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GASTRIC CANCER

At the time of diagnosis, gastric cancers are localized and surgically resectable in approximately 50% of patients; however, regional nodal metastases or direct invasion of surrounding organs or structures are frequently encountered and preclude cure by surgery alone in many patients. Analyses of patterns of relapse after complete surgical resection demonstrate that subsequent relapse of cancer is common in both the tumor bed and nodal regions as well as systemically.

The standard of care for resectable gastric cancer for patients who can tolerate a surgical procedure is surgical resection. For patients with lower risk lesions (confined to gastric wall, nodes negative; T1–2N0M0 [Table 2 ]) adjuvant treatment is usually not recommended except in select instances. Because both local and systemic relapses are common after resection of high-risk gastric cancers (beyond wall, nodes positive, or both; T3–4N0, TanyN+), adjuvant treatment is indicated for these patients. The results of phase III trials that demonstrate a survival benefit for preoperative irradiation, postoperative chemoradiation, or perioperative chemotherapy with epirubicin, cisplatin, and continuous-infusion 5-FU (ECF) versus surgery alone will be summarized and future trial designs will be discussed.


Table 2. 
TNM Staging for Carcinoma of the Stomach*

Stage

T

N

M

0

TIS

0

0

IA

1

0

0

IB

1

1

0

2

0

0

II

1

2

0

2a/b

1

0

3

0

0

IIIA

2a/b

2

0

3

1

0

4

0

0

NIB

3

2

0

IV

4

1-3

0

1-3

3

0

Any

Any

0

 TIS, carcinoma in situ; intraepithelial tumor without invasion of the lamina propria; T1, tumor invades lamina propria or submucosa; T2, tumor invades the muscularis propria (T2a) or the subserosa (T2b); T3, tumor penetrates the serosa (visceral peritoneum) without invasion of adjacent structures; T4, tumor invades adjacent structures; N0, no regional lymph node metastasis; N1, metastasis in 1–6 regional nodes; N2, metastasis in 7–15 regional nodes; N3, metastasis in more than 15 regional nodes; M0, no distant metastasis; M1, distant metastasis.

* Metastases to other intra-abdominal lymph nodes such as hepatoduodenal, retropancreatic, mesenteric, or para-aortic are considered distant metastases within this system but are N3 or N4 in the Japanese Research Society Classification.

 

For patients with locallyadvanced disease that seems unresectable for cure, several treatment options seem to have a favorable impact on disease control and survival. These options include primary external beam irradiation (EBRT) plus concomitant chemotherapy, maximal resection plus intraoperative irradiation (IORT), and preoperative chemotherapy or chemoradiation before resection. Results of these approaches will be summarized and future trial design will be discussed.

In the setting of metastatic disease, many active chemotherapy agents can produce meaningful response alone or in combination with other agents, but the duration of response is often limited. Trials now exist that demonstrate both a survival and quality-of-life benefit for multidrug chemotherapy versus best supportive care for individuals with metastatic cancers.

EPIDEMIOLOGY AND ETIOLOGY

In 2007, cancer of the stomach had an expected incidence in the United States of 21,260 cases and an expected number of 11,210 deaths. Despite these impressive figures, age-adjusted gastric cancer death rates have decreased markedly in the United States since 1930 from approximately 28 to 2.3 in 100,000 females and from 38 to 5.2 in 100,000 males (Fig. 1). Of the 45 countries in which age-adjusted death rates for gastric cancer were compared for 2000 (Fig. 2), the United States ranked forty-fifth for both males and females. Kyrgyzstan ranked first for both males (47.0 in 100,000) and females (18.9 in 100,000).

Figure 1. Age-adjusted (to U.S. 1970 standard population) cancer death rates in the United States from 1930 to 2003 in selected sites for females (A) and males (B). Females have a steady decrease in death rates for stomach, breast, and colorectal cancers. From 1960 to 1998, a continual increase in death rates occurred for lung cancer in females. For males, a similar decrease in death rates occurred with gastric cancer. An increase in death rates for lung cancer existed in males from 1930 to 1990 with a continual decrease during the 1990s.

Figure 2. Age-adjusted (to World Health Organization world standard population) death rates for gastric cancer from 2000 in 45 countries for females (A) and males (B). Rates in the United States, Canada, and United Kingdom are compared with selected countries, including the 15 countries with the highest death rates.

The causes of the decline in the U.S. rates are incompletely understood, but environmental factors, chiefly dietary, are suspected. Within the United States the lowest incidence is in whites, Chinese, and Filipinos, with a higher incidence in U.S. Japanese. However, epidemiologists have noted a significant decrease in incidence among migrants from high-incidence countries (such as Japan and Chile) to low-incidence countries. Although there is an overall reduction in gastric cancer incidence, there has been a steady rapid increase in the incidence of gastroesophageal junction and proximal gastric cancers.

Factors that have been associated with a higher incidence of gastric cancer include smoked or salted foods, foods contaminated with aflatoxin, low intake of fruits and vegetables, low socioeconomic status, and possibly a decreased use of refrigeration. Possible occupational relationships include coal mining and rubber or asbestos workers. Precursor pathologic conditions include pernicious anemia, achlorhydria atrophic gastritis, gastric ulcers, and adenomatous polyps. Between 5% and 10% of individuals with pernicious anemia subsequently develop malignancy. Prior partial gastrectomy for benign gastric or duodenal ulcer disease produces an increased risk of subsequent malignancy in the gastric remnant with latency periods of 20 years or more.

Several studies have shown a three- to sixfold increased risk of gastric cancer in individuals with Helicobacter pylori infection versus those with no infection, but the precise role of this bacterium in the etiology of gastric cancer remains unknown. A variety of bacterial, patient, and environment factors most likely act in combination to affect the development of gastric carcinoma. The increased association of H. pylori with gastric cancer seems to be mainly with distal gastric cancers and intestinal-type malignancy. Only a minority of H. pylori-infected individuals develop gastric cancer, and data do not yet exist on the effect of treatment of the H. pylori infection on subsequent malignancy.

PREVENTION AND EARLY DETECTION

Early detection would markedly improve the prognosis of gastric cancer in the United States, because surgical resection has a high cure rate with lesions limited to the mucosa or submucosa. However, the incidence of such early gastric cancers is less than 5% in most U.S. series. In Japan the incidence of carcinomas confined to the mucosa or submucosa was only 3.8% in the 1955 to 1956 period. However, by 1966 the incidence of early lesions had increased to 34.5% because of vigorous screening procedures, leading to 5-year survival rates of 90.9% in this cohort of patients. Although mass screening has been useful in Japan to detect early cancers, defined high-risk populations have not existed in the United States in the past to justify the expense of widespread screening endeavors. Whether screening of individuals with H. pylori infection would be of value is not yet known. Individual practitioners should use upper gastrointestinal (GI) series or preferably endoscopy to screen patients who have occupational or precursor risk factors or individuals with persistent dyspepsia or gastroesophageal symptoms.

Germline mutations in the CDH1 gene, which encodes the E-cadherin protein, have recently been recognized in families with hereditary diffuse gastric adenocarcinoma. Carriers of these mutations have a 70% lifetime risk of developing gastric cancer. Several reports of prophylactic gastrectomy have demonstrated the routine presence of microscopic intraepithelial carcinomas in patients having regular endoscopic surveillance that includes multiple random biopsies. Early total gastrectomy has been recommended for this small patient population because of the lack of effective early tumor detection by less aggressive techniques. Microscopic evaluation of the proximal and distal resection margins for complete removal of the gastric mucosa is necessary, because residual gastric mucosa can degenerate and result in a gastric cancer.

PATHOLOGY

The terms gastric cancer and stomach cancer usually refer to adenocarcinoma, which accounts for 90% to 95% of all gastric malignancies. Other histologic types include lymphoma (usually intermediate- or high-grade histologic types), leiomyosarcoma, carcinoid, adenoacanthoma, and squamous cell carcinomas. The site of origin within the stomach has changed in frequency in the United States over recent decades, with more proximal lesions now being diagnosed and treated. The largest percentage of gastric cancers still arises within the antrum or distal stomach (around 40%), are least common in the body of the stomach (around 25%), and are of intermediate frequency in the fundus and esophagogastric junction (around 35%).

Gastric carcinomas have been categorized by using both microscopic (Fig. 3) and gross pathologic features. The Lauren classification system includes an intestinal type with improved prognosis that predominates in regions with high prevalence of gastric cancer, as well as a diffuse histologic type, with poor prognosis, which occurs more commonly in countries with low prevalence of stomach cancer. Grossly, gastric cancers can be categorized according to Borrmann's five types: I, polypoid or fungating; II, ulcerating lesions surrounded by elevated borders; III, ulceration with invasion of the gastric wall; IV, diffusely infiltrating (linitis plastica); and V, unclassifiable. The Japanese Research Society for Gastric Cancer has a classification system that divides lesions into protruded (I); superficial (II) with elevated (IIa), flat (IIb), and depressed (IIc) subtypes; and excavated (III) types.

Figure 3. Photomicrographs demonstrating histopathologic features of gastric cancer. A–C, Gastric adenocarcinoma, intestinal type. A, The neoplasm shows complex gland formation (arrows). This type would be regarded as moderately differentiated or grade 2 in a four-grade system. (×125.) B, This tumor infiltrates the superficial portion of the submucosa. Typical of intestinal-type adenocarcinoma, the pre-existing gastric epithelium is obliterated. (×42.5.) C, This tumor extends into perigastric serosa and, in view of the more irregular gland formation, would be graded with grade 3 of 4. (×42.5.) D–F, Diffuse-type gastric adenocarcinoma. D, Diffuse-type adenocarcinomas often contain signet cells (arrows). (×225.) E, Linitis plastica. Note how the underlying mucosa, submucosa, and muscularis propria appear thickened but are otherwise intact, in contrast to intestinal-type adenocarcinomas (B). (×22.5.) F, Linitis plastica at high power. Neoplastic cells may be very subtle (arrows). This tumor extended to the peritoneal surface and had metastasized. (×125.)

Pathways of tumor spread

Direct extension

The stomach is surrounded by a number of organs and structures that can be involved by direct extension once a lesion has extended beyond the gastric wall. These structures include the omenta, pancreas, diaphragm, transverse colon or mesocolon, duodenum, jejunum, spleen, liver, superior mesenteric and celiac vessels, abdominal wall, left adrenal gland, and kidney. Adherence from inflammatory conditions can mimic direct extension of tumor, but all adhesions between a gastric carcinoma and adjacent structures must be regarded as malignant.

Lymphatics

Abundant lymphatic channels are present within the submucosal and subserosal layers of the gastric wall. Microscopic or subclinical spread well beyond the visible gross lesion (intramural spread) occurs via these lymphatic channels. Accordingly, frozen sections of the gastric resection margins should be obtained intraoperatively to ensure that margins of resection are uninvolved microscopically. The submucosal lymphatic plexus is also prominent in the esophagus and the subserosal plexus in the duodenum, allowing both proximal and distal intramural tumor spread.

Because of the numerous pathways of lymphatic drainage from the stomach, it is difficult to perform a complete nodal dissection (Fig. 4). Although initial drainage is usually to lymph nodes along the lesser and greater curvatures (perigastric or N1 nodes using the Japanese Research Society for Gastric Cancer designation), primary node drainage includes nodes along all three branches of the celiac axis (common hepatic, splenic, left gastric) and the celiac artery itself (Japanese N2 nodes). Node groups that are more distal include hepatoduodenal, peripancreatic, root of mesentery (N3), periaortic, and middle colic (N4). When proximal gastric lesions extend into distal esophagus, the paraesophageal nodal system is at risk for involvement.

Figure 4. Classification and anatomic location of lymph node groups. Involvement of nodes along the lesser or greater curvature (groups 1–6) constitutes N1 disease, and the celiac axis and its three branches are N2 (7–11), N3 (12–14), and N4 (15, 16). N1: 1, right paracardial; 2, left paracardial; 3, lesser curvature; 4, greater curvature; 5, suprapyloric; 6, infrapyloric. N2: 7, left gastric artery; 8, common hepatic artery; 9, celiac artery; 10, splenic hilus; 11, splenic artery. N3: 12, hepatic pedicle; 13, retropancreatic; 14, mesenteric root. N4: 15, middle colic artery; 16, para-aortic.

Hematogenous spread

For malignancies confined to the stomach, venous drainage is primarily to the liver via the portal system. At initial exploration, liver involvement is found in up to 30% of patients, predominantly as a result of hematogenous metastases but sometimes because of direct tumor extension. For lesions that extend proximally to involve the esophagus or posteriorly, the lung may be at risk for distant metastases.

Peritoneal involvement

Because the stomach is an intraperitoneal organ, peritoneal dissemination is possible once a lesion extends beyond the gastric wall to a free peritoneal (serosal) surface. Peritoneal spread may initially be a localized process limited by surrounding organs and ligaments (gastrohepatic, gastrosplenic, and gastrocolic).

BIOLOGIC CHARACTERISTICS

Prognostic factors

The most meaningful prognostic indicators relate to extent of tumor. With either hematogenous metastasis or peritoneal seeding, prognosis is almost uniformly fatal. Recent immunohistochemical analysis of bone marrow aspirates has shown the presence of tumor cells to be an independent predictor of adverse outcome; however, confirmatory studies have yet to be published. Survival decreases with progressive direct tumor extension both within and beyond the gastric wall. Lymph node involvement, per se, is not as important as the number and location of nodes. Minimal lymph node involvement adjacent to the primary lesion results in the most favorable prognosis in node-positive patients, but even micrometastases in regional nodes may adversely impact survival. The solitary finding of either involved lymph nodes or complete penetration of the gastric wall is usually not as ominous as the presence of both (Table 1).

Table 1. Extent of initial disease versus survival rates in stomach cancer[*]

5-YEAR SR (%)

Extent of Disease

Dockerty[†]

Kennedy

>5-yr DFS University of Minnesota Reoperation Series[21]

LYMPH NODES -

Mucosa only

100

85

>Mucosa but within wall

61

52

Through wall

44

47

LYMPH NODES +

Lymph node extent

15

19

Regional only

17

Nonregional

5

Extent of primary

Within wall

40

Through wall

12

DFS, disease-free survival; SR, survival rate.

* Compilation of data from various series.

Percentages are only of patients who left the hospital.

 

The tumor grade and the grossand histologic pathologic appearance of the primary malignancy seem to provide some prognostic information, but none of these factors is a prognostic variable independent of the tumor stage. Prognosis is generally worse with higher grade and diffuse-type carcinomas, which usually present with higher pathologic stages of disease (Fig. 3). Borrmann types I and II carcinomas have a relatively favorable 5-year survival rate, but patients with type IV tumors (linitis plastica) fare very poorly.

Some investigators have suggested that tumors of the gastric cardia may have epidemiologic factors different from cancers of the distal stomach and may exhibit different tumor biology. The prognosis is worse for cardia lesions, and flow cytometry reveals a greater incidence of aneuploidy when compared with tumors of the antrum and body.

Flow cytometry provides valuable prognostic information for gastric cancer and may be an independent prognostic factor. As noted previously, aneuploidy is associated with unfavorable tumor location such as the cardia but is also associated with lymph node metastasis and direct tumor extension. Unfavorable DNA flow cytometry characteristics seem to relate closely to an unfavorable prognosis. In one series in which multivariate analysis of DNA ploidy was analyzed with other known prognostic factors such as stage, age, and sex, DNA ploidy carried statistically significant independent prognostic information.

The presence of several peptides including estrogen receptor, epidermal growth factor receptor, the e-erb-b2 protein, and plasminogen activator inhibitor type 1 seems to affect prognosis adversely. The expression of epidermal growth factor receptor and high levels of epidermal growth factor correlate with a higher incidence of primary tumor infiltration, poor histologic differentiation, and linitis plastica. The pathophysiologic relationship between these peptide receptors and poor patient prognosis is not clear. Gastric cancers with class II major histocompatibility complex antigen expression (human leukocyte antigen [HLA]-DR) have a better prognosis, but the loss of expression is not an independent prognostic factor.

CLINICAL MANIFESTATIONS, PATIENT EVALUATION, STAGING

Neither patient symptoms nor routine physical examination will lead to an early diagnosis of gastric cancer. The most common presenting symptoms and signs are loss of appetite, abdominal discomfort, weight loss, weakness (due to anemia), nausea and vomiting, and melena. The duration of symptoms is less than 3 months in nearly 40% of patients and longer than 1 year in only 20%.

Evaluation of the patient

Positive findings on physical examination are those of advanced disease. Findings may include an abdominal mass (representing the primary tumor, hepatic metastasis, or ovarian metastasis [Krukenberg's tumor]), remote node metastasis (left supraclavicular [Virchow's node]; periumbilical [Sister Mary Joseph node]; or left axillary [Irish's node]), ascites, or a rectal shelf (peritoneal seeding).

The diagnosis of gastric cancer is usually confirmed by upper GI endoscopy, or radiographs. Double-contrast radiographs may reveal small lesions limited to the superficial (inner) layers of the gastric wall. Endoscopy is now the preferred initial diagnostic test, because it allows direct tumor visualization, cytologic testing, and histologic biopsy that yield the diagnosis in 90% or more of patients with exophytic lesions. Ulcerated cancers and linitis plastica lesions may be harder to diagnose endoscopically, but multiple biopsies and washings enhance the probability of accurate diagnosis. Endoscopic ultrasonography (EUS) has a high degree of accuracy in determining depth of tumor invasion (i.e., does the lesion extend beyond the muscularis propria?) but is less accurate in detecting regional nodal metastasis. Ultrasound-guided fine-needle aspiration for cytologic test allows the assessment of regional lymph nodes and some distant metastatic sites (e.g., liver), further enhancing the ability of EUS to determine tumor stage and resectability.

The extent of disease at exploration or laparoscopy is usually more extensive than is suggested on upper GI radiography or endoscopy. Abdominal CT scan is valuable in determining the abdominal extent of disease with regard to larger liver metastasis (1 cm or greater), involvement of celiac or periaortic nodes, or extragastric extension (may help determine which lesions extend to surgically unresectable structures). CT scan is of little value, however, in ruling out peritoneal metastases or small hepatic metastasis. Diagnostic laparoscopy allows visualization of small serosal or liver metastases and may give added information with regard to the amount of direct extension of the primary tumor. Distant (hematogenous) metastases should be ruled out with a chest radiograph, serum liver chemistries, and abdominal CT scan, or liver ultrasonography (we prefer CT scan to ultrasonography because of the additional information concerning regional nodal status, extragastric extent of disease, and extension within the distal esophagus). CT scans also provide valuable tumor localization information should irradiation be indicated. If a proximal gastric tumor extends to involve the esophagus, CT scan of the chest is useful in determining mediastinal node involvement or parenchymal lung metastases.

Staging

With the development of laparoscopic general surgery, diagnostic laparoscopy is commonly used to assess for distant metastasis or unresectable locally advanced abdominal cancers. Several groups have reported the use of laparoscopy in stomach cancer patients. Metastatic disease was documented laparoscopically in 35% to 40% of patients. The sensitivity for metastases was 85% or greater and this technique was particularly sensitive in detecting liver and peritoneal disease. Laparoscopy is more sensitive and accurate in staging patients with regard to intra-abdominal metastases than either ultrasound or CT scan. Many surgeons now routinely perform laparoscopy in all gastric cancer patients who do not require palliation, to avoid nontherapeutic laparotomy.

The current TNM (tumor, lymph node, metastasis) staging system is depicted in Table 2 and is acknowledged as the standard system for reporting outcomes in stomach cancer. Several comparison studies, including some from Japan, have shown better prediction of prognosis using the AJCC TNM system compared with other staging systems, including that of the Japanese Research Society for Gastric Cancer.

PRIMARY THERAPY AND RESULTS

Surgical method

Surgical excision of the gastric and nodal components of disease remains the primary therapy for all potentially curable gastric carcinomas. Based on pathologic findings, the Japanese Research Society for Gastric Cancer has defined four categories of surgical resection: (1) absolute curative (no peritoneal or hepatic metastases, no serosal involvement, and a level of lymph nodes removed beyond those involved); (2) relative curative (same as 1 but nodal involvement to the level excised); (3) relative noncurative (complete gross tumor excision but curative criteria not met); and (4) absolute noncurative (residual cancer). Most curable tumors can be removed with adequate margins by subtotal gastrectomy; total gastrectomy is used when mandated by proximal cancer location or disease extent. Routine total gastrectomy does not improve survival by providing wider margins and eliminating multicentric disease but may increase the rates of patient morbidity and mortality. A randomized study showed similar survival rates with subtotal and total gastrectomy. Surgical resection alone, including endoscopic mucosal resection in selected patients, is an excellent treatment for gastric carcinomas limited to the mucosa or submucosa without nodal involvement (TIS or T1N0M0). These early gastric cancers now occur with an incidence of over 30% in Japan but still less than 5% in the United States and other Western countries. At least one Japanese report showed similar excellent results for T2 cancers if lymph nodes were uninvolved. For the more invasive gastric carcinomas, curative or palliative resection is indicated for 50% to 60% of patients at the time of disease presentation, but only 25% to 40% of these patients will have potentially curative surgical procedures. Increasingly subtotal and total laparoscopic gastrectomies are being performed safely and without apparent compromise of patient outcome.

Only one prospective randomized trial exists with regard to the extent of gastric resection, but extensive experience exists with various different surgical procedures, and appropriate generalizations can be made. The preferred treatment for lesions arising in the body or antrum of the stomach is a radical distal subtotal resection (Fig. 5). This removes approximately 80% of the stomach along with the first portion of the duodenum, the gastrohepatic and gastrocolic omenta, and the nodal tissue adjacent to the three branches of the celiac axis. Extensive or proximal cancers will require a total gastrectomy to achieve an adequate proximal gastric margin (Fig. 6). Total gastrectomy provides no advantage when subtotal gastrectomy will provide a 5-cm clearance of the gross tumor. The propensity for gastric carcinoma to spread via submucosal and subserosal lymphatics dictates the need for a 5-cm surgical resection margin of normal stomach beyond the visible tumor. It may be necessary to extend the resection to include some (or additional) esophagus or duodenum if frozen-section pathologic evaluation of the surgical margins fails to confirm the adequacy of proximal and distal resection margins. If total gastrectomy is necessary, a splenectomy is sometimes performed, particularly in gastric cancers of the proximal third of the stomach, and tumors of the body near the greater curvature. These cancers are more apt to metastasize to lymph nodes in the splenic hilum that cannot be completely excised without a splenectomy. The value of routine splenectomy has been addressed in a prospective randomized trial. No benefit of splenectomy was apparent in this trial.

Figure 5. A, Radical subtotal gastrectomy. The extent of resection for this tumor of the antrum includes the distal 80% of the stomach, the lesser and greater omenta, the perigastric lymph nodes (Japan N1), and lymph nodes along the left gastric, celiac, and common hepatic arteries (Japan N2). B, Radical subtotal gastrectomy reconstruction. After closure of the duodenal stump and lesser curvature of the stomach, the gastric remnant and proximal jejunum are anastomosed end to side in an antecolic position. The spleen and distal pancreas have been left in situ.

Direct spread beyond the gastric wall should be treated with en bloc extended resection to achieve negative margins of resection, if a curative resection is contemplated. These extended resections are potentially curative but increase perioperative morbidity and mortality. Common examples of local tumor extension include involvement of the body or tail of the pancreas (treated by distal pancreatectomy and splenectomy), invasion of the transverse mesocolon (often requires transverse colectomy), and involvement of the spleen (splenectomy) or left lobe of the liver (usually requires wedge resection with a 1-cm or wider clearance).

The optimal extent of lymph node dissection for gastric cancer remains controversial. The presence and extent of lymph node metastasis correlate with the depth of primary tumor invasion. Japanese surgeons universally advocate regional lymph node removal for all but in situ or intestinal mucosal tumors as a means to improve both local control and survival. Because more distal nodes can be involved with metastasis in 11% of patients with negative perigastric nodes, a wider regional nodal dissection is deemed necessary for cure. A recent study of sentinel lymph node biopsies in gastric cancer patients in Japan demonstrated that 37% of tumors drained to N2 nodes, either in combination with N1 sentinel nodes (32%) or as the sole site of lymphatic drainage (5%). When performing a radical subtotal gastrectomy and omentectomy, all N1 and N2 nodes should be removed (D2 dissection; see Fig. 4) (N1, perigastric nodes; N2, nodes along the left gastric, common hepatic, celiac, and splenic arteries). Some surgeons in Japan routinely remove N3 lymph nodes (D3 dissection, usually portal and retropancreatic). A recently completed prospective trial of D2 versus D3 dissections determined that the more extensive lymphadenectomy did not increase complication rates, but no long-term survival outcomes are available for this study.

Thus far, randomized trials have not demonstrated either disease-free or overall survival advantage for extended lymphadenectomy (D2 dissection). A large multicenter phase III study that accrued 711 curable gastric cancer patients in the Netherlands noted significantly higher morbidity and mortality rates with the more extensive nodal dissection (Table 3). A randomized study from the United Kingdom that included 400 patients with gastric adenocarcinoma also demonstrated higher morbidity and mortality rates in the extended lymphadenectomy cohort (Table 3). Neither the Dutch nor the British trial demonstrated any improvement in overall or disease-free survival (Table 3). In the Dutch study, patients who did not undergo a splenectomy or distal pancreatectomy had an improvement in relapse-free survival ([RFS] 71% vs. 59% at 5 years, P = 0.02). Splenectomy and pancreatectomy had significant adverse impact on survival in both trials. Preliminary data from a Japanese trial comparing D2 and D3 resections and an Italian study comparing D1 and D2 resections did not show increased morbidity with extended lymphadenectomy. Results for disease-free and long-term overall survival are not yet available from either study.

Table 3. Extent of surgery: randomized trials of Dl versus D2 dissection

5-YR SURVIVAL (%)

OPERATIVE MORTALITY (%)

Series

No. of Patients

Dl

D2

Dl

D2

PValue

Dutch

711

45

47

4

10

<0.05

MRC[*]

400

35

33

6.5

13

<0.05

Both trials showed significantly increased morbidity and mortality with more extensive dissections.

* Defined D1 dissection as resection of AJCC nodes (those within 3 cm of primary tumor).

 Any potential survival benefitseen with the extended node dissection performed in Japan may be due to the phenomenon of a stage migration rather than superior surgical therapy. In Japan and the United States gastric resection specimens are handled quite differently. Japanese pathologists evaluated an average of 62 nodes in subtotal gastrectomy specimens and as many as 100 in total gastrectomy cases, including lymph nodes less than 3 mm in diameter. This number compares with an average of 12 and 13 nodes examined after subtotal and total gastrectomy, respectively, at Memorial Sloan-Kettering. Patient survival after a curative operation significantly improves when more than 15 lymph nodes are pathologically examined. Failure to evaluate an adequate number of regional lymph nodes probably results in the understaging of many gastric cancer patients. N2 nodes cannot be defined as positive if they are not resected and examined; involvement of resected N1 nodes cannot be assessed if the specimen is not thoroughly evaluated by the pathologist. Most patients with more than six lymph node metastases or with lymph node metastasis not adjacent to the primary tumor still have a very poor outcome. Extended lymph node dissection seems reasonable for experienced surgeons who can perform this procedure without significantly increased surgical morbidity or mortality, because it improves pathologic staging.

Endoscopic laser surgery has been used in selected individuals with early gastric cancer. Small lesions (≤3 cm) that are not ulcerated, do not involve the submucosa, and are well differentiated infrequently have lymph node metastasis (<5%). As many as 75% of these select tumors can be completely removed endoscopically. Although early gastric cancer may have a long natural history before progression, standard surgical resection rather than endoscopic removal is still preferable for most Western patients.

Survival after surgery alone

Overall survival results with surgery alone remain poor, despite improved perioperative treatment, which has resulted in a substantial decline in postoperative mortality rate (median of 4.6% in the 1980s). A large review from Europe reported excellent 5-year survival rate for early gastric cancer patients (83%) but a marked diminution in survival for more invasive cancers. Excellent survival in excess of 90% has been achieved throughout the world with surgical resection of lesions confined to the mucosa or submucosa  (Table 4). In contrast, for gastric cancers with deeper invasion or nodal involvement, survival decreases proportionally to the degree of invasion or involvement (Table 4). When N1 or N2 nodes are involved, Western reports continue to show 5-year survival rates of 10% to 30%, whereas Japanese authors report 5-year surgical cure rates of 25% to 60% (vs. <10% with N3 or N4) (Table 4). Although pathologic staging differences, different tumor biology, and more radical surgical extirpation have been proposed as explanations, the cause of the difference in U.S. and Japanese results with N1 or N2 disease remains uncertain. Even in the Orient half of all individuals with more invasive gastric cancer die of their disease, a fact that underlies the need for new nonsurgical therapies.

Table 4. Comparison of 5-year survivals following surgery for gastric carcinoma

5-YR SURVIVAL (%)

Tumor Classification

Nodal Status

United States

Japan

T1

NO

90

90

T2

NO

52

60

T3

NO

47

30

T4

NO

15

5

N1

20

53

N2

10

26

N3

10

N4

3

Relapse patterns after «curative resection»

Local regrowth or failure in the tumor bed and regional lymph nodes, or distant failures via hematogenous or peritoneal routes are all common mechanisms of failure after “curative resection” in clinical, reoperative, and autopsy series. For lesions of the esophagogastric junction, both the liver and lungs are common sites of hematogenous spread. With gastric lesions that do not extend to the esophagus, the initial site of hematogenous spread is usually the liver, and many relapses could be prevented if an effective “abdominal” therapy could be combined with treatment of the primary tumor and regional lymph nodes.

Local-regional failures occur commonly within the region of the gastric bed and nearby lymph nodes (Table 5). Tumor relapse in anastomoses, the gastric remnant, or the duodenal stump is also frequently seen. In a University of Minnesota reoperative analysis, local-regional failure occurred as the only evidence of relapse in 29% of the 86 patients with relapse (23% of the 105 evaluable patients at risk) and as any component of failure in 88%. More extensive operative procedures including routine splenectomy, omentectomy, and radical lymph node dissection neither improved survival nor decreased the incidence of local or regional regrowth in the reoperative analysis. Subsequent relapse within the scope of the initial node dissection occurred in a high percentage of the patients even when radical node dissections were performed (removal of N1, N2, and sometimes N3 nodes; Table 6). This indicates the difficulty of obtaining a complete lymph node excision encompassing this anatomic location.

Table 5. Gastric cancer: patterns of local-regional failure in clinical, reoperation, and autopsy series

INCIDENCE—ANY COMPONENT

MGH (Clinical) (N = 130)

U. Minn. (Reoperation) (N = 105)

McNeer et al (Autopsy) (N = 92)

Thomson and Robins (Autopsy) (W=28)

Failure Area

No. (%)

No. (%)

No. (%)

No. (%)

Gastric bed

27(21)

58(55)

48 (52)

19(68)

Anastomosis or stumps

33 (25)

28 (27)

55 (60)

15(54)

Abdominal or stab wound

5(5)

Lymph node(s)

11 (8)

45 (43)

48 (52)

Table 6. Operative method versus patterns of failure—reoperation series[*][†]

LOCAL-REGIONAL

PERITONEAL SEEDING

DISTANT METASTASES

Alone

Component

Alone

Component

Alone

Component

Operative Procedures[†]

No. of Failures/Total at Risk (%)

No. (%)

No. (%)

No. (%)

No. (%)

No. (%)

No. (%)

Method 1 (pre-1950)

25/36

9(25)

23 (64)

1 (3)

12(33)

7(19)

Method 2 (1950-1954)

29/32

6(19)

24 (75)

1 (9)

17(53)

3(9)

9(28)

Method 3 (1954 on)

26/37

8(22)

23 (62)

1 (3)

15(41)

2(5)

7(19)

Totals

80/105[*]

23 (22)

70 (67)

3(3)

44 (42)

5(5)

23 (22)

*

186 Patients with failure, 80 evaluable by all parameters.

Data represent number of patients with failure; data in parentheses represent percentage total group at risk who had complete follow-up.

Method 1 (pre-1950), subtotal or total gastrectomy, greater omentectomy, regional node dissection; method 2 (1950–1954), method 1 plus splenectomy, total omentectomy, additional node dissection regarding splenic, suprapancreatic, and central celiac axis; method 3 (1954 on), methods 1 and 2 plus extension of node dissection to porta hepatis and pancreaticoduodenal (intent: total lymph node dissection of all primary node areas equivalent to D2 or D3 dissection).

Patterns of failure by stagewere analyzed in detail in a series of 130 patients who underwent resection performed with curative intent at the Massachusetts General Hospital (MGH). Local-regional failure occurred as any component of failure in 49 patients (38%) and as the sole failure in 21 (16% of 130 patients at risk and 24% of the 88 patients with disease progression). The incidence of local-regional failure by stage was in excess of 35% for T3N0, T4N0, T3N1–3, and T4N1–3 lesions. The sites at highest risk for local-regional failure included the gastric bed (27 of 130 patients, 21%) and the anastomosis or gastric remnant (33 of 130 patients, 25%). The true incidence of gastric bed, regional lymph node, and peritoneal failures may be higher, because this was neither a reoperative nor an autopsy series (comparative findings in Tables 5 and 6). In a more recent clinical analysis of patterns of relapse, D'Angelica and colleagues found that 50% of patients with relapse had a local-regional component. Some additional information on patterns of relapse by stage exist in both the University of Minnesota reoperation analysis and the University of Washington autopsy analysis. Although patterns of failure data are more accurate in such analyses, patient selection is biased.

All these data suggest that the development of an effective therapy for local-regional disease as an adjuvant to surgery could potentially benefit at least 20% of patients. However, effective systemic therapy is also essential to improve the outcome for resected high-risk gastric cancer patients.

ADJUVANT TREATMENT AFTER COMPLETE RESECTION—RESULTS

Adjuvant systemic chemotherapy

The results of surgery alone for resectable gastric cancer have already been presented and justify the evaluation of adjuvant chemotherapy with regard to an attempt to reduce systemic risks of relapse and thereby improve survival. Although many active single agents exist and several drug combinations have been associated with response rates of 40% or more, randomized North American and European (Western) trials have generally failed to show positive survival findings for adjuvant chemotherapy. Differences in outcome have been noted between Western and Asian studies.

Initial trials to assess the benefit of adjuvant chemotherapy in the United States were conducted by the Veterans Administration in 1957 testing single agents. Survival was not improved with the adjuvant use of either single-agent 5-fluorodeoxyuridine (FUDR) or triethylenethiophosphoramide (thiotepa) when compared with surgery alone.

In subsequent North American and European trials, the potential benefit of multidrug regimens that had shown benefit in the metastatic setting were evaluated in the adjuvant setting. These regimens included: (1) a combination of 5-fluorouracil (5-FU) and methyl-CCNU (MeCCNU); (2) FAM, a combination of 5-FU, doxorubicin (adriamycin), and mitomycin C; and (3) FAMTX, a combination of 5-FU, doxorubicin, and methotrexate. Although a trial from the Gastrointestinal Tumor Study Group (GITSG) demonstrated a survival advantage for the 71 patients assigned to combination chemotherapy with 5-FU and MeCCNU when compared with an equal number of control patients assigned to surgery alone (P < 0.03), subsequent studies performed by the Eastern Cooperative Oncology Group (ECOG), and the Veterans Administration could not confirm a survival advantage for patients treated with the same adjuvant chemotherapy. Phase III trials testing the use of either FAM or FAMTX in an adjuvant setting also failed to demonstrate a survival advantage when compared with a surgery-alone control arm.

Mixed results have been seen in trials performed in Asia. Nakajima and colleagues have performed a series of adjuvant studies in individuals with resected gastric cancer. In their first study, mitomycin C was given on a twice-a-week schedule for 5 weeks, but no survival benefit was seen for the whole cohort of patients. In a subsequent three-arm adjuvant trial, patients were randomized to surgery alone, mitomycin C alone, or the combination of twice-weekly MFC (mitomycin C, 5-FU, and cytosine arabinoside). Forty-two patients were entered in each arm of the study. At 5 years a survival benefit for MFC-treated patients was seen when compared with surgical control subjects. No significant benefit was seen for the mitomycin C arm. These same investigators studied the regimen of MFC followed by either long-term oral 5-FU or ftorafur compared to surgery alone. A significant survival benefit was seen for individuals with stages I to III disease treated with MFC and oral 5-FU. In a fourth study the role of adjuvant mitomycin C and 5-FU followed by oral uracil and tegafur was evaluated in patients undergoing complete resection for early-stage gastric cancer. When compared to a control group, adjuvant therapy for this group of patients showed no benefit over surgery alone.

Many of the trials reported from North America, Europe, and Asia were underpowered to adequately assess any potential differences between the control and treatment arms in regard to overall survival. Accordingly, a clinically meaningful result may have been missed. In an attempt to better determine the benefit of adjuvant therapy after potentially curative surgery for stomach cancer, several meta-analyses have been performed.

The two most recent meta-analyses both showed a significant survival advantage to the use of chemotherapy following surgical resection of gastric cancer. In one of the meta-analyses, 21 randomized clinical trials before 2000 were summarized. This analysis included 3658 patients enrolled in trials from Europe and North America. Whereas a variety of individual trials had failed to show benefit to adjuvant therapy, the meta-analysis indicated that adjuvant chemotherapy reduces the risk of death by 18% (hazard ratio [HR] 0.82, 95% CI 0.75–0.89, P < 0.001). An expanded meta-analysis that included Asian trials showed similar results.

Six subsequent phase III trials of adjuvant postoperative chemotherapy have been performed with a surgery-alone control arm, but only two demonstrated a survival benefit from the adjuvant chemotherapy (Table 7). Neri and associates treated surgically resected node-positive patients with the addition of adjuvant epirubicin, 5-FU, and leucovorin (68 patients) and compared them to 69 surgery-alone control patients. A significant improvement in 5-year survival was noted in patients receiving the adjuvant chemotherapy (30% vs. 13%, P < 0.01). In the large Japanese trial by Sasako and coworkers, 1059 patients with stomach cancer were randomized to either surgery alone or to surgery followed by 1 year of treatment with the oral fluoropyrimidine S-1. Although this trial has been published only in abstract form, a hazard ratio in favor of decreased deaths at 3-years was noted (HR 0.68, 95% CI 0.52–0.87).

Table 7. Gastric cancer—randomized phase III trials, adjuvant postoperative chemotherapy versus surgery only

OVERALL SURVIVAL

Reference

Regimen

No. of Patients

Interval

Percentage

PValue

Neri et al

5-FU,epirubicin, LV

69

5 yr

30

<0.01

Surgery alone

68

13

Bajetta et al

EAP, 5-FU + LV

137

5 yr

52

0.87

Surgery alone

137

48

Nashimotoet al

5-FU, MMC, Ara-C

127

5 yr

91.2

0.13

Surgery alone

123

86.1

Chipponi et al

5-FU, cisplatin

101

5 yr

39

NS

Surgery alone

104

39

Bouche et al

5-FU, cisplatin

127

5 yr

46.6

0.22

Surgery alone

133

41.9

Sasako et al

S-1

529

3 yr

80.5

0.0015

Surgery alone

530

70.1

Ara-C, cytosine arabinoside; EAP, epirubicin, doxorubicin, and cisplatin; 5-FU, 5-fluorouracil; LV, leucovorin; MMC, mitomycin C.

Summary—adjuvant systemic chemotherapy

The role of chemotherapy in the adjuvant postoperative treatment of resected high-risk stomach cancer remains uncertain. Except for the recent Japanese trial with S-1, individual trials have generally not shown clinically meaningful benefit. Future trial design must include adequate statistical power to detect meaningful differences in outcome. Surgery-alone control arms will probably not be feasible in future trials in view of survival benefit achieved with either perioperative chemotherapy or adjuvant combined-modality chemotherapy–radiation therapy when compared with a surgery-alone control arm (subsequent sections).

Intraperitoneal therapy

The use of postoperative intraperitoneal chemotherapy has been evaluated based on the pharmacokinetic advantage of intraperitoneal chemotherapy and the finding that many patients relapse in the peritoneum after surgical resection. A variety of phase II and III trials have been performed.

Building on early promising results from phase II trials, several phase III studies have evaluated the role of intraoperative or postoperative intraperitoneal therapy in patients undergoing potentially curative surgery. In an early study by Dixon and colleagues patients were randomized to surgery alone or to surgery followed by intraperitoneal thiotepa. No significant difference in survival was seen between the two groups. In a more recent study Sautner and associates examined the use of postoperative intraperitoneal cisplatin compared with surgery alone in a group of 67 patients. Although the primary lesion was resected in each case, 21% of the individuals had localized peritoneal carcinomatosis. No survival benefit was seen for the treated patients.

In a phase III trial from Japan, 113 patients were randomized to surgery alone or intraoperative mitomycin C at the time of surgery. For patients who underwent curative surgery, intraperitoneal therapy led to a significant improvement in 2- and 3-year overall survival. No difference in survival was seen for patients with macroscopic peritoneal carcinomatosis.

In a single-institution phase III trial from Korea, 248 patients with clinical stage II or III gastric cancer were randomized to surgery alone or to receive intraperitoneal mitomycin C on day 1 and intraperitoneal 5-FU on days 2 to 5. Overall, 110 of the 248 patients had either stage I or stage IV disease. When 5-year survival was calculated for the entire group, benefit to adjuvant therapy was seen (P = 0.0278). In a subset analysis, however, the benefit was limited to patients with stage III or IV disease.

The use of intraperitoneal therapy in the adjuvant setting remains investigational and requires further evaluation. Until further studies show clear benefit to this approach, the use of intraperitoneal therapy should be restricted to controlled clinical trials.

Adjuvant irradiation

Postoperative irradiation

Irradiation has only been minimally evaluated as the sole adjuvant treatment following complete surgical resection in randomized phase III trials (Table 8). Adjuvant EBRT reduced local-regional failures when compared with the surgery-alone control arm in a British adjuvant trial, but no survival benefits were found. Although phase III trials from Japan and China suggest some survival benefit for IORT versus a surgery-alone control arm, the advantage was found only in subset analyses. At the National Cancer Institute, Sindelar and coworkers performed a small randomized trial of IORT versus EBRT following complete surgical resection; this trial demonstrated improved local control with IORT but no survival benefit. A surgery-alone control arm did not exist in the National Cancer Institute trial. Phase II studies combining EBRT and IORT have been conducted in Pamplona (Spain) and the United States (by the Radiation Therapy Oncology Group [RTOG]) and are still under way in Lyon (France).

Table 8. Surgery ± adjuvant therapy for resected gastric or gastroesophaged junction cancer

SURVIVAL

LOCAL-REGIONAL RE

LAPSE

Treatment

No. of Patients

Median (mo.)

Long-term (%)[*]

PValue

No.

Percentage

PValue

Reference

PHASE III TRIALS

1.British Stomach Group (3 yr)

15

115

a. Surgery alone

145

20

39

27

b. Postop chemo

138

19

26

19

c. Postop EBRT

153

12

15

10

2. Japan—Surgery ± IOERT[*]

S/IOERT

110/101

S/IOERT

116

a. Stage 1

43/24

93% vs. 87%

b. Stage II

11/20

62% vs. 84%

c. Stage III

38/30

37% vs. 62%

d. Stage IV

18/27

0 vs. 15%

3. China—Surgery ± IOERT[†]

100/100

117

a. Stage III (5 yr)

30% vs. 65%

<0.01

b. Stage III (8 yr)

22% vs. 52%

4. Mayo Clinic[†]

128

a. Surgery alone

23

15

4

54

b. Postop EBRT+ 5-FU

39

24

23

0.05

39

5. China-Beijing

122

a. Surgery alone

199

20

52

b. Preop EBRT

171

30

0.009

39

<0.025

6. U.S.GI Intergroup (INT 0116)

(3-yr)

(3-yr)

129,130

a. Surgery alone

275

27

41

31

b. Postop EBRT + 5-FU leucovorin

281

36

50

0.005

48

0.001

7. British MAGIC Trial[§]

(3-yr)

(5-yr)

172

a. Surgery alone

253

NA

31

23

23

b. Perioperative ECF Chemo

250

NA

44

36

0.009

38

<0.001

PHASE II TRIALS

1. MGH

a. Surgery alone

110

38 (B2, B3)

46

42

80

15 (C1-3)

b. Postop EBRT + Chemo

14

24

43 (4 yr)

2

14

123

2. TJUH

a. Total group T3, T4, or N+

120

125

• Surgery alone

70

12

13

17/38

45

• Postop Chemo, EBRT, both

50

19

17

<0.05

13/36

36

• Postop EBRT + Chemo

20 of 50

19

21

3/16

19

b. T3/T4, N1/N2 (surg ± adjuv)

44,30

9 vs. 13

4 vs. 22

0.04

3. South Korea

a. Surgery alone (D2 resection)

446

62.6

51

21.7

133

b. Postop EBRT + Chemo

544

95.3

57

0.02

14.9

0.005

 

Chemo, chemotherapy; EBRT, external beam irradiation; 5-FU, 5-fluorouracil; ECF, epirubicin, cisplatin, 5-FU; IOERT, intraoperative electron irradiation; MGH, Massachusetts General Hospital; postop, postoperative, preop, preoperative; S, surgery; TJUH, Thomas Jefferson University Hospital.

*

Long-term survival = 5-year data unless otherwise specified.

Advantage to IOERT in subset analyses—Japan stages II–IV, China stage III (37% of patients).

Survival data based on intent to treat, relapse data on actual treatment.

§

Three-year survival estimated from published survival curves.

The British Stomach Cancer Group completed a prospectively randomized trial of surgery only versus postoperative FAM or EBRT (45 Gy in 25 fractions ± 5-Gy boost). A total of 436 patients were randomized and followed for a minimum of 12 months; arms were well balanced with regard to prognostic factors. No patient survival differences by treatment arm were seen (median, 15 months). However, local-regional failure was documented in only 15 of 153 (10%) in the EBRT arm versus 39 of 145 (27%) in the surgery-alone arm, and 26 of 138 (19%) in the FAM group. Interpretation of the results is complicated by the inclusion of 93 patients (21%) with resection but gross residual disease (British Stomach Cancer Group stage IVAi) and 78 (18%) with gross total resection but microscopically positive resection margins. Neither group of patients would be candidates for current gastric surgical adjuvant trials in the United States. In addition, nearly one third of patients randomized to receive adjuvant treatment did not receive the assigned therapy. Of 153 patients randomized to the EBRT arm, only 104 (68%) received a dose of 40.5 Gy or more, and 36 (24%) received none. Only 62% of patients received six or more cycles of chemotherapy. The results in this study are similar to results seen in the adjuvant treatment of rectal cancer, in which adjuvant pre- and postoperative irradiation as a single adjuvant modality improve local control but do not increase patient survival in most trials, unless combined with chemotherapy.

Takahashi and Abe reported results from a large Japanese trial in which 211 patients were randomized on the basis of day of hospital admission to receive either surgery only or surgery plus IORT (28–35 Gy). Five-year survival rates for Japanese stages II to IV were improved approximately 15% to 25% in the IORT group versus those treated with surgery alone (stage II, 84% vs. 62%; stage III, 62% vs. 37%; stage IV, 15% vs. 0%). This magnitude of survival improvement correlates nicely with the approximately 20% of patients who fail only local-regionally after complete surgical resection. Although the data are intriguing, this method of randomization is susceptible to bias in treatment selection, and the trial failed to stratify for important prognostic factors.

In an analysis from Beijing, individuals with stage III (serosal involvement or node-positive tumors) or stage IV (unresectable metastasis or adjacent organ involvement) disease were randomized to surgery alone or IORT (single dose, 25–40 Gy). In their most recent report of 200 patients, a survival advantage with IORT was demonstrated for only stage III patients (65% vs. 30% 5-year survival; 52% vs. 22% 8-year survival; P < 0.01).

Preoperative irradiation

Randomized trials testing preoperative irradiation have been performed in both Russia and China. All have reported a positive survival benefit when compared with surgery-alone control arms.

Three prospective randomized Russian trials have evaluated preoperative irradiation in potentially resectable gastric cancer. The first trial randomly assigned 293 patients to receive either surgery alone, surgery after preoperative EBRT (20 Gy in four fractions), or surgery after the same EBRT plus daily hyperthermia. The survival rates at 3 and 5 years were improved in both irradiation arms compared with surgery alone, and the improvement with combined EBRT and hyperthermia was statistically significant at both 3 and 5 years. The second trial compared preoperative EBRT (20 Gy) with surgery alone in 279 patients. Both 3- and 5-year survival rates were increased, and no increase in operative morbidity was observed. The third trial compared surgery alone to preoperative EBRT (32 Gy with concomitant inhalation of 8% oxygen) plus surgery. A survival advantage was observed with preoperative treatment, and the resection rate was increased by 17%. There are some methodologic uncertainties with all three of these trials, and their applicability to Western gastric carcinoma is not clear.

A double-blind randomized trial from Beijing, conducted from 1978 to 1989, compared a surgery-alone control arm (N = 199) with preoperative EBRT plus surgery (N = 171) for individuals with adenocarcinoma of the gastric cardia. Irradiation was given with 8-MV photons or cobalt with anteroposterior-posteroanterior (AP-PA) fields to a dose of 40 Gy in 20 fractions of 2 Gy over 4 weeks. Surgery was performed 2 to 4 weeks after completion of irradiation. Both downstaging of disease and improvements in radical resection rates were found with the addition of preoperative EBRT (radical resection rates of 80% vs. 62% with preoperative EBRT vs. surgery alone).

Survival and local-regional disease control were improved in the patients assigned to preoperative EBRT versus surgery alone (Table 8). The 5- and 10-year survival rates were 30% versus 20% and 20% versus 13%, respectively (P = 0.009 Kaplan-Meier log rank). The divergence in survival curves began in the first year of follow-up and persisted through 9 years. Local and regional disease control were also improved with combined-modality treatment with local relapse rates of 39% versus 52% (P < 0.025) and regional node relapse rates of 39% versus 54% (P < 0.05). The rates of distant metastases were the same at 24% versus 25%. The improvements in survival and disease control (local-regional) were accomplished with no increase in treatment-related morbidity or mortality rates (operative mortality 0.6% vs. 2.5% with or without preoperative EBRT; intrathoracic leak rates were 1.8% and 4.2%, respectively).

In view of the survival advantage with or without disease control and radical resection rates demonstrated for preoperative EBRT in four published trials from Russia and China, such approaches need to be evaluated further in U.S. and European study groups. As suggested by the authors from the Beijing trial, factors to be evaluated include radiation dose escalation to 45 to 50 Gy (1.8- to 2.0-Gy fractions) and the addition of chemotherapy (maintenance, concurrent with EBRT).

Adjuvant irradiation plus chemotherapy

Postoperative external-beam irradiation therapy plus chemotherapy

Phase II single-institution gastric cancer trials that showed promise for combination postoperative adjuvant therapy were reported from MGH, Israel (Hadassah), Thomas Jefferson University Hospital, the University of Pennsylvania, and the Mayo Clinic. Gunderson and associates, from the MGH, reported a median survival time of 24 months and 4-year survival rate of 43% in 14 patients who had complete resection of tumors with extension beyond the wall, nodal involvement, or both. Patients received postoperative irradiation (45–52 Gy, 1.8 Gy/day) plus concomitant 5-FU-based chemotherapy. Subsequent local-regional relapse was documented in only 2 of the 14 (14%), in contrast to a 42% incidence in similar high-risk patients treated with surgery alone at MGH.

A prospective randomized trial conducted at the Mayo Clinic included 62 patients with poor-prognosis completely resected gastric cancers who were randomized to either surgery alone or surgery followed by irradiation (37.5 Gy in 24 fractions over 4–5 weeks) plus concomitant 5-FU (15 mg/kg, days 1–3 by IV bolus). A nonstratified, prerandomization scheme was used with a 2 : 3 ratio favoring treatment. Informed consent was requested only of the 39 patients randomized to treatment. Of the 39 patients, 10 refused further therapy and were observed. When analyzed by intent to treat, the adjuvant arm had statistically significant improvement in both relapse-free and overall survival (5-year OS 23% vs. 4%; P < 0.05; Tables 8 and 9). When patient outcome was compared by actual treatment received (29 adjuvant treatment, 33 surgery alone), 5-year survival rate still favored the adjuvant group (20% vs. 12%), but the differences were not statistically significant in view of small patient numbers. As seen in Table 9 , the 10 patients who refused assignment to adjuvant treatment had more favorable prognostic findings than the other two groups of patients. When the two groups with equally poor prognostic factors were compared, the 5-year OS rate was 20% versus 4%, with an advantage to those receiving adjuvant treatment. When analyzed by treatment delivered, local-regional relapse was decreased with adjuvant treatment (54% incidence with surgery alone vs. 39% with irradiation plus 5-FU).

Table 9. Randomized Gastric Adjuvant Trial at the Mayo Clinic (surgery ± irradiation + 5-fu)

Adjuvant EBRT + 5-FU (%; N= 29)

Surgery Control (%; N = 23)

Refused Adjuvant (%; N= 10)

PATHOLOGIC CHARACTERISTICS

Cardia

55

56

30

Ulcerative

72

70

50

Grade 2

7

9

3

Grades 3,4

93

91

70

Adjuvant EBRT + 5-FU (%)

Surgery Control (%)

P Value

FIVE-YEAR SURVIVAL

Treatment intent (total patients)

(N = 39)

(N = 23)

Overall survival

23%

4%

<0.05

Treatment delivered (total patients)

(N = 29)

(N = 33)

Overall survival

20%

12%

Disease-free survival

17%

9%

LOCAL FAILURE

Treatment delivered

39%

54%

      EBRT, external-beam irradiation; 5-FU, 5-fluorouracil.

Because of conflicting resultsin earlier small phase III studies, a confirmatory U.S. GI trial (INT 0116) was initiated to evaluate postoperative combined 5-FU-based chemotherapy and irradiation to the gastric bed and regional nodes versus surgery only in completely resected but high-risk gastric cancer patients. Eligibility included patients with stages IB, II, IIIA, IIIB, and IV nonmetastatic adenocarcinoma of the stomach or gastroesophageal junction (extension beyond muscularis propria [T2–4N0] or involved nodes [T1–2N1–3]). After an en bloc resection, 556 patients were randomized to either surgery alone or postoperative combined-modality therapy consisting of one 5-day cycle of 5-FU plus leucovorin followed by concurrent chemoradiation (45 Gy in 25 fractions plus concurrent 5-FU and leucovorin, 4-day cycle on week 1, 3-day cycle on week 5) and subsequently by two additional 5-day cycles of 5-FU and leucovorin given at 1-month intervals. Nodal metastases were present in 85% of patients. With median follow-up period of 5 years, RFS at 3 years is 48% for adjuvant treatment and 31% for observation (P = 0.001); 3-year OS rate is 50% for treatment and 41% for observation (P = 0.005; see Table 8). The median OS in the surgery-only group was 27 months, as compared with 36 months in the chemoradiation therapy (CRT) group. The median duration of RFS was 30 months in the CRT group and 19 months in the surgery-only group. Patterns of relapse were based on the site of first relapse only and were categorized as local, regional, or distant. Local recurrence occurred in 29% of the patients who relapsed in the surgery-only group and 19% of those who relapsed in the CRT group. Regional relapse—typically abdominal carcinomatosis—was reported in 72% of those who relapsed in the surgery-only group and 65% of those who relapsed in the CRT group. Extra-abdominal distant metastasis was diagnosed in 18% of those who relapsed in the surgery-only patients and 33% of those who relapsed in the CRT group. Treatment was tolerable, with 3 (1%) toxic deaths. Grade 3 and 4 toxicity occurred in 41% and 32% of cases, respectively.

The results of the large randomized phase III U.S. GI trial (INT 0116) demonstrate a clear survival advantage to the use of postoperative CRT in resected high-risk patients. Furthermore, the results strongly support the integration of postoperative CRT into the routine care of individuals with curatively resected high-risk carcinoma of the stomach and gastroesophageal junction. This approach is now viewed by many as the standard of care in the United States.

Quality control of irradiation field design in INT 0116 was conducted during the cycle of chemotherapy given before the start of concurrent CRT. The initial quality control provided the mechanism to correct most of the major or minor deviations (35% incidence) in irradiation field design before the start of treatment, and resulted in only a 6.5% final major deviation rate. Use of initial quality control may have been a key factor in achieving a positive survival advantage for adjuvant CRT.

Postoperative chemoradiation plus D2 resection

Because extended node dissections were not commonly performed as a component of surgery in the U.S. GI trial INT 0116, some have questioned whether postoperative CRT would give added benefit following a D2 nodal resection. Although this is unlikely to be tested in a phase III trial, a recent South Korea analysis evaluated the potential role of postoperative CRT in a series of 990 patients with D2 resection who were at high risk for relapse. Disease and patient characteristics and the method of chemoradiation treatment paralelled the U.S. GI INT 0116 trial. Both disease control and survival were improved in the 544 patients who received postoperative CRT when compared with the 446 patients treated with surgery alone (5-year OS, 57% vs. 51%, P = 0.02; 5-year RFS, 54.5% vs. 47.9%, P = 0.016; local-regional relapse, 14.9% vs. 21%, P = 0.005; Tables 8 and 10).

Table 10. Surgery (D2 resection) + postoperative chemoradiation for gastric cancer, South Korea series

5-YEAR OVERALL SURVIVAL

5-YEAR RELAPSE-FREE SURVIVAL

Stage

Surgery Alone

Postop CRT

P Value

Surgery Alone

Postop CRT

P Value

II

70.9

78.8

0.04

66.6

76.2

0.03

IIIA

43.9

61.6

0.001

42.3

57.6

0.0015

NIB

20.5

40.8

0.0045

17.5

39.6

0.006

IV (MO)

12.1

26.4

0.015

11.3

26.3

0.025

Total

51.0

57.1

0.02

47.9

54.5

0.02

   Postop CRT, postoperative chemoradiation therapy.

Preoperative external beam irradiation therapy plus chemotherapy

Randomized trials testing preoperative EBRT plus chemotherapy for gastric cancer alone have not yet been published, but the Walsh and colleagues trial for adenocarcinoma of the esophagus and gastric cardia certainly has relevance. Patients were randomized to either immediate surgery (control arm) versus preoperative EBRT (40 Gy in 15 fractions), 5-FU (15 mg/kg/day continuous infusion [this is approximately equivalent to 600 mg/m2] for 5 days, weeks 1 and 6), and cisplatin (75 mg/m2 on the first day of each 5-FU infusion), followed by surgical resection 8 weeks after completion of EBRT plus chemotherapy. A highly significant difference in survival was observed with combined-modality therapy (intent to treat median survival time, 16 vs. 11 months, 3-year survival rate, 32% vs. 6%; P = 0.01; actual treatment median survival time, 32 vs. 11 months; P = 0.001; 3-year survival rate, 37% vs. 7%; P = 0.006). Survival rates for the control group of patients were inferior to other historical data.

A confirmatory intergroup trial was attempted in North America for patients with either esophagus or esophagogastric junction cancers (squamous or adenocarcinoma) but was stopped because of poor accrual. Despite the low accrual, patients randomized to trimodality treatment had a survival benefit when compared with patients randomized to surgery alone (median survival 54 vs. 21.6 months; 5-year OS, 39% vs. 16%, P = 0.008.

Summary—adjuvant irradiation alone or plus chemotherapy

In summary, both preoperative irradiation and postoperative CRT have been demonstrated to be superior to surgery alone for resectable gastric and gastroesophageal cancers in randomized phase III trials. Future preoperative irradiation trials should evaluate the addition of concurrent and maintenance chemotherapy. Postoperative CRT trials are evaluating more aggressive chemotherapy both as concurrent and maintenance components of treatment.

Irradiation techniques

The irradiation field should include unresected or residual tumor or the tumor bed plus major nodal regions. The pattern of tumor bed and nodal failures in the reoperative series from the University of Minnesota is demonstrated in Figure 7A in conjunction with an idealized, shaped AP-PA irradiation portal that incorporates the areas of local-regional relapse. The tumor bed and nodal volumes are reconstructed with the aid of preoperative and postoperative imaging studies and surgical clip placement. In Figure 7B the idealized AP-PA field is superimposed on the organs and structures that define irradiation tolerance.

Figure 7. A and B, Patterns of failure in the University of Minnesota gastric cancer reoperative series with superimposed idealized irradiation fields, and relationship to dose-limiting organs or structures (A). •, local failures in surrounding organs or tissues; ˆ, lymph node failures; *, lung metastases; +, liver metastases.

Dose-limiting organs and structures in the upper abdomen are numerous (stomach, small intestine, liver, kidneys, and spinal cord). With properly shaped fields, doses of 45 to 50.4 Gy in 1.8- to 2.0-Gy fractions can be delivered to stomach and small intestine with a 5% or less risk of severe toxicity. In most patients a portion of both kidneys will be within the AP-PA treatment field, but at least two thirds to three fourths of one kidney should be excluded (can include entirety of both kidneys to the level of 20 Gy if necessary). For patients with gastroesophageal junction or proximal to mid-gastric cancers (Figs. 8 and 9), one half to two thirds of the left kidney can often be spared as a result of accurate field definition, which is aided by pre- and postoperative imaging studies and clip placement. The pancreaticoduodenal nodes can be included, if indicated, while sparing 75% to 90% of the right kidney. However, for distal gastric lesions with narrow or positive duodenal resection margins, the duodenal circumference may need to be included as target volume (Fig. 10). In such instances 50% or more of the right kidney is within the field, and two thirds to three fourths of the left kidney should be spared. Chronic renal problems are infrequent when these techniques are utilized.  

Figure 8. Postoperative irradiation fields based on preoperative radiographs following complete resection of a proximal gastric cancer (T3N2M0); patient was randomized to the irradiation chemotherapy arm on the intergroup gastric adjuvant study. A–D, Reconstruction of tumor bed/target volumes with preoperative upper gastrointestinal radiograph (A) and CT scans (B and D). CT cuts demonstrated thickened gastric wall proximally (B and C) and normal thickness distally (D), as well as relationship of the stomach to surrounding organs including liver and spleen (B), liver, body and tail of pancreas, and splenic flexure (C), and head of pancreas (D). E and F, AP-PA irradiation field (E) with cross-hatched blocks encompasses all the left kidney but less than 20% of the right. Nodal groups at risk and preoperative gastric duodenal locations (-•-•) are demonstrated on the AP-PA and lateral (F) simulation fields. CEL, celiac; PH, porta hepatis; SH, splenic hilum; SMA, superior mesenteric artery.

Figure 9. Patient is a 54-year-old male with a T3N1 adenocarcinoma of the distal esophagus extending into the proximal stomach who was treated with preoperative concurrent CRT at Mayo Clinic in Arizona (45 Gy in 25 fractions over 5 weeks to extended field and 50.4 Gy in 28 fractions within boost field). CT simulation was performed with intravenous and oral contrast, and structures of interest were delineated (A–D). The normal thickness of the more proximal esophageal wall (A) contrasts with the markedly thickened distal esophagus wall seen at the level of the adenocarcinoma (B). An enlarged gastrohepatic node (C) was biopsy positive for adenocarcinoma at the time of pretreatment EUS. Other delineated organs/structures were celiac artery, body and head of pancreas, porta hepatis, and splenic hilum (B–D). Three-dimensional conformal irradiation fields (E and F) were designed to include the primary tumor (red) with at least 5-cm margins of esophagus proximally and stomach distally (to include potential submucosal tumor spread) plus nodal volumes (periesophageal and celiac, as per Table 79-12 ; decision was made to also include porta hepatis, suprapancreatic and splenic hilar nodes in view of the documented gastrohepatic nodal disease [also shown in red]). Lateral fields (F) were used as a component of treatment for purpose of sparing heart and spinal cord. The patient subsequently had a laparoscopic esophagogastrectomy, mediastinal and celiac node dissection, pyloroplasty, and neck anastamosis (esophagogastrostomy) at Mayo Clinic Hospital in Arizona. Pathologic examination revealed a 3.5 × 2.5 × 1.0 cm ulcerated mass at the esophagogastric junction that microscopically consisted of paucicellular and acellular mucin and rare tumor cells floating in mucin with 0/20 positive nodes.

Figure 10. Optimized postoperative irradiation fields for patient with T3N2 antral primary tumor (Table 13). A–C, Structures of interest were delineated at time of CT simulation. D and E, Irradiation fields were designed with the aid of digitally reconstructed radiographs. A dose volume histogram was performed to be certain that appropriate volumes of liver and at least one kidney were excluded beyond certain dose levels. A, Gastric remnant (lavender) is demonstrated along with the body/tail of pancreas (red-orange), splenic hilum (light green), and porta hepatis (dark blue). B, Head of pancreas (yellow) and kidneys (left, yellow green; right, yellow orange) are delineated in addition to the body/tail of the pancreas. C, The celiac artery (light blue), antral tumor bed (red), and duodenum (medium blue) are shown together with the head of pancreas and kidneys. A four-field technique of AP (D), PA, and paired lateral fields (E) was designed. The fields included the gastric remnant (lavender), tumor bed (red), head of pancreas (yellow), first and second part of the duodenum (medium blue, cross-hatched), pertinent nodal volumes (perigastric, pancreaticoduodenal, porta hepatis [dark blue cross-hatched], suprapancreatic), and the optional nodal volume of splenic hilum (light green cross-hatched). D, AP field (field margins as shown in medium blue exclude approximately two thirds of the left kidney while including approximately 90% of the right kidney). Exclusion of the optional splenic hilar nodes would not have allowed any additional sparing of the left kidney in view of the adjacency of the gastric remnant and the splenic hilum. E, Right lateral field demonstrated exclusion of the spinal cord (turquoise) along with substantial portions of both kidneys. F, The dose volume histogram, combining dose from all four fields, demonstrated that the dose volume of 20 Gy included about 30% of the left kidney versus approximately 75% of the right kidney. With regard to the liver, about 30% receives a dose of 30 Gy and about 25% receives a dose of 35 Gy and 40 Gy.


With preoperative or primary CRT for individuals with gastroesophageal junction or proximal gastric lesions, a 3- to 5-cm margin of distal esophagus should be within the irradiation field (Fig. 9). If the lesion extends beyond the gastric wall with proximal lesions, a major portion of the left hemidiaphragm should be included. In either instance, Cerrobend blocks or multi-leaf collimators should be used to decrease the volume of irradiated heart (Figs. 8 through 10) and lung when technically feasible. For patients with gastroesophageal junction cancers, preoperative EBRT fields can usually be much more conservative than postoperative fields with regard to both heart and lung volumes, and are preferred, if preoperative imaging and EUS demonstrate indications for preoperative adjuvant treatment (Fig. 9). Lateral or oblique fields can be used as a component of treatment to decrease the volume of heart within the irradiation field (Fig. 9).

More routine use of multiple field techniques should be considered when preoperative imaging exists to allow accurate reconstruction of target volumes (Figs. 8 through 10]). Single-institution data suggest that multiple field arrangements may produce less toxicity. When patients are treated preoperatively, paired lateral fields are usually combined with AP-PA fields to achieve improve dose homogeneity (Fig. 9). Dependent on the posterior extent of the gastric fundus, either oblique or more routine lateral portals can be used to deliver a 10- to 20-Gy component of irradiation to spare spinal cord or kidney. When lateral fields are used, liver and kidney tolerance limits the use of lateral fields to 20 Gy or less for patients with gastric cancer; for patients with gastroesophageal junction cancers the contribution from lateral fields would preferably be limited to 10 to 15 Gy because of lung tolerance. With the wide availability of three-dimensional treatment-planning systems, it may be possible to target more accurately the high-risk volume and to use unconventional field arrangements and/or intensity-modulated radiation therapy to produce superior dose distributions. To accomplish this without marginal misses it will be necessary to both carefully define and encompass the various target volumes, because use of oblique or noncoplanar beams could exclude target volumes that would be included in AP-PA fields or nonoblique four-field techniques (AP-PA and lateral).

In individual patients the idealized field must be modified depending on the surgical/pathologic extent of disease and site of the primary tumor. The relative risk of nodal metastases at a specific nodal location is dependent on both the site of origin of the primary tumor and other factors including width and depth of invasion of the gastric wall. Tumors that originate in the proximal portion of the stomach and the gastroesophageal junction have a higher propensity of spread to nodes in the mediastinum and pericardial region but a lower likelihood of involvement of nodes in the region of the gastric antrum, periduodenal area, and porta hepatis. Tumors that originate in the body of the stomach can spread to all nodal sites, but have the highest likelihood of spreading to nodes along the greater and lesser curvature, near the location of the primary tumor mass. Tumors that originate in the distal stomach have a high likelihood of spread to the periduodenal, peripancreatic, and porta hepatis nodes, but they have a lower likelihood of spread to the nodes near the cardia of the stomach, the periesophageal and mediastinal nodes, or to the splenic hilar nodes (Fig. 10). Any tumor originating in the stomach has a high propensity of spread to nodes along the greater and lesser curvature, although they are most likely to spread to those sites in close anatomic proximity to the primary tumor mass.

Recently, guidelines for defining the clinical target volume for postoperative radiation fields have been developed based on location and extent of the primary tumor (T category) and location and extent of known nodal involvement (N category). Table 11 presents general guidelines on the impact of T and N categories on inclusion of the remaining stomach (gastric remnant), tumor bed and nodal sites, and Tables 12 and 13 present treatment guidelines based on TN stage for two of the four primary sites (esophagogastric junction, proximal, mid-, and distal stomach). In general, for individuals with node-positive disease there should be wide coverage of tumor bed, remaining stomach, resection margins, and nodal drainage regions. For node-negative disease, if there is a good surgical resection with pathologic evaluation of at least 10 to 15 nodes, and there are wide surgical margins on the primary tumor (at least 5 cm), treatment of the nodal beds is optional. Treatment of the remaining stomach should depend on a balance of the probable normal tissue morbidity and the perceived risk of local relapse in the residual stomach.

Table 11. General guidelines of impact of T and N categories on inclusion of remaining stomach, tumor bed, nodal sites within irradiation fields

TN Stage

Remaining Stomach[*]

Tumor Bed

Nodes

T1-2 (not into subserosa) NO

N

N

N

T2N0-into subserosa[†]

Variable

Y

N

T3N0

Variable

Y

N

T4N0

Variable

Y

Variable

T1-2N+

Y

N

Y

T3-4N+

Y

Y

Y

 

 

 

 

*  Inclusion of the remaining stomach is preferable in most patients if two thirds of one kidney can be excluded. This is dependent on the extent of surgical resection and uninvolved margins (in cm).

  Posterior wall T2N0 lesions, or those that extend beyond muscularis propria, especially tumors located in the proximal or distal stomach, are at risk for local relapse. In addition, patients with low-stage disease with close or positive surgical margins should be considered for treatment to the tumor bed.

Table 12. Impact of site of primary lesion and TN category on irradiation treatment volumes for the gastroesophageal junction: general guidelines

Site or Primary and TN Category

Remaining Stomach

Tumor Bed Volumes[*]

Nodal Volumes

Tolerance Organs or Structures

GE junction

If allows exclusion of 2/3 R kidney

T-category dependent

N-category dependent

Heart, lung, spinal cord, kidneys, liver

T2N0 with invasion of subserosa

Variable dependent on surgical pathologic findings[†]

Medial left hemidiaphragm; adjacent body of pancreas

None or perigastric, periesophageal[†]

T3N0

Variable dependent on surgical pathologic findings[†]

Medial left hemidiaphragm; adjacent body of pancreas

None or perigastric, periesophageal, mediastinal, celiac[*]

T4N0

Preferable but dependent on surgical pathologic findings[†]

As for T3N0 plus site(s) of adherence with 3- to 5-cm margin

Nodes related to site of adherence, ± perigastric, periesophageal, mediastinal, celiac

T1-2N+

Preferable

Not indicated for T1, as above for T2 into subserosa

Periesophageal, mediastinal, proximal perigastric, celiac

T3-4N+

Preferable

As for T3, T4N0

AsforT1-2N+andT4N0

*

Use preoperative imaging (CT, barium swallow), surgical clips, and postoperative imaging (CT, barium swallow).

For tumors with wide (>5 cm) surgical margins confirmed pathologically, treatment of residual stomach is optional, especially if this would result in substantial increase in normal tissue morbidity.

Optional node inclusion for T2–3N0 lesions if adequate surgical node dissection (D2 dissection) and at least 10–15 nodes examined pathologically.

Table 13. Impact of site of primary gastric lesion and TN stage on irradiation treatment volumes—antrum/pylorus/distal third of stomach: general guidelines

Site or Primary TN Category

Remaining Stomach

Tumor Bed Volumes[*]

Nodal Volumes

Tolerance Organs or Structures

Pylorus/distal third stomach

Yes but spare 2/3 of one kidney, usually left

T-category dependent

N-category dependent

Kidneys, liver, spinal cord

T2N0 with invasion of subserosa

Variable dependent on surgical pathologic findings[†]

Head of pancreas (± body), 1st and 2nd duodenum

None or perigastric; optional pancreaticoduodenal, porta hepatis, celiac, suprapancreatic[†]

T3N0

Variable dependent on surgical pathologic findings[†]

Head of pancreas (± body), 1st and 2nd duodenum

None or perigastric; optional pancreaticoduodenal, porta hepatis, celiac, suprapancreatic[†]

T4N0

Preferable but dependent on surgical pathologic findings[†]

AsforT3N0plussite(s)of adherence with 3- to 5-cm margin

Nodes related to site(s) of adherence ± perigastric, pancreaticoduodenal, porta hepatis, celiac, suprapancreatic

T1-2N+

Preferable

Not indicated for T1

Perigastric, pancreaticoduodenal, porta hepatis, celiac, suprapancreatic; optional, splenic hilum

T3^N+

Preferable

As for T3, T4N0

AsforT1-2N+andT4N0

 

*

Use preoperative imaging (CT, barium swallow), surgical clips, and postoperative imaging (CT, barium swallow).

For tumors with wide (>5 cm) surgical margins confirmed pathologically, treatment of residual stomach is optional if this would result in substantial increased normal tissue morbidity.

Optional node inclusion for T2–3N0 lesions if adequate surgical node dissection (D2 dissection) and at least 10–15 nodes examined pathologically.

LOCALLY ADVANCED DISEASE (BORDERLINE RESECTABLE, UNRESECTABLE, AND RESIDUAL)—TREATMENT AND RESULTS

The term locally advanced disease has different interpretations depending on the author and institution. In our institution and for the purposes of this chapter, this term refers to primary cancers that the surgeon would not expect to resect with negative pathologic margins (i.e., locally unresectable for cure as determined at surgical exploration or as defined preoperatively with CT scan, EUS, laparoscopy, or other studies; locally recurrent cancers with no evidence of metastasis). Other authors use the term also to include lesions that are completely resected but have high-risk factors for local recurrence or distant metastasis (nodal involvement, extension beyond gastric wall, or both).

Surgical aspects

The extent of the surgical procedure must be tempered by the knowledge that cure is at best improbable. Patients with symptomatic obstruction, hemorrhage, and ulceration, and the rare patient with perforation can be successfully relieved of symptoms by even a limited gastric resection. Radical subtotal or total gastrectomy may be indicated in some patients whose cancers cannot be completely resected with negative pathologic margins for symptomatic palliation. Our own results with total gastrectomy in advanced gastric cancer showed good quality of life when this procedure was indicated for bulky or proximal malignancies, but symptom relief was less likely for patients with linitis plastica. Although resection of adjacent organs should be undertaken if all the gross tumor can be removed, it is rarely justified if residual tumor would remain. If sites of residual disease or adherence are judiciously marked with clips, postoperative irradiation plus chemotherapy can be delivered with greater accuracy.

Primary irradiation or chemoradiation

Although some patients with no resection have long-term survival using irradiation alone or plus chemotherapy, this approach is not a viable alternative to surgical resection plus adjuvant therapy as indicated, because the initial bulk of disease and the limited tolerance of the stomach and surrounding organs prevent a suitable therapeutic ratio between cure and complications. When locally advanced disease is diagnosed before surgical exploration, preoperative radiation would preferably be used in combination with chemotherapy (concomitant and maintenance), followed by restaging and an attempted resection of all gross primary and lymph node disease.

Irradiation alone

The available literature suggests that adenocarcinoma of the stomach is radiation responsive. Wieland and Hymmen used 60 Gy when feasible (1.5 to 2.0 Gy daily) with 11% (9 of 82) 3-year and 7% (5 of 72) 5-year survival rates. Takahashi compared historical control subjects with patients who were unresectable or who had palliative procedures and received postoperative radiation therapy (unknown if chemotherapy also used). The average survival time for the irradiated group was 9 to 10 months longer, with 74% 1-year (32 of 43) and 27% 2.5-year survival rates (12 of 43). Takahashi and Abe reported 15% 5-year survival rate with a single dose of IORT (28–35 Gy) in a group of 27 patients with stage IV disease. Three of the four long-term survivors had residual disease after resection. In the same study, 18 stage IV patients were randomized to a surgery-alone control arm; the 5-year survival rate was 0%.

Irradiation plus chemotherapy

Most early reports of combined irradiation and chemotherapy for gastric cancer involved patients with residual or unresectable primary disease, and most phase III trials in this setting show an advantage for combined-modality treatment over single-modality treatment. In a randomized series from the Mayo Clinic, 5-FU was used during the first 3 days of irradiation in one half of the patients (irradiation, 35–37.5 Gy in 4 to 5 weeks; 5-FU, 15 mg/kg for 3 days, week 1 of irradiation). For the combined-treatment group, mean and overall survival was improved (13 months vs. 5.9 months and 3 of 25 patients or 12% vs. 0 of 23 patients surviving over 5 years; Table 14). In a randomized study by the GITSG, the combination of irradiation and 5-FU followed by maintenance 5-FU plus MeCCNU resulted in statistically superior long-term survival when compared with 5-FU plus MeCCNU alone (3- and 4-year survival rates of 18% vs. 6% to 7%; P < 0.05). GITSG performed a second trial in which combined irradiation plus chemotherapy did not produce a survival advantage when compared with chemotherapy alone. Because 46% of patients on the combined arm either did not receive full-course irradiation or had a major deviation in the delivery of the irradiation, the results are difficult to interpret. In a randomized European Organization for Research and Treatment of Cancer (EORTC) trial of external irradiation with or without 5-FU, residual disease after resection was identified in 22 patients. The three long-term survivors (14%) received both irradiation and 5-FU.

Table 14. Unresectable or residual gastric cancer: treatment results

Group or Institution

Treatment Arms

EBRT Dose/Schedule (Gy)

Chemotherapy

No. of Patients

Results (Failure Patterns and Survival)

RANDOMIZED

Mayo Clinic

EBRT±5-FU

35-40 Gy;9-12 Gy/wk

5-FU 15 mg/kg,d 1-3, wk 1 EBRT

48

Increased SR for EBRT + 5-FU with mean SR 13 vs. 5.9 mo and 3/25 (12%) vs. 0/23 5-yr SR

GITSG study g274

Chemo ± EBRT

50 Gy/8 wk/2 wk split after 25 Gy/3 wk

5-FU 500 mg/m2, d 1-3, wkl +6 EBRT plus 5-FU/MeCCNU maint vs. 5-FU + MeCCNU

90

Advantage in long-term SR with EBRT + CTat 18% vs. 7%(P<0.05)

Japan

Operation ± IORT[*]

IORT, 28^K) Gy

None

110 surgery, 101 IORT

Increased 5-yr SR for 27 patients with IORT + resection for stage IV disease vs. 18 patients with surgery alone (15% vs. 0%)

NONRANDOMIZED

MGH

EBRT ± Chemo

45-55 Gy in 5-6.5 wk

5-FU 500 mg/m2, 3 d wk 1 EBRT ± maint FAM or 5-FU MeCCNU

32

Median SR res(m) 24 mo, res(g) 15 mo, unresected 14 mo; survival ≥30 mo, unresected 0%, residual after resection -10%

Mayo Clinic

EBRT ± Chemo ± IOERT

45-54 Gy in 6-6.5 wk; IOERT boost 13 patients

5-FU 500 mg/m2 3d wkl, wk 5 or 5-FU 400 mg/m2 leucovorin 20 mg/m2

87

Median SR res(m) 17 mo, res(g) 9 mo, unresectable 12 mo, locally; recurrent 10 mo; 4-year SR <9%; res(m) and res(g); 18% unresectable or locally recurrent

 

Chemo, chemotherapy; EBRT, external-beam radiation therapy; GITSG, Gastrointestinal Tumor Study Group; IORT, intraoperative radiation; maint, maintenance; MGH, Massachusetts General Hospital; res(m), microscopic residual; res(g), gross residual; SR, survival. For other abbreviations, see footnotes to Table 7 and 8.

*

Treatment method based on date of hospitalization.

Data from nonrandomized single-institution or group analyses also suggest that the combination of external irradiation and chemotherapy may have an impact on disease control and survival. In published series from the Mayo Clinic  and MGH, long-term survival of 10% or more was demonstrated in patients who received external irradiation plus chemotherapy following subtotal surgical resection with residual disease (MGH) or with unresectable lesions. In a University of Pennsylvania analysis of individuals with unresected adenocarcinoma of the esophagogastric junction or esophagus, local control was better with combined-versus single-modality treatment (irradiation, 1 of 23 or 4%; chemotherapy, 0 of 8; irradiation plus chemotherapy, 11 of 21 or 52%). Median survival time with the combined-modality treatment was 10 months compared with 5 months for irradiation alone. In a Mayo Clinic North Central Cancer Treatment Group (NCCTG) dose escalation pilot study, external irradiation was combined with 5-FU plus low-dose leucovorin (400 mg/m2 and 20 mg/m2, respectively, for 3–4 days, weeks 1 or 1 plus 5 of irradiation). Two of six patients with locally advanced gastric cancer were alive and free of disease beyond 3 years.

Published analyses from both GITSG and MGH suggest an improvement in survival if partial resection with gross residual disease or gross total resection with microscopic residual can be accomplished. In the GITSG series 3-year survival rate was about 25% as compared with 10% in partially resected versus unresected patients. In the MGH analysis, median survival with irradiation plus chemotherapy was 24 months for microscopic residual, 15 months with gross residual, and 14 months in unresected patients. Four-year survival rate was 0% in unresected patients as compared with 10% in those with residual disease after maximal resection.

In the most recent Mayo Clinic analysis of irradiation alone or plus chemotherapy for gastric or esophagogastric cancers, an improvement in median survival was also suggested for patients with gross total resection but microscopic residual disease when compared with higher risk subsets of patients. In this analysis, the results of irradiation or chemoirradiation therapy were evaluated in 87 patients with either locally advanced primary or locally recurrent adenocarcinoma of the stomach or gastroesophageal junction treated from July 1980 through January 1996 at the Mayo Clinic. Of those with primary lesions, 28 had unresectable disease, and 39 had resection but residual disease (microscopic, 28; gross, 10). An additional 21 presented with a local or regional relapse with no evidence of abdominal (liver, peritoneal) or extra-abdominal metastasis (lung, other). Chemotherapy with 5-FU (alone or plus leucovorin) was given during or following EBRT in 75% of the individuals with microscopic residual disease and 92% of the other subgroups (concomitant with EBRT in 84%). An intraoperative electron radiation therapy (IOERT) supplement to EBRT was given in 13 patients. Median survival time in primary cancer patients with microscopic residual was 16.7 months compared with 9.2 months in patients with subtotal resection and gross residual or 12 months in those with unresectable disease. Patients who presented with local or regional relapse had a median survival of 10 months.

Prognostic factor analyses showed that long-term survival seemed slightly poorer in patients who had resection before irradiation or CRT in the latest Mayo Clinic analysis. Actuarial 4-year survival rate was 0% versus 9% in individuals with gross residual disease after partial resection (1 of 11 patients alive with no evidence of disease 2 years after treatment), 9% in those with microscopic residual after gross total resection, and 18% in patients with unresectable primary or locally recurrent cancers. The survival trends may be a reflection of both treatment sequence and higher irradiation dose; 12 of 13 patients with EBRT plus IOERT had unresectable primary or locally recurrent cancers. In the 21 patients with locally or regionally recurrent cancers, irradiation dose greater than 54 Gy had a trend for improved survival (median survival, 25.6 vs. 5.5 months; P = 0.06). If patients with microscopic residual disease are excluded, an increase in the number of cycles of chemotherapy seemed to correlate with an improvement in median survival (median survival 5.2 months with less than two cycles, 11.5 months with two or three cycles, and 14.5 months with four or more cycles; P = 0.014).

Although problems with excess toxicity from combined CRT were encountered in the GITSG study, such problems were minimal or nonexistent in the MGH series of 46 patients. In the latter series, 43 of 46 patients received both irradiation and chemotherapy, but shaped radiation portals and single-fraction size of 1.8 Gy or less were used.

Neoadjuvant and perioperative chemotherapy

The use of adjuvant preoperative (neoadjuvant) chemotherapy has been less well studied than has adjuvant postoperative therapy. Due to the frequent inability of adjuvant postoperative systemic therapy to prolong survival in surgically managed gastric cancer, several investigators have pursued the approach of neoadjuvant (preoperative) chemotherapy in an attempt to increase resectability and improve survival. These studies involve a mix of patients including those determined surgically or clinically unresectable for cure, those with “locally advanced” disease (as defined by the study authors), and those with clinically operable lesions. Some patients were staged clinically by a variety of methods, making it difficult to know which patients were truly resectable before neoadjuvant treatment.

Unresectable disease

Seven different trials have assessed the potential benefit of preoperative chemotherapy for patients with initially “unresectable” stomach cancer. Each of the trials was small in size. The seven trials combined included 155 patients and demonstrated that preoperative chemotherapy in this subset of patients was feasible and resulted in clinical response rates of 30% to 68%. Curative resections were possible in as few as 8% or as many as 73% of patients. This wide range of resectability probably reflects patient selection rather than superiority of any one regimen. Unfortunately, pathologic complete responses (CRs) were uncommon except for the Wilke trial (pathologic CR in 5 of 34 patients or 15%).

Borderline resectable and locally advanced disease

Three phase II studies have tested the use of preoperative systemic treatment in individuals defined by the study authors as having “locally advanced” stomach cancer. Presumably this represents a mix of clinically resectable and unresectable or borderline resectable patients. Resectability rates ranged from 60% to 77%, which seems to be higher than for patients with unresectable cancers. It is likely that more patients in these trials were potentially (borderline) resectable before neoadjuvant chemotherapy.

Kang and associates have presented an updated report of the only phase III trial of neoadjuvant chemotherapy in locally advanced or borderline resectable gastric cancer. In the trial, 107 patients were randomized to receive two to three cycles of etoposide, 5-FU, and cisplatin followed by surgery versus surgery alone. Of the 53 patients randomized to preoperative treatment, 47 (89%) were explored and 37 (70%) were resected for cure. A 7% complete pathologic response rate was noted. In the control group of 54 patients, 100% were explored and 61% curatively resected. Median survival was 43 versus 30 months in favor of neoadjuvant treatment, but this difference did not reach statistical significance (P = 0.114).

Resectable disease

Several investigators have examined the role of neoadjuvant chemotherapy in patients with clinically resectable disease. Ajani and colleagues have performed two phase II studies of preoperative chemotherapy in this setting.  In their first study, 25 patients were treated with two cycles of etoposide, 5-FU, and cisplatin preoperatively. Three cycles were administered postoperatively if a positive response to neoadjuvant treatment could be detected endoscopically or radiographically. All 25 patients underwent surgery, and 72% were resected for cure. No pathologic complete responses were seen, and the median survival was 15 months overall. Following the report of Wilke and coworkers of pathologic complete response to chemotherapy with epirubicin, doxorubicin, and cisplatin (EAP), Ajani and associates treated 48 potentially curable patients with three cycles of preoperative EAP and two cycles following surgery if a response to preoperative treatment was observed. Of the 85% of patients who underwent exploration, 77% were resectable. Although 12% of patients achieved a complete clinical response, no pathologic complete responders were seen. The overall median survival was 15.5 months. Unfortunately, in this group of resectable patients with potentially smaller tumor burdens, the impressive results obtained with neoadjuvant EAP in Wilke's study could not be reproduced.

One of the few randomized trials to assess the potential benefit of preoperative chemotherapy to surgery alone in potentially resectable patients failed to show any benefit in outcomes.  In this Dutch trial, 59 patients were randomized to either FAMTX followed by surgery (N = 29) or surgery alone (30). Patients with T1 tumors, tumors arising from the gastric cardia, or evidence of distant metastases were excluded from participation. The study was closed early as a result of poor accrual. No benefit was seen with the addition of FAMTX before surgery (Table 15).

Table 15. Recent randomized phase III chemotherapy versus surgery-only trials (neoadjuvant, perioperative) for gastric cancer

OVERALL SURVIVAL

Reference

Regimen

No. of Patients

Interval

Percent

P Value

NEOADJUVANT

Hartgrink et al

FAMTX

29

5 yr

21

0.17

Surgery alone

30

34

PERIOPERATIVE

Cunningham et al

ECF

250

5 yr

36

0.009

Control

253

23

 5-FU, 5-fluorouracil; FAMTX, 5-FU, doxorubicin, and methotrexate; ECF, epirubicin, cisplatin, and 5-FU.

Preoperative systemic and postoperative intraperitoneal chemotherapy

Recently, other investigators have examined the usefulness of combining preoperative chemotherapy and postoperative treatment with intraperitoneal chemotherapy in view of the high peritoneal failure rate following resection of gastric cancer. Initial attempts to use intraperitoneal chemotherapy alone in the adjuvant setting did not show benefit.

Kelsen and associates studied 56 patients with high-risk (clinical stage T3–4) gastric cancer as determined by EUS. Patients received three cycles of neoadjuvant FAMTX. Following surgery, patients were treated with intraperitoneal 5-FU and cisplatin along with infusional 5-FU for three cycles. Fifty (89%) patients were explored and 34 (61%) resected for cure. When the initial EUS result was compared to the final pathologic staging, 51% of these patients were downstaged. No complete pathologic responses were observed, and the median survival was 15.3 months.

Crookes and colleagues updated their promising results with a somewhat similar trial design. Fifty-nine potentially resectable patients received two cycles of 5-FU, leucovorin, and cisplatin preoperatively, and two cycles of intraperitoneal 5-FUDR and cisplatin were given postoperatively to resected patients. Ninety-five percent of the patients underwent exploration, and 68% had a curative resection. The rate of pathologic CR was only 9%, but the median survival is estimated to be an impressive 52 months.

In a more recent phase II trial, 32 evaluable patients with locally advanced but potentially resectable stomach cancer received two cycles of systemic cisplatin and irinotecan. Twenty-nine patients were able to undergo surgery, and 25 had an R0 resection. Patients with resection subsequently received two cycles of intraperitoneal FUDR and cisplatin. Preoperative chemotherapy led to downstaging in 50% of the patients. With a median follow-up of 28 months, 10 (31%) were alive without relapse, 4 (13%) were alive with relapse, and the remainder had died from either disease (41%) or other causes (16%). Of the 25 patients with an R0 resection, none had a local relapse. A phase III trial of this approach has not yet been reported.

Summary

Preoperative systemic treatment may have certain advantages, such as the potential of reducing tumor bulk and increasing resectability. Micrometastatic disease may also be addressed earlier using this approach. Potential negatives to preoperative treatment include toxicity, delay in definitive therapy, and possibly increased surgical morbidity and mortality rates.

The high response rates achieved with neoadjuvant chemotherapy are of interest, and this form of treatment will undoubtedly be the subject of further investigation as new and more active systemic therapies are developed. Thus far, however, no survival advantage has been demonstrated in phase III trials, and neoadjuvant chemotherapy should be considered investigational. Resectability rates in neoadjuvantly treated patients seem higher than the median rate of 40% from several surgical studies, but the patients in these studies are highly selected. Except for the trials in which some patients were unresectable on the basis of prior exploration, the successful operations in these reports may not have been influenced by neoadjuvant chemotherapy. In general, pathologic CR rates are low (≤15%), and no proof exists that clinically staged patients are made more resectable by such treatment. The impact of preoperative systemic treatment on survival is even less clear. The one randomized trial that has been reported shows a nonsignificant improvement in survival for neoadjuvant treatment in borderline resectable/locally advanced disease. Newer technologies such as EUS may identify patients who will do poorly with standard therapy alone and would be reasonable candidates for future neoadjuvant studies. The reports of combined systemic and intraperitoneal approaches are provocative and may warrant future phase III trials, because only through such studies will any impact on survival be determined.

Perioperative chemotherapy

The use of perioperative chemotherapy was recently addressed in a phase III trial referred to as the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial. A total of 503 patients with resectable adenocarcinoma of the stomach (372 patients), gastroesophageal junction (58 patients), or lower esophagus (73 patients) were randomized to either surgery alone or to perioperative chemotherapy with three cycles of epirubicin, cisplatin, and continuous-infusion 5-FU (ECF) before surgery and three cycles of ECF after surgery. With a median follow-up of 4 years, patients randomized to receive perioperative chemotherapy had significantly improved OS when compared with patients randomized to receive surgery alone (5-year OS 36% vs. 23%; HR for death 0.75; 95% CI 0.60–0.93; P = 0.009).

In general the use of ECF was well tolerated in the preoperative setting. The incidence of overall postoperative complications was similar (45.7% vs. 45.3%) as well as 30-day mortality rates (5.6% vs. 5.9%). Of the 237 patients who started chemotherapy, 215 completed the planned three cycles of preoperative therapy. Of the 209 patients who went to surgery, 137 started postoperative chemotherapy. The most common reasons for not starting chemotherapy included disease progression, early death, postoperative complications, and patient choice. Overall 103 patients completed all six cycles of chemotherapy.

Preoperative chemoradiation

Several series of neoadjuvant chemotherapy for initially unresectable have demonstrated high rates of local-regional relapse in patients who were resected after the neoadjuvant chemotherapy. In the neoadjuvant EAP phase II trial reported by Wilke and associates, 15 of the 34 initially unresectable patients (44%) could subsequently be resected, and 5 of 15 were pathologic complete responders (15% of the original 34). Median survival was 18 months for the entire study group. In an update of these data at an international gastrointestinal cancer symposium in Germany, results were reported in a series of 21 patients who had total resection after EAP chemotherapy for locally unresectable disease. Of 21 patients 14 had relapsed, and 11 of 14 had a local-regional component of disease (79% of relapses, 52% of group at risk). Plukker and coworkers studied 20 patients with unresectable gastric cancer. Seventeen of the patients had undergone laparotomy, and three patients were deemed unresectable on the basis of CT imaging. After receiving up to four courses of sequential 5-FU and high-dose methotrexate, 14 patients (70%) underwent attempted resection. Eight of 20 patients (40%) were found to be resectable for cure, but subsequent local relapse occurred in five of eight.

In view of the high incidence of local-regional relapse in several series of patients resected after neoadjuvant chemotherapy for initially unresectable lesions, irradiation would be logical to incorporate into the study design of trials for patients with borderline or unresectable cancers. As previously noted, the phase III study by Walsh and colleagues compared preoperative 5-FU and cisplatin plus radiation therapy followed by surgery (N = 58) versus surgery alone (N = 55) in individuals with esophageal and gastric cardia adenocarcinoma. Pathologic CR was found in 13 of 52 patients (25%) who had surgery after preoperative CRT. Both median and long-term survival were improved with the preoperative treatment (P = 0.01). Thirty-five percent of the patients had lesions of the gastric cardia; however, there were more of these patients in the control group (42% vs. 28%). The positive esophagus/gastric cardia trial by Walsh and associates and high pathologic CRs in similar pilot studies with gastric cancer led to a U.S. GI Intergroup confirmatory trial of neoadjuvant combined-modality therapy in carcinoma of the esophagus and gastroesophageal junction. Although this study was stopped because of inadequate accrual, a survival advantage was demonstrated for trimodality treatment versus the surgery-alone control arm (P = 0.008).

PALLIATION OF THE INCURABLE PATIENT

This section is limited to discussion of patients with documented hematogenous or peritoneal metastasis. Patients with locally unresected disease are occasionally cured and were discussed in the previous section (5-year survival rate of 5% to 20%).

Surgery

Surgical intervention in the patient with metastatic gastric cancer requires sound judgment. The underlying health and function (performance status) of the patient, the estimated duration of patient survival, and the nature of the symptoms must all be taken into account before deciding to proceed with an operation. Resection for palliation is generally better than bypass or intubation in appropriate selected patients, leading to better symptomatic relief and often longer survival. Laparoscopic procedures, including subtotal and total gastrectomy, are feasible and are becoming increasingly popular. Obstructing lesions may be resected with excellent palliation, but endoluminal stents, endoscopic laser treatments, or gastrostomy tube placement should be considered for poor operative candidates. Although significant hemorrhage from an ulcerating or necrotic polyploid tumor may be temporarily controlled by endoscopic techniques, stabilization and urgent surgical intervention should be undertaken when appropriate. A perforated gastric cancer usually presents as an emergency and may be unrecognized preoperatively. Aggressive treatment with gastric resection should be carried out in the fit patient, but pain control and hydration alone are preferable for the moribund or unfit patient.

Irradiation alone or plus chemotherapy

If palliative resection is not indicated in symptomatic patients with metastases, a shortened course of irradiation alone or plus concurrent 5-FU-based chemotherapy could be used (37.5 Gy in 15 fractions over 3 weeks), to be followed by systemic treatment. Patients who have proximal lesions with esophageal obstruction may be candidates for laser ablation instead of irradiation. If laser is successful in overcoming obstruction, patients could proceed directly to treatment with chemotherapy.

Chemotherapy

Overview

Several clinical trials assessing the benefit of chemotherapy have been performed, including several that compared chemotherapy to best supportive care. Six trials assessed the potential benefit of early forms of chemotherapy for advanced gastric cancer compared to an untreated control group. In the largest of these trials 193 patients were randomized to either 5-FU + MeCCNU or to no treatment. The median survival time was 22 weeks for control subjects and 25 weeks for those who received at least one 6-week course of chemotherapy. Patients who died in the first 2 months were excluded from these figures. Median survival, estimated from survival curves, was in the 8- to 10-week range for all the patients, with no apparent difference between the two groups. It is of interest that a quality-of-life analysis was done in this trial and that it was published in 1978. Pain, well-being, and performance status were assessed at 8 and 16 weeks. Results of this quality-of-life analysis slightly favored the patients treated with chemotherapy, but few patient results were available for the 16-week time point. Subsequent trials with chemotherapy versus best supportive care have in general demonstrated a trend toward improved survival and quality of life with the use of chemotherapy.

The initial trials with chemotherapy reported response rates of 10% or higher and included agents such as 5-FU, mitomycin C, doxorubicin, epirubicin, cisplatin, BCNU (carmustine), methotrexate, etoposide, chlorambucil, and hydroxyurea. More recently a variety of new chemotherapy drugs have become available. Some have shown promising response rates in advanced gastric cancer, as discussed in the following sections, including docetaxel, irinotecan, and oxaliplatin. Multiple phase II trials of combination chemotherapy have built upon the promising activity seen with a variety of single agents. Many of the combinations have shown promising activity based on initial results, only to be shown to be less active and more toxic in subsequent phase II and III trials. It has therefore been important to interpret the results of initial phase II trials with caution. With some of the more recent combinations showing promise, using drugs such as docetaxel or oxaliplatin, older regimens such as FAM, FAMTX, and the combination of etoposide, leucovorin, and 5-FU are now less commonly used.

Fluoropyrimidines

A number of trials with 5-FU have been performed over the last several decades culminating in a recent series of phase III trials (Table 16). In a trial that mixed 254 patients with either adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma of the esophagus or stomach, patients were randomized to either protracted-infusion 5-FU or protracted-infusion 5-FU with mitomycin C. The overall response rates were 16% and 19%, respectively, with median survivals of 6.3 and 5.3 months (P = 1.0), respectively. In a phase III trial performed in Japan, 280 patients with advanced stomach cancer were randomized to receive one of three protocols: protracted-infusion 5-FU, continuous-infusion 5-FU combined with cisplatin, or the oral fluoropyrimidine UFT combined with mitomycin C. This trial also showed no advantage of the two combinations over the benefits obtained with 5-FU alone. In a third phase III trial the potentially promising combinations of etoposide + leucovorin + 5-FU, infusional 5-FU + cisplatin, and FAMTX were compared. A total of 399 patients with advanced carcinoma of the stomach were randomized. All three regimens showed modest activity with no significant difference in the primary outcome measures.

Table 16. Recent randomized phase III trials of chemotherapy for advanced or metastatic stomach cancer

Reference

Regimen

No. of Patients

Response(%)

Overall Survival (mo)

P Value

Tebbutt et al

PVI 5-FU

123

16.1

6.3

1.0

PVI 5-FU + MMC

127

19.1

5.3

Ohtsu et al

5-FU

105

11.4

7.1

0.11

5-FU + cisplatin

105

34.3

7.3

UFTM

70

8.6

6.0

Vanhoefer et al

ELF

132

9

7.2

0.77

5-FU + cisplatin

134

20

7.2

FAMTX

133

12

6.7

Van Cutsem et al

DCF

227

37

9.2

0.02

5-FU + cisplatin

230

25

8.6

Cocconi et al

PELF

98

39

7.7

0.19

FAMTX

97

22

6.9

Cunningham et al

ECF

249

NS

9.9

NS

EOF

241

9.3

ECX

235

9.9

EOX

239

11.2

 DCF, docetaxel, cisplatin, and 5-FU; ECF, epirubicin, cisplatin, and 5-FU; ECX, epirubicin, cisplatin, and Capecitabine; ELF, etoposide, leucovorin, and 5-FU; EOF, epirubicin, oxaliplatin, and 5-FU; EOX, epirubicin, oxaliplatin, and capecitabine; FAMTX, 5-FU, doxorubicin, and methotrexate; 5-FU, 5-fluorouracil; MMC, mitomycin C; NS, not stated; PELF, cisplatin, epirubicin, leucovorin, and 5-FU; PVI, protracted venous infusion; UFTM, uracil, tegafur, MMC.

While these 5-FU-based phaseIII trials were under way a variety of phase II trials and several additional phase III trials were performed evaluating potentially more promising agents or combinations.

Taxanes

Taxanes have been evaluated in a variety of phase II trials. Two North American trials of single-agent paclitaxel have been reported. Paclitaxel (210 mg/m2 over 3 hours every 3 weeks) as a single agent in previously untreated patients with metastatic gastric cancer provided a response rate of 11% and a median survival of 5.8 months. In a separate trial, assessing two different infusion schedules (200 mg/m2 over 3 hours vs. 24 hours every 3 weeks), an overall response rate of 17% was seen with a higher rate occurring in those receiving a 24-hour infusion. The median survival in this trial was 8 months. In several trials performed in Japan, using paclitaxel (210 mg/m2 over 3 hours every 3 weeks) as a single agent in the treatment of previously untreated patients with advanced gastric cancer, response rates of 23% and 28% were reported with a median survival of 7.7 and 11.2 months. Subsequent trials have assessed paclitaxel in combination with other chemotherapy agents. Phase II trials assessing paclitaxel in combination with cisplatin have given response rates of 33% to 46%, with median survivals of 8.9 to 13.8 months. The use of low-dose paclitaxel in combination with cisplatin did not seem to alter outcome, with a response rate of 44% and overall survival of 12.1 months in a phase II trial performed in Korea. A response rate of 33% and a median survival of 7.5 months have been reported in a small phase II trial with paclitaxel and carboplatin. Paclitaxel in combination with 5-FU and leucovorin has been assessed in several phase II trials. In two trials using a 24-hour infusion of 5-FU response rates of 46% to 48% and median survivals of 11 months were reported.

Docetaxel as a single agent has been evaluated in several phase II trials. In several single-institution trials of docetaxel 100 mg/m2 every 3 weeks, a response rate of 17% and 24% was reported along with a median survival of 7.8 months in one of the trials. Other trials assessed lower doses of docetaxel (60 mg/m2 or 75 mg/m2) and have reported similar results with response rates of 18% to 24% and a median survival of 11 months with the 75-mg/m2 dose.

Subsequent trials have evaluated docetaxel in combination with several other chemotherapy agents. The combination of docetaxel, 5-FU, and leucovorin has been evaluated in several phase II trials from Europe and Korea. This combination led to a response rate of 26% to 28% and a median survival of 7.7 to 9.7 months. In a randomized phase II trial the combination of docetaxel and 5-FU was compared to paclitaxel and 5-FU. Similar response (33% and 42%) and median survival (9.3 and 9.9 months) rates were reported for the two regimens. Several trials have assessed the combination of capecitabine and either weekly or every-3-week docetaxel and reported response rates of 39% to 60% and median survivals of 9.4 to 12 months.

The combination of docetaxel and cisplatin has been evaluated in several clinical trials as either the two-drug combination or in combination with other chemotherapy agents. With the two-drug combination in phase II trials the reported response rate was 28% to 46% and median survival of 10.4 to 11.5 months. Given the apparent promising activity of this combination, other trials explored the added benefit of 5-FU and reported response rates of 40% to 43% and median survivals of 9.0 to 9.7 months. A multicenter randomized phase II trial, involving 158 patients, assessed docetaxel and cisplatin with or without 5-FU as potential support for a phase III trial. In this trial the combination of docetaxel and cisplatin gave a response rate of 26% and a median survival of 10.5 months. The addition of 5-FU increased the response rate to 43%; however, the median survival was only 9.6 months.

In a subsequent phase III trial (Table 16) the combination of docetaxel, cisplatin, and 5-FU was compared to cisplatin and 5-FU. Overall survival was significantly longer with docetaxel, cisplatin, and 5-FU (P = 0.02). The response rate was also higher with this combination (69% vs. 59%, P = 0.01). However, the combination of docetaxel, cisplatin, and 5-FU was also more toxic, with 69% of patients developing treatment-related grade 3 or 4 adverse events compared with 59% of patients receiving cisplatin and 5-FU. Neutropenia and neutropenic fever were both significantly higher with the three-drug combination.

Platinums

Platinum-containing regimens have been the focus of many different trials. Many of the trials conducted in the past focused on the use of cisplatin, whereas more recent trials have begun to evaluate the potential use of oxaliplatin. The combination of 5-FU and cisplatin has been evaluated in several trials and provided a response rate of 41% to 45% and a median survival of 7 to 11 months. Given the apparent activity of this combination, a variety of phase III trials have compared 5-FU and cisplatin to other regimens (Table 16). The response rates in these larger trials were 20% to 51%, whereas the median survival was 7.2 to 8.6 months.

Building on this two-drug combination a variety of trials have assessed the combination of either 5-FU, cisplatin, and doxorubicin (FAP) or EAP. The FAP combination resulted in response rates of 31% to 50% and median survivals of 9 to 12 months in phase II trials. A phase III study, however, could not show an advantage for FAP over 5-FU alone. Less favorable outcomes were noted for the combination of EAP in phase II trials. This combination also caused significant toxicity, with a toxic death rate averaging 12%. The combination of cisplatin, epirubicin, leucovorin, and 5-FU (PELF) was compared to FAMTX in a randomized phase III trial. Although both the overall and CR rates with PELF were significantly higher (overall, 39% vs. 22%; CR, 13% vs. 2%), only a nonsignificant improvement in overall survival was seen with PELF (Table 16).

The ECF combination has been recognized as a potentially more promising cisplatin-containing regimen. Based on the results of phase II trials, this regimen showed activity at least comparable to other platinum regimens, but with less toxicity. A subsequent phase III trial of patients with previously untreated locally advanced or metastatic gastroesophageal cancer compared ECF to the combination of FAMTX. The overall response rate (45% vs. 21%; P = 0.0002) and median survival (8.9 vs. 5.7 months; P = 0.0009) were both significantly higher with ECF. The global quality-of-life scores were also better in patients receiving ECF.

Both carboplatin and oxaliplatin have been evaluated as potential alternatives to cisplatin. Only limited trial data are available for carboplatin. Carboplatin as a single agent has minimal activity. However, the combination of carboplatin and paclitaxel has a reported response rate of 33% and median survival of 7.5 months with only moderate toxicity.

Oxaliplatin was initially developed for colorectal cancer but has been evaluated as a potential treatment option for gastric cancer when used in combination with 5-FU and other chemotherapy agents. Although the use of 5-FU and leucovorin alone result in response rates of 5% to 12% with short median survivals, the addition of oxaliplatin seems to significantly improve response and overall survival. A variety of schedules using the combination of 5-FU, oxaliplatin, and leucovorin have been evaluated in phase II trials, including FUFOX, FOLFOX, and XELOX. These regimens have generally shown similar results with response rates of 38% to 65% and median overall survivals of 8.6 to 11.5 months. No phase III trials have yet been reported using one of these combinations.

Given the potentially promising activity of ECF, as described previously, a recent phase III trial for gastroesophageal cancer was conducted to assess the potential benefit of replacing cisplatin with oxaliplatin and infusional 5-FU with capecitabine using a 2 × 2 design (Table 16). This trial enrolled 1002 patients from 61 centers, and the results have been presented in a meeting abstract. Using a noninferiority statistical design for the trial, the combination of epirubicin, oxaliplatin, and capecitabine (EOX) was shown to be the most active of the four regimens evaluated. Compared with ECF, patients receiving EOX had both an improved 1-year survival (46.8% vs. 37.7%) and a statistically improved median survival (11.2 months versus 9.9 months; HR, 0.80, 95% CI, 0.65–0.97).

Oral fluoropyrimidines

The recent use of oral fluoropyrimidines in gastric cancer has focused on capecitabine and S-1. As a single agent in previously untreated patients capecitabine provided an overall response rate of 23% using a 3-week treatment schedule in a trial performed in Japan. OS was 10 months. Various combinations of capecitabine and other chemotherapy drugs, such as cisplatin or docetaxel, have been evaluated. The majority of recent trials, including a phase III trial as described previously, have evaluated capecitabine as a potential replacement for 5-FU.

The drug S-1 is an oral fluoropyrimidine in which the 5-FU prodrug tegafur is combined with two 5-FU-modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil), and potassium oxonate (oteracil), at a molar ratio of 1 : 0.4 : 1. The dose-limiting side effects of S-1 are primarily nonhematologic and mainly diarrhea, nausea, and vomiting. There is also a difference in metabolism of the tegafur component of S-1 in Asians and whites related to polymorphic differences in the CYP2A6 gene. This has led to different tolerable doses of S-1 in studies conducted in Asia compared with those conducted in Western populations. A variety of trials using S-1, alone or in combination with other chemotherapy drugs, have been performed in Asia, Europe, and North America. S-1 as a single agent has a reported response rate of 26% to 32%.Based on the early evidence of activity, S-1 has been evaluated in combination with cisplatin in several phase II trials. In these trials a response rate of 49% to 55% and OS of approximately 11 months were reported.

Irinotecan

The topoisomerase-I inhibitor irinotecan (CPT-11) has activity in gastric cancer, though limited as a single agent. In a phase II trial it provided a median survival of 6.4 months with a 14% response rate. CPT-11 has been evaluated in combination with other potentially active chemotherapy drugs. In combination with docetaxel a response rate of 46% and OS of 8.2 months has been reported. Similar response rates and OS have been reported for CPT-11 and cisplatin, CPT-11 and capecitabine, CPT-11 and mitomycin C, and CPT-11 and oxaliplatin. The addition of the antiangiogenic agent bevacizumab to the combination of CPT-11 and cisplatin in a phase II trial did increase the response rate to 65% and the OS to 12.3 months. The combination of CPT-11 with leucovorin and infusional 5-FU (FOLFIRI) in a randomized phase II trial also showed promising results, with a response rate of 40% and overall survival of 11.3 months. Phase III trials with these combinations have not been reported.

Summary

In summary, it is clear that chemotherapy may result in response rates of up to 50% or more in selected groups of patients with advanced gastric cancer. There is now growing evidence from both recent phase II and III trials indicating that chemotherapy seems to prolong survival over what would be expected with best supportive care. In recent trials median survival times have begun to clearly increase, with subsequent improvement in outcome measures including overall survival for treated patients compared to what had been observed in the prior several decades of clinical trials. However, it is not clear that there yet exists a standard treatment for advanced gastric cancer. Investigation of new agents and combinations must continue, and any “new standards” should be tested in controlled clinical trials looking at survival, quality of life, and cost analysis endpoints.

THE FUTURE

Completely resected lesions

Many patients with gross complete resection of their gastric cancer are not cured with surgery alone. The final results of the British and Dutch multicenter trials evaluating the value of extended lymphadenectomy demonstrated that the procedure produced greater morbidity with no impact on survival. Because experienced surgeons have performed extended node dissection without significant increases in surgical morbidity or mortality rates, use of the procedure is still reasonable in node-positive patients. Such patients will still be at high risk for local-regional and systemic relapse, however, and should receive postoperative CRT (Table 17). This philosophy is supported by the nonrandomized South Korea analysis by Kim and associates, which appeared to demonstrate an advantage in disease control and survival in 544 patients who received postoperative CRT following D2 resection versus the 446 surgery-alone patients (5-year OS, 57% vs. 51%, P = 0.02; 5-year RFS, 54.5% vs. 47.9%, P = 0.016).

Table 17. Treatment algorithm for gastric or gastroesophageal junction cancer, Mayo Clinic Cancer Center

TNM Extent[*]

Surgery

Irradiation (Alone or with Chemo)

Chemotherapy

T1-2N0M0

Radical subtotal gastrectomy and regional nodes

Not routinely recommended, except posterior wall T2N0M0

NR

T1-2N1-3M0; T3N0-3M0

Radical subtotal and regional nodes

Postop EBRT-Chemo, 45-50 Gy; evaluate preop EBRT-Chemo, gastric; prefer preop EBRT-Chemo, GE junction[†]

5-FU + leucovorin bolus wk 1,5—CCRT and maint; evaluate maint ECF in current U.S. Gl Intergroup phase III

T4N0-3M0

Radical subtotal and regional nodes; attempt en bloc resection, involved organ(s)

Preop EBRT-Chemo, 45-50 Gy; attempt resection and IOERT

5-FU + leucovorin, bolus wk 1, 5; evaluate alternate CCRT including infusion; 5-FU; evaluate other maint chemo (ECF, other)

TanyNanyM1

Palliative if feasible

Palliative CCRT if indicated

MACT; ICT phase 1, II, or III

 CCRT, concurrent chemoradiotherapy; EBRT, external beam irradiation; EBRT-Chemo, external beam irradiation + chemotherapy; eval, evaluate; ICT, investigational chemotherapy clinical trials; IOERT, intraoperative electron irradiation; MACT, multiagent chemotherapy; maint, maintenance; NR, not recommended; postop, postoperative; preop, preoperative

* For TNM definitions, see Table 2 .

We prefer preop CRT for gastroesophageal (GE) junction cancer found to be T1–2N1–3M0 or T3N0–3M0 on endoscopic ultrasonography, because one can usually design safer EBRT fields with preop CRT rather than postop CRT. If transhiatal resection is performed, keeping the reconstructed stomach in the mediastinal midline, postop CRT can be given more safely than if Ivor-Lewis resection is performed.

With regard to replacementpostoperative CRT trials, the U.S. GI Intergroup replacement phase III randomized trial was designed to build on the positive results of INT 0116 by testing 5-FU infusion versus bolus 5-FU + leucovorin as the concurrent chemotherapy during EBRT, and ECF chemotherapy versus 5-FU + leucovorin as the maintenance component of chemotherapy. A phase II trial tested the tolerance of the more aggressive infusional 5-FU and ECF regimen in a multicenter trial involving CALGB institutions together with the Mayo Clinic. The irradiation treatment fields in both the phase II and successor phase III trials are based on idealized field design related to site of the primary lesion and TN stage of disease.

On the basis of encouraging results with preoperative chemotherapy and CRT for locally advanced or borderline resectable disease and the survival advantage for perioperative ECF chemotherapy versus surgery alone for resectable gastroesophageal cancers in the British phase III MAGIC trial, future phase III studies should evaluate preoperative chemotherapy (alone or followed by postoperative CRT) and preoperative CRT in combination with resection for patients with potentially resectable lesions. Although some investigators and institutions may prefer to simply replace postoperative adjuvant CRT with perioperative ECF chemotherapy, it would seem advantageous to attempt to combine the advances in disease control and survival found with both approaches, in that neither approach by itself resulted in optimal outcomes. This philosophy is being tested in part in the current U.S. GI INT trial by the comparison of ECF versus 5-FU + leucovorin as the maintenance component of chemotherapy. A randomized phase II study was conducted by RTOG to evaluate several combinations of preoperative CRT, and results are awaited. Because some of the newer chemotherapy drug combinations have CR rates of about 20%, the hope is that these regimens will lower systemic relapse rates more than previous combinations. This change has not yet been demonstrated in phase III trials.

Locally advanced disease (unresectable for cure)

For patients with locally advanced disease that appears unresectable for cure, it seems reasonable to build on existing positive segments of treatment data (EBRT plus chemotherapy, IORT, preoperative chemotherapy, preoperative chemoradiation) plus patterns of relapse information. External irradiation plus chemotherapy or IORT alone or added to EBRT has controlled disease and produced long-term survival in 10% to 20% of patients in most single-institution analyses and randomized trials in patients with residual disease after resection. Neoadjuvant chemotherapy for unresectable disease has resulted in subsequent total resection of disease in 20% to 73% of patients in several European trials with EAP, FAMTX, or other regimens. However, the incidence of subsequent local-regional relapse is significant, even after total resection. It would be of interest to merge these components of treatment.

Following preoperative chemotherapy, patients with marginal gross total or subtotal resection with residual disease or resection but high-risk factors for relapse (beyond the gastric wall, nodes positive, or both) should be placed on studies that evaluate IORT, postoperative EBRT, or both in conjunction with concurrent and maintenance chemotherapy. For patients who are unresectable after preoperative (neoadjuvant) chemotherapy but still have localized tumor on the basis of preoperative staging (including laparoscopy) or exploratory laparotomy, EBRT plus concurrent chemotherapy should be given. Decisions regarding attempts at later resection alone or plus IORT could be individualized by institution.

An alternate approach is to initiate treatment with preoperative CRT followed by restaging, resection (alone or plus IORT), and postoperative maintenance chemotherapy. Questions to be addressed with this approach include whether to give several cycles of multiagent chemotherapy before initiating concomitant CRT or whether to start with concomitant CRT, how many cycles of chemotherapy to deliver, and which agents to give both with irradiation and as the systemic component of treatment.

Metastatic Disease

Recent trials with newer chemotherapy agents in combinations such as EOX and docetaxel, cisplatin and 5-FU (DCF) are beginning to show meaningful increases in overall survival. However, it is unlikely that significant advances will be made through the addition of other new chemotherapy drugs to those already available. Advances will more likely occur through the use of targeted therapies. Trials with targeted therapy used alone or in combination with chemotherapy are under way. Ultimately the goal must focus on improvements in both overall survival and response rate, while continually focusing on quality of life. Adequately powered trials in both the phase II and phase III settings will be important in providing meaningful answers.

Treatment algorithm by tumor, lymph node, and metastasis disease extent

The contents of this section are supported by Table 17 and Figures 11 and 12.

Figure 11. Treatment algorithm: newly diagnosed gastric cancer adjuvant therapy precedes surgery.

Figure 12. Treatment algorithm: newly diagnosed gastric cancer, surgery precedes adjuvant therapy.

T1–2N0M0

Total surgical resection of the adenocarcinoma with a radical subtotal gastrectomy and reconstruction with gastrojejunostomy is recommended as standard treatment. Patients with posterior-wall T2N0M0 lesions should be evaluated for postoperative adjuvant CRT.

T1–2N1–3M0; T3N0–3M0

Postoperative CRT is the preferred standard of treatment in the United States based on demonstrated improvement in survival (disease-free and overall) when compared with a surgery-alone control arm in the phase III U.S GI trial (INT 0116).

Our institutions prefer the use of preoperative CRT for patients who have T1–2N1–3M0 or T3N0–3M0 gastroesophageal junction cancers at the time of EUS, because we can usually design safer EBRT fields for preoperative CRT rather than postoperative CRT. If transhiatal resection is performed, keeping the reconstructed stomach in the mediastinal midline, postoperative CRT can be given more safely than if Ivor-Lewis resection is performed.

T4N0–3M0

Preoperative CRT followed by restaging, gross total resection (may include en bloc resection of adjacent organs), and IOERT is recommended for potentially resectable T4N0–3 lesions in institutions with IOERT capability. Postoperative CRT has also been used for completely resected lesions.

For patients with locally unresectable T4N0–3M0 gastric cancers, preoperative or primary CRT or multiple-drug chemotherapy can be used, preferably in the setting of controlled prospective clinical trials. For patients with good performance status, the treatment approach would preferably involve preoperative CRT, restaging, and surgical resection with an attempt at marginal gross total resection and IOERT.

TanyNanyM1

Multidrug chemotherapy combinations are the preferred treatment for patients with metastatic cancers. Patients should be placed on controlled trials if available. Palliative irradiation can be used for painful metastatic lesions but is otherwise not indicated. Palliative resection may be indicated for patients with obstruction or bleeding, if total gastrectomy can be avoided.

Nutritional support during chemoradiation therapy

Many patients who receive preoperative CRT (with plans to proceed to surgical resection) or primary CRT may require parenteral or enteral hyperalimentation during treatment. This feeding may also be necessary in subsets of patients with borderline performance status who are candidates for postoperative CRT. Improvement in nutritional status may require stent placement during endoscopy, feeding jejunostomy, or percutaneous endoscopic gastrostomy tube placement. Feeding jejunostomy may be preferable to percutaneous endoscopic gastrostomy tube placement for patients receiving preoperative CRT, so as to preserve later use of the stomach for reconstruction.

 

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