State of the Art Oncology in EuropeFont: aaa

Gastric cancer

1. GENERAL INFORMATION

1.1 Epidemiology

1.1.1 Incidence and mortality

Stomach cancer is one of the most common cancers in Europe ranking sixth (Ferlay 2004) after lung, breast, colorectal, prostate, and bladder cancers with an estimated 174,000 new cases per year in 2002 (almost 6% of new cancer cases) (Ferlay 2004). There is a marked geographic variation in the incidence of gastric cancer. The annual age-standardized incidence rate is higher in eastern (29.6/100.000 in men) and southern Europe (18/100.000 in men) than in northern (5.9/100.000 in women) and western Europe (6.6/100.000 in women) (Figure 1) (Ferlay 2004). The main epidemiological feature of gastric cancer is the steady decline observed in most affluent countries in the last 50 or more years (Correa 1994; Aragones 1997). In Italy (Kelley 2003), there has been a consistent downward trend in both incidence and mortality in both sexes. It is notable that this decrease is first manifest, particularly in men, around 55 years of age. The decline in mortality has occurred at a slightly faster rate than that for incidence. Similar trends have been observed in many countries (Kelley 2003). In contrast to the overall decreasing trend, there has been an increase of cancers localised to the cardia which is evident in several populations (Devesa 1998; Powell 1990). The male-to-female ratio in incidence rates is about 1.5 to 1 (Ferlay 2004).

Figure 1 
Stomach cancer in 2002: incidence and mortality rates (age-standardised) in Europe

carcinoma stomaco_figure1

Figure 2
Incidence and mortality trendes for stomach cancer in men, Italy 1988-2002

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1.1.2 Survival

In Europe, the relative survival from stomach cancer (Verdecchia 2007) in 2000-2002 was poor in both sexes: 25% at five years. Five-year survival was slightly better in people under 45 years (35%); however, stomach cancers were rare in this age group. Survival declined slowly with increasing age up to 74 years, but fell sharply in patients over 74 years (19%). There are major differences in survival for patients with stomach cancer between European countries. Five-year survival were lower than 20% at 5-years in the UK and Ireland. In addition to the stage at diagnosis, the case mix (by sub-site) also contributes to these survival differences: cancer of the cardias and gastroesophageal junction (with poor prognoses) comprised 2-3% of all gastric cancers in almost all countries, whereas the proportions of pyloric, antral and curvature cancers (with better prognoses) varied from country to country (Verdecchia 2003). Both 5-and 10-year survival slightly improved in Europe over the period 1991-2002 for stomach cancer. The profiles of 5-year and 10-year survival were similar, although 10-year survival was lower (difference of less than 5 percentage points), indicating the tendency for death to occur mainly within 5 years of diagnosis, although some risk persists beyond this period (Verdecchia 2007).

1.1.3 Prevalence

The prevalence of stomach cancer is the number of people living with a diagnosis of stomach cancer. In Europe, for both sexes, stomach cancer accounts for 4% of the total cancer prevalence (Micheli 2002). In 1992 the prevalence was 85 per 100,000. The 5 year prevalence, that is the number of living people with a diagnosis of stomach cancer made 5 or less years before the index date, was 37 per 100,000. This last figure indicates the need for clinical follow-up and treatment for recurrences. Slightly less than 50% of all patients with stomach cancer were long-term survivors that is people living with a diagnosis made 5 or more years before the index date.

1.2 Aetiology and Risk Factors

1.2.1 Aetiological factors

Migrant populations from high-risk countries show a marked diminution in risk when they move to a lower risk area. The change seems to depend on the age at migration. In Japanese migrants to the USA, there is quite a substantial fall in the risk between the migrant generation and US-born Japanese (Kolonel 1981). These data fit with the observations concerning the importance of childhood environment in determining risk (Coggon 1990).

Diet
Food and nutrition play an important role in prevention and causation of stomach cancer. Recently, the World Cancer Research Fund and the American Institute for Cancer Research (AICR) (WCRF/AICR 2007) in their extensive report on the scientific literature on diet, physical activity and prevention of cancer, have concluded that stomach cancer is mostly preventable by appropriate diets and associated factors. After a systematic literature review of 722 publications a panel of experts reached the following conclusions.
– There is strong evidence that non-starchy vegetables, including specifically allium vegetables, as well as fruits protect against stomach cancer.
– There is also strong evidence that salt, and also salt-preserved foods, are causes of this cancer.
– There is limited evidence suggesting that pulses (legumes), including soya and soya products, and also foods containing selenium protect against stomach cancer.
– There is also limited evidence suggesting that chilli, processed meat, smoked foods, and grilled (broiled) and barbecued (charbroiled) animal foods are causes of stomach cancer.
It has been estimated that most cases of this cancer are preventable by appropriate diets and associated factors.

Tobacco
The relationship between smoking and stomach cancer has been recognised. The European Prospective Investigation Into Cancer and Nutrition (EPIC) project (Gonzalez 2003) found a significant association between cigarette smoking and gastric cancer risk: the hazard ratio (HR) was 1.45, 1.7 and 1.8 for ever smokers, current male and current female smokers respectively. The HR increased with intensity and duration of cigarette smoking. Combined high use of cigarettes (>20/day) and alcohol (>5 occasions/14 days) increased the risk of noncardia gastric cancer nearly 5-fold compared to nonusers (Sjodahl 2007). Approximately 18% of gastric cancer may be attributable to tobacco smoking (Sjodahl 2007).

Helicobacter pylori
Infection with the bacterium Helicobacter pylori (H Pylori) is established as a necessary cause of almost all cases of stomach cancer. However, infection with the H Pylori is not sufficient cause of stomach cancer (WCRF/AICR 2007) Helicobacter pylori was isolated in 1982, and was recognised as a human carcinogen by IARC in 1994, but the specific mechanisms of action in the complex process of stomach cancer are not known (HCCG 2001). H. pylori infection does not increase the risk of cancer in the gastric cardia (Eslick 2006; Laheij 1999). The association between the infection and the subsequent risk of non-cardia gastric cancer is about sixfold. Assuming an average prevalence of H pylori of 35% in industrialized countries, a risk of 6 suggests that about 65% of non-cardia gastric cancers are attributable to H pylori infection and therefore potentially preventable by control of the infection (HCCG 2001). However, a recent meta-analysis reported a two-fold increased risk of developing gastric cancer. Almost of the studies did not take into account the major potential confounders or sources of interaction (diet, smoking, salt intake) (Eslick 2006). One of the major problems in determining a true casual association with H pylori and a disease is related to its high world-wide prevalence making associations with many conditions possible (Eslick 2006).

Familiar gastric cancer
Approximately 10-15% of gastric cancers arise in individuals with a family history of the condition (Barber 2006).The risk of stomach cancer is increased in first-degree relatives of patients with the disease by approximately two-to threefold (Dhillon 2001).

1.3 Early Diagnosis

1.3.1 Screening

In Japan about 6 milion people are screened annually by X-ray (photofluoroscopy) (Miki 2006). Serum pepsinogen test, is a new and potentially useful method, and was introduced for mass screening to identify individual with atrophic gastritis which are at high risk for gastric cancer (Miki 2006). A meta-analysis on the validity of pespinogen testing for gastric cancer carcinoma, dysplasia, or for chronic atrophic gastritis screening concluded that further studies of this test in the management of high-risk patients seem to be worthwhile (Dinis-Ribeiro 2004). At the moment, none randomised trials have been conducted in order to evaluate the efficacy of specific screening programmes. Thus, screening programme is not recommended for stomach cancer.

2. PATHOLOGY AND BIOLOGY

2.1 Biological Data

2.1.1 Histogenesis

Gastric carcinomas do not arise de novo from normal epithelium, but occur through successive changes. These are well-characterized for the intestinal type of human gastric cancer, whereas, lesions predisposing to the development of the diffuse type of gastric cancer are not yet well understood. The development of the intestinal type gastric cancer includes the transformation of the normal mucosa into a mucosa that resembles intestinal epithelium (intestinal metaplasia). The presence of intestinal metaplasia increases the risk of gastric cancer, which is proportional to the extent of the surface area involved by metaplasia (Stemmermann 1994). Subsequently, intestinal metaplasia may progress to dysplasia, and ultimately to carcinoma. By contrast, diffuse type gastric cancer presumably arises as single-cell changes in the mucus-neck region of the gastric glands. Then, these cells may proliferate and invade out from the crypt into the lamina propria. An hypothesis about gastric carcinogenesis was proposed in 1975 by Correa et al. (Correa 1975; Correa 1985). According to this hypothesis, gastric carcinogenesis is a multistage and multifactorial process which involves irritant environmental and other factors, acid secretion, bacterial overgrowth, and bacterial production of nitrites or N-nitroso compounds from dietary nitrates. The result of a cascade of events is the progressive spectrum of histological states ranging from normal gastric epithelium to gastric adenocarcinoma of intestinal type (Correa 1992).2.1.2 Dysplasia

There is general agreement that the term dysplasia implies a neoplastic, noninvasive, process in the gastric mucosa and is thought to be the immediate precursor lesion of invasive cancer. Invasion of the lamina propria by neoplastic cells is required before rendering a diagnosis of intramucosal carcinoma. By convention, the term adenoma is reserved for circumscribed polypoid or sessile lesions, whereas the term dysplasia indicates a flat diffuse lesion that is grossly difficult to distinguish from the surrounding mucosa. Dysplasia now incorporates also the term carcinoma in situ. Three grades of dysplasia may be encountered: low, moderate, and severe; this classification is based on nuclear features and structural complexity of the epithelial layer. However, some authors recommend that two only grades of dysplasia should be distinguished: high-grade and low-grade (Noffsinger 2002). This simplifies the diagnostic problem and permits a two-tiered management strategy (Goldstein 1997). Low-grade dysplasia generally does not progress or progresses slowly, and a careful follow-up with repeated biopsies is an optimal strategy; high-grade dysplasia may be associated with a concomitant cancer in up to 60% of cases, and a further 25% will develop cancer within 15 months (Lansdown 1990). For high-grade dysplasia, endoscopic resection or, sometime, gastrectomy is needed.2.2 Histological types2.2.1 Histotypes

Adenocarcinoma accounts for over 95% of all malignant gastric neoplasms, and generally the term gastric cancer refers to adenocarcinoma of the stomach. Although no normal lymphoid tissue is found in the gastric mucosa, the stomach is the most common site for lymphomas of the gastrointestinal tract. Other malignant tumours include squamous cell carcinoma, adenoacanthoma, carcinoid tumours, and leiomyosarcoma. Malignant tumours of the stomach can be classified based on gross morphological and histopathological features. Macroscopically, the most widely used classification system is that of Borrmann (Borrmann 1926). According to this classification, gastric cancer appearance may be divided into four types:

Type I Polypoid: well circumscribed polypoid tumours

Type II Fungating: polypoid tumours with marked central infiltration

Type III Ulcerated: ulcerated tumours with infiltrative margins

Type IV Infiltrating: linitis plasticaMicroscopically, gastric cancer may assume different histological patterns. Several classifications have been proposed based on the morphologic features of gastric tumours; however, the histological classification proposed by the World Health Organization (WHO 2000) is recommended.

Adenocarcinoma
Intestinal type
Diffuse type
Papillary adenocarcinoma
Tubular adenocarcinoma
Mucinous adenocarcinoma (greater than 50% mucinous)
Signet-ring cell carcinoma (greater than 50% signet-ring cells)
Adenosquamous carcinoma
Squamous cell carcinoma
Small cell carcinoma
Undifferentiated carcinoma
Other

Tubular carcinomas have well-defined glandular lumens. Papillary adenocarcinomas are exophytic lesions with elongated slender or plump finger-like processes, in which fibrovascular cores and connective tissue support cells. Mucinous carcinomas are sometimes also referred to as colloid carcinomas, and contain abundant mucin secreted by the tumour cell, creating mucous lakes. They are defined by the large amounts of extracellular mucin retained within the tumour. Signet-ring cell carcinomas are composed of cells containing unsecreted mucous in the cytoplasm to compress the nucleus to the edge of the cell. Signet-ring cells produce marked desmoplasia, and often demonstrate an infiltrative gross appearance. Some signet-ring tumours appear to form a linitis plastica-type tumour by spreading intramurally, usually not involving the mucosa. Other rare variants of epithelial tumours include adenosquamous carcinomas and squamous cell carcinomas. Finally, there are the undifferentiated carcinomas, which contain no glandular structures or other features such as mucous secretions. The term “carcinoma, NOS (not otherwise specified)” is not part of the WHO classification. Another simple and widely used classification is by Lauren (Lauren 1965), who differentiates gastric cancers into two major types: intestinal or diffuse. This classification, based on tumour histology, characterizes two varieties of gastric adenocarcinomas, which have different pathology, epidemiology, aetiologies, and behavior (Hermanek 1995a). The intestinal type consists of a differentiated cancer with a tendency to form glands. By contrast, the diffuse form exhibits low cell cohesion and tends to replace the gastric mucosa by signet-ring cells. About 16% of cases will be unclassifiable or of mixed type. Ming (Ming 1977) proposed a classification based on the growth pattern of the cancer: the prognostically favourable expanding type, and the poor prognosis infiltrating type.

2.2.2 Early Gastric Cancer (EGC)

This term originated in Japan and refers to adenocarcinomas whose growth is confined to the mucosa or submucosa regardless of the presence or absence of lymph node metastases (Hirota 1993). EGC is classificated based on the gross appearances of tumours according to the Japanese Gastroenterological Endoscopic Society (Murakami 1971) into three main types, one of which (type II) has three subtypes.

Type I Polypoid
The tumour protrudes above the mucosal surface more than 0.5 cm in height

Type II Superficial
IIa Elevated: Flat elevation that thickens the mucosa, less than 0.5 cm in height
IIb Flat: Minimal or no alteration in height of mucosa
IIc Depressed: Superficial, and slightly depressed, erosion

Type III Excavated
Prominent depression, characterized by ulcer-like excavation.

The median duration between diagnosis and progression is in the range of 37 months (Tsukuma 1983), whereas 8 years may be necessary for EGC to progress to advanced stage of disease (Adachi 1990). The percentage of EGCs identified in Japan is higher (30% to 50%) than that in Western Countries, where screening programmes are not performed (Fenoglio-Preiser 1996). The importance of correctly identifying EGC lies in the excellent results achieved with surgical treatment and in the good prognosis of patients with EGC after surgery.

2.3 Grading

2.3.1 Clinical implications

Adenocarcinomas are graded based on the degree of glandular differentiation into well, moderately, and poorly differentiated subtypes, based on the extent of glandular differentiation (Broder 1925).

Grade X Cannot be assessed
Grade 1 Well differentiated (greater than 95% of tumour composed of glands)
Grade 2 Moderately differentiated (50% to 95% of tumour composed of glands)
Grade 3 Poorly differentiated (49% or less of tumour composed of glands)

Tubular adenocarcinomas are not typically graded but are low-grade and would correspond to grade 1. Signet-ring cell carcinomas are not typically graded but are high-grade and would correspond to grade 3. Small cell carcinomas and undifferentiated carcinomas are not typically graded but are high-grade tumours and would correspond to grade 4.

2.4 Particular histological types considered elsewhere

2.4.1 Rare tumours

This chapter does not include management of rarer tumours that can occur in the stomach such as carcinoid tumours, leiomyosarcomas, haematopoietic and lymphoid neoplasms.

3. DIAGNOSIS

3.1 Signs and symptoms

Unfortunately, most patients with gastric cancer at an early stage have mild or no symptoms. The main reason for late diagnosis is that patients typically present with vague and non-specific symptoms: mild upper gastrointestinal distress (heartburn), flatulence, abdominal fullness prematurely after meals, excessive belching, and at this point only rarely nausea/vomiting and pain occur. Approximately 30% of all patients with EGC have a long history of dyspepsia, which is indistinguishable from chronic peptic ulcer disease. In patients with proximal or cardioesophageal junctions tumours, dysphagia may be present. Gastrointestinal bleeding is usually occult, and only occasionally massive. The presence of a palpable abdominal mass generally indicates regional extension of disease. As the tumour becomes more extensive, unexplained weight loss, anorexia, a decline in general health, vomiting, anaemia, and haematemesis are symptoms corresponding to an advanced stage of disease. Manifestations of metastatic disease may be abdominal pain, liver enlargement, the presence of ascites, jaundice, or palpable lymph nodes, such as those in the left side of the neck (Virchow’s node) or the left axillary nodes. Peritoneal metastatic spread may be evident as a palpable ovary on pelvic examination (Krukenberg tumour) or Blumer’s rectal shelf, resulting from drop metastases into the peritoneal reflection in the prerectal and postvesical space. Patients with advanced gastric cancer infrequently present paraneoplastic conditions, such as cutaneous syndromes (dermatomiositis or acantosis nigricans), microangiopathic haemolytic anaemia, and chronic intravascular coagulation leading to arterial and venous thrombi (Trousseau’s syndrome). In the US, EGC lesions make up 6-8% of all gastric cancers, whereas in Japan they represent up one third of such cases (White 1985). This difference is attributable to the fact that in Japan there is a widespread population screening for gastric cancers.3.2 Diagnostic strategy3.2.1 Diagnostic studies

Two alternative investigations for examining the gastric mucosa are the radiographic upper gastrointestinal examination and endoscopy. These are complementary and should not be considered mutually exclusive. An upper gastrointestinal series is often the first examination performed to evaluate symptoms related to the oesophagogastric tract. However, the diagnosis of gastric cancer should always be confirmed by endoscopy. It has been suggested that the investigation of dyspeptic patients aged over 40 can increase the proportion of EGCs detected to 26% and the proportion of operable cases to 63% (Hallissey 1990).3.2.2 Radiological techniques and their indication according to the diagnostic question

The development and refinement of double-contrast barium techniques over the past two decades have improved the radiologist’s ability to detect gastric cancer and characterize gastric ulcers. The double-contrast upper gastrointestinal series is better than a single-contrast examination in detecting gastric cancer: double-contrast techniques allow for visualization of mucosal details, and may indicate a reduced distensibility of the stomach, which may be the only sign of the presence of a diffuse infiltrative carcinoma. Furthermore, barium radiological studies provide a useful evaluation of extrinsic lesions that are causing compression and contour defects in the gastrointestinal tract, and the assessment of the degree of obstruction. Advantages of barium examination are low cost, lower percentages of side-effects and complications, and high sensitivity (ranging from 85% to 95%) for the diagnosis of gastric carcinomas (Low 1994).

A crucial problem for radiologists is the differentiation of a benign tumour from a malignant ulcer or even a lymphoma. Early gastric carcinoma may have some of the signs of a benign ulcer (extension of the crater beyond the gastric wall, and folds radiating from its margins), and partial healing may occur in an early malignant ulcer in up to 70% of such ulcers (Sakita 1971). Conversely, approximately 95% of gastric ulcers are found to be benign (Levine 1994). The radiographic findings of malignant ulcers may include: the irregularity of the ulcer crater; the distortion or obliteration of surrounding normal areae gastricae; the presence of nodular, irregular radiating folds, which may stop well short of the ulcer crater; fused, clubbed, or amputated tips of folds; the absence of projections beyond the expected gastric contour when viewed in profile; the presence of tumour mass forming an acute angle with gastric wall (Halvorsen 1996).3.2.3 Endoscopy and pathologic assessment

Upper gastrointestinal endoscopy is the procedure of choice for the diagnosis of symptomatic gastric cancer, although barium upper gastrointestinal studies have been performed as the primary investigation. As a rule, endoscopy is most effective in evaluating intraluminal GI disease, focal and diffuse, benign and malignant. The procedure can be informative, but it is less effective in assessing abnormal motility, extrinsic compression, and degree of luminal obstruction. Newer upper gastrointestinal endoscopes are thin, highly manoeuvrable, and safe for the patient. Thus endoscopy may result in a comfortable, rapid examination that requires only mild sedation for the patients (Winawer 1975; Silvis 1976). Although more invasive and expensive than barium upper gastrointestinal radiography, endoscopy is more accurate and may avoid multiple procedures, with their associated added costs. The specifity of barium studies versus primary endoscopy is similar (Dooley 1984). No randomised trial has shown any benefit of endoscopy over barium studies; however, endoscopy allows for a full macroscopic assessment of the gastric mucosa and for the histological confirmation of the type of the lesion (Boyce 1994). The diagnostic accuracy of endoscopy and biopsy for primary upper GI cancer is in the range of 95% (Kurihara 1981; Kurtz 1985; Graham 1982). Less than 5% of all gastric ulcers that go to endoscopy and biopsy are malignant (Graham 1985; Isenberg 1983). Thus, when a gastric ulcer is considered benign radiographically, endoscopy and biopsy are not necessary. However, complete healing of the ulcer should be demonstrated on a repeated barium examination. When there is a doubt radiographically regarding the benign nature of a gastric ulcer, or if a lesion has not completely healed within approximately six weeks, or if the area remains nodular or irregular, endoscopy and biopsy should be performed (Levine 1987). Some authors recommend the use of endoscopy in all patients with gastric ulcers found on upper gastrointestinal series, because some benign-appearing gastric ulcers are actually malignant (Kurtz 2001). If suspicion remains after endoscopy, the examination should be repeated within 6 to 8 weeks. Diagnosis of malignancy should be confirmed histologically. Since the accuracy of diagnosis increases with the number of biopsies taken (Sedgwick 1991), multiple biopsies are recommended. Many endoscopists perform eight to ten biopsies. Usually, a minimum of six biopsies should be taken from any lesion: one from each quadrant of the ulcer and two from the centre. Biopsies should be taken from the edge of an ulcer, rather than the base; otherwise, only necrotic material may be obtained. Brush cytology of these lesions may be used to complement histology, thus raising the diagnostic yield for gastric cancer to almost 100% for all types except linitis plastica (Witzel 1976; Qizilbash 1980). In fact, special problems may arise in some cases of diffuse carcinoma, as the intramucosal component may be small in comparison to an extensive submucosal and mural involvement (Levine 1988). However, one must always be aware of the possibility of an infiltrating gastric carcinoma or a submucosal lymphoma, if the stomach fails to distend normally with insufflations of air during endoscopy, or when endoscopy shows hypertrophic mucosal folds without mucosal abnormalities. Infiltrating cancers may be less successfully subjected to biopsy, although a tissue diagnosis is still achieved in most cases with large biopsy forceps and needle aspiration cytology (Iishi 1986). Multiple blind biopsies sometimes lead to a tissue diagnosis in this situation. The European Society for Gastrointestinal Endoscopy has proposed a standardization of the endoscopic report in the field of digestive endoscopy (Rey 2001).3.2.4 Biological markers

A great deal of effort has been spent in search of serological markers that would enable the early detection and diagnosis of gastric cancer. Over the past years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities related to the development and progression of gastric cancer (Stadtlander 1999; Yasui 2001). Their effectiveness for diagnosis remains to be determined. Tumour antigens either in the sera (CEA, CA19.9, CA72.4, CA50) or in the gastric juice (CEA, CA19.9, fetalsulfoglycoprotein) have not been found useful for diagnostic purposes. CEA and CA19.9 in particular are elevated in approximately 30 to 40% of primary gastric cancer patients, but significantly higher levels of such antigens were typically found in patients with more advanced disease, rather than in patients at early stage of disease (Hakama 1994; Posner 1994; Nakane 1994; Pectasides 1997).

4. STAGING

4.1 Stage classifications

4.1.1 Criteria for stage classification

Treatment decisions are usually made in reference to the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) (Green 2002; UICC 2002).4.1.2 TNM Classification (UICC 2002)
Primary tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ: intraepithelial tumour without invasion of the lamina propria
T1 Tumour invades lamina propria or submucosa
T2 Tumour invades muscularis propria or subserosa
T2a Tumour invades muscularis propria
T2b Tumour invades subserosa
T3 Tumour invades the serosa (visceral peritoneum) without invasion of adjacent structures
T4 Tumour directly invades adjacent structures

Notes:
1. Intramural extension into the duodenum or oesophagus is classified by the depth of greatest invasion in any of these sites, including the stomach.
2. A tumour may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments or into the greater or lesser omentum without perforation of the visceral peritoneum covering these structures. In this case, the tumour would be classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or omenta, the tumour is classified as T3.
3. The adjacent structures of the stomach are the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

Regional lymph nodes (N): a minimum of 15 lymph nodes* must be examined
NX Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1 to 6 regional lymph nodes
N2 Metastasis in 7 to 15 regional lymph nodes
N3 Metastasis in more than 15 regional lymph nodes

*Note: the regional lymph nodes are the perigastric nodes, found along the lesser and greater curvatures, and the nodes located along the left gastric, common hepatic, splenic, and celiac arteries. A regional lymphadenectomy specimen will ordinarily contain at least 15 lymph nodes. Involvement of other intra-abdominal lymph nodes, such as hepatoduodenal, retropancreatic, mesenteric, and para-aortic, is classified as distant metastasis (Green 2002).

Distant metastasis (M):
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

4.1.3 Stage grouping

Stage 0
Stage 0 is defined as the following TNM grouping:
Tis, N0, M0: (carcinoma in situ)

Stage I
Stage I is defined as any of the following TNM groupings:
T1, N0, M0
T1, N1, M0
T2a/b, N0, M0
Stage I may be divided into 2 subgroups:
IA T1, N0, M0
IB T1, N1, M0
T2a/b, N0, M0

Stage II
Stage II is defined as any of the following TNM groupings:
T1, N2, M0
T2a/b, N1, M0
T3, N0, M0

Stage III
Stage III is defined as any of the following TNM groupings:
T2a/b, N2, M0
T3, N1, M0
T4, N0, M0
T3, N2, M0
Stage III may be divided into 2 subgroups:
IIIA T2a/b, N2, M0
T3, N1, M0
T4, N0, M0
IIIB T3, N2, M0

Stage IV Stage IV is defined as the following TNM grouping:
T4, N1, M0
T4, N2, M0
any T, N3, M0
any T, any N, M1

4.2 Staging procedures

4.2.1 Preoperative staging: standard and optional procedures

The following are standard suggestions for the staging of patients with potentially curable gastric cancer on a type C basis.
History: In addition to the personal medical history, the family history of gastric cancer, hereditary non-polyposis colon cancer syndrome, Li-Fraumeni syndrome, and other cancers should be obtained.
Physical examination: Check for abdominal palpable mass, hepatomegaly, ascites, and lymphadenopathy. In women, rule out synchronous ovarian pathology, breast, ovarian and endometrial cancer.
Laboratory data: Blood count, CEA, CA19.9, and liver chemistries.
Gastric evaluation: Endoscopy is the diagnostic method of choice, as it allows direct visualization of tumour, and biopsy of the lesion.
Instrumental work-up: Once the diagnosis is confirmed, the next issue is defining the extent of disease. A preoperative chest X-ray is recommended procedure on a type C basis in all patients with advanced gastric cancer. Abdominal and pelvic CT scan is recommended on a type C basis to evaluate the local extent of tumour and to diagnose distant disease (Dux 1999; Davies 1997; Adachi 1997; Takao 1998; Paramo 1999). Many studies have reported on the accuracy of CT scan in estimating the T-stage of gastric cancer. Overall, the diagnostic accuracy of CT increases with the progression of disease. Sensitivity in EGC ranges between 23 and 56%, and increases to 92-95% in T4 lesions (Halvorsen 1996; Tschmelitsch 2000). The criterion used for diagnosing direct infiltration of adjacent organs is the lack of a fat plane between the gastric wall mass and the adjacent organ. Regarding lymph node involvement, lymph node size correlates with metastases, but the main difficulty is to diagnose metastases in small lymph nodes. Lymph nodes are interpreted as tumour-infiltrated if they are visible or if their size is more than 10 mm. However, enlarged lymph nodes at CT scan do not always contain tumoral cells (Fukuya 1995), and a differentiation between tumour-infiltrated lymph nodes and inflammatory enlarged lymph nodes is not possible by CT scan (Dux 1997; Rossi 1997; Sussman 1988; Isozaki 1996). The accuracy of CT in detecting metastatic disease is dependent on the bulk of metastatic tumour, as it will fail to detect the majority of hepatic metastases < 1 cm and small volume of peritoneal disease. Intraperitoneal spread may be better demonstrable when peritoneal implants and ascites are visualized. Endoscopic ultrasonography (EUS) has improved the local accuracy in estimating the depth of tumour invasion and lymph node involvement. The accuracy of EUS in determining the extent of infiltration of the primary tumour ranges from 67% to 92% (Pollack 1996), and it is superior to CT for determining the overall T-stage (Dittler 1993; Botet 1991; Grimm 1991). Problems sometimes still arise in differentiating the T2 (subserosal invasion) from the T3 stage. EUS can visualize metastatic lymph nodes, but only in the gastric wall. Therefore, EUS offers improved sensitivity for preoperative staging of gastric cancer compared to other methods, such as CT. Nevertheless, its use is limited by the ability to underestimate microscopic nodal metastases or more distant node metastases (e.g., T2-stage).
MRI imaging so far has not achieved clinical importance; it is, however, helpful in the characterization of liver lesions. Preliminary data confirm that adenocarcinoma of the stomach is a fluorodeoxyglucose avid tumour; prospective comparisons will be necessary to evaluate the utility of positron emission tomography (PET) (Gupta 1996; Tschmelitsch 2000) before this becomes standard. At the present time, these procedures must still be regarded as investigational.

4.2.2 Surgical staging

Surgical staging of gastric cancer includes the assessment of the extension of tumour through the gastric wall and onto adjacent structures, such as diaphragm, coeliac trunk, pancreas, and the presence of liver metastases, or distant nodal spread of disease. The risk of finding peritoneal metastases at the time of laparotomy is 25-37% after an otherwise, unremarkable CT scan (Roder 1998; Burke 1997). Laparoscopy represents a method for assessing resectability based on local tumour infiltration, and is superior to radiological methods in detecting peritoneal spread (Stell 1996; Bonavina 1997; Conlon 1996). Laparoscopy results may indicate the need for a revision of the clinical stage of the disease and the management of the patient. Direct inspection of the primary lesion and the movement of the stomach can assess the T stage; particularly, the T2 and T3 stages can be differentiated with high accuracy. It is possible to inspect suspicious lymph nodes, and to obtain biopsy specimens from various sites. The peritoneal spread of a tumour is easily visualized and confirmed by a video-guide biopsy. The most important concerns are whether staging laparoscopy should be performed immediately before scheduled surgery or as a separate intervention (Cuschieri 2001). However, patients with more advanced tumours (i.e., T3, T4, or linitis plastica) should undergo laparoscopy before laparotomy to role out occult intraperitoneal disease. This option is to be considered as suitable for individual clinical use on a type C basis.
Laparoscopic ultrasound (LUS) compensates for the major two limitations of laparoscopy: the lack of tactile sensation of structures and the inspection limited to the surface view. LUS permits visual inspection of the whole abdominal cavity, provides an opportunity to inspect inaccessible regions, such as the lesser sac, and to detect even small liver metastases.

5. PROGNOSIS

5.1 Prognosis of operable disease

5.1.1 Prognostic and risk factors

Although its incidence in developed countries has declined over the last three decades, gastric cancer remains the second most common cancer worldwide (Parker 1997). Prognosis continues to be poor, with 5-year survival rates of approximately 20% (Allum 1989a; Wanebo 1993; Akoh 1992). Recurrence following surgery is a major problem, and is often the ultimate cause of death. Tumour remaining in a patient after gastric resection with curative intent is categorized by a system known as R classification and indicates the amount of residual disease left after tumour resection: R0 indicates no gross or microscopic residual tumour, R1 indicates microscopic residual tumour, and R2 shows macroscopic residual disease. This obvious and important prognostic factor was not always reported in the past, making interpretation of survival results difficult (Hermanek 1995b). Two prognostic factors are standard on a type C basis: the degree of penetration of the tumour through the gastric wall, and the presence of lymph node involvement. These two factors also form the basis for all staging systems developed for this disease. The relationship between T stage and survival is well defined. Several reports from Japan, Europe, and the United States have demonstrated the significant prognostic importance of advanced T stage (Alexander 1997). In the past, the N stage classification was based on the anatomical location of lymph nodes. Although the prognostic significance of such a classification may be relevant, it is very complicated for practice. In 1997, the AJCC/UICC N stage was changed and became based on the number of positive lymph nodes (UICC/AJCC 1997). This new classification has fewer methodological problems, and it seems more reproducible provided that a minimum of 15 nodes are removed and analyzed. Apart from TNM classification and R0 resection, many other factors have been considered for prognostic purposes. Most multivariate analyses have shown no effect on prognosis of the tumour histological classification proposed by the WHO, independent of stage, with the exception of the rare small cell carcinoma of the stomach, which has an unfavourable prognosis (Van Krieken 2001). Other histological prognostic factors were considered the Laurén classification (intestinal or diffuse type), or the Ming classification (expanding or infiltrating type). For all stage groupings, grading correlates with outcome (Rohde 1989; Carriaga 1995). Macroscopic tumour configuration types as described by Borrmann has been shown to have prognostic significance in several large studies; I and II Borrmann types (polypoid and ulcerating cancers) seem to have a better prognosis than III and IV Borrmann types (infiltrating cancers). However, the prognostic value of tumour configuration has not been confirmed in other studies (Van Krieken 2001). The adverse prognostic factor of tumour size is controversial. Tumour site has been shown to be an independent prognostic factor in gastric carcinoma, with proximal carcinomas (i.e., tumours of the upper third of the stomach, including the gastric cardia and gastroesophageal junction) having a poorer prognosis than distal cancers (Van Krieken 2001). Lymphatic, venous, or perineural invasion have been shown to be adverse prognostic factors (Van Krieken 2001; Bunt 1995a). Several studies have reported a positive surgical resection margin associated with a significant decrease in overall survival (Hartgrink 2000; Siewert 1998; BSCG 1984; Fujimoto 1997). The ratio of lymph nodes metastases (number of metastatic lymph nodes to the total number of dissected lymph nodes) appears to be an important prognostic factor and the best classification factor for lymph node metastasis (Takagane 1999). Different survival rates have been reported between patients having undergone surgical intervention for the treatment of gastric carcinoma in Japan and Western countries. However, when using a similar staging classification and similar prognostic characteristics, the prognosis for gastric cancer in Japan and Germany may be the same (Bollschweiler 1993). Tumour volume, measured from serial tissue sections of gastric carcinoma by using a computer graphics analysis, seems to be of prognostic significance (Kikuchi 2000). In a recent report by Maehara et al. (Maehara 2000), multivariate analysis revealed that the 10 factors of depth of invasion, lymph node metastasis, lymph node dissection, tumour size, liver metastasis, peritoneal dissemination, lymphatic invasion, vascular invasion, lesion in the whole stomach, and lesion in the middle stomach were independent factors for determining the prognosis. Although most reports (Moriguchi 1993) have suggested a dismal prognosis for young patients with gastric cancer, one study has suggested that young patients (< or = 39 years) do not have a worse prognosis than older patients (Lo 1999). Women appeared to have a better prognosis than men in one study (Maguire 1996), but this was not confirmed in other reports (Maehara 1992). Preoperative serum CEA levels have a predictive value in determining tumour stage and prognostic information for patients with potentially resectable gastric cancer during the preoperative period (Tachibana 1998). Curatively resected gastric cancer patients with higher preoperative plasma CEA levels have a poorer prognosis than those with lower levels, despite the adjustment for the effects of major prognostic factors (Sakamoto 1996; Nakane 1994; Maehara 1994). Others have found that higher CEA levels in peritoneal washings in gastric cancer patients at the time of laparotomy are prognostic of poor survival (Irinoda 1998; Nishiyama 1995). In a retrospective study (Kampschoer 1989) on 1000 patients with primary gastric cancer, who had curative surgery performed at the National Cancer Center Hospital in Japan from 1976 to 1981, an analysis revealed a statistically significant adverse influence of blood transfusion on survival (57% of transfused as compared to 80.8% of nontransfused patients, respectively; p = 0.0001). However, after stratifying patients into stages and applying proportional regression analyses, blood transfusion did not appear to have any effect on prognosis (relative risk ratio, 1.16; p = 0.28).5.1.2 Biologic prognostic factors

In the last decades, many studies have suggested the role that genetic alterations may have in the development and progression of gastric cancer (Becker 2000). Molecular pathology may be helpful not only to understand the disease pathogenesis, but also to give useful prognostic molecular markers. Overexpression of p53 as demonstrated by immunohistochemistry, has been reported in 17%-91% of invasive tumours (Fenoglio-Preiser 2003), whereas the reported incidence pf p53 mutations in invasive carcinomas range from 0% to 77% (Yamada 1991; Correa 1994). Assessment of the role of p53 in gastric cancer in relation to prognosis has produced conflicting results (Tahara 1996; Kubicka 2002; Maeda 1998; Fonseca 1994; Victorzon 1996 ; Ichiyoshi 1997). Published studies have reported conflicting and even contradictory results since they have involved immunohistochemical detection of the protein, which has been performed with different antibodies, detection techniques, or methods of interpretation. Other suggested biological prognostic factors were p21 expression (Xiangming 2000), VEGF expression (Maeda 1998) or microvessel count density (Araya 1997), overexpression of EGF-r (Jonjic 1997), cyclin D2 overexpression (Takano 2000), BAT-26 alterations (Wu 2002), uPA (urokinase-type plasminogen activator) and PAI-1 (PA inhibitor) (Nekarda 1994; Okusa 1999), the serum level of soluble receptor for IL-2 (SolIL-2R) (Saito 1999; Maeta 1998), or some proliferation-related factors, such as S-phase fraction, Ki-67 or proliferating cell nuclear antigen (PCNA) (Kikuyama 1998; Rugge 1994; Yonemura 1994; Kimura 1991; Abad 1998; Sendler 2001). Recent data on the correlation between molecular markers and response to chemotherapy are still controversial (Catalano 2001). Using immunohistochemical p53 analysis of pre-treatment endoscopical samples, two studies have reported a relationship between p53 staining and response to chemotherapy (Cascinu 1998a; Nakata 1998). Thymidylate synthase expression seemed to be related to response to chemotherapy (Lenz 1996; Yeh 1998). A gene potentially involved in chemoresistance, ERCC-1 (excision repair cross-complementing), has been shown to be more highly expressed in non-responsive gastric cancer patients than responsive patients (Metzger 1998). However, these data arise from retrospective studies, and well designed, prospective trial are warranted to further define the role of molecular markers in predicting response and survival of patients with gastric cancer.

6. TREATMENT

6.1 Overall treatment strategy

6.1.0 Overall treatment strategy

Surgical resection of the primary tumour and regional lymph nodes is the treatment of choice for gastric cancer. The extent of disease, the operative procedure, and patient selection are crucial in optimizing outcome. Adjuvant therapy (mainly, chemotherapy ± radiotherapy) still warrants further evaluation for high-risk (T3-4, N+) gastric cancer patients. Neoadjuvant therapy may reduce tumour mass enabling resection with potentially curative intent. When the disease is metastatic, treatment of gastric cancer is exclusively palliative or symptomatic.

6.2 Surgical treatment

6.2.1 Extent of gastric resection

Total gastrectomy should be recommended on a type C basis for patients with lesions located in the proximal or middle third of the stomach, or when a diffuse type gastric cancer is found, which is commonly seen in patients in whom the whole stomach is involved (Maruyama 1996). More controversies exist for tumours arising from the distal (antral) stomach. Some surgeons suggest total gastrectomy for this type of cancer. By contrast, data from prospective randomised trials (Gouzi 1989; Robertson 1994; Bozzetti 1997) concluded that management of distal lesions by total gastrectomy did not offer any advantage over subtotal gastrectomy. In a French study (Gouzi 1989), 169 patients with antral gastric cancer were randomised to either a distal gastrectomy or total gastrectomy. Post-operative overall morbidity, mortality, and overall survival were comparable between groups. Robertson et al. (Robertson 1994) compared D1 subtotal gastrectomy with total gastrectomy combined to a more extended lymph nodes dissection (D3 lymphadenectomy). However, no difference in overall survival was detected, while total gastrectomy produced a higher rate of morbidity and mortality. In the 1990s, the Italian Gastrointestinal Tumor Study Group (Bozzetti 1999; Bozzetti 1997) conducted a trial in which 624 patients with cancer in the distal half of the stomach received either subtotal gastrectomy or total gastrectomy. In the subtotal gastrectomy group of patients, complications and death occurred in 9% and 1%, respectively, compared with 13% and 2%, respectively, for patients undergoing total gastrectomy. No difference in overall survival was demonstrated (5-year survival rates, 65.3% versus 62.4%, respectively; p = NS). Based on these data, for patients with distal gastric cancer subtotal gastrectomy should be recommended on a type 1 level of evidence. When performing a gastrectomy, there needs to be microscopic examinations from proximal and distal sections. A 5 cm free proximal margin is required for gastric cancer of the infiltrative type, whereas a margin of 2 cm may be sufficient for expanding tumours (Maruyama 1996). The pylorus seems to act as a barrier to extension of the cancer, and infiltration of distal margin is rare: a 2-3 cm distal surgical margin for pylorus may be sufficient. When the tumour invades the oesophagus, distal oesophagectomy should be performed.

6.2.2 Role and extent of lymphadenectomy

Considerable controversy has surrounded the notion of what defines an adequate lymphadenectomy for potentially curative treatment of gastric cancer. The Japanese Classification for Gastric Carcinoma has categorized the regional lymph nodes into various topographic regions or lymph node stations (JGCA 1998). In D1 dissections, the perigastric lymph nodes along the lesser and greater curvatures of the stomach are removed (station 1-6; N1 level). The standard D2 dissections (N2 level) add the removal of nodes along the left gastric artery (station 7), common hepatic artery (station 8), coeliac trunk (station 9), splenic hilus and splenic artery (stations 10, 11). The D3 dissections (N3 level) included the removal of lymph nodes along the hepatoduodenal ligament (station 12), the posterior surface of the head of the pancreas (station 13), and the root of the mesentery (station 14). Finally, D4 resections add stations 15 and 16 in the paracolic region and along the abdominal aorta (paraaortic lymph nodes). In Japan, complete removal of the N1 and N2 nodes is considered standard practice for curative resection, based on evidence from large, retrospective studies (Maruyama 1996). Japanese surgeons are highly convinced of the survival benefits of D2 resection, and are reluctant to conduct randomised clinical trials comparing D2 and D1 lymphadenectomies (Maruyama 1987). Nevertheless, in Western countries it is still matter of debate whether D2 dissection adds therapeutic benefit in terms of overall survival for patients undergoing this procedure. Available reported trials comparing D2 and D1 lymphadenectomies have failed to support extended lymph node dissection. Particularly, four prospective randomised trials (Dent 1988; Robertson 1994; Cuschieri 1999; Bonenkamp 1999) have evaluated the role of D1 or D2 dissections in the management of gastric cancer, and all these studies did not show any advantage in terms of overall survival in favour of D2 lymphadenectomy. Given the small sample size in the trials by Dent et al. (Dent 1988) in South Africa and Robertson et al. (Robertson 1994) in Hong Kong, two larger, prospective, European randomised trials (Cuschieri 1996; Cuschieri 1999; Bonenkamp 1995; Bonenkamp 1999) were launched. In the British Medical Research Council (MRC) trial, among the 400 patients judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (13 vs. 6.5%, respectively; p = 0.04), and experienced more complications (46 vs. 28%, respectively; p < 0.001), without any gain in 5-year survival (35% for D1 resection and 33% for D2 resection, HR=1.10; 95% CI, 0.87-1.39) (Cuschieri 1996; Cuschieri 1999). The Dutch Gastric Cancer Study Group (Bonenkamp 1995; Bonenkamp 1999) conducted a similar trial involving 80 Dutch hospitals and enrolling 711 evaluable patients with curable disease. The morbidity was significantly higher in the D2 group than that in the D1 group (43% versus 25%, respectively; p < 0.001); D2 dissection produced more postoperative deaths compared to D1 dissection (10% and 4%, respectively; p = 0.004), and longer hospital stays (median 16 days and 14 days, respectively; p < 0.001). Although overall 5-year survival rates were not significantly different between patients undergoing D2 and D1 resections, a marginal benefit of D2 resection was observed in the subsets of stage II and IIIA patients (Bonenkamp 1999). Mature data on overall survival of this trial were recently published (Hartgrink 2004a). After a median follow-up of 11 years, at that time, survival rates are 30% for D1 and 35% for D2 resection (p=0.53). Undoubtly, D2 dissection improves the quality of nodal staging. The rationale of performing D2 dissection is that it achieves a R0 resection due to the clearance of the metastatic N2 level lymph nodes that cannot be removed with a limited D1 dissection. About 50% of patients with metastatic lymph nodes, and undergoing a D2 dissection, have positive N2 level lymph nodes (Roukos 1998; Bunt 1995b; Roukos 1999a; Katai 1998). Therefore, in the case of a gastric cancer with N2 level metastasis, D1 lymphadenectomy could not achieve a radical resection by surgery alone, given the presence of residual disease at the N2 level nodes and the potential risk of relapse if they were not radically resected by a D2 dissection. A proportion of patients with N2 disease are cured by D2 lymphadenectomy, and would not have a chance of cure with a lesser dissection. The major criticism against D2 lymphadenectomy is the increased morbidity and mortality associated with this procedure. Postoperative mortality assessed by a nationwide Japanese registry, with 75% of patients undergoing a D2 or D3 resection, is now very low, in the range of less than 1% (Maruyama 1999). Comparable short-term results from Western surgeons experienced in D2 dissection have been reported (Smith 1991; Sue-Ling 1993; Roukos 1998; Siewert 1998; Degiuli 1998). Surgeons’ experience with the technique of D2 dissection is the predominant factor for the safety of this procedure (Siewert 1998; Brennan 1999). The lack of experience of surgeons in one (MRC) trial and distal pancreatico-splenectomy routinely performed in both European (MRC and Dutch) trials were considered factors that contributed to the increased morbidity and mortality ascribed to D2 dissection (Brennan 1999). Although the survival benefit of D2 lymphadenectomy is unproven in randomised trials, many authors (Allum 2002; Kodera 2002; Roukos 1999b) affirm the necessity of D2 dissection for increasing R0 resection and, possibly, improving overall survival in some selected node-positive patients. The importance of surgical expertise and skill, which are factors decreasing postoperative morbidity and mortality, are also highly strssed (Cuschieri 1996; Bonenkamp 1995). Retrospective studies from several centres in Japan, Europe, and USA have reported improved survival for patients who underwent more radical extended lymphadenectomy procedures. In a Tawaneese prospective randomised trial, D3 surgery was for the first time proven to improve the survival compared with D1 (Wu 2006). In the intention-to-treat population (n=221), 5-year overall survival was 59.5% for the D3 group and 53.9% for the D1 group (p=0.041). Extended lymphadenectomy was associated with more complications than limited lymphadenectomy (17.1% versus 7.3%, respectively; p = 0.012), but this did not lead to significant mortality (no death in either group). A multi-institutional randomized controlled trial (Sano 2004; Sasako 2006) was conducted on behalf of the Japan Clinical Oncology Group (JCOG 9501) to evaluate the survival benefit and operative complications of D2 gastrectomy and extended para-aortic dissection (PAND). A total of 523 patients with potentially curable gastric adenocarcinoma (T2-subserosa, T3, or T4) were randomised. Although the morbidity for the PAND group (28.1%) was slightly higher than the standard group (20.9%) (p=0.067), there was no difference in the incidence of four major complications (anastomotic leak, pancreatic fistula, abdominal ascess, pneumonia), and hospital mortality between the two groups. Based on available published data, at least a D1 lymphadenectomy is recommended on a type C basis. In patients where there is a suspicion of N2 nodes, a D2 resection should be advised and should performed by surgeons experienced with this technique. In cases where D1 dissection is performed, at least 15 nodes should be removed in patients with resectable cancer.

6.2.3 Role of splenectomy

Because the removal of Station 10 lymph nodes is greatly facilitated by performing splenectomy, another much-debated issue has arisen: whether or not to perform splenectomy in the radical resection of the proximal stomach. The incidence of metastasis at splenic hilum lymph nodes is highly related to the depth of invasion and the tumour location. Positive splenic hilar nodes are rare in cancers arising from the distal and middle third of the stomach (0-1.9%), whereas they are found in approximately 15% of proximal tumours, and 20.7% for tumours that infiltrate the whole stomach (Okajima 1995). Overall survival, morbidity and mortality after spleen resection is another area of discussion. A large American database (Wanebo 1997) suggested a better survival for patients who did not receive splenectomy compared with patients having splenectomy (5 year survival, 31% versus 20.9%, respectively; p < 0.0001), and a significantly reduced survival outcome was found among patients with stage II and III disease. The above-mentioned European trials (Bonenkamp 1999; Cuschieri 1999) comparing D1 and D2 gastrectomy consistently confirmed the adverse effect of splenectomy. In a prospective randomised clinical trial (n=187), total gastrectomy (TG) was compared with total gastrectomy plus splenectomy (TGS) in order to assess early and late results associated with the more extensive approach. All patients received a D2 lymphadenectomy. Operative mortality was similar after both operations (3% after TG and 4% after TGS). Septic complications after surgery were higher after TGS compared with TG (P < .04). However, five-year survival rates were not statistically different between the groups or in subset analysis according to stage of disease (Csendes 2002). Another randomised clinical trial compared TGS with TG alone (Yu 2006). The Authors found no significant difference in 5-yar-survival between the two groups (54.8% with TGS versus 48.8% with TG alone; p=0.503). Moreover, splenectomy was associated with slightly higher morbidity and mortality rates. Although splenectomy remains integrated in the JCGC definition of D2 resection for proximal gastric cancer, splenectomy had no impact on survival in patient with metastatic lymph nodes along the splenic artery or at hilum of the spleen (Hartgrink 2004a; Yu 2006), as metastasis in these lymph nodes confers a poor prognosis. In most patients, the spleen and splenic hilar nodes should be not removed on a type 1 level of evidence, unless there is direct infiltration through the gastric serosa into the spleen or there are enlarged splenic hilar nodes, when splenectomy is necessary to facilitate R0 resection and to achieve long-term tumour control.

6.2.4 Role of distal pancreatectomy

In addition to splenectomy, distal pancreatectomy ensures complete removal of lymph nodes along the splenic artery (station 11). Pancreaticosplenectomy carried a major risk for surgical complications in the Dutch trial (Sasako 1997), whereas in the British trial pancreaticosplenectomy carried a marked adverse effect on morbidity, mortality, and overall survival (Cuschieri 1999). It seems as if splenectomy and pancreaticosplenectomy, but not the extended lymphadenectomy, had been responsible for the increased morbidity and mortality in the D2 group of the European trials. In a subset analysis of the British trial, patients undergoing D2 resections without splenectomy or pancreaticosplenectomy had a survival curve superior to the curve for D1 group (Cuschieri 1999). The Dutch trial also revealed that pancreatectomy had significant detrimental effect on morbidity and mortality, without any survival benefit in favour of patients with metastatic lymph node in station 11 (Hartgrink 2004a). In a recent trial, comparing D1 dissection with D2 dissection pancreaticosplenectomy was avoided unless direct invasion of the tumour to the pancreas was observed. Among 191 eligible patients, surgical complications were observed in 16.7% of patients, and hospital mortality was 3.1% (Degiuli 1998). This trial indicates that comparable results with those of Japanese authors may be achieved after gastrectomy in Western patients, provided that they are treated in experienced centers. The finding of lymph node metastases over the pancreatic surface that was not penetrating into parenchyma, has prompted some surgeons to perform an excision of the splenic artery nodes without pancreatectomy (Maruyama 1995). The distal pancreatectomy should be recommended on a type 1 level of evidence only when there is direct invasion of the pancreas by the tumour through the gastric serosa.

6.3 Neoadjuvant treatment

6.3.1 Neoadjuvant chemotherapy

In Western countries, the majority of patients are diagnosed with locally advanced gastric cancer, namely T3-4N0-2M0 disease. A curative resection may be performed in about half of these patients, and even after an R0 resection two third of the patients will show recurrence within 2-3 years (Rougier 1994). For this group of high-risk patients, an optimal strategy which may possibly prolong disease free-survival and overall survival of such patients, is the administration of preoperative chemotherapy. In this setting, neoadjuvant chemotherapy may also allow the down-staging of an unresectable primary tumour, thus enabling the performance of a potentially R0 resection, and the eradication of occult micrometastatic disease. Preoperative assessment of resectability of gastric cancer is critical. CT scan is useful for detecting of both tumour invasion of adjacent organs and liver metastases. EUS is quite accurate for the assessment of the exact T-category, and laparoscopy may exclude peritoneal tumour spread and allow an assessment of the presence of tumour cells by peritoneal lavage. The accuracy of prediction of lymph node status may be increased by adding EUS to CT scan (ASGE 2000). Assessing response in patients with localized tumours is another important and controversial issue. It is difficult to measure the tumour mass precisely in locally advanced gastric cancer. Also, it is arduous assessing the degree of tumour shrinkage precisely in a locally advanced gastric cancer, and no method of defining an objective response is universally available. Phase II studies of neoadjuvant chemotherapy have demonstrated that such treatment can be given with acceptable toxicity and with no apparent increase in operative morbidity or mortality. In patients with potentially resectable gastric cancer, numerous phase II trials have shown that preoperative chemotherapy is able to increase the rate of R0 resection, ranging from 72% to 87% (Ajani 1991; Leichman 1992; Ajani 1993; Alexander 1995; Ajani 1999). Four randomised trials have compared preoperative chemotherapy before surgery with surgery alone for operable gastric cancer patients (Songun 1999; Hartgrink 2004b). Patients allocated to chemotherapy received four courses of 5-fluorouracil (5FU), doxorubicin, and methotrexate (FAMTX). In the chemotherapy group (n=27), 56% of patients had curative resections versus 62% in the surgery alone arm (n=29). With a median follow-up of 83 months, the median survival was 18 months in the FAMTX group versus 30 months in the surgery alone group (p=0.17). Poor downstaging may be explained by the relatively poor activity of the FAMTX regimen, as 17/27 patients had no benefit (stabilization or progression of disease) from chemotherapy. Similar disappointing results were observed with the use of preoperative oral 5FU (Fujii 1999). More recently, Cunningham et al. (Cunningham 2006a) reported the results of a large randomised trial in operable gastric and lower oesophageal cancers. Patients were randomised to surgery alone or to 3 cycles of preoperative chemotherapy with epirubicin, cisplatin, and 5FU (ECF regimen) followed by surgery and three additional post-operative cycles of ECF. After a median follow-up of four years, the perioperative chemotherapy group had a 5-year survival rate of 36% versus 23% for the surgery alone group (HR=0.75, 95% C.I., 0.60-0.93; p=0.009), and a better progression-free survival (HR=0.66, 95% C.I., 0.53-0.81; p < 0.001). Resection was considered curative in 79.3% of patients in the chemotherapy group compared with 70.3% of those receiving surgery alone (p=0.03). Morbidity and operative mortality were comparable among the two arms. Chemotherapy-related toxicity was acceptable, and grade 3-4 neutropenia was reported in 24% of patients. However, 86% of patients assigned to receive perioperative chemotherapy completed preoperative chemotherapy, and only 42% completed all protocol treatment. This could be a possible limitation of the trial together to the lower 5-year survival of the surgery alone group of patients. However, this trial provides a new option for the treatment of localized, resectable gastric cancer. Finally, preoperative chemotherapy (2-3 cycles of 5FU and cisplatin) for resectable gastric, cardia, and lower oesophagus cancers (Boige 2007) improved overall survival compared to surgery alone (5-year surival rate, 38% versus 24%, respectively; HR= 0.69, 95% CI, 0.50-0.95; p=0.02). For unresectable gastric cancer, in phase II studies, neoadjuvant chemotherapy achieved a resectability rate ranging from 40% to 78% (Fink 1999; Cascinu 1998b; Cascinu 2002; Kelsen 1996; Schuhmacher 1994; Rougier 1994; Plukker 1991; Wilke 1989). Toxicity was tolerable and, again, operative morbidity and mortality were not negatively affected. Trials are not comparable for the heterogeneity of regimens used, and given the different definition of unresectable disease based on preoperative staging (laparoscopy and/or EUS were not always required), patients with both locally advanced and earlier-stage tumours were included. Two small randomised trials have compared neoadjuvant chemotherapy prior to surgery versus surgery alone in patients with unresectable gastric cancer (Kang 1996; Yonemura 1993). Kang et al. (Kang 1996) reported the preliminary results of a small trial of neoadjuvant cisplatin, etoposide, and 5FU therapy versus surgery alone. Fifty-three patients received preoperative chemotherapy, and 54 underwent immediate operation. Curative resection rate was higher in the chemotherapy group compared to the control arm (78% and 61%, respectively; p = 0.049). However, survival was not significantly increased by preoperative chemotherapy (3.58 years versus 2.48 years for surgery alone; p=0.114). In the other randomised trial, the survival rate was significantly better in the neoadjuvant chemotherapy group (n=29) than in the surgery control (n=26) group (17 months versus 8 months, respectively; p < 0.05). Chemotherapy consisted of cisplatin, mitomycin C, UFT, etoposide and was given preoperatively in the chemotherapy group, or post-operatively to patients who firstly underwent operation. However, the resectability rates were not significantly improved with chemotherapy as compared to the control group (Yonemura 1993). It is unclear as to whether one chemotherapy regimen, including those containing cisplatin, is markedly superior to another. New active agents for gastric cancer, such as docetaxel, paclitaxel, and irinotecan have been introduced into neoadjuvant regimens, and data will be available in the next future. Based on the published data, perioperative ECF or 5-FU/Cisplatin based regimens chemotherapy should be considered to fit patients with stage II/IV M0 gastric cancer.

6.3.2 Neoadjuvant radiotherapy

A Chinese study (Zhang 1998) indicated a significant survival benefit for neoadjuvant radiotherapy compared with surgery alone (5-year survival rates, 30.1% versus 19.8%, respectively; p = 0.0094). Three hundred seventy patients with operable gastric cardia adenocarcinoma were randomly assigned to preoperative radiotherapy (40 Gy) followed by surgery, or to surgery alone. R0 resection was improved by radiotherapy (80% versus 62% for surgery alone; p < 0.001) without increasing morbidity and mortality. Preoperative radiation therapy improved local control, whereas no difference in distant failure was observed. Recently, Skoropad et al. (Skoropad 2002) reported the results of a randomised trial on preoperative radiotherapy (given at a dose of 20 Gy) compared to surgery alone. No significant difference in overall survival was detected between the two treatment groups. Neoadjuvant radiotherapy is described as safe and well tolerated, but further randomised trials are required to assess the benefit in terms of overall survival of radiotherapy given preoperatively.

6.3.3 Neoadjuvant immunotherapy

Three different randomised trials have explored neoadjuvant immunochemotherapy in patients with gastric cancer. All trials have failed to demonstrate a significant advantage for neoadjuvant intratumoural injection of streptococcus pyogenes preparation (OK-432) (Gouchi 1997), infusional propionibacterium avidum KP-40 (Peters 1990), and protein-bound polysaccharide (PSK) (Terashima 1998) compared with surgery alone.

6.4 Adjuvant treatment

6.4.1 Adjuvant chemotherapy

The prognosis for patients with gastric cancer is largely dependent on the stage of the disease at the time of diagnosis. Patients with EGC have a cure rate exceeding 70% to 80% after operation alone, whereas patients with stage T3N0 gastric cancers have at least a 50% chance of dying within 5 years, and the percentage cure rates are dismal for patients with lymph node metastases. The need for additive treatment after surgery for patients with high-risk gastric cancer is obvious. In the past decades numerous randomised trials of adjuvant chemotherapy have been conducted, by using different drugs and combinations, such as thiotepa or 5-fluorodeoxyuridine (Longmire 1968; Serlin 1969), 5FU/nitrosourea-containing regimens (GTSG 1982; Schlag 1982; Higgins 1983; Engstrom 1985; IGTSG 1988), 5FU/mitomycin-based regimens (Imanaga 1977; Nakajima 1984; Yamamura 1986; Allum 1989b; Nakajima 1999), mitomycin-based chemotherapy (Nakajima 1978; Grau 1993; Estape 1991; Carrato 1995; Grau 1998; Cirera 1999), 5FU/anthracycline-containing regimens (Coombes 1990; Hallissey 1994; Lise 1995; Macdonald 1995; Krook 1991; Neri 1996; Tsavaris 1996), and other 5FU-based regimens (Huguir 1980; Ochiai 1983). Results have been often disappointing, and a significant benefit in terms of prolonged survival for adjuvant chemotherapy compared with a control arm was reported only in some trials (Imanaga 1977; GTSG 1982; Grau 1993; Neri 1996; Grau 1998; Cirera 1999). However, given the small number of patients enrolled into the different series and the absence of data confirming the improved survival in previously reported studies, results of these trials should not be considered positively. A prospective combined analysis of two randomised clinical trials (Nitti 2006), conducted on patients with gastric cancer and treated with adjuvant chemotherapy (FAMTX or FEMTX), failed to show a survival benefit in comparison with surgery alone (HR=0.98; p=0.86). In 2006, an Italian Group presented at the ASCO Meeting (De Vita 2006) the results of a randomised trial of adjuvant chemotherapy (epirubicin, leucovorin, 5FU, and etoposide) versus surgery alone. The 5-year overall survival was 48% in the treatment arm and 43.5% in the control arm, but this absolute gain at 5 years of 4.5% did not translate into a significant advantage (p=0.610). More recent phase III randomised trials have evaluated the incorporation of cisplatin into 5FU-based regimens (Ducreux 2000; Bouche 2005; Bajetta 2002; Di Costanzo 2003; Chipponi 2004; Cascinu 2007). However, this change did not lead to an improvement of outcome for patients receiving adjuvant chemotherapy. A French study, comparing adjuvant chemotherapy with 5FU and cisplatin or surgery alone, was stopped due to insufficient accrual after 260 patients were enrolled into the trial (Ducreux 2000). Adjuvant chemotherapy did not improve survival of treated patients, and these results were confirmed after a median follow-up of more than 7 years (Bouche 2005). Data from the Italian group of Bajetta et al. (Bajetta 2002) evaluated the efficacy of a mixed adjuvant therapy consisting of two courses of etoposide, doxorubicin, and cisplatin (EAP) plus two cycles of 5FU and leucovorin (Machover regimen). After a median follow-up of 66 months, no significant increase of overall survival in favor of adjuvant chemotherapy was detected (HR=0.93; 95% CI, 0.65-1.34). A benefit from chemotherapy was suggested for patients with six or more involved lymph nodes (Bajetta 2002). In another Italian trial (Di Costanzo 2003), including 258 patients with stage Ib trough IV (M0) gastric cancer, the PELF (cisplatin, epirubicin, leucovorin, 5FU) regimen reduced mortality by 9%, but it did not reach statistical significance (HR=0.91; 95% C.I., 0.64-1.28). Chipponi et al. (Chipponi 2004) proposed an adjuvant trial in which patients received chemotherapy (5FU, leucovorin, and cisplatin), or follow-up. The 5-year survival rate was similar among the two arms (39%). In 2007, Cascinu (Cascinu 2007) et al. published the results of a GISCAD (Italian Group for the Study of Digestive Tract Cancer) trial whose aim was to investigate the efficacy of an intensive regimen (weekly PELF regimen, PELFw) compared to a 5FU/leucovorin combination in high-risk radically resected gastric cancer patients (n=400). The 5-year survival rates were 52% in the intensive arm and 50% in the 5FU/leucovorin arm. Less than 10% of patients in either arm experienced a grade 3-4 toxicity, but only 9.4% in the intesive PELF arm and 43% in the 5FU/leucovorin arm completed the treatment. The 5-year survival rate of 50% in both arms was much higher than that reported in previous studies in which patients had a similar stage of disease, and ranging from 20% to 30%. The long survival time in this trial was possibly due mainly to the high quality of surgery, as 79% of patients underwent a D1 or D2 resection, a high number of lymph nodes were examined in both arms, and in more than 75% of patients at least 15 lymph nodes were resected. The high percentage of D1/D2 lymphadenectomy may contribute to the low incidence of local recurrences in the trial (only 2.5% and 4.5% of patients experienced local recurrence in the 5-FU/LV arm and in the PELFw arm, respectively). Again, an important limitation of adjuvant chemotherapy was the poor compliance with treatment in both arms, as reported in other trials (Bouche 2005; Chipponi 2004; Cunningham 2006a). S-1 is a fourth-generation oral fluoropyrimidine derivative, that has been developed mainly in Japan. A phase I/II study conducted by Koizumi et al. (Koizumi 2000) showed high activity as a single agent for advanced gastric cancer. S-1 was tested as adjuvant chemotherapy for gastric cancer patients after curative D2 resection of stage II/III disease (Sasako 2007). After the first interim analysis showing the reduced risk of death for S-1 plus surgery versus surgery alone, the data and safety monitoring committee recommended to stop the trial. The final data on 1059 patients reported 3-years overall survival of 80.5% in the S-1 group versus 70.1% in the control group (HR=0.66; 95% CI, 0.51-0.85; p=0.0015). The proportion of patients who could complete the S-1 therapy reached 65.8%, and grade 3-4 toxicity was rare. Based on these data, Japanese Authors recommended S-1 adjuvant chemotherapy for stage II/III gastric cancer patientsafter curative D2 dissection.

6.4.2 Meta-analysis of Adjuvant Chemotherapy Trials

Six literature-based meta-analyses on adjuvant chemotherapy have been published (Hermans 1994; Earle 1999; Mari 2000; Panzini 2002; Hu 2002; Janunger 2002). In an earlier analysis, Hermans et al. (Hermans 1993) reviewed 11 trials of post-operative adjuvant treatment (systemic chemotherapy ± immunotherapy, intraperitoneal chemotherapy, and radiotherapy), reported since 1980, and compared with a no-treatment control arm. The study concluded that adjuvant therapy did not improve survival. After some criticisms were made of these conclusions, two further trials, previously omitted, were added in a later brief report; the revision of the meta-analysis (Hermans 1994) suggested a significant effect in favour of adjuvant therapy (odds ratio 0.82; 95% CI, 0.68-0.98). The meta-analysis of Earle and Maroun (Earle 1999) found a small, but significant survival benefit for patients undergoing adjuvant chemotherapy. The meta-analysis considered 13 trials performed in Western countries and including 1990 patients. The crude odds ratio for death for patients receiving adjuvant chemotherapy was 0.80 (0.66 to 0.97) with a relative risk of 0.94 (0.89 to 1.00). Mari et al. (Mari 2000) performed a systematic review of all randomised clinical trials of adjuvant chemotherapy compared with surgery alone, and published before January 2000. Overall, 20 articles were considered for the analysis, and 3658 patients (2180 deaths) were recorded. Chemotherapy reduced the risk of death by 18% (HR 0.82; 95% CI, 0.75-0.89, p < 0.001), but results were not improved when anthracyclines were incorporated into regimens. The authors concluded that chemotherapy produced a small survival benefit and suggested that for high-risk gastric cancer patients a 5FU-based regimen may be considered. In the meta-analysis by Panzini et al. (Panzini 2002) conducted on 17 trials (3118 patients), a significant advantage in terms of survival for adjuvant chemotherapy (odds ratio 0.72; 95% CI, 0.62-0.84) was suggested, and a statistical analysis excluded the presence of significant heterogeneity between the trials. Finally, Hu et al. (Hu 2002) reviewed 14 trials (restricted to those published in Chinese languages or English) involving 4543 patients treated with intravenous chemotherapy for resected gastric cancer. Chemotherapy had a positive treatment effect compared with surgery alone (odds ratio 0.56; 95% CI, 0.40-0.79). Finally, Janunger et al. (Janunger 2002) included 21 randomised studies that used adjuvant systemic chemotherapy. They found a significant survival benefit for the patients treated with chemotherapy compared with controls (odds ratio 0.84; 95% CI, 0.74-0.96). In conclusion, five different literature-based meta-analyses (Hermans et al. considered also other types of adjuvant treatment) detected a small, but statistically significant survival benefit favouring adjuvant chemotherapy. Subgroup analysis suggested that the benefit of adjuvant chemotherapy is greater in lymph node-positive patients (Earle 1999; Mari 2000). However, the meta-analyses have methodological limits, are review of the literature rather than a pooled analysis of individual patient data, and involve a variety of chemotherapy regimens, most of which had 5FU in common. Therefore, their conclusions may not be generalized. The benefit of adjuvant chemotherapy in gastric cancer patients should be confirmed in large, prospective, randomised trials with a surgery-only control arm and, possibly, involving newer and more effective chemotherapy regimens.

6.4.3 Adjuvant intraperitoneal chemotherapy

A significant proportion – up to 50% – of patients curatively resected for gastric cancer develop clinically evident peritoneal carcinomatosis at a site of failure. This frequent event supported the use of intraperitoneal therapy after resection of the primary gastric cancer. In the past, cisplatin, mitomycin, or 5FU were commonly used for this purpose (Schiessel 1989; Sautner 1994; Hagiwara 1992; Hamazoe 1994; Rosen 1998; Yu 1998). Intraperitoneal cisplatin did not show survival benefits (Schiessel 1989; Sautner 1994). Survival results with mitomycin were controversial, as one out three randomised trials (Hagiwara 1992; Hamazoe 1994; Rosen 1998) detected a benefit for patients receiving intraperitoneal therapy (Hagiwara 1992); however, the small sample size hampers interpretation of the study. Yu et al. (Yu 1998) reported on the largest trial in this context. Two hundred forty-eight patients were randomised to intraperitoneal therapy (mitomycin C and 5FU) or to observation alone. The intraperitoneal arm had a higher morbidity and mortality rates and did not show a significantly better outcome (overall survival, 38.7% versus 29.3% for control arm; p=0.219). A meta-analysis considered thirteen reports of randomised controlled trials comparing surgery with versus without adjuvant intraperitoneal chemotherapy (Yan 2007). Only hyperthermic intraoperative intraperitoneal chemotherapy with or without postoperative intraperitoneal chemotherapy after resection of advanced gastric cancer was associated with an improved overall survival (HR=0.45, 95% CI, 0.29-0.68, p=0.0002; HR=0.60, 95% CI, 0.43-0.83, p=0.002; respectively). However, intraperitoneal chemotherapy was also found to be associated with increased risks of intra-abdominal abscess and neutropenia.

6.4.4 Adjuvant radiotherapy

Two randomised trials of adjuvant radiotherapy versus surgery alone have been performed (Hallissey 1994; Kramling 1996). In a three-arm randomised trial reported by the British Stomach Cancer Group (Hallissey 1994), adjuvant chemotherapy (5FU, doxorubicin, mitomycin) and adjuvant radiotherapy were compared to surgery alone. In the other report (Kramling 1996), patients received adjuvant intra-operative radiotherapy or surgery alone. Both trials concluded that there was no evidence of a benefit for adjuvant radiotherapy.

6.4.5 Adjuvant chemoimmunotherapy

Data from randomised trials comparing adjuvant chemoimmunotherapy with surgery alone were conflicting. The studies used chemotherapy alone or in addition to Bacillus Calmette-Guerin (BCG), levamisole, PSK or OK-432. Results with levamisole (IGTSG 1988) or PSK (Imaizumi 1990) were negative, while adjuvant chemoimmunotherapy with BCG achieved a significant survival improvement versus control (Popiela 1982; Ochiai 1983). Contrasting results were reported with the use of OK-432, also in larger randomised trials (Yamamura 1986; Jakesz 1988; Imaizumi 1990; Kim 1992 ; Kim 1997; Sato 2004). In two trials (Nakazato 1994; Kim 1998), adjuvant chemoimmunotherapy improved survival, but it was compared to chemotherapy alone and not to a surgery-only control arm. Before accepting immunotherapy as a standard adjuvant treatment, large-scale confirmatory trials are necessary.

6.4.6 Adjuvant chemoradiotherapy

As results with adjuvant radiotherapy alone have been disappointing, investigators have tried to improve the efficacy of radiation therapy by using concomitant 5FU chemotherapy, as a radiosensitizer (Dent 1979; Moertel 1984). Dent et al. found only a non-statistically significant improvement of survival favouring chemoradiotherapy. Moertel and coworkers (Moertel 1984) detected a better 5-year survival rate in the treated group compared to the control group (20% versus 4%, respectively; p = 0.024). However, the inadequate number of patients in these studies limited the interpretation of such results. Recently, the Southwest Oncology Group (SWOG) reported the results of a national Intergroup trial (INT 116) (Macdonald 2001) in which patients following potentially curative resection of gastric cancer (stage Ib through IV M0) received observation alone (n=275) or adjuvant radiochemotherapy (n=281). The treatment consisted of one cycle of daily 5FU 425 mg/m2 and leucovorin 20 mg/m2 for 5 consecutive days, followed one month later by radiation therapy to a dose of 4500 cGy given with 5FU 400 mg/m2/day and leucovorin 20 mg/m2/day on days 1 through 4 and the last 3 days of radiotherapy. One month after completion of radiation, two additional cycles of chemotherapy with 5FU 425 mg/m2 and leucovorin 20 mg/m2, daily, for 5 consecutive days at monthly intervals were administered. After a median follow-up of 5 years, compared to surgery alone, 5-year overall survival was improved by 11.6% (40% versus 28.4%, respectively; p < 0.001), and relapse-free survival was increased from 25% to 31% (p < 0.001) in the radiochemotherapy group. Grade 3 and 4 toxicities (mainly, haematological and gastrointestinal) occurred in 41% and 32% of the patients, respectively, in the chemoradiotherapy group; three patients (1%) died from toxic effects of treatment. The authors concluded that adjuvant 5FU plus leucovorin and radiotherapy should be considered for all patients with high-risk gastric cancer. However, this approach still leaves several issues open to discussion, which makes most European and Asian oncologists reluctant to consider adjuvant radiochemotherapy as standard of care for patients with gastric cancer. Even though the type of lymphadenectomy was not mandated by the study protocol, only 10% of the patients received a D2 resection, 36% had a D1 dissection, and 54% a D0 dissection. Therefore more than half of the patients had a lymph node dissection in which fewer than (or none of) the six perigastric lymph node stations included in the D1 dissection were removed. It is possible that radiochemotherapy may compensate for the effects of a suboptimal lymph node dissection. Similar survival figures to those in the treatement arm have been reported in the literature with surgery alone when an adequate lymphadenectomy has been performed. Furthermore, much of the benefit of chemoradiation therapy was related to improved local control rather than prevention of distant disease, and although patients treated with radiochemotherapy experienced fewer locoregional recurrences, distant recurrences were equivalent between the two arms. In a follow-up analysis of the Intergroup 0116 trial, no significant interaction between surgical or pathological variables and the favourable effect of adjuvant treatment was detected, however, this analysis was considered underpowered. More interestingly, the authors concluded that surgical undertreatment clearly undermined survival (Hundahl 2002). In 2005, Kim et al. (Kim 2005) published the results of an observational study suggesting clinical benefit for adjuvant radio-chemotherapy. The population consisted of 544 patients with D2 gastrectomy for gastric cancer and treated with postoperative 5FU, leucovorin, and radiotherapy. Relapse rate and survival were matched (during the same period, 1995-2001) with those of 446 patients who received surgery without further adjuvant treatment. Postoperative chemoradiotherapy prolonged significantly survival (95.3 months versus 62.6 months for control; p=0.02) and disease-free survival (75.6 months versus 52.7 months for control; p=0.016).

6.4.7 Criteria for suggesting an adjuvant treatment

Adjuvant treatment is recommended when the risk is high. The 5-year survival for stages I, II, III is 80-91%, 61-72%, and 29-44%. However, among each stage of disease, there is a wide variation in prognosis depending upon depth of tumour penetration and number of positive lymph node metastasis.

A. Depth of tumour penetration (T stage): invasion of subserosa by tumour is considered the limit between patients at high or low risk. Tumours invading the muscularis propria are characterized by a good prognosis. In the recent revision of TNM classification, separation of T2 into T2a (tumour invades muscolaris propria) and T2b (tumour invades subserosa) was justified because post-surgical survival following resection for cure has a 5-year survival of 62% for T2a lesions and of 40% for T2b lesions. T3 and T4 lesions have a much worse prognosis than T1-T2 tumours; 5-year survival of patients with T3 tumours is 26-34% and drops to 0-14% for T4 tumours.
B. Number of lymph node metastasis (N stage): risk of relapse and survival are also highly dependent on the number of lymph node metastases. Patients with no lymph node metastasis have a 5-year survival of about 80%. N1 (1-7 lymph node metastasis) tumours have a 5-year survival of 35%, and 5-year survival (< 5%) decreases dramatically as more than 15 lymph nodes (N3) are involved.

6.4.8 Conclusions

a.Perioperative chemotherapy (ECF) may be recommended on a type 2 level of evidence for stage II-IV M0 disease.
b. Based on the results of Intergroup 0116 trial, adjuvant chemoradiation therapy may be recommended on a type 2 level of evidence after limited (D0, D1) lymph node dissection in patients with stage II through IV M0 disease.
c.There are insufficient data from randomised trials to recommend intraperitoneal therapy, neoadjuvant or adjuvant radiotherapy, neoadjuvant or adjuvant immunotherapy either alone or in combination outside of a clinical trial.
d. There is no recommendation for the systematic use of adjuvant chemotherapy in patients with EGC.
e. There is no recommendation for the use of adjuvant chemotherapy in patients with stage II node-negative tumours, largely because D2 dissection has proven remarkably successful.
f. Subgroup analysis from different meta-analyses and prospective trials suggests that benefit from adjuvant chemotherapy may be greatest in patients with lymph node metastases.
g. For patients with lymph node metastases and optimally resected (D2 lymphadenectomy, at least 15 lymph nodes examined), chemotherapy as adjuvant therapy may be recommended on a type 3 level of evidence.
h. Eligible patients should be also considered for entry into carefully controlled clinical trials comparing different postoperative chemotherapy regimens, postoperative radiochemotherapy, or other approach (intraperitoneal, immunotherapy, biological therapy), alone or in combination with a surgery arm.

6.5 Treatment of localised and locally advanced disease

6.5.1 Overall treatment strategy for stage 0, I, II, III, IV

STAGE 0 GASTRIC CANCER
Stage 0 gastric cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.
Treatment options are:
1. Local excision
2. Endoscopic mucosal resection

STAGE I GASTRIC CANCER
Stage T1N0M0 and T1N1M0 (EGC), T2N0M0

Surgical resection including regional lymph node dissection is the treatment of choice for patients with stage I gastric cancer. For tumours located in the proximal or middle third of the stomach, or tumours involving the stomach diffusely, total gastrectomy is the procedure of choice. For distal tumours, retrospective series and randomised trials have shown the validity of subtotal gastrectomy compared to total gastrectomy, with the advantage of quality of life, lower morbidity, and comparable survival. Surgical margins should be in healthy tissue: a sufficient length of oesophagus should be resected for gastroesophageal junction tumours. There is now a consensus that a limited lymph node dissection (D1) should be performed for EGC (Tsujitani 1999). Patients with T2N0 cancers are at high risk of having metastatic disease in level N2 nodes, and thus an R0 resection is achievable only by D2 lymph node dissection. However, until now, survival benefit of D2 lymphadenectomy is highly debated. The traditional surgical resection is associated with survival rates of more than 90% and a low (2-3%) rate of relapse at 10 years in several series of patients with EGCs from centers in both the West and Japan (Sue-Ling 1992; Sano 1993; Hochwald 2000). Recent reports of the histopathologic features of patients with EGC show that lymph node metastasis is rare in patients with mucosal cancer, and is mostly restricted to the perigastric nodes in patients with node-positive EGC (Nakamura 1999; Namieno 1998; Kunisaki 2001; Korenaga 1986; Iriyama 1989). Tumours limited to the mucosa carry a risk of 1% to 3% for lymph node metastasis (Kunisaki 2001; Nakamura 1999; Namieno 1998; Kofuji 1997; Gotoda 2000; Yamao 1996), whereas the incidence of lymph node metastasis ranges from 11% to 20% for tumours invading the submucosa (Kunisaki 2001; Nakamura 1999; Namieno 1998; Kofuji 1997; Gotoda 2000; Yamada 2001; Yasuda 1999; Kurihara 1998). Based on these studies, and given the diminished quality of life after gastric resection, for carefully selected cases more conservative surgical approaches have been proposed, including endoscopic mucosal resection (EMR) and limited gastric resection. Laparoscopic wedge resection and EMR may be justified for gastric cancer with depth of invasion confined to the mucosal layer only, a lesion smaller than 2 cm, and intestinal-type cancer. However, a wider application of EMR and laparoscopic wedge resection is still limited by some factors, such as the absence of long-term follow-up, the preoperative diagnostic accuracy of depth of invasion in staging mucosal from submucosal cancers, which is at best 70% despite the use of EUS, and the possible presence of micrometastasis in perigastric lymph nodes.
Standard treatment options:
1. Total gastrectomy if the lesion is in the body or proximal stomach; distal oesophagectomy is necessary if the lesion involves the cardioesophageal junction.
2. Subtotal (distal) gastrectomy if the lesion arises from the antrum.
3. Total gastrectomy if the tumour involves the stomach diffusely.
4. A D1 lymphadenectomy is recommended.
5. EMR or laparoscopic wedge resection for mucosal tumours are under investigation.
6. Postoperative treatments (chemoradiation therapy, chemotherapy) are not recommended.

STAGE II GASTRIC CANCER
Stage T1N2M0, T2N1M0, T3N0M0

Total or partial gastrectomy is indicated according to location, size and type of tumour. Total gastrectomy is necessary for lesions which are located in the proximal stomach, or for diffuse type gastric cancer, or when a tumour free margin is not available. Partial gastrectomy may be sufficient for tumours that are located in the antrum. In this stage of disease, survival benefit with D2 dissection is still highly debated (Siewert 1998; Bozzetti 1999; Cuschieri 1999). The German prospective, non-randomised trial by Siewert et al. (Siewert 1998) reported improved 5-year survival rates following D2 dissection (55% versus 27% for patients receiving a D1 dissection; p < 0.001), and the benefit was more evident in patients with stage II of disease. After a radical resection, for patients with stage II cancer the risk of loco-regional as well as distant failure is high. Meta-analyses suggest that adjuvant chemotherapy is recommended for lymph node positive cancers; however, to date no randomised clinical trial has shown a benefit for this subset of patients, and no single regimen has proven to be effective for post-operative adjuvant chemotherapy. Post-operative chemoradiation therapy may be considered (Macdonald 2001), but to date this approach needs further evaluation and confirmation. Preoperative and postoperative chemotherapy (ECF regimen) without radiation therapy was recently proven to improve overall survival of patients with stage II or higher adenocarcinoma of the stomach and the lower third of the esophagus. Neoadjuvant chemoradiation therapy may be considered in the setting of clinical trials.
Standard treatment options:
1. Total gastrectomy if the lesion is in the body or proximal stomach; distal oesophagectomy is necessary if the lesion involves the cardioesophageal junction
2. Subtotal (distal) gastrectomy if the lesion arises from the antrum
3. Total gastrectomy if the tumour involves the stomach diffusely
4. A D1 lymphadenectomy is recommended with at least 15 lymph nodes removed in the specimen; a D2 lymphadenectomy should be considered by surgeons experienced with this technique in cases where there is suspicion of positive N2 nodes
5. Perioperative chemotherapy (ECF regimen) should be recommended.
6. Postoperative chemoradiation therapy for selected patients (D0 lymphadenectomy) and for patients who were not offered preoperative (periooperative) chemotherapy.

STAGE III GASTRIC CANCER
Stage T2N2M0, T3N1M0, T3N2M0, T4N0M0

Patients with stage III gastric cancer have a dismal prognosis, as most patients radically resected for their cancer will have a disease relapse. Total or partial gastrectomy is indicated according to the location, size and type of tumour. Total gastrectomy is necessary for lesions which are located in the proximal stomach, or for diffuse type gastric cancer, or when a tumour free margin is not available. Partial gastrectomy may be sufficient for tumours that are located in the distal (antral) stomach. Approximately 30% of the patients with resectable gastric cancer have positive N2 level nodes, so that an R0 resection may be achieved by a D2 lymphadenectomy. In the German study, the stage IIIA survival rate was improved by D2 dissection (38% versus 25% for patients receiving a D1 dissection; p=0.03). In the Dutch trial, 5-year survival was doubled among the patients who had D2 dissection compared with that of patients receiving D1 dissection. Meta-analysis suggest that adjuvant chemotherapy is recommended for stage III gastric cancer patients; however, to date no randomised clinical trial has shown a benefit for this subset of patients, and no single regimen has proven to be effective for post-operative adjuvant chemotherapy. Most of the patients in the Intergroup trial had stage IIIA and IIIB disease. Median overall survival was 36 months for the adjuvant chemoradiation therapy group as compared to 27 months for the surgery-alone group (p=0.005) However, 49% to 53% of patients with stages IIIA and IIIB tumours received a D0 dissection, which is less than a D1 dissection of the N1 level nodes (Macdonald 2001; Hundahl 2002). This strategy needs further evaluation and it may be proposed for patients suboptimally resected (e.g., D0/D1 lymphadenectomies) in order to improve locoregional control of disease. Preoperative and postoperative chemotherapy (ECF regimen) without radiation therapy was recently proven to improve overall survival of patients with stage II or higher adenocarcinoma of the stomach and the lower third of the esophagus. In the T4 cancers, extensive radical surgery is the only way to achieve R0 resection. Preoperative chemotherapy may decrease the tumour mass, thus enabling a potentially curative resection and increasing, hopefully, survival.
Standard treatment options:
1. Total gastrectomy if the lesion is in the body or proximal stomach; distal oesophagectomy is necessary if the lesion involves the cardioesophageal junction
2. Subtotal (distal) gastrectomy if the lesion arises from the antrum
3. Total gastrectomy if the tumour involves the stomach diffusely
4. A D2 lymphadenectomy is recommended when performed by experienced surgeons with this procedure, since for most patients with stage III cancer there is a suspicion of N2 nodes; otherwise, consider a D1 lymph node dissection
5. Perioperative chemotherapy (ECF regimen) should be recommended.
6. Postoperative chemoradiation therapy for selected patients (D0 lymph node dissection, D1 lymphadenectomy) and for patients who were not offered preoperative (periooperative) chemotherapy.

STAGE IV M0 GASTRIC CANCER
Stage T1-3N3M0, T4N1-3M0

Most patients with stage IV with no evidence of distant metastatic disease are not amenable for a R0 resection, except for those with N3 disease. Preoperative and postoperative chemotherapy (ECF regimen) without radiation therapy was recently proven to improve overall survival of patients with stage II or higher adenocarcinoma of the stomach and the lower third of the esophagus. Patients with resectable T4 disease as judged at surgical exploration or at preoperative staging should undergo combined resection of involved adjacent organs in order to achieve radicality. For unresectable tumours at diagnosis, eligible patients should be considered for clinical trials of chemoradiation therapy or chemotherapy. No standard chemotherapy regimen is available for reccomendation outside clinical trials; however, a regimen containing 5FU and cisplatin should be considered for patients with good performance status. Suitable endpoints are prolongation of survival, symptoms control, and maintenance of quality of life.
Standard treatment options:
1. Radical gastrectomy with resection of involved adjacent organs
2. A D2-3 lymphadenectomy is recommended
3. Perioperative chemotherapy (ECF regimen) should be recommended.
4. Postoperative chemoradiation therapy for selected patients (D0 lymph node dissection, D1 lymphadenectomy) and for patients who were not offered preoperative (periooperative) chemotherapy.
5. Patients with stage IV M0 cancers are all candidates for adjuvant and neoadjuvant clinical trials.

6.6 Treatment of metastatic disease

6.6.0 Overall treatment strategy for stage IV M1

Stage IV gastric cancer denotes distant metastatic disease. Since the late 1970s, despite a general improvement in terms of response rates, median duration of survival continues to be dismal, even though it is occasionally possible to observe long-term survivors. The role of systemic chemotherapy in advanced or metastatic gastric cancer still remains palliation. Many chemotherapeutic agents have been studied in gastric cancer. 5FU is the cornerstone of chemotherapy regimens for gastric cancer. Response rates with 5FU as single agent are about 20-30% (Comis 1974; Cocconi 1982), administered either by bolus intravenous injections or by continuous infusion. The major side effects of 5-FU are mucositis, diarrhoea, myelosuppression, and (when using a continuous infusion) the hand-foot syndrome. Other active single-agents used in the treatment of gastric cancer were mitomycin C, anthracyclines (doxorubicin, epirubicin), cisplatin, or etoposide. Using these agents, response rates ranged between 6% to 30% (Hill 1998). Several new agents have been identified as having substantial activity in advanced gastric cancer, e.g. the taxanes, paclitaxel and docetaxel, irinotecan, UFT (mostly used in Japan), but response rates with single agents generally show no improvement (Schoffski 2002).

6.6.1 FAM and FAM Variants

Since the 1970s, various attempts have been made to improve the results of chemotherapy by using combination chemotherapy regimens. One early combination regimen incorporated 5FU with MeCCNU, but a randomised comparison found no benefit over 5FU alone (Baker 1976). 5FU was also combined with doxorubicin and BCNU (FAB), but again this regimen proved to have no survival advantage over doxorubicin alone or 5FU plus BCNU (Levi 1986; Schnitzler 1986). 5FU, doxorubicin, and mitomycin C (FAM) was a promising combination and widely used in the 1980s. In the initial report of this regimen, 26 of 62 patients (42%) achieved a partial response (Macdonald 1980), and prompted a large randomised study (Douglass 1984), in which FAM achieved the longest median survival and a better response rate than AM (doxorubicin, mitomycin), FAMe (5FU, doxorubicin, MeCCNU), and FMe (5FU, MeCCNU). The FAM regimen was thereafter regarded as the standard regimen for future trials. In another phase III trial, the North Central Cancer Treatment Group compared single-agent 5FU to 5FU plus doxorubicin and to FAM (Cullinan 1985). Investigators did not notice any significant differences in the palliative effect between these three treatment regimens.

6.6.2 Fluorouracil, Doxorubicin, and Methotrexate

During the 1980s new second-generation regimens were developed. One of these regimens was the combination of high-dose methotrexate followed by 5FU in combination with doxorubicin (the FAMTX regimen). An impressive response rate of 63% upset the oncology community (Klein 1983), and the European Organization for Research and Treatment of Cancer (EORTC) launched a multicenter prospective randomised trial comparing FAMTX with FAM. Two hundred and thirteen patients were randomised. The response rate of 41% for FAMTX was significantly superior to the 9% response rate for FAM (p < 0.0001). Survival among FAMTX patients was also superior (42 weeks compared with 29 weeks for FAM group; p=0.004). There were no major differences in the toxicity, and the toxic death rate of the two combinations was similar (FAMTX, 4%; FAM, 3%) (Wils 1991). To develop a regimen with less toxicity, Wilke et al. (Wilke 1990) tested a schedule in which 5FU was added to high-dose leucovorin and etoposide (ELF regimen). Fifty-one patients older than 65 years of age or with cardiac disease were treated. The overall response rate was 53%, including 12% complete remissions. Grade 3 to 4 myelosuppression was reported in 20% of patients. The Authors recommended ELF as a suitable regimen for elderly patients or patients with cardiac risk factors.

6.6.3 Cisplatin-Based Chemotherapy

Another second-generation regimen was a combination of etoposide, doxorubicin, and cisplatin (EAP). Based on the high activity reported in a phase II trial (Preusser 1989), EAP was subsequently tested in the context of a phase III randomised trial (Kelsen 1992). EAP compared to FAMTX achieved a similar activity, but EAP was significantly more toxic than FAMTX, as 13% versus 0% of patients, respectively, had a treatment-related mortality (p=0.04). In view of the significant toxicity difference, the study was closed and EAP was abandoned (O’Connell 1992). Kim et al. (Kim 1993) compared 5FU and cisplatin (PF) to 5FU alone and to the FAM regimen. This smaller trial had 54 to 57 patients per arm. The response rate for the cisplatin-containing combination was 51%, significantly better than the 25% to 26% for the non-cisplatin-containing arms. Also a significant benefit in terms of time to progression for PF was demonstrated, although the improved median survival failed to reach statistical significance. A cisplatin, epirubicin, and etoposide (EEP) combination was compared to FEP (5FU, epirubicin, and cisplatin), but response rates were quite similar along each group of treatment (Icli 1998). In 1990s, EORTC promoted a large randomised trial to compare the clinical efficacy and tolerability of ELF or PF with that of the reference protocol FAMTX (Vanhoefer 2000). After a median follow-up of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with PF, and 6.7 months with FAMTX, with no significant differences. Nonhaematological and haematological toxicities of the three regimens were acceptable. However, the modest clinical efficacy (response rates, 9% versus 20% versus 12%, respectively) of the three investigated regimens led the authors to suggest that each regimen should no longer be regarded as standard treatment for advanced gastric cancer. An interesting and active 5FU/cisplatin combination was developed at the Royal Marsden Hospital. The regimen, ECF, consisted of cisplatin and epirubicin added every three weeks to continuous infusion 5FU 200 mg/m2 for 24 weeks (Findlay 1994). In 1997, Webb et al. (Webb 1997) reported the results of a trial in which patients with advanced oesophageal, oesophagogastric junction, or gastric cancer were randomised to either ECF (n=126) or FAMTX (130). ECF yielded a better overall response rate compared with FAMTX (45% and 21%, respectively; p = 0.0002), higher median time of survival (8.9 and 5.7 months, respectively; p = 0.0009) and median failure-free survival duration (7.4 and 3.4 months, respectively; p = 0.00006). This trial also demonstrated improved/prolonged high quality of life with the ECF regimen compared to FAMTX (Webb 1997). In the update analysis of this study (Webb 1997), data on long-term survival confirmed the superior overall survival showed at 2 years (14% for ECF versus 5% for FAMTX; p=0.03). As one third of the patients had a locally advanced gastric cancer patients, which has a better prognosis than metastatic cancer, and approximately 40% of patients had adenocarcinoma of the oesophagus or esophagogastric junction, caution was used by some authors in interpreting the ECF regimen as standard treatment for patients with advanced or metastatic gastric cancer. However, another study (Ross 2002) confirmed the good activity of this schedule in a similar subset of patients. ECF was compared to MCF, a regimen in which epirubicin was substituted by mitomycin in order to ameliorate the tolerability of MCF (Ross 2002). ECF had a comparable overall survival, tumour response, median failure-free survival, but quality of life was superior with ECF compared with MCF. Based on these and previous results, the authors considered ECF as a regimen to be offered to all oesophagogastric cancer patients with good performance status and the standard treatment for future trials. Another attempt to ameliorate results in the treatment of gastric cancer was performed by the Italian Oncology Group for Clinical Research, which launched a randomised phase III trial comparing the FAM regimen to a cisplatin, epirubicin, leucovorin, and 5FU (PELF) regimen (Cocconi 1994). Nonhaematological toxicity was significantly more frequent with PELF compared with FAM, including two treatment-related deaths. However, PELF had a significantly higher overall response rate than did FAM (43% and 15%, respectively; p = 0.001). Conversely, time to progression, duration of response, and survival durations were not significantly different. The PELF regimen was further evaluated in another phase III trial in which patients with advanced gastric cancer were randomised to receive the PELF regimen or FAMTX, the new standard regimen at that time (Cocconi 2003). The overall response rates were 39% and 22%, respectively (p=0.009). There were no differences in terms of time to progression, duration of response, and median survival. Most of the toxicities were similar in the two groups, but nausea/vomiting and diarrhoea were significantly more severe with PELF, and mucositis significantly more severe in FAMTX group. In 1997, by a rapid publication on the Journal of Clinical Oncology, Cascinu et al. (Cascinu 1997) proposed an intensive PELF regimen, where cisplatin, epirubicin, leucovorin, and 5FU were administered on a weekly basis in addition to glutathione and filgrastim. Of 105 patients treated, 65 patients achieved an objective response for an overall response rate of 62%. The median survival duration of all 105 patients was 11 months. Forty patients (38%) experienced WHO grade 3 to 4 toxicity, mainly in terms of anaemia, neutropenia, thrombocytopenia, and mucositis. However, the positive results reported by this schedule were not evaluated in the setting of a phase III trial. Based on the positive results from phase II trials (Louvet 2002; De Vita 2005; Lordick 2005; Ajani 2002; Roth 2000; Bouche 2004; Pozzo 2004), many new drugs were investigated in the context of phase III randomised trials, such as oxaliplatin, capecitabine, irinotecan, and docetaxel. In 2006, Cunningham et al. (Cunningham 2006b) presented at the ASCO Meeting the conclusive data of a large international randomised phase III trial launched by the MRC (REAL-2 trial). The study had a 2 x 2 factorial design with ECF as the reference arm, and tried to show if capecitabine could replace protracted venous infusion 5FU, and whether oxaliplatin could replace cisplatin for the first-line treatment of patients with advanced oesophagogastric cancer (n=1002). The REAL-2 study was designed to demonstrate non-inferiority of capecitabine over 5FU, and oxaliplatin over cisplatin in the per-protocol population. Capecitabine was shown to be non-inferior to 5FU (HR, 0.86; 95% CI, 0.8-0.99), and oxaliplatin was shown to be non-inferior to cisplatin (HR, 0.92; 95% CI, 0.8-1.1) in the two-by-two comparisons. Median and 1-year survivals were highest for EOX (epirubicin, oxaliplatin, and capecitabine) (46.8% and 11.2 months) compared to ECF (37.7% and 9.9 months; p=0.02). Response rates were 47.9% for EOX, 46.4% for EOF (epirubicin, oxaliplatin, and 5FU), 42.4% for ECX (epirubicin, cisplatin, and capecitabine), and 40.7% for ECF (no significative difference among the four treatment arms). Oxaliplatin-based regimens were generally well tolerated with less incidence of severe neutropenia, alopecia and nephrotoxicity, but higher incidence of severe peripheral neuropathy and diarrhea. A further study reported at ASCO 2006 demonstrated the similar activity of capecitabine over 5FU (Kang 2006). In this trial comparing protracted venous infusion of 5FU and cisplatin (FP) versus capecitabine and cisplatin (XP), progression-free-survival (primary endpoint) was 5.6 months versus 5.0 months, respectively (HR=0.81, CI 95%, 0.63-1.04). The XP arm achieved a better response rate than FP (41% versus 29%; p=0.03), and a trend for better overall survival (10.5 months versus 9.3 months). There were no major differences in grade 3 to 4 toxicity between the two treatment arms. S-1, a fourth-generation oral fluoropyrimidine derivative, has been developed mainly in Japan. A phase I/II study conducted by Koizumi et al. (Koizumi 2003) found an impressive 74% for a S-1/cisplatin combination, with median survival reaching 12 months. Based on these results, a phase III study (Narahara 2007) comparing S-1 alone with S-1 plus cisplatin has been conducted to evaluate the efficacy and safety for S-1/cisplatin as a standard treatment for advanced gastric cancer patients (n=305). The overall survival for S-1/cisplatin arm was superior to S-1 arm (p=0.0366; HR=0.77, 95% CI, 0.60-0.98), and the response rate for the combination regimen (54% versus 31.1%). Patients receiving S-1/cisplatin had more severe neutropenia, anemia, nausea, and anorexia than those treated with S-1 alone, but treatment was generally well tolerated. As the combination regimen met the primary endpoint of the trial, the Authors concluded that the S-1/cisplatin combination could be regarded as one of first-line standard treatment. More recently, Boku et al. (Boku 2007) presented the results of a 3-arm large Japanese phase III trial, in which S-1 showed a similar overall survival compared to 5FU alone and irinotecan/cisplatin combination (median survival times, 11.4 versus 10.8 versus 12.3 months; respectively). In another phase III trial (Al-Batran 2006), investigators compared an oxaliplatin-based regimen (FLO; 5-FU, leucovorin, and oxaliplatin) versus a cisplatin-based regimen (FLP; 5FU, leucovorin, and cisplatin) to demonstrate superiority of FLO for time-to-progression (TTP) on an intention-to-treat basis. The TTP was not significantly different between the FLO and FLP (5.7 versus 3.8 months, respectively; p = 0.081), whereas the response was better among patients receiving FLO (34% versus 25% for FLP; p=0.007). FLO was associated with significantly less NCI-CTC grade 1-4 leukopenia, nausea, alopecia, fatigue, and renal toxicity, and with predictably more peripheral neuropathy (chi-square for trend p < 0.05). Two different phase II randomised studies have produced acceptable response rates and toxicity profile for irinotecan-based regimens (Pozzo 2004; Bouche 2004). In 2005, Dank et al. (Dank 2005) reported the results of a phase III randomised trial which aimed to show the better TTP of an irinotecan-based regimen (IF; irinotecan, leucovorin, and 5FU) compared to the standard CF. The Authors reported a trend towards better TTP for IF compared to CF (5.8 months versus 4.2 months, respectively), but this was not statistically significant. Severe diarrhoea was higher in the IF group, but severe stomatitis, neutropenia, febrile neutropenia, and nausea were higher in the CF group. More patients withdrew from the study due to drug-related adverse events with CF than with IF (21.5% versus 10%; p=0.004), including 5 toxic deaths with CF versus 1 with IF. Whilst efficacy was not improved, the favourable toxicity profile suggests that irinotecan could be used as an alternative regimen in selected patients. Of the taxanes, docetaxel and pacltaxel, only the former has been evaluated in the context of a phase III trial, V-325, recently published on the Journal of Clinical Oncology (Van Cutsem 2006). Four hundred fourty-five patients were randomised to receive either the DCF (docetaxel, cisplatin, and 5FU) regimen or the standard CF (cisplatin and 5FU) regimen. TTP was the primary endpoint of the study. DCF had a better TTP (5.6 months versus 3.7 months, respectively; p < 0.001; risk reduction 32%), and better response rate (37% versus 25%, respectively; p = 0.01) than CF. Authors also found a better overall survival for DCF (9.2 months versus 8.6 months; p=0.02). However, the addition of docetaxel to CF resulted in some increase in toxicity, maily hematologic: grade 3/4 neutropenia (82% versus 57%, respectively) and febrile neutropenia (29% versus 12%) were more frequent with DCF than CF. The quality of life was however maintained better in the patients treated with the DCF regimen, despite more toxicity. A clinical benefit was also demonstrated with the DCF compared to the CF regimen. Recently, Wagner et al. (Wagner 2006) published a systematic review and meta-analysis to assess efficacy and tolerability of chemotherapy in advanced gastric cancer. The results of this analysis were:
– Combination versus single agent, mainly 5FU-based chemotherapy, showed significant overall survival benefits in favor of combination chemotherapy (HR=0.83; 95% CI, 0.74 to 0.93);
– Overall treatment-associated toxicities were higher in the combination chemotherapy arms, although this was usually not statistically significant in the individual trials. In six randomised trials, the overall rate of treatment-related deaths was 1.7% for combination therapy versus 0.8% for single-agent therapy with 5FU, and the difference was not statistically significant (OR=2.33; p=0.285).
– Comparisons of FU/cisplatin-containing regimens with versus without anthracyclines demonstrates a statistically significant benefit in overall survival in favor of the three-drug combination (HR=0.77; 95% CI, 0.62 to 0.91)
– 5FU/anthracycline-containing combinations with versus without cisplatin results in a statistically significant benefit in overall survival in favor of the three-drug regimen (HR=0.83; 95% CI, 0.76 to 0.91)
– Among the three-drug combinations, the difference in the percentage of treatment-related deaths (3.3% for ECF versus 0.6% for PELF) is likely to be attributed to the administration of 5FU as bolus versus continuous infusion (OR=5.36; 95% CI, 1.1 to 27.4; p=0.028).
– Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly 5FU/cisplatin) resulted in a non significant survival benefit in favor of the irinotecan-containing regimens (HR=0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination
– Rates of treatment-related deaths were 0.7% in the irinotecan-containing arm versus 2.6% in the nonirinotecan containing arm (OR=0.275; p=0.166). In two of three studies included in this comparison, irinotecan/FU combinations were compared against cisplatin/FU.
The conclusions of the Authors were that best survival results are achieved with three-drug regimens containing 5FU, an anthracycline, and cisplatin. Among these, regimens including 5FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of 5FU, such as epirubicin, cisplatin, and continuous-infusion 5FU. Unfortunately, this meta-analysis did not provide informations regarding the use of docetaxel (Wagner 2007).
Targeting vascular endothelial growth factor (VEGF) has proved to be a successful strategy in many cancers where its integration with conventional cytotoxic drugs has translated into survival benefits. Development of bevacizumab, a humanised monoclonal antibody directed against VEGF, in gastric cancer has, however, lagged behind. In a phase II study (Shah 2006), bevacizumab in combination with irinotecan and cisplatin achieved a response rate of 65% (95% CI, 46 to 80%), with a TTP of 8.9 months (95% CI, 5.7 to 9.9 months), and overall survival of 12.3 months (95% CI, 11 to 17 months). Possible bevacizumab-related grade 3/4 toxicities included hypertension, gastrointestinal hemorrhage and perforation, and thromboembolism. Targeting the epidermal growth factor receptor (EGFR) pathway through monoclonal antibodies directed against EGFR, such as cetuximab, has also proved to be a successful strategy in the treatment of gastric cancer. In a phase II trial (Pinto 2007), cetuximab combined with FOLFIRI (FOLCETUX study) for the first-line treatment of patients (n=38) with advanced metastatic gastric or gastro-oesophageal junctional cancers demonstrated a response rate of 44% (95% CI, 27.5-60.9%). The median TTP was 8 months (95% CI, 7-9), and the median expected survival time was 16 months (95% CI, 9-23). Grade 3-4 toxicity included neutropenia (42.1%) and acne-like rash (21.1%), a characteristic adverse event associated with this class of agent. Even if these data are interesting and encouraging, definitive phase III studies with the use of biologic agents are highly warranted. Despite the use of many drugs and different combinations, at the moment no standard chemotherapy may be recommended. Combination chemotherapy remains the cornerstone of treatment for advanced gastric cancer. Recently, several new cytotoxic agents have demonstrated activity in phase III setting, and include docetaxel, irinotecan, oxaliplatin and capecitabine, thereby increasing the potential treatment options for the disease. From the point of view of median survival, there are little differences from one regimen to another, especially for regimens including cisplatin and 5FU. A three-drugs regimen should be recommended on a type 1 clinical evidence for fit patients with advanced gastric cancer. Whether CF should always be combined with docetaxel as frontline therapy for untreated patients with advanced gastric cancer remains an open question, but docetaxel should become part of the front-line therapy of advanced gastric cancer. As DCF is an intensive and toxic combination, potentially more tolerable regimens incorporating docetaxel, which is clearly active in the treatment of advanced gastric cancer, should be developed (such as with oral fluoropyrimidines, or oxaliplatin). Given the favourable side effect profile, IF may be considered a reasonable alternative to a platinum-based regimen as first-line treatment of selected patients with advanced gastric cancer, but it provides no efficacy advantage. Taken together activity and side effect profile of oxaliplatin-based chemotherapy, oxaliplatin is an alternative to cisplatin in certain patients, and provides another treatment option for the treatment of gastric cancer. The use of oral cytotoxic agents may have potential advantages, such as the patient convenience and preference, and the avoidance of central venous access lines with the associated potential line-related complications.

6.6.4 Chemotherapy for metastatic disease: Treatment versus Supportive Care

Four randomised trials (Murad 1993; Pyrhonen 1995; Scheitauer 1995; Glimelius 1997) have explored the role of chemotherapy in addition to best supportive care compared with best supportive care alone. In all of these trials, the option for the initiation of chemotherapy at the time of symptomatic or objective progression was at the discretion of the treating physician. In one trial the research ethics committee required the provision of chemotherapy upon request in the control group. These series were relatively small, mainly because of the atypical design of the studies (chemotherapy versus no initial chemotherapy, chemotherapy at progression of disease or upon request), and the fact that when the interim analysis showed a benefit in favour of chemotherapy this led to the closure of the study. Patients randomised to receive best supportive care alone, even when allowed to receive chemotherapy later, had a median survival of 3 to 5 months compared to patients randomised to immediate chemotherapy, who had a median survival of 8 to 11 months. Overall, survival was prolonged by approximately 6 months (range, 3-9 months). These data strongly support the conclusion that systemic chemotherapy has a real, although modest effect on survival in patients with advanced disease. It is noteworthy that none of the regimens used in the best supportive care trials included cisplatin or the more recently used combinations. There is good evidence that the standard management of patients with advanced or metastatic disease, without any relevant comorbidity, an ECOG performance status of 0 to 2, and without peritoneal carcinomatosis, should be with palliative systemic chemotherapy, instituted at the earliest stage post-diagnosis on a type 1 level of evidence. By contrast, patients with several metastatic sites, an ECOG performance status of 2 or greater, and the presence of comorbidity have a lower chance of response to chemotherapy. This makes attendance or supportive care as needed the recommended treatment choice in the majority of cases. However, the decision of whether or not to start chemotherapy must be individualized, keeping in mind that the treatment of stage IV disease is basically palliative, and the main aims of therapy in this setting are symptom control, maintenance of quality of life and, possibly, improvement of survival.
In the meta-analysis reported by Wagner et al. (Wagner 2006), three eligible studies including 184 patients were included. The overall HR of 0.39 (95% CI, 0.28 to 0.52) in favour of the chemotherapy arms demonstrates a convincing benefit in overall survival over best supportive care alone, which translated to a benefit in weighted mean average survival of approximately 6 months.

6.6.5 Chemotherapy and Quality of Life

The effect of chemotherapy on quality of life (QoL) has only been evaluated in a few phase II studies with a small number of patients. Six randomised trials have addressed the issue of QoL (Glimelius 1997; Webb 1997; Ross 2002; Adjani 2007a; Adjani 2007b) in patients with advanced gastric cancer. All the trials assessed QoL by the EORTC QLQ-C30 questionnaire, which evaluates different aspects of functional status and treatment (impact of disease, toxicity) (Ringdal 1993; Hjermstad 1995). Only one trial compared chemotherapy (ELF or 5FU/leucovorin) with a best supportive care arm (Glimelius 1997). Authors aimed to estimate any gain in the quantity and QoL produced by chemotherapy. More patients in the chemotherapy group had an improved or prolonged high QoL for a minimum of 4 months compared with those in the best supportive care group (45% versus 20%, respectively; p < 0.05). Moreover, the average quality-adjusted survival was longer in the group of patients randomised to chemotherapy than in the best supportive care group (median, 6 months versus 2 months, respectively; p = 0.03). In the other five trials, QoL was evaluated mainly with questionnaire (eg, EORTC QLQ-C30 and/or EQ-5D). QoL during chemotherapy was better with ECF than FAMTX (Webb 1997) and MCF (Ross 2002), with DCF than CF (Van Cutsem 2006; Adjani 2007a ; Adjani 2007b), while it results similar among the treatment arms in the comparison IF versus CF (Dank 2005), and in the REAL-2 trial (ECF versus ECX versus EOF versus EOX) (Cunningham 2006b).

6.6.6 Chemotherapy for metastatic disease: suggested schedules

In metastatic gastric cancer, four randomised trials of chemotherapy versus best supportive care indicated that chemotherapy produces advantage in terms of QoL and survival. However, no clear standard systemic chemotherapy regimen is available. 5FU is one of the most effective and widely used drugs, and a 5FU-based combination therapy should be recommended on a type 1 level of evidence. By the addition of other different drugs, higher response rates are at best around 45%, as seen in phase III randomised studies, and overall survival generally is lower than 11-12 months. The incorporation of biologic agents to conventional therapy may help to gain some advantage, thus increasing overall survival of advanced gastric cancer beyond 12 months. Other strategies, such as sequential administration, or two-drug combination regimens, still need further evaluation. The major distinctive features of each regimen are summarized along with their pros and cons.

A) DCF regimen: docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, and 5FU 750 mg/m2/day i.v. by continuous infusion days 1-5, every 3 weeks. DCF has shown a good activity as front-line therapy, but toxicity was equally evident. Haematologic toxicity was mainly characterized by grade 3-4 neutropenia (84%), febrile neutropenia (29%); other toxicities are represented by stomatitis and diarrhoea.
B) ECF regimen: 5FU was administered as a continuous i.v. infusion at a dose of 200 mg/m2/day using a portable pump for up to 6 months. Epirubicin 50 mg/m2 i.v. and cisplatin 60 mg/ m2 i.v. infusion with standard hydration were given as an inpatient every 3 weeks to a maximum of eight cycles. The regimen has good activity, as established in phase III trials. The main toxicities were alopecia, neutropenia, nausea/vomiting.
C) EOX regimen: Epirubicin 50 mg/m2 i.v., oxaliplatin 130 mg/m2 i.v., and capecitabine 625 mg/m2 twice daily per os, continuously, were given every 3 weeks to a maximum of eight cycles. Compared to ECF, this combination achieve less alopecia, neutropenia, and nephrotoxicity, but more diarrhea, peripheral neuropathy, and lethargy.
D) FLO regimen: 5FU 2,600 mg/m2 administered as a continuous infusion over 24h, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2, every two weeks. Activity of this schedule is in the same range of the other newer regimens. FLO is associated with significantly less leukopenia, nausea, alopecia, fatigue, and renal toxicity, and more peripheral neuropathy than the 5FU/cisplatin combination.
E) XP regimen: capecitabine 1,000 mg/m2 daily in two-divided doses, days 1-14, and cisplatin 80 mg/m2, day 1. Cycles are repeated every three weeks. Activity is similar to that of newer regimens, with the advantage of reduced hospitalization time and simplified regimen. Capecitabine compared to 5FU is associated with more hand-foot syndrome.
F) IF regimen: irinotecan (CPT-11) 80 mg/m2 i.v.as 30-min infusion, followed by leucovorin 500 mg/m2 i.v. over 2 hours, followed by 5FU 2,000 mg/m2 i.v. over 22 h, weekly for 6 weeks, every 7 weeks. This 5FU/irinotecan-based regimen has a better safety profile compared to a 5FU/cisplatin-based combination, and may be considered for first-line treatment in patients unfit to receive cisplatin combinations.
G) PELF regimen: cisplatin at a dose 40 mg/m2 days 1,5; epirubicin 30 mg/m2 days 1,5; S-leucovorin 250 mg/m2 i.v. bolus days 1-4; 5FU 300 mg/m2 i.v. bolus, days 1-4; cycles are repeated every 3 weeks. Hematologic toxicity is common, mainly of grade 1 to 2. The prevalent non-haematologic side effects are nausea/vomiting, stomatitis, and diarrhoea.
H) Weekly PELF regimen: Weekly administration of cisplatin 40 mg/m2, epirubicin 35 mg/m2, 6S-leucovorin 250 mg/m2, 5FU 500 mg/m2, glutathione 1.5 g/m2, on day 1, followed by filgrastim 5 ?g/kg subcutaneously on days 2-7. One cycle of therapy consisted of eight 1-week treatments.
This highly active regimen has been evaluated in the context of a phase II trial. Severe toxicity, mainly anaemia, neutropenia, thrombocytopenia, or mucositis was experienced by 40 (38%) patients. No treatment-related deaths were recorded.

Older regimens
I) PF (CF) regimen: 5FU was given as a continuous i.v. infusion in a dose of 1 g/m2/day for 5 consecutive days, and cisplatin 100 mg/m2 was given as a 1-hour infusion. Cycles are repeated every 4 weeks. This regimen is no longer considered standard by many authors since it has been proven to achieve oly modest activity. The main toxicities of the PF regimen are neutropenia, nausea/vomiting and mucositis.
L) FAMTX regimen: methotrexate at a dose of 1,500 mg/m2 i.v. followed 1 hour later by 5FU at a dose of 1,500 mg/m2 i.v. on day 1 and doxorubicin at a dose of 30 mg/m2 i.v. on day 15. Cycles are repeated every 29 days. Hydration (diuresis = 100 mL/h) and alkalinization of the urine are required before administration of methotrexate, and leucovorin rescue (30 mg orally every 6 hours for 48 hours) is started 24 hours after methotrexate. Plasma levels of methotrexate are monitored at 24 and 48 hours after methotrexate administration, and leucovorin rescue at 30 to 60 mg every 6 hours is administered until the plasma levels are less than 2.5 x 106 mol/L. The major drawback of the regimen is the necessity of hospitalization. The main toxicity is represented by neutropenia.
M) ELF regimen: leucovorin at a dose of 300 mg/m2 given as a 10-minute i.v. infusion, followed immediately by etoposide 120 mg/m2 given as a 50-minute i.v. infusion, followed by bolus 5FU 500 mg/m2 for 3 consecutive days. The cycles were repeated every 3 weeks. This regimen has modest activity, but it is well tolerated in elderly patients and has the advantage of being an outpatient protocol.
N) FAM regimen: 5FU was given at a dose of 600 mg/m2 i.v. on days 1, 8, 29, and 36; doxorubicin 30 mg/m2 i.v. on days 1 and 29; and mitomycin 10 mg/m2 on day 1. The same cycle was repeated every 8 weeks. This regimen has a modest activity and acceptable toxicity.

6.6.7 Surgical treatment of metastatic disease

Many patients with metastatic disease have symptoms as dysphagia, obstruction and bleeding, which may make palliative resection of the primary tumour necessary. Survival for patients with advanced gastric cancer is relatively poor (3 to 5 months) without any treatment; therefore, any proposed operation should have a good chance of providing symptomatic relief and survival advantage, minimizing postoperative morbidity, mortality rates, and the need for prolonged hospitalization (Ouchi 1998; Isozaki 1993; Maekawa 1996). Several reports suggest that resection of the primary tumour may be beneficial in terms of survival (Bozzetti 1987; Haugstvedt 1989; Meijer 1983; Monson 1991). Although the approximate median survival is in the order of only 8 to 12 months after palliative resection, the procedure can provide relief from obstruction, bleeding, and pain (Meijer 1983; Ekbom 1980; Bozzetti 1987). When resection of cancer is not possible, sometime a bypass of the obstructing lesion may be performed. However, relief of symptoms after gastrojejunostomy occurs rather temporarily (Meijer 1983; Ekbom 1980; Bozzetti 1987), and given the increased operative mortality and morbidity, gastrojejunostomy does not translate into a survival advantage compared to total or proximal palliative gastrectomy (Ekbom 1980; Meijer 1983). In the absence of extensive metastatic disease, patients who are considered surgically incurable may receive a palliative resection, which can be performed with acceptable morbidity and mortality (Thompson 1993). Another important issue is QoL, which is strongly influenced by the adverse effects of palliative surgery. In the Dutch Gastric Cancer Trial (Hartgrink 2002), the median overall survival of patients undergoing palliative resection was better than that of unresected patients (8.1 months and 5.4 months, respectively; p < 0.001). The mortality rates were not significantly different between the groups, whereas higher morbidity rates and longer median hospital stay were observed in the resection group. Age should be taken into account when considering a palliative resection. Patients over 70 years of age may have a significantly higher morbidity and longer hospital stay compared with those aged 70 years or less (Hartgrink 2002). The benefit of palliative resection seems to be closely related to the number of metastatic sites. An aggressive approach may be recommended in patients with one positive sign of advanced gastric cancer (Isozaki 1993; Maekawa 1996; Hartgrink 2002), but when two or more signs of incurability were found, the survival advantage for patients having palliative resection disappears. Hartgrink et al. (Hartgrink 2002) noted that in patients with one positive sign of advanced disease (unresectable tumour, liver metastasis, peritoneal metastasis, or distant lymph node involvement) who had a resection, median survival was 10.5 months compared with 6.7 months for those who had not a resection (p=0.034). Interestingly, palliative resection does not seem to be influenced by the extent of peritoneal involvement, which affects negatively the QoL but not survival (Ouchi 1998), provided that no evidence of liver metastasis is encountered (Kikuchi 1998). In certain cases of inoperable disease, palliative laparoscopy may improve QoL with reasonable risk and inconvenience for the patient compared to laparotomy. Indications for laparoscopy include surgical access for enteral nutrition and enteric bypass procedures for obstructing gastric cancers (Cuschieri 1995). In conclusion, in selected patients with symptomatic advanced gastric cancer, resection of the primary disease appears to provide symptomatic relief with acceptable morbidity and mortality, even in the presence of macroscopic residual disease. The criteria for deciding whether one patient may benefit from a palliative operation has not yet been well established, and the data available represent retrospective analyses of patients who were selected for operation. Palliative resection or bypass may be suitable for individual clinical use on a type 3 level of evidence for patients with obstructive lesions, bleeding gastric cancers, or for patients under 70 years of age with tumour load restricted to one metastatic site.

6.6.8 Other palliative treatments

Gastric cancer is relatively resistant to radiotherapy. Moderate doses of external-beam irradiation are used only to palliate symptoms (bleeding, obstruction and pain) in the majority of patients and not to improve survival (Moertel 1969; Falkson 1976; Klaassen 1985; Mantell 1982). A variety of endoscopic methods is available for the palliation of symptoms related to obstruction. Laser ablation of tumour tissue may be effective, but relief appears to be transient and repeated treatments are required (Loizou 1992). The use of plastic and expandible metal stents has been associated with a success rate higher than 85% among selected patients with gastroesophageal tumours or tumours in the cardia (Knyrim 1993; Cusumano 1992).

Possible management options are:
1. Palliative chemotherapy.
2. Surgical resection/anastomosis or bypass of obstructing lesions in selected cases
3. Endoscopic laser therapy or placement of expandible stents
4. Radiation therapy to the primary tumour to palliate bleeding, obstruction, or pain. Palliative radiation therapy may also be targeted to other sites of metastases for similar indications
5. Clinical trials investigating new drugs and biological therapy

7. LATE SEQUELAE

Early recurrence of gastric cancer is difficult to identify and there are few opportunities to salvage patients with recurrent disease. It is unusual to see local-regional failure as the only component of relapse and in most cases relapse is associated with distant progression of disease and the disease is so not curable. Most of the local failures are distributed in the gastric bed (more than 75%), followed by the anastomosis or stump, and in the regional lymph nodes (Gunderson 1982; Allum 1989b). Locally recurrent gastric cancers, such as those in the anastomosis or stump, may be resectable, particularly if the surgeon can perform a subtotal gastrectomy. However, even when a single local recurrence happens, the presence of a large volume of disease would preclude performing a re-operation Some authors have investigated a surgical curative approach for patients with hepatic metastases (Ambiru 2001; Okano 2002; Ochiai 1994; Bines 1993; Saito 1996). However, median survival of patients undergoing liver metastasis resection is similar to that of patients treated with systemic chemotherapy. Palliative chemotherapy remains the standard treatment for patients with gastric cancer who have a disease relapse. These patients are considered ideal candidates for phase I and II trials and new biological approaches.Possible management options are:

1. Palliative chemotherapy

2. Surgical resection/anastomosis or bypass of obstructing lesions, whenever possible

3. Palliative surgery

4. Radiotherapy to the primary tumour to palliate bleeding, obstruction, or pain. Palliative radiation therapy may also be targeted to other sites of metastases for similar indications

5. Endoscopic laser therapy or placement of expandible stents

6. Clinical trials investigating new drugs and biological therapy.

8. FOLLOW-UP

8.1 General aims

In a general population of patients treated curatively for gastric cancer approximately 40-60% of them will develop a recurrence. About 75% to 80% of these will occur within two years, and in nearly 98% of patients within 5 years from surgery (Wu 2003; Shiraishi 2000). Local-regional disease as the only site of failure occurs in 23-56% of patients; by contrast, distant organ metastases as single site of relapse is quite rare (6%), and are generally found in the setting of advanced locoregional or peritoneal disease. Peritoneum followed by liver metastases are the most frequent distant sites of relapse (Gunderson 1982; Landry 1990; Katai 1994 ; Wu 2003). Locoregional relapses are mainly described at the anastomosis or stump, following subtotal (distal) or total gastrectomy, and lymph node relapse, mostly at the mesenteric or para-aortic sites rather than the regional lymph nodes. Re-operation for cure after recurrence at the site of the primary tumour can only be performed sucessfully in a limited group of patients, particularly in those patients treated with subtotal gastrectomy (Wu 2003; Yoo 2000). In one third of recurrences, CEA test and imaging procedures may anticipate the onset of symptoms by at least two months (Lacueva 1995). However, these techniques for routine follow-up give little advantage for diagnosing gastric cancer recurrence over clinical surveillance alone, and offer no improvement in terms of survival. In fact, to date, there have been no large-scale randomised trials documenting the efficacy of a standard, postoperative monitoring programme (Huguier 1992; Bohner 2000), as the early detection of recurrence is limited by the absence of potentially curative treatments. The major aims in the follow-up strategy are the early detection of local relapse (generally, the stump) amenable to treatment with curative intent, and the assessment and treatment of disorders related to the nutritional status of patients after gastrectomy (e.g., dumping syndrome), or other functional disorders related to recurrence.

8.2 Suggested protocols

Clinical issues on follow-up after radical gastrectomy include whom, when, and how often, or even whether, we should survey individuals at risk. Postoperative monitoring should be reserved primarily for the detection of asymptomatic local recurrences that can be curatively resected. The impact of follow-up on overall mortality of patients with recurrent gastric cancer is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. Careful follow-up for gastric cancer after radical resection is recommended on a type R basis. Follow-up strategies may include careful physical examination every 3-4 months for the first 2 years, and every 6 months thereafter, and endoscopy every 6 months within two years, and every year thereafter. Periodic determinations of serum CEA and CA19.9 levels, and laboratory studies may lead to the earlier identification and management of recurrent disease (Marrelli 2001). Abdomen US or CT scan and chest X-ray may be performed every 6 months within 2 years and every year for the next three years.

INDEX

 

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Dr. Giordano Beretta (Associate Editor)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy.
mail: beregd@iol.it

Dr. Vincenzo Catalano (Author)
Azienda Ospedaliaera Ospedale San Salvatore – Pesaro, Italy
mail: catalano_v@yahoo.it

Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
mail: filippo.de-braud@ieo.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Prof. Roberto Labianca (Associate Editor)
Ospedali Riuniti – Bergamo, Italy
mail: rlabian@tin.it

Prof. Eric Van Cutsem (Reviewer)
University Hospital Gasthuisberg – Leuven, Belgium
mail: eric.vancutsem@uz.kuleuven.ac.be