Gastric Cancer: Molecular Mechanisms, Diagnosis, and Treatment


Risk factors for gastric cancer


Definite risk factors

Probable risk factors

Atrophic gastritis

High dietary salt intake

Intestinal metaplasia

Obesity

High grade dysplasia

Tobacco smoking

Helicobacter pylori infection

Nitroso compounds

Epstein-Barr virus


Pernicious anemia


History of gastric ulcers


Family history of gastric cancer





11.2.1 Diet


In case-control studies, the risk of gastric cancer has been shown to be decreased in individuals with a diet rich in fruits and vegetables [4, 5]. A high dietary intake of salt and salt-preserved foods has been strongly associated with an increased risk of gastric cancer, and is a probable risk factor for developing gastric cancer (Table 11.1) [6, 7]. Nitroso compounds, present in fried foods and processed meats, may also contribute to the risk of developing gastric cancer [8, 9].


11.2.2 Presence of Precursor Lesions


The pathologic findings of atrophic gastritis, intestinal metaplasia, and dysplasia have been found to lead to an increased risk of “intestinal type “gastric cancer (Table 11.1) [10]. No defined precancerous lesions have been linked to diffuse type gastric cancer. It has been suggested that a sequential series of changes in the gastric mucosa may occur, sometimes in response to H. pylori infection, from atrophic gastritis to intestinal metaplasia, to high grade dysplasia followed by intestinal type adenocarcinoma [10].

Atrophic gastritis is an autoimmune disorder that has been associated with an increased risk of gastric adenocarcinoma [11, 12]. In this condition, there is progressive atrophy of the glandular epithelium which leads to a loss of parietal and chief cells [11]. In previous prospective and retrospective studies, the progression rate of chronic atrophic gastritis to gastric cancer is as high as 11 % [11, 13].

Intestinal metaplasia is a potentially reversible change in the gastric epithelium, most commonly caused by chronic infection with Helicobacter pylori or reflux injury [14, 15]. In some studies, a greater than tenfold increased risk has been shown [10]. It is considered to be a pre-malignant lesion [10, 15].

Patients with high-grade dysplasia have an increased rate of progression to gastric cancer, estimated to be as high as 57 % [16]. Some patients found to have high grade dysplasia may already have gastric cancer in other sites in the stomach [16, 17].


11.2.3 Pernicious Anemia


Pernicious anemia has been associated with an increased risk of intestinal-type gastric cancer (Table 11.1) [1820]. This may be because pernicious anemia occurs as a result of chronic atrophic gastritis, which is a risk factor for gastric cancer [18]. Due to the increased risk of gastric cancer in this population, a single endoscopy is recommended to evaluate for the presence of premalignant lesions [17].


11.2.4 Helicobacter pylori


Discovered in 1982, Helicobacter pylori is a spiral shaped, gram-negative rod found on the gastric mucosa [21]. It is now apparent that the presence of Helicobacter pylori is associated with the development of gastritis, peptic ulcers, and gastric cancer [2224]. H. pylori increases the risk of gastric cancer as high as sixfold [24]. In 1994, the International Agency for Research on Cancer (IARC) classified H. Pylori as a group A carcinogen for gastric cancer [25]. In 2004, the prevalence of H. pylori was as high as 76 % in developing countries, and 58 % in developed countries [26].

The mechanism by which H. pylori leads to carcinogenesis is unknown, however, it has been hypothesized that oxidative stress modifies DNA molecules of gastric epithelial cells [23]. Another mechanism postulated is that H. pylori causes a chronic inflammatory response, leading to atrophy of the gastric glands followed by intestinal metaplasia, dysplasia, and finally gastric adenocarcinoma [23].

The outcome of infection with H. pylori is highly variable, and is dependent on the associated virulence factors, most commonly cagA (cytotoxin-associated gene) or vacA (vacuolating cytotoxin gene) [23]. The vacA virulence factor is present in all of the strains of H. pylori. The risk of gastric cancer is increased with the presence of infection with cagA-positive strains [23]. Host factors may also affect the outcome of infection with H. pylori, including the presence of certain polymorphisms such as IL-1B, IL1RN, TNF, and IL-10. Treatment to eradicate H. pylori decreases the risk of developing gastric cancer [27, 28].


11.2.5 Epstein-Barr Virus


Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) accounts for 7–10 % of all gastric cancers [2933]. In this condition, EBV is present in the gastric carcinoma cells. On the molecular level, EBV-associated gastric carcinomas have a characteristic appearance of DNA methylation of the promoter region of several cancer-associated genes [30, 31]. This causes silencing and downregulation of the expression of these genes [31]. The rationale for how this could cause gastric cancer is currently unknown. Clinically, EBVaGC has a male predominance, and is predisposed to occur in the proximal stomach [29, 31, 33]. EBV-associated gastric cancers also have a lower frequency of lymph node metastases [33]. Pathologically, a high proportion of EBVaGC are seen in diffuse-type gastric cancers [31]. The prognosis of Epstein-Barr virus-associated gastric carcinomas may be better than non-EBV associated gastric cancers, however, more research is needed to make this determination [33].


11.2.6 Other Risk Factors


Cohort studies have shown that obesity is associated with an increased risk of gastric cancer [34, 35]. Tobacco smoking has also been found to increase the risk of gastric cancer [36]. The consumption of alcohol has been associated with higher incidences of gastric cancer in multiple studies [37, 38]. Many studies have shown an increased risk of gastric cancer in patients with a history of prior gastric surgery, typically 15 years or more post-surgery [39, 40].

A family history of gastric cancer strongly increases the risk of gastric cancer [4143]. This increase in risk may be due to genetic susceptibility, but may also be due to factors such as common diet or exposure to smoking. Gastric cancer can also be seen in the presence of familiar cancer syndromes, including hereditary diffuse gastric cancer, hereditary non-polyposis colon cancer, familial adenomatous polyposis, and Peutz-Jeghers syndrome [43].



11.3 Screening


Currently, there is no standardized screening program for gastric cancer in the United States due to the relatively low incidence of this malignancy in this country. Endoscopy as screening for upper gastrointestinal cancers in healthy individuals has not shown to be cost-effective, although may be beneficial and cost-effective in those with pre-cancerous lesions [17, 44, 45].

In certain countries with higher incidences of gastric cancer, such as Japan, Korea, Chile, and Venezuela, annual mass screening programs for gastric cancer have been implemented [46]. However, the type of screening and frequency of screening is variable. The type of screenings include upper endoscopy, serum pepsinogen tests, barium x-ray studies (photofluorography), endoscopic ultrasound, CT scan, and H. pylori antibody testing. In Japan, where gastric cancer is the leading cause of death from cancer, gastric cancer screening was implemented in 1983 for residents greater than or equal to 40 years old, with photofluorography as the recommended screening test [46]. In regions of high prevalence, screening with endoscopy has shown a benefit in terms of cancer stage at time of diagnosis in the Asian population. In a large retrospective study of 2,485 patients with gastric cancer, endoscopy intervals of 3 years or less were associated with an earlier stage of gastric cancer of diagnosis [47].

Surveillance endoscopies are recommended in certain high-risk or premalignant conditions. For patients with established Barrett’s esophagus, surveillance every 3 years is recommended. Patients with high grade dysplasia should undergo surveillance endoscopy every 3 months for 1 year. As patients with pernicious anemia have an increased risk of gastric cancer due to atrophic gastritis, a single endoscopy is recommended to evaluate for the presence of premalignant lesions in this population. Screening endoscopy is also recommended in patients with a history of severe caustic esophageal injury, tylosis, or familial adenomatous polyposis. As adenomatous gastric polyps may recur following resection, surveillance endoscopies are recommended every 3–5 years. There is insufficient evidence to recommend screening endoscopies in patients with achalasia or patients with a history of prior gastric surgery [17].

At this time, there is no recommended serum biomarker for the screening of gastric cancer. Potential biomarkers under investigation include serum trefoil factor 3 and microRNAs (miRNAs) miRNA-421 and MiR-106a [48, 49].


11.4 Pathology


Gastric cancers can be classified based on their anatomical location, morphology, or histology. Anatomical locations for gastric cancer include the gastroesophageal junction, proximal stomach (gastric cardia and fundus), and distal stomach (body and antrum). Cancer of the proximal stomach has a poorer prognosis when compared to the distal stomach [50]. Distal gastric cancers are more likely to be associated with Helicobacter pylori infection, and are more often seen in older males. Typically, distal gastric cancers are of the intestinal type [50].

Over 95 % of gastric cancers are adenocarcinomas, with the remaining percentage comprised of gastric lymphomas, gastrointestinal stromal tumors (GIST), squamous cell carcinomas, small cell carcinomas, and carcinoid tumors [50]. Adenocarcinomas are typically classified by either the Lauren criteria or the 2010 World Health Organization (WHO) classification [5053]. The Lauren criteria categorize gastric cancers into “intestinal type,” “diffuse type,” and “indeterminate type,” while the WHO classifies gastric cancers into papillary, tubular, mucinous, and poorly cohesive carcinomas [5053].



  • Intestinal type adenocarcinomas. Intestinal type adenocarcinomas are seen in approximately 54 % of cases, while diffuse and indeterminate types are seen less frequently in 32 % and 15 % of cases, respectively [53]. Intestinal type adenocarcinomas have a stronger association with Helicobacter pylori infection [50, 53, 54]. Histologically, intestinal type gastric cancers have a similar appearance to adenocarcinomas of the intestines, with tumor cells adhering together and forming glandular or tubular structures [51]. This type of gastric cancer is more commonly seen in geographic areas such as Asia, South America, and Eastern Europe [55]. Patients with intestinal type gastric cancer have a higher incidence of blood vessel invasion and metastases to the lung and liver.


  • Diffuse type adenocarcinomas. Diffuse type adenocarcinomas are more commonly seen in younger patients and females. Histologically, diffuse type adenocarcinomas consist of small clusters of cells or scattered poorly cohesive cells with a diffuse infiltrative margin. There is little to no gland formation, and tumor cells can have a signet-ring appearance [50]. Patients with diffuse type gastric cancer are more likely to have spread to the pleura and peritoneum, by the lymphatic system [50]. Diffuse type adenocarcinomas have a more uniform geographic distribution [55].

The four main histologic subtypes of gastric cancer as categorized by the 2010 WHO classification include tubular, papillary, mucinous, and poorly cohesive adenocaricinomas [52]. Uncommon other subtypes include squamous cell carcinoma, carcinosarcoma, choriocarcinoma, and adenosquamous carcinoma, amongst others.


11.5 Molecular Pathogenesis


In addition to environmental risk factors for gastric cancers, there are a number of molecular and genetic alterations that contribute to gastric carcinogenesis. Patients may be predisposed to the development of gastric cancer due to the presence of specific mutations. Many molecular aberrations have been associated with gastric cancer, including changes in p53, cyclin E, CD44, KRAS, CDH1, HER2, FGFR2, TFF1 and MET [50]. A number of abnormalities can occur in the development of gastric cancer, including oncogene activation, inactivation of tumor suppressor genes, overexpression of growth factors, and inactivation of DNA repair genes [53]. The major molecular alterations which are associated with gastric cancer are as follows:


11.5.1 p53 Mutation


When a mutation is present, the tumor suppressor gene p53 can alter cell cycle regulation as well as DNA repair and synthesis. The p53 mutation is the most frequent mutation seen in gastric cancers and is present in approximately 60 % of cases [50, 56]. This genetic alteration is also seen in H. pylori associated conditions such as chronic gastritis, intestinal metaplasia and dysplasia, and it has been suggested that H. pylori causes changes in the p53 gene leading to the development of gastric cancer [57].


11.5.2 APC (Adenomatous Polyposis Coli) Mutation


A mutation in APC, a multidomain protein, is the second most common mutation seen in gastric cancer. This protein functions in multiple processes, including cell adhesion and cell migration as well as chromosome segregation. This mutation is seen more frequently with intestinal type adenocarcinomas and can be seen in up to 30–40 % of these cancers. The APC mutation has also been found in premalignant lesions such as intestinal metaplasia [50].


11.5.3 CDH1 Mutation


CDH1 mutations have been seen in sporadic diffuse type gastric cancer as well as hereditary diffuse gastric cancer. Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant condition in which about one-third of patients will have a mutation in the tumor suppressor gene CDH1, or E-cadherin [58]. In this condition, a germline mutation in CDH1 causes inactivation of an allele of E-cadherin, leading to mutation, methylation, and loss of heterozygosity, which leads to gastric cancer [50]. Carriers of this gene have an 80 % lifetime risk of developing gastric cancer. According to the International Gastric Cancer Consortium, people with a strong family history of gastric cancer may be candidates for testing for CDH1, and may benefit from a prophylactic gastrectomy [50, 58].


11.5.4 Beta-catenin/Wnt Signaling


Wnt1, a ligand that activates the Wnt signaling pathway, has been found to contribute to the self-renewal of cancer stem cells, and as a result may affect tumor progression and the development of chemoresistance [59]. In gastric cancer, overexpression of Wnt1 increased the proliferation rate of gastric cancer cells. Previous studies have shown that the activation of Wnt1 signaling leads to acceleration of the proliferation of gastric cancer stem cells. Given this finding, studies are currently ongoing to determine if drugs targeting the Wnt signaling pathway, such as salinomycin, can be used successfully in the treatment of gastric cancers [59].


11.5.5 HER2 (Human Epidermal Growth Factor Receptor 2) Overexpression


HER2 overexpression is also associated with gastric adenocarcinomas, more commonly in intestinal type adenocarcinomas and in those located in the proximal stomach [53]. This finding has important clinical implications as discovered in the phase III ToGA (Trastuzumab for Gastric Cancer) study. This study showed that the monoclonal antibody trastuzumab against the HER2 receptor led to improved overall survival when combined with chemotherapy in patients with HER2 positive metastatic gastric or gastroesophageal junction cancers [60], leading to the approval of this agent in this patient population. According to the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that all patients with newly diagnosed metastatic gastric adenocarcinoma be tested for HER2-neu status [53, 61].


11.5.6 MET Overexpression


MET is an oncogene which is overexpressed in intestinal type adenocarcinomas. The MET oncogene encodes a tyrosine kinase receptor which has been found to bind hepatocyte growth factor. MET inhibitors are a potential area of interest in the treatment of intestinal type adenocarcinomas [50, 56].


11.5.7 FGFR2 (Fibroblast Growth Factor 2) Amplification


FGFR2 overexpression is more commonly expressed in diffuse type adenocarcinomas, and has been seen in 10 % of gastric cancers [50, 56]. Clinical trials are currently underway to determine if tyrosine kinase inhibitors such as dovitinib with activity against FGFR2 will lead to improved responses in gastric cancer [62].


11.5.8 KRAS Mutation


KRAS mutations, located on codons 12 and 13, are found in approximately 5 % of gastric cancers, typically in intestinal type gastric cancers. KRAS amplification has been associated with a poorer prognosis in gastric cancer [50, 56].


11.5.9 RUNX3 Expression


RUNX3, a transcription factor which helps to regulate apoptosis, is expressed in nearly 50 % of gastric cancers [50]. This transcription factor may act as a tumor suppressor gene [63]. The expression of RUNX3 is associated with an improved prognosis [50].


11.5.10 Aberrant Methylation of CpG


Aberrant methylation of CpG (CpG island methylation, or CIMP) is seen in 50 % of gastric cancers and is also seen in infection with H. pylori. CIMP may lead to the inactivation of tumor suppressor genes, which leads to unrestrained cell growth and subsequent cancers [50].


11.6 Diagnosis



11.6.1 Clinical Presentation


The most common presenting symptoms of gastric cancer include unintentional weight loss, abdominal pain, nausea, dysphagia, melena, early satiety, and ulcer-type pain [64]. On physical examination, a palpable abdominal mass may be identified [64]. If metastatic disease is present, the patient may have ascites, a Sister Mary Joseph’s node (periumbilical nodule), or a Virchow’s node (left supraclavicular adenopathy) [65, 66]. Rarely, a paraneoplastic syndrome can be seen, with findings such as seborrheic keratosis, hypercoagulable state, polyarteritis nodosa, or membranous glomerulonephritis [6769].


11.6.2 Diagnostic Testing


Upper gastrointestinal endoscopy with biopsy is the most sensitive and specific method for diagnosing gastric cancer. Upper endoscopy allows for anatomic visualization of the tumor, and also allows for biopsy collection to obtain a tissue diagnosis. In order to accurately assess for gastric cancer, it is recommended to biopsy any concerning gastric ulcer. Multiple biopsies should be taken in order to achieve the highest sensitivity for diagnosis [70].


11.7 Staging


Gastric cancer staging is used to determine if resectable disease is present at time of diagnosis [71]. Gastric cancer is primarily staged using the American Joint Committee on Cancer staging system AJCC 7th edition, revised in 2010 (Tables 11.2 and 11.4) [72]. In the AJCC TNM staging criteria, T stage is categorized based upon the depth of tumor invasion. N stage is determined based upon the number of positive regional lymph nodes (Table 11.3). Metastatic disease includes disease spread to distant organs or other intraabdominal lymph nodes such as retropancreatic, portal, or mesenteric lymph nodes [72].


Table 11.2
TNM staging of gastric cancer











































































Primary tumor (T)


Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria

T1

Tumor invades lamina propria, muscularis mucosae, or submucosa

T1a

Tumor invades lamina propria or muscularis mucosae

T1b

Tumor invades submucosa

T2

Tumor invades muscularis propria

T3

Tumor penetrates subserosal connective tissue without invasion of visceral peritoneum or adjacent structures

T4

Tumor invades serosa (visceral peritoneum) or adjacent structures

T4a

Tumor invades serosa (visceral peritoneum)

T4b

Tumor invades adjacent structures

Regional lymph nodes (N)


Nx

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1–2 regional lymph nodes

N2

Metastasis in 3–6 regional lymph nodes

N3

Metastasis in seven or more regional lymph nodes

N3a

Metastasis in 7–15 regional lymph nodes

N3b

Metastasis in 16 or more regional lymph nodes

Distant metastasis


M0

No distant metastasis

M1

Distant metastasis


Adapted from American Joint Commission on Cancer (AJCC), 7th edition, 2010 [72]



Table 11.3
Regional lymph nodes [72]








































Regional lymph node locations for tumors along the greater curvature

Regional lymph node locations for tumors along the lesser curvature

Regional lymph node locations for tumors along both sites

Greater curvature

Lesser curvature

Pancreaticolienal

Greater omental

Lesser omental

Peripancreatic

Gastroduodenal

Left gastric

Splenic

Gastroepiploic

Cardioesophageal


Pre-pyloric antrum

Common hepatic


Pancreaticoduodenal

Celiac



Hepatoduodenal




Table 11.4
AJCC staging of gastric cancer




























































































































Stage

T

N

M

0

Tis

N0

M0

IA

T1

N0

M0

IB

T2

N0

M0


T1

N1

M0

IIA

T3

N0

M0


T2

N1

M0


T1

N2

M0

IIB

T4a

N0

M0


T3

N1

M0


T2

N2

M0


T1

N3

M0

IIIA

T4a

N1

M0


T3

N2

M0


T2

N3

M0

IIIB

T4b

N0

M0


T4b

N1

M0


T4a

N2

M0


T3

N3

M0

IIIC

T4b

N2

M0


T4b

N3

M0


T4a

N3

M0

IV

Any T

Any N

M1


Adapted from AJCC 7th edition, 2010 [72]

The staging evaluation of a patient with newly diagnosed gastric cancer can include computerized tomography (CT) scan, endoscopic ultrasound. The roles of positron emission tomography (PET) and staging laparoscopy are controversial at this time.


11.7.1 CT Scan of the Abdomen


CT scan of the abdomen is used early on in the staging workup of gastric cancer to attempt to identify the presence of metastatic disease [61]. CT scans can assess common sites of metastases, including the liver, adnexa, peritoneum, and distant lymph nodes. However, peritoneal disease or sites with sub-centimeter disease may remain undetected by conventional CT scans [73]. Also, CT scans are less accurate in assessing for tumor depth, which is needed for accurate T staging [74].


11.7.2 Endoscopic Ultrasound (EUS)


The National Comprehensive Cancer Network (NCCN) guidelines recommend endoscopic ultrasound in the initial staging of gastric cancer in patients with no known M1 disease [61]. Endoscopic ultrasound is sensitive and specific in assessing T and N stages, as this procedure is able to detect depth of tumor invasion [71, 75]. EUS has improved specificity and sensitivity for more advanced lesions than with early disease [71]. Proceeding with endoscopic ultrasound allows for fine needle aspiration of suspicious appearing lymph nodes and can therefore assist with N staging as well [71]. Endoscopic ultrasound is the imaging method of choice for gastric cancers [76].


11.7.3 Positron Emission Tomography/CT (PET/CT) Scan


PET/CT scan has a higher sensitivity and specificity for the detection of distant metastatic disease when compared to CT scan alone, and therefore is suggested in the workup of gastric cancer by the NCCN guidelines [61, 77]. However, PET/CT scan is less accurate than staging laparoscopy in the detection of peritoneal carcinomatosis. Also, diffuse type gastric adenocarcinomas are typically not FDG (18-fluorodeoxyglucose) avid, therefore limiting the role of PET/CT in this clinical setting [78]. The role of PET scan in gastric cancer is still evolving. In 10 % of cases, PET scans can identify occult metastatic disease leading to fewer unnecessary surgical procedures, and can be considered in the staging workup of gastric cancer [79].


11.7.4 Staging Laparoscopy


Staging laparoscopy allows for the direct assessment of the liver, peritoneal cavity, and regional lymph nodes, which allows for a more accurate staging of gastric cancer and may prevent unnecessary laparotomy [80]. Staging laparoscopy also allows for the collection of peritoneal washings, which is useful as it is known that negative visible disease with no overt peritoneal metastases and positive peritoneal cytology is a marker of poor prognosis and can be consider a contraindication to attempting curative resection [80, 81]. However, given the invasiveness, NCCN guidelines recommend that staging laparoscopy be considered to evaluate for peritoneal spread only in patients with locoregional M0 disease following staging with EUS, CT scan, and PET/CT scan [61]. Specifically, staging laparoscopy is only recommended when considering chemoradiation or surgery, and not if palliative resection is planned [61].


11.8 Treatment


Treatment is dependent on stage at diagnosis, and can vary from surgical resection to systemic chemotherapy.


11.8.1 Treatment of Resectable Disease



11.8.1.1 Surgical Resection


The primary treatment of early stage gastric cancer is surgical resection. Surgical resection techniques include gastrectomy with lymph node dissection, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD).

Patients must be carefully selected to receive endoscopic resection of gastric cancer. Selected patients should meet the following criteria: (1) high probability of an en bloc resection, (2) tumor size <20 mm without ulceration or <10 mm by Paris classification, and (3) tumor histology of an intestinal type adenocarcinoma, confined to the mucosa, with the absence of venous or lymphatic invasion [82].

Endoscopic mucosal resection is less invasive when compared to gastrectomy and is used in patients with early gastric cancer in whom the risk of lymph node metastasis is low [83]. In these selected patients, EMR has a comparable long-term survival to gastrectomy [83]. However, if the cancer is incompletely resected, the patient may need to undergo a second EMR or a gastrectomy [84]. In endoscopic submucosal dissection, a high-frequency knife dissects directly along the submucosa layer, which allows for a more accurate and larger en bloc R0 resection [85]. Endoscopic resection by EMR or ESD can be complicated by gastric perforation and bleeding [83, 86, 87].

Gastrectomy with lymphadenectomy remains the most widely used approach for resection of gastric cancer. Total gastrectomy is preferred for lesions in the upper one-third of the stomach as the Roux-en-Y reconstruction is associated with a lower incidence of GERD, and subtotal gastrectomy may fail to remove the lesser curvature LN. Subtotal gastrectomy is performed for lesions in the lower two-third of the stomach [88]. The 5-year survival rate after pylorus-sparing gastrectomy is approximately 96–98 % [89, 90]. Laparoscopic gastrectomy is an alternative to open gastrectomy with lower intraoperative and postoperative morbidity, however, more long-term outcomes data is needed [91].

Many studies have evaluated the benefits of D1 versus D2 resections in gastric cancer. Initially, preliminary results of the European MRC randomized controlled trial of 400 patients comparing D1 versus D2 resection found that D2 gastric resections were associated with higher morbidity and mortality. In long-term follow up, the classical Japanese D2 resection had no survival advantage over D1 resection [92].

The Dutch Gastric Cancer Group Trial examined outcomes in patients dependent on the extent of lymph node dissection. There was no difference in overall survival between the D1 (limited) and D2 (extended) groups (p = 0.53), and morbidity (p < 0.001) and mortality (p = 0.004) were significantly higher in the D2 group [93]. The 15 year follow up of the D1D2 trial found that when compared to standardized limited (D1) lymphadenectomy, standardized extended (D2) lymphadenectomy is associated with a lower rate of locoregional recurrence as well as a lower rate of gastric cancer related death rates [94].

The large JCOG 9501 randomized controlled trial compared standard D2 lymphadenectomy to extended lymphadenectomy (D2 gastrectomy combined with para-aortic lymphadenectomy) in 523 patients with gastric cancer, and found that para-aortic lymphadenectomy could be added without increasing surgical complications if performed by specialized surgeons [95].

Few studies have examined D3 (levels 1, 2, and 3) resection, however, a randomized controlled trial of 221 patients with gastric cancer showed that D3 nodal dissection offered a survival benefit for patients when performed by experienced surgeons [96]. Similar data was also seen in retrospective studies [97].

D2 resection is currently the recommended surgical practice in patients with resectable gastric cancer, and should be performed by experienced surgeons at institutions which routinely perform these procedures [94, 98]. The addition of adjuvant chemoradiation also lowers the local recurrence rates [98].


11.8.1.2 Neoadjuvant or Perioperative Chemotherapy


Neoadjuvant or perioperative chemotherapy is the primary treatment method practiced in Europe for localized gastric cancers. The goal of neoadjuvant chemotherapy is to downstage a locally advanced gastric tumor before surgical resection is attempted. The MAGIC trial, a randomized controlled trial of 503 patients with resectable gastric cancer, examined the benefit of perioperative chemotherapy and surgery versus surgery alone. This study concluded that ECF (epirubicin 50 mg/m2, cisplatin 60 mg/m2, and fluorouracil 200 mg/m2/day) given for three cycles prior to surgery and three cycles postoperatively decreased tumor size and stage and increased overall survival and progression-free survival compared to surgery alone. Perioperative chemotherapy with ECF was overall tolerated well, with myelosuppression, nausea, and vomiting as the most common grade 3 or 4 toxicities. However, this important study is limited in that only 42 % of patients in the perioperative chemotherapy group completed all protocol treatment, and 34 % of patients who completed preoperative chemotherapy and surgery did not undergo postoperative chemotherapy [99]. In perioperative chemotherapy, ECF can be modified to replace cisplatin with oxaliplatin, and to replace fluorouracil with capecitabine [100].

Perioperative chemotherapy with fluorouracil and cisplatin may also be given, as seen in the French FNLCC/FFCD trial [101]. In this multicenter phase III trial of 224 patients with resectable adenocarcinoma of the lower esophagus, GE junction, or stomach, patients were randomized to receive perioperative chemotherapy and surgery versus surgery alone. Patients with potentially resectable gastric adenocarcinoma that received two to three cycles of preoperative chemotherapy (cisplatin and fluorouracil) and three to four cycles of postoperative chemotherapy were more likely to undergo R0 resection and had fewer node-positive tumors. Patients who received perioperative chemotherapy also had a reduction in the risk of disease recurrence and risk of death. Grade 3–4 toxicity was seen in 38 % of patients who received chemotherapy and surgery, most commonly neutropenia. Despite this, postoperative morbidity was similar between the two groups [101].

Finally, the EORTC 40954 trial, a phase III randomized controlled trial of 144 patients, attempted to examine neoadjuvant chemotherapy and surgery versus surgery alone. The trial was stopped for poor accrual. While no survival benefit could be detected, this trial did show a significantly increased rate of R0 resection in the neoadjuvant chemotherapy group when compared to the surgery alone group (81.9 % versus 66.7 %, p = 0.036). The number of postoperative complications was higher in the neoadjuvant group compared to the surgery alone group, but this was not statistically significant (27.1 % vs. 16.2 %, p = 0.09) [102].

As a result of these trials, current recommendations for the treatment of localized gastric cancer include perioperative chemotherapy or postoperative chemotherapy plus chemoradiation [61] (Table 11.5).


Table 11.5
Chemotherapy for resectable gastric cancer
















































Preoperative chemotherapy

Perioperative chemotherapya

Postoperative chemotherapy

Preferred regimens
   

Paclitaxel and carboplatin

ECF (epirubicin, cisplatin, and fluorouracil)

Fluoropyrimidine – before and after fluoropyrimidine-based chemoradiation [103, 105]

Cisplatin and fluorouracil

Epirubicin, oxaliplatin, and fluorouracil

Capecitabine and oxaliplatin

Oxaliplatin and fluorouracil

Epirubicin, cisplatin, and capecitabine

Capecitabine and cisplatin [106]

Cisplatin and capecitabine

Epirubicin, oxaliplatin, and capecitabine


Oxaliplatin and capecitabine

Fluorouracil and cisplatin


Other regimens



Irinotecan and cisplatin



Docetaxel or paclitaxel and fluoropyrimidine




Adapted from NCCN guidelines, gastric cancer [61]

a3 cycles preoperative, 3 cycles postoperative

Mar 25, 2016 | Posted by in INTERVENTIONAL RADIOLOGY | Comments Off on Gastric Cancer: Molecular Mechanisms, Diagnosis, and Treatment

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