syndrome may occur as the result of involvement of Auerbach's plexus due to local
extension or to malignant obstruction near the gastroesophageal junction. Nausea or
early satiety from poor distensibility of the stomach have been noted in cases of an
aggressive form of diffuse-type gastric cancer called “linitis plastica". Occult
gastrointestinal bleeding with or without iron deficiency anemia is not uncommon,
while overt bleeding (i.e., melena or hematemesis) is seen in less than 20% of cases.
The presence of a palpable abdominal mass is the most common physical finding and
generally indicates long-standing, advanced disease. Patients may also present with
signs or symptoms of distant metastatic disease. The most common metastatic
distribution is to the liver, peritoneal surfaces, and nonregional or distant lymph nodes.
Less commonly, ovaries, central nervous system, bone, pulmonary or soft tissue
metastases occur. Since gastric cancer can spread via lymphatics, the physical
examination may reveal a left supraclavicular lymphadenopathy (Virchow's node),
which is the most common physical examination finding of metastatic disease, a
periumbilical nodule (Sister Mary Joseph's node), or a left axillary node (Irish node).
Peritoneal spread can present with an enlarged ovary (Krukenberg's tumor), or a mass
in the cul-de-sac on rectal examination (Blumer's shelf). However, there are patients
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with ovarian metastasis without other peritoneal disease. Ascites can also be the first
indication of peritoneal carcinomatosis. A palpable liver mass can indicate metastases,
although metastatic disease to the liver is often multifocal or diffuse. Jaundice or
clinical evidence of liver failure is seen in the preterminal stages of metastatic disease.
2.1.2 Diagnosis
Even though a delay in diagnosis has not been associated with a poorer prognosis, a
prompt diagnostic evaluation should be commenced when gastric cancer is suspected
or when new-onset of dyspepsia in older age is noticed (Talley NJ, Vakil N, and the
Practice Parameters Committee of the American College of Gastroenterology.
Guidelines for the management of dyspepsia Am J Gastroenterol 2005;100:2324-37).
The early use of upper endoscopy in patients presenting with gastrointestinal
complaints may be associated with a higher rate of early gastric cancer detection.
Approximately 25% of patients have a history of gastric ulcer. All gastric ulcers should
be followed to complete healing, and benign-appearing gastric ulcers should be
evaluated by biopsy and histologic assessment, since the diagnosis of early gastric
cancer offers the greatest opportunity for surgical cure and long-term survival. A single
biopsy has 70% sensitivity for diagnosing an existing gastric cancer, while performing
seven biopsies from the ulcer margin and base increases the sensitivity to greater than
98%.
The diagnosis of a particularly aggressive form of diffuse-type gastric cancer, so called "linitis
plastica", can be difficult by endoscopy. Poor distensibility of the stomach or the classic
appearance on barium swallow (described as a leather-flask appearance) may suggest the
presence of this disease. Because these tumors tend to infiltrate the submucosa and
muscularis propria, superficial mucosal biopsies may be falsely negative. For this reason, the
combination of strip and bite biopsy techniques should be used when there is a suspicion of a
diffuse type of gastric cancer [Tsendsuren et al., 2006].
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2.1.3 Endoscopic Staging
Endoscopy with multiple (>7) biopsies providing adequate material for histologic
interpretation have become an important tool to assist with diagnosis, treatment
planning and follow up examinations. Endoscopic mucosal resection (EMR) of 1.5 cm
focal nodules can be performed in the setting of early stage disease to provide
accurate T-staging, with the potential of being therapeutic. En bloc excision by
endoscopic submucosal dissection (ESD) has been shown to be more effective than
EMR in curing early gastric cancer, but requires greater skills and instrumentation to
perform and has a significant risk of complications, including perforation [Karita and
Tada, 1994; Yahagi et al., 2004].
Endoscopic ultrasound (EUS) could be used in the initial clinical staging of gastric
cancer, since it provides evidence of depth of tumor invasion (T-stage) and presence
of abnormal or enlarged lymph nodes likely to harbor cancer (N-assessment). This is
especially important in patients who are being considered for EMR [Botet et al., 1991;
Bentrem et al., 2007; Okada et al., 2010] and could be coupled to FNA. Sometimes, it
is difficult to distinguish T2 from T3 lesions, and most errors in staging are due to
understaging nodal involvement and the depth of primary tumor invasion; however,
overstaging can also occur, and is attributed to inflammation around the tumor or to
lymph nodes [Tsendsuren et al., 2006].
EUS staging is perhaps of greatest utility for patients with early gastric cancer because
accurate assessment of submucosal invasion is essential before considering the
option of endoscopic mucosal resection. EUS findings alone rarely affect decisions
regarding the need for laparotomy, except when considering patients for a neoadjuvant therapy clinical trial, because individuals with T1 disease are generally
excluded from such studies. However, even patients with locoregionally advanced
tumors may still be candidates for surgery, particularly if a palliative resection would be
considered. EUS is not recommended for pretreatment evaluation of gastric cancer.
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December 7-9, 2011
2.1.4 Endoscopic Surveillance
Endoscopic surveillance following definitive treatment of gastric cancer requires
careful attention to detail for mucosal surface changes, and multiple (4-6) biopsies of
any visualized abnormalities. Strictures should be biopsied to rule-out neoplastic
cause. EUS performed in conjunction with endoscopy exams has a high sensitivity for
recurrent disease. EUS-guided FNA should be performed if suspicious lymph nodes or
areas of wall thickening are seen [Lightdale et al., 1989].
Endoscopic tumor ablation can be performed for the short-term control of bleeding.
Endoscopic insertion of expandable metal stents is effective in long-term relief of
tumor obstruction at the EGJ or the gastric outlet, though surgical gastro-jejunostomy
may be more efficacious for those with longer-term survival [Schmidt et al., 2009; Vakil
et al., 2001].
Long-term palliation of anorexia, dysphagia or malnutrition may be achieved with
endoscopic or radiographic assisted placement of feeding jejunostomy (PEJ) or
gastrostomy (PEG) in selected cases where the distal stomach is uninvolved by tumor,
or the placement of a feeding jejunostomy (PEJ) [Shike et al., 1996].
Recommendations

Upper GI dyspeptic symptoms in patients aged more than 55 years old
must be an indication for upper GI endoscopy. (LOE III, SOR A)

Endoscopic staging with multiple (>7) biopsies is the most sensitive
diagnostic modality of gastric cancer. Strip and bite biopsies are required
to detect carcinoma infiltrating the submucosa and muscularis propria
(linitis plastica). (LOE III, SOR A)

Endoscopic ultrasound gives information of T and N stage of the disease.
EUS findings may guide treatment strategy in case of neo-adjuvant
treatment planning, and for confirmation of an early lesion suitable for
EMR. (LOE III, SOR B)
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
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Endoscopic surveillance involves careful inspection of the gastrojejunal
mucosa and multiple biopsies of any suspicious lesion. EUS-guided FNA is
recommended in case of suspicious lymph nodes or areas of wall
thickening. (LOE III, SOR B)
2.2 GASTRIC POLYPS
The widespread use of endoscopic examinations has resulted in increased detection
of gastric polyps. Depending on histological type, some polyps have malignant
potential or require further investigation, especially if they appear as an expression of
a genetic disease or if they indicate an increased risk of intestinal and extra-intestinal
malignancy [Goddard et al., 2010]. The comprehension of the nature of gastric polyps
provides guidance for endoscopists who encounter these lesions.
2.2.1 Fundic gland polyps
Fundic gland polyps are the most common type of benign gastric polyps found on
upper endoscopy. They usually occur as sporadic, almost always in the absence of
Helicobacter pylori. They are usually multiple, sessile polyps, less than 10 mm in
diameter, located in the body and fundus. Histopathologically, they show cystically
dilated fundic glands lined by normal gastric corpus type mucosa, and the frequency of
dysplasia is low (<1% of sporadic FGPs). Since the malignant potential of these polyps
is very weak, if biopsy confirms the nature of the polyp, no follow-up is needed. Their
association with long-term proton pump inhibitors intake has been studied, and the
results are controversial. It seems that even there is an increase in the risk of fundic
gland polyps in subjects on PPI therapy, the risk of dysplasia is small [Jalving et al.,
2006]. Fundic gland polyps are also common in patients with familial adenomatous
polyposis and they develop dysplasia in 30-50% of cases. Since the presence of
numerous fundic gland polyps may be a manifestation of FAP, colonic investigation
maybe is needed to exclude FAP. If biopsy confirms the nature of the polyp, OGD
needs to be repeated every 2 years.
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2.2.2 Hyperplastic polyps
Hyperplastic polyps occur as solitary usually in the antrum or as multiple throughout
the stomach. Histopathologically, they consist of elongated tortuous glands lined by
hyperplastic foveolar type epithelium and may contain varying degrees of chronic or
active inflammation. Hyperplastic polyps’ formation may be associated with HP
infection and high serum gastrin level and up to 80% have been found to regress after
eradication of H pylori [Hongo et al., 2010]. Polypectomy has been suggested due to
the chance of causing blood loss, gastric obstruction, or because of the risk of
neoplasia especially if polyps exceed 2 cm in size.
2.2.3 Adenomatous polyps
Adenomatous polyps occur sporadically or in association with familial adenomatous
polyposis. They are usually solitary and located in the antrum on a background of
atrophic gastritis and intestinal metaplasia. Their histology consists of dysplastic
epithelium hence they are strong associated with gastric adenocarcinoma progression.
The larger the polyp, the greater the probability that the polyp contains foci of
adenocarcinoma, and in polyps larger than 2 cm the risk for focus of adenocarcinoma
is as high as 50% [Carmack et al., 2009]. All adenomatous polyps should be removed
and endoscopic follow up is required at 6 months.
2.2.4 Hamartomatous polyps
Hamartomatous polyps include juvenile polyps, polyps of Peutz-Jeghers’ syndrome,
and Cowden’s disease. Juvenile polyps are solitary and histologically have
inflammatory infiltrate without neoplastic potential. Multiple polyps are associated with
juvenile polyposis and gastric malignancy in over 50% of cases. OGD every 3 years
after age 18 is recommended [Goddard et al., 2010]. Peutz-Jeghers’ syndrome is
characterized by mucocutaneous pigmented lesions and polyps histologically easily
recognized by the presence of hyperplastic glands and a unique smooth muscle core
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that arborizes throughout the polyp. Peutz-Jeghers’ syndrome increases the risk of
gastrointestinal cancer and extra-intestinal malignancies such as breast, colon,
stomach, small intestine, ovaries, endometrial, pancreatic and lung cancers. Removal
of polyps in order to prevent polyp-related complications and annual screening of other
susceptible organs is recommended [Beggs et al., 2010]. Cowden’s syndrome is
characterized by orocutaneous hamartomatous tumors, gastrointestinal polyps,
abnormalities of the breast, thyroid gland and genitourinary system. Gastrointestinal
polyps are generally benign and histologically indistinguishable from gastric
hyperplastic polyps. Since there is no association with gastric malignancy in cases of
Cowden’s syndrome, no further OGD is recommended.
2.2.5 Familial adenomatous polyposis
Most polyps found in the stomach are usually benign fundic gland polyps and gastric
adenomatous polyps occur in only 10% of gastric polyps, usually in the antrum.
Duodenal and periampullary polyps occurring in 50-90% of patients are usually
adenomas and require frequent surveillance. Surveillance should be guided according
to the number and the size of polyps, the histological type and presence of dysplasia
and could be varied from 6 months to 4 years intervals. Endoscopic treatment of
duodenal dysplasia is associated with high recurrence rates and complications. Partial
gastrectomy, local duodenal resection or pancreaticoduodenectomy may be justified in
some patients [Brosens et al., 2005].
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3. HEREDITARY GASTRIC CANCER
3.1 INTRODUCTION AND DIAGNOSIS
1-3% of gastric cancers arise as a result of inherited gastric cancer predisposition
syndromes. Most cases represent diffuse type adenocarcinomas and are referred to as
hereditary diffuse gastric cancer (HDGC). Other syndromes include familial intestinal
gastric cancer, hereditary non-polyposis colorectal cancer (HNPCC), Li-Fraumeni
syndrome, familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS)
[Caldas, 1999; Pharoah, 2001].
HDGC diagnostic criteria include [Park, 2000; Kaurah, 2007]:
1. At least two documented cases of diffuse gastric cancer in first or second degree
relatives, at least one diagnosed before the age of 50 years.
2. At least three documented cases of diffuse gastric cancer in first or second degree
relatives regardless of age.
3. A single documented case of diffuse gastric cancer before the age of 40 years.
4. Personal or family history of diffuse gastric cancer and lobular breast cancer, at
least one before the age of 50 years.
Between 25-50% of HDGC cases carry inactivating germline mutations of the tumor
suppressor gene E-cadherin (CDH1), which are inherited in an autosomal dominant
pattern. Mutation carriers have a 60-80% lifetime risk of developing gastric cancer and
40-60% of lobular breast cancer in women. Median age at diagnosis of gastric cancer
is 38 years [Fitzgerald, 2010].
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Diagnostic approach of hereditary gastric cancer
1. Obtain family pedigree at least for 3 generations.
2. Confirm pathological diagnosis of identified cases.
3. Discuss lifetime risk.
4. Obtain informed consent for genetic testing.
5. Perform DNA analysis (sequencing and MLPA) in blood sample.
3.2 MANAGEMENT
For all individuals with suspected familial predisposition of gastric cancer, a baseline
upper GI endoscopy should be performed.
Helicobacter pylori screening should be done routinely and eradicated if identified.
All CDH1 mutation carriers should be referred for total D0 gastrectomy in early adult
life (>18) in specialized centers after appropriate counseling about the morbidity of the
operation [Norton, 2007; Fitzgerald, 2010].
Individuals who decline gastrectomy and those who do not carry a mutation or carry
mutations of undetermined significance, are offered active surveillance at least 10
years earlier from the age of the youngest affected relative. In the absence of mutation
and positive family history for HDGC, according to the criteria defined above, active
surveillance is indicated [Lynch, 2008].
3.3 SURVEILLANCE
The proper use of terminology is screening for high-risk individuals vs surveillance for
identified mutation carriers.
Offer prophylactic gastrectomy in mutation carriers. If individual declines, consider
annual endoscopy with random biopsies, ideally under a research protocol.
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Endoscopy protocol
1. Refer to specialized center.
2. Use of white light high definition endoscope and take multiple biopsies.
3. Screen for Helicobacter pylori and eradicate if identified.
Individuals should also be screened for breast and colorectal cancer if an identified
mutation carrier in the family suffered from CRC.
Screen for breast cancer
1. Breast self-exam monthly, starting at age 35.
2. Annual mammogram and MRI.
3. Insufficient date to recommend prophylactic mastectomy or chemoprevention with
tamoxifen.
Screen for CRC
Consider annual colonoscopy beginning at age 40, or 10 years younger than the
youngest diagnosis of colon cancer in the family.
Recommendations
1. Diagnosis

Identify individuals with suspected familial predisposition of gastric cancer.

Search for E-cadherin mutations and HNPCC if diagnostic criteria of either
are met. (LOE V, SOR B)
2. Management

Perform baseline endoscopy. (LOE III, SOR A)

Screen for Helicobacter pylori and eradicate if present. (LOE III, SOR A)

Offer prophylactic gastrectomy in early adult life to CDH1 mutation carriers.
(LOE III, SOR A)
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3. Surveillance

Perform annual endoscopy in persons with absence of mutation (LOE IV,
SOR B) or mutation-carriers that decline gastrectomy (LOE IV, SOR A).
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4. IMAGING WORK UP AT STAGING
4.1 CROSS SECTIONAL IMAGING MODALITIES
The accurate staging of gastric cancer is the most important prognostic factor for patient
management. Presently, endoscopic ultrasonography (EUS) is the most reliable method for
assessing the primary tumor and evaluating T and N stage with high diagnostic rates. The
accuracy of EUS for gastric cancer staging varies among different authors with ranges
between 64.8% and 92% for T staging and 50% and 90% for N staging, with a few
incidences of overstaging and understaging [Tsendsuren et al., 2006].
Multidetector CT provides relatively valuable results of T and N staging, including
differentiation between T1a, T1b, and T2 gastric cancers [Lee et al., 2010]. The use of
the combination of virtual gastroscopy and dynamic contrast-enhanced MPR images
obtained at multi–detector row CT after air and water distention of the stomach can
improve tumor detection rates as well as accuracy rates in T and N staging of gastric
cancers [Chen et al., 2007]. Virtual gastroscopy from images obtained in air-distended
stomach provides an excellent overview of abnormal mucosal lesions within the
stomach lumen [Lee, 2000]. The technique is most helpful in the detection of type IIa,
IIc, and III early gastric cancer mucosal lesions. These lesions are usually missed at
CT due to absence of thickening of the gastric wall.
At CT, positive lymph nodes are identified on the basis of size, shape, and
enhancement pattern. CT in general is relatively insensitive and also nonspecific for
detecting nodal metastases due to its inability to detect microscopic nodal invasion,
which is common in gastric cancer, and the presence of reactive nodes that may be
greater than 10 mm [Monig et al., 1999].
The role of FDG PET in the preoperative staging of gastric cancer is considered to be
still uncertain but it is most useful in detecting advanced disease [Podoloff et al.,
2007]. PET is not yet accepted because it cannot provide the exact T stage and N
stage of the disease. PET is not helpful in T staging because it is a functional imaging
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December 7-9, 2011
modality. In primary tumor detection, variable levels of FDG uptake have been found.
Gastric adenocarcinomas, such as mucinous carcinoma, signet ring cell carcinoma,
and poorly differentiated adenocarcinomas, tend to show significantly lower FDG
uptake than other histologic types of gastric cancer do.
Recommendations

Multidetector CT with a dedicated protocol is the imaging modality of
choice in the initial assessment of gastric cancer. (LOE II, SOR B)

EUS should be considered as a complementary technique for the
evaluation of T stage and N stage (with the addition of EUS-guided
biospies). (LOE II, SOR B)

FDG PET is not recommended for the initial preoperative staging of gastric
cancer, specifically in early disease. (LOE II, SOR B)
4.2 HISTOPATHOLOGICAL FEATURES
4.2.1 Specimen Preparation
The surgical specimen is preferably sent to the pathology department immediately
after removal from the patient. The specimen should be received fresh or fixed and
opened along the anterior margin of the greater curve.
4.2.2 Gross Description
The gross description report must contain at least: a) the nature of the specimen (partial, total
gastrectomy), b) length of greater and lesser curvatures of the stomach, length of duodenum
and length of esophagus, c) site of the tumor, d) distance from the proximal and distal margin,
e) tumor size at three dimensions (tumor size as a prognostic index is contradictory) and f)
macroscopic appearance according to Bormann types (polypoid: type 1, fungating: type 2,
ulcerated: type 3 and diffuse infiltrating: type 4). Several studies have shown that infiltrating type
has a poor prognosis.
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December 7-9, 2011
4.2.3 Microscopic Description
A pathology report of gastric cancer specimen should include:
Histological Type and Grade
The Lauren classification is the most in use. According to this classification, gastric
adenocarcinoma is classified as intestinal, diffuse and mixed type [Allum et al., 2002;
Burroughs et al., 1999; Novelli, 2007; Stanley et al., 2000]. According to the WHO
classification, gastric carcinomas are divided in adenocarcinoma of intestinal and
diffuse type, papillary, tubular, mucinous adenocarcinoma, signet-ring carcinoma,
adenosquamous
carcinoma,
squamous
carcinoma,
small
cell
carcinoma,
undifferentiated carcinoma and others [Novelli, 2007; Stanley et al., 2000].
Grade of differentiation of gastric adenocarcinoma is considered a major prognostic
factor. Well and moderately differentiated lesions show a better prognosis than poorly
differentiated tumors [Burroughs et al., 1999; Novelli, 2007; Stanley et al., 2000].
Depth of Invasion
Depth of invasion (T stage) is assessed according to TNM staging system as follow:
T1: tumor in the lamina propria or/and submucosa
T1a: tumor invades lamina propria or muscularis mucosae
T1b: tumor invades submucosa
T2: tumor invading the muscularis propria
T3: tumor penetrating the subserosa connective tissue without invasion of visceral
peritoneum or adjacent structures
T4: tumor invading serosa (visceral peritoneum) or adjacent structures
T4a: tumor invading serosa (visceral peritoneum)
T4b: tumor invading adjacent structures
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December 7-9, 2011
Lymphatic, Vascular, Perineural Invasion
There is evidence that lymphatic, extramural-vascular, or perineural invasion are
associated with poor prognosis.
Distal and Proximal Resection and Circumferential Margins
Status of the proximal and distal resection margin is of great prognostic value. There is
evidence that R0 resection (no residual tumor at the distal and proximal margins) is a
significant and independent prognostic factor of outcome.
For tumors located at the cardia, the status of circumferential resection margin of the
esophagus should be reported [Burroughs et al., 1999; Novelli, 2007].
Lymph Nodes
At least 12 lymph nodes should be identified in the resected specimen for an adequate
N staging according to 6th UICC classification. The number of the involved over the
total number of lymph nodes should be reported. According to the 7th UICC TNM
system, N staging depends on the positive lymph nodes as follow:






N0: negative lymph nodes
N1: 1-2 positive regional lymph nodes
N2: 3-6 positive regional lymph nodes
N3: seven or more positive regional lymph nodes
N3a: 7-15 positive regional lymph nodes
N3b: 16 or more positive regional lymph nodes
The minimum number of the lymph nodes that should be identified in a surgical
specimen is not clarified in the 7th UICC classification.
Other Prognostic Factors
There is increasing evidence [Chiaravalli et al., 2001; Solcia et al., 2007] that other
histopathological features such as T- lymphocytes peri-tumoral, intra-tumoral
infiltration and macro-satellite instability (MSI) and specific histologic subtypes
(medullary carcinoma) should be assessed. Also, most recently, evaluation of the Her2 gene status by immune-histo-chemistry, or FISH (fluorescence in situ hybridization),
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December 7-9, 2011
or real-time quantitative polymerase chain reaction (PCR), or CISH (chromogenic in
situ hybridization) is proposed as significant predictive factors. It has been shown that
overexpression of the HER-2 gene is associated with intestinal type adenocarcinomas
and well to moderate differentiated carcinomas, according to WHO classification [Min
et al., 2007; Washington, 2010].
No reactivity or membranous staining in < 10% of tumor cells
Reactivity only in part of the membrane in >10% of cells
Weak to moderate complete or basolateral membranous reactivity
Moderate to strong complete or basolateral
membranous reactivity in >10 of cells
score 0 (negative)
score 1 ( negative)
score 2( equivocal)
score 3 ( positive)
For biopsies, the cut off is 5 positive tumor cells. Some investigators consider that
biopsies with cohesive IHC score 3 focally or FISH positivity <10% of cells are positive.
Recommendations

The macroscopic pathological evaluation of a gastric cancer specimen
should include the maximum tumor diameter, and the site and the
macroscopic appearance of the tumor. (LOE III, SOR A)

The microscopic histopathological evaluation of a gastric cancer specimen
should include the depth of invasion (anatomical layer), the histological type
and
grade,
the
status
of
resection
margins
(proximal,
distal
and
circumferential), any presence of vascular or/and perineural invasion and ratio
of number of involved to total number of lymph nodes. (LOE III, SOR A)
 Maximum tumor diameter
 Site of tumor
 Macroscopic appearance of the tumor
 Depth of invasion (anatomical layer)
 Histological type
 Histological grade
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December 7-9, 2011
 Resection margins (proximal, distal and circumferential)
 Vascular, perineural invasion
 Lymph node status
 HER-2
4.2.4 Gastric endoscopic mucosal resection specimen
The specimen must be stretching and pinning on firm surface (wax). The margins
should be inking as well the deep margin. At the gross description, the size of the
specimen, appearance and the dimension of the lesion must be included. Blocks
should be taken at 2mm interval.
In the histological report, the histological type, histological grade, depth of invasion and
the status of the margins must be described. Clearance of the depth margin is
important for the local recurrence risk. Some authors showed that patients with a
clearance of minimum 2mm do not recur. In the cases with extension of the carcinoma
at the margin, the recurrence rate is 37-50%. Another important finding is the
lymphatic or vascular invasion.
The histological grade, depth of invasion and the lymphovascular invasion play an
important role for the lymph node or/and distant metastasis.
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December 7-9, 2011
5. NEO-ADJUVANT, PERI-OPERATIVE AND ADJUVANT
CHEMOTHERAPY
5.1 NEO-ADJUVANT CHEMORADIOTHERAPY
The rationale for neo-adjuvant radiochemotherapy in gastric cancer is that tumor
response and downstaging might facilitate R0 resection. Several single arm
prospective studies and retrospective analyses have suggested efficacy of
preoperative chemoradiotherapy. An early pilot study assessing the feasibility of
preoperative chemoradiotherapy showed significant pathological response in over
60% of patients with complete response in about 10% [Lowy et al., 2001]. In the
RTOG 9904 phase II study of preoperative chemotherapy (5FU/cisplatin/leucovorin)
followed by chemo-RT (45Gy and 5FU infusion and weekly paclitaxel) [Ajani et al.,
2006], pathological complete response was achieved in 26% of patients, R0 resection
in 77% and D2 lymphadenectomy in 50%. Median survival was 23 months, and 1 year
survival was 72%; however, for complete responders, 1-year OS was 82% compared
to 69% of those who achieved less than PR. In addition, neoadjuvant radiotherapy has
been evaluated in a few randomized trials. Zhang et al. randomized 370 patients with
cancer of the gastric cardia to 40Gy preoperative RT followed by surgery versus
surgery alone [Zhang 1998]. They reported improved local control (61% vs 48%),
statistically significantly improved in 5 and 10 year survival (overall survival at 10 years
20% versus 13% in the surgery group) and also higher resection rates while operative
morbidity and mortality did not differ between arms. In another trial, a trend for
improved survival was reported with a short course RT (20Gy in one week) delivered
immediately before surgery with 10 year survival of 32% versus 18% in the surgery
group [Skoropad, 2002]. In the meta-analysis published by Fiorica in 2007, which
included 4 trials of preoperative radiotherapy, 3 and 5-year mortality was significantly
reduced by preoperative radiotherapy.
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December 7-9, 2011
In a recent phase III study [Stahl et al., 2009], 119 patients with adenocarcinomas of
the gastroesophageal junction were randomized to preoperative chemotherapy or
chemoradiotherapy. Although the trial was closed early, the combined treatment
increased the pathological complete response rate and also the 3-year survival (27%
vs 47%). In all the above studies, patients with locally advanced disease (T3-T4, N+)
were included. Despite a significant amount of accumulating data on this issue [Oscar
Matzinger et al., 2009], the value of preoperative chemoradiation remains uncertain
and needs to be evaluated in prospective randomized studies.
Acute toxicity of radiotherapy to the stomach is generally moderate, including mainly
nausea, anorexia, pain, fatigue and myelosuppression with concurrent chemotherapy.
Preoperative chemoradiotherapy is generally better tolerated than postoperative
treatment, and patients are more likely to receive the prescribed doses of both
chemotherapy and radiotherapy. While there is a potential for increased surgical
morbidity and mortality, trials of preoperative chemoRT have yielded conflicting
results. The RTOG study reported a 21% grade 4 toxicity but no treatment related
deaths. In general, neoadjuvant chemoradiotherapy is associated with acceptable
toxicity.
Recommendation

Preoperative chemoradiotherapy could be considered for patients with
resectable T3-4, LN+ disease. (LOE II, SOR C)
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December 7-9, 2011
5.2 ADJUVANT CHEMORADIOTHERAPY
A number of retrospective series and prospective studies suggested significant benefit
from adjuvant chemoradiotherapy in reducing locoregional recurrences after radical
resection of gastric cancer. An early randomized trial by the British Stomach Cancer
Group showed a significant reduction in locoregional recurrence rates with
postoperative radiotherapy compared to surgery alone but no difference in survival
(10% vs 29%) [Hallisey et al., 1994]. The INT0116 study randomized 556 patients with
resected stage IB-IV M0 tumors to observation or postoperative chemoradiotherapy
(5FU/Leucovorin before, during and after RT of 45Gy in 25 fractions). With a follow-up
over 10 years, this trial showed that postoperative chemoradiotherapy significantly
decreased local failure (29% vs 19%) while improved median survival (27 vs 36
months), RFS (31% vs 48%) and OS (41% vs 50%) for all patient groups except those
with diffuse histology [Macdonald et al., 2001, 2003]. Given that no differences were
noted in rates of distant metastatic disease, the overall survival benefit has been
attributed to improvements in locoregional control, suggesting that chemotherapy is
exerting its maximum effect as a radiosensitizer. The trial was criticized because of the
suboptimal extent of surgery; the beneficial effect of chemoradiation appeared greatest
in patients who had a D1 or less than D1 resection. Although D2 lymph node
dissection was recommended, it was only performed in 10% of cases and 54% did not
even have clearance of the D1 nodal regions. Nevertheless, the results of this study
have established postoperative chemoradiotherapy as the standard of care in the
USA. A large non-randomized observational study suggested a clinical benefit from
postoperative chemoradiation after optimal D2 dissection [Kim et al., 2005]. Mature
results of two recent phase III trials (CALGB 80101, CRITICS) are pending. Alternative
chemoradiation regimens with newer agents and RT techniques have been evaluated
in small phase II studies with promising results [Leong et al 2001]. A meta-analysis of
the randomized trials in which radiotherapy (postoperative, preoperative, and
intraoperative) was compared to surgery alone or surgery plus chemotherapy in
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December 7-9, 2011
resectable gastric cancer showed a statistically significant 5-year survival benefit with
the addition of radiotherapy [Valentini et al., 2009].
Radiotherapy should be planned following CT simulation with 3-dimensional treatment
planning and should be delivered with high energy linear accelerator using a 3 or 4field technique. The target volume should include the tumor/gastric bed, the
anastomosis of stumps and pertinel lymph nodes, being based on the detailed surgical
report and the quality assessment of the fresh specimen. A dose of 45-50.4Gy in 2528 daily fractions (1.8Gy per fraction) is recommended depending on margin status
and presence of residual micro- or macroscopic disease. Every effort should be made
to reduce radiation doses to vital organs (liver, kidneys, spinal cord, lungs, heart)
below tolerance levels. The use of IMRT may be appropriate in selected cases to
reduce dose to normal structures, however, the use of this technique in gastric cancer
remains investigational.
Recommendations

Postoperative chemo-RT could be considered for patients with IB-IV stage
disease, especially in the occurrence of D0 and D1 dissection. (LOE II, SOR B)

Postoperative chemo-RT should be considered after R1 and R2 resection,
if reoperation is not feasible. (LOE III, SOR C)

Radiotherapy should be planned following CT simulation with 3dimensional treatment planning and should be delivered with high energy
linear accelerator using a 3 or 4-field technique, at a dose of 45-50.4Gy in
25-28 daily fractions (1.8Gy per fraction).
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December 7-9, 2011
5.3 PERIOPERATIVE AND ADJUVANT CHEMOTHERAPY
Following radical resection of gastric cancer, adjuvant treatment with chemotherapy or
chemoradiotherapy has been tested in many randomized control trials (RCT) in
various countries. The use of perioperative chemotherapy as a combined modality
therapy in the setting of locally-confined disease appears to confer a clinically and
statistically significant improvement in progression-free and overall survival. This
approach has become standard of care in most European and Australasian countries.
By contrast, most patients in North America are routinely treated with primary
resection
followed
by
post-operative
5FU-based
adjuvant
chemoradiation.
Nevertheless, the two approaches have never been compared in a randomized
fashion and cross-trial comparison cannot establish superiority for either strategy due
to important differences in the populations of the trials conducted so far.
At the moment, level A evidence exists only for perioperative chemotherapy (MRC
MAGIC trial, NEJM 2006, UK), post-operative chemoradiotherapy (Intergroup Study
0116, NEJM 2001, US), and post-operative chemotherapy (CLASSIC trial, ASCO
2011, Korea), (S-1 trial, NEJM 2007, Japan). There are important differences in these
four studies regarding the studied population, type and quality of surgery, timing of
studies etc.
The peri-operative chemotherapy, as tested in the MAGIC study, consisted of three
cycles of Epirubicin, Cisplatin and 5-fluorouracil (ECF) before and after surgery,
demonstrated a 13% improvement in overall survival (from 23% to 36,3%)
[Cunningham et al., 2006] (For treatment details, see APPENDIX I) Similar findings
regarding the benefit of peri-operative chemotherapy were recently reported in another
phase III study by Ychou et al. (LOE I, SOR A) [Ychou et al., 2011]. Because of the
non-inferiority of capecitabine (X) with 5-fluorouracil (5-FU) in advanced disease and
because it obviates the need for an indwelling central venous access device, many
centers use ECX in the perioperative setting [LOE IV, SOR A] The post-operative
chemoradiotherapy approach is supported by the North American Intergroup
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December 7-9, 2011
randomized study 0116, which demonstrated a 15% improvement in 5-year overall
survival (OS) [LOE I, SOR A]. (For treatment details, see APPENDIX I) Two other
phase III studies on Asian patients have been recently published and showed that
adjuvant chemotherapy, with S-1 (an oral fluoropyrimidine) for 12 months or
capecitabine plus oxaliplatin for six months, resulted in a significant improvement of
survival. [Sakuramoto et al., 2007; Bang et al., 2011] (For treatment details, see
APPENDIX I)
Two meta-analyses of RCTs on adjuvant chemotherapy in gastric cancer have been
published over the last few years. The first meta-analysis demonstrated a small
survival benefit for adjuvant chemotherapy, with an apparently greater benefit noted in
the five studies from Asia [relative risk 0.74, 95% confidence interval (CI) 0.64–0.85]
compared with the 14 studies conducted outside Asia (relative risk 0.90, 95% CI 0.85–
0.96) [LOE I, SOR A] [Liu et al., 2008]. The second meta-analysis from the GASTRIC
(Global Advanced/Adjuvant Stomach Tumor Research International Collaboration)
Group analyzed data from 17 RCTs (3838 patients) and confirmed the survival benefit
from the addition of adjuvant chemotherapy over surgery alone [HR, 0.82; CI, 0.760.90; p<0.001]. Though there was heterogeneity of the chemotherapy regimens used
in all these trials, it was reported that fluoropyrimidine-based regimens were active and
associated with reduced risk of death in resected gastric cancer compared to surgery
alone. [GASTRIC Group, Paoletti et al., 2010]
Targeted therapies
There is no evidence, so far, regarding potential benefit from the addition of a targeted
agent in the adjuvant setting GC. Therefore, use of any targeted agent should be
considered only in the context of a clinical trial.
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December 7-9, 2011
Recommendations

Patients with gastric cancer should be discussed in the context of a
multidisciplinary team meeting prior to any radical treatment, in order to
achieve the most appropriate management from diagnosis to staging and
treatment.

Patients with clinical and pathological stage IA and IB (only T2,N0) do not
derive additional benefit from adjuvant therapy.

In patients with proper pre-operative staging and D2 surgery, adjuvant
treatment options include chemotherapy with fluoropyrimidine and
platinum agent for 6-8 cycles (LOE I, SOR A) or chemoradiotherapy
according to Intergroup 0116 study regimen (LOE II, SOR B).

If peri-operative chemotherapy is opted for, this should comprise 3 cycles
of platinum-5FU based chemotherapy before and 3 cycles of the same
regimen after surgery. (LOE I, SOR A)

If no proper pre-operative management or adequate surgery (D0, no
peritoneal biopsies) was performed, the adjuvant treatment should be
individualized.
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December 7-9, 2011
GC PROPOSED TREATMENT ALGORITHM
New Pt with GC,
stage Ia, Ib T2N0
proceed to
operation after
proper staging
New Pt with GC,
stage Ib-III
discussion at MDT
prior to operation
peri-operative CTx
(ECF, ECX, FP)
Final document
surgery and
adjuvant
CTx (OX) or
CRT (5-FU)
operated without
discussion at MDT
discussion at MDT
and individualised
management
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December 7-9, 2011
APPENDIX I
Phase III Randomized controlled trials of perioperative or adjuvant treatment in gastric
and gastro-esophageal junction cancer
Study
Disease stage and study
design
Stage Ib-III
Arm 1: Surgery
Arm 2: 3 cycles ECF 
Surgery  3 cycles ECF
Treatment details
INT 0116
(postoperative
Stage Ib-IV(M0)
Arm 1: Surgery
5FU 425 mg/m2 + L 20mg/m2 (d1-5)
chemoradiotherapy)
Arm 2: Surgery 
1 cycle 5FU/L +
5FU/L/RT for 5 weeks +
2 cycles 5FU/L
Stage II-III
Arm 1: Surgery
Arm 2: Surgery  S-1
Stage II-IIIb
Arm 1: Surgery
Arm
2: Surgery 
Capecitabine + Oxaliplatin
MAGIC study
(perioperative
chemotherapy)
S-1
Postoperative
chemotherapy
CLASSIC
Postoperative
chemotherapy
Primary
endpoint
3DFS
Arm1: 23%
Arm2: 35%
mOS
Arm1: 20mo
Arm2: 24mo
Epirubicin 50mg/m2
Cisplatin 60mg/m2
5-FU 1000mg/m2 d1-21
(3 weeks cycles)
RT
4500cGy
(25#,
5d/week
mOS
Arm1: 27 mo
x Arm2: 36 mo
Comments
D
resection
at
surgeons’ discretion
Only 65% received
postoperative
chemotherapy
36% D0 resection
54% D1 resection
10% D2 resection
5weeks) with 5FU 400 mg/m 2 + L
20mg/m2 (with #1-4 and #23-25)
S-1 orally 80 mg/m2 for 4 weeks on- 3 years OS
2 weeks off (for 1 year)
Arm1: 70,1%
Arm2: 81.1%
Capecitabine 1000 mg/m2 BID d1- 3 years DFS
Arm1: 74%
14 Oxaliplatin 130 mg/m2 d1
Arm2: 59%
Every 3 weeks for 6
months (8 cycles)
≥ D2 resection
Japanese only Pts
D2 resection
Korean, Chinese and
Taiwanese Pts
Abbreviations: 5FU; 5-fluorouracil, BID; twice a day, DFS; disease free survival, L; leucovorin, mOS; median overall survival; Pts;
patients, RT; radiotherapy
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December 7-9, 2011
6. SURGICAL TREATMENT
For patients with early stage gastric cancer (Tis- T1a), the use of endoscopic mucosal
resection (EMR) [Soetikno et al., 2005] and endoscopic submucosal dissection (ESD)
[Yahagi et al., 2004] is indicated [Ono et al., 2001]. The endoscopic approach offers a
residual and recurrence- free survival rate of 98% and 93% [Oda et al., 2006]. This
stands true, in particular after en bloc ESD resection of lesions less than 5mm in
diameter [Cao et al., 2009; Hoteya et al., 2009; Nakamoto et al., 2009; Watanabe et
al., 2010]. However, the success of these methods depends on the experience of the
individual center, and is more technically demanding in case of ESD. In centers
lacking such experience, patients with early gastric cancer should be treated by
surgical local excision.
For gastric cancers invading the submucosa, there is an increased risk for lymph node
metastasis in comparison with that of mucosal invasion alone (21% vs 3.4%) [Hyung
et al., 2004]. This is the reason for which these patients cannot be offered a local
excision (endoscopic or surgical). A type of gastrectomy is recommended (distal,
subtotal or total), depending on the location of the tumor, and requires a surgical
margin greater than 4cm [Ito et al., 2004]. D1 lymph node dissection is also
recommended.
For tumors invading the muscularis propria (T2), the standard procedure for patients fit
for surgery should be gastrectomy with extended lymph node dissection (D2). This
procedure has been proven to be the most beneficial, regarding the long term survival
of patients, as it has been shown in a long term follow up in the Dutch trial [Songun et
al., 2010]. Also, an American trial of 1377 patients, regarding the influence of the
extended lymphadenectomy in advanced gastric cancer patients, underlines the need
for resection of a large number of lymph nodes and highlights the impact in survival,
depending on the number of resected negative lymph nodes (more than 15 for N2 or
more than 20 for N3) [Schwarz et al., 2007]. Resection of the spleen and pancreas
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December 7-9, 2011
should be performed only when there is a direct invasion of these organs. A
prophylactic splenectomy for the removal of negative lymph nodes near the spleen is
not recommended, according to a randomized clinical trial [Yu et al., 2006]. This is a
modification of D2 lymph node dissection (mD2) which is often described as D1.5 or
D1+ (figures 1,2). On the other hand, surgery alone is not recommended for fit patients
of these stages. Results published by the British Medical Research Council, showed a
survival rate of 36% after preoperative chemotherapy as compared to 23% after
surgery alone, in 503 patients [Cunningham et al., 2006]. The results of this study
have established preoperative chemotherapy as another option to the standard of care
for patients with resectable gastric cancer. When neoadjuvant therapy is performed,
the time to surgery is traditionally 6 to 8 weeks after the end of radiotherapy. There
are, though, retrospective reports showing that this time interval can be longer, without
any additional technical problems [Kim, 2012; Ruol, 2010].
Another treatment option for patients fit for surgery with resectable disease has been
evaluated in a large randomized trial from Japan (ACTS GC), regarding the adjuvant
use of chemotherapy after gastrectomy with D2 lymph node dissection. The study
showed a clear benefit for these patients undergoing adjuvant chemotherapy as
compared to those treated with surgery alone (80,1% versus 70,1% respectively)
[Sakuramoto et al., 2007].
Despite the advancements in staging of the disease, there is a group of patients who
unexpectedly present with advanced disease at laparotomy. For this reason,
exploratory laparoscopy and even peritoneal lavage cytology is proposed in order to
avoid unnecessary resections [Mezhir et al., 2010].
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December 7-9, 2011
Table. Treatment of Gastric Cancer According to Stage
Tis, T1a
EMR or ESD or surgery [local excision] (if EMR or ESD
not available)
T1b
Surgery (+ D1 lymphadenectomy)
Surgery (mD2) + chemo
T2- 4 , N0-3, M0
OR
Chemotherapy + surgery (mD2) + chemotherapy
OR
Chemotherapy + surgery (D0-1) + chemoradiation
OR
Surgery (D0-1) + chemoradiation
Recommendations

Tis and T1a cancers can be treated by EMR in centers of excellence (LOE
III, SOR B). Alternatively local excision is recommended.

T1b should have surgery with D1 lymph node dissection (LOE III, SOR B).

For T2- T4 N0- 3 M0, preoperative chemotherapy improves survival over
surgery alone (LOE I, SOR A).

For T2-T4 N0-3 M0, surgery with extended lymph node dissection followed
by either adjuvant chemotherapy or chemoradiation are alternative
strategies (LOE I, SOR A).

Staging laparoscopy and peritoneal fluid cytology should be considered prior
to surgery or perioperative chemotherapy for T4 or bulky tumors, in order to
identify M1 patients and modify the treatment plan (LOE III, SOR B).
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Gastric Cancer
December 7-9, 2011
FIGURE 1
Definition of the extent of lymph node dissection in gastric cancer (total
gastrectomy) Japanese gastric cancer treatment guidelines 2010 (ver. 3)
Japanese Gastric Cancer Association
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Suggestions, Opinions & Recommendations for the
Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer
December 7-9, 2011
Figure 2
Definition of the extent of lymph node dissection in gastric cancer (distal
gastrectomy) Japanese gastric cancer treatment guidelines 2010 (ver. 3)
Japanese Gastric Cancer Association
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Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer
December 7-9, 2011
7. LOCALLY ADVANCED DISEASE
(Initially not amenable to R0 resection, T3-4 N1-3 M0)
7.1 DEFINITION SELECTION CRITERIA
The purpose of the preoperative evaluation is to initially stratify patients into two
clinical groups: those with locoregional, potentially resectable (stage I to III) disease
and those with locally advanced unresectable disease or with systemic (stage IV)
involvement. Although staging is most accurately determined through surgical
pathology, clinical staging directs the initial approach to therapy: Gastric cancer often
presents with incurable disease with serosal invasion, peritoneal dissemination, and or
lymph node metastases. Also, in about 40% of patients in whom the preoperative
intention was a curative resection subsequently had a palliative operation according to
the surgeon’s opinion postoperatively. As a result there were many incomplete
resections and recurrence of tumor within 12 months and a one-year postoperative
survival of only 53%. Careful staging allows the clinician to select the most appropriate
therapy, minimizes unnecessary surgery, and maximizes the likelihood of benefit from
the selected treatment.
The only widely accepted criteria of unresectability for gastric cancer are the presence
of distant metastases, and invasion of a major vascular structure, such as the aorta, or
disease encasement or occlusion of the hepatic artery or celiac axis/proximal splenic
artery. Distal splenic artery involvement is not an indicator of unresectability; the
vessel can be resected en bloc with a left upper quadrant exenteration: stomach,
spleen and distal pancreas.
In addition, the presence of locoregional lymph node metastases that are located
topographically distant from the tumor (e.g., celiac nodes with a primary tumor on the
greater curvature of the stomach) may not necessarily be considered an indicator of
unresectability. However patients who have bulky lymph nodes involvement fixed to
the pancreatic head that might indicate the need for a Whipple procedure are at a high
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December 7-9, 2011
risk for occult metastatic disease. In these cases, it is probably best to consider
staging laparoscopy or upfront chemotherapy rather than upfront surgery. Also,
evidence of unresectability is the metastasis in lymph nodes, which are considered
outside of the surgical field such as those behind or inferior to the pancreas,
aortocaval region or in the porta hepatis (these nodes would fall into areas that would
be defined as third or fourth echelon nodes in the Japanese nomenclature). Finally,
linitis plastica is considered to be a contraindication to potentially curative resection
from many surgeons since its present is associated with an extremely poor prognosis.
Patients with locally advanced gastric cancer that is deemed inoperable initially should
be treated with palliative chemotherapy and may be reassessed for surgery if a
response is achieved. Treatments for palliation of advanced-inoperable gastric cancer
can be either local or systemic. While cytotoxic chemotherapy is the most effective
treatment modality for patients with metastatic disease and it may adequately palliate
dysphagia, other symptoms such as nausea, pain, obstruction, perforation, or bleeding
from a locally advanced or locally recurrent primary tumor often require
multidisciplinary management using endoscopic, surgical, radiotherapeutic or other
approaches. The survival benefit from combined modality therapy has become clearer
over time, although there is no consensus as to the optimal approach. The treatment
strategy should be decided in the context of a multidisciplinary team.
Recommendations

In patients with locally advanced gastric cancer, after completion of initial
treatment, restaging is recommended and if the disease has become
resectable, medically fit patients should be offered surgical resection (LOE
II, SOR B).
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December 7-9, 2011
7.2 MANAGEMENT OF LOCALLY ADVANCED GASTRIC CANCER
7.2.1 Radiotherapy
External-beam RT (45-50.4Gy) as a single modality has minimal value in patients with
locally advanced unresectable or inoperable gastric cancer and does not improve
survival. However when used concurrently with 5FU, improves survival. Moerel et al.
assessed 5FU plus RT compared with RT alone in the treatment of locally advanced
unresectable gastric cancer. Patients receiving combined modality treatment had a
significantly better median survival (13 vs 6 months) and 5-year OS (12% vs 0). In
another study by the Gastrointestinal Tumor Study Group (GITSG), patients with
unresectable gastric cancer received either combination chemotherapy (5FU-methlCCNU) or split-course RT with intravenous bolus 5FU followed by maintenance 5FU
and methyl-CCNU, showed that a small fraction of patient with unresectable cancer
can be cured with combined modality treatment. Several ongoing studies with newer
agents, including cisplatin, taxanes and irinotecan, initially followed by radiotherapy
concurrently with 5-FU or capecitabine report promising preliminary results [Saikawa
et al., 2008]. A phase II study of paclitaxel based chemoradiotherapy in gastric
carcinomas reported a 20% pathological complete response and R0 resection in 78%
of patients with acceptable toxicity [Ajani, 2005]. Neoadjuvant chemoradiation with
cisplatin-etoposide after induction chemotherapy with cisplatin/5FU is also feasible for
locally advanced EGJ carcinomas. The German POET study showed higher rates of
complete response and a trend towards survival benefit with chemoradiation [Stahl,
2009].
In patients with symptomatic locally advanced or recurrent disease, radiotherapy is
recommended for locoregional control. Hypo-fractionated radiotherapy (45-50Gy) is an
effective and well-tolerated modality to manage bleeding, pain and occasionally
obstruction [Kim et al., 2005].
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December 7-9, 2011
Recommendations

Radiotherapy (a dose of 45-50Gy) concurrently with fluoropyrimidine or
taxane based chemotherapy is recommended to medically fit patients with
unresectable loco-regional disease as well as to medically unfit patients
with loco-regional disease.

After completion of initial treatment, patients should be restaged and if the
disease has become resectable, medically fit patients should be offered
surgical resection.
7.2.2 Chemotherapy
Chemotherapy significantly improves survival comparing with BSC in patients with
advanced disease, [Wagner et al., 2005; Wagner et al., 2006]. A randomized trial
showed that the administration of ECF or FAMTX in patients with locally advanced
disease achieved objective responses that allowed curative surgery [Webb et al.,
1997]. The current standard of care for these patients is chemotherapy as neoadjuvant, based on the extrapolation of the results of the MAGIC trial [Cunningham,
2006], and, following that, re-assessment of the status of the disease with intent to
surgery. Chemotherapy regimens that have been used in this disease setting are ECF
and ECF-like (EOX, ECX, e.tc), while FAMTX, CF and TCF are considering
reasonable alternatives. Trastuzumab in combination with cisplatin/fluoropyrimidine
should be considered for patients with HER2-positive gastric tumors based on the
results
achieved
in
the
metastatic
setting.
Adjuvant
chemotherapy
or
chemoradiotherapy should be offered in case of curative resection as in patients with
initially resectable disease [Macdonald, 2001; Sakuramoto, 2007]. The use of other
targeted agents should be confined to the context of clinical trials (grade B).
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December 7-9, 2011
Recommendations

Systemic chemotherapy followed by disease re-assessment with intent to
surgery is the treatment of choice for medically fit patients with locally
advanced, initially inoperable, gastric cancer (LOE II, SOR B).

Chemotherapy with palliative intent should be offered in inoperable
patients with locally advanced disease (LOE II, SOR B)
7.2.3 Management of Peritoneal Disease
Peritoneal carcinomatosis (PC) from gastric cancer is characterized by the presence of
tumor nodules of various sizes, number and distribution on parietal or/and visceral
peritoneal surfaces. Prognosis is very poor and a median survival of less than 6
months is expected. To tackle this problem, a more aggressive treatment strategy in
the
form
of
cytoreductive
surgery
(CRS)
plus
hyperthermic
intraperitoneal
chemotherapy (HIPEC) has been proposed, over the past three decades references.
Cohort studies suggest that CRS plus HIPEC could improve outcome of patients with
PC from gastric cancer [Glehen et al., 2010]. Non-randomized comparative studies
also suggest the superior efficacy of CRS plus HIPEC over CRS alone for the
treatment of gastric PC [Spiliotis et al., 2011]. Most recently, a phase III randomized
trial has demonstrated that, for synchronous gastric PC, CRS plus HIPEC with
mitomycin and cis-platinum versus CRS alone improves survival (11months versus
6.5months, p<0.04) with acceptable morbidity [Yang et al., 2011).
Recommendations

In locally advanced unresectable gastric cancer, palliative interventions, by
means either of endoscopy or of surgery, are recommended to alleviate
symptoms form obstruction and bleeding. (LOE III, SOR C)

In advanced gastric cancer patients with peritoneal spread of the disease,
there is some evidence that cyto-reductive surgery plus hyperthermic
peritoneal chemotherapy (HIPEC) may be occasionally offered to patients
who also respond to systemic treatment. (LOE IV, SOR D)
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December 7-9, 2011
FLOW CHART
Locally advanced
unresectable
Good PS (0-1)
Palliative surgery
Poor PS (≥2)
as necessary
Neoadjuvant
Chemo-
chemotherapy
Radiotherapy
1. palliative
surgery
2. chemotherapy
3. palliative care
Re – evaluate for surgery
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8.
TREATMENT
OF
METASTATIC
December 7-9, 2011
DISEASE
AND
PALLIATIVE CARE
8.1 IMAGING
For the evaluation of distant metastasis, multidetector CT is currently the method of
choice [Habermann et al., 2004]. MRI has an additional role only in the assessment of
indeterminate liver lesions.
PET/CT is complementary to CT in detecting distant metastasis at advanced stage of
the disease. Peritoneal dissemination is a poor prognostic factor. Detection of
peritoneal metastases may change the surgical strategy from curative to palliative or
deter the surgeon from laparotomy altogether. Increasingly sophisticated CT scans
facilitate diagnosis of peritoneal metastases prior to visual inspection during surgery.
PET may give additional sensitivity to CT. Diffuse uptake of tracer that obscures the
serpiginous outline of the bowel may be an indicator of peritoneal metastases, as well
as discrete areas of local uptake along areas within the peritoneal cavity that are
otherwise anatomically unexplained [Lim et al., 2006].
PET/CT could also be considered for the evaluation of therapeutic response and to
help making the decision of continuing the ongoing therapy or redirecting the patient to
other salvage therapies. A 35% decrease in uptake between pre-chemotherapy and
PET scan taken 2 weeks after initiation of therapy predicts response with accuracy of
85% [Hopkins and Young, 2011]. The value of PET/CT in the evaluation or recurrent
gastric cancer has also been proven in many studies [Yoshioka et al., 2003].
Some studies have revealed that there is a significant discordance between the two
techniques (CT and PET/CT). This situation is mainly contributed to the sclerotic bone
lesions and the millimetric lung nodules that PET/CT fails to show. The clinical
significance of this discordance is uncertain as the millimetric nodules are sometimes
proved to be non-malignant in the clinical course. Lung nodules that do not show FDG
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December 7-9, 2011
uptake and no change in size or characteristics in consecutive CT examinations
should be clinically accepted as nonmetastatic [Ozkan et al., 2011]. Concerning
skeletal metastases, not sclerotic but lytic lesions can be apparently diagnosed by
PET/CT [Fogelman et al., 2005].
Recommendations

Multidetector CT is currently the method of choice in the assessment of
metastatic disease (LOE II, SOR B)

MRI is indicated only for the differential diagnosis of equivocal liver lesions
(LOE III, SOR B)

PET/CT is complementary to CT in detecting distant metastasis at locally
advanced gastric cancer (LOE III, SOR B)

PET/CT could be considered for the evaluation of tumor response to
therapy and in clinical suspicion of tumor recurrence non depicted on CT
(LOE II, SOR B)
8.2 CHEMOTHERAPY FOR ADVANCED OR METASTATIC
DISEASE
Palliative treatment options include chemotherapy, or clinical trial or best supportive
care. Patients with a Karnofsky performance score of 60 or less or an ECOG
performance score of 3 or more should probably be offered best supportive care only.
Patients with better performance status may be offered chemotherapy, if possible
within a clinical trial.
Chemotherapy can provide palliation and improved survival in patients with advanced
and metastatic disease. Older agents such as mitomycin, 5-fluorouracil, cisplatin, and
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December 7-9, 2011
etoposide have demonstrated activity. Newer agents such as irinotecan, oxaliplatin,
docetaxel, and capecitabine have also shown activity as single agent as well as in
combination regimens. The basic two classes of drugs include a fluoropyrimidine and
a platinum compound. Based on the patient’s performance status and organ function,
a third agent may be added.
In a randomized comparison between chemotherapy and best supportive care vs. best
supportive care alone for advanced gastric cancer, OS (8 months vs. 5 months,
though not statistically significant) and time to progression (5 months vs. 2 months, P =
0.03) were longer in patients receiving chemotherapy [Glimelius et al., 1997]. A metaanalysis of randomized trials that compared chemotherapy and supportive care in
patients with advanced gastric cancer also showed that chemotherapy increased the
one-year survival rate and improved the quality of life [Casaretto et al., 2006].
8.2.1 First-line therapy
In a large phase III RCT, patients with histologically confirmed adenocarcinoma,
squamous or undifferentiated cancer of the oesophagus, GE junction or stomach were
randomized to receive one of the four epirubicin-based regimens (epirubicin, cisplatin,
5-fluorouracil [ECF]; epirubicin, oxaliplatin, 5-fluorouracil [EOF]; epirubicin, cisplatin
and capecitabine [ECX]; and epirubicin, oxaliplatin and capecitabine [EOX]) in the
REAL2 phase III trial [Cunningham et al., 2008]. Results from this study suggest that
capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin respectively,
in patients with previously untreated oesophagogastric cancer. As compared with
cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia,
alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of
grade 3 or 4 diarrhoea and neuropathy. The toxic effects from 5-fluorouracil and
capecitabine were not different.
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December 7-9, 2011
ML 17032, another phase III randomized trial, evaluated the combination of
capecitabine and cisplatin (XP) versus the combination of 5-fluorouracil and cisplatin
(FP) as first-line treatment in patients with advanced gastric cancer [Kang et al., 2006].
Overall response rate (41% for XP vs. 29% for FP, P = 0.03) and non-inferior for PFS
(5.6 for XP vs. 5.0 for FP, P = 0.003). No difference was seen for OS between the two
arms. The results of this study suggest that capecitabine is as effective as 5fluorouracil in the treatment of patients with advanced gastroesophageal cancers.
An individual-patient data meta-analysis of the REAL-2 and ML17032 trials suggested
that OS was superior in the 654 patients treated with capecitabine-based combinations
compared with the 664 patients treated with 5-fluorouracil-based combinations (HR
0.87, 95% CI 0.77-0.98, P = 0.02) although no significant difference in PFS between
treatment groups was seen [Okines et al., 2009].
The V325 study compared Cisplatin infusional 5FU chemotherapy to a three-drug
regimen (docetaxel, cisplatin, infusional 5FU) [Van Cutsem, 2006]. DCF was superior
in terms of RR (37% vs. 25%, P = 0.01), TTP (HR 1.47, 95% CI 1.19-1.82), OS (HR
1.29, 95% CI 1.0-1.6), though at a cost of enhanced toxicity, including a 29% rate of
febrile neutropenia. Several attempts have been made to decrease the toxicity of the
DCF combination by testing modified regimens [Ajani, 2008] and most new trials use
one
of
these
regimens for advanced gastric cancer.
Another novel oral
fluoropyrimidine S-1 has shown promise in advanced gastric cancer, both as a single
agent and in combination with cisplatin in early phase studies. In a randomized phase
III trial conducted in Japan (SPIRITS trial), 298 patients with advanced gastric cancer
were randomized to S-1 plus cisplatin versus S-1 alone [Koizumi et al., 2008]. Median
OS (13 vs. 11 months; HR 0.77, 95% CI 0.61-0.98) and PFS (6.0 vs. 4 months, P <
0.0001) were significantly longer for the combination of S-1 and cisplatin compared
with S-1 alone.
Results of First Line Advanced Gastric Cancer Study (FLAGS) comparing the
combination of cisplatin and S-1 (CS) with cisplatin and 5-fluorouracil (CF) in patients
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December 7-9, 2011
with advanced gastric/gastroesophageal adenocarcinoma were recently presented
[Ajani et al., 2009]. In this study, 1053 patients were randomized to either CS or CF.
The investigational CS regimen had similar efficacy compared to CF with improved
safety. Additional studies are needed to confirm the activity of S-1 in the US and
western hemisphere.
Irinotecan as a single agent or in combination has been explored in single arm and
randomized clinical trials. The results of a randomized phase III study comparing
weekly irinotecan with infusional 5-FU and folinic acid to cisplatin with infusional 5-FU
in patients with advanced adenocarcinoma of the stomach or GE junction showed noninferiority for PFS but not for OS and improved tolerance of the irinotecan containing
regimen; it can therefore be an alternative when platinum-based therapy cannot be
delivered [Dank et al., 2008]. In another randomized multicenter phase II study,
Moehler et al. compared capecitabine combined with irinotecan or cisplatin in
metastatic adenocarcinoma of the stomach or GE junction [Moehler et al., 2010].
There were no significant differences in overall response rates (37.7% and 42.0%
respectively), and median PFS (4.2 months and 4.8 months respectively, P = 0.56),
although there was a trend towards better median OS in the irinotecan arm (10.2 vs.
7.9 months, P = 0.13). The results of this study need to be validated further in larger
studies. Irinotecan has not produced level 1 evidence for prolongation of survival in
patients with advanced gastric cancer; therefore, its use is preferred in the second or
third line setting.
Oxaliplatin has also being tested for advanced gastric cancer, mostly as part of the
FOLFOX regimen. In a randomized clinical trial, FOLFOX-4 regimen was tested
against the paclitaxel with cisplatin and 5-FU regimen in 94 patients with advanced
gastric cancer [Li et al., 2011]. No significant difference was observed between the two
arms in RR, disease control rate, median survival and one-year survival. Several
single-arm phase II trials have also tested the FOLFOX regimen and its modifications
in elderly patients, providing an option when more toxic chemotherapy cannot be
tolerated.
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8.2.2 Second-line therapy
A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie
(AIO) comparing irinotecan to best supportive care in the second-line setting showed
that irinotecan significantly prolonged OS compared to best supportive care [ThussPatience et al., 2009]. Median survival was 123 days in the irinotecan arm compared
to 72.5 days in the best supportive care only arm (HR 2.85, 95% CI 1.41-5.79).
Second-line chemotherapy with irinotecan, fluorouracil and leucovorin (FOLFIRI) was
also active and well tolerated in patients with metastatic gastric cancer not previously
treated with fluoropyrimidines [Di Lauro et al., 2009].
8.2.3 Targeted Therapies
The overexpression of epidermal growth factor receptor (EGFR), vascular endothelial
growth factor receptor (VEGFR) and HER2-neu has been associated with poor
prognosis in patients with gastric and esophageal cancers. In clinical trials,
trastuzumab (anti-HER2 antibody), bevacizumab (an anti-VEGFR antibody) and
cetuximab
(anti-EGFR antibody) have
been
evaluated
in combination
with
chemotherapy in the treatment of patients with advanced gastric and GE junction
adenocarcinoma.
The ToGA study is the first randomized, prospective, multicenter, phase III trial to
evaluate the efficacy and safety of trastuzumab in patients with HER2-neu-positive
gastric and EGJ adenocarcinoma in combination with cisplatin and a fluoropyrimidine
[Bang et al., 2010]. The results of this study confirmed that trastuzumab plus standard
chemotherapy is superior to chemotherapy alone in patients with HER2-neu-positive
advanced gastric cancer. 594 patients with HER2-neu-positive gastroesophageal and
gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were randomized
to receive trastuzumab plus chemotherapy (5-fluorouracil or capecitabine and
cisplatin) or chemotherapy alone. HER2 positivity was defined as HER2 IHC 3+ or
FISH+. There was a significant improvement in the median OS with the addition of
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December 7-9, 2011
trastuzumab to chemotherapy compared to chemotherapy alone (13.5 vs. 11.1
months; HR 0.74, 95% CI 0.60-0.91). The most striking survival advantage (16.5 vs 11
months) was seen in patients harbouring tumor IHC HER2 3+ and IHC 2+ with FISH+.
Safety profiles were similar, with no unexpected adverse events in the trastuzumab.
There was also no difference in symptomatic congestive heart failure between arms.
This establishes that trastuzumab plus chemotherapy as a new standard of care for
the treatment of patients with a HER2-neu-expressing advanced gastric and EGJ
adenocarcinoma. The use of trastuzumab in combination with an anthracycline is not
recommended. Although no randomized trials have been reported as yet, it is
reasonable to administer a trastuzumab-containing regimen for second-line treatment
for trastuzumab-naive patients. There is no evidence currently to support continuation
of trastuzumab with different chemotherapy agents beyond first-line treatment, as is
the case for advanced breast cancer.
The safety and efficacy of lapatinib, bevacizumab, erlotinib, sorafenib, and cetuximab,
has been evaluated in multiple phase II studies. The AVAGAST phase III trial
randomized patients with advanced gastric cancer to cisplatin and a fluoropyrimidine
with or without bevacizumab and failed to show improvement of its primary endpoint,
OS (HR 0.87, 95% CI 0.73-1.03) [Ohtsu et al., 2011]. However, response rates (46.0%
vs. 37.4%, P = 0.0315) and median PFS (HR 0.80, 95% CI 0.68-0.93) were improved
with the addition of bevacizumab. Ongoing phase III trials are underway to confirm the
efficacy and safety of the above mentioned agents in combination with standard
chemotherapy in patients with advanced gastric and EGJ adenocarcinoma.
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December 7-9, 2011
Conclusions
First-line therapy
 DCF or its modifications
 ECF or its modifications
 Regimens
incorporating
platinum
salts
(cisplatin
or
oxaliplatin)
with
a
fluoropyrimidine
 Trastuzumab with active chemotherapy for patients who are HER2-neu-positive, as
determined by a standardized method (IHC 3+ or IHC 2+ and FISH+).
Second-line therapy
 Trastuzumab with active chemotherapy for patients who are HER2-neu-positive, if
not used as first-line therapy
 Docetaxel
 Irinotecan-based single agent or combination therapy
Recommendations

Regimens should be chosen in the context of performance status, medical
comorbidities, toxicity profile, and HER2-neu expression.

The backbone of a modern chemotherapy regimen for advanced gastric
cancer consists of a platinum compound with a fluoropyrimidine (LOE I,
SOR A). An alternative regimen for patients intolerant to platinum is a
fluoropyrimidine/irinotecan combination (LOE II, SOR C).

Two-drug regimens are preferred. The use of three-drug regimens for
advanced disease should be reserved for patients who are medically fit,
with a good performance status (ECOG performance status of 0 or 1), and
with access to frequent toxicity assessment.
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
December 7-9, 2011
Infusional 5-FU and capecitabine may be used interchangeably (except as
indicated). Infusion is the preferred route compared with bolus 5-FU (LOE I,
SOR A).

Cisplatin and oxaliplatin may be used interchangeably depending on
toxicity profile (LOE I, SOR A).

Trastuzumab
with
chemotherapy
for
HER2-neu
overexpressing
adenocarcinoma according to TOGA trial (LOE I, SOR A) for combination
with cisplatin and fluoropyrimidine (not recommended for use with
anthracyclines) is standard treatment approach.

Recent phase III data support the administration of second line therapy
(irinotecan or docetaxel) in selected fit patients.

Administration of second-line trastuzumab in combination with nonanthracycline cytotoxic compounds in cases of patients with HER2overexpressing gastric cancers not treated with trastuzumab in the firstline setting could be considered (LOE V, SOR C).
8.3 PALLIATIVE AND SUPPORTIVE CARE
The goal of best supportive care is to prevent, reduce, and relieve suffering, and
improve the quality of life for patients and their caregivers, regardless of disease
stage. In patients with unresectable or locally advanced cancer, palliative interventions
undertaken to relieve major symptoms may also result in prolongation of life. Best
supportive care is always indicated for patients with advanced gastric cancer. The
decision to offer best supportive care alone or with chemotherapy is dependent on the
patient’s performance status.
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December 7-9, 2011
8.3.1 Chemoradiotherapy
In patients with symptomatic locally advanced or recurrent disease radiotherapy is an
effective and well tolerated modality to palliate persistent symptoms [Tey et al., 2006].
With moderate doses, 30-40Gy, 50-75% patients experience improvement of
symptoms such as bleeding, outlet obstruction or pain with palliation lasting the
majority of patients’ lives. Bleeding can often be stopped with radiation doses of 20Gy
in 5 fractions in one week. There is some evidence that patients receiving combined
chemotherapy and higher dose radiotherapy have better local tumor control and longer
duration of response [Kim et al., 2008]. Currently, there is increasing interest in the use
of Strereotactic Body RadioTherapy (SBRT) in the treatment of small liver metastases,
by delivering high doses of radiation (21Gy in 7 fractions).
Recommendations

Radiotherapy with or without chemotherapy could be considered for
palliation in metastatic gastric cancer (LOE II, SOR B).
8.3.2 Surgery
There is no important role for surgery in patients with liver metastasis from gastric
cancer. There are sporadic reports in the literature with limited number of patients
included, and therefore of limited scientific value. Liver metastasis from gastric cancer
is usually associated with extra-hepatic disease including peritoneal dissemination,
lymph nodes metastasis etc references.
In the published series, resection rate is reported to around 20%, and survival is rather
unsatisfactory, as patients develop intra-hepatic as well as distant recurrence.
Prognostic factors of liver metastases resectability are the stage of the primary tumor,
the number of liver metastasis, the timing of diagnosis in case of metachronous
lesions, and status of surgical margins after resection. It has been suggested that
patients with metastatic liver disease from gastric cancer are candidates for resection
when there is no serosa, venous or lymphatic invasion of the primary tumor, metastatic
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lesions are unilobar and show a maximum diameter of <4cm. Radiofrequency ablation
can be used in combination with chemotherapy when the tumor is <3cm in diameter,
but the level of evidence is very low references.
Recommendations

The role of surgery in liver metastasis form gastric cancer is limited, and
recommended when primary gastric lesion is limited to the gastric
muscular wall, and metastases are unilobar and <4cm in diameter (LOE III,
SOR C)

Evidence of radiofrequency ablation of liver metastases is of very low level
(LOE IV, SOR C)
8.4 TUMOR-RELATED SYMPTOMS
In patients with unresectable or locally advanced cancer, palliative interventions
provide relief of symptoms and improve the nutritional status and overall quality of life.
The optimal management is debated and the choice of palliative methods should be
based upon anatomical features, patient preferences, and available expertise so,
multimodality interdisciplinary approach is encouraged. Methods for palliation of
dysphagia
include
endoscopic
therapies,
radiation
therapy,
brachytherapy,
chemotherapy or surgery. In a study from Homs et al, single dose brachytherapy was
associated with fewer complications and better long-term relief of dysphagia compared
with metal stents (Homs, 2004). For patients with complete esophageal obstruction,
endoscopic
lumen
restoration,
external
beam
RT
and
chemotherapy
are
recommended. There are several endoscopic approaches providing palliation from
malignant dysphagia such as dilation, laser and photodynamic therapy and stent
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Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer
December 7-9, 2011
placement. Esophageal dilation can be performed with the use of dilating balloons or
bougies to temporarily relieve obstruction from tumors or treatment related strictures.
Long-term palliation of dysphagia can be achieved with endoscopic tumor ablation by
Nd:YAG laser and PDT, or endoscopic and radiographic assisted insertion of
expandable metal or plastic stents [Lightdale et al., 1995; Vakil et al., 2001]. Placement
of self-expanding metal stents is the preferred treatment for patients with
tracheoesophageal fistula and those who are not candidates for chemoradiation or
those who failed to achieve adequate palliation with such therapy [Ross, 2007].
Surgical or radiographic assisted placement of feeding jejunostomy or gastrostomy
tubes may be necessary to provide adequate hydration and nutrition and long-term
palliation of anorexia and dysphagia. Percutaneous endoscopic gastrostomy in the
preoperative setting may compromise the gastric vasculature, thereby interfering with
the creation of the gastric conduit in the reconstruction during esophagectomy and
should be avoided.
External beam RT and/or endoscopic therapy may be indicated in patients with brisk
bleeding from the cancer. Bleeding that occurs primarily from the tumor surface may
be controlled with endoscopic coagulation techniques such as argon plasma
coagulation but bleeding could also be secondary to tumor related aorto-esophageal
fistulization.
Recommendations

Patients with acute severe bleeding should undergo prompt endoscopic
assessment. Endoscopic hemostatic interventions appropriate to the
findings should be carried out. Interventional radiology angiographic
embolization, external beam radiation therapy may control bleeding if
endoscopy fails (LOE V, SOR C).

External beam radiation therapy may successfully palliate pain at primary
or metastatic sites (LOE V, SOR C).
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Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer

December 7-9, 2011
Endoscopic relief of obstruction by means of balloon dilation, placement of
expandable stent for relief of outlet obstruction or esophageal stent for
EGJ/cardia obstruction or percutaneous endoscopic gastrostomy is
warranted in patients with shorter life expectancy (LOE V, SOR C).

Surgical palliative resection is applied either at the time of diagnosis of an
otherwise noncurable disease or after failure of endoscopic methods to
control bleeding or relieve obstruction (LOE V, SOR C).
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Diagnosis, Management, Treatment and Surveillance of
Gastric Cancer
December 7-9, 2011
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POSITION STATEMENT
According to current evidence and practice, patients with “esophageal cancer” and
“gastric cancer” should be referred for care to highly specialized centers with adequate
case volume, as this ensures better outcomes in terms of morbidity, mortality, local
recurrence and survival. At those centers, a multidisciplinary team of surgeons,
oncologists, pathologists, radiotherapists and radiologists should be on charge, caring
for the patients at any stage of the treatment from the initial evaluation to the follow-up,
according to the recommendations listed above.
Audit and quality control of therapeutic services require compulsory patient’s full data
collection and registration according to regional or national programs. Registered data
should include all preoperative characteristics, intraoperative outcomes and quality of
surgery parameters, postoperative morbidity and mortality, follow-up details and
oncological outcomes, as also defined above. A case-mixed adjusted feedback is
crucial in the whole process of the “quality assurance” concept. If suboptimal
performance is encountered, the responsible treating team should be instructed to
improve results by further and more intensive training or to cease treating such cases.
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