Epidemiology

Although the incidence of gastric carcinoma is decreasing in Western countries, it remains the fourth most frequent cancer diagnosed and the second most lethal cancer worldwide, behind only lung cancer. The number of new cases of gastric carcinoma worldwide was recently estimated as over 600,000 in males and 330,000 in females.³ It is the third most common cancer in males and the fifth most common cancer in females worldwide.⁴ Sixty percent of cases occur in developing countries.⁵ The areas with the highest incidence rates are Eastern Asia, South America, and Eastern Europe. Regions in which gastric carcinoma is least frequent are North America, Western Europe, and parts of Africa. There is approximately a 20-fold difference in the incidence rates between Japan and some white populations in the United States.⁵ In the United States, approximately 21,520 new cases of gastric carcinoma were expected to be diagnosed during 2011, with 10,340 estimated deaths from the disease during the same period.⁶

Of the several classification systems that have been proposed to describe gastric carcinoma, the Lauren classification is the most widely used. The Lauren classification describes tumors based on the microscopic configuration and growth pattern into intestinal and diffuse types.^7,8 Diffuse cancers are noncohesive and diffusely infiltrate the stomach. These often exhibit deep infiltration of the gastric wall and show little or no gland formation. These tumors are often associated with marked desmoplasia and inflammation with relative sparing of the overlying mucosa. The intestinal type, conversely, shows recognizable gland formation similar in microscopic appearance to the colonic mucosa. The glandular formation ranges from well- to poorly differentiated tumors and grows in expanding rather than infiltrative patterns.⁵ Intestinal cancers are believed to be related to environmental factors and are thought to arise secondary to chronic atrophic gastritis. The diffuse cancers, conversely, are less related to environmental factors and occur more often in young patients.⁵ The relative incidence of diffuse cancers is believed to have increased mainly owing to the decrease in the incidence of intestinal cancers.⁹

There are regional differences in the pathology and anatomic location of gastric carcinoma. A predominance of the Lauren intestinal type of adenocarcinoma occurs in high-risk areas, whereas the Lauren diffuse type is relatively more common in low-risk areas. Proximal gastric carcinomas and cancers of the gastroesophageal junction are more common in the West, and distal gastric carcinoma is more common in high-risk regions. At the M. D. Anderson Cancer Center, 41% of all UGI cancers involve the gastroesophageal junction.¹⁰ A steady decline in the incidence and mortality rates of gastric carcinoma has been observed worldwide over the past several decades. This is mainly due to a decrease in the intestinal variety of gastric carcinoma, the incidence of diffuse cancer being relatively stable.⁵

Etiology and Risk Factors

Because gastric carcinoma is more common in Asian than in Western countries, ethnic origin was thought to be an important contributory factor for the observed difference.¹¹ Although first-generation Asian immigrants to Western countries carry the same high susceptibility for gastric carcinoma as their counterparts in their native country, subsequent generations acquire risk levels approaching that of the population of their adopted countries. This epidemiologic pattern underlines the importance of environmental factors in the pathogenesis of gastric carcinoma.¹² Diets poor in fruits and vegetables and rich in smoked or poorly preserved food, salt, nitrates, and nitrites; infection with Helicobacter pylori; and smoking have all been currently implicated as significant risk factors in the development of gastric carcinoma in several studies.^13–15 Chronic atrophic gastritis, previous gastric surgery, gastric polyps, and obesity, as well as low socioeconomic status, are also associated with an increased risk of gastric carcinoma.^16,17

Gastric carcinoma is also seen as a part of the hereditary nonpolyposis colon cancer syndrome and other gastrointestinal (GI) polyposis syndromes such as Peutz-Jeghers syndrome and familial adenomatous polyposis.¹⁷ Mutations in the E-cadherin gene are a well-recognized cause of hereditary diffuse gastric cancer.¹⁸

Anatomy

Being a derivative of the foregut, the stomach is almost entirely supplied by the branches of the celiac trunk (Figure 15-1). The left gastric artery, arising from the celiac axis, and the right gastric artery, a branch of the hepatic artery, supply the lesser curvature in the gastrohepatic ligament and form an anastomotic arcade along the lesser curvature. The left and right gastroepiploic arteries, branches of the splenic artery and the gastroduodenal artery, supply the greater curvature of the stomach and traverse the gastrosplenic ligament and the gastrocolic ligament, respectively. The gastrocolic ligament is the supracolic part of the greater omentum. Numerous short gastric arteries, branches of the splenic artery, also supply the greater curvature. A rich lymphatic network accompanies these vessels, creating a conduit for lymphatic drainage, and traverses these complex ligamentous structures. The various ligamentous attachments can be identified by noting vascular landmarks on cross-sectional imaging (Table 15-1).²⁰ These ligamentous structures are important to understand because they represent the critical conduits for local extension of primary gastric carcinoma.

Figure 15-1 The blood supply of the stomach. The stomach is predominantly supplied by the branches of the celiac artery, being a derivative of the foregut. The greater curvature is supplied by the left and right gastroepiploic arteries, which are branches of the splenic and pancreaticoduodenal arteries. The lesser curvature is supplied by the left and right gastric arteries, which are branches of the celiac and common hepatic artery. In addition, several short gastric arteries (not shown) from the splenic artery supply the posterior wall of the stomach and the fundus. SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Table 15-1 The Various Ligamentous Attachments of the Stomach Can Be Identified by Identifying Vascular Landmarks on Cross-Sectional Imaging

From Vikram R, et al. Pancreas: peritoneal reflections, ligamentous connections, and pathways of disease spread. Radiographics. 2009;29:e34.

The stomach is divided for descriptive purposes into the fundus, body, pyloric antrum, and pylorus by imaginary lines drawn on its external surface (Figure 15-2). The fundus is dome-shaped, immediately under the left dome of the diaphragm, and is superior to the cardiac orifice. It lies above an imaginary line drawn horizontally at the level of the cardia (incisura cardia) to the greater curvature. At the lower end of the lesser curvature is a constant external notch (incisura angularis). The body extends from the cardia to the incisura angularis. A slight groove, the sulcus intermedius on the greater curvature of the stomach, separates the body from the pyloric antrum. The antrum extends from an imaginary line drawn from the incisura angularis to the sulcus intermedius. The pylorus is the narrowest part of the stomach, measuring only about 1 to 2 cm in length, and terminates into the duodenum (see Figure 15-2).²¹

Figure 15-2 The different parts of the stomach. The incisura cardia, sulcus intermedius, and incisura angularis are the landmarks used to divide the stomach into the fundus, body, and pyloric antrum.

Tumor Detection and Staging

EGD has replaced UGI double-contrast barium study as the modality of choice to detect and diagnose gastric carcinoma owing to its specificity and the advantage of obtaining a tissue biopsy and also the ability to perform EUS, which offers a reliable way to T-stage the tumor.³³ However, some reports indicate that endoscopy and UGI barium studies are equally sensitive in detection of primary gastric carcinoma.^34,35 Gastric carcinoma has various appearances on GI barium studies. These include plaquelike lesions, sessile or pedunculated polypoid lesions, ulcerated lesions, and nondistention of the stomach as in the scirrhous type of carcinoma or linitis plastica with diffuse loss of mucosal detail (Figure 15-4).

Figure 15-4 A, Double-contrast barium meal study in a 54-year-old patient shows a mucosal mass (arrows) due to adenocarcinoma at the greater curvature. B, Linitis plastica seen on double-contrast barium study. The body of the stomach fails to distend (arrows). Irregularity of the mucosa is also seen due to the diffuse infiltrative process.

EUS is superior to all other modalities in visualizing the different layers of the gastric wall and, thus, is most accurate in preoperative local (T) staging of gastric tumors with a accuracy rate of 78% to 94%.^36,37 Despite this, it is not uncommon (particularly for T2 tumors) that there is discordance with the actual pathologic specimen. The gastric wall layers appear as a five-layered structure on EUS with alternating hyperechoic and hypoechoic bands: serosa, muscularis propria, submucosa, deep mucosa, and superficial mucosa.³⁸ Tumors generally are hypoechoic or hyperechoic and are seen disrupting this regular pattern. EUS is also valuable in assessing smaller perigastric lymph nodes (Figure 15-5). EUS is of little to no benefit after preoperative therapy.

Figure 15-5 Endoscopic ultrasound shows the loss of the normal alternating hyper- and hypoechoic bands caused by the gastric carcinoma. Here, the tumor is seen infiltrating through the serosa (arrows). Enlarged perigastric lymph nodes (arrowheads) are also visualized.

CT is generally less accurate than EUS for T staging of gastric tumors. However, with the latest development in multidetector scanners, optimization of gastric distention, negative oral contrast, and dynamic contrast-enhanced CT with multiplanar reconstructions, the accuracy of CT in T staging appears to have improved.³⁹ The normal gastric wall shows a two- to three-layered structure: an inner, markedly enhancing mucosal layer; a submucosal layer with low attenuation; and an outer muscular-serosal layer with moderate enhancement (Figure 15-6).⁴⁰ T staging is assessed by studying the integrity of these layers. On CT, T1 and T2 lesions are limited to the gastric wall. T3 lesions, however, may show slight blurring of the serosal contour with associated stranding of perigastric fat.⁴¹ T4 lesions spread via ligamentous attachments and peritoneal reflections in T4 lesions (Figures 15-7 and 15-8). The early phase of the multiphase dynamic CT study after intravenous contrast is considered optimal in determining the depth of tumor invasion as well as defining the vascular anatomy of the stomach.⁴² Takao and coworkers,⁴³ in a study on 108 patients with gastric carcinoma using a multiphasic protocol CT, report a tumor detection rate and T staging accuracy of 98% and 82% for advanced gastric carcinomas. However, the detection and accuracy of T staging in early gastric carcinomas was significantly low at 23% and 15%, respectively. Use of multiplanar re-formatting (MPR) in coronal and sagittal planes appears to improve detection and T staging.^39,44 To improve the quality of three-dimensional (3D) imaging, however, thinner slices of at least 1.25-mm slice thickness are required. Advanced postprocessing techniques with volume rendering to produce an endoscopic-type image (virtual gastroscopy) have also been described.⁴⁵

Figure 15-6 Axial computed tomography (CT) scan with intravenous contrast. The normal stomach shows three layers: an enhancing mucosa, low-attenuation stripe of muscularis, and an outer enhancing serosa (arrows). A tumor in the lesser curve (asterisk) shows loss of the anatomic detail indicating involvement of the submucosa and muscularis.

Figure 15-7 Diffuse thickening of the cardia and lesser curve of the stomach due to adenocarcinoma shows soft tissue infiltration of the gastrohepatic ligament and extending into the hepatic fissure (arrows).

Figure 15-8 Carcinoma of the greater curvature of the stomach (not shown) with tumor extension along the gastrosplenic ligament (arrows).

The major advantage of MRI is multiplanar capability and better tissue contrast. However, the use of MRI in staging gastric carcinoma is limited owing to respiratory and cardiac motion, although some smaller studies report that MRI is comparable with CT for T staging.⁴⁶ Fat-suppressed 3D T1-weighted postcontrast acquisitions can demonstrate the mucosal lesion in the arterial phase. Loss of rugae and diffuse thickening and enhancement of the gastric mucosa and wall represent diffuse scirrhous tumors or linitis plastica (Figure 15-9).

Figure 15-9 Fat-suppressed three-dimensional (3D) T1-weighted postcontrast magnetic resonance imaging (MRI) acquisition shows loss of rugae and diffuse thickening and enhancement of the gastric mucosa and wall representing diffuse scirrhous tumor or linitis plastica. An enlarged gastroepiploic node (arrow) is also seen.

Fluoro-2-deoxy-D-glucose (FDG)-PET and PET/CT perform inconsistently in detection of gastric carcinoma and are not useful in the T staging of gastric carcinomas because of the normal background uptake of FDG in the gastric mucosa and also the variability in FDG uptake depending on the tumor’s histologic type. Signet-ring carcinoma (diffuse type) and poorly differentiated adenocarcinoma show little to no uptake (Figure 15-10).^47,48 The use of water to distend the stomach appears to improve the specificity of PET/CT for diagnosis to a modest degree.⁴⁹ However, owing to its poor performance, the role of PET/CT in diagnosis and T staging of gastric carcinoma is uncertain.

Figure 15-10 Axial CT scan with intravenous and oral contrast shows diffuse thickening of the stomach due to infiltrating carcinoma, signet-cell variety (linitis plastica). Right, A fused positron-emission tomography (PET)/CT scan shows poor uptake of fluoro-2-deoxy-D-glucose (FDG). Left, Increased activity in the kidney (asterisk) is also noted in the PET/CT.

Lymph Node Staging

Nodal staging is challenging even with the current advances in imaging technology owing to significant limitation in detecting microscopic metastases by currently available imaging modalities. Owing to the lack of any reliable indicator to detect metastatic lymph nodes on cross-sectional imaging, size is the major criterion used, with a presumed upper limit of 8 to 10 mm in short-axis diameter(Figure 15-11; see also Figure 15-9).This parameter has significant shortcomings. In a prospective study in patients with gastric carcinoma, Monig and colleagues reported that 80% of lymph nodes less than 5 mm in size were benign but 55% of metastatic lymph nodes were also less than 5 mm in diameter, clearly demonstrating the weakness of any size criterion as a parameter on imaging modalities.^46,50

Figure 15-11 A, Enlarged left gastric lymph nodes (arrows). There is thickening of the lesser curvature caused by infiltrative gastric adenocarcinoma of the proximal stomach. B, Enlarged celiac lymph node (arrow) in a patient with gastric adenocarcinoma of the proximal stomach.

In addition to the challenges faced by CT regarding the staging of lymph nodes, MRI also suffers owing to movement artifact due to peristalsis and breathing.⁵¹ Hence, CT is marginally better in staging lymph nodes (73% vs. 65%).^46,52 Use of lymphotrophic ultrasmall superparamagnetic iron oxide (USPIO) particles—ferumoxtran-10—for detecting metastatic lymph nodes showed some promise in staging distant lymph nodes such as those in the retroperitoneal and para-aortic regions. Owing to movement artifact, the nodes in the perigastric region are not clearly assessed. Tatsumi and associates⁵³ demonstrated a sensitivity of 100% and a specificity of 92.6% in detecting metastatic lymph nodes using lymphotrophic USPIO particles in MRI. Currently, the USPIO is not commercially available in the United States, which limits its clinical application.

Morphology and echo texture are used to identify metastatic lymph nodes by EUS. Because of the proximity to the probe, this is an excellent modality to detect nodes in the immediate vicinity of the stomach such as the perigastric lymph nodes. For surgical planning, however, the important stations—station III and station IV nodes—are not adequately staged by this modality because they are beyond the focal zone of the transducer.

FDG-avid nodes on PET/CT are likely malignant, and hence, PET/CT enjoys a higher specificity than CT or MRI. However, PET/CT suffers from inherently poor resolution and, hence, poor sensitivity.⁵⁴ In addition, the previously mentioned lack of FDG avidity for diffuse type cancers is a severe limitation (see Figure 15-10). Therefore, the likelihood of this modality improving nodal staging is remote unless there is technologic innovation with widespread availability of high-resolution PET/CT scanners.

Metastatic Gastric Carcinoma

Involvement of distant lymph nodes such as the right supraclavicular lymph node (Virchow node) is considered distant metastasis, and curative surgery is not feasible in such patients (Figure 15-12). According to the American Joint Committee on Cancer (AJCC) staging, the presence of cancer in hepatoduodenal, retropancreatic, mesenteric, and para-aortic, is classified as distant metastasis.²⁵

Figure 15-12 Maximum intensity projection FDG-PET study in a patient with gastric carcinoma. There is intense uptake in the primary tumor (long arrow) and a metastatic left supraclavicular node (short arrow).

Gastric carcinoma frequently metastasizes to the liver owing to its portal venous drainage. The metastatic deposits most often are hypovascular with or without a rim of enhancement. Hence, a routine scan during portal venous phase is adequate.

CT scan of the chest is considered essential in patients to stage gastric carcinoma and to look for pulmonary metastases. Even though postmortem studies have put the incidence of pulmonary metastasis in gastric carcinoma as high as 25%, such a picture is not commonly seen in the clinical setting.⁴⁰

Advanced gastric carcinoma metastasizes much more frequently into the peritoneum, typically to the omentum (Figure 15-13), ovaries (Krukenberg’s tumor, usually bilateral) (Figure 15-14), or rectovesicular pouch (Blumer’s shelf tumor).⁴⁰ Ascites in gastric carcinoma was shown in one study to be associated with positive free tumor cells (40% sensitivity and 97% specificity) and peritoneal metastasis (51% sensitivity and 97% specificity).⁵⁵

Figure 15-13 Soft tissue masses (arrows) in the greater omentum in a patient with gastric carcinoma form extensive peritoneal metastases (omental cake).

Figure 15-14 Coronal reconstruction of a CT scan performed with intravenous contrast. Diffuse thickening of the stomach from infiltrative gastric adenocarcinoma (arrows). There are bilateral predominantly cystic ovarian masses (asterisks) from secondary deposits.

Although laparoscopy predates CT in staging peritoneal disease, it remains superior to all other imaging modalities in small-volume peritoneal disease. Its sensitivity for detecting peritoneal disease is quoted as 96%.⁵⁶ Various factors are likely to affect the ability of CT to detect peritoneal metastasis, including size, location, and morphology of the deposits and the presence or paucity of intra-abdominal fat.^11,57 On CT, peritoneal metastasis can be seen as a nodular mass, peritoneal plaque, or infiltrative soft tissue mass lesion.⁴¹ A diffusely thickened and enhancing peritoneal lining can be a manifestation of diffuse peritoneal carcinomatosis.

MRI is considered superior to CT scan by some authors in detecting extra-gastric metastasis.^51,58 Owing to factors such as greater soft tissue resolution and greater sensitivity to contrast enhancement, and the recent development of hepatobiliary contrast agents, MRI can be superior to CT in detecting hepatic metastases (Figure 15-15).⁵⁸ Its multiplanar capabilities make it useful in detecting peritoneal metastasis, but laparoscopic staging has been proved to be superior to both CT and MRI in detecting peritoneal involvement.

Figure 15-15 Large metastatic mass in the right lobe of the liver with central area of necrosis and rim enhancement. A, Axial fat-suppressed T2-weighted MRI. B, Axial fat-suppressed T1-weighted MRI with intravenous contrast.

The value of PET/CT is limited by the poor FDG avidity of some subtypes, notably the signet-ring cell variety. However, in some instances, it may be useful in detecting distant metastasis that may not be seen on conventional imaging. In fact, there are a few authors reporting that use of PET/CT changed management by detecting unsuspected metastasis.^59,60 However, there are currently no data to support the widespread use of PET/CT in routine use.

PET may be useful in detecting peritoneal metastases in some instances. Some studies have shown that PET has a greater sensitivity than CT in detecting peritoneal metastasis.^61,62 There are two distinct patterns described in peritoneal metastasis in PET.⁴¹ One is a diffuse increase in uptake in which the silhouette of the abdominal organs such as the liver and spleen is obscured, indicating diffuse peritoneal carcinomatosis. The second is nodular increase in uptake in areas not corresponding to the normal anatomic locations of nodes or other solid organs (Figure 15-16). The detectability of metastasis has benefited considerably from combined PET/CT because of its ability to distinguish abnormal uptake from bowel activity.⁶² It should be remembered, however, that certain histologic types of gastric tumors such as signet-cell carcinoma and poorly differentiated adenocarcinoma (the most common type of gastric carcinoma to spread to the peritoneum) have little to no FDG uptake, and therefore, their metastatic deposits may not be picked up on PET.⁴⁷

Figure 15-16 Coronal PET scan of a patient with gastric carcinoma with multiple nodular FDG-avid peritoneal deposits (arrows).

Surgery

The surgeons dealing with gastric carcinoma will have to make a series of choices in designing the most appropriate surgery for a particular patient by taking into consideration the location of the cancer (proximal versus distal), type of cancer (intestinal versus diffuse), stage of the cancer, reconstruction options, and lastly, patient factors such as overall fitness and risk of surgery.⁶³

After staging, all newly diagnosed gastric carcinoma will need to be grouped as localized or metastatic disease. For localized disease, surgery is the only chance for cure for these patients. However, several caveats are important to remember, especially among patients with localized disease, which are for all practical purposes divided into three groups: (1) early disease, (2) localized resectable, and (3) localized but unresectable.

For early gastric carcinoma, endoscopic mucosal resection (EMR) or limited resections may be used. EMR is a technique developed and popularized for use in select patients with early gastric carcinoma. These cancers are generally T1a tumors less than 2 cm, either flat or protuberant, and have no ulceration or involvement of the submucosa.^64,65 In the United States, because early gastric carcinoma is not common, expertise with EMR is limited.

Resection of small T1b tumors with only a cuff of surrounding stomach tissue with limited dissection of lymph nodes is occasionally performed. However, there are no data that directly compare these techniques to the more conventional surgery. However, the outstanding survival results (approaching 100%) for properly selected patients for EMR attest to its appropriate use. Laparoscopic gastrectomy or laparoscopic-assisted gastrectomy is also practiced in some centers with improved postoperative morbidity.⁶⁶ However, there are no data to compare the long-term survival in these patients, and some series describe a slightly higher incidence of positive margins of resection.^63,67

Aggressive gastric surgery has been practiced for many decades in the East and is followed by many surgeons who see large numbers of gastric carcinoma patients in the West. This includes an extended lymph node dissection along with appropriate luminal resection. The extent of lymphadenectomy is a subject of considerable debate.^63,68 D1 lymphadenectomy and D2 lymphadenectomy are commonly followed. A meta-analysis of several trials found no significant difference in the mean 5-year survival of patients who underwent gastrectomy with D1 and D2 dissection (mean weighted 5-yr survival of 41% and 42.6%, respectively).⁶⁹ However, with the T3 and T4 lesions, patients with a D2 lymphadenectomy had a slightly better outcome but this was not statistically significant. In two large prospective, randomized trials of D2 versus D1 dissection in Western patients, D2 lymphadenectomy clearly resulted in a significant increase in mortality. But a subgroup analysis showed that there was a very strong and independent association between postoperative mortality and splenectomy.⁶⁹ These studies have substantial issues that limit the applicability of their conclusions. At high-volume centers here and elsewhere, D2 dissection is routinely performed with mortality rates that are lower than that for the D1 dissection in the randomized trials. In the authors’ institute, spleen-sparing D2 lymphadenectomy is routinely performed, with an operative mortality rate of 2% or less (in patients who are usually receiving neoadjuvant therapy).¹⁹

More radical dissections with D3 and D4 lymphadenectomy that include para-aortic nodes are less commonly performed even in Asian countries, particularly after the publication of the Japan Clinical Oncology Group (JCOG) 95-01 randomized trial, which demonstrated no benefit and increased morbidity.^68,70

Surgery is also sometimes used for palliation of intractable symptoms not responding to conservative management. The symptoms of advanced gastric carcinoma include pain, vomiting, GI bleeding, and anorexia. Although anorexia is not relieved by palliative surgery, intractable nausea and vomiting due to gastric obstruction may be helped by either inserting a duodenal stent or gastric bypass surgery.⁷¹ These procedures, however, are fraught with potential problems and should be considered only in extenuating circumstances. However, the use of palliative surgery for gastric carcinoma has decreased over the past few decades with development and improvement of the nonsurgical techniques as well as recognition of the severely limited prognosis for patients with stage IV disease and this degree of symptoms.

Chemotherapy and Radiation Therapy

Traditionally, the universally accepted standard treatment for patients with potentially resectable disease was surgery alone. In those patients, in whom curative surgery is not possible, the treatment is often time-limited to chemotherapy with or without definitive chemoradiotherapy. The use of chemoradiotherapy is extrapolated from results of earlier unresectable localized esophageal cancer studies, most notably the Radiation Therapy Oncology Group (RTOG) 85-01 trial in which the relapse-free survival and OS rates were improved with concurrent chemoradiotherapy.⁷²The Intergroup 123 trial, in which patients with localized but unresectable esophageal cancer were treated with either standard-dose (50.4 Gy) radiotherapy or higher-dose (64.8 Gy) radiotherapy while concurrently on a chemotherapy regimen of weekly cisplatin and 5-fluorouracil (5-FU) once every other week, suggested some surprising results, indicating that combining standard-dose radiotherapy with chemotherapy results in similar survival outcomes without adding significant toxicity. Currently, many physicians consider concurrent chemoradiotherapy as standard therapy where possible.

Although surgery remains the modality with the best chance for durable survival, the survival figures, particularly in the Western countries, are not satisfactory. Hence, many clinical trials to assess the additional survival advantage of adjuvant multimodality therapy in patients with localized resectable disease have been performed. Many of the older studies were inadequately designed to answer this question, and their results were inconsistent. Results from more recent clinical trials during the 2000s have firmly established that adjuvant therapy to surgery improves survival outcomes. Another confounding factor that has not been completely resolved regards to the timing of adjuvant therapy (pre-, post-, or perioperative). Results from many clinical studies had shown variable results regarding the benefit of postoperative chemotherapy. Results of several meta-analyses are available that suggest a benefit with postoperative chemotherapy. However, subgroup analysis demonstrates that the benefit is restricted to patients in Asian countries. Whereas postoperative chemotherapy with S1 is the standard of care for Japanese and Asian patients with resectable gastric carcinoma, management of resectable gastric carcinoma in Western countries is predominantly guided by two positive randomized phase III studies.^1,2,73–76

In the United States, the Intergroup 116 conducted a phase III randomized adjuvant therapy.⁷⁷ Gastric carcinoma patients after R0 resection were then randomized to receive either observation or postoperative therapy. Postoperative therapy consisted of one cycle of chemotherapy with bolus 5-FU and leucovorin, followed by 4 to 5 weeks of concurrent chemoradiotherapy, then two more cycles of chemotherapy. Macdonald and coworkers,¹ reported their results in the 2001 issue of the New England Journal of Medicine, showing that postoperative chemotherapy plus chemoradiotherapy improved the 3-year survival rates from 41% to 50%. Although applauded for being the first adjuvant trial that completed as well as demonstrated statistically significant results, Intergroup 116 was also criticized on several points. First, only approximately 10% of patients had D2 and 50% had D1 lymph node dissection.⁷⁵ Most would argue that the additional therapy after surgery may not have been necessary if patients had optimal resection. Second, it was found that many patients’ radiotherapy fields had to be revised when their treatment plans were centrally reviewed, prompting some critics to suggest that community practice is not the best place to practice multimodality therapy. Third, only those patients who did well after surgery were enrolled and randomized onto the study, introducing a selection bias and arguably limited applicability of results to other subgroups of patients. It is also important to note that only 64% of the patients completed the full postoperative course, highlighting the difficulty in patient compliance with multimodality, intense, postoperative therapy. Overall, despite all its criticisms, the results of the Intergroup 116 established that additional postoperative therapy with chemotherapy-chemoradiotherapy improves survival outcome after surgery.

The MAGIC (The Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial, reported by Cunningham and colleagues,² with perioperative chemotherapy showed an improvement in survival with addition of perioperative chemotherapy using epirubicin, cisplatin plus infusional 5-FU (ECF); three cycles were given before and after surgery. Patients on the perioperative chemotherapy arm compared with those on surgery alone arm had better median OS (30 mo vs. 18 mo) and more were able to have curative surgery (74% vs. 68%).² These results offer another option into the management of patients with resectable gastric carcinoma. Unfortunately, because there is no head-to-head comparison between the American postoperative chemoradiotherapy and the U.K. perioperative chemotherapy, it is not clear which option is superior. Several observations can be made when the results of Intergroup 116 and MAGIC are combined. It is clear that surgery alone for patients with locally advanced gastric carcinoma is not adequate. Survival can be improved with additive therapy; possibly similar with either approach. Therapy given preoperatively potentially can downstage and improve the surgical cure rate. Therapy given postoperatively is associated with less tolerance and compliance, with more patients unable to finish therapy. In order for the patients to get the maximum amount of effective therapy, it is apparent that therapy has to be given before surgery. It may not be as important to know which one is better as to be able to have options for patients before going into their curative surgery.

The decision of which therapy should be given with surgery for patients with resectable gastric carcinoma remains unanswered. Therefore, treatment options for patients are both perioperative chemotherapy and postoperative chemotherapy-chemoradiotherapy. The role of postoperative (adjuvant) chemotherapy may be more appropriate for patients in Asian countries.

Ongoing phase III studies may clarify the role of multimodality therapy added to surgery. Currently, CALGB 80101 and MAGIC 2 are ongoing studies in the United States and the United Kingdom, respectively. In Asian countries, ongoing phase III studies are also accruing to determine more effective chemotherapy in the postoperative settings. These and other ongoing studies hopefully will clarify the optimal additive therapy to surgery.