Adenocarcinoma of the stomach: a review

On January 29, 1881, in Vienna, Austria, Dr. Theodor Billroth performed the first successful operation for gastric cancer. Two previous attempts by other surgeons had resulted in early postoperative deaths; Dr. Billroth's patient survived the surgery but died a few months later from metastatic disease (1). Today surgeons are still challenged by similar obstacles in gastric cancer, notably the dismal result of incomplete resection.

INCIDENCE AND ETIOLOGY

Worldwide, gastric cancer is the fourth most common cancer (2). In the West, the incidence of gastric cancer has steadily decreased since the 1930s due to better living conditions and dietary changes. It is now the eighth most common cause of cancer death (Figure 1). The incidence in the USA is 5.2 per 100,000 vs 12 to 15 per 100,000 in Europe and 93 per 100,000 in Japan (3–5). In 2002, there were 21,600 newly diagnosed gastric cancers and 12,400 deaths due to gastric cancer in the USA (6, 7). The median age of diagnosis is 70 years for men and 74 years for women (3, 8). The incidence is twice as high in men as in women and increases with age (9).

Figure 1.

Incidence of gastric cancer according to race and gender, 1973–2001. Source: National Cancer Institute (reference 7).

The vast majority of gastric cancers are attributed to environmental factors, the most common being infection with Heli cobacter pylori. H. pylori was discovered in 1984 by Drs. Marshall and Warren as an inciting cause for peptic ulcer disease and has since been linked to gastric cancer (10). This organism is found in 72% of antral gastric cancers and results in a 9-fold increased risk of developing cancer. Inoculation most likely occurs in childhood through the oral-fecal pathway and is transmitted person to person (11), which partially explains why the incidence decreases as countries become more developed. Palayo Correa theorizes that preexisting infection with H. pylori causes inflammation and atrophy, leading to reduced acid and bacterial overgrowth. Chronic atrophic gastritis can progress to metaplasia, then to dysplasia, and finally to carcinoma (12–14). It is also possible that more virulent strains of H. pylori (i.e., the Cag A strain) may cause cancer (15). This mechanism is more likely to apply to distal cancers compared with more proximal cancers. Food intake is thought to be contributory as well; diets high in salt and preserved, smoked foods as well as low in fresh fruits and vegetables appear to be a risk factor. A Swedish population-based case-control study evaluated the absolute risk reduction from changes in diet. It was estimated that 25,000 people would have to eat a high-fruit diet to prevent one gastric cancer (16). However, certain carcinogens in foods, such as nitrosamines and nitrosamides, in the presence of achlorhydria along with the decreased antioxidant effect of fruits and vegetables may enhance the risk of developing chronic atrophic gastritis. Proximal tumors, however, appear to have a different mechanism, as many pathology specimens fail to demonstrate dysplasia or metaplasia (17, 18).

Genetic factors have been difficult to prove. Although many molecular studies have been and are being performed to uncover the genetic basis for gastric cancer formation, no causal relationships have been proven. Gastric cancer is part of several inherited disorders, including Lynch syndrome and PeutzJeugers syndrome (19). A directly inherited tendency was described in the family of Napoleon Bonaparte (1). More recently, the Maori tribe in New Zealand has demonstrated a hereditary inheritance with mutations in the E-cadherin/CDHI gene that regulates cell adherence. Several recent studies have further supported the role of E-cadherin mutations in familial gastric cancer (20–23). The lack of E-cadherin prevents binding to alpha-, beta-, or gammacatenins by preventing normal cell'to-cell adhesion (24). The loss of normal adhesion may allow cells to detach and invade locally more easily. Abnormal cellular adhesions contribute to the raised, irregular edges seen in many tumors. Decreased expression of E-cadherin is noted more commonly in signet ring and mucinous adenocarcinomas. Loss of heterozygosity in the p53 gene also appears to be quite high in gastric cancer. Inactivation of p53 may be important in the late pathogenesis of gastric cancer (25, 26). Microsatellite instability is found in approximately 16% to 36% of gastric cancers. Adenomatous polyposis coli (APC) gene mutations are also found in approximately 30% of gastric cancers. The loss of APC function allows for increased levels of beta-catenins, which bind with lymphoid-enhancer factor 1 and become a growth-promoting transcription factor that modulates gene expression and stimulates cancer formation (27–30). Several studies are currently looking at alterations in growth factors such as bcl-2, C-met, K-sam, and c-erbB2 as markers for advanced disease and possible sources for immunotherapy (31–33). Elevated levels of vascular endothelial growth factor also appear to portend a worse prognosis. The ultimate goal for this genetic research is to uncover a more complete understanding of gastric cancer, allowing the development of specific therapy such as monoclonal antibodies to specific abnormal proteins.

Histologically, the Lauren classification scheme denotes two main subgroups for gastric cancer. The intestinal type is more commonly seen in Asian patients and the elderly. It typically involves the distal stomach and has glandlike structures that mimic intestinal glands. The diffuse or signet ring type is more common in Western cultures, younger patients, and individuals with blood type A. It is more frequently found in the proximal stomach, and the tumors are more poorly differentiated and lack glandular structures (9, 34, 35).

The anatomic location of gastric cancer is changing. In recently published European epidemiologic data, a 4% to 5% increase per year in proximal or cardiac cancers has been noted (3, 36). This rate parallels the increase in distal esophageal adenocarcinomas, suggesting a relationship to bile or alkaline reflux (37, 38). Proximal gastric cancers, referred to as esophagogastric junction cancers or cardiac cancers, have increased in the USA from 29% in 1984 to 52% in 1993 (39, 40). These cancers tend to have a worse prognosis secondary to the later onset of diagnosis and the more extensive lymph node drainage that involves the mediastinal, abdominal, and retroperitoneal lymphatics (41, 42).

Proximal cancers have been subclassified by Siewert and Stein based on location of the majority of tumor mass (43). A type I esophagogastric junction tumor is >2.5 cm above the cardia and is treated as an esophageal tumor. A type II tumor is located from about 2.5 cm above cardia to 2 cm below cardia. The presence of goblet cells is suggestive of Barrett's esophagus and not of stomach origin (44). Type III tumors are >2.5 cm below the cardia. A proximal negative margin is required for complete tumor excision. Of note, patients with proximal cancers have survival rates similar to those of patients with distal esophageal adenocarcinomas, comparing stage for stage (45). Several studies have shown similar genetic abnormalities for proximal cancers and esophageal adenocarcinoma, including loss of the Y chromosome, gain of chromosome 20, loss of chromosome 5, p53 mutations, and microsatellite instability; these abnormalities can make determining the true organ of origin difficult (46–50). Several studies have also noted differences between esophageal and proximal gastric cancer. Proximal gastric cancers are associated with H. pylori infections and often have inflammation, whereas esophageal cancers are rarely associated with H. pylori and have much less inflammation (51, 52).

Distal gastric cancers, on the other hand, have continued to decrease in incidence. This decrease may be due to better living conditions, better dietary habits, and eradication of H. pylori with antibiotics. Distal cancers are seen most commonly in Asia (51).

DIAGNOSIS AND STAGING

In the pursuit of cure, attempts have been made to diagnose gastric cancer in its early stage. Tumors confined to the mucosa and submucosa are termed early gastric cancer, which is discussed separately from most gastric cancer due to its overall favorable prognosis; the 5-year survival is >90% (53). Most cases of early gastric cancer in the USA are diagnosed outside of a formal screening program and are found during evaluations for symptoms. Early gastric cancer is more frequently encountered in Asian countries where screening for gastric cancer occurs. In the USA, it accounts for < 10% of gastric cancers (54–56).

Gastric cancer spreads fairly predictably in a local fashion within the gastric wall and then to adjacent lymph nodes. Once it does reach the serosa, it can spread into the peritoneal cavity and then spread distantly. This sequential manner of spread has encouraged the surgical pursuit of extensive local and lymph node resections. Even if lymph node biopsy results are negative, several factors are diagnostic of more aggressive disease. Investigators from Memorial Sloan-Kettering demonstrated predictors of poor survival in lymph node–negative patients, including male gender, serosal invasion, presence of vascular invasion, and neural invasion. Age, tumor location, Lauren histologic classification, and extent of lymphadenectomy had no effect on survival. Vascular invasion portends a more aggressive tumor, a poorer survival rate, and a higher likelihood of metastasis for equal size and location. A T1 lesion with vascular invasion was associated with a 5-year survival of 57% compared with 97% for a T1 lesion without vascular invasion (57).

Symptomatic findings in early stage disease are relatively vague and nonspecific, often mimicking peptic ulcer disease. Most commonly, patients complain of epigastric discomfort. Patients may also present with anemia, weight loss, early satiety, anorexia, and, rarely, an upper gastrointestinal bleed (1). The increased use of proton pump inhibitors and antiulcer therapy may contribute to later time of diagnosis due to resolution of common vague symptoms (58). One study suggested that 30% of gastric cancer patients were treated with proton pump inhibitors for their symptoms (59).

Physical examination findings, if present, portend more advanced disease. In general, patients may appear cachectic or jaundiced from obstruction by lymph nodes surrounding the common bile duct. The presence of disease in several lymph nodes is attributed to metastatic spread of gastric cancer. Virchow's node is a hard lymph node in the left supraclavicular fossa. The Sister Mary Joseph lymph node is a firm nodule in the umbilicus, often from tumor extending down the falciform ligament, and may cause a bloodstained discharge from the umbilicus. Irish's node is an enlarged left axillary lymph node. A Krukenberg tumor is gastric cancer metastatic to the ovary. A positive Blumer's shelf finding may indicate metastatic tumor high on the anterior rectal wall on rectal examination. Some patients may have a firm, palpable abdominal mass or present with malignant ascites (1, 60).

Early endoscopy should be considered in patients of recent Asian emigration as well as patients who have had previous gastric surgery or who have a positive family history or concerning symptoms. Patients with previous gastric surgery for ulcer disease are 2.4 times more likely to develop gastric cancer (60). Because of the low incidence of gastric cancer in the USA, no formal program is in place for screening, unlike in Japan and other Asian countries. A patient with a history of chronic atrophic gastritis or intestinal metaplasia also needs to be considered for annual surveillance, as there is an 8% to 10% risk of developing cancer over a 10-year period (61).

Definitive diagnostic investigation begins with upper endoscopy, as >90% of cases will be diagnosed in this manner. Typical gastric cancer appears as an irregular ulcer with raised edges or an ulcer that is polypoid and fungating. Multiple biopsies, usually 6 or more, are required to minimize the false-negative rate. Even patients with gastric ulcers that appear benign should undergo endoscopy again after 6 weeks of medical treatment. Gastric ulcers need to be biopsied until they are completely healed (60). If the stomach appears undistensible, a barium upper gastrointestinal series may be more diagnostic of linitis plastica than esophagogastroduodenoscopy with biopsies, as the tumor diffusely infiltrates the submucosa of the stomach. If an upper gastrointestinal series is ordered, gastric cancer often appears elevated and irregular with nonradiating rugal folds. Once the diagnosis is made, a computed tomography (CT) scan is required to stage the cancer and evaluate for metastatic disease. Bulky adjacent lymphadenopathy in the periaortic region, ascites, and a thickened omentum can be evaluated on CT and suggest metastatic disease. Obliteration of the lesser sac and invasion to surrounding vessels can also be visualized (1) (Figure 2). Endoscopic ultrasound can be used to assess the tumor depth and to further evaluate adjacent lymphadenopathy. Endoscopic ultrasound—guided fine-needle aspiration of adjacent lymph nodes can also be performed. Staging laparoscopy may be required to assess for unresectability. Positron emission tomography scans can also be used to assist in staging. Laparotomy, however, is still the gold standard for staging (60).

Figure 2.

Computed tomography findings in advanced unresectable gastric cancer before (upper panels) and after (lower panels) chemotherapy. Note the disappearance of ascites and omental thickening. Reprinted with permission from reference 1.

Gastric cancer is staged using the TNM staging system (3, 6) (Table 1). The most important prognostic indicators are lymph node involvement followed by tumor depth. The number of positive nodes is more important than the location of the nodes in determining survival (57,62–64). Risk of lymph node spread can be predicted by tumor depth. The chance of positive nodes is <4% for a T1a (mucosal) lesion, 23% for a T1b (submucosal) lesion, 44% to 50% for a T2 (muscularis propria) lesion, and 64% for a T3 (to serosa) lesion (9, 57, 63).

Table 1.

American Joint Committee on Cancer staging system for gastric cancer

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria
T1	Tumor invades lamina propria or submucosa
T2	Tumor invades muscularis propria or subserosa*
T2a	Tumor invades muscularis propria
T2b	Tumor invades subserosa
T3	Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures†‡
T4	Tumor invades adjacent structures†‡
Regional lymph nodes (N)
NX	Regional lymph node(s) cannot be assessed
N0	No regional lymph node metastasis§
N1	Metastasis in 1 to 6 regional lymph nodes
N2	Metastasis in 7 to 15 regional lymph nodes
N3	Metastasis in more than 15 regional lymph nodes
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage grouping
0	Tis, N0, M0
I A	T1, N0, M0
IB	T1, N1, M0 T2a/b, N0, M0
II	T1, N2, M0
	T2a/b, N1, M0
	T3, N0, M0
IMA	T2a/b, N2, M0
	T3, N1, M0
	T4, N0, M0
NIB	T3, N2, M0
IV	T4, N1-3, M0
	T1-3, N3, M0
	Any T, Any N, M1

*A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T3.

†The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

‡Intramural extension to the duodenum or esophagus is classified by the depth of greatest invasion in any of these sites, including the stomach.

§A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 6th ed. (2002) published bySpringer-Verlag New York, http://www.springer-ny.com.

SURGICAL TREATMENT

The primary successful treatment is still surgical resection. It is the only single-modality treatment capable of curing gastric cancer. The goal of a surgical cure requires complete resection to an R0 status (no residual tumor), as the stage of disease is the most important predictor of outcome. On average in Western cultures, 20% to 30% of patients present with inoperable cancer secondary to metastatic disease. Of the remaining 75% progressing to surgery, 20% of patients have unresectable cancer at the time of surgery, 25% have cancer with positive microscopic margins and are thus not cured, and 30% have a curative procedure performed (60).

The approach to surgery is determined by 1) the incision(s) needed, 2) the extent of gastric/esophageal resection needed, and 3) the extent of lymph node dissection needed. Surgery may of course be required for palliation secondary to bleeding and obstruction and may even be offered as an option in prolonging life.

Controversy remains over the extent of lymph node dissection required with gastric resection. The great majority of gastric cancers that recur and metastasize do so first in the regional lymph nodes before spreading to the peritoneum, liver, or lung. The standard of care varies worldwide, with most Asian countries encouraging extended lymphadenectomy. The majority of surgeons in the USA, on the other hand, excise the N1 lymph nodes, which are in the immediate perigastric region. This resection is called a D1 resection. A D2 resection, as described in the 2002 American Joint Committee on Cancer manual, includes nodes along the celiac access and its named branches and along the middle colic, superior mesenteric artery, and periaortic nodes (65–67). Asian studies suggest that a minimum of 15 nodes are required to adequately stage the disease and to truly declare a patient node negative (68). Several studies in Europe and the USA, however, have failed to show any significance in survival and even have shown an increase in perioperative morbidity and mortality with more extensive lymph node resections (65, 66,69–71) (Table. 2). A recent Dutch trial performed with Japanese moderators present showed no difference in survival and an increase in perioperative morbidity and mortality with extended lymphadenectomy (66). However, in a recent paper from Memorial Sloan-Kettering Cancer Center, a D2 resection was still recommended due to identification of 20% incidence of skip metastasis to D2 nodes. Survival was slightly improved only for patients who had T3 disease and were node negative (9, 57, 63, 71).

Table 2.

Results of studies comparing D1 and D2 lymph node dissection

First author (reference)	Patients D1/D2	Morbidity (%) D1/D2	Mortality (%) D1/D2	5-Year survival (%) D1/D2
Bonenkamp (66)	380/331	25/43	4/10	45/47
Cuschieri (69)	200/200	28/46	6.5/13	35/33
Dent (71)	22/21	15/30	0/0	78/76 (3 yrs)

In Japan, improvement in survival has been shown with more extensive lymphadenectomy. This has been attributed to more intense pathologic assessment of specimen lymph nodes, leading to up-staging, and possibly a difference in biology. Distal cancers are more common in Japan, whereas proximal cancers are more common in the USA. Also, there may be a difference in interpreting pathology and intraoperative findings, as many Western patients may be understaged (1, 72, 73).

At present, a computer database of >8000 patients, called the Maruyama program, is being compiled in Japan to help predict the most likely spread of tumor based on 7 variables, including tumor size, depth, and grade. These data may help guide the extent of dissection and improve the accuracy of removing involved nodes (74, 75).

In contrast to the emphasis on extensive lymphadenectomy, there is an interest in performing a more limited node dissection with sentinel node biopsy. This technique generally relies on intraoperative injection of isosulfan blue dye with direct visualization of the first node or nodes. This technique has been proposed for early gastric cancer when a local excision may be performed. Even when a complete lymphadenectomy is anticipated, some have proposed that the sentinel node technique should be performed to identify unsuspected patterns of drainage and to allow for a more thorough pathologic assessment of the first sentinel node, including serial sectioning and immunohistochemistry. Comparative studies in Japan demonstrate a detection rate of >95% and a sensitivity of 90% for sentinel lymph node biopsy vs a D2 dissection (Table 3). No clinical trials have been performed to give a definitive recommendation. Critics of this technique note the extensive drainage to the celiac axis, liver, mediastinum, and retroperitoneal basins (9).

Table 3.

Comparison of sentinel lymph node studies

First author (reference)	Number of patients/T category	Method	Detection rate (%)	Sensitivity (%)	Node-positive patients (%)
Kitagawa (76)	127/T1 18/T2	Tc-99m sulfur colloid	95	92	17
Ichikura (77)	62/T1,2	Dye, ICG	100	87	24
Hiratsuka (78)	44/T1 30/T2	Dye, ICG	99	90	14

Tc-99m indicates technetium 99m; ICG, indocyanine green.

The removal of the spleen and distal pancreas to achieve adequate lymphadenectomy has largely been abandoned because several studies demonstrated that survival is worse with resection. This result may be secondary to a more advanced tumor or to the immunomodulatory effects of splenectomy on cancer recurrence as well as an increased risk of infection (79). If tumor is grossly invading the spleen or the tail of the pancreas, resection should be performed for tumor reduction. No tumor should purposefully be left behind if a curative resection is being attempted.

Gastric resections are determined by tumor location. Proximal cancers are further subcategorized according to type of tumor. A type I tumor is considered an esophageal cancer and treated with an esophagogastrectomy, usually requiring both an abdominal and thoracic approach. A type II tumor usually requires an esophagogastrectomy to achieve 6- to 7-cm proximal margins. A type III proximal gastric tumor can be treated with either a total or proximal subtotal resection. Several studies have demonstrated no survival difference in type of resection as long as margins are negative (80–86). Body and midstomach tumors typically require a total resection to gain adequate margins of at least 6 cm (87). Pylorus-preserving distal gastrectomies are often done for early gastric cancers or more proximal tumors. Total gastrectomy should be considered for T3 disease. Tomita et al monitored 32 patients over 5 years to compare pylorus-preserving vs traditional resections and concluded that pylorus-preserving resections decrease reflux, dumping, and gastritis, but patients have increased sensation of fullness and early satiety secondary to gastric atony. Symptoms can be reduced with preservation of hepatic and pyloric branches of the vagus nerve (88). Local excision of gastric cancer has been proposed for early gastric cancer (T1 mucosal disease). This stage of cancer is rarely seen in the USA. However, the Japanese have reported good results from treating the lesion endoscopically with local resection or with more limited open or laparoscopic gastric resections.

Reconstruction can be performed using a Roux-en-Y, Billroth I, or Billroth II anastomosis. A Roux-en-Y anastomosis tends to eliminate troublesome bile reflux. Long-term follow-up studies demonstrate no nutritional difference in reconstruction choices; however, short-term function is better with a Tanner 19 anastomosis (similar to a J-pouch) vs a straight gastrojejunostomy anastomosis (89, 90). A feeding jejunostomy is commonly placed to allow for nutritional replacement, especially during postoperative chemotherapy and radiation.

SURGICAL COMPLICATIONS

The major postoperative complications include anastomotic leak, aspiration, hemorrhage, infection, thromboembolism, and pneumonia. Infection rates increase with splenectomy. Most often patients with a leak will present with tachycardia, hypotension, a decrease in hematocrit, and a left pleural effusion.

Long-term complications are related to loss of receptive relaxation, antral contraction, and secretory function, especially with a total gastrectomy. Patients may complain of early satiety and may have weight loss and nutritional deficits (i.e., B₁₂ from loss of intrinsic factor; iron and calcium if there is bypass of the duodenum). Dumping syndrome, which may include bloating, epigastric pain, diarrhea, and fainting, is related to rapid entry of osmotically active material into the small intestine. This rapid entry causes a shift of fluid from the intravascular space and results in symptoms of hypovolemia. Late dumping may produce fainting symptoms, but these typically occur a few hours postprandial and are secondary to an excessive rise in insulin due to the rapidity of intestinal carbohydrate load and a resulting hypoglycemia.

NEOADJUVANT THERAPY

Preoperative, or neoadjuvant, therapy is another controversial issue. Most trials have not demonstrated a significant benefit in overall survival (91–96) (Table 4). A recently published European study, designated as the MAGIC trial, involved 503 patients treated with pre- and postoperative epirubicin/cisplatinum/5- fluorouracil (5-FU) vs surgery alone. Treated patients showed improved survival, but the trend was not statistically significant. Tumors in treated patients were significantly smaller, allowing for a better rate of curative resection (79% vs 69% of patients receiving surgery alone), but again, survival was not significantly improved (89, 90). Preoperative chemoradiation at present is considered investigational as no phase III trials have demonstrated a survival advantage (9, 94, 101). Preoperative external-beam irradiation has been evaluated-especially for stage III and stage IV disease—as the tumor may be downsized, allowing for a better chance of curative resection (60, 96).

Table 4.

Neoadjuvant treatment trials

First author (reference)	Number of patients	Regimen	R0 resection rate (%)	Survival (months)
Ajani (91)	104	Preop FAMTX, postop 5-FU/CDDP vs preop and postop EAP	61 vs 77	15 vs 16
Ott (92)	49	Preop PLF	76	32
Kang (93)	107	Surgery vs PEF and surgery	61 vs 78 (P = 0.049)	30 vs 42 (P = 0.11)
Songun (94)	56	Surgery vs preop FAMTX and surgery	62 vs 56 (NS)	13.1 vs 12.8 (NS)
Skoropad (95)	78	Surgery vs preop RT 20 Gy IORT and surgery	(Data not shown)	9 vs 21 (NS)
Zhang (96)	370	Surgery vs 40 Gy and surgery	79 vs 89 (P = 0.01)	20 vs 30 (P=0.0094)

FAMTX indicates 5-FU, doxorubicin, methotrexate; CDDP, cisplatin; EAP, etoposide, doxorubicin, cisplatin; PLF, cisplatin, 5-FU/leucovorin; PEF, cisplatin, etoposide, 5-FU; NS, not significant; RT, radiotherapy; IORT, intraoperative radiotherapy.

Multiple trials have been performed evaluating multiple drug combinations postoperatively over the past 20 years. No clear treatment option has been shown to make a significant overall survival difference. A recent Intergroup trial by Macdonald et al evaluated postoperative therapy with 5-FU/leucovorin and radiation vs surgery alone. A significant benefit from postoperative treatment was noted in patient survival (from 26 to 35 months) and relapse-free interval (from 19 to 30 months). This study was criticized for poor surgical technique; lymph nodes were removed in <40% of the procedures (99–101). A recent metaanalysis of multiple adjuvant trials suggested a small benefit from treatment (relative risk 0.94, 95% confidence interval [CI] 0.89–1.00) (98) (Figure 3). Trials in which most patients had node-positive disease demonstrated the greatest benefit (relative risk 0.91, 95% CI 0.85–0.99) compared with trials in which most patients had node-negative disease (relative risk 1.00, 95% Cl 0.90–1.11). At present, studies are comparing surgery with epirubicin, cisplatinum, and 5-FU pre- and postoperatively because this therapy appears to be more effective than 5-FU/leucovorin alone (99). Current treatment options are multiple, and most are in clinical trials. Epirubicin/cisplatinum/5-FU protocol vs docetaxel/cisplatinum/5-FU are options also being compared (98, 99 101–103).

Figure 3.

Metaanalysis of randomized trials that compared adjuvant chemotherapy with observation after curative resection of gastric cancer. Cl indicates confidence interval. Reprinted from reference 98 with permission from Elsevier.

Survival data are varied in the literature based on country of origin and extent of resection. The following data are based on studies performed in the USA and Europe. Most Asian survival rates are significantly better. According to Kooby et al (59), the 5- and 10-year survival rates for patients with node-negative disease are 79% and 66%. The survival rate at 5 years for T1 with no positive nodes was 93%; for T2, 84%; and for T3, 52%. According to the National Cancer Data Bank, overall survival for stage IA is 78%; for stage IB, 58%; for stage II, 34%; for stage IIIA, 20%; for stage IIIB, 18%; and for stage IV, 7% over 5 years. Survival for R0 is 35% and increases to 79% if the cancer is node negative (Table 5). The presence of carcinomatosis indicates a survival of <6 months (57, 63, 104).

Table 5.

Five-year survival^*

Node negative
	T1	93%
	T2	84%
	T3	52%
	R0	79%
Overall survival
	Stage IA	78%
	Stage IB	58%
	Stage II	34%
	Stage IIIA	20%
	Stage IIIB	18%
	Stage IV	7%

*Data from references 7 and 57.

Many new therapies are being assessed as alternatives to current postoperative treatments. Immunotherapy options such as tumor vaccines and specific tumor protein antibodies are being examined. Photodynamic therapy is still being evaluated, but no completed studies have been reported (1, 60).

Intraperitoneal hyperthermic chemotherapy using mitomycin C is also being used at some centers to treat locally advanced gastric cancer. The effectiveness of intraperitoneal chemotherapy could be due to the high rate of local recurrence in the gastric bed. Surgical intervention may cause tumor spillage at the time of surgery and may further stimulate proliferation by releasing growth factors secondary to the surgical intervention itself. Surgery will stimulate a fibrous reaction that can compromise systemic delivery of chemotherapy and may trap and protect tumor cells from chemotherapeutic exposure (105–110). In this approach, the cancer is debulked as thoroughly as possible, and intraperitoneal hyperthermic mitomycin C is circulated in the peritoneal cavity for 2 hours. The addition of hyperthermia to 42°C improves the penetration of mitomycin C into the residual tumor from 100 to 1000 μm at normothermic temperatures to 3000 μm at hyperthermic temperatures (111–113). These patients then undergo standard postoperative chemotherapy and radiation regimens. In several Japanese, French, and US studies, significant survival and relapse-free improvements have been reported for patients treated with postoperative intraperitoneal mitomycin C and hyperthermia (105, 114 116–118). Yu et al specifically evaluated 248 patients treated for curative gastric resection with and without intraoperative chemotherapy. They noted a 5-year survival of 54.1% with treatment vs 38.1% with no treatment (P = 0.0278) (115, 118).

CONCLUSION

In summary, distal gastric cancers are decreasing in incidence worldwide, but proximal cancers are becoming more common. The only chance of curing gastric cancer is surgical resection with R0 status. Postoperative chemotherapy and radiation offer some survival benefit, but more successful therapeutic options are needed. Intraperitoneal chemotherapy at the time of surgery may be effective in reducing local recurrence.

The pathophysiology, surgical options, and therapeutic challenges are changing and expanding in breadth and complexity. Continued pursuits hold promise for a better century for successful cures of gastric cancer.