GASTRIC CANCER

The American Cancer Society estimated that about 26,240 cases of stomach cancer (16,520 in men and 9,720 in women) will be diagnosed in 2018.⁽¹⁾ Median age at diagnosis is 68 years.⁽²⁾ Gastric cancer is the 15th most common cancer in the United State.⁽²⁾

Stomach cancer is the fourth most common cause of death from cancer.⁽³⁾ The World Health Organization estimates that in 2015, gastric cancer accounted for 754,000 deaths worldwide.⁽⁴⁾

In Pakistan one study shows that carcinoma stomach was seen mostly in young male patients, presenting late with advanced disease in stage III and IV in emergency. Only 33% tumors were resectable while 66.7% patients were managed by palliative treatment. Overall mortality was 13.3% due to its late presentation. Mortality rate of gastric cancer in Pakistan is 6541 deaths per year.⁽⁵⁾

Ooi et al identified three oncogenic pathways that are deregulated in the majority (>70%) of gastric cancers: the proliferation/stem cell, NF-kappa β, and Wnt/beta-catenin pathways. Their study suggests that interactions between these pathways may play an important role in influencing disease behavior and patient survival.⁽⁷⁾

The intestinal type of non-cardiac gastric cancer is generally thought to arise from Helicobacter pylori infection, which initiates a sequence that progresses from chronic non-atrophic gastritis to atrophic gastritis, then intestinal metaplasia, and finally dysplasia. This progression is known as Correa’s cascade. In a population-based cohort study, Swedish researchers found that after 2-year latency, patients with precancerous gastric lesions were at higher risk for gastric cancer than the general Swedish population, and that risk increased steadily with progression through Correa’s cascade. The researchers estimated that the 20-year gastric cancer risk in patients with particular gastroscopy findings was as follows:⁽⁸⁾

• Normal mucosa – One in 256
• Gastritis – One in 85
• Atrophic gastritis – One in 50
• Intestinal metaplasia – One in 39
• Dysplasia – One in 19

Hematogenous and lymphatic spread

Understanding the vascular supply of the stomach allows understanding of the routes of hematogenous spread. The vascular supply of the stomach is derived from the celiac artery. The left gastric artery, a branch of the celiac artery, supplies the upper right portion of the stomach. The common hepatic artery branches into the right gastric artery, which supplies the lower portion of the stomach, and the right gastroepiploic branch, which supplies the lower portion of the greater curvature.

Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer. The lymphatic drainage of the stomach is complex. Primary lymphatic drainage is along the celiac axis. Minor drainage occurs along the splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas.

Prognosis without treatment: An early report from Japan suggested that without treatment, 63 percent of patients with early gastric cancer will progress to advanced stage disease within five years (6 to 88 months).⁽⁹⁾ Early gastric cancer may represent a meta-stable biologic state, with doubling times on the order of several years, versus advanced cancer with doubling times of less than a year.

Prognosis following treatment: The overall five-year survival rate for treated early gastric cancer in most modern era series is over 90 percent: nearly 100 percent for mucosal tumors, and 80 to 90 percent for submucosal tumors.^(10-13) Survival rates are similar between patients who undergo endoscopic resection and those who undergo surgical resection (five-year survival of 96 and 94 percent in one study).^(14-16)

Early gastric cancer has no associated symptoms; however, some patients with incidental complaints are diagnosed with early gastric cancer. Most symptoms of gastric cancer reflect advanced disease. All physical signs in gastric cancer are late events. By the time they develop, the disease is almost invariably too far advanced for curative procedures.

Signs and symptoms of gastric cancer include the following:

• Indigestion
• Nausea or vomiting
• Dysphagia
• Postprandial fullness
• Loss of appetite
• Melena or pallor from anemia
• Hematemesis
• Weight loss
• Palpable enlarged stomach with succussion splash
• Enlarged lymph nodes such as Virchow nodes (i.e., left supraclavicular) and Irish node (anterior axillary)

Late complications of gastric cancer may include the following features:

• Pathologic peritoneal and pleural effusions
• Obstruction of the gastric outlet, gastroesophageal junction, or small bowel
• Bleeding in the stomach from esophageal varices or at the anastomosis after surgery
• Intrahepatic jaundice caused by hepatomegaly
• Extrahepatic jaundice
• Inanition from starvation or cachexia of tumor origin

Screening for gastric cancer is controversial, and recommendations for screening differ based on the incidence of gastric cancer. Universal or population-based screening for gastric cancer has been implemented in some countries with a high incidence of gastric cancer (e.g. Japan, Korea, Venezuela, and Chile).^(17-19)

In areas of low gastric cancer incidence, screening for gastric cancer with upper endoscopy should be reserved for specific high-risk subgroups.^(20-31)

Individuals at increased risk for gastric cancer include those with the following:

• Gastric adenomas
• Pernicious anemia
• Gastric intestinal metaplasia
• Familial adenomatous polyposis
• Lynch syndrome
• Peutz-Jeghers syndrome

Juvenile polyposis syndrome

Studies for staging of stomach cancer may include the following:

• Upper gastrointestinal (GI) tract endoscopy and biopsy
• Chest/abdomen/pelvic computed tomography (CT) with oral and intravenous contrast
• Positron emission tomography (PET) – CT evaluation if no evidence of M1 disease is found, and if clinically indicated
• Complete blood cell count (CBC) and comprehensive chemistry profile
• Endoscopic ultrasound if no evidence of M1 disease is found
• Endoscopic resection for early-stage cancers
• Biopsy of metastatic disease as clinically indicated
• HER2-neutesting if metastatic adenocarcinoma is documented or suspected

Imaging Studies

Esophagogastroduodenoscopy has a diagnostic accuracy of 95%. This relatively safe and simple procedure provides a permanent color photographic record of the lesion. This procedure is also the primary method for obtaining a tissue diagnosis of suspected lesions. Biopsy of any ulcerated lesion should include at least 6 specimens taken from around the lesion because of variable malignant transformation. In selected cases, endoscopic ultrasound may be helpful in assessing depth of penetration of the tumor or involvement of adjacent structures.

Double-contrast upper GI series and barium swallows may be helpful in delineating the extent of disease when obstructive symptoms are present or when bulky proximal tumors prevent passage of the endoscope to examine the stomach distal to an obstruction (more common with gastroesophageal [GE]-junction tumors). These studies are only 75% accurate and should for the most part be used only when upper GI endoscopy is not feasible.

Chest radiograph is done to evaluate for metastatic lesions.

CT scan or MRI of the chest, abdomen, and pelvis assess the local disease process as well as evaluate potential areas of spread (i.e. enlarged lymph nodes, possible liver metastases).

Endoscopic ultrasound allows for a more precise preoperative assessment of the tumor stage. Endoscopic sonography is becoming increasingly useful as a staging tool when the CT scan fails to find evidence of T3, T4, or metastatic disease. Institutions that favor neoadjuvant chemoradiotherapy for patients with locally advanced disease rely on endoscopic ultrasound data to improve patient stratification.

Histologic Findings

Adenocarcinoma of the stomach constitutes 90-95% of all gastric malignancies. The second most common gastric malignancies are lymphomas. Gastrointestinal stromal tumors formerly classified as either leiomyomas or leiomyosarcomas account for 2% of gastric neoplasms. Carcinoids (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) are the remaining tumor histologic types.

Adenocarcinoma of the stomach is subclassified according to histologic description as follows: tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.

Pathology specimens are also classified by gross appearance. In general, researchers consider gastric cancers ulcerative, polypoid, scirrhous (i.e. diffuse linitis plastica), superficial spreading, multicentric, or Barrett ectopic adenocarcinoma.

Intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic gastritis, retained glandular structure, little invasiveness, and a sharp margin. The pathologic presentation classified as epidemic by the Lauren system is associated with most environmental risk factors, carries a better prognosis, and shows no familial history.

The second type, diffuse, infiltrative, endemic cancer, consists of scattered cell clusters with poor differentiation and dangerously deceptive margins. Margins that appear clear to the operating surgeon and examining pathologist often are determined retrospectively to be involved. The endemic-type tumor invades large areas of the stomach. This type of tumor is also not recognizably influenced by environment or diet, is more virulent in women, and occurs more often in relatively young patients. This pathologic entity is associated with genetic factors (such as E-cadherin), blood groups, and a family history of gastric cancer.

Staging

The 2017 American Joint Committee on Cancer (AJCC) Cancer Staging Manualpresents the following TNM classification system for staging gastric carcinoma.⁽³²⁾

Primary tumor (T)

See the list below:

• TX – Primary tumor cannot be assessed
• T0 – No evidence of primary tumor
• Tis – Carcinoma in situ, intraepithelial tumor without invasion of 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/organs

Regional lymph nodes (N)

See the list below:

• NX – Regional lymph node(s) cannot be assessed
• N0 – No regional lymph node metastases
• N1 – Metastases in 1-2 regional lymph nodes
• N2 – Metastases in 3-6 regional lymph nodes
• N3 – Metastases in 7 or more regional lymph nodes
• N3a – Metastases in 7-15 regional lymph nodes
• N3b – Metastases in 16 or more regional lymph nodes

Distant metastasis

See the list below:

• M0 – No distant metastasis
• M1 – Distant metastasis

Prognostic features

Two important factors influencing survival in resectable gastric cancer are depth of cancer invasion through the gastric wall and presence or absence of regional lymph node involvement.

In about 5% of primary gastric cancers, a broad region of the gastric wall or even the entire stomach is extensively infiltrated by malignancy, resulting in a rigid thickened stomach, termed linitis plastica. Patients with linitis plastica have an extremely poor prognosis.

Margins positive for presence of cancer are associated with a very poor prognosis.

The greater the number of involved lymph nodes, the more likely the patient is to develop local and systemic failure after surgery.

Clinical Staging

See the list below:

• Stage 0 – Tis, N0, M0
• Stage I – T1-2, N0, M0
• Stage IIA – T1-2, N1-3, M0
• Stage IIB – T3, N0, M0 or T4a, N0, M0
• Stage III – T3, N0, M0 or; T4a, N1-3, M0
• Stage IVA – T4b, any N, M0
• Stage IVB – Any T, any N, M1

Laboratory Studies

The goal of obtaining laboratory studies is to assist in determining optimal therapy. Useful studies may include the following:

• A complete blood cell count (CBC) can identify anemia, which is present in approximately 30% of patients and may be caused by bleeding, liver dysfunction, or poor nutrition
• Electrolyte panels and liver function tests also are essential to better characterize the patient’s clinical state
• Carcinoembryonic antigen (CEA) is increased in 45-50% of cases
• Cancer antigen (CA) 19-9 is elevated in about 20% of cases

Surgical resection is the principal therapy for gastric cancer, as it offers the only potential for cure. The most common procedures are total, subtotal, or distal gastrectomy. The choice of procedure and the extent of nodal dissection are determined by the ability to obtain clear microscopic margins. In patients who present with regionally advanced disease, removal of involved adjacent organs (e.g. the spleen) may be required.

Neoadjuvant chemotherapy has an established role in the management of gastric cancer. Perioperative chemotherapy, or postoperative chemotherapy plus chemoradiation, are preferred for localized gastric cancer. Because of lower toxicity, two-drug cytotoxic regimens (e.g. fluoropyrimidine and oxaliplatin) are preferred for patients with advanced disease.

Surgery

The surgical approach in gastric cancer depends on the location, size, and locally invasive characteristics of the tumor.

Types of surgical intervention in gastric cancer include the following:

• Total gastrectomy, if required for negative margins
• Esophagogastrectomy for tumors of the cardia and gastroesophageal junction
• Subtotal gastrectomy for tumors of the distal stomach
• Lymph node dissection: Controversy exists regarding extent of dissection; the National Comprehensive Cancer Network (NCCN) recommends D2 dissections over D1 dissections; a pancreas- and spleen-preserving D2 lymphadenectomy provides greater staging information and may provide a survival benefit while avoiding its excess morbidity when possible.⁽³³⁾

Chemotherapy

Anti-neoplastic agents and combinations of agents used in managing gastric cancer include the following:

• Platinum-based combination chemotherapy: First-line regimens include epirubicin/cisplatin/5-FU or docetaxel/cisplatin/5-FU; other regimens include irinotecan and cisplatin; other combinations include oxaliplatin and irinotecan
• Trastuzumab in combination with cisplatin and capecitabine or 5-FU: For patients who have not received previous treatment for metastatic disease
• Ramucirumab for the treatment of advanced stomach cancer or gastroesophageal (GE) junction adenocarcinoma in patients with unresectable or metastatic disease following therapy with a fluoropyrimidine- or platinum-containing regimen

Neoadjuvant, adjuvant, and palliative therapies

Potentially useful therapies in gastric cancer include the following:

• Neoadjuvant chemotherapy
• Intraoperative radiotherapy (IORT)
• Adjuvant chemotherapy (e.g. 5-FU)
• Adjuvant radiotherapy
• Adjuvant chemoradiotherapy
• Palliative radiotherapy
• Palliative-intent procedures (e.g. wide local excision, partial gastrectomy, total gastrectomy, simple laparotomy, gastrointestinal anastomosis, bypass)

The main goals of a cancer treatment is to cure or considerably prolong the life of patients and to ensure the best possible quality of life to cancer survivors.

To view, “Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology”, please click on below link:

http://www.jnccn.org/content/14/10/1286.full

To view, “Gastric Cancer: ESMO Clinical Practice Guidelines”, please click on below link:

http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Gastric-Cancer

Most doctors recommend careful follow-up, with a physical exam and review of symptoms every 3 to 6 months for the first few years, then at least yearly after that. Lab tests might also be done. Scans are not usually needed at each visit, but should be done if there are any suspicious symptoms or physical findings.

If you have had surgery, you should meet with a nutritionist, who can help you adjust to changes in your eating habits.

People who have had surgery: especially if they had the upper part of their stomach removed (in either a subtotal or total gastrectomy) — will probably need to have their vitamin blood levels tested regularly and may need to get vitamin supplements, which may include B12 injections. (The pill form of vitamin B12 isn’t absorbed if the upper part of the stomach has been removed.)

There is no sure way to prevent stomach cancer, but there are things you can advise to patient that could lower the risk.

• Diet, nutrition, body weight, and physical activity

The dramatic decline of stomach cancer in the past several decades is thought to be a result of people reducing many of the known dietary risk factors. This includes greater use of refrigeration for food storage rather than preserving foods by salting, pickling, and smoking. To help reduce risk, avoid a diet that is high in smoked and pickled foods and salted meats and fish.

A diet high in fresh fruits and vegetables can also lower stomach cancer risk. Citrus fruits (such as oranges, lemons, and grapefruit) may be especially helpful,  but grapefruit and grapefruit juice can change the blood levels of certain drugs you take, so it’s important to consider this with patient.

The American Cancer Society recommends that people eat a healthy diet, with an emphasis on plant foods. This includes eating at least 2½ cups of vegetables and fruits every day. Choosing whole-grain breads, pastas, and cereals instead of refined grains, and eating fish, poultry, or beans instead of processed meat and red meat may also help lower your risk of cancer.

Studies that have looked at using dietary supplements to lower stomach cancer risk have had mixed results so far. Some studies have suggested that combinations of antioxidant supplements (vitamins A, C, and E and the mineral selenium) might reduce the risk of stomach cancer in people with poor nutrition to begin with. But most studies looking at people who have good nutrition have not found any benefit to adding vitamin pills to their diet. Further research in this area is needed.

Although some small studies suggested that drinking tea, particularly green tea, may help protect against stomach cancer, most large studies have not found such a link.

• Being overweight or obese may add to the risk of stomach cancer:

On the other hand, being physically active may help lower your risk.

The American Cancer Society recommends staying at a healthy weight throughout life by balancing calorie intake with physical activity.  Aside from possible effects on the risk of stomach cancer, losing weight and being active may also have an effect on the risk of several other cancers and health problems.

• Avoiding tobacco use

Tobacco use can increase the risk of cancers of the proximal stomach (the portion of the stomach closest to the esophagus).

• Treating H pylori infection

It is not yet clear if people whose stomach linings are chronically infected with the H pylori bacteria but who do not have any symptoms should be treated with antibiotics. Some early studies have suggested that giving antibiotics to people with H pylori infection might lower the number of pre-cancerous lesions in the stomach and reduce the risk of developing stomach cancer. But not all studies have found this. More research is needed to be sure that this is a way to prevent stomach cancer in people with H pylori infection.

• Aspirin use

Using aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen, seems to lower the risk of stomach cancer. These medicines can also lower the risk of developing colon polyps and colon cancer. But they can also cause serious (and even life-threatening) internal bleeding and other potential health risks in some people.

• For people at greatly increased risk

Only a small percentage of stomach cancers are known to be caused by hereditary diffuse gastric cancer syndrome. But it’s very important to recognize it, because most people who inherit this condition eventually get stomach cancer.  A personal history of invasive lobular breast cancer before age 50 as well as having close family members who have had stomach cancer suggests that they might be at risk for having this syndrome. These people can talk to a genetics professional about getting genetic testing. If the testing shows the person has a mutation (abnormal change) in the CDH1 gene, many doctors will recommend they have their stomach removed before the cancer develops.

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