Cancer of the Stomach and Gastroesophageal Junction

Introduction


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), 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, preoperative 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. Results of Surveillance, Epidemiology, and End Results (SEER) analyses and meta-analyses that support the role of adjuvant treatment will be summarized.

For patients with locally advanced 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 radiation therapy (EBRT) plus concomitant chemotherapy, maximal resection plus intraoperative radiation therapy (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

In 2012, cancer of the stomach had an expected incidence in the United States of 21,320 cases and an expected number of 10,540 deaths.1 Age-adjusted gastric cancer death rates have decreased markedly in the United States since 1930 from approximately 28 to 2.3 in 100,000 women and from 38 to 5.2 in 100,000 men. Of the 45 countries in which age-adjusted death rates for gastric cancer were compared for 2000 (E-Fig. 75-1), the United States ranked 45th for both men and women.2 Kyrgyzstan ranked first for both men (47.0 in 100,000) and women (18.9 in 100,000).

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 (GEJ) and proximal gastric cancers.

Etiology and Biological Characteristics

Etiology
 

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.3,4 Possible occupational relationships include coal mining and rubber or asbestos workers. Precursor pathological 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.5,6

Several studies have shown a threefold 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.7-9 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.

There has been a dramatic increase in the incidence of gastroesophageal and gastric cardia carcinoma during the past few decades, similar to the increase in distal esophagus adenocarcinomas, suggesting that they may have similar etiologies. Although the reasons for these changes are unknown, they may be related to the increased incidence of esophageal reflux and Barrett esophagus.

Biological Characteristics

Prognostic Factors
 

The most meaningful prognostic indicators relate to extent of tumor. With either hematogenous metastasis or peritoneal seeding, prognosis is almost always 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.10,11 Survival decreases with progressive direct tumor extension both within and beyond the gastric wall.12,13 Lymph node involvement, per se, is not as important as the number and location of nodes.14-16 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.17 The solitary finding of either involved nodes or complete penetration of the gastric wall is usually not as ominous as the presence of both12,15 (E-Table 75-1).

The tumor grade and the gross and histologic pathological 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 pathological stages of disease (see Fig. 75-1). 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.18,19

Some investigators have suggested that tumors of the gastric cardia may have epidemiological factors different from cancers of the distal stomach20,21 and may exhibit different tumor biology.22 The prognosis is worse for cardia lesions,23,24 and flow cytometry reveals a greater incidence of aneuploidy when compared with tumors of the antrum and body.25 

Flow cytometry provides valuable prognostic information for gastric cancer and may be an independent prognostic factor.25,26 As noted previously, aneuploidy is associated with unfavorable tumor location such as the cardia25,27 but is also associated with lymph node metastasis26,27 and direct tumor extension.26 Unfavorable DNA flow cytometry characteristics seem to relate closely to an unfavorable prognosis.25,26 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.26 The presence of several peptides including estrogen receptor,28 epidermal growth factor receptor,29 the c-erbb2 protein,30 and plasminogen activator inhibitor type 119 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 pathophysiological 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.31 

Molecular Biology


The molecular biology of gastric cancer reflects the heterogeneity of its causes and its histologic subtypes. Identification of the genetic and phenotypic variables may lead to more directed treatment approaches and more accurate prediction of clinical outcomes. Changes that may affect the behavior of gastric tumor cells involve four major types of alterations.

Loss of tumor suppressor gene function, especially inactivation of the p53 gene, plays a key role in tumor suppression and cell-cycle regulation.32 The p53 gene puts a brake on DNA replication and triggers programmed cell death in response to DNA damage.33 Loss of p53 function is associated with the development of gastric cancer, impacts the effectiveness of chemotherapy and irradiation,34,35 and predisposes cells to genetic instability.

A second aberration affecting gastric epithelial cells is alterations in mismatch repair genes, including HMSH3 and HMLH1, which account for replication errors throughout the genome. Mutations in these genes generate genetic instability and are associated with an increased tendency for the development of colorectal and gastric tumors.36,37

Two protooncogenes, c-met and K-sam, are associated with scirrhous carcinoma of the stomach. Overexpression of c-met correlates with tumor progression and metastasis, and K-sam encodes a tyrosine kinase receptor family.38K-sam has a tendency to be activated in women with gastric cancer younger than 40 years of age and c-met to be amplified in men older than 50 years of age.39,40

Modern molecular biology observations confirm the heterogeneity of human gastric cancer.41 Gastric cancers with class II major histocompatibility complex antigen expression (HLA-DR) have a better prognosis, but the loss of expression is not an independent prognostic factor.42

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.43 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 frequent presence of microscopic intraepithelial carcinomas in patients having regular endoscopic surveillance that includes multiple random biopsies.44-46 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.46

Pathology and Pathways of Spread

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%).47

Gastric carcinomas have been categorized by using both microscopic (Fig. 75-1) and gross pathological 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.48 Grossly, gastric cancers can be categorized according to Borrmann’s49 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.50

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 (E-Fig. 75-2). 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).50 Node groups that are more distal include hepatoduodenal, peripancreatic, root of mesentery (N3), periaortic, and middle colic (N4). When proximal gastric lesions extend into the distal esophagus, the paraesophageal nodal system is at risk for involvement.

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).

Clinical Manifestations, Patient Evalution, 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 tumor]), remote node metastasis (left supraclavicular [Virchow node]; periumbilical [Sister Mary Joseph node]; or left axillary [Irish node]), ascites, or a rectal shelf (peritoneal seeding).

The diagnosis of gastric cancer is usually confirmed by upper GI endoscopy, or radiographs (see diagnostic algorithm in Table 75-1). 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 direct biopsy for histology 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 gastric washings for cytology enhance the probability of accurate diagnosis. Endoscopic ultrasound (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.51-53 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 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 ultrasound. We prefer CT scan to ultrasound 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 required in determining mediastinal node involvement or parenchymal lung metastases. Positron emission tomography fused with CT (PET/CT) is a valuable imaging tool to both rule out occult metastatic disease and to determine response to treatment.

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 groups54,55 have reported the use of laparoscopy in stomach cancer patients. Metastatic disease was documented laparoscopically in 35% to 40% of patients.54-56 The sensitivity for metastases was 85% or greater55,56 and this technique was particularly sensitive in detecting liver and peritoneal disease. Laparoscopy is more sensitive and accurate in staging patients with regard to intraabdominal metastases than either ultrasound or CT scan.56,57 Many surgeons now routinely perform laparoscopy in all gastric cancer patients who are deemed candidates for surgical resection, to avoid nontherapeutic laparotomy. The current TNM (tumor, lymph node, metastasis) staging system is depicted in Table 75-2 and is acknowledged as the standard system for reporting outcomes in stomach cancer.58 Several comparison studies, including some from Japan,59,60 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: Surgical Method—Gastric Cancer

Surgical excision has traditionally been the first treatment for gastric carcinoma. Because many patients have occult distant metastases at presentation and improved results have been demonstrated with preoperative chemotherapy61,62, neoadjuvant treatment is appropriate when preoperative staging is consistent with ≥T3 primary tumors and/or ≥N1 disease. The increasing prevalence of proximal gastric cancers, especially in the developed world, has resulted in more operations encompassing a thoracic component of resection to obtain an adequate proximal margin and remove intrathoracic lymph nodes at risk for metastasis.

Surgical excision of the gastric and nodal components of disease remains the primary therapy for all potentially curable gastric carcinomas. Based on pathological 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 category 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).50 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 it may increase the rates of patient morbidity and mortality. A randomized study63 showed similar survival rates with subtotal and total gastrectomy. Surgical resection alone, including endoscopic mucosal resection in selected patients,64 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 more than 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.65 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, subtotal66 and total67 laparoscopic gastrectomies are being performed safely and without apparent compromise of patient outcome. Laparoscopic gastrectomy has reduced morbidity and mortality in controlled trials compared with open resection of mostly clinical early gastric cancers (pathological T1/T2, N0 cancers). Longterm results comparing patient survivals and large controlled trials comparing laparoscopic and open gastrectomy in advanced gastric cancers have yet to be reported.

Only one prospective randomized trial63 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. 75-2). This procedure 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. 75-3). 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 pathological 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. Routine splenectomy is no longer practiced because of the increased complications found in randomized controlled68,69 and retrospective studies. A splenectomy should be performed when worrisome, palpable nodes are present in the splenic hilum.

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.70,71 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.72 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.73 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.72 A recent study of sentinel lymph node biopsies in gastric cancer patients in Japan74 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 a radical subtotal gastrectomy and omentectomy is performed, all perigastric (D1) lymph nodes along the lesser curvature and those on the greater curvature distal to the site of transection should be removed. In many major cancer centers, the lymph nodes adjacent to the celiac axis and its branches (D2) are also resected with a limited increase in postoperative morbidity (D2 dissection; see E-Fig. 75-2 regarding D2 dissection; 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 more recent randomized trial comparing a Japan D2 versus extended D2 resections75 shows a very low operative mortality and low morbidity with no significant increase in complications, nor as yet, any improvement in patient survival.

Thus far, randomized trials76,77 have not demonstrated either disease-free or overall survival (OS) advantage for extended lymphadenectomy (D2 dissection). A large multicenter phase III study that accrued 711 curable gastric cancer patients in the Netherlands76 noted significantly higher morbidity and mortality rates with the more extensive nodal dissection (Table 75-3). 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 (see Table 75-3).77 Neither the Dutch76 nor the British trial77 demonstrated any improvement in overall or disease-free survival (see Table 75-3). In the Dutch study,76 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.76,77 Preliminary data from a Japanese trial comparing D2 and extended D2/D3 resections75 and an Italian study comparing D1 and D2 resections78 did not show increased morbidity with extended lymphadenectomy. Results for disease-free and long-term OS are not yet available from either study.

Any potential survival benefit seen with the extended node dissection performed in Japan may be due to the phenomenon of a stage migration rather than superior surgical therapy.79 In Japan and the United States, gastric resection specimens are handled quite differently.80 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.81 This number compares with an average of 12 and 13 nodes examined after subtotal and total gastrectomy, respectively, at Memorial SloanKettering.82 Patient survival after a curative operation significantly improves when more than 15 lymph nodes are pathologically examined.83,84 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.16 Extended lymph node dissection seems reasonable for experienced surgeons who can perform this procedure without significantly increased surgical morbidity or mortality, because it improves pathological staging.75,78,85

Endoscopic laser surgery has been used in selected individuals with early gastric cancer.64,86 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.

Primary Therapy: Surgical Method—GEJ Cancer

Although adenocarcinomas arising at or near the GEJ are often classified as esophageal carcinoma, there has been a concerted effort to differentiate treatment approach based on location and cell origin.87-93 Feith, Siewert, and colleagues defined adenocarcinomas of the GEJ into three separate types87,94:

Type I: Adenocarcinoma of the distal esophagus, arising as intestinal metaplasia of the esophagus and possibly infiltrating the GEJ from above
Type II: Adenocarcinoma of the cardia, arising from cardiac epithelium or short segments with intestinal metaplasia at the GEJ
Type III: Subcardial gastric carcinoma, infiltrating the GEJ and distal esophagus from below.

Surgical resection has remained controversial as to the necessary extent of proximal esophageal resection, distal gastric resection, and lymph node dissection.95-101 Complete macroscopic and microscopic resection (R0) provides patients with the best survival.89,94,97,98,100-103 The main goal of lymph node dissection is to optimize staging and reduce locoregional relapse, and lymph node involvement is recognized as a major prognostic factor in GEJ adenocarcinoma.96,99,103,104 Decisions as to the type of surgical resection should be based on achieving an R0 resection and can include transhiatal, transthoracic, partial, and total gastrectomy.

For Type I GEJ cancers, surgical resection should include esophagectomy with at least 6 to 8 cm of proximal margin.89,96,98,100,105 Either transhiatal or transthoracic esophagectomy can be used to achieve an R0 resection.

Both transhiatal and transthoracic esophagectomy include an identical abdominal procedure to assess metastases, mobilize the stomach, and create a gastric tube that will replace the resected esophagus and proximal stomach. Lymph node dissection is also performed along the celiac axis and peripancreatic region. The abdominal portion of the operation can be done either open or with laparoscopy depending on surgeon experience and preference (E-Fig. 75-3A).

Transthoracic cases will then be completed through a right side of the chest approach. Either open posterolateral thoracotomy or minimally invasive thoracoscopy can be used (E-Fig. 75-3B). The transthoracic approach allows extensive mediastinal lymphadenectomy to be performed as well as resection of periesophageal fat and adhesions. The gastric tube is brought up into the chest through the diaphragm and anastomosed to the proximal esophagus in the upper thorax. Multiple anastomotic techniques have been described.106 For minimally invasive esophagectomy (MIE), we have successfully used an OrVil EEA (U.S. Surgical Corps.) which allows a 25-mm anvil to be advanced through the mouth while attached to an orogastric tube (E-Fig. 75-3C).105,107 The anvil is then pulled through a small opening made in the proximal esophagus (E-Fig. 75-3D) and attached to the pin of the stapler that has been advanced through the back wall of the gastric conduit (E-Fig. 75-3E). There have been no large randomized trials on MIE versus open options for GEJ adenocarcinoma; therefore, evidence-based recommendations cannot be made. There is some suggestion of fewer pulmonary complications and faster recovery with MIE.107-110

Transhiatal procedures are completed through a cervical incision on the left neck. The esophagus is freed through this incision and hand dissection from below the diaphragm allows the specimen to be brought up through the neck incision (E-Fig. 75-3F). The conduit is anastomosed to the proximal esophagus in the neck. This can be performed with hand sewing or stapling devices (E-Fig. 75-3G). Generally a formal mediastinal lymphadenectomy is not performed with this technique.

Surgical resection for Type II GEJ cancers can be performed with a proximal gastrectomy and partial esophagectomy. The transthoracic approach is preferred providing a two-field extended lymphadenectomy and tension-free anastomoses given the additional gastric margin needed.

Type III GEJ cancers require extensive gastric resection to provide an inferior margin of 2 to 3 cm and a superior margin of 4 to 5 cm.95,111 A total gastrectomy with partial esophagectomy and Rouxen-Y bile diversion through an abdominal approach is generally necessary to achieve R0 resection.95,111,112 These cancers are treated similar to pure gastric cancers. The strategy for GEJ cancers is most often multidisciplinary, but surgery remains a critical part of the treatment plan for resectable carcinomas. Surgical techniques continue to evolve in an attempt to minimize patient morbidity and mortality.

 

Primary Therapy: Survival After Surgery Alone

OS 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).113 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.114 Excellent survival in excess of 90% has been achieved throughout the world with surgical resection of lesions confined to the mucosa or submucosa.65,115,116 In contrast, for gastric cancers with deeper invasion or nodal involvement, survival decreases proportionally to the degree of invasion or involvement (see E-Table 75-2). When N1 or N2 nodes are involved, Western reports continue to show 5-year survival rates of 10% to 30%,117 whereas Japanese authors report 5-year surgical cure rates of 25% to 60% (vs. <10% with N3 or N4)118,119 (see E-Table 75-2). The improved results seen in Japan compared to the United States likely reflect improved pathological staging with more extensive nodal dissection and possibly differences in tumor biology between the two countries.

Recent randomized, controlled trials have shown significantly improved survival for patients with all but the earliest gastric cancers.120 Even in the Far East, patients with locally advanced gastric cancers benefit from multimodality therapy, because cancer-related death occurs in more than 50% of patients following resection alone. 

Primary Therapy: 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,121,122 reoperative,13,123 and autopsy123-126 series. For lesions of the GEJ, 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 75-4). Tumor relapse in anastomoses, the gastric remnant, or the duodenal stump is also frequently seen. In a University of Minnesota reoperative analysis,13,123 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 survival127 nor decreased the incidence of local or regional regrowth in the reoperative analysis.13,123 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; E-Table 75-3).123,128 This indicates the difficulty of obtaining a complete lymph node excision encompassing this anatomic location and provides a partial explanation for the lack of survival benefit with a D2 versus D1 node dissection in phase III trials previously discussed.75-78,129 In a more recent clinical analysis of patterns of relapse from Memorial Sloan Kettering Cancer Center, 50% of patients with relapse had a local-regional component.122

Patterns of failure by stage were analyzed in detail in a series of 130 patients who underwent resection performed with curative intent at the Massachusetts General Hospital (MGH).121 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 localregional failure by stage was in excess of 35% for T3N0, T4N0, T3N1–3, and T4N1–3 lesions. The sites at highest risk for localregional 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 (see comparative findings in Table 75-4 and E-Table 75-3). Some additional information on patterns of relapse by stage exist in both the University of Minnesota reoperation analysis13,123 and the University of Washington autopsy analysis.126 Although patterns of failure data are more accurate in such analyses, patient selection is biased.

The above studies demonstrate significant relapse rates at local, regional, and distant sites following surgical resection alone. This emphasizes and supports the need for multimodality therapy in patients with locally advanced gastric cancers.

Adjuvant and Neoadjuvant Therapy

Adjuvant therapy with chemotherapy, irradiation, or a combination of these approaches has been used to enhance the potential benefit of surgery for patients with resectable stomach or GEJ cancer. Clinical trials have assessed therapy given prior to surgery (neoadjuvant), following surgery (adjuvant), or both before and after surgery (perioperative). The results of surgery alone for resectable gastric cancer have already been presented and justify the evaluation of both adjuvant irradiation and systemic chemotherapy with the intent of reducing local-regional and systemic risks of relapse and thereby improving survival.

Neoadjuvant Systemic Chemotherapy

Neoadjuvant therapy has the potential advantage of downstaging gastric cancer and thereby enhancing the potential for resection. It also has the potential to eliminate micrometastatic disease prior to surgery and at a time patients may be more likely to tolerate systemic therapy. A retrospective analysis of 220 patients receiving either 5-fluorouracil (5-FU) alone or 5-FU and cisplatin prior to surgery compared with 100 patients treated with surgery alone suggested a benefit to neoadjuvant therapy.130 Patients receiving neoadjuvant therapy had a significantly longer 5-year survival. However, prospective clinical trials with neoadjuvant therapy are limited.

Several phase II trials of neoadjuvant trials have been reported and have shown mixed results. Ajani and colleagues have performed two phase II studies of preoperative chemotherapy in this setting.131,132 In their first study, 25 patients were treated with two cycles of etoposide, 5-FU, and cisplatin preoperatively.132 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 pathological complete responses were seen, and the median survival was 15 months overall. Following the report of Wilke and coworkers of pathological complete response to chemotherapy with epirubicin, doxorubicin, and cisplatin (EAP),133 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.131 This trial failed to support the findings of the trial reported by Wilke. Of the 85% of patients who underwent exploration, 77% had resectable cancer. Although 12% of patients achieved a complete clinical response, no pathological complete responders were seen. The overall median survival was 15.5 months.

One of the few randomized trials to assess the potential benefit of preoperative chemotherapy to surgery alone in patients with potentially resectable cancer failed to show any benefit in outcomes (Table 75-5).134,135 In this Dutch trial, 59 patients were randomly assigned to either 5-FU, doxorubicin, and methotrexate (FAMTX) followed by surgery (N = 29) or surgery alone. Patients with T1 tumors, tumors arising from the gastric cardia, or evidence of distant metastases were excluded from participation. The trial was closed early as a result of poor accrual. No benefit was seen with the addition of FAMTX before surgery. In a separate phase III trial neoadjuvant chemotherapy with cisplatin, 5-FU, and leucovorin followed by surgery was compared to surgery alone.136 Patients randomly assigned to chemotherapy received two 48-day cycles of chemotherapy. The trial was closed early for poor accrual. No benefit could be demonstrated for the addition of neoadjuvant therapy as measured by OS (hazard ratio [HR]: 0.84; 95% CI: 0.52, 1.35, P = 0.466) in the 144 patients enrolled after a median follow-up of 4.4 years.

Adjuvant Systemic Chemotherapy

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.137,138 

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-FU and methyl-chloroethylcyclohexyl-nitrosourea (MeCCNU; lomustine); (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),139 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.11,12 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.140-148 A phase III trial of cisplatin, epirubicin, 5-FU, and leucovorin (PELF) also failed to show any significant benefit.149

Mixed results have been seen in trials performed in Asia. Nakajima and colleagues have performed a series of adjuvant trials in individuals with resected gastric cancer.150-153 In their first trial, 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.150 In a subsequent threearm adjuvant trial, patients were randomly assigned to surgery alone, mitomycin C alone, or the combination of twice-weekly MFC (mitomycin C, 5-FU, and cytosine arabinoside).153 Forty-two patients were entered in each arm of the trial. 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 with surgery alone.152 A significant survival benefit was seen for individuals with stages I to III disease treated with MFC and oral 5-FU. In a fourth trial, 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.151 When compared with a control group, adjuvant therapy for this group of patients showed no benefit over surgery alone.

Given the success of the oral fluoropyrimidine S-1 in advanced gastric cancer, a Japanese trial of surgery followed by adjuvant S-1 for 1 year compared with surgery alone for patients with resected stage II or III gastric cancer was performed (Table 75-5).154 A total of 529 patients were randomly assigned to the S-1 group and 530 to the surgery-alone group. The 3-year and 5-year OS improved with the use of S-1 (5-year HR: 0.669; 95% CI: 0.540, 0.793).154,155

Five other 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 75-5).156-161 Neri and associates treated surgically resected node-positive patients with the addition of adjuvant epirubicin, 5-FU, and leucovorin (68 patients) and compared them with 69 surgery-alone control patients.161 A significant improvement in 5-year OS was noted in patients receiving the adjuvant chemotherapy (30% vs. 13%, P < 0.01).

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 OS. 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 metaanalyses have been performed. A meta-analysis of 17 phase II and III randomized trials showed a significant survival advantage (OS, DFS) to the use of chemotherapy following surgical resection of gastric cancer compared with surgery alone with a median follow-up exceeding 7 years.162

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 (Table 75-5).61 A total of 503 patients with resectable adenocarcinoma of the stomach (372 patients), GEJ (58 patients), or lower esophagus (73 patients) were randomly assigned 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 randomly assigned 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.

In a separate phase III trial in France, 224 patients with potentially resectable adenocarcinoma of the lower esophagus, GEJ, or stomach were randomly assigned to either perioperative chemotherapy and surgery (n = 113) or to surgery alone (n = 111).163 Chemotherapy consisted of two or three cycles of cisplatin and infusional 5-FU prior to surgery and three to four cycles after surgery. In this trial, perioperative chemotherapy resulted in a significant improvement in 5-year OS (38 vs. 24%, HR: 0.69, 95% CI: 0.50, 0.95, P = 0.02) and DFS (34 vs. 19%, HR: 0.65, 95% CI: 0.48, 0.89, P = 0.003). Grade 3 or 4 toxicity, consisting primarily of neutropenia, occurred in 38% of the patients receiving chemotherapy.

Summary—Neoadjuvant, Adjuvant, and Perioperative Systemic Chemotherapy


The benefits of chemotherapy for potentially resectable high-risk stomach cancer have mainly been demonstrated with perioperative chemotherapy. The role of adjuvant chemotherapy for resected highrisk stomach cancer remains uncertain. Except for the Japanese trial with S-1, individual trials have generally not shown clinically meaningful benefit. Chemotherapy used alone in the postoperative setting is not of clear value. 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 chemoradiation when compared with a surgeryalone control arm (see 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 randomly assigned to surgery alone or to surgery followed by intraperitoneal thiotepa.137 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.164 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 randomly assigned to surgery alone or intraoperative mitomycin C at the time of surgery.165 For patients who underwent curative surgery, intraperitoneal therapy led to a significant improvement in 2- and 3-year OS. No difference in survival was seen for patients with macroscopic peritoneal carcinomatosis. In a separate trial from Japan, 88 patients with peritoneal cytology-positive lavage fluid, but without macroscopic peritoneal metastases, were randomly assigned in the operating room to surgery alone, surgery plus intraoperative peritoneal chemotherapy, or a combination of surgery, intraoperative peritoneal therapy, and “extensive intraoperative peritoneal lavage.”166 The 5-year OS was 43.8% for the extensive intraoperative peritoneal lavage group, compared with 4.6% for those receiving only intraoperative chemotherapy and 0% for those receiving only surgery.

In a single-institution phase III trial from Korea, 248 patients with clinical stage II or III gastric cancer were randomly assigned to surgery alone or to receive intraperitoneal mitomycin C on day 1 and intraperitoneal 5-FU on days 2 to 5.167 Overall, 110 of the 248 patients had either stage I or stage IV disease. When 5-year OS 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.

Given the small size of most trials of adjuvant intraperitoneal therapy, a meta-analysis was performed.168 Ten of the 13 trials included in the meta-analysis were deemed to be of “fair” quality and 3 to be of “poor” quality. With these recognized limitations, the use of hyperthermic intraoperative intraperitoneal chemotherapy was associated with an improved OS.

Preoperative Systemic and Postoperative Intraperitoneal Chemotherapy
 

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.164,165,167,169-172

Kelsen and associates studied 56 patients with high-risk (clinical stage T3–4) gastric cancer as determined by EUS.171 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 pathological staging, 51% of these patients were downstaged. No complete pathological responses were observed, and the median survival was 15.3 months.

Crookes and colleagues updated their promising results with a somewhat similar trial design.169 Fifty-nine patients with potentially resectable cancer 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 pathological 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.172 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 of Intraperitoneal Chemotherapy
 

The use of intraperitoneal therapy in the adjuvant setting remains investigational and requires further evaluation. Until further appropriately designed, prospective clinical trials 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 75-6). 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.173 Although phase III trials from Japan174 and China175 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 coworkers176 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.

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).173 A total of 436 patients were randomly assigned 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 randomly assigned to receive adjuvant treatment did not receive the assigned therapy. Of 153 patients randomly assigned 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.

Intraoperative Irradiation


Takahashi and Abe174 reported results from a large Japanese trial in which 211 patients were randomly assigned on the basis of day of hospital admission to receive either surgery only or surgery plus IORT (28 to 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 randomly assigned to surgery alone or IORT (single dose, 25–40 Gy).175 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.177-179 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.177 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.178 The third trial compared surgery alone with 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%.179 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.180 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 during 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 (see Table 75-6). The 5-year 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-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 advantage in survival 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 EBRT Plus Chemotherapy

 

Phase II single-institution gastric cancer trials that showed promise for combination postoperative adjuvant therapy were reported from MGH,181 Israel (Hadassah),182 Thomas Jefferson University Hospital,183 the University of Pennsylvania,184 and the Mayo Clinic.185 Gunderson and associates,181 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 to 52 Gy, 1.8 Gy/d) plus concomitant 5-FU-based chemotherapy. Subsequent local-regional relapse was documented in only 2 of the 14 (14%), in contrast with a 42% incidence in similar high-risk patients treated with surgery alone at MGH.121

A prospective randomized trial conducted at the Mayo Clinic included 62 patients with poor-prognosis completely resected gastric cancers who were randomly assigned to either surgery alone or surgery followed by irradiation (37.5 Gy in 24 fractions over 4 to 5 weeks) plus concomitant 5-FU (15 mg/kg, days 1 to 3 by IV bolus).186 A nonstratified, prerandomization scheme was used, with a 2:3 ratio favoring treatment. Informed consent was requested only of the 39 patients randomly assigned 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; Table 75-6 and E-Table 75-4). 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 75-6, 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.186 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).

Because of conflicting results in 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.120 Eligibility included patients with stages IB, II, IIIA, IIIB, and IV nonmetastatic adenocarcinoma of the stomach or GEJ (extension beyond muscularis propria [T2–4N0] or involved nodes [T1–2N1–3]). After an en bloc resection, 556 patients were randomly assigned 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 75-6). 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. Extraabdominal distant metastasis was diagnosed in 18% of those who relapsed in the surgery-only group 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. 120 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 GEJ. 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. 187 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.

An updated long-term outcomes analysis was performed of INT 0116 with more than 10-year median follow-up. 188 Overall and relapse-free survival data demonstrate continued strong benefit from adjuvant postoperative chemoradiation (OS: HR 1.32, P = 0.0046; RFS: HR 1.51, P < 0.0001). Reduction in local-regional relapse accounted for the majority of overall relapse reduction.

The successor 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. The irradiation treatment fields in both the phase II and successor phase III trials were based on idealized field design related to site of the primary lesion and TN stage of disease. 189 Preliminary results did not demonstrate improvements in survival when compared with the chemoradiation control arm from INT 0116. 190

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. A South Korea analysis by Kim et al. evaluated the potential role of postoperative CRT in a series of 990 patients with D2 resection who were at high risk for relapse. 191 Disease and patient characteristics and the method of chemoradiation treatment paralleled 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 75-6 and 75-7).

A phase III randomized trial was subsequently conducted in South Korea in 458 patients to compare postoperative chemotherapy with capecitabine plus cisplatin (XP [n = 228] versus XP plus concurrent chemoradiation (n = 230 patients). 192 Patients on the chemoradiation arm received 2 cycles of XP followed by 45 Gy/25 fractions/5 wk plus concurrent capecitabine 825 mg/m 2 twice daily during EBRT. On univariate analysis, 3-year DFS was slightly higher in the CRT arm at 78.2% versus 74.2% (P = 0.0862); in the subgroup of 396 patients with involved nodes, patients in the CRT arm achieved superior 3-year DFS (77.5 vs. 72.3%, P = 0.0365). On multivariate analysis with stage and treatment arm, the addition of EBRT to XP demonstrated significantly prolonged DFS with an HR of 0.6865, P = 0.0471.

Preoperative EBRT Plus Chemotherapy

 

Randomized trials testing preoperative EBRT plus chemotherapy for gastric cancer alone have not yet been published, but four phase III trials for patients with esophagus cancer (alone or combined with GEJ or cardia lesions) included patients with adenocarcinoma. This includes studies by Walsh et al., 193 Urba et al., 194 Tepper et al., 195 and van Hagen et al. 196

In the Dublin trial by Walsh et al., patients were randomly assigned to either immediate surgery (control arm) versus preoperative EBRT (40 Gy in 15 fractions), 5-FU (15 mg/kg/d continuous infusion [this is approximately equivalent to 600 mg/m 2 ] for 5 days, weeks 1 and 6), and cisplatin (75 mg/m 2 on the first day of each 5-FU infusion), followed by surgical resection 8 weeks after completion of EBRT plus chemotherapy. 193 A highly significant difference in survival was observed with combined-modality therapy (intent to treat median survival time, 16 vs. 11 months, 3-year OS, 32% vs. 6%, P = 0.01). Survival rates for the control group of patients were inferior to other historical data.

Urba and colleagues found a borderline survival advantage for patients treated with preoperative chemoradiation versus surgery alone in a small single-institution trial of 100 patients at the University of Michigan. 194 Preoperative treatment consisted of EBRT (45 Gy/1.5 Gy BID/3 wk) plus concurrent three-drug chemotherapy (5-FU, cisplatin and vinblastine). Patients with either squamous cell carcinoma (SCC) or adenocarcinoma were eligible; 75 patients had adenocarcinoma. Survival differences favoring chemoradiation were seen after several years of follow-up but did not reach statistical significance in view of the small series (3-year OS 30 vs. 16%, P = 0.09 on multivariate analysis).

 Two confirmatory studies have also shown an advantage to pre- operative chemoradiation versus surgery alone for esophageal or GEJ cancers (squamous or adenocarcinoma)—U.S. GI Intergroup and Cross phase III trials. 195,196 The U.S. GI Intergroup trial was performed in North America but was stopped prematurely because of poor accrual. Despite the low accrual (n = 56), patients randomized to trimodality treatment had a survival benefit when compared with patients randomized to surgery alone (median OS 54 vs. 21.6 months; 5-year OS, 39% vs. 16%, P = 0.008). 195 In the larger Cross trial (n = 368 patients), trimodality treatment again had a survival advantage over surgery alone (median OS 50 vs. 24 months, 2-year OS 67% vs. 52%, 3-year OS 59% vs. 48%, P = 0.011). 196

GEJ—Preoperative Chemoradiation Versus Chemotherapy (POET Trial)

 

The POET phase III trial by Stahl et al. included 120 eligible patients with T3-4 adenocarcinoma of the GEJ treated with either preoperative chemoradiation (CRT; n = 60) or chemotherapy alone (n = 60). 197 All patients received 2 cycles of PLF chemotherapy weeks 1 to 6/7 to 13 (cisplatin 50 mg/m 2 /1 h on days 1, 15, and 29; leucovorin 500 mg/m 2 /2 h and 5-FU 2 mg/m 2 /24 h infusion on days 1, 8, 15, 22, 29, and 36) followed by either PLF alone (weeks 14 to 17) or CRT with 30 Gy EBRT/15 × 2 Gy/3 wk (weeks 14 to 17) plus concurrent PE week 1 of EBRT (cisplatin 50 mg/m 2 /1 h on days 2 and 8; etoposide 80 mg/m 2 /1 h days 3 to 5). Outcomes analyses trends favored preoperative CRT over chemotherapy alone with regard to both OS (P = 0.07) and freedom from local relapse (P = 0.06; Table 75-6).

SEER Analysis, Gastric Cancer—Adjuvant Irradiation or Chemoradiation

 

Coburn et al. evaluated the impact of postoperative adjuvant EBRT or CRT in 4,041 patients who had resection of nonmetastatic gastric adenocarcinoma from May 2000 to December 2003 (SEER database). 198 Patients treated with postoperative EBRT (alone or plus concurrent chemotherapy) versus surgery alone had improved median OS for stages III (31 vs. 24 months, P = 0.005) and IVM0 (20 vs. 15 months, P < 0.001) and the difference approached significance for stage II (P = 0.0535). Adjusted analysis using a propensity score suggested that the benefit of adjuvant irradiation was similar for stage II and III patients (HR of death 0.733 and 0.773 respectively).

Meta-Analyses, Gastric/Esophageal Cancer—EBRT, Chemoradiation, Chemotherapy

 

A meta-analysis by Fiorica et al. evaluated the impact of adjuvant EBRT or CRT in the reduction of all-cause mortality in patients with resectable gastric adenocarcinoma (nine published phase III trials—four preoperative EBRT and five postoperative CRT). 199 For patients treated with preoperative EBRT, the HR for all-cause mortality was 0.62 (P = 0.002). In patients treated with postoperative CRT, the HR for all-cause mortality was 0.45 (P < 0.00001).

An Australian meta-analysis published by Gebski et al. evaluated the impact of either preoperative CRT or preoperative chemotherapy in patients with resectable esophagus adenocarcinoma or SCC. 200 For patients treated with preoperative CRT, the HR for all-cause mortality was 0.81 (P = 0.002), with similar results for patients with adenocarcinoma (HR: 0.75, P = 0.02) and SCC (HR: 0.84, P = 0.04). In patients treated with preoperative chemotherapy, the HR for all-cause mortality was 0.90 (P = 0.05), with significant benefit found for patients with adenocarcinoma (HR: 0.78, P = 0.014) but no benefit for those with SCC (HR: 0.88, P = 0.12).

Summary—Adjuvant Irradiation Alone or Plus Chemotherapy

 

In summary, both preoperative irradiation 180 and postoperative CRT 120,188 have been demonstrated to be superior to surgery alone for resectable gastric and gastroesophageal cancers in randomized phase III trials and meta-analyses. Preoperative chemoradiation has been shown to be potentially advantageous to preoperative chemotherapy alone in the POET phase III trial for GEJ cancers. 197

 

Irradiation Techniques

For patients who receive postoperative EBRT following surgical resection or exploratory laparotomy, 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 reopera-tive series from the University of Minnesota is demonstrated in Figure 75-4A in conjunction with an idealized, shaped AP-PA irradiation portal that incorporates the areas of local-regional relapse. 13,123 The tumor bed and nodal volumes are reconstructed with the aid of preoperative and postoperative imaging studies and surgical clip placement. In Figure 75-4B, the idealized AP-PA field is superimposed on the organs and structures that define irradiation tolerance. For individual patients, the idealized field needs to be modified depending on the surgical or pathological extent of disease (based on primary site and TN extent of disease) and the adjacency of tolerance organs and structures.

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 GEJ have a higher propensity to 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 a lower likelihood of spread to nodes near the cardia of the stomach, the periesophageal and mediastinal nodes, or splenic hilar nodes. 260 Any tumor originating in the stomach has a high propensity to 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.

With preoperative or primary chemoradiation for GEJ or proximal gastric cancers, because of the risk of submucosal or subserosal lymphatic spread, a > 5-cm margin of uninvolved esophagus/proximal stomach should be included proximally, and the distal/lateral field extent should include a > 5-cm margin of uninvolved stomach (E-Fig. 75-4; Figs. 75-5 and 75-6). If the lesion extends beyond the gastric/ GEJ wall, a major portion of the left hemidiaphragm should be included. Cerrobend blocks or multi-leaf collimators should be used to decrease the volume of irradiated heart and lung, when technically feasible. 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. IMRT may improve dose distribution, especially relative to the heart, when compared with three-dimensional (3D) conformal techniques for patients with GEJ cancers treated with preoperative chemoradiation (see Fig. 75-7), but there is uncertainty whether this will improve short-term or long-term treatment tolerance.

With postoperative irradiation of GEJ cancers, the irradiation field may include the anastomotic site and some or all of the remaining stomach. Postoperative fields are larger than preoperative fields unless an involved field approach is chosen for select T3N0 patients.

 

Dose-Limiting Organs/Structures

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. 201 In most patients, a portion of both kidneys will be within the 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 GEJ or proximal to midgastric cancers (E-Fig 75-4 and Fig. 75-5), 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. 75-6). 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 used. 181,189,190,202

 

Multifield Irradiation Techniques

Sophisticated conformal irradiation techniques based on CT-based planning should be used routinely for optimal sparing of normal organs and structures (heart, lung, kidneys, spinal cord). This includes 3D conformal techniques and intensity-modulated radiation therapy (IMRT).

More routine use of multiple field techniques should be considered even for postoperative irradiation, when preoperative imaging exists to allow accurate reconstruction of target volumes (see E-Fig. 75-4, Figs. 75-5 and 75-6). Single-institution data suggest that multiple field arrangements may produce less toxicity. 185 When patients are treated preoperatively, paired lateral fields are usually combined with AP-PA fields to achieve improved dose homogeneity (see Fig. 75-5). 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 the 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 GEJ cancers, the contribution from lateral fields would preferably be limited to 10 to 15 Gy because of lung tolerance.

With the wide availability of 3D conformal treatment-planning systems based on CT imaging, it may be possible to target more accurately the high-risk volume and to use unconventional field arrangements and/or IMRT 203-206 to produce superior dose distribu- tions. 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). The extent of disease identified on diagnostic endoscopy and EUS and PET/CT should be carefully incorporated into target definition and field design.

When treating patients with distal esophageal or GEJ cancers, irradiation dose to the heart and lung is of particular concern. This is especially true in the neoadjuvant setting because of the risks of perioperative morbidity. Wang et al. found that the volume of lung spared from doses ≥ 5 Gy (V5) was the only independent predictor of perioperative pulmonary complications. 207 Because IMRT may result in increased volume of lung exposed to low doses, it has not gained widespread acceptance over standard four-field conformal treatment design. Care must be taken when choosing beam angles for IMRT to minimize lung V5. However, at Mayo Clinic in Arizona, a retrospective review demonstrated a decrease in lung and heart doses in patients treated with IMRT compared with 3D conformal techniques. 205 This preliminary experience with IMRT has not appeared to compromise early clinical outcomes with respect to disease control or treatment tolerance. At a median follow-up of 27 months, 2-year OS was 55%. In addition, even with the increased use of minimally invasive surgery, there has been no evidence of excessive perioperative complications. 208 The dosimetric improvements of IMRT with regard to the heart may be most significant for reducing long-term cardiac toxicity, which will require longer follow-up of surviving patients in order to detect the full clinical benefits. Hybrid IMRT and conformal plans may also be used to improve target conformality while minimizing the dose to the lungs. 206 Figure 75-7 demonstrates a hybrid IMRT preoperative irradiation treatment plan for a typical GEJ cancer patient.

Acceptable treatment plans can be achieved with either 3D conformal or IMRT planning techniques. The varying length of esophagus required to be treated in patients with distal esophageal and GEJ cancers requires individualization of treatment planning.

 

Idealized Treatment Field Guidelines

  Guidelines for defining the clinical target volume for postoperative radiation fields have been developed by Tepper and Gunderson based on location and extent of the primary tumor (T category) and location and extent of known nodal involvement (N category). 189,190

Table 75-8 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 75-9 and 75-10 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 pathological 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.

 

 

Locally Advanced Disease (Borderline Resectable, Unresectable and Residual)

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 pathological 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 pathological 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. 209 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. 41,42 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 210 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 211 compared historical control subjects with patients who had unresectable cancer or who had palliative procedures and received postoperative radiation therapy (unknown whether 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 174 reported 15% 5-year survival rate with a single dose of IORT (28 to 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 randomly assigned 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, 212 5-FU was used during the first 3 days of irradiation in one-half of the patients (irradiation, 35 to 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 75-11). In a randomized study by the GITSG, 213,214 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. 215 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. 216 The three long-term survivors (14%) received both irradiation and 5-FU.

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 217 and MGH, 181 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 184 of individuals with unresected adenocarcinoma of the esophagogastric junction or esophagus, local control was better with combinedversus 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 and 20 mg/m 2 , respectively, for 3 to 4 days, week 1 or 1 plus 5 of irradiation). 218 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. 213,214 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. 181 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. 219 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 GEJ 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 extraabdominal 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, 213 such problems were minimal or nonexistent in the MGH series of 46 patients. 181 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 Chemotherapy

Because of 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

 

Six different trials have assessed the potential benefit of preoperative chemotherapy for patients with initially “unresectable” stomach cancer. 133,220-225 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. Pathological complete responses (CRs) were uncommon except for the Wilke trial (pathological CR in 5 of 34 patients). 133 More recently, in a single arm trial, Sym and coworkers evaluated the combination of docetaxel, cisplatin, and capecitabine. 226 Thirty-six of 49 patients were able to undergo surgery, with 31 achieving an R0 resection. The median OS was 12.1 months for the entire group. The median OS for patients undergoing surgery had not been reached at the time of the report.

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. 227-229 Presumably, this represents a mix of patients with clinically resectable and unresectable or borderline resectable cancer. Resectability rates ranged from 60% to 77%, which seems to be higher than for patients with initially 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. 230 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 pathological 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).

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 had unresectable disease on the basis of prior exploration, the successful operations in these reports may not have been influenced by neoadjuvant chemotherapy. In general, pathological 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. 230 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.

Treatment of Metastatic Disease and 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. 236 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. 237-242 In the largest of these trials, 193 patients were randomly assigned to either 5-FU + MeCCNU or to no treatment. 238 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. 237,239-241

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 rarely used.

Fluoropyrimidines

 

Both intravenous (5-FU) and oral fluoropyrimidines (capecitabine, S-1) have been evaluated in trials for stomach or esophagogastric cancers. 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 75-12). 243-245 In a trial that mixed 254 patients with either adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma of the esophagus or stomach, patients were randomly assigned to either protracted-infusion 5-FU or protracted-infusion 5-FU with mitomycin C. 244 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 randomly assigned 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. 243 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. 245 A total of 399 patients with advanced carcinoma of the stomach were randomly assigned. All three regimens showed modest activity, with no significant difference in the primary outcome measures.

The recent use of oral fluoropyrimidines in gastric cancer has focused primarily 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. 246 OS was 10 months. Various combinations of capecitabine and other chemotherapy drugs, such as cisplatin or docetaxel, have been evaluated. 247-250 The majority of recent trials, including several phase III trials 251,252 as described below, 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. 253 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%. 254 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. 255-257

S-1 was directly compared with continuous-infusion 5-FU in a randomized phase III trial in Japan. 258 This trial was designed to evaluate the noninferiority of S-1 (n = 234) versus 5-FU (n = 234), using median OS as the primary end point. S-1 was noninferior to 5-FU, supporting its potential use as a substitute to 5-FU.

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/m 2 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. 259 In a separate trial, assessing two different infusion schedules (200 mg/m 2 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. 260 In several trials performed in Japan using paclitaxel (210 mg/m 2 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. 261-263 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. 264,265 The use of low-dose paclitaxel in combination with cisplatin did not seem to alter outcome, with a response rate of 44% and OS of 12.1 months in a phase II trial performed in Korea. 266 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. 267 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. 267,268

Docetaxel as a single agent has been evaluated in several phase II trials. In several single-institution trials of docetaxel 100 mg/m 2 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. 269,270 Other trials assessed lower doses of docetaxel (60 or 75 mg/m 2 ) and have reported similar results, with response rates of 18% to 24% and a median survival of 11 months with the 75-mg/m 2 dose. 271-273

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. 274-276 In a randomized phase II trial, the combination of docetaxel and 5-FU was compared with paclitaxel and 5-FU. 277 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. 249,278

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. 279-282 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. 283,284 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. 285 In this trial, the combination of docetaxel and cisplatin had 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 (see Table 75-12) the combination of docetaxel, cisplatin, and 5-FU was compared with cisplatin and 5-FU. 286 OS 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; treatment-related grade 3 or 4 adverse events developed in 69% of patients, compared with 59% of patients receiving cisplatin and 5-FU. Neutropenia and neutropenic fever were both significantly higher with the three-drug combination. A modified regimen of docetaxel, cisplatin, and 5-FU showed improved tolerability and led to a subsequent phase II trial in combination with bevacizumab. 287 A separate trial of a low-dose weekly regimen produced minimal toxicity, but only modest clinical benefit. 288

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. 289-293 Given the apparent activity of this combination, a variety of phase III trials have compared 5-FU and cisplatin with other regimens (see Table 75-12). The response rates in these larger trials were 20% to 51%, and the median survival was 7.2 to 8.6 months. 245,286,294,295

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. 296-298 A phase III study, however, could not show an advantage for FAP over 5-FU alone. 299 Less favorable outcomes were noted for the combination of EAP in phase II trials. 300,301 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 OS was seen with PELF (see Table 75-12). 302

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. 303-306 A subsequent phase III trial of patients with previously untreated locally advanced or metastatic gastroesophageal cancer compared ECF with the combination of FAMTX. 307 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. 308,309 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. 267

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, 310,311 the addition of oxaliplatin seems to significantly improve response and OS. A variety of schedules using the combination of 5-FU, oxaliplatin, and leucovorin have been evaluated in phase II trials, including FLO, FUFOX, FOLFOX, and XELOX. These regimens have generally shown similar results with response rates of 38% to 65% and median OSs of 8.6 to 11.5 months. 312-317 In a phase III trial of 5-FU and leucovorin with either oxaliplatin or cisplatin, equivalent outcomes were seen. 318 With 220 patients randomly assigned, a nonsignificant trend in progression-free survival (PFS) and OS was noted.

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 (see Table 75-12). 319 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 vs. 9.9 months; HR: 0.80, 95% CI: 0.65, 0.97, P = 0.02). 251 In a smaller trial of 316 patients randomly assigned to either capecitabine and cisplatin or 5-FU and cisplatin, the combination of capecitabine and cisplatin showed significant noninferiority for PFS (5.6 vs. 5.0 months, HR: 0.81, 95% CI: 0.63, 1.04, P < 0.001). 252 A metaanalysis of these two trials concluded that the capecitabine combinations result in a significantly improved OS. 320

Two phase III trials have assessed the activity of S-1 in combination with cisplatin in patients with advanced stomach or esophagogastric adenocarcinoma. In the SPIRITS trial conducted in multiple centers in Japan, 150 patients were randomly assigned to receive S-1 alone and 148 to S-1 and cisplatin. 321 The addition of cisplatin resulted in a significant improvement in PFS (6.0 vs. 4.0 months, HR: 0.57, 95% CI: 0.44, 0.73, P < 0.0001) and OS (13.0 vs. 11.0 months, HR: 0.77, 95% CI: 0.61, 0.98; P = 0.04). The addition of cisplatin did result in a higher rate of grade 3 and 4 hematologic toxicity, nausea, and anorexia. In a separate trial (FLAGS) conducted in 24 countries and involving 1,053 patients (1% Asian), S-1 and cisplatin was compared with 5-FU and cisplatin. 322 Although the combination of S-1 and cisplatin had significantly less toxicity, no difference was seen in median OS.

Irinotecan

 

The topoisomerase-I inhibitor irinotecan 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. 323 Irinotecan 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. 324 Similar response rates and OS have been reported for irinotecan and cisplatin, irinotecan and capecitabine, irinotecan and mitomycin C, and irinotecan and oxaliplatin. 325-328 The addition of the antiangiogenic agent bevacizumab to the combination of irinotecan and cisplatin in a phase II trial did increase the response rate to 65% and the OS to 12.3 months. 329 The combination of irinotecan with leucovorin and infusional 5-FU (FOLFIRI) in a randomized phase II trial also showed promising results, with a response rate of 40% and OS of 11.3 months. 330 Phase III trials with these combinations have not been reported.

Continuous infusion 5-FU was compared to irinotecan and cisplatin in a randomized phase III trial in Japan. 258 This trial was designed to evaluate the superiority of irinotecan and cisplatin, using median OS as the primary end point. With 236 patients randomly assigned to irinotecan and cisplatin and 234 to 5-FU, 5-FU provided an equivalent outcome. The median survival for those receiving 5-FU was 10.8 months versus 12.3 months for those receiving irinotecan and cisplatin (HR: 0.85, 95% CI: 0.70, 1.04, P = 0.0552). A randomized trial compared the combination of irinotecan, 5-FU, and leucovorin with 5-FU and cisplatin. 331 Equivalent outcomes were seen as measured by OS and time to progression. However, the irinotecan-containing regimen was better tolerated.

Targeted Therapy

 

A variety of molecularly targeted therapies have been evaluated in patients with esophagogastric cancers. In general, the targeted therapies are intended to enhance and not replace chemotherapy. Multiple studies have indicated that markers of enhanced angiogenesis are correlated with worse outcomes. Many studies in particular have shown that high levels of vascular endothelial growth factor (VEGF) are predictive of poor survival. 332-334 Based on this observation, several clinical trials have evaluated the benefit of bevacizumab added to chemotherapy. Several phase II trials have suggested benefit to the use of bevacizumab. 335,336 However, a multinational randomized phase III trial (Avastin in Gastric Cancer [AVAGAST]) for patients with advanced stomach or GEJ cancers of capecitabine or 5-FU combined with cisplatin (n = 387) alone or in combination with bevacizumab (n = 387) failed to show any significant benefit in OS. 337 The median survival for patients receiving chemotherapy alone was 10.1 months compared to 12.1 months for those receiving bevacizumab (HR: 0.87, 95% CI: 0.73, 1.03, P = 0.1002).

Trials focusing on targeting Her-2 overexpression, however, have shown benefit in appropriately selected patients. Approximately 20% of patients with esophagogastric cancers show overexpression of Her- 2. 338 In the ToGA trial patients with adenocarcinoma of the stomach or GEJ, overexpressing Her-2, were randomly assigned to either chemotherapy alone, with capecitabine or 5-FU combined with cisplatin (n = 296), or chemotherapy with trastuzumab (n = 298). 339 Overexpression of Her-2 was based on preset criteria specific to stomach cancer. Median OS increased from 11.1 months to 13.8 months (HR: 0.74, 95% CI: 0.60, 0.91, P = 0.0046). A significant improvement in PFS and response rates were also seen.

A number of phase II trials have also explored the use of epidermal growth factor receptor (EGFR) inhibitors in esophagogastric cancers. The EGFR inhibitor cetuximab appears to have minimal activity as a single agent. 340 With no completed phase III trials of an EGFR inhibitor having been reported, the benefit of an inhibitor combined with chemotherapy remains uncertain. In one randomized phase II trial of matuzumab combined with chemotherapy (epirubicin, cisplatin, capecitabine) compared with chemotherapy alone, no apparent benefit was seen to the addition of matuzumab. 341

As with other targeted therapies, the ability to appropriately select patients for use of a specific agent will likely require molecular markers that correlate with response. Targeted therapies will undoubtedly have an increasing role in the treatment of esophagogastric cancers. Their role continues to be reliant on the development and completion of phase III trials specifically evaluating their use.

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 esophagogastric 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 OS 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.

For patients with metastatic disease, the activity of the chemotherapy needs to be balanced with the toxicities of the regimen used. Although three-drug regimens have shown higher response rates and improved survival, their use is limited by their toxicity. Consideration should be given to the use of two-drug combinations in older patients or patients with a less robust performance status. In patients with tumors overexpressing Her-2, the addition of trastuzumab to a two-drug regimen may provide improved survival while limiting toxicity.

 

 

 

Future Possibilities/Clinical Trials/Treatment Algorithm

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, 75,78 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 75-13). 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). 192 Early results from the South Korea phase III trial suggest that postoperative chemoradiation improved 3-year DFS in node-positive patients who had a D2 node dissection. 193

The U.S. GI Intergroup replacement phase III randomized trial was designed to build on the positive results of INT 0116 120,187,188 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. Preliminary analyses did not demonstrate improvements in survival with the more aggressive experimental arm when compared with the chemoradiation control arm from INT 0116. 190

On the basis of encouraging results with preoperative chemoradiation (CRT) 193-197 for patients with locally advanced adenocarcinoma of the esophagus and/or GEJ (i.e. POET trial) and the survival advantage for perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancers in the British and French phase III trials, 61,163 future phase III studies should evaluate preoperative chemotherapy (alone or followed by preoperative or postoperative CRT) and preoperative CRT in combination with resection for patients with potentially resectable gastric cancers. 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 relapse or survival outcomes.

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

 

It is unlikely that significant advances will be made through the addition of other new chemotherapy drugs to those already available. Molecular profiling of tumors may allow more individualized approaches to patient care. With this type of approach advances will more likely occur through the use of targeted therapies, as demonstrated with trastuzumab. A variety of trials with targeted therapy used alone or in combination with chemotherapy are under way. Ultimately, the goal must focus on improvements in both OS 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 75-13 and Figures 75-8 and 75-9.

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 (see next discussion).

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). 129,187,188

Our institutions prefer the use of preoperative CRT for patients who have T1–2N1–3M0 or T3N0–3M0 GEJ 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. For patients who are at high risk for surgical resection following preoperative CRT (medical comorbidities), if there is a clinical complete response based on endoscopy and PET/CT, surgery may reasonably be kept in reserve for local relapse. 344

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 or GEJ 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

 

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 support 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.

 

 

 

 

Conclusions

In summary, gastric and GEJ malignancies present a variety of challenges. Innovative combined-modality approaches will be needed to improve survival with acceptable morbidity. This treatment may include combinations of EBRT plus chemotherapy, IORT, and resection for the local component of disease, systemic or intraperitoneal chemotherapy for the abdominal component, and systemic treatment (chemotherapy, other) for the extraabdominal risks of relapse. For patients with metastatic disease, the availability of growth factors may allow more aggressive multidrug approaches.

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The complete reference list is available online at www.expertconsult.com.

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