The Washington Manual of Oncology, 3 Ed.

Esophageal and Gastric Cancer

Maria Baggstrom • A. Craig Lockhart

 I. ESOPHAGEAL CANCER

1. Subjective. Patients with esophageal cancer often do not have symptoms until the esophageal lumen is greatly narrowed. The most common symptom for patients with esophageal cancer is dysphagia. Ninety-five percent of symptomatic patients will report dysphagia. It typically begins with solid food only but often progresses to occurring with liquids as the esophageal lumen becomes blocked by the cancer. Other common symptoms include weight loss (50%), regurgitation (40%), pain on swallowing (20%), and cough (20%).
2. Objective. Physical examination findings are varied. It may be normal, show cachexia only, or there may be evidence of metastases such as supraclavicular lymphadenopathy, hoarseness from recurrent laryngeal nerve involvement, pleural effusion, hepatomegaly, or bony tenderness.
3. Workup. Symptoms or signs suggesting esophageal cancer should prompt further evaluation. The most important test is an esophagogastroduodenoscopy (EGD). This test allows visualization, localization, and biopsy of an esophageal lesion. If an esophageal cancer is found, a complete blood count (CBC), comprehensive metabolic panel (CMP), and a computed tomography (CT) of the chest and abdomen are indicated.

 CT is an excellent initial staging tool, but depending on the CT results as well as the tumor location, further specialized testing may be necessary. If the patient does not have evidence of metastasis on CT, consultation with a thoracic surgeon and a radiation oncologist should follow.

 In the absence of metastatic disease and if the patient is considered a candidate for curative surgery, an endoscopic ultrasound should be performed. This procedure, involving insertion of an ultrasound probe into the esophagus and stomach, allows the most precise assessment of depth of tumor involvement, length of esophagus affected, and magnitude of lymph node metastases, particularly paraesophageal and celiac nodes. A biopsy of suspicious lymph nodes can be done during the study.

 Positron emission tomography (PET) scans are an important part of the staging evaluation of patients without clear evidence of metastasis on CT. FDG (2-fluoro-2-deoxy-D-glucose)-avid lymph nodes located in regions where therapy would be altered should be biopsied to confirm metastasis.

 A primary tumor located above the carina increases the risk for tracheoesophageal fistula, indicating the need for bronchoscopy. Patients with tracheoesophageal fistulas often present with postprandial coughing and may sometimes have aspiration pneumonias.

1. Staging. Esophageal cancer staging depends on the tumor, node, metastases (TNM) system established by the American Joint Commission for Cancer (AJCC) and the International Union Against Cancer (UICC). The most recent edition of the AJCC for the staging of esophageal cancers includes tumors that include the gastroesophageal junction and tumors extending to the proximal 5 cm of the stomach.
2. Therapy
3. Therapy for localized esophageal cancer
4. General considerations. The treatment of esophageal cancer requires a multidisciplinary approach. It frequently involves a combination of surgery, radiation, chemotherapy, and supportive treatments. The functional status of the patient and location of the tumor play a key role in determining the management of the patient. Patient comorbidities may preclude the use of potentially curative therapies.
5. Surgery. Surgery is considered the standard therapy for stage I, II, and III esophageal cancers located outside the cervical esophagus. If an early-stage cancer is located in the cervical esophagus, however, the preferred treatment is a combination of chemotherapy and radiation.

 The best chance for surgical cure involves removal of the entire tumor and draining lymph nodes with adequate proximal and distal margins. The three most frequently used approaches for resection are: (a) the Ivor Lewis approach, in which a laparotomy and right thoracotomy are performed for esophageal resection and gastric mobilization with an anastomosis in the upper thorax; (b) transhiatal esophagectomy, through a cervical and abdominal approach with cervical anastomosis; and (c) left thoracoabdominal approach, with an anastomosis below the aortic arch. After an esophagectomy, most patients are reconstructed with a primary esophagogastric anastomosis in the neck or chest.

 Esophageal resection is a major surgery with a mortality rate of approximately 4% in experienced hands. Other complications of the surgery may include anastomotic leak, chylothorax, damage to the left recurrent laryngeal nerve, severe hemorrhage, and pulmonary embolus.

 The cure rates from surgery are dependent on the stage of the cancer. Thirty percent to fifty percent of patients with stage I esophageal cancer will be cured by surgery alone. For patients with stage IIA and IIB disease, the 5-year survivals following surgery are 15% to 30% and 5% to 15%, respectively. Locoregional relapse after surgical resection ranges from 15% to 25%.

1. Neoadjuvant and adjuvant therapy. In patients with locally advanced cancers, neoadjuvant and adjuvant treatment with chemoradiotherapy have been shown to improve outcomes in randomized phase III trials.

 The most prominent study evaluating neoadjuvant chemoradiotherapy is the CROSS trial (N Engl J Med 2012;366:2074). In the CROSS study, 368 patients with resectable esophageal cancers of both histologic subtypes (squamous and adenocarcinoma) were randomly assigned to immediate surgery or weekly administration of neoadjuvant carboplatin (doses titrated to an area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m²) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days/ week), followed by surgery. Median overall survival was 49.4 months in the chemoradiotherapy–surgery group versus 24 months in the surgery group (hazard ratio [HR], 0.657; 95% confidence interval [CI], 0.495 to 0.871; P=0.003). For patients with locally advanced but surgically resectable esophageal cancers, neoadjuvant chemoradiotherapy is recommended by the National Comprehensive Cancer Network (NCCN).

 Postoperative chemoradiotherapy has a role in the treatment of selected patients with esophageal cancer (New Engl J Med 2001;345:725). The SWOG 9008/INT 0116 randomized 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction, stage IB through IVM0, to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil/m²/day, plus 20 mg of leucovorin/m²/day, for 5 days, followed by 4,500 cGy of radiation at 180 cGy per day, given 5 days per week for 5 weeks, with modified doses of fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. The median overall survival in the surgery-only group was 27 months, compared with 36 months in the chemoradiotherapy group; the HR for death was 1.35 (95% confidence interval, 1.09 to 1.66; P=0.005). The HR for relapse was 1.52 (95% CI, 1.23 to 1.86; P<0.001). Since approximately 20% of the patients in this study had lesions at the gastroesophageal junction, this approach is commonly applied to patients with adenocarcinomas of the distal esophagus who have not received preoperative therapy. Patients with gross or microscopic residual disease following surgery are felt to benefit from combined modality chemoradiotherapy. Adjuvant chemoradiotherapy in patients with squamous cell cancers without residual disease after resection is less defined. In the current NCCN Guidelines, observation is recommended for those with squamous cell carcinoma.

14. Therapy for unresectable locally advanced esophageal cancer. The standard of care for unresectable locally advanced esophageal cancer is concurrent chemoradiotherapy. Herscovic et al., randomized 120 patients to radiation alone (64 Gy) or cisplatin 75 mg/m² on day 1 and 5-FU 1,000 mg/m²/day continuous intravenous infusion on days 1 to 4 to be repeated in weeks 1, 5, 8, and 11 along with 50 Gy of radiation over 5 weeks. The median survival for the chemoradiotherapy arm was 14.1 months versus 9.3 months in the radiation-alone arm. The 5-year survival for chemoradiotherapy was 27%, as compared with 0% in the radiation-alone group (N Engl J Med 1992;326:1593). Eighty-five percent of the patients had squamous cell esophageal cancers; therefore, there is more clinical data to apply this approach in patients with tumors that have squamous cell histology. However, this approach is also often used in patients with adenocarcinomas who are not candidates for curative surgery.
15. Endoscopic treatment of superficial esophageal cancers. Patients who undergo frequent endoscopic evaluations because of a history of Barrett’s Esophagus, high-grade dysplasia, or long-standing acid reflux are sometimes found to have superficial esophageal cancers. Esophagectomy has been the standard treatment for these conditions with high cure rates but also significant impact on quality of life. More recently, endoscopic approaches (e.g., endoscopic mucosal resection [EMR], photodynamic therapy [PDT], and laser therapy) have increased in use for selected patients with encouraging results. These approaches should be considered only in patients who have a very low risk of lymph node metastases (T stage less than T1b) or are poor candidates for esophageal surgery.
16. Therapy for metastatic esophageal cancer
17. General considerations. Metastatic esophageal cancer is incurable, and the toxicity of therapy must be weighed against its potential benefit. Palliative therapy for swallowing and nutritional support are especially important. There are a number of options for palliation of swallowing. These include esophageal dilatation, stent placement, brachytherapy, external beam radiation, and laser therapy. In regard to nutritional support, patients with metastatic esophageal cancer frequently require a gastrostomy tube.
18. Chemotherapy. Several chemotherapeutic agents have activity in esophageal cancer. Unfortunately, no large phase III trials comparing chemotherapeutic regimens have been performed in recent years. The agents that have the most activity in esophageal cancer are cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, vinorelbine, oxaliplatin, and irinotecan. In general, platinum-based doublets have the highest response rate and are typically used as first-line therapy. It is a common practice, and listed in the NCCN, that patients with metastatic cancers of the esophagus, regardless of histology, can be treated similarly to patients with gastric adenocarcinomas. For patients with metastatic adenocarcinoma of the esophagus, it is recommended that the tumor be tested for HER2-neu status to determine whether trastuzumab should be added to chemotherapy (Lancet 2010;376:687). NCCN currently lists platinum-based and 5-FU–based chemotherapeutic regimens as category 1 recommendations (strongest recommendation). There are three category 1 regimens, epirubicin cisplatin, 5-FU (ECF), docetaxel, cisplatin, 5-FU (DCF), and fluorouracil with cisplatin. Three-drug regimens should be reserved for patients with excellent performance status, good organ function, and easy access to medical care.
19. Course of the disease. Metastatic esophageal cancer has a poor prognosis with a median survival of approximately 10 months despite systemic chemotherapy. Three fourths of the patients have mediastinal node involvement or distant spread at the time of diagnosis. Death often occurs from progression of their metastatic disease or aspiration pneumonia from local disease.
20. Complications. Complications of the esophageal cancer include hemorrhage, obstruction, tracheoesophageal fistula, and aspiration pneumonia.
21. Epidemiology. Esophageal cancer is a commonly found neoplasm and is the seventh most common cause of cancer death in the world. There is vast geographic variation in the incidence of this cancer. The incidence in the United States is about 5 per 100,000, although in African American men, it may be as high as 18 per 100,000, whereas China and Iran have an incidence of 20 per 100,000. In parts of Africa, Central America, and Western Asia, the incidence is only 1.5 per 100,000.

 The two most common pathologic subtypes of esophageal cancer are squamous cell carcinoma and adenocarcinoma. Other histologic types such as sarcomas, small cell carcinomas, and lymphomas are extremely rare. Of the two most common histologies, squamous cell tumors make up 98% of malignancies in the upper and middle one-third of the esophagus, whereas adenocarcinoma is found predominantly in the lower third. Previously, squamous cell carcinoma was the most frequent subtype, but over the past 30 years, the incidence of adenocarcinoma has been increasing rapidly in the Western world. The reason for this shift is unknown. In non-Western countries, squamous cell cancers represent the majority of esophageal cancers, with adenocarcinomas remaining relatively unusual.

 The incidence of esophageal cancer increases with age and is rarely found among patients younger than 40 years. Squamous cell carcinoma affects African American men six times more than it affects White men, whereas adenocarcinoma affects Whites four times as much. All subtypes of esophageal cancers affect men three times as often as they do women.

 Several factors can increase the risk of developing esophageal cancer. The long-term use of tobacco and alcohol are predisposing factors for development of squamous cell carcinoma of the esophagus. Dietary factors such as inadequate vegetable and fruit intake may also increase the risk of the development of this cancer. Nitrosamines and their precursors (found in pickled vegetables, moldy or fermented foods, and smoked fish) are known to promote cancerous changes in the esophagus. Tylosis, a rare genetic syndrome, carries the highest risk of developing squamous cell carcinoma from chronic inflammation and stasis (1,000-fold risk). It is an autosomal dominant trait characterized by hyperkeratosis of the palms and soles that may produce defective vitamin A metabolism. Other conditions associated with esophageal cancer are head and neck malignancies, celiac disease, and gastroesophageal reflux disease.

 Barrett’s esophagus increases the risk of adenocarcinoma by 30 to 125 times that of the healthy patient population. In this disorder, the normal squamous epithelium of the esophagus is destroyed by chronic gastroesophageal reflux of acid, pepsin, and bile, and is ultimately replaced by a specialized intestinal columnar epithelium.

1.  Research initiatives. The role of many targeted therapies is currently being studied. Optimizing neoadjuvant chemoradiation is also an important area of research.
2. GASTRIC CANCER
3. Subjective. Gastric cancer usually presents with nonspecific constitutional symptoms. The most common is weight loss that occurs in approximately 80% of patients. Other common symptoms include anorexia, early satiety, fatigue, vague stomach pain, dysphagia (from gastroesophageal [GE] junction tumors), GI bleeding, and vomiting (from gastric outlet obstruction).
4. Objective. The physical findings in gastric cancer are typically manifestations of metastatic disease. Several eponymic terms have been created to describe specific sites of metastatic gastric cancer. Virchow’s node describes metastasis to the left supraclavicular node. Sister Mary Joseph’s node is a periumbilical lymph node metastasis. A Krukenberg tumor is a gastric cancer metastatic to the ovaries. Blumer’s shelf describes a “drop metastasis” into the perirectal pouch. Other common physical findings in patients with metastatic gastric cancer include cachexia, palpable abdominal masses, hepatomegaly from metastatic involvement and malignant ascites.
5. Workup. EGD is useful for the evaluation of suspected gastric cancer. This technique allows visualization of lesions and easy biopsy. EGD is used in the Japanese screening program for gastric cancer, which is credited with the increased proportion of early gastric cancers diagnosed in that country.

 Once a diagnosis of gastric carcinoma is made, further staging is necessary. As in esophageal cancer, CT scans and PET/CT are used to evaluate for metastatic disease. In cases where surgical resection for cure is being considered, endoscopic ultrasound may be used to evaluate the tumor depth and involvement of local lymph nodes. Unfortunately, metastatic peritoneal deposits may not be seen on routine imaging, and a diagnostic laparotomy is necessary to rule this out before embarking on definitive therapy.

 Gastric cancer is staged according to the AJCC TNM criteria.

1. Therapy
2. Localized gastric adenocarcinoma
3. Surgery. Surgery is the most effective curative therapy for gastric cancer. In the United States, patients with resected stage I cancer have a 5-year survival of 58% to 78%. For stage II, survival ranges from 20% to 34%, and for stage III from 8% to 20%.

 Patients with cancers localized to the distal stomach may be cured with subtotal gastrectomy. Other sites are usually treated with total gastrectomy. With surgical resection, the standard of care surgery should include a D2 lymph node dissection that removes the perigastric nodes along the greater and lesser curvature (the N1 group of nodes) as well as the nodes along the left gastric artery, the common hepatic artery, the celiac artery, and the splenic artery (the N2 group of nodes). The tail of the pancreas and the spleen are sometimes removed additionally in a D2 dissection, although this procedure has been noted to increase morbidity and mortality (Lancet Oncol 2010;11:439).

 The NCCN Guidelines recommend a D2 resection along with an examination of at least 15 lymph nodes. In Asian countries, D2 dissections are routinely completed. In the United States, D2 resections are less commonly achieved owing to concerns about greater morbidity. Patients should therefore be referred for surgery at centers with experience in these procedures.

1. Neoadjuvant and adjuvant therapy. Adjuvant therapies have been tried in an attempt to improve survival following resection. Adjuvant radiotherapy alone has not shown benefit. Adjuvant chemoradiotherapy, however, clearly has benefit for some patients. This is based on the Intergroup 116 (INT-116) study. In this study, 556 patients with at least stage IB gastric carcinoma, who had undergone definitive resection to negative margins, were randomized to observation or 5 months of therapy. The adjuvant therapy consisted of one cycle consisting of 5-FU (425 mg/m²) plus leucovorin (20 mg/m²) daily for 5 days. One month of rest followed this cycle of chemotherapy. Combination chemoradiotherapy was then started. Radiation dose of 4,500 cGy was given over 5 weeks with 5-FU (400 mg/m²) and leucovorin (20 mg/m²) on days 1 to 4 and for the last 3 days of radiation. A 1-month rest then followed. Then 5-FU (425 mg/m²) plus leucovorin (20 mg/m²) on days 1 to 5 was repeated monthly for two cycles. Adjuvant therapy increased overall survival from 27 months to 36 months (p<0.005) (N Engl J Med 2001;345:725). In the INT-116 study, a D2 resection was recommended for the study participants; however, only 10% of the patients received this type of surgery.

 Adjuvant chemotherapy studies had not clearly shown a benefit until the recent CLASSIC study was reported (Lancet 2012;379:315). In this study, 1035 patients with stage II-IIIB gastric cancers who had undergone a D2 gastrectomy with curative intent were randomized to adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1,000 mg/m²) twice daily (on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m²) (on day 1 of each cycle) for 6 months versus surgery only. Three-year disease-free survival was 74% (95% CI 69 to 79) in the adjuvant group and 59% (53 to 64) in the surgery-only group (HR 0·56, 95% CI 0·44 to 0.72; p<0·0001). Therefore, adjuvant chemoradiotherapy is considered standard of care for patients who have had completely resected stage IB or more advanced gastric adenocarcinoma where adjuvant chemotherapy without radiation can be considered for patients who have had a D2 resection. For patients who had positive margins at resection, combination chemoradiation is also considered standard of care.

 Neoadjuvant/perioperative chemotherapy has been tested to make unresectable cancers operable and to improve overall survival. The most prominent trial is the MAGIC trial, where 503 patients with at least stage II adenocarcinoma of the stomach, gastroesophageal junction, and distal esophagus were randomized to surgery alone or chemotherapy, in addition to surgery (N Engl J Med 2006;355:11). The chemotherapeutic regimen was ECF (epirubicin 50 mg/m² on day 1, cisplatin 60 mg/m² on day 1, and 5-FU 200 mg/m² by c.i.v.i. on days 1 to 21) every 3 weeks for three cycles before surgery and then three cycles after surgery. The chemotherapy arm showed a statistically significant downsizing of the tumor as well as significant improvement in survival. The 5-year survival was 36% in the chemotherapy arm versus 23% in the surgery-only arm. Interestingly, only 42% of the patients randomized to chemotherapy were able to complete the three postoperative cycles. On the basis of the results of Intergroup 116, the CLASSIC and the MAGIC trials, it is clear that surgery alone is not sufficient therapy for gastric cancer. What remains unclear is the role for adjuvant or neoadjuvant versus perioperative therapy and the role of radiation therapy RT. Currently, NCCN recommends (with equal category 1 ratings) perioperative chemotherapy in patients who have not had surgery or adjuvant chemoradiotherapy in patients who have had surgery. Adjuvant chemotherapy as a single modality can be considered in patients who have undergone a D2 resection.

1. Therapy for medically unresectable patients. Combination chemoradiation is considered a standard of care for medically unresectable localized gastric adenocarcinoma. It typically combines 5-FU with 4,500 to 5,000 cGy of radiation, but a taxane-based regimen can also be considered. Combination chemotherapy as a single modality is also a consideration. Notably, only a very small percentage of patients can be cured with chemoradiotherapy alone.
2. Metastatic gastric adenocarcinoma
3. Chemotherapy. Chemotherapy has been shown to improve survival and quality of life in patients with metastatic gastric carcinoma. Several chemotherapeutic agents have activity in gastric cancer, including 5-FU, cisplatin, oxaliplatin, irinotecan, capecitabine, anthracyclines, and taxanes. In a recent Cochrane meta-analysis, combination chemotherapy appears to offer a small survival benefit over single-agent chemotherapy. Commonly used combination chemotherapeutic regimens include CF (cisplatin 100 mg/m² on day 1 every 4 weeks, and infusional 5-FU 1,000 mg/m²/day on days 1 to 5 every 4 weeks), DCF (docetaxel 75 mg/m² on day 1 every 3 weeks, cisplatin 75 mg/m² on day 1 every 3 weeks, and infusional 5-FU 750 mg/m²/day on days 1 to 5 every 3 weeks), ECF (epirubicin 50 mg/m² on day 1 every 3 weeks, cisplatin 60 mg/m² on day 1 every 3 weeks, and infusional 5-FU 200 mg/m²/day continuously), EOF (epirubicin 50 mg/m² on day 1 every 3 weeks, oxaliplatin 130 mg/m² on day 1 every 3 weeks, and infusional 5-FU 200 mg/m²/day continuously), EOX (epirubicin 50 mg/m² on day 1 every 3 weeks, oxaliplatin 130 mg/m² on day 1 every 3 weeks, and capecitabine 625 mg/m² p.o. b.i.d. continuously), FOLFOX (oxaliplatin 85 mg/m² on days 1 and 15 every 4 weeks, leucovorin 400 mg/m² on days 1 and 15 every 4 weeks, 5-FU bolus 400 mg/m² on days 1 and 15, 5-FU infusion 800 mg/m²/day on days 1, 2, 15, and 16 every 4 weeks), and FOLFIRI (irinotecan 180 mg/m² on days 1 and 15 every 4 weeks, leucovorin 400 mg/m² on days 1 and 15 every 4 weeks, 5-FU 1,200 mg/m²/day on days 1,2,15, and 16 every 4 weeks). Despite interesting phase III trials comparing combination chemotherapies such as the TAX 325, which showed an increased time to tumor progression for DCF compared with CF (J Clin Oncol 2007;25:3205) and the REAL-2 trial, with least equivalence of EOX, ECF, EOF, and ECX (N Engl J Med 2008;358:36), there is no clear standard of care first-line combination chemotherapy. Also, there is no clear standard of care for second-line chemotherapy regimens. Randomized trials have shown a survival benefit for second-line therapy in selected patients versus best supportive care. Common regimens in this setting include irinotecan or docetaxel.
4. Targeted therapies. HER2-neu, also known as ERBB2, a member of the ERBb family of receptors associated with tumor cell proliferation, apoptosis, adhesion, migration, and differentiation, is overexpressed in approximately 20% of gastric cancers and is a clinically validated cancer target. Trastuzumab, a monoclonal antibody against HER2, was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastroesophageal junction cancers in the ToGA study (Lancet 2010 28;376:687). Patients with HER2 overexpressing gastric or gastroesophageal junction cancers were randomly assigned to study treatment with capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Median overall survival was 13.8 months (95% CI 12 to 16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10 to 13) in those assigned to chemotherapy alone (HR 0.74; 95% CI 0.60 to 0.91; p=0.0046). Therefore, HER2 testing is recommended for all patients with metastatic gastroesophageal cancers.

 Antiangiogenic therapies have a proven role in a variety of malignancies and recent clinical trials in patients with gastric and gastroesophageal junction adenocarcinomas have validated the use of this treatment strategy in these cancers. Ramucirumab is a monoclonal antibody VEGFR-2 antagonist that is FDA approved for treatment of patients with gastric and gastroesophageal junction adenocarcinomas. The RAINBOW study (Lancet Oncology 2014 - 15(11):1224–35) was a randomized phase 3 trial comparing ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinomas. Patients receiving the combination regimen had improved overall survival (median 9.6 months versus 7.4 months; hazard ratio 0.807 [95% CI 0.678-0.962]; p=0.017). In the REGARD study (Lancet 2014 - 383(9911):31–9), patients with previously treated advanced gastric or gastroesophageal junction adenocarcinomas were randomized to receive ramucirumab monotherapy or placebo. The patients receiving ramucirumab had improved median overall survival (5.2 months versus 3.8 months; hazard ratio 0.776, [95% CI 0.603-0.998]; p=0.047). Therefore, ramucirumab in combination with paclitaxel or as monotherapy, is considered a standard second-line treatment option for patients with advanced gastric cancers.

1. Other palliative procedures. Debulking/diverting surgery may improve quality of life in selected patients with discrete obstructing tumors. Radiotherapy may palliate bleeding or painful metastases. Other procedures are similar to those discussed earlier for esophageal cancer.
2. Course of the disease. The median survival of patients with metastatic gastric cancer is approximately 10 months. Common sites of metastasis include the liver, peritoneum, and lymph nodes.
3. Complications. Gastric cancer can lead to hemorrhage, gastric obstruction, and malignant ascites. Anastomotic leaks are the most common complication of gastrectomy. Development of B12 deficiency following gastric surgery is also a concern.
4. Pathology. Ninety percent of gastric carcinomas are adenocarcinomas. The rest are non-Hodgkin’s lymphomas (NHLs) and leiomyosarcomas (gastrointestinal stromal tumors [GIST]).

 Two classification systems for gastric adenocarcinoma are used. The Lauren classification divides gastric adenocarcinomas into the intestinal and diffuse types. The intestinal type arises from a background of intestinal metaplasia and shows differentiation resembling that of a colonic adenocarcinoma. Intestinal type is predominant in endemic areas, affects older patients, and often metastasizes first to the liver. The diffuse type is poorly differentiated, affects younger patients, and has a tendency to metastasize to the peritoneum, resulting in implants and malignant ascites. Patients with the intestinal type appear to have better outcomes overall.

 The Borrmann classification divides adenocarcinomas by their growth pattern. Types I and II are polypoid and heaped-up ulcers, respectively, and are associated with the intestinal type. Type III is an ulcerated infiltrating tumor, and type IV, diffusely infiltrating. This last type is also referred to as linitis plastica or leather bottle stomach and is associated with the diffuse type of adenocarcinoma. GE-junction tumors are usually the diffuse type. The boundaries between these groupings are not sharp, and some tumors are not easily categorized.

93. Epidemiology. Gastric cancer was once the most common malignancy in the United States, but its incidence has decreased since the 1930s. Worldwide, gastric cancer is surpassed only by lung cancer in frequency. It is the most frequent visceral cancer in Japan, where the incidence reaches 93.3 per 100,000. The high incidence in Japan has resulted in the creation of an endoscopic screening program, which is credited with the high frequency of early-stage cancers (50%) in Japanese patients. In contrast, more than 80% of Western patients have advanced cancers at diagnosis.

 The intestinal and diffuse types of gastric cancer differ in regard to epidemiology and risk factors. The intestinal type is associated with consumption of large amounts of salt and preserved foods, and possibly with Helicobacter pylori infection. These irritants lead to intestinal metaplasia of the stomach, which can then transform into frank malignancy. Other predisposing factors include achlorhydria associated with pernicious anemia and previous partial gastrectomy for peptic ulcer. It is thought that the lack of stomach acid in these conditions predisposes to intestinal metaplasia. Despite this, long-term use of H₂ blockers does not appear to be a risk factor.

 The intestinal type of gastric cancer is more prevalent in Japan, where preserved and salty foods are widely consumed. The decrease in the incidence of gastric cancer in the United States may relate to the availability of refrigeration and a dietary shift toward fresh foods. Asian patients may have genetic predispositions increasing cancer risk as well, as the rate decreases in Japanese immigrants in the United States who adopt local diets, but remains elevated as compared with the U.S. populace as a whole. The diffuse type is more sporadic and is not associated with diet. It is the most common form found in the United States.

1.  Research areas. The role of many targeted therapies is currently being studied. Using molecular genomics to improve the classification of the different tumors as well as to guide therapy is an active area of research.

SUGGESTED READINGS

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376(9742):687–697.

Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379(9813):315–321.

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

Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593.

Macdonald J, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725.

Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11(5):439–449.

van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366(22):2074–2084.