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Suggestions, Opinions & Recommendations

for the Diagnosis, Management, Treatment and Surveillance of Gastric

Cancer

2011Hellenic 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 December 7-9, 2011

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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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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 meta-

analyses 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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Contents

LEGAL DISCLAIMER..................................................................................................2

EVIDENCE LEVEL AND RECOMMENDATION GRADE............................................3

1. GENERAL CONSIDERATIONS...............................................................................61.1 MOLECULAR BASIS..........................................................................................71.2 PROGNOSTIC AND PREDICTIVE FACTORS...................................................7

2. DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS..............................................92.1 CLINICAL PRESENTATION, DIAGNOSIS AND STAGING................................9

2.1.1 Clinical features........................................................................................92.1.2 Diagnosis................................................................................................102.1.3 Endoscopic Staging................................................................................112.1.4 Endoscopic Surveillance.........................................................................12

2.2 GASTRIC POLYPS...........................................................................................132.2.1 Fundic gland polyps................................................................................132.2.2 Hyperplastic polyps.................................................................................142.2.3 Adenomatous polyps..............................................................................142.2.4 Hamartomatous polyps...........................................................................142.2.5 Familial adenomatous polyposis.............................................................15

3. HEREDITARY GASTRIC CANCER.......................................................................163.1 INTRODUCTION AND DIAGNOSIS.................................................................163.2 MANAGEMENT.................................................................................................173.3 SURVEILLANCE...............................................................................................17

4. IMAGING WORK UP AT STAGING......................................................................204.1 CROSS SECTIONAL IMAGING MODALITIES.................................................204.2 HISTOPATHOLOGICAL FEATURES...............................................................21

4.2.1 Specimen Preparation............................................................................214.2.2 Gross Description...................................................................................214.2.3 Microscopic Description..........................................................................224.2.4 Gastric endoscopic mucosal resection specimen...................................25

5. NEO-ADJUVANT, PERI-OPERATIVE AND ADJUVANT CHEMOTHERAPY......265.1 NEO-ADJUVANT CHEMORADIOTHERAPY....................................................265.2 ADJUVANT CHEMORADIOTHERAPY.............................................................285.3 PERIOPERATIVE AND ADJUVANT CHEMOTHERAPY..................................30

6. SURGICAL TREATMENT......................................................................................35

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7. LOCALLY ADVANCED DISEASE.........................................................................407.1 DEFINITION SELECTION CRITERIA...............................................................407.2 MANAGEMENT OF LOCALLY ADVANCED GASTRIC CANCER...................42

7.2.1 Radiotherapy..........................................................................................427.2.2 Chemotherapy........................................................................................437.2.3 Management of Peritoneal Disease........................................................44

................................................................................................................................... 45

8. TREATMENT OF METASTATIC DISEASE AND PALLIATIVE CARE.................468.1 IMAGING...........................................................................................................46

8.2 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE..................478.2.1 First-line therapy.....................................................................................488.2.2 Second-line therapy................................................................................518.2.3 Targeted Therapies................................................................................51

8.3 PALLIATIVE AND SUPPORTIVE CARE...........................................................548.3.1 Chemoradiotherapy................................................................................558.3.2 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 factorsAdvanced 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 factorsMany 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

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in the cul-de-sac on rectal examination (Blumer's shelf). However, there are patients

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

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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].

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 neo-

adjuvant therapy clinical trial, because individuals with T1 disease are generally

excluded from such studies. However, even patients with locoregionally advanced

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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.

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

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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)

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

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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.

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.

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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

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

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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 cancer1. 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 cancer1. 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 CRCConsider 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)

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Offer prophylactic gastrectomy in early adult life to CDH1 mutation carriers. (LOE III, SOR A)

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

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stage of the disease. PET is not helpful in T staging because it is a functional imaging

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,

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ulcerated: type 3 and diffuse infiltrating: type 4). Several studies have shown that infiltrating type

has a poor prognosis.

4.2.3 Microscopic Description

A pathology report of gastric cancer specimen should include:

Histological Type and GradeThe 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 InvasionDepth 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)

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T4b: tumor invading adjacent structures

Lymphatic, Vascular, Perineural InvasionThere is evidence that lymphatic, extramural-vascular, or perineural invasion are

associated with poor prognosis.

Distal and Proximal Resection and Circumferential MarginsStatus 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 NodesAt 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

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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 Her-

2 gene status by immune-histo-chemistry, or FISH (fluorescence in situ hybridization),

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 score 0 (negative)Reactivity only in part of the membrane in >10% of cells score 1 ( negative)Weak to moderate complete or basolateral membranous reactivity score 2( equivocal)Moderate to strong complete or basolateralmembranous reactivity in >10 of cells 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

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Site of tumor

Macroscopic appearance of the tumor

Depth of invasion (anatomical layer)

Histological type

Histological grade

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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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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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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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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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 4-

field 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 25-

28 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 3-

dimensional 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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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

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chemoradiotherapy approach is supported by the North American Intergroup

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, 0.76-

0.90; 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 therapiesThere 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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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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GC PROPOSED TREATMENT ALGORITHM

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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)

surgery and adjuvant

CTx (OX) or CRT (5-FU)

operated without discussion at MDT

discussion at MDT and individualised

management



APPENDIX IPhase III Randomized controlled trials of perioperative or adjuvant treatment in gastric

and gastro-esophageal junction cancerStudy Disease stage and study

designTreatment details Primary

endpointComments

MAGIC study(perioperative

chemotherapy)

Stage Ib-IIIArm 1: SurgeryArm 2: 3 cycles ECF Surgery 3 cycles ECF

Epirubicin 50mg/m2

Cisplatin 60mg/m2

5-FU 1000mg/m2 d1-21(3 weeks cycles)

3DFSArm1: 23%Arm2: 35%mOSArm1: 20moArm2: 24mo

D resection at surgeons’ discretion

Only 65% received postoperative chemotherapy

INT 0116(postoperative

chemoradiotherapy)

Stage Ib-IV(M0)Arm 1: Surgery

Arm 2: Surgery 1 cycle 5FU/L +5FU/L/RT for 5 weeks +2 cycles 5FU/L

5FU 425 mg/m2 + L 20mg/m2 (d1-5)

RT 4500cGy (25#, 5d/week x

5weeks) with 5FU 400 mg/m2 + L

20mg/m2 (with #1-4 and #23-25)

mOSArm1: 27 moArm2: 36 mo

36% D0 resection54% D1 resection10% D2 resection

S-1Postoperative chemotherapy

Stage II-IIIArm 1: SurgeryArm 2: Surgery S-1

S-1 orally 80 mg/m2 for 4 weeks on- 2 weeks off (for 1 year)

3 years OSArm1: 70,1%Arm2: 81.1%

≥ D2 resection

Japanese only PtsCLASSICPostoperative chemotherapy

Stage II-IIIbArm 1: SurgeryArm 2: Surgery Capecitabine + Oxaliplatin

Capecitabine 1000 mg/m2 BID d1-

14 Oxaliplatin 130 mg/m2 d1Every 3 weeks for 6 months (8 cycles)

3 years DFSArm1: 74%Arm2: 59%

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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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,

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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

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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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).

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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).

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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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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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

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the pancreatic head that might indicate the need for a Whipple procedure are at a high

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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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-methl-

CCNU) 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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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 neo-

adjuvant, 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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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)

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Locally advanced unresectable

Good PS (0-1) Poor PS (≥2)

Neoadjuvant chemotherapy Chemo-Radiotherapypalliative surgerychemotherapypalliative care

Palliative surgery as necessary



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)

FLOW CHART

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Re – evaluate for surgery



8. TREATMENT OF METASTATIC 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

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proved to be non-malignant in the clinical course. Lung nodules that do not show FDG

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.

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Chemotherapy can provide palliation and improved survival in patients with advanced

and metastatic disease. Older agents such as mitomycin, 5-fluorouracil, cisplatin, and

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 meta-

analysis 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

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grade 3 or 4 diarrhoea and neuropathy. The toxic effects from 5-fluorouracil and

capecitabine were not different.

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 5-

fluorouracil 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 <

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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

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 non-

inferiority 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

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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.

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 [Thuss-

Patience 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

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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

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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ConclusionsFirst-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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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 non-anthracycline cytotoxic compounds in cases of patients with HER2-overexpressing gastric cancers not treated with trastuzumab in the first-line 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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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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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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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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9. REFERENCES

Ajjani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiation in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 2005;20:1237-1244.

Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS). Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium; 2009 January 15-17; San Francisco, USA.

Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologia response. J Clin Oncol 2006;24:3953-3958.

Ajani JA. Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction: evolution of the docetaxel, cisplatin, and 5-fluorouracil regimen. Cancer. 2008;113:945-55.

Allum H W, Griffin S M, Watson A, Colin-Jones D, on behalf of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, British Society of Gastroenterology, and the British Association of Surgical Oncology. Guidelines for the management of oesophageal and gastric cancer. Gut 2002 50 Suppl V v1-v23

An JY, Kim JY, Choi MG, et al. RF ablation for hepatic metastasis from gastric adeno-carcinoma. Yonsei Med J 2008;49:1046-51.

Anderson WF, Camargo MC, Fraumeni JF Jr, Correa P, Rosenberg PS, Rabkin CS. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 2010; 303: 1723-8.

Bang Y, Kim Y.W, Yang H et al. Adjuvant capecitabine and oxaliplatin for gastric cancer: Results of the phase III CLASSIC trial. J Clin Oncol 29: 2011 (suppl; abstr LBA4002)

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376: 687-97.

Final document



Becker K, Mueller JD, Schulmacher C, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003; 98: 1521-30.

Beggs AD, Latchford AR, Vasen HF, Moslein G, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 2010;59:975-86

Bentrem D, Gerdes H, Tang L, Brennan M, Coit D. Clinical correlation of endoscopic ultrasonography with pathologic stage and outcome in patients undergoing curative resection for gastric cancer. Ann Surg Oncol. 2007;14:1853-9.

Biffi R, Fazio N, et al. Surgical outcome after docetaxel-based neoadjuvant chemotherapy in locally-advanced gastric cancer. World J Gastroenterol 2010; 16(7): 868-874.

Botet JF, Lightdale CJ, Zauber AG, et al. Endoscopic ultrasound in the pre-operative staging of gastric cancer: A comparative study with dynamic CT. Radiology 1991;181:426-32.

Burroughs H S, Biffin H B A, Pye K J, Williams T G. Oesophageal and gastric cancer pathology reporting : a regional audit. J Clin Pathology 1999; 52: 435-439.

Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet 1999; 36: 873-880.

Cao Y, Liao C, Tan A, et al. Meta- analysis of endoscopic submucosal dissection versus endoscopic mucosal resection for tumors of the gastrointestinal tract. Endoscopy 2009;41:751-7.

Carmack SW, Genta RM, Graham DY, and Lauwers GY. Management of gastric polyps: a pathology-based guide for gastroenterologists. Nat Rev Gastroenterol Hepatol 2009;6:331-41

Casaretto L, Sousa PL, Mari JJ. Chemotherapy versus support cancer treatment in advanced gastric cancer: a meta-analysis. Braz J Med Biol Res. 2006;39:431-40.

Chen CY, Hsu JS, Wu DC, et al. Preoperative local staging with 3D multi–detector row CT: correlation with surgical and histopathologic results. Radiology 2007; 242:472-82.

Final document



Chiaravalli AM, Crnaggia M, Furlan D, Capella C, Fiocca R, Tagliabue G, Klersy C, Solcia E, The role of histological investigation in prognostic evaluation of advance gastric cancer Virchows Arch 2001; 439: 158-169.

Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11-20.

Cunningham D, Starling N, Rao S, et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46.

Dank M, Zaluski J, Barone C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008;19:1450-7.

Di Lauro L, Fattoruso S. I, Giacinti L, Vici P, Sergi D, and Lopez M. Second-line chemotherapy with FOLFIRI in patients with metastatic gastric cancer (MGC) not previously treated with fluoropyrimidines. J Clin Oncol. 27(15S):4549.

Ferlay J, Autier P, Boniol M et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581–592.

Fiorica F, Cartei F, Enea M, et al. The impact of radiotherapy on survival in resectable gastric carcinoma: a meta-analysis of literature data. Cancer Treat Review 2007;33:729-740.

Fitzgerald RC, Hardwick R, Huntsman D, et al, International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010; 47(7): 436.

Fogelman I, Cook G, Israel O, et al. Positron Emission Tomography and Bone Metastases. Semin Nucl Med 2005; 35:135-142.

Fuchs CS, Tepper JE, Niedzwiecki D et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101. J Clin Oncol 29: 2011 (suppl; abstr 4003)

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GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group, Paoletti X, Oba K, Burzykowski T et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis: JAMA. 2010; 303(17):1729-37.

Glehen O, Gilly F, Arnieu C, et at: Peritoneal carcinomatosis from gastric cancer: A multi-institutional analysis of 159 pts treated by CRS + HIPEC. Ann Surg Oncol 2010;17:2370-7.

Glimelius B, Ekström K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997;8:163-8.

Goddard AF, Badreldin R, Pritchard DM, Walker MM, Warren B, on behalf of the British Society of Gastroenterology. The management of gastric polyps. Gut 2010;59:1270-6

Habermann CR, Weiss F, Riecken R, et al. Preoperative staging of gastric adenocarcinoma: comparison of helical CT and endoscopic US.Radiology 2004; 230(2):465-471.

Hallisey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five year follow-up. Lancet 1994;343:1309-1312.

Henson DE, Dittus C, Younes M, Nquyen H, Albores-Saavedra J. Differential trends in the intestinal and diffuse type of gastric carcinoma in the United States 1973-2000: increase in the signet ring cell type. Arch Pathol Lab Med 2004; 128: 765-76.

Homs MY, Steyerberg EW, Eijkenboom WM, et al. Single-dose brachytherapy versus metal stent placement for the palliation of dysphagia from oesophageal cancer: multicentre randomised trial. Lancet 2004;364:1497-1504.

Hongo M, Fujimoto K; Gastric Polyps Study Group. Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan. J Gastroenterol 2010;45(6):618-24.).

Hopkins S, Yang G. FDG PET imaging in the staging and management of gastric cancer. J Gastrointest Oncol 2011; 2(1):39-44.

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Hoteya S, Iizuka T, Kikuchi D, et al. Benefits of endoscopic submucosal dissection according to size and location of gastric neoplasm, compared with conventional mucosal resection. J Gastroenterol Hepatol 2009;24:1102-6.

Hyung WJ, Cheong JH, Kim J, et al. Application of minimally invasive treatment for early gastric cancer. J Surg Oncol 2004;85:181-5.

International Gastric Cancer Association Consensus Meeting 2009, Krakow, Polland 2009.

Ito H, Clancy TE, Osteen RT, et al. Adenocarcinoma of the gastric cardia: what is the optimal surgical approach? J Am Coll Surg 2004;199:880-6.

Jalving M, Koornstra JJ, Wesseling J, Boezen HM, DE Jong S, Kleibeuker JH. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther 2006;24(9):1341-8

Kakeji Y, Morita M, Maehara Y, et al. Strategies for treating liver metastasis for gastric cancer; Surg Today 2010;40:287-94.

Kang Y, Kang WK, Shin DB, et al. Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): efficacy and safety results. J Clin Oncol. 2006;24(18S):LBA4018.

Karita M, Tada M. Endoscopic and histologic diagnosis of submucosal tumors of the gastrointestinal tract using combined strip biopsy and bite biopsy. Gastrointest Endosc 1994;40:749.

Kattan MW, Karpeh MS, Mazumdar M, Brennan MF. Postoperative nomogram for disease –specific survival after R0 resection for gastric cancer. J Clin Oncol 2003; 21: 3647-50.

Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297(21): 2360.

Kim J, Correa A, et al. Does the timing of esophagectomy after chemoradiation affect outcome? Ann Thorac Surg 2012;93:207-13

Kim S, Lim DH, Lee J, et al. An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric

Final document



resection with D2 nodal dissection for adenocarcinoma of the stomach. Int J Rad Oncol Biol Phys 2005;23:4509-4517.

Kim S, Lim DH, Lee J, et al. An observational study suggesting clinical benefit for adjuvant + postoperative chemoradiation in population of over 500 cases for adenocarcinoma of the stomach. Intern J Rod Oncol Biol Physiol 2005;63:1279-85.

Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215-21.

Kubo A, Corley DA. Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2006; 15: 872–878.

LAA Brosens, JJ Keller, GJA Offerhaus, M Goggins, FM Giardiello. Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut 2005;54:1034-43

Lee DH. Two-dimensional and three-dimensional imaging of gastric tumors using spiral CT. Abdom Imaging 2000; 25:1-6.

Lee J, Lee JM, Kim SH, et al. Gastric cancer: Diagnostic performance of 64-Channel multidetector CT in the evaluation of gastric cancer: differentiation of mucosal cancer (T1a) from submucosal involvement (T1b and T2). Radiology 2010; 255:805-14.

Leong T, Joon DL, Willis D, et. Adjuvant chemoradiation for gastric cancer using epirubicin, cisplatin and 5-fluoruracil before and after 3-dimentional conformal radiotherapy with concurrent 5-fluoruracil: a multicenter study of the trans-tasman radiation oncology group. Int J Rad Oncol Biol Phys 2011;79:690-695.

Li XD, Shen H, Jiang JT, et al. Paclitaxel based vs oxaliplatin based regimens for advanced gastric cancer. World J Gastroenterol. 2011;17:1082-7.

Lightdale CJ, Botet JF, Kelsen DP, Turnbull AD, Brennan MF. Diagnosis of recurrent upper gastrointestinal cancer at the surgical anastomosis by endoscopic ultrasound. Gastrointest Endosc 1989;35:407-12.

Lightdale CJ, Heier SK, Marcon NE, et al. Photodynamic therapy with porfimer sodium versus thermal ablation therapy with Nd:YAG laser for palliation of esophageal cancer: a multicenter randomized trial. Gastrointest Endosc 1995;42:507-12.

Final document



Lim JS, Yun MJ, Kim MJ, et al. CT and PET in stomach cancer: preoperative staging and monitoring of response to therapy. Radiographics 2006; 26(1):143-56.

Liu TS, Wang Y, Chen SY, Sun YH. An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer. Eur J Surg Oncol 2008; 34: 1208–1216.

Lowy AM, Feig BW, Janjan N, et al. A pilot study of preoperative chemoradiotherapy in resectable gastric cancer. Annals Surg Oncol 2001;8:519-524.

Lynch HT, Kaurah P, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer 2008; 112: 2655-2663.

Macdonald JS, SmalleySR, Benedetti J, et al chemotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach. N Engl J Med 2001;345:725-730.

Macdonald JS, SmalleySR, Benedetti J, et al. Postpoperative combined radiation and chemotherapy improves disease-free survival (DFS) and overall survival (OS) in resected adenocarcinoma of the stomach and gastroesophageal junction: update of the results of Intergroup Study INT-0116. American Society of Clinical Oncology.2004.

Manca R, Luinetti O. A combined histologic and molecular approach identifies three groups of gastric cancer with different prognosis. Virchows Arch 2009.

Mezhir JJ, Shah MA, Jacks LM, et al. Positive Peritoneal Cytology in Patients with Gastric Cancer: Natural History and Outcome of 291 Patients. Ann Surg Oncol 2010;PMID:20585870.

Min A Kim, Eun Ji Jung, Hye Seung Lee, Hee Eun Lee, Yoon Kyung Jeon, Han-Kwang Yang, Woo Ho Kim. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Human Pathology 2007; 38: 1386-1393.

Moehler M, Kanzler S, Geissler M, et al; Arbeitsgemeinschaft Internistische Onkologie, Germany. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2010;21:71-7.

Final document



Monig SP, Zirbes TK, Schroder W, et al. Staging of gastric cancer: correlation of lymph node size and metastatic infiltration. AJR Am J Roentgenol 1999; 173:365-7.

Nakamoto S, Sakai Y, Kasanuki J, et al. Indications for the use of endoscopic mucosal resection for early gastric cancer in Japan: a comparative study with endoscopic submucosal dissection. Endoscopy 2009;41:746-50.

NJ Talley, N Vakil, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia Am J Gastroenterol 2005;100:2324-37

Norton JA, Ham CM, Van Dam J, et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007; 245: 873-879.

Novelli M. The Royal College of Pathologists. Dataset for the histopathological reporting of gastric carcinoma (2nd edition). January 2007 puplications @rcpath.org

Oda I, Saito D, Tada M, et al. A multicenter retrospective study od endoscopic resection for early gastric cancer. Gastric Cancer 2006;9:262-70.

Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-76.

Okada K, Fujisaki J, Kasuga A, et al., Endoscopic ultrasonography is valuable for identifying early gastric cancers meeting expanded-indication criteria for endoscopic submucosal dissection. Surg Endosc 2010;25:1279-84.

Okano K, Maeba T, Ishimura K, et al. Hepatic resection for metastatic tumor from gastric cancers, Ann Surg 2002;235:86-91.

Okines AF, Norman AR, McCloud P, Kang YK, Cunningham D. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol. 2009;20:1529-34.

Onines A, Verheij M, Allum W, et al. Gastric Cancer: ESMO Clininal practice guidelines for diagnosis, treatment and follow-up, Ann Oncol 2010;Suppl 5:50-4.

Ono H, Kondo H, Gotoda T, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225-9.

Final document



Oscar Matzinger, Erich Gerber, Zvi Bernstein, Philippe Maingon, Karin Haustermans, Jean Franqois Bosset, Akos Gulyban, Philip Poortmans, Laurette Collete, Abraham Kuten. EORTC-ROG expert option: Radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiotherapy and Oncology 92 (2009)164-175.

Ozkan E, Araz M, Soydal C, et al. The role of 18F-FDG-PET/CT in the preoperative staging and post-therapy follow up of gastric cancer: Comparison with spiral CT. World Journal of Surgical Oncology 2011; 9:75.

Park JG, Yang HK, Kim WH, Caldas C, Yokota J, Guilford PJ. Report on the first meeting of the International Collaborative Group on Hereditary Gastric Cancer. J Natl Cancer Inst 2000; 92(21): 1781.

Parkin DM, Bray F, Ferlay J, et al. (2005). Global cancer statistics, 2002. CA Cancer J Clin 55: 74-108.

Pharoah PD, Guilford P, Caldas C, International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121: 1348-1353.

Pluschnig U, Zacherl J, Schoppmann S, et al; Medical University of Vienna, Vienna, Austria. Locally advanced gastric cancer treated with neoadjuvant chemotherapy: Epirubicin, oxaliplatin, and capecitabine (EOX). J Clin Oncol 29: 2011 (suppl 4; abstr 136)

Podoloff DA, Advani RH, Allred C, et al. NCCN Task Force Report: Positron emission tomography (PET)/computed tomography (CT) scanning in cancer. J Natl Compr Canc Netw 2007; 5(Suppl 1):S1-S22, quiz S23-2.

Powell J, McCon Key CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer 1990; 62: 440-3

Ross WA, Alkassab F, Lynch PM, et al. Evolving role of self-expanding metal stents in the treatment of malignant dysphagia and fistulas. Gastrointest Endosc 2007;65:70-76.

Ruol A, Rizzetto C, Castoro C, et al. Interval Between Neoadjuvant Chemoradiotherapy and Surgery for Squamous Cell Carcinoma of the Thoracic Esophagus. Ann Surg 2010;252:788–796

Final document



Saikawa Y, KubotaT, Kumagai K, et al. Phase II study of chemoradiotherapy with S-1 and low dose cisplatin in inoperable and advanced gastric cancer. Int J Rad Oncol Biol Phys 2008;71:173-179.

Sakamoto Y, Sano T, Shimada K, et al, Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer. J Surg Oncol 2007;95:534-9.

Sakuramoto S, Sasako M, Yamaguchi T et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357:1810–1820.

Schmidt C, Gerdes H, Hawkins W, et al. A prospective observational study examining quality of life in patients with malignant gastric outlet obstruction. Am J Surg 2009;198:92-9.

Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007;14:317-28.

Shike M, Latkany L, Gerdes H, Bloch AS. Direct percutaneous endoscopic jejunostomies for enteral feeding. Gastrointest Endosc 1996;44:536-40.

Skoropad V, Berdov B, Zagrebin V. Consentrated preoperative radiotherapy for resectable gastric cancer: 20 years follow up of a randomized trial. J Surg Oncol 2002;80:72-77.

Soetikno R, Kaltenbach T, Yeh R, et al. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol 2005;23:4490-8.

Solcia E, Klersy C, Mastracci L, Alberizzi P, Candusso ME, Diegoli M, Tava F, Riboni R, Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11:404-5.

Spiliotis J, Halkia E, Efstathiou E. Peritoneal carcinomatosis 2011; It’s about time for chemosurgery. Journal BUON 2011;16:1-9.

Stahl AD, Walz MK, Stusche M, et al. Phase III comparison of preoperative chemotherapy compared to chemoradiotherapy in ppatients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009;27:851-856.

Stanley R, Hamilton R, Lauri Aaltonen. Pathology and Genetics. Tumours of the Digestive System. WHO Classification of tumours publ IARCPress 2000.

Final document



Sumin Chae, Anbok Lee, Joo-Ho Lee. The effectiveness of the new7th UICC N classification in the prognosis evaluation of gastric cancer patients: a comparative study between the 5th /6th and 7th UICC N classification. Gastric Cancer 2011; 14:166-171.

Tamura G. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol 2006;12:192-8.

Tey J, Back MF, Shakespeare TP, et al. The role of palliative radiation therapy in symptomatic locally advanced gastric cancer. Int J Rad Oncol Biol Phys 2007;67:385-388.

The American Joint Committee on Cancer’s, Cancer Staging Hand book, Springer 2009.

Thuss-Patience PC, Kretzschmar A, Deist T, et al. Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol. 2009;27(15S):4540.

Tsendsuren T, Jun SM, Mian XH. Usefulness of endoscopic ultrasonography in preoperative TNM staging of gastric cancer. World J Gastroenterol 2006;12:43.

Tsendsuren T, Jun SM, Mian XH. Usefulness of endoscopic ultrasonography in preoperative TNM staging of gastric cancer. World J Gastroenterol 2006;12:43-7.

Vakil N, Morris AI, Marcon N, et al. A prospective, randomized, controlled trial of covered expandable metal stents in the palliation of malignant esophageal obstruction at the gastroesophageal junction. Am J Gastroenterol 2001;96:1791-6.

Valentini V, Cellini F, Minsky BD, et al. Survival after radiotherapy in gastric cancer: a systematic review and meta-analysis. Radiot Oncol 2009;92:176-183.

Van Cutsem E, Moiseyenko VM, Tjulandin S, et al; V325 Study Group. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24:4991-7.

Wagner AD, Grothe W, Behl S, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD004064.

Final document



Wagner AD, Grothe W, Haerting J, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta‐analysis based on aggregate data. J Clin Oncol. 2006 Jun 20;24(18):2903-9.

Wagner AD, Grothe W, Haerting J, et al. Combination chemotherapies in advanced gastric cancer: An updated systematic review and meta-analysis. J Clin Oncol 2007;25(18 Suppl): Suppl Abs. 4555.

Washington K. 7th Edition of AJCC Cancer Staging Manual: Stomach Ann Surg Oncol 2010;17:3077-3079.

Watanabe T, Kume K, Taip M, et al. Gastric mucosal cancer smaller than 7 mm can be treated with conventional endoscopic mucosal resection as effectively as with endoscopic submucosal dissection. Hepatogastroenterology 2010;57:668-73.

Waters JS, Norman A, Cunningham D, et al. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 1999;80:269e72.

Webb A, Cunningham D, Scarffe JH, et al. Randomised trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methrotrexate in advanced oesophagogastric cancer. J Clin Oncol 1997;15:261e7.

Yahagi N, Fujishiro M, Kakushima N, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (thin type). Dig Endosc. 2004;16:34-8.

Yang X, Huang C, Suo T, et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: Final results of phase III randomized trial. Ann Surg Oncol 2011;18:1575-81.

Ychou M, Boige V, Pignon JP et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: a FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29:1715-21

Yoshioka T, Yamaguchi K, Kubota K, et al. Evaluation of 18F-FDG PET in patients with advanced, metastatic, or recurrent gastric cancer.J Nucl Med 2003; 44(5):690-9.

Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg 2006;93:559-63.

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Zhang ZX, Gu XZ, Yin WB, et al. Randomised clinical trial of the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of the gastric cardia – report on 370 patients. Int J Rad Oncol Biol Phys 1998;42:929-934.

POSITION STATEMENTAccording 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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· web viewjaundice or clinical evidence of liver failure is seen in the preterminal stages of...

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