University of Alabama at Birmingham, Birmingham, Alabama
Worldwide, gastric carcinoma represents the second or third 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. The incidence of this cancer has increased dramatically, especially in patients younger than 40 years. An estimated 22,400 new cases and 12,100 deaths from gastric carcinoma were expected in the United States in 2003.
Most gastric cancers are adenocarcinomas (more than 90%) of two distinct histologic types: intestinal and diffuse. The other gastric cancers are predominantly non-Hodgkin lymphomas or leiomyosarcomas. Differentiating between adenocarcinoma and lymphoma is critical because the prognosis and treatment for these two entities differ considerably.
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 and is stable or its incidence is declining. These cancers in particular are associated with H. pylori infection, as proposed by Correa. In this carcinogenesis model, the interplay of environmental factors leads to glandular atrophy, relative achlorhydria, and increased gastric pH. This results in bacterial overgrowth, and H. pylori and bacteria produce nitrites and nitroso compounds causing further development of 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.
The “endemic” form of carcinoma is more common in younger patients and exhibits an undifferentiated signet-ring histology. There is a predilection for 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, and a carcinogenesis model has not been proposed although it is also 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 (see Fig. 5.1).
FIG. 5.1. Two histological types of gastric adenocarcinoma. A: Intestinal B: Diffuse.
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:
Clinical findings at presentation may demonstrate the following symptoms:
Gastric carcinomas spread by direct extension, invading into adjacent structures. The disease may also spread by lymphatic vessels:
The liver is the most common site of hematogenous dissemination, although pulmonary metastases are also seen.
Central Nervous System (CNS) Syndromes:
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification (see Table 5.1).
TABLE 5.1. TNM Classification of Cancer Staging Designated by the American Joint Committee on Cancer (AJCC)
TABLE 5.2. Five-year Survival with Respect to Location of Tumor
MANAGEMENT OF GASTRIC CANCER
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 the D2 procedure improves survival when compared with D1 dissection. The high rate of recurrence and poor survival of patients following surgery provides a rationale for the early use of adjuvant treatment. Adjuvant chemotherapy or adjuvant radiotherapy, when used alone, does not improve survival following resection. However, the results of the Intergroup 0116 study are promising in showing that the combination of 5-fluorouracil (5-FU)–based chemotherapy with radiotherapy significantly prolongs disease-free and overall survival when compared to no adjuvant treatment. In advanced gastric cancer, chemotherapy enhances quality of life and prolongs survival when compared with the best supportive care. There is no agreed standard of treatment in this setting. Of the commonly used regimens, epirubicin plus cisplatin and 5-FU (ECF) probably has the strongest claim 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.
Although complete surgical resection of the tumor and adjacent lymph nodes remains the only chance for cure, up to 80% of gastric cancer in patients in the United States is advanced at diagnosis. Surgical extirpation 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 (Table 5.2).
Current Issues Are:
Subtotal versus Total Gastrectomy
FIG. 5.2. (A and B) Total gastrectomy (TG).
FIG. 5.3. (A and B) Subtotal gastrectomy (SG).
Extended Lymph Node Dissection
The regional lymph nodes include N1 and N2 lymph node groups (lesser and greater curvature of perigastric, left gastric, common hepatic, splenic, and celiac axis nodes). D2 lymphadenectomy involves more extensive N2 lymph-node–group resection and is reported to improve survival in patients with T1, T2, and some serosa-involved T3 lesions. Factors such as operative time, hospitalization length, and transfusion requirements, and thus morbidity, are all increased. The greatest benefit of extended lymph node dissection (ELD) may occur in early gastric cancer lesions with small tumors and superficial mucosal involvement because up to 20% of such lesions have occult lymph node involvement. The routine use of D2 lymphadenectomy continues to be studied.
Routine splenectomy for tumors that do not adhere to or invade the spleen is not beneficial.
Palliative surgery is considered in patients with obstruction, bleeding, or pain, and despite operative mortalities of 25% to 50%, the results from the gastrojejunostomy bypass surgery alone indicate a twofold increase in mean survival. The selection of patients most likely to benefit from this palliative effort requires further evaluation.
TABLE 5.3. Failure Areas following Surgery
The available data on the role of neoadjuvant preoperative therapy are not yet 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 locoregional, that is, potentially resectable, tumors. In contrast, in patients with locally advanced tumors (i.e., patients in whom complete tumor removal with primary surgery seems unlikely), neoadjuvant therapy increases the likelihood of complete tumor resection on subsequent surgery. However, only those patients with objective histopathologic response to preoperative therapy seem to benefit from this approach.
The most commonly administered chemotherapeutic agents with objective response rates in gastric cancer include 5-FU, doxorubicin, cisplatin, methotrexate, mitomycin, etoposide, and doxorubicin.
Chemotherapy Versus Best Supportive Care
Four studies have randomized patients with metastatic gastric cancer to either combination chemotherapy or best supportive care (BSC). Two studies used fluorouracil, doxorubicin, and methotrexate (FAMTX) and two studies used etoposide, fluorouracil, and leucovorin (ELF) as the primary chemotherapeutic agents. In all four studies, a significant survival benefit was noted for patients randomized to chemotherapy (see Table 5.4).
TABLE 5.4. Chemotherapy Versus Best Supportive Care (BSC)
Single Agents Versus Combination Regimens
Monotherapy with single agents results in 15% to 20% response rates. 5-FU is the most extensively studied, producing a 20% response rate. In addition, mitomycin-C (MMC), adriamycin, and carmustine (BCNU) have shown similar results. More recent studies using well-defined response criteria, have, however, failed to produce such results, showing response rates of less than 10% for 5-FU and adriamycin. Cisplatin has been used recently and has shown promising results in more than one study. Complete responses with single agents are, however, rare, and partial regressions are relatively brief. Newer agents being investigated include taxotere, taxol, oxaliplatin, irinotecan, and oral forms of 5-FU (see Table 5.5).
TABLE 5.5. Single-agent Chemotherapy in Advanced Gastric Cancer
Better understanding of the pharmacology of many chemotherapeutic agents, including 5-FU, the main drug used in advanced gastric cancer, has led to the development of combination regimens. Various combinations of active agents have been reported to improve the response rate among patients with advanced gastric carcinoma, approaching 30% to 60%. However, the
North Central Cancer Treatment Group (NCCTG) observed no difference in overall survival among 252 patients randomized to receive 5-FU, doxorubicin, and semustine (methyl-CCNU) (FAMe); 5-FU, doxorubicin, and cisplatin (FAP); or 5-FU alone.
Most commonly used combination regimens include FAM (fluorouracil, doxorubicin, mitomycin-C), FAP, ECF, ELF, FLAP (fluorouracil, leucovorin, doxorubicin, cisplatin), PELF (cisplatin, epidoxorubicin, leucovorin, fluorouracil with glutathione and filgrastim), FAMTX, and FUP (fluorouracil, cisplatin) (Tables 5.6, 5.7, and 5.8).
TABLE 5.6. Combination regimens
TABLE 5.7. Randomized studies in advanced gastric cancer using second-generation regimens
TABLE 5.8. Regimens and doses of agents
Newer chemotherapeutic agents, including irinotecan, gemcitabine, oxaliplatin, and taxanes, show promising activity and are currently being tested in phase III trials.
Taxotere has already been investigated in two phase II clinical trials. In the European trial, a 24% response rate was reported in a series of 33 patients with advanced gastric cancer. It is interesting that patients who had their primary tumor removed responded better than those patients who did not. In a Japanese study, 20% of patients who showed no response to previous chemotherapy had a partial response to 60 mg per m2 of 3- or 4-weekly doses of taxotere. Docetaxel has also been shown to lack cross-resistance with other drugs in the treatment of gastric cancer and is likely to be at least additive to cisplatin and 5-FU. Phase II results of docetaxel–cisplatin has yielded response rates similar to those achieved by ECF and PELF. Adding 5-FU to docetaxel–cisplatin has achieved an objective response rate (ORR) of 52% versus 45% for docetaxel–cisplatin alone in a randomized phase II trial. Docetaxel-based regimens demonstrate acceptable tolerability despite predictable hematotoxicity. Neutropenia, the major toxicity, is manageable by dose modification or by using prophylactic granulocyte colony stimulating factor. Several phase III trials are now ongoing, including a large-scale trial of docetaxel–cisplatin–5-FU versus cisplatin–5-FU.
Irinotecan (CPT-11) has also been used alone or in combination with cisplatin in phase I–II clinical studies. Response rates of 23% and 41%, respectively, with acceptable toxicity were reported. In the first study, objective responses were observed in 20% of pretreated patients (mostly with 5-FU).
Using Capecitabine (Xeloda) instead of 5-FU in combination regimen is also under evaluation in randomized trials.
S-1 is a novel oral fluoropyrimidine derivative composed of tegafur (5-FU prodrug), 5-chloro-2,4-dihydroxypyridine (inhibitor of 5-FU degradation), and potassium oxonate (inhibitor of gastrointestinal toxicities). A phase II trial has revealed a response rate of 53.6%, whereas a retrospective study showed an overall response rate of 32% (44% of patients were chemo naïve).
Use of Stents
The use of plastic and expansile metal stents has been associated with successful palliation of obstructive symptoms in more than 85% of patients with tumors in the gastroesophagus and in the cardia.
TREATMENT OF GASTRIC CANCER ACCORDING TO STAGE
Stage 0 Gastric Cancer
Stage 0 indicates gastric cancer confined to the mucosa. On the basis of experience in Japan, where stage 0 is diagnosed 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.
Stage I Gastric Cancer
Stage II Gastric Cancer
Stage III Gastric Cancer
Stage IV Gastric Cancer
Patients with No Distant Metastases (M0)
Patients with Distant Metastases (M1)
All newly diagnosed patients with hematogenous or peritoneal metastases should be considered as candidates for clinical trials if possible. In some patients, chemotherapy may provide substantial palliative benefit and occasional durable remission, although it does not prolong life or provide a cure.
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 survival. Investigators have reported their experience with systemic and intraperitoneal (IP) 5-FU and cisplatin in conjunction with R0 resection of high-risk gastric cancer. Thirty-four patients (17 male and 17 female; median age 59 years, range 26 to 77 years) received an R0 resection (18 patients received SG, 2 patients received proximal gastrectomy, and 14 received TG) and adjuvant IV or IP 5-FU or cisplatin for histologically confirmed T2–4 N0–3 gastric adenocarcinoma at Memorial Sloan-Kettering Cancer Center. Patients who received radiation therapy or preoperative chemotherapy were excluded. A case-matched analysis of these 32 patients and 170 randomly selected matched controls was performed. The control group was chosen from a pool of 614 patients who underwent resection alone between 1985 and 1997, excluding those patients who had M1 disease or preoperative chemotherapy. A 5:1 match ratio was used to select patients by sex, T staging, and N staging. At a median follow-up of 131 months for survivors, the median survival was found to be 25 months in the IP group versus 26 months for the matched-control group. five- and 10-year actuarial survival was 37% and 37% for the IP group versus 30% and 18% for the matched controls. None of these findings were statistically significant. The recurrence rate was 61% in the IP chemotherapy group, with 66% occurring locally or at an intraperitoneal site, which was not better than the matched controls. All patients were evaluated for toxicity, and there was one death from cardiac arrest during IP chemotherapy treatment. Acute grade III or IV toxicity was observed in 14 (44%) patients, consisting of nausea or vomiting, diarrhea, and hematologic toxicity, but all the toxic responses resolved. It was concluded that adjuvant IP 5-FU and cisplatin can be delivered with low mortality and significant morbidity. This regimen did not alter survival or alter the pattern of recurrence. Better agents are needed to improve the efficacy of this mode of therapy. Patients at higher risk, with serosal involvement or contiguous structure invasion, can also receive prophylaxis with continuous hyperthermic peritoneal perfusion (CHPP) perioperatively.
In most countries, screening of the general populations is not practical because of low incidence of gastric cancer. However, screening is worthwhile 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 such guidelines are available in the United States.
PRIMARY GASTRIC LYMPHOMA
Epidemiology and Pathology
Primary gastric lymphoma (PGL) is an uncommon malignancy that is increasing in incidence and represents approximately 2% to 7% of primary gastric malignancies. In the United States, there will be an estimated 22,400 cases of gastric malignancy per year, which indicates that an estimated 448 to 1,568 new cases of gastric lymphoma would have occurred in 1997. The incidence of PGL has been increasing over the last 20 years without any clear explanation. Incidence of PGL increases with age, with a peak in the sixth to seventh decades. A slight male predominance has been reported in several series. There are three types of gastric lymphomas:
Most gastric lymphomas are B-cell lymphoma, most commonly having diffuse, large cell features. Most gastric lymphomas appear to arise in the lamina propria from which they infiltrate into the submucosa, eventually spreading to regional lymph nodes.
Up to 40% of gastric lymphomas are low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. These indolent, low-grade lymphomas are characterized by aggregates of lymphoid tissue in mucosal sites with the following features: large reactive follicles, prominent marginal zones containing cells with angular nuclei reminiscent of centrocytes, infiltration of the gastric epithelium by lymphoid cells, and plasma cells underlying the superficial epithelium. Heavy- and light-chain gene rearrangements of monoclonal immunoglobin are identified in the lymphomas.
Symptoms of PGL that are most common at presentation are abdominal pain and weight loss. Bleeding is less common, and patients rarely present with perforation.
Stage IE and stage IIE PGL present in patients with an equal prevalence. Stage IE disease is seen in 36% to 72% of patients at presentation and stage IIE disease is seen in 28% to 64% of patients.
Presentation with high-grade and low-grade disease is also equal, with 34% to 65% of disease presenting as high-grade lymphoma, 12% to 17% presenting as intermediate-grade lymphoma, and 35% to 65% presenting as low-grade lymphoma.
Diagnosis of PGL by endoscopic evaluation has markedly improved over the last decade. In recent series, successful endoscopic diagnosis of lymphoma was made in 92% to 100%
of the patients. A large review of 3,157 patients with PGL reported data on the sensitivity of endoscopic diagnosis for 848 patients. A diagnosis of cancer was made in 79% of patients, with a diagnosis of lymphoma made in only 54%. This indicates that 25% of the patients were diagnosed with cancer that was not thought to be lymphoma. The review also stated that the success of endoscopic evaluation and biopsy in diagnosing gastric lymphoma has improved markedly in recent decades. In a review of patients treated from 1980 to 1990, the correct preoperative diagnosis was made in only 57% of patients, but an improvement was noted over time. A diagnosis rate of 44% was seen between 1980 and 1984 compared with 64% from 1985 to 1990. Other series report a correct diagnosis by endoscopy in 38% to 92% of patients. Techniques that have led to a higher rate of success include the use of larger biopsy forceps, multiple biopsies, and the use of brushings. If an ulcer is present, the biopsy should be at the edge of the ulcer crater at multiple sites.
Staging of gastric lymphoma based upon the Ann Arbor system includes stage IE, which indicates a 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.
Treatment of PGL is highly variable, with no consensus established on the most effective therapy. To date, only one randomized clinical trial comparing treatments has been published. Treatment decisions must, therefore, be based on retrospective studies that address the treatment of this uncommon malignancy. These retrospective studies are difficult to compare and mostly represent nonrandomized data with significant stage and grade variation. Selection bias is evident in some series; patients with more advanced disease and more aggressive histology receive more aggressive therapy. There is a need for prospective randomized trials to evaluate the different treatments of this malignancy.
Impact of Association with H. Pylori on Treatment of PGL
Evidence for a strong association between gastric lymphoma and gastric infection by Helicobacter pylori has been shown. A simplified treatment algorithm that outlines the treatment of low-grade lymphoma is shown in Fig. 5.4.
FIG. 5.4. Simplified algorithm outlining the treatment of low-grade lymphoma.
Treatment of Low-grade and High-grade Primary Gastric Lymphoma
The initial therapy is based upon the type of PGL. Low-grade MALT lymphoma is treated initially by eradicating H. pylori. Complete regression after proven eradication is followed with serial endoscopies. For patients with stages IE and IIE1 non-MALT lymphoma and low-grade MALT lymphoma not responding to treatment of H. pylori infection, surgical resection is indicated. Surgical resection has the advantage of allowing accurate staging, grading, and cure with surgery alone. This allows chemotherapy to be given only to those patients with high-grade lymphoma and avoids chemotherapy in those patients with favorable histology. Chemotherapy after surgical resection is indicated in those patients with positive lymph nodes, residual disease, and high-grade lymphoma found in the pathologic specimen. We feel that all high-grade lymphomas, both MALT and non-MALT in origin, should be treated initially with chemotherapy. This is shown in Fig. 5.5.
FIG. 5.5. Mucosa-associated lymphoid tissue (MALT) and non-MALT should be initially treated with chemotherapy.
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