Worldwide, gastric carcinoma represents the third or fourth most common malignancy. The frequency of occurrence of gastric carcinoma at different sites within the stomach has changed in the United States over recent decades. Cancer of the distal half of the stomach has been decreasing in the United States since the 1930s. However, over the last two decades, the incidence of cancer of the cardia and gastroesophageal junction has been rapidly rising, particularly in patients younger than 40 years. There were nearly 22,000 new cases and 10,800 deaths from gastric carcinoma in the United States in 2008.
RISK FACTORS
- Age at onset is fifth decade
- Male-to-female ratio is 1.7:1
- African American-to-white ratio is 1.8:1
- Precursor conditions include chronic atrophic gastritis and intestinal metaplasia, pernicious anemia (10-20% incidence), partial gastrectomy for benign disease, Helicobacter pylori infection (especially childhood exposure—three- to fivefold increase), Ménétrier’s disease, and gastric adenomatous polyps. These precursor lesions are largely linked to distal (intestinal type) gastric carcinoma.
- Family history: first degree (two- to threefold); the family of Napoléon Bonaparte is an example; familial clustering; patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome II) are at increased risk; recently, germline mutations of E-cadherin (CDH1 gene) have been linked to the rare entity of familial diffuse gastric cancer and lobular breast cancer.
- Tobacco use results in a 1.5- to threefold increased risk for cancer.
- High salt and nitrosamine food content from fermenting and smoking process
- Deficiencies of vitamins A, C, and E; β-carotene; selenium; and fiber
- Blood type A
- Alcohol
- The marked rise in the incidence of gastroesophageal and proximal gastric adenocarcinoma appears to be strongly correlated to the rising incidence of Barrett’s esophagus.
In most countries, screening of the general populations is not practical because of a low incidence of gastric cancer. However, screening is justified in Japan where the incidence of gastric cancer is high. Japanese screening guidelines include initial upper endoscopy at age 50, with follow-up endoscopy for abnormalities. No screening guidelines are available in the United States. PATHOPHYSIOLOGY
Most gastric cancers are adenocarcinomas (more than 90%) of two distinct histologic types: intestinal and diffuse. In general, the term “gastric cancer” is commonly used to refer to adenocarcinoma of the
stomach. Other cancers of the stomach include non-Hodgkin’s lymphomas (NHL), leiomyosarcomas, and gastrointestinal stromal tumors (GIST). Differentiating between adenocarcinoma and lymphoma is critical because the prognosis and treatment for these two entities differ considerably. Although less common, metastases to the stomach include melanoma, breast, and ovarian cancers.
Intestinal Type
The epidemic form of cancer is further differentiated by gland formation and is associated with precancerous lesions, gastric atrophy, and intestinal metaplasia. The intestinal form accounts for most distal cancers with a stable or declining incidence. These cancers in particular are associated with H. pylori infection. In this carcinogenesis model, the interplay of environmental factors leads to glandular atrophy, relative achlorhydria, and increased gastric pH. The resulting bacterial overgrowth leads to production of nitrites and nitroso compounds causing further gastric atrophy and intestinal metaplasia, thereby increasing the risk of cancer.
This form is more common in areas of the world where gastric carcinoma is endemic. The recent decline in gastric carcinoma in the United States is likely the result of a decline in the incidence of intestinal type lesions. Intestinal type lesions are associated with an increased frequency of overexpression of epidermal growth factor receptor erbB-2 and erbB-3.
Diffuse Type
The endemic form of carcinoma is more common in younger patients and exhibits undifferentiated signet-ring histology. There is a predilection for diffuse submucosal spread because of lack of cell cohesion, leading to linitis plastica. Contiguous spread of the carcinoma to the peritoneum is common. Precancerous lesions have not been identified. Although a carcinogenesis model has not been proposed, it is associated with H. pylori infection. Genetic predispositions to endemic forms of carcinoma have been reported, as have associations between carcinoma and individuals with type A blood. These cancers occur in the proximal stomach where increased incidence has been observed worldwide. Stage for stage, these cancers have a worse prognosis than do distal cancers. Diffuse lesions have been linked to abnormalities of fibroblast growth factor systems, including the K-sam oncogene as well as E-cadherin mutations. The latter results in loss of cell-cell adhesions.
Molecular Analysis
- Loss of heterozygosity of chromosome 5q or APC gene (deleted in 34% of gastric cancers), 17p, and 18q (DCC gene)
- Microsatellite instability, particularly of transforming growth factor-β type II receptor, with subsequent growth-inhibition deregulation
- p53 is mutated in approximately 40% to 60% caused by allelic loss and base transition mutations.
- Mutations of E-cadherin expression (CDH1 gene on 16q), a cell adhesion mediator, is observed in diffuse-type undifferentiated cancers and is associated with an increased incidence of lobular breast cancer.
- Epidermal growth factor receptor overexpression, specifically Her2/neu and erbB-2/erbB-3 especially in intestinal forms
- Epstein-Barr viral genomes are detected.
- Ras mutations are rarely reported (less than 10%) in contrast to other gastrointestinal cancers.
Gastric carcinoma, when superficial and surgically curable, typically produces no symptoms. Among 18,365 patients analyzed by the American College of Surgeons, patients presented with the following symptoms: weight loss (62%), abdominal pain (52%), nausea (34%), anorexia (32%), dysphagia (26%), melena (20%), early satiety (18%), ulcer-type pain (17%), and lower-extremity edema (6%).
Clinical findings at presentation may include: anemia (42%), hypoproteinemia (26%), abnormal liver functions (26%), and fecal occult blood (40%). Medically refractory or persistent peptic ulcer should prompt endoscopic evaluation.
Gastric carcinomas primarily spread by direct extension, invading adjacent structures with resultant peritoneal carcinomatosis and malignant ascites. The liver, followed by lung, are the most common sites of hematogenous dissemination. The disease may also spread as follows:
- To intra-abdominal nodes and left supraclavicular nodes (Virchow’s node)
- Along peritoneal surfaces, resulting in a periumbilical nodule (Sister Mary Joseph node, named after the operating room nurse at the Mayo Clinic, or periumbilical lymph nodes, which form as tumor spreads along the falciform ligament to subcutaneous sites)
- To a left anterior axillary lymph node resulting from the spread of proximal primary cancer to lower esophageal and intrathoracic lymphatics (Irish node)
- To enlarged ovary (Krukenberg tumor; ovarian metastases)
- To a mass in the cul-de-sac (Blumer shelf), which is palpable on rectal examination
Paraneoplastic Syndromes
- Skin syndromes: acanthosis nigricans, dermatomyositis, circinate erythemas, pemphigoid, and acute onset of seborrheic keratoses (Leser-Trélat sign)
- Central nervous system syndromes: dementia and cerebellar ataxia
- Miscellaneous: thrombophlebitis, microangiopathic hemolytic anemia, membranous nephropathy
Carcinoembryonic antigen (CEA) is elevated in 40% to 50% of cases. It is useful in follow-up and monitoring response to therapy, but not for screening. α-Fetoprotein and CA 19-9 are elevated in 30% of patients with gastric cancer. STAGING
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification (Table 5.1). Of note, alternative staging systems are used by Japanese cancer centers.
| TABLE 5.1. TNM classification of gastric cancer staging designated by the American Joint Committee on Cancer 2002 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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- Initial upper gastrointestinal endoscopy and double-contrast barium swallow identify suggestive lesions and have diagnostic accuracy of 95% and 75%, respectively, but add little to preoperative staging otherwise.
- Endoscopic ultrasonography assesses the depth of tumor invasion (T staging) and nodal involvement (N staging) with accuracies up to 90% and 75%, respectively.
- Computerized tomographic scanning is useful for assessing local extension, lymph node involvement, and presence of metastasis, although understaging occurs in most cases.
- Whole-body 2-[18F]fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) is currently under investigation in gastric cancer, but appears to be less reliable than in esophageal cancer.
Pathologic staging remains the most important determinant of prognosis (Table 5.2). Other prognostic variables that have been proposed to be associated with an unfavorable outcome include the following:
- Older age
- Male gender
- Location of tumor
- Weight loss greater than 10%
- Diffuse versus intestinal histology (5-year survival after resection, 16% vs. 26%, respectively)
- High-grade or undifferentiated tumors
- Four or more lymph nodes involved
- Aneuploid tumors
- Elevations in epidermal growth factor or P-glycoprotein level
- Overexpression of thymidylate synthase
- Overexpression of ERCC1, p53, and Her-2
- Loss of p21 and p27
| TABLE 5.2. Disease-specific survival (DSS) after complete resection by American Joint Committee on Cancer stage grouping | |||||||||||||||||||||||||||
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Standard of Care
Although surgical resection remains the cornerstone of gastric cancer treatment, the optimal extent of nodal resection remains controversial, with randomized studies failing to show that more extensive procedures improve survival when compared with less extensive. The high rate of recurrence and poor survival of patients following surgery provides a rationale for the use of adjuvant or perioperative treatment. Adjuvant radiotherapy alone does not improve survival following resection. After complete surgical resection, either adjuvant chemoradiotherapy (chemoRT) or perioperative chemotherapy alone appear to confer survival advantages. The results of the Intergroup 0116 study show that the combination of 5-fluorouracil (5-FU)-based chemoRT significantly prolongs disease-free and overall survival when compared to no adjuvant treatment. Similarly, the use of polychemotherapy pre- and postoperatively can increase disease-free and overall survival compared to observation.
In advanced gastric cancer, chemotherapy enhances quality of life and prolongs survival when compared with the best supportive care. There are numerous therapeutic options in this setting without a clear standard of care. Of the commonly used regimens, triple combination chemotherapy with either docetaxel, cisplatin, and 5-FU (DCF) or epirubicin, oxaliplatin, and capecitabine (EOX) probably have the strongest claims to this role. However, there is a pressing need for assessing new agents, both cytotoxic and molecularly targeted, in both the advanced and adjuvant settings.
Resectable Disease
Surgery
Complete surgical resection of the tumor and adjacent lymph nodes remains the only chance for cure. Unfortunately, only 20% of U.S. patients with gastric cancer have disease at presentation amenable to such therapy. Resection of gastric cancer is indicated in patients with stages I, II, and III disease, with minimal lymph node involvement. Tumor size and location dictate the type of surgical procedure to be used. Current surgical issues include subtotal versus total gastrectomy, extent of lymph node dissection, and palliative surgery. SUBTOTAL VERSUS TOTAL GASTRECTOMY Subtotal gastrectomy (SG) may be performed for proximal cardia or distal lesions, provided that the fundus or cardioesophageal junction is not involved (Fig. 5.1). Total gastrectomy (TG) is more appropriate if tumor involvement is diffuse and arises in the body of the stomach, with extension to within 6 cm of the cardia. TG is associated with increased postoperative complications, mortality, and quality-of-life decrement, necessitating thorough consideration of complete gastric resection (Fig. 5.2).
EXTENT OF LYMPH NODE DISSECTION
Regional lymph node dissection is important for accurate staging and may have therapeutic benefit as well. The extent of lymphadenectomy is categorized by the regional nodal groups removed (Table 5.3). At least 15 lymph nodes must be reported for accurate AJCC staging. D2 lymphadenectomy is reported to improve survival in patients with T1, T2, and some serosa-involved T3 lesions as compared to D1. However, factors such as operative time, hospitalization length, and transfusion requirements,
and thus morbidity, are all increased. The routine inclusion of splenectomy in D2 resections is no longer advocated given higher postoperative complications. The greatest benefit of more extensive lymph node dissection may occur in early gastric cancer lesions with small tumors and superficial mucosal involvement as up to 20% of such lesions have occult lymph node involvement.
Radiation Therapy
- For patients with locally advanced or metastatic disease, moderate doses of external-beam radiation can be used to palliate symptoms of pain, obstruction, and bleeding, but do not routinely improve survival.
- Local or regional recurrence in the gastric or tumor bed, the anastomosis, or regional lymph nodes occurs in 40% to 65% of patients after gastric resection with curative intent (Table 5.4). The high frequency of such relapses has generated interest in perioperative therapy. Radiotherapy (RT) in this setting is limited by the technical challenges inherent in abdominal irradiation, optimal definition of fields, diminished performance status, and nutritional state of many patients with gastric cancer.
- A prospective randomized trial from the British Stomach Cancer Group failed to demonstrate a survival benefit for postoperative adjuvant radiation alone, although locoregional failures had decreased from 27% to 10.6%.
- Attempts to improve the efficacy and minimize toxicity with newer RT techniques have been investigated. Sixty patients who underwent curative resection at the National Cancer Institute were randomized to either receive adjuvant intraoperative radiotherapy (IORT) or conventional RT. IORT failed to afford a benefit over conventional therapy in overall survival and remains unavailable to many outside of a clinical trial.
- In patients with locally unresectable pancreatic and gastric adenocarcinoma, the Gastrointestinal Tumor Study Group (GITSG) has shown that combined-modality therapy is superior to either RT or chemotherapy alone. On the basis of this concept, combined chemoRT (typically in combination with 5-FU) has been evaluated both in the neoadjuvant (preoperative) and the adjuvant (postoperative) settings.
| TABLE 5.3. Classification of regional lymph node dissection | ||||||||||||
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Aside from gastroesophageal junction tumors, the available data on the role of neoadjuvant chemoRT for gastric cancer are not conclusive. Although neoadjuvant therapy may reduce the tumor mass in many patients, several randomized, controlled trials have shown that, compared with primary resection, a multimodal approach does not result in a survival benefit in patients with potentially resectable tumors. In contrast, for some patients with locally advanced tumors (i.e., patients in whom complete tumor removal with upfront surgery seems unlikely), neoadjuvant chemoRT may increase the likelihood of complete tumor resection on subsequent surgery. However, predicting those likely to benefit from this approach remains an ongoing research question.
Adjuvant chemoRT has been evaluated in the United States. In a phase 3 Intergroup trial (INT-0116), 556 patients with completely resected stage IB to stage IV M0 adenocarcinoma of the stomach and gastroesophageal junction were randomized to receive best supportive care or adjuvant chemotherapy (5-FU and leucovorin) and concurrent radiation therapy (45 Gy). With >6-year median follow-up, median survival was 35 months for the adjuvant chemoRT group as compared to 27 months for the
surgery-alone arm (P = 0.006). Both 3-year overall survival (50% vs. 41%; P = 0.006) and relapse-free survival (48% vs. 31%; P < 0.0001) favored adjuvant chemoRT. Although treatment-related mortality was 1% in this study, only 65% of patients completed all therapy as planned and many had inadequate lymph node resections (54% D0). Regardless, adjuvant chemoRT is considered a standard of care in the United States.
| TABLE 5.4. Failure areas following curative surgery | ||||||||||||||||||||||||
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In Japan, patients who underwent complete surgical resection for stage II and III gastric cancer with D2 lymphadenectomy appeared to benefit from adjuvant S-1, a novel oral fluoropyrimidine. In a randomized controlled trial, patients were randomized to 1 year of monotherapy or surveillance only. The study was closed early after interim analysis confirmed a 3-year overall survival (80% vs. 70%; P = 0.002) and relapse-free survival (72% vs. 60%; P = 0.002) advantage in favor of adjuvant chemotherapy.
In Europe, focus has recently been on the role of more potent polychemotherapy regimens in the perioperative setting without RT. The UK Medical Research Council recently reported the results of a randomized controlled trial of three cycles of pre- and postoperative epirubicin, cisplatin, and 5-FU (ECF) to surgery alone in patients with resectable stage II-IV nonmetastatic gastric cancer; 503 patients were stratified according to surgeon, tumor site, and performance status. Perioperative chemotherapy improved 5-year overall survival (36% vs. 23%; P = 0.009) and reduced local and distant recurrence. There appeared to be significant downstaging by chemotherapy treatment, with more patients deemed by the operating surgeon to have had a “curative” resection (79% vs. 70%; P = 0.03), had smaller tumors (median 3 vs. 5 cm; P < 0.001), had T1/T2 stage tumors (52% vs. 37%; P = 0.002), and had N1/N2 stage disease (84% vs. 71%; P = 0.01). Toxicity was feasible with postoperative complications comparable; however nearly one-third of patients who began with preoperative chemotherapy did not receive postoperative chemotherapy due to progressive disease, complications, or patient request. In Europe, perioperative polychemotherapy is now considered a standard of care.
Unresectable or Metastatic Disease
Primary goals of therapy should focus on improvement in symptoms, delay of disease progression, pain control, nutritional support, and quality of life. Although a role for palliative surgery and radiotherapy exist (see previous sections), chemotherapy remains the primary means of palliative treatment in this setting. The most commonly administered chemotherapeutic agents with objective response rates in advanced gastric cancer include mitomycin, antifolates, anthracyclines, fluoropyrimidines, platinums, taxanes, and topoisomerase inhibitors.
Palliative Surgery
This should be considered in patients with obstruction, bleeding, or pain, despite operative mortalities of 25% to 50%. Gastrojejunostomy bypass surgery alone may provide a twofold increase in mean survival. The selection of patients most likely to benefit from this palliative effort requires further evaluation.
Use of Stents
Plastic and expansile metal stents are associated with successful palliation of obstructive symptoms in more than 85% of patients with tumors in the gastroesophagus and in the cardia.
Chemotherapy Versus Best Supportive Care
Four randomized studies in patients with metastatic gastric cancer have demonstrated a survival advantage to combination chemotherapy over best supportive care (BSC) (Table 5.5). Two studies used
fluorouracil, doxorubicin, and methotrexate (FAMTX) and two studies used etoposide, fluorouracil, and leucovorin (ELF) as the primary regimens.
| TABLE 5.5. Chemotherapy versus best supportive care (BSC) | ||||||||||||||||||||||||
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Monotherapy with single agents (Table 5.6) results in a 10% to 30% response rate with mild toxicities. 5-FU is the most extensively studied, producing a 20% response rate. Complete responses with single agents are rare and disease control is relatively brief.
COMBINATION CHEMOTHERAPY
Various combinations of active agents have been reported to improve the response rate (20-50%) among patients with advanced gastric carcinoma (Table 5.7). While utilizing 5-FU as a backbone, FAMTX (5-FU, doxorubicin, methotrexate) became an international standard after direct comparison to FAM (5-FU, doxorubicin, mitomycin) supporting a superiority with a survival advantage for FAMTX. The addition of cisplatin into combination regimens was supported by subsequent studies in both Europe and the United States.
Historically, the most commonly used combination regimens include FAMTX, FAM, FAP, ECF, ELF, FLAP (5-FU, leucovorin, doxorubicin, cisplatin), PELF (cisplatin, epidoxorubicin, leucovorin, 5-FU with glutathione and filgrastim), and FUP or CF (5-FU, cisplatin).
NEWER CHEMOTHERAPY AGENTS
Newer chemotherapeutic agents, including irinotecan, docetaxel, paclitaxel, and alternative platinums and fluoropyrimidines, have shown promising activity as single agents and are being actively incorporated into combination therapy (see Tables 5.6 and 5.7). A complete review of all agents is beyond the scope of this chapter.
Docetaxel has recently become FDA approved in combination with cisplatin and 5-FU (DCF) in patients with advanced or metastatic gastric cancer based on the results of a large phase 3 international trial; 445 patients were randomized to receive cisplatin and 5-FU with or without docetaxel. The addition of docetaxel resulted in an improvement in tumor response (37% vs. 25%; P = 0.01), time to progression (5.6 vs. 3.7 months; P < 0.001), and median survival (9.2 vs. 8.6 months; P = 0.02) with a doubling of 2-year survival (18% vs. 9%). These findings were at the cost of anticipated increased
toxicity, however, maintenance of quality of life and performance status indices were longer for DCF. In a Japanese study, 20% of patients who showed no response to previous chemotherapy had a partial response to monotherapy with docetaxel. Predictable neutropenia can be managed by dose modification or by using prophylactic granulocyte colony stimulating factor.
| TABLE 5.6. Single-agent chemotherapy with activity in advanced gastric cancer | ||||||||||||||
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| TABLE 5.7. Randomized studies of combination chemotherapy in advanced gastric cancer | ||||||||||||||||||||||||||||||||||||
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Capecitabine is an oral fluoropyrimidine that has been substituted for infusional 5-FU in a variety of settings. It was formally evaluated with encouraging results in combination with a platinum alternative (see oxaliplatin).
Oxaliplatin is a third-generation platinum with much less nephrotoxicity, nausea, and bone marrow suppression than cisplatin. In a recently reported two-by-two designed study in patients with advanced gastric cancer, standard ECF chemotherapy was modified with oxaliplatin substituted for cisplatin and capecitabine substituted for 5-FU; 1,002 patients were randomly allocated between the four arms (ECF, EOF, ECX, and EOX). Capecitabine and oxaliplatin appeared as effective as 5-FU and cisplatin, respectively. Response rates and progression-free survival were nearly identical between the groups, with the EOX regimen showing superiority in overall survival over ECF (11.2 vs. 9.9 months; P = 0.02).
Biologic/Targeted Agents
New biologic therapies aimed to inhibit or modulate targets of aberrant signal transduction in gastric cancer are actively being investigated. Inhibition of angiogenesis, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGFR) pathways are an early focus (Table 5.8) based on the
availability of effective agents and success in advanced colorectal cancer. Until the results of ongoing large randomized studies are known, use of these agents should be restricted to clinical trials.
| TABLE 5.8. Efficacy data on selected targeted therapy use in advanced gastric cancer | ||||||||||||||||||||||||||||||||
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Stage 0 Gastric Cancer Stage 0 indicates gastric cancer confined to the mucosa. Based on the experience in Japan, where stage 0 is diagnosed more frequently, it has been found that more than 90% of patients treated by gastrectomy with lymphadenectomy will survive beyond 5 years. An American series has confirmed these findings. No additional perioperative therapy is necessary. Stage I Gastric Cancer
- One of the following surgical procedures is recommended for stage I gastric cancer:
- Distal SG (if the lesion is not in the fundus or at the cardioesophageal junction)
- Proximal SG or TG, with distal esophagectomy (if the lesion involves the cardia)
- TG (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia or distal antrum)
- Regional lymphadenectomy is recommended with all of the previously noted procedures
- Splenectomy is not routinely performed
- Distal SG (if the lesion is not in the fundus or at the cardioesophageal junction)
- Postoperative chemoRT is recommended for patients with stage IB disease.
Stage II Gastric Cancer
- One of the following surgical procedures is recommended for stage II gastric cancer:
- Distal SG (if the lesion is not in the fundus or at the cardioesophageal junction)
- Proximal SG or TG, with distal esophagectomy (if the lesion involves the cardia)
- TG (if the tumor involves the stomach diffusely or arises in the body of the stomach and extends to within 6 cm of the cardia)
- Regional lymphadenectomy is recommended with all of the previously noted procedures
- Splenectomy is not routinely performed
- Distal SG (if the lesion is not in the fundus or at the cardioesophageal junction)
- Postoperative chemoRT or perioperative chemotherapy is recommended.
Stage III Gastric Cancer
- Radical surgery: Curative resection procedures are confined to patients who do not have extensive nodal involvement at the time of surgical exploration.
- Postoperative chemoRT or perioperative chemotherapy is recommended.
Patients Without Distant Metastases (M0)
Neoadjuvant polychemotherapy can be considered to improve resectability. Radical surgery is performed if possible, either followed by postoperative chemoRT or perioperative chemotherapy.
Patients With Distant Metastases (M1) All newly diagnosed patients with hematogenous or peritoneal metastases should be considered as candidates for clinical trials. For many patients, chemotherapy may provide substantial palliative benefit and occasional durable remission, although the disease remains incurable. Balancing the risks to benefits of therapy in any individual patient is recommended.
Peritoneal Carcinomatosis
In approximately 50% of patients with advanced gastric cancer, the disease recurs locally or at an intraperitoneal site, and this recurrence has a negative effect on quality of life and survival. Intraperitoneal (IP) 5-FU, cisplatin, and/or mitomycin have been used at select centers. IP chemotherapy administration does not routinely alter survival and should be reserved for clinical trial or practice at an experienced center.
POSTSURGICAL FOLLOW-UP
- Follow-up in patients following complete surgical resection should include routine history and physical, with liver function tests and CEA measurements being performed.
- Evaluation intervals of every 3 to 6 months for the first 3 years, then annually thereafter have been suggested.
- Symptom-directed imaging and laboratory workup is indicated, without routine recommendations otherwise.
- If TG is not performed, annual upper endoscopy is recommended due to a 1% to 2% incidence of second primary gastric tumors.
- Vitamin B12 deficiency develops in most TG patients and 20% of SG patients, typically within 4 to 10 years. Replacement must be administered at 1,000 mcg subcutaneously or intramuscularly every month indefinitely.
PRIMARY GASTRIC LYMPHOMA
Gastric lymphomas are uncommon malignancies representing 3% of gastric neoplasms and 10% of lymphomas.
Classification and Histopathology Gastric lymphomas can be generally classified as primary or secondary:
- Primary gastric lymphoma (PGL) is defined as a lymphoma arising in the stomach, typically originating from mucosa-associated lymphoid tissue (MALT). PGL can spread to regional lymph nodes and can become disseminated. Most are of B-cell NHL origin, with occasional cases of T-cell and Hodgkin’s lymphoma seen. Examples of PGLs include extranodal marginal zone B-cell lymphoma of MALT type previously called low-grade MALT lymphoma, diffuse large B-cell lymphoma (DLBCL) previously called high-grade MALT lymphoma, and Burkitt’s and Burkitt’s-like lymphoma. This section will primarily address PGLs.
- Secondary gastric lymphoma indicates involvement of the stomach associated with lymphoma arising elsewhere. The stomach is the most common extranodal site of lymphoma. In an autopsy series, patients who died from disseminated NHL showed involvement of the gastrointestinal tract in 50% to 60% of cases. Examples of secondary gastric lymphoma include several common advanced-stage systemic NHLs, particularly mantle cell lymphoma.
- The prevalence of PGL has been increasing over the last 20 years without a clear explanation.
- PGL incidence rises with age, with a peak in the sixth to seventh decades with a slight male predominance.
- Risk factors include H. pylori-associated chronic gastritis (particularly low-grade MALT lymphoma), autoimmune diseases, and immunodeficiency syndromes including AIDS and chronic immunosuppression.
Diagnosis
Clinical symptoms that are most common at presentation include abdominal pain, weight loss, nausea, vomiting, and early satiety. Frank bleeding is uncommon and patients rarely present with perforation.
Findings on upper endoscopy are diverse and may be identical to typical adenocarcinoma. Since PGL can infiltrate the submucosa without overlying mucosal changes, conventional pinch biopsies may miss the diagnosis. Deeper biopsy techniques should be employed. If an ulcer is present, the biopsy should be at multiple sites along the edge of the ulcer crater. Specimens should be pathologically evaluated by both standard techniques to determine histology and H. pylori positivity as well as flow cytometry to determine clonality and characteristics of any infiltrating lymphocytes. The latter requires fresh tissue placed in saline, not preservative.
Staging
Staging of gastric lymphoma is identical to systemic lymphoma staging using the Ann Arbor system. For example, stage IE indicates disease limited to the stomach, without nodal spread. Stage IIE1 is a tumor in the stomach that spreads to adjacent contiguous lymph nodes. Stage IIE2 is a tumor in the stomach that spreads to lymph nodes that are noncontiguous with the primary tumor. Patients present with stage IE and stage IIE PGL with an equal prevalence ranging between 28% and 72%. Presentation with high-grade and low-grade disease is also equal, with 34% to 65% of disease presenting as high-grade lymphoma and 35% to 65% presenting as low-grade lymphoma. CT scanning of the chest and abdomen is important to determine the extent of lymphoma nodal involvement. FDG-PET scanning and bone marrow biopsy may be useful in high-grade PGL staging.
Treatment
Treatment of PGL is dependent primarily by stage and histologic grade of the lymphoma. However, given the rarity of the disease and lack of clinical trial data, treatment recommendations are based primarily on retrospective studies. Extranodal marginal zone B-cell lymphoma of MALT type is usually of low-grade histology (40-50%) and confined to the stomach (70-80% stage IE). Very good epidemiologic data support H. pylori-induced chronic gastritis as a major etiology for this tumor. Eradication of H. pylori infection with antibiotics should be the initial standard treatment. Complete histologic regression of the lymphoma has been demonstrated in 50% to 80% of patients treated in this manner with good long-term disease free survival. Radiation therapy can provide durable remission for cases that relapse or are H. pylori-negative. More advanced stage or aggressive histologies at presentation should be treated like DLBCL.
Previously called high-grade MALT lymphoma, DLBCL is a more aggressive PGL. Eradication of H. pylori provides less reliable and durable disease control. Gastrectomy was the traditional treatment of choice; however, this appears to be no longer necessary. Five hundred eighty-nine patients with stage IE and IIE1 DLBCL PGL were randomized to receive surgery, surgery plus radiotherapy, surgery plus chemotherapy, or chemotherapy alone. Chemotherapy was 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Overall survivals at 10 years were 54%, 53%, 91%, and 96% respectively. Late toxicity and complications were more frequent and severe in those receiving surgery. Gastric perforation or bleeding as a result of initial chemotherapy was not evident. Organ preservation has been a major advance for this disease with the use of chemotherapy.
Highly aggressive PGLs including Burkitt’s and Burkitt’s-like lymphoma have seen dramatic improvement in survival over the past decade as a result of potent chemotherapy combinations for systemic disease as well as better treatment of underlying immunodeficiency states (i.e., highly effective antiretroviral therapy for AIDS).
