Brian G. Czito, Manisha Palta, and Christopher G. Willett
ANATOMY
The stomach begins at the gastroesophageal (GE) junction and ends at the pylorus. The stomach is generally divided into anatomic regions, including the gastric cardia (the region surrounding the superior opening of the stomach where it connects with the GE junction/level of the lower esophageal sphincter), the fundus (situated superiorly, a rounded portion superior to the body and to the left of the cardia), the body (a large, central portion of the stomach), and the pyloric canal (distally, connecting to the duodenum). The pylorus is composed of two parts: the pyloric antrum, which connects to the body of the stomach, and the pyloric canal, which empties into the duodenum (Fig. 58.1). The pylorus communicates with the duodenum of the small intestine via the pyloric sphincter (valve). This valve regulates the passage of chyme from stomach to duodenum and prevents backflow of chyme from duodenum to stomach. A plane passing through the incisura angularis on the lesser curvature divides the stomach into the body and the pyloric portion (antrum). The anterior surface of the stomach is covered with peritoneum of the greater sac. At the left and cranially, it abuts the diaphragm. In view of the increasing incidence of gastric cancer at the GE junction, it is important to note that there is either no or variable visceral peritoneal covering at the most proximal portion of the GE junction.1 Positive radial margins at this site are often “true” positive margins, whereas many other positive margins in the stomach are free serosal margins unless the tumor is adherent to an adjacent organ or structure. The right portion of the anterior gastric surface is adjacent to the left lobe of the liver and the anterior abdominal wall. Posteriorly, the stomach is covered with peritoneum of the lesser sac or omental bursa. The stomach contacts many visceral structures; from superior to inferior, it is adjacent to the spleen, left adrenal gland, superior portion of the left kidney, ventral portion of the pancreas, and transverse colon. The hepatogastric ligament or lesser omentum is attached to the lesser curvature and contains the left gastric artery and the right gastric branch of the hepatic artery. Histologically, the wall of the stomach has five layers: the mucosa, the submucosa, muscular layer, subserosa, and serosa. The muscularis layer is composed of an outer longitudinal layer, a middle circular layer, and inner oblique layer.
The stomach’s vascular supply is derived from the celiac axis. The celiac artery usually has three branches: the left gastric artery, which supplies the upper right portion of the stomach; the common hepatic artery, which gives rise to the right gastric artery supplying the lower right portion of the stomach, and the right gastroepiploic branch supplying the lower portion of the greater curvature; and the splenic artery, which gives rise to the left gastroepiploic supplying the upper portion of the greater curvature and the short gastric arteries supplying the fundus. Variations in this normal vascular supply are common. The celiac axis originates at or below the pedicle of T12 in approximately 75% of patients and at or above the pedicle of L1 in 25% of patients.2 The lymphatic drainage of the stomach follows the arterial supply. Although most lymphatics ultimately drain to the celiac nodal basin, lymph drainage sites can include the splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas.
EPIDEMIOLOGY
Gastric cancer is estimated to afflict 21,320 people in the United States in 2012 and result in 10,540 deaths.3 Worldwide, gastric cancer remains a significant cause of cancer-related mortality, with nearly one million new cases annually and an estimated 700,000 deaths, making it the second-leading cause of cancer-related deaths. During the past 70 years, there has been a significant decline in the incidence of gastric cancer in both sexes in Western countries. The causes of this decline are unknown.4,5 Although the overall decrease in gastric cancer incidence is encouraging, there has been a steady and dramatic increase in the incidence of proximal lesser curvature, cardia, and GE junction tumors over the past 20 years, especially in White males.6 In contrast to the increasing incidence of more proximal gastric cancers seen in the Western Hemisphere and parts of Europe, distal tumors continue to comprise most gastric cancers in the Far East and other parts of the world.
Risk factors implicated in gastric cancer development include consumption of smoked, pickled, and salted foods; low intake of fruits and vegetables; low socioeconomic status; smoking; decreased use of refrigeration; and dried meat/fish consumption.4,7 Pernicious anemia is associated with gastric cancer, with 5% to 10% of patients with pernicious anemia developing gastric cancer. Prior subtotal gastrectomy for benign lesions also carries a 25% risk for subsequent malignancies, with latency periods of 15 to 40 years.8 Villous adenomas are clearly premalignant; hyperplastic or hamartomatous polyps occur more frequently and are apparently benign. Gastric ulcers carry no increased risk, although previous distal gastrectomy for benign disease confers a 1.5- to 3-fold relative risk for development of gastric cancer, with a latency period of 15 to 20 years. Additionally, patients with a family history of nonhereditary gastric cancer have a higher risk for developing similar disease, with a very small percentage of patients developing gastric cancer in the context of an inherited syndrome. The presence of Helicobacter pylori is associated with a three to six times greater risk of gastric cancer than if infection is absent. The increased association of H. pyloriappears to be confined to those with distal gastric cancer and intestinal-type malignancy.9 Although this association of H. pylori infection with gastric cancer may provide new insight into the pathogenesis of this tumor, only a small minority of infected people develop gastric carcinoma, and there are no firmly established data regarding the screening of infected patients or the effect of treatment for infection on subsequent malignancy.
Historically, gastric adenocarcinomas have been diagnosed as intestinal or diffuse types. Intestinal types are more prevalent in high-incidence areas and responsible for much of the observed global ethnic variation of disease.10 In contrast, diffuse gastric cancer incidence is fairly uniform among geographic regions or race and more uncommon than intestinal type. More recently, there has been an emergence of another distinct subtype—proximal gastric cancers. These are often grouped with GE junction and distal esophageal adenocarcinomas, with a rapidly rising incidence in industrialized nations. The risks factors for these individual types appear to vary significantly. Risk factors of intestinal, noncardia gastric cancers appear to center around inflammatory causes and environmental factors, including H. pylori, chronic gastritis, tobacco, high salt intake, and alcohol consumption. The less common diffuse gastric cancer subtype appears to be distinct, with E-cadherin mutations/silencing thought to be a common precursor event with this histology. Hereditary diffuse gastric cancer is a genetic syndrome in which there is loss of function/mutation in the E-cadherin gene. In proximal gastric cancer (and in contrast to intestinal types), H. pylori infection has been found to be potentially protective, possibly through associated atrophic gastritis and reduced acid production with subsequent reduction in gastroesophageal reflux disease (GERD). This possible association remains an ongoing area of study.10
FIGURE 58.1. Gastric anatomy. (From Tortora GJ, Grabowski SR. Principles of anatomy and physiology, 9th ed. New York: John Wiley & Sons, Inc. Copyright 1996. Reprinted with permission of John Wiley & Sons, Inc.)
PATTERNS OF SPREAD
Cancer of the stomach may extend directly into the omenta, pancreas, diaphragm, transverse colon or mesocolon, and duodenum. Peritoneal contamination with carcinomatosis is possible after a lesion extends beyond the gastric wall to a free peritoneal (serosal) surface.11
Microscopic or subclinical spread beyond the visible gross lesion occurs frequently because of the abundant lymphatic channels within the submucosal and subserosal layers of the gastric wall. The submucosal plexus in the esophagus and subserosal plexus in the duodenum allow proximal and distal spread.
It is difficult to perform a complete node dissection because of the numerous pathways of lymphatic drainage from the stomach (Fig. 58.2). Initial drainage is to lymph nodes along the lesser and greater curvatures (i.e., gastric and gastroepiploic nodes) but also includes the celiac axis, porta hepatis, splenic, suprapancreatic, pancreaticoduodenal, adjacent para-aortics, and distal paraesophageal system. The relative risks for nodal involvement in gastric cancer depend on the location of the primary tumor as well as extent of gastric wall involvement.
Gastric venous drainage is primarily to the liver by the portal system. Liver involvement is found in as many as 30% of patients at initial exploration, and it can occur as a result of venous metastasis, peritoneal-based spread, and direct extension (Fig. 58.3).
CLINICAL PRESENTATION
The most common presenting symptoms of stomach cancer are loss of appetite, early satiety, abdominal discomfort, unintentional weight loss, anemia-related weakness, nausea and vomiting, and tarry stools. Duration of symptoms is <3 months in almost 40% of patients and >1 year in 20%. Physical examination can reveal advanced disease, for which the presentation may include an abdominal mass (epigastric or liver mass as well as a periumbilical node [i.e., Sister Mary Joseph node]), palpable left supraclavicular nodes (i.e., Virchow’s node), or a rectal shelf (representing peritoneal seeding [i.e., Blumer’s shelf]).
DIAGNOSTIC WORKUP
Diagnosis is usually confirmed by upper gastrointestinal endoscopy as well as imaging studies in some instances. Double-contrast x-ray studies may reveal small lesions limited to the inner layers of the gastric wall. Endoscopy with direct visualization, cytology, and biopsy yields the diagnosis in ≥90% of exophytic lesions; however, infiltrative (linitis plastica), small (<3 cm), or cardia lesions may be more difficult to diagnose endoscopically. Endoscopic ultrasonography is the most accurate method of determining depth of tumor invasion (intramural vs. extramural extension) prior to resection but is less accurate in detecting regional nodal metastases.12,13 In some institutions, needle biopsies of suspicious nodes are performed at the time of endoscopic ultrasound.
Abdominal computed tomography (CT) is useful in determining the abdominal extent of disease and may help to determine which lesions extend to surgically unresectable structures but are of lesser value in detecting small lymph node metastases or peritoneal spread. Distant metastases should be ruled out with contrast-enhanced CT of the chest, abdomen, and pelvis. CT may provide valuable tumor localization information if irradiation is indicated. If a proximal gastric cancer extends to involve the esophagus, CT of the chest will help to rule out involvement of mediastinal nodes or the lung parenchyma.
Helical CT may be more useful than conventional CT in identifying smaller lymph nodes, which are particularly relevant to staging of gastric cancer patients. In a single-institution experience, 58 patients underwent nodal dissection for gastric cancer.14 A total of 1,082 nodes were resected, and 138 were metastatic. Helical CT was able to identify 1.1% of the 649 lymph nodes that were 1 to 4 mm in diameter, 45.1% of the 355 nodes of 5 to 9 mm, and 72% of the nodes >9 mm. For nodes ≥5 mm, the sensitivity for identifying metastatic nodes was greater than for nonmetastatic nodes (75.2% vs. 41.8%, respectively).
The value of laparoscopy in the staging of gastric cancer remains a subject of study. In one study of 71 patients with CT criteria of resectable disease, 69 completed laparoscopic evaluation.15 Forty-one of the 69 patients proceeded to laparotomy with curative intent, and 38 of 41 patients had resection of all gross tumor. Pathologic evidence documented hepatic metastasis in three patients with a negative CT scan of the liver, and one of them was detected by laparoscopy. Laparoscopy confirmed disease in 16 of 17 patients with peritoneal metastases (avoiding 12 laparotomies, 17%). The combination of CT scan and laparoscopy for staging information yielded a resectability rate of 93% in patients defined as potential candidates for curative gastric cancer surgery. Similarly, a large series from Memorial Sloan-Kettering Cancer Center of >600 patients with potentially resectable gastric adenocarcinoma by conventional imaging underwent laparoscopic staging, resulting in distant metastases being detected in 31% of patients.16 A systematic review on the role of diagnostic laparoscopy showed that change in patient management occurred in 9% to 60% of patients initially deemed resectable by preoperative imaging, predominantly through the identification of patients with metastatic disease who would not benefit from either laparotomy or neoadjuvant therapy, thereby avoiding unnecessary interventions. This primarily related to patients with advanced (T3, T4) gastric cancer, with relatively minimal benefit in early-stage patients, prompting the authors to recommend diagnostic laparoscopy for patients with locally advanced-stage disease.17 In addition, peritoneal fluid can be sampled for cytology at laparoscopy. If positive, this is a poor prognostic indicator and the patient should be considered as having M1 disease.
Overall treatment planning in gastric cancer may be improved by accurate preoperative classification of key prognostic factors, namely depth of invasion (T category) and lymph node involvement (N category). A prospective study in 108 patients evaluated endogastric ultrasonography (EUS), CT, and intraoperative surgical assessment for T and N classification.18 T-staging was accurately characterized by CT in 43% of the cases, EUS in 86% of cases, and intraoperative assessment in 56% of cases. Staging of N1 and N2 lymph nodes was correct with CT in 51% of the cases, 74% with EUS, and 54% with intraoperative assessment. Advanced gastric tumors tended to be more accurately staged with CT, although CT, in general, overstages the T-category and understages the N category. EUS showed a high accuracy for all the T-categories, although it also tends to understage N-categories. Finally, intraoperative assessment was equally accurate for all N-categories but tended to overstage early T-stages and to understage N-categories. A meta-analysis and systematic review of the role of EUS in T- and N-staging in nearly 2,000 patients with gastric cancers suggested the sensitivity for detecting T1, 2, 3, and 4 disease was 88, 82, 90, and 99%, respectively, with nodal staging sensitivity for N1 and N2 disease 58 and 65%, respectively, also suggesting that accuracy was higher with more advanced disease.19 Another systematic review concluded that EUS, multidetector CT, and MRI achieve similar results in terms of diagnostic accuracy of T-staging and assessing serosal involvement. Given that most experience has been gained with EUS, this was felt to remain as the first-choice imaging modality in the preoperative T-staging of gastric cancer.20 However, it should be remembered that EUS accuracy highly depends on the experience and expertise of the operating physician.
FIGURE 58.2. Locations of gastric lymph node stations. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol2009;92:164–175, with permission from Elsevier.)
The positron emission tomography (PET) scan has a lower detection rate in some cases of gastric cancers owing to the low fluorine-18 fluorodeoxyglucose (FDG) accumulation in patients with diffuse or mucinous tumors.21Approximately 40% of gastric carcinomas, notably above histologies, may not be detected with PET scan.22 PET alone has been described as displaying a lower sensitivity when compared to CT in detecting nodal involvement, although specificity is improved.23 Given this, PET alone is likely not an adequate diagnostic procedure for evaluation of gastric cancer and generally should be used in conjunction with CT scan for correlation, allowing more accurate preoperative staging than either modality alone. A suggested diagnostic evaluation for gastric cancer is shown in Table 58.1.
A prospective report analyzed the potential involvement of bone marrow at the time of radical surgery after obtaining material through aspiration and the use of monoclonal antibody CK-2 directed to component 18 of the intracellular cytokeratin.24 Among the 180 patients evaluated, 53% had a positive test showing malignant cells in the bone marrow. The finding was correlated with pT (p = .07) and Borrmann’s classification (p = .02) (see later discussion).25 The estimation of tumor cell contents in the bone marrow (<3 é 106) was related significantly to overall and disease-free survival (p = .04 and p <.007, respectively). The multivariate analyses detected that bone marrow malignant involvement was an independent prognostic factor for disease-free survival in pT1 to pT2 stages (p = .004), intestinal histologic subtypes (p <.008), and N0 patients (p = .004).
FIGURE 58.3. Patterns of failure in 82 evaluable patients in the University of Minnesota Reoperation series. A: Large bold circles indicate local failures in surrounding organs or tissues; large open circles indicate lymph node failures. B: Asterisk (*) indicates lung metastasis; plus (+) indicates liver metastasis. Superimposed irradiation portals encompass postsurgical gastric remnant, anastomoses, duodenal stump, gastric bed structures, and primary and secondary areas of lymph node drainage; broken lines represent upper and total abdomen fields. (From Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of failure in a reoperation series [second or symptomatic looks]. Clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982;8:1, with permission from Elsevier.)
TABLE 58.1 DIAGNOSTIC WORKUP FOR GASTRIC CANCER
STAGING
The current tumor-node-metastasis (TNM) system is depicted in Table 58.2.26 In the most recent American Joint Committee on Cancer (AJCC) staging of gastric cancers, cancers whose midpoint is in the lower thoracic esophagus, GE junction, or within the proximal 5 cm of the stomach (cardia) and extending to the GE junction or esophagus are staged as esophageal neoplasms. All other cancers with a midpoint in the stomach lying more than 5 cm distal to the GE junction or those within 5 cm of the GE junction (but not involving the GE junction or esophagus) are staged using the gastric cancer staging system. Potential drawbacks of this system are that it is based primarily on surgical outcomes and not entirely suitable in considering clinical baseline staging and preoperative therapy.
TABLE 58.2 AMERICAN JOINT COMMITTEE ON CANCER 2010 GASTRIC CANCER STAGING
TABLE 58.3 EXTENT OF INITIAL DISEASE COMPARED WITH SURVIVAL RATES FOR CANCER OF THE STOMACH
PATHOLOGY
Adenocarcinomas account for 90% to 95% of all gastric malignancies. Lymphomas, including both favorable and unfavorable histologies, are the second most common malignancies. Rarely, leiomyosarcomas (2%), carcinoid tumors (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) occur.
The site of origin of gastric cancers within the stomach has changed in the United States over recent decades, and proximal lesions are being diagnosed and treated more frequently. Although the highest frequency is still in the antrum/distal stomach (approximately 40%), the lowest frequency is now in the body rather than proximal portion of the stomach (approximately 25%), with intermediate frequency in the proximal stomach and GE junction (approximately 35%). Several investigators have reported an increased frequency of cardia lesions. As described previously, cardia lesions appear to have different epidemiologic factors, exhibit different tumor biology, and have an inferior prognosis from lesions in the other sites.27–28,29–31 Gastric cancers sometimes are categorized according to Borrmann’s five types. Type I tumors are polypoid or fungating; type II are ulcerating lesions surrounded by elevated borders; type III have ulceration with invasion of the gastric wall; type IV are diffusely infiltrating (linitis plastica); and type V are unclassifiable.25
PROGNOSTIC FACTORS
The most important prognostic indicators reflect tumor extent. If hematogenous or transperitoneal spread is present, the outcome is, essentially, uniformly fatal. Survival rates decrease with progressive tumor extension within or beyond the gastric wall.27,32,33,34 The number of involved lymph nodes also has a significant impact on survival. Lymph node involvement is important, as are the number and locations of nodes affected.27,34,35,36 Minimal node involvement adjacent to the primary lesion only moderately affects prognosis.32,36,37 The finding of either involved lymph nodes or complete wall penetration is usually not as ominous as the presence of both32,34,36,38 (Table 58.3). Additional prognostic indicators include a poor performance status, elevated alkaline phosphatase levels, and ethnicity.39 In one study, Asian-Pacific Islanders born in the United States were compared to those born abroad, finding that only foreign-born Asian-Pacific Islanders had a more favorable survival compared to indigenous Caucasians.40
Flow cytometry is also prognostically valuable; aneuploidy is associated with unfavorable tumor location, lymph node metastasis, and primary tumor invasion.41–43 Unfavorable DNA flow cytometry correlates with a poor prognosis.41 The prognosis is worse for cardia lesions, and flow cytometry reveals a greater incidence of aneuploidy.43 The gross pathologic appearance of the primary lesion also reveals prognostic information, although it is not known whether this factor is independent of tumor stage. Patients with Borrmann type I and II tumors have relatively favorable 5-year survival rates, although patients with type IV (linitis plastica) fare poorly.37,44–46
The molecular biology of gastric cancer reflects the heterogeneity of its causes and its histologic subtypes. Identification of the genetic and phenotypic variables existing among gastric cancers may lead to more directed therapeutic approaches and a more accurate prediction of clinical outcome. 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, appears to play a critical role. The p53 gene is located on the short arm of chromosome 17 and plays a key role in tumor suppression and cell-cycle regulation.47 The p53 gene halts DNA replication and triggers programmed cell death in response to DNA damage.48 Loss of p53 function allows malignancy to develop, affects the effectiveness of chemotherapy and irradiation, and predisposes cells to genetic instability.49,50 The latter is particularly important because p53 mutations occur early in tumorogenesis.51
A second major aberration affecting gastric epithelial cells is the impact of alterations in mismatch repair genes. Two such genes, hMSH3 and hMLH1, on chromosome 2 and 3, respectively, account for replication errors throughout the genome. Mutations in these genes are implicated in cancer family syndromes and hereditary nonpolyposis colorectal cancer, which is a disease associated with an increased tendency for the development of gastric tumors.52 Mutations in these genes generate genetic instability and have the potential to lead to further alterations in oncogenes.
Two proto-oncogenes, c-met and k-sam, are associated with scirrhous carcinoma of the stomach. The former encodes hepatocyte growth factor, which is a potent endogenous promoter of gastric epithelial cell growth.53 Its overexpression correlates with tumor progression and metastasis.54 The latter encodes a tyrosine kinase receptor family.54 In scirrhous carcinoma, c-met and k-sam amplification may occur independently. There is a tendency for k-sam to be activated in women <40 years of age and c-met to be amplified in men >50 years of age.51,55
Peptide receptors, including estrogen receptors and epidermal growth factor receptors, are associated with adverse prognoses.56,57 Epidermal growth factor receptors and levels correlate with higher rates of primary tumor infiltration, poorer histologic differentiation, and linitis plastica.58 The pathophysiologic relation between these peptide receptors and their association with poor prognoses is not well understood.
Modern molecular biology observations confirm the heterogeneity of human gastric cancer. Genetic alterations detected and potentially associated with a worse prognosis include CD44 expression; telomerase reactivation; p53 gene inactivation; dysfunction of repair genes such as hMSH3 and hMLH1; overexpression of proto-oncogenes such as erb-B2, bcl-2, c-met, and k-sam; estrogenic receptor expression; and presence of viral genomes.59 Gastric cancers with class II major histocompatibility complex antigen expression have a better prognosis; however, the loss of expression is not an independent prognostic factor.58 Illustrating the importance of understanding and potential exploitation of these genetic alterations, a recent randomized study was conducted in patients with HER2 overexpression. Patients with locally advanced or metastatic gastric or GE cancer (the ToGA trial) were randomized to determine whether trastuzumab (an antibody against the HER2 gene product/receptor) enhanced treatment efficacy when added to cisplatin and 5-fluorouracil (5-FU)/capecitabine therapy. This study showed that the addition of trastuzumab achieved a significant improvement in overall and progression-free survival.59a These and other data have led to the initiation of the Radiation Therapy Oncology Group (RTOG) 1010 trial, which randomized patients with esophageal/GE junction tumors to receive preoperative radiation therapy concurrent with paclitaxel/carboplatin, with or without trastuzumab, followed by resection.
GENERAL MANAGEMENT
Surgical Management
Operative attempts are highly successful if disease is limited to the mucosa; however, the incidence of such early lesions at diagnosis is <5% in most U.S. series. In Japan, the incidence of lesions initially confined to the mucosa or submucosa was only 3.8% in 1955 and 1956, although by 1966, as a result of screening procedures, this figure had increased to 34.5%, with corresponding survival rates of 90.9%.60 For very early gastric cancer, endoscopic mucosal resection and endoscopic submucosal dissection have been successfully used as less radical alternatives to standard surgery. Endoscopic laser surgery has been applied successfully to patients with very early gastric cancer whose tumors are inoperable because of complicating medical illness. Small lesions that are pedunculated, noninvasive, and well differentiated have lymph node metastasis in <5% of cases and can be completely removed endoscopically in 75% of cases.61 Radiation therapy with chemotherapy may be considered as adjuvant therapy in selected situations. These approaches in early gastric cancer (uncommonly seen in Western society) require meticulous patient selection and remain a topic of investigation.
Curative or palliative surgical resection is possible for 50% to 60% of patients at the time of initial disease presentation. However, only approximately 25% to 40% are eligible for potentially curative resection. Generally, patients with evidence of peritoneal involvement, distant metastases, or locally advanced disease (including encasement of unresectable/major blood vessels) are generally considered to have unresectable disease. Palliative resection is usually reserved for rare cases, including symptomatic palliation of bleeding uncontrolled by other methods. In some instances, unresectable tumors may be debulked successfully, with sites of minimal residual disease marked judiciously with clips. This may palliate and permit accurate delivery of postoperative radiation therapy. In patients with gastric outlet obstruction, gastrojejunostomy may be performed and preferable to endoscopic placement of stents in patients with expected longer survival.
No prospective randomized trials have definitively established optimal surgical therapy.62 Generally, it is recommended that gastric cancer surgery be performed by experienced surgeons in high-volume centers, entailing removal of the perigastric lymph nodes (D1) as well as those along the main vessels of the celiac trunk (D2), with the goal of examining ≥15 lymph nodes (discussed later).6 The preferred treatment for gastric carcinoma, especially for lesions arising in the body and antrum, is a radical subtotal gastrectomy. This operation removes approximately 80% of the stomach along with the node-bearing tissue, the gastrohepatic and gastrocolic omenta, and the first portion of the duodenum. Larger lesions may require total gastrectomy. For more proximal tumors, both proximal and total gastrectomy may be appropriate depending on extent of disease. There appears to be no advantage to performing total gastrectomy if subtotal gastrectomy produces satisfactory margins (i.e., 5 cm). Patients treated with total gastrectomy characteristically have 5-year survival rates of 10% to 15%, and those undergoing radical subtotal gastrectomy have 5-year survival rates of 25% to 45%.35,63,64 The inferior survivorship of patients undergoing total gastrectomy probably reflects larger tumors and unfavorable proximal lesions that prompt such a procedure. The value of splenectomy has not been addressed in prospective randomized trials; however, retrospective Japanese data do not support a survival benefit.47,65 Because routine splenectomy has not shown significant improved outcomes and potentially increases complication rates, complete removal of splenic nodes is not commonly performed by Western surgeons. The use of laparoscopic approaches in gastric cancer resection may reduce blood loss while potentially decreasing length of postoperative hospital stay and remains the subject of ongoing investigation. In patients who undergo adjuvant chemoradiotherapy, it may be prudent to place feeding jejunostomy at the time of resection.
The propensity for gastric carcinoma to spread via the submucosal lymphatics suggests that a 5-cm margin of normal tissue proximally and distally may be optimal. It may be necessary to include a portion of esophagus or duodenum to achieve adequate margins. Frozen-section pathologic evaluation of surgical margins has been advocated to confirm their adequacy.35 The importance of careful evaluation of longitudinal margins is emphasized in several series (Table 58.4) with documented positive pathologic margins in approximately one-quarter of “curatively” resected specimens.66–68,69,70–73 The approximate 25% positive longitudinal margin correlates almost precisely with the incidence of locoregional recurrence in the anastomosis or stump, as discussed later in this chapter.
Although R0 resection with adequate lymph node sampling is a primary goal for gastric cancer surgery, approximately half of patients end up with uninvolved margins. Although the longitudinal margin is routinely evaluated, equally important but frequently not assessed are the radial or circumferential margins. The incidence of radial margin positivity is not well reported in the literature (most of the series referenced in Table 58.4 addressed longitudinal margins alone). The rising incidence of T3 and T4 GE tumors will likely result in an increasing rate of microscopically positive radial margins. Because the perigastric tissue surrounding the GE junction and distal esophagus has no serosa, lesions that extend to the pathologic radial margin represent a true positive margin in a large percentage of cases.
The extent of lymph node dissection is controversial. At resection, it is recommended at least 15 lymph nodes be retrieved to reduce stage migration. In a D0 dissection, there is generally incomplete removal of the lymph nodes along the greater and lesser curvature. D1 dissection refers to removal of nodes along the lesser curvature (nodal stations 1, 3, and 5) and greater curvature (nodal stations 2, 4, and 6) (Fig. 58.2). In addition, more extensive lymph node dissection, including removal of nodes along the left gastric artery (nodal station 7), common hepatic artery (nodal station 8), celiac trunk (nodal station 9), and splenic artery (nodal stations 10 and 11) are referred to as a D2 dissection. In series with rigorous pathologic evaluation of these nodes,74 the likelihood of discovering lymph node metastasis increases markedly in both D1 and D2 procedures. There appears to be a small subset of patients who have limited metastasis in the celiac axis, superior pancreatic, or retroduodenal chains and may be cured by a D2 lymph node resection.75 Data from the Surveillance Epidemiology and End Results (SEER) database show that the number of nodes examined correlated with overall survival, potentially reflecting improved staging in these patients.76 Japanese researchers advocate complete lymph node removal to improve the rates of local control and survival. Several nonrandomized clinical trials suggested that extended lymphadenectomy may improve survival.77–78,79–80 Others81 reported that increasingly radical lymphadenectomies failed to improve survival or reduce the risk of locoregional failure. At least four prospective randomized trials of lymphadenectomies have been reported74,82–86,87 and show no survival advantage with more extensive lymph node dissection. Additionally, morbidity and mortality rates have been significantly higher for patients undergoing more extensive nodal dissection. An even more extensive lymph node dissection may entail para-aortic nodal dissection. However, a Japanese trial comparing D2 lymphadenectomy versus the same with para-aortic nodal dissection did not show any differences in overall or relapse-free survival between the groups, indicating the later approach should not be used in patients with curable gastric cancer.88 However, other important principles of lymph node dissection have been elucidated through these trials. The first is that as more lymph node areas are dissected and as pathologic lymph node evaluation is more rigorous, considerable stage migration occurs. This stage migration produces an apparent improvement in stage-specific survival without improvement in survival in the group overall.
TABLE 58.4 POSITIVE MARGINS IN RESECTED LONGITUDINAL GASTRIC SPECIMENS
TABLE 58.5 PATTERNS OF FAILURE AFTER “CURATIVE” RESECTION OF GASTRIC CANCER
TABLE 58.6 PATTERNS OF LOCOREGIONAL FAILURE AFTER RESECTION OF GASTRIC CANCER
Failure Patterns After Surgical Resection
Local failures in the tumor bed and/or regional lymph nodes and distant failures by hematogenous or peritoneal routes are common mechanisms of failure after “curative” resection in clinical, reoperative, and autopsy series38,89, 90–92,93 (Tables 58.5 and 58.6). For GE junction lesions, the liver and lungs are common sites of distant metastases. With gastric lesions that do not extend to the esophagus, the initial site of distant metastasis is usually the liver, and many failures could be prevented if an effective abdominal treatment could be combined with treatment to the primary site. In the series of Landry et al.,94 50 of 88 (57%) failing patients had disease progression within the abdomen only. Abdominal treatment also could address peritoneal seeding, which occurs in 23% to 43% of postgastrectomy patients.89–92,93,94,95,96,97
Locoregional failures occur commonly in organs and structures of the gastric bed and in lymph nodes (Table 58.6). Clinically detectable locoregional recurrence following surgical resection alone generally exceeds 25%. However, reoperation and autopsy series have suggested that these rates are much higher.98 Failures in the anastomoses, gastric remnant, or duodenal stump also are frequent, as suggested by the incidence of positive longitudinal resection margins (Tables 58.4 and 58.6). As is true for most sites, clinical series underestimate the true incidence of locoregional failure when compared with reoperative or autopsy series (Table 58.5). Progressive extension of the operative procedure to include routine splenectomy, omentectomy, and radical lymph node dissection neither improved survival nor decreased the incidence of locoregional failures in the University of Minnesota series.38,96 Subsequent failure in areas of initial node dissection occurred frequently, even with radical node dissections38 (Fig. 58.3). The high rate of regional node relapse provides a partial explanation for the lack of survival benefit with a D2 (extended lymphadenectomy) versus D1 (limited lymphadenectomy) node dissection in the phase III surgical trials discussed previously.
Indications for Radiation Therapy
The results of the U.S. Gastrointestinal Intergroup Gastric Adjuvant Trial has changed the standard of care in the United States to the use of both chemotherapy and radiation therapy in the postoperative setting for patients with disease extension through the gastric wall and/or with nodes positive for tumor (discussed later).99 Postoperative irradiation plus concurrent and maintenance 5-FU–based chemotherapy is recommended for patients with stage IB-IV and M0 gastric cancer.99 Quality control of irradiation field design was conducted during the cycle of chemotherapy given before the start of concurrent chemoirradiation. The up-front 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.
Radiation therapy, usually administered with concomitant 5-FU–based chemotherapy, is also indicated for locally confined gastric cancer that either is not technically resectable or occurs in medically inoperable patients. In this setting, therapy can be administered with curative or palliative intent, depending on the clinical situation. Those who undergo gastric resection with incomplete tumor resection or have truly positive margins of resection also are managed appropriately by combined-modality postoperative therapy.
RADIATION THERAPY TECHNIQUES
Simulation
When gastric cancer patients are simulated, the radiation oncologist should know the extent of disease based on imaging (barium swallow, CT, PET) as well as endoscopic procedures. CT simulation is appropriate for treatment planning. During simulation, the patient is positioned, straightened, and immobilized on the simulation table. An immobilization device is used to minimize variation in daily setup. Arms are generally placed overhead, and knees are supported underneath the legs. The administration of oral contrast to delineate the stomach is generally used and may help define the extent of mucosal irregularity. It may be advisable to have the patient come in with an empty stomach. The patient is placed on the CT simulator in the treatment position, and a scan of the entire area of interest with margin is obtained. At minimum, 3- to 5-mm slices should be used, allowing accurate tumor characterization as well as improved quality of digitally reconstructed radiographs. If patients lose >10% of their body weight during therapy, consideration should be given to repeat CT planning. Arterial phase IV contrast is generally used to delineate mediastinal and abdominal vascular nodal basins, including the celiac axis, and to allow the radiation oncologist to discern normal vasculature from other adjacent normal structures, potential adenopathy, and so forth. The tumor (if the patient is surgically naïve) and vital structures are then outlined on each slice on the treatment-planning system, enabling a three-dimensional (3D) treatment plan to be generated. The use of respiratory gating or breath-hold techniques may help to reduce target motion with respiration and, therefore, avoidance of normal tissue irradiation associated with larger margins used in free-breathing approaches. Four-dimensional (4D) CT scan may be appropriate to assess tumoral motion, facilitating appropriate margin placement on the target volumes.
Treatment Planning
Target Design
For a detailed description of target and field design in proximal gastric cancer involving the GE junction, the reader is referred to Chapter 53. In the design of radiation fields for neoadjuvantly treated or locally unresectable gastric cancer (as well as in the re-creation of tumoral volumes in adjuvantly treated patients), it is important to define varying target volumes, including gross disease as well as potential areas of subclinical involvement (i.e., the gross tumor volume [GTV] and clinical target volume [CTV], respectively). Defining GTV (including re-creation of volumes in the adjuvant setting) is based on multiple studies, including endoscopic descriptions (from both esophagogastroduodenoscopy and endoscopic ultrasound) as well as cross-sectional imaging. Gastric wall thickening correlating to the GTV can frequently be visualized on diagnostic and radiation planning CT. Similarly, EUS appears to be the most reliable test in detecting lymphadenopathy related to nodal spread. The endoscopist should be encouraged to accurately define not only the primary disease extent on EUS but also depth of penetration and potential involvement of adjacent structures, which can also be used to help guide GTV delineation. Similarly, EUS may allow detection of lymph nodes that may not be appreciated on CT or PET imaging, and the endoscopist should describe the size as well as location (e.g., relationship to tumor or adjacent structures). Additionally, radiographic areas of lymphadenopathy should similarly be included in the GTV. In GTV design, basing potential nodal involvement (and therefore target volumes) on nodal size is problematic given that metastatic nodes may frequently be below the resolution of conventional imaging. Therefore, it is not appropriate to rely exclusively on imaging modalities to define areas of subclinical spread for gastric cancer, realizing established pathologic patterns of spread data is important in determining radiation field design.
The identification of potential direct and nodal pathways for spread of subclinical disease (i.e., CTV definition) in gastric cancer is also of paramount importance. These areas vary significantly depending on site of origin of disease, making gastric cancer planning somewhat complex. As described previously, the stomach is characterized by a rich network of lymphatics that facilitates early lymph node spread of disease. Some authors have recommended dividing the stomach into three equal lengths (upper/proximal, middle, and distal), with tumors classified by location of the bulk of their masses in these respective sites. Therefore, practically speaking, the stomach can be divided into proximal (remembering that in the AJCC seventh edition staging system, involvement of the GE junction by proximal third tumors would be classified as an esophageal tumor), middle, or distal segments (Fig. 58.4).
Primarily based on extensive analysis of patterns of nodal spread from surgical series, Japanese investigators have developed lymph node station classifications (the Japanese classification of gastric carcinoma of the Japanese Gastric Cancer Association) that have been validated in other series (Fig. 58.2). Based on this system, general recommendations for CTV definition for tumors in varying parts of the stomach are as follows. Proximal third stomach tumors should include the contour of the stomach with exclusion of the pylorus and antrum (keeping a minimal margin of 5 cm from the GTV). Middle third tumors should include the contour of the stomach from the cardia to the pylorus. Distal third tumor CTVs should include the stomach except for the cardia/fundus, again keeping a minimal margin of 5 cm from the GTV. If pyloric/duodenal invasion is present, the CTV would be expanded along the duodenum with a margin of 3 cm from the tumor. Nodal volumes to be included are further described later, and it has been recommended that the CTV consist of a 5-mm margin around corresponding vessels. If target motion is not accounted for, the minimal recommended 3D margins to the CTV to obtain the internal target volume (ITV) are 1.5 cm in all directions, taking into account physiologic organ motion, particularly respiratory motion. The PTV can then be defined as the ITV volume plus a 3D margin of 5 mm.101
Field Design
Based on the likely sites of locoregional failure (Table 58.6), in resected patients, the gastric/tumor bed, anastomosis and gastric remnant, and regional lymphatics should be included in most patients.38,93,96,97,100 Major nodal chains at risk include the lesser and greater curvature, celiac axis, pancreaticoduodenal, splenic, suprapancreatic, porta hepatis, and, in some, para-aortics to the level of mid-L3.
FIGURE 58.4. Subdivision of the stomach into equal lengths along greater and lesser curves. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009;92:164–175, with permission from Elsevier.)
FIGURE 58.5. Suggested lymph node station coverage for tumors of the proximal third of the stomach without involvement of the GE junction. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009;92:164–175, with permission from Elsevier.)
FIGURE 58.6. Suggested lymph node nodal coverage of patients with middle third gastric carcinomas. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol2009;92:164–175, with permission from Elsevier.)
FIGURE 58.7. Suggested nodal coverage for primary gastric cancers of the distal third of the stomach. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol2009;92:164–175, with permission from Elsevier.)
FIGURE 58.8. Optimized postoperative irradiation fields for patient with T3N1 antral primary. Structures of interest were delineated at time of computed tomography simulation (A–D), and irradiation fields were designed with the aid of digitally reconstructed radiographs (E–H). A: Gastric remnant (teal). B:Gastric remnant plus body/tail of pancreas (dark blue), splenic hilum (salmon), and porta hepatis (medium blue). C: Head of pancreas (magenta) and kidneys (left, orange; right, light green) are delineated in addition to body/tail of pancreas and splenic hilum. D: Celiac artery (yellow) and duodenum (yellow–green) are shown together with head of pancreas and kidneys. A four-field technique of AP (anteroposterior), PA (posteroanterior), and paired laterals was designed to include the gastric remnant (teal), tumor bed (head of pancreas [magenta], first and second part of duodenum [yellow–green cross hatched]), pertinent nodal volumes (perigastric, pancreaticoduodenal, porta hepatic [medium blue cross hatched], celiac [yellow cross hatched], and suprapancreatic) and the optional nodal volume of splenic hilum (salmon cross hatched). E: Initial AP field (field margins as shown in medium blue exclude approximately two-thirds of the left kidney while including about 50% of the right kidney). Exclusion of the optional splenic hilar nodes would have allowed additional but minimal sparing of the left kidney in view of the adjacency of gastric antrum and splenic hilum. F: Initial right lateral field demonstrated exclusion of the spinal cord. G: Reduced AP field with exclusion of splenic hilar nodes and most of the gastric remnant. H: Reduced right lateral field.
FIGURE 58.9. Examples of locations of varying nodal stations and anatomic structures on axial CT slices. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol2009;92:164–175, with permission from Elsevier.)
The relative risk of nodal metastases at a specific nodal location depends on both the site of origin of the primary tumor102,103 and other factors including width and depth of invasion of the gastric wall. On the basis of previously described patterns of failure data, general guidelines in terms of field design can be made as illustrated in Figures 58.5 through 59.7 and discussed later. These are general guidelines, and all plans should be individualized according to available imaging and endoscopic data, and generalized portals based on patterns of failure data frequently need to be modified on the basis of the individual patient’s initial extent of disease.102,103 As seen in Figures 58.5 to 58.7, gastric tumors (i.e., without GE junction involvement) that originate in the proximal portion of the stomach have a higher propensity of spread to nodes in the 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. Nodal basins are similar to upper-third tumors with the exception of inclusion of nodal basins along the pyloric region, common hepatic artery, and additional coverage along the greater curvature. Tumors that originate in the distal stomach, in the region of the gastric antrum, have a high likelihood of spread to the periduodenal, peripancreatic, and porta hepatis nodes, whereas they have a lower likelihood of spread to the nodes near the cardia of the stomach, the periesophageal and mediastinal nodes, or to the splenic hilar nodes—that is, there is less emphasis placed on more proximal nodes (including coverage of the splenic artery course, including splenic hilum) and more comprehensive coverage of pancreaticoduodenal nodal basins. Figure 58.8 shows an example of 3D fields for a T3N1 antral tumor. Figure 58.9 shows examples of varying nodal locations on axial CT images. Any tumor originating in the stomach has a high propensity of spread to nodes along the greater and lesser curvature, although they are most likely to spread to those sites in close anatomic proximity to the primary tumor mass.
Additional guidelines for defining the CTV for postoperative irradiation fields have been developed based on location and extent of the primary tumor (T-stage) and location and extent of known nodal involvement (N-stage).103Table 58.7 presents general guidelines on the impact of T- and N-stages on inclusion of the remaining stomach (gastric remnant), tumor bed, and nodal sites, whereas Tables 58.8–58.10 present treatment guidelines based on TN-stage within each of three primary sites (proximal, mid, and distal stomach). With proximal gastric lesions or lesions at the GE junction, a 3- to 5-cm margin of distal esophagus should be included; if the lesion extends through the entire gastric wall, a major portion of the left hemidiaphragm should be included. In these circumstances, blocking can decrease the volume of irradiated heart. For unresectable lesions with moderate periesophageal extension, it may not be possible to exclude an adequate amount of heart with anteroposterior/posteroanterior (AP/PA) fields, and the use of lateral or oblique fields for a portion of treatment is likely indicated. In general, for patients with node-positive disease, there should be wide coverage of tumor bed, remaining stomach, resection margins, and nodal drainage regions. For node-negative disease, if there is a good surgical resection with pathologic evaluation of at least 15 nodes, and there are wide surgical margins on the primary tumor (at least 5 cm), treatment for the nodal beds may be optional. Treatment for the remaining stomach should depend on a balance of the likely normal tissue morbidity and the perceived risk of local relapse in the residual stomach.
TABLE 58.7 GENERAL GUIDELINES OF IMPACT OF T- AND N-STAGE ON INCLUSION OF REMAINING STOMACH, TUMOR BED, AND NODAL SITES WITHIN IRRADIATION FIELDS
TABLE 58.8 IMPACT OF SITE OF PRIMARY GASTRIC LESION AND TN STAGE ON IRRADIATION VOLUMES: CARDIA/PROXIMAL ONE-THIRD OF STOMACH (GENERAL GUIDELINES)
TABLE 58.9 IMPACT OF SITE OF PRIMARY GASTRIC LESION AND TN STAGE ON IRRADIATION VOLUMES: BODY/MIDDLE ONE-THIRD OF STOMACH (GENERAL GUIDELINES)
TABLE 58.10 IMPACT OF SITE OF PRIMARY GASTRIC LESION AND TN STAGE ON IRRADIATION VOLUMES: ANTRUM/PYLORUS/DISTAL ONE-THIRD OF STOMACH (GENERAL GUIDELINES)
Although parallel-opposed AP/PA fields are a practical arrangement for tumor bed and nodal irradiation, multifield techniques should be used if they can improve long-term tolerance of normal tissues. Tightly contoured AP/PA fields should be designed to spare as much normal tissue as possible (Figs. 58.10 and 58.11). In institutional series, the average irradiation field measured 15 cm é 15 cm.33,104,105 More routine use of multifield techniques should be considered when preoperative imaging exists to allow accurate reconstruction of target volumes. Single-institution data suggest that multifield arrangements may produce less toxicity. Although AP/PA fields can be weighted anteriorly to keep the spinal cord dose at acceptable levels, a four-field technique, if feasible, can spare spinal cord with improved dose homogeneity. Depending on the posterior extent of the gastric fundus, either obliqued or more routine lateral portals can be used to deliver a 10- to 20-Gy component of irradiation to spare spinal cord or kidney. When lateral fields are used, liver and kidney tolerance limits the use of lateral fields to ≤20 Gy. Patients should be treated with high-energy photons when possible. With the wide availability of 3D treatment-planning systems, it may be possible to more accurately target the high-risk volume and to use unconventional field arrangements to produce superior dose distributions. To accomplish this without marginal misses, it will be necessary to both carefully define and encompass the various target volumes because the 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 laterals). Although, historically, two-dimensional (2D)-based radiation planning has been carried out primarily using anatomic landmarks as well as fluoroscopic barium swallow to determine field borders (Figs. 58.10 and 58.11), contemporary treatment planning using CT-based planning allows improved visualization of both target and nontarget structures, along with 3D reconstruction and creation of a “beams eye” view of varying fields, allowing improved conformality around target structures and improvements in normal tissue sparing. Because volumetric data can be obtained by CT scans, dose-volume histogram data can also be generated. A variety of 3D techniques are presently used and described later.
Because it is important to account for daily setup uncertainty as well as physiologic internal organ motion (secondary to respiration, peristalsis, cardiac motion, etc.), an additional margin must be added to a CTV. Interfraction variability in stomach location occurs, often owing to variations in gastric filling. Intrafraction changes in target shape and location may be attributable to respiratory motion, which, particularly in the superior to inferior direction, may frequently exceed 1 to 1.5 cm.98 In effort to reduce this, kilovoltage radiographic matching can be used with particular emphasis on matching of surgical clips. An additional technique that may improve treatment accuracy is cone-beam CT, which allows direct target matching within a given fraction. Similarly, movement related to respiratory motion can be assessed using 4D CT, which images the patient in all phases of respiration (similar to what is performed fluoroscopically but using CT). Similarly, respiratory gating techniques may allow reduction in the target volume/smaller margins, allowing for treatment during a more stationary phase of the respiratory cycle (either in expiration or breath-hold).98
Another potential approach in the treatment for gastric cancer is the use of intensity-modulated radiation therapy (IMRT). IMRT also uses CT-based planning, again allowing 3D reconstruction of varying structures. However, IMRT differs from 3D planning through the delivery of radiation dose by partitioning a radiation field into multiple smaller fields of various shapes and sizes, varying the dose intensity between each area. This is carried out with either dynamic IMRT (where collimating leaves move in and out of the radiation beam path during treatment) or “step-and-shoot” IMRT (where the leaves change the radiation field shape while the beam is turned off). Either method is particularly effective at conforming radiation dose to the target structures while avoiding dose to normal tissue. Radiation oncologists must determine which structures are most critical and weight their importance during the treatment-planning process. Importantly, the greater the number of “avoidance” normal structures, the more difficult it is to meet all dose constraints. IMRT utilizes “inverse planning,” where an intended prescription dose is placed on target volumes and dose constraints are placed on normal tissue structures. Thereafter, computer software algorithms allow design of unconventional treatment fields that would not otherwise be possible with standard planning methods. Radiation oncologists and medical physicists critically evaluate numerous plans until dose constraints are satisfactorily met. The result should be a series of radiation doses that closely conform to the target volumes while minimizing dose to normal tissues. IMRT may be appropriate in selected cases to reduce doses to normal structures, including heart, liver, and kidneys. A potential disadvantage of IMRT is the possibility of delivering low doses of radiation therapy to normal tissue areas that might not normally be irradiated using 2D or 3D techniques. Another potential disadvantage to IMRT is possible dose inhomogeneity, leading to potential “hot spots” in normal organs. Because IMRT requires precise target definition, the potential for “marginal miss” increases and careful, accurate target delineation is of paramount importance. With setup uncertainty and physiologic organ motion, care must be taken to ensure accurate and reproducible setup, including, with the use of immobilization devices, possible respiratory gating/breath-hold techniques. Block margins may be minimized with efforts to reduce intrafractional position variability, including breath-hold techniques. Generally, high-energy photons (10 to 18 MV) are recommended when using 3D conformal or IMRT therapy, potentially facilitating a reduction in the integral dose.
Multiple dosimetric studies comparing IMRT to two-field and 3D conformal radiation therapy plans have shown significant reductions in kidney, liver, heart, lung, and spinal cord dose. Although IMRT may result in improved normal tissue sparing, many of the acute toxicities encountered during radiation may persist given that many symptoms arise from radiation of the target, including gastric mucosa. The value of IMRT may lie primarily in normal organ sparing with potential reductions in long-term toxicity in surviving patients. There is ongoing investigation into further enhancements of this technique using volumetric modulated arc therapy and helical tomotherapy. This may also become important with the integration of newer/novel systemic agents, in conjunction with radiation therapy, of which many act as potent tumoral (and normal organ) radiation sensitizers and may reduce treatment-related toxicities as well as avoidance of treatment interruptions.98
FIGURE 58.10. Simulation film for T3 antral tumor with two of five peritumoral lymph nodes metastatically involved (radical subtotal gastrectomy with D1 node dissection). Simulation film identifies areas at risk for recurrence, including preoperative gastric/tumor bed (defined by preoperative computed tomography [CT] scan), anastomotic sites and gastric stump (staple line seen on precontrast simulation films and marked on postintravenous pyelogram/postcontrast film), and regional lymphatics (celiac, porta hepatis, superior mesenteric artery, and splenic nodes identified on CT, and pancreaticoduodenal nodes lie in C-loop of duodenum identified by preoperative CT). The right kidney is spared for approximately three-fourths of its volume, whereas the left kidney has about one-third of its volume blocked. (From Smalley SS, Gunderson L, Tepper J, et al. Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation. Int J Radiat Oncol Biol Phys 2002;52:283–293, with permission from Elsevier.)
FIGURE 58.11. Simulation film for a T4 (diaphragm invasion) gastroesophageal junction tumor with 4 of 15 involved lymph nodes (total gastrectomy with modified R3 node dissection). Areas at risk for recurrence include preoperative gastric/tumor bed (defined by preoperative upper gastrointestinal radiographs and hemoclips placed at time of resection to mark tumor bed and diaphragm invasion), anastomotic sites and stump (anastomosis visualized at juncture of residual distal esophagus and jejunum), and regional lymphatics (including the celiac, porta hepatis, and pancreaticoduodenal areas as well as the distal paraesophageal nodes). (From Smalley SS, Gunderson L, Tepper J, et al. Gastric surgical adjuvant radiotherapy consensus report: rationale and treatment implementation. Int J Radiat Oncol Biol Phys 2002;52:283–293, with permission from Elsevier.)
Dose Constraints
In radiation therapy planning of gastric cancer, normal tissue tolerance should always be considered. The spinal cord dose is generally limited to 45 Gy using 1.8-Gy fractions (and potentially less when delivered with novel systemic agents). Accurate delineation of adjacent organs including lungs, liver, kidneys, heart, and spinal cord are important. Varying dose-volume normal organ constraints have been suggested. Historically, heart dose constraints have included include maintaining one-third, two-thirds, and total heart volumes <45, 40, and 30 Gy, respectively. Recommended heart constraints include keeping <30% of the cardiac volume to a total dose of 40 Gy and <50% receiving 25 Gy, minimizing dose to the left ventricle. In the setting of potentially significant volumes of heart in the radiation field, consideration of 4D CT and/or respiratory gating techniques can be made. It is recommended that at least 70% of one physiologically functioning kidney receive a total dose <20 Gy and that collectively ≤50% of the combined functional renal volume should receive >20 Gy.100 In some patients, a portion of both kidneys will fall within the treatment field; however, at least two-thirds to three-fourths of one kidney should be excluded beyond a dose of 20 Gy. For proximal gastric lesions, ≥50% of the left kidney is commonly within the irradiation portal, and the right kidney must be appropriately spared. For distal lesions with narrow or positive duodenal margins, a similar amount of right kidney often is included, and every effort must be taken to spare enough left kidney to maintain function. Late renal sequelae have not been encountered with these techniques.33,70,106 One should also consider the possibility of impaired kidney function in the context of varying comorbidities, using nuclear medicine renal studies to assess individual renal function in such situations or where significant volumes of kidneys are anticipated to be within the radiation field. Generally, 70% of the liver parenchyma should be kept to a dose <30 Gy. Many of these constraints can be achieved through the use of 3D planning with appropriate and careful design of shielding blocks/multileaf collimation and dose-volume histogram analysis, with the use of IMRT in select cases.
Doses of Radiation
Generally, doses in the range of 45 to 50.4 Gy should be delivered at 1.8 Gy per fraction. Although primarily limited by normal tissue contrasts in the upper abdomen, several series have reported improved locoregional control with radiation dose escalation in the adjuvant setting. A report from Mayo Clinic investigators reported high locoregional control rates with radiation doses >54 Gy.105 Similarly, a report from Italian investigators treating patients adjuvantly with hyperfractionated radiation therapy to a dose of 55 Gy, with concurrent 5-FU, showed an in-field recurrence rate of only 7.5% and survival rate of 52% with a median follow-up >5 years.107 With regimens using single daily fractions, the usual dose is 45 delivered in 1.8- to 2-Gy fractions over 5 weeks, with a field reduction after 45 Gy in patients receiving boost-field treatments. Reduced boost fields to small areas of residual disease and a small volume of stomach or small intestine sometimes can be cautiously carried to doses of 55 to 60 Gy with multifield techniques. In such instances, informed consent should include a discussion of an increased risk of grade 3 to 4 gastrointestinal toxicity.
TABLE 58.11 UNRESECTABLE OR RESIDUAL GASTRIC CANCER: TREATMENT RESULTS OF RANDOMIZED TRIALS
RESULTS OF THERAPY
Locally Advanced Unresectable or Subtotally Resected Gastric Cancer
For patients with locally advanced unresectable or subtotally resected gastric carcinoma, radiotherapeutic approaches both with and without chemotherapy have been used because these tumors appear localized without clinically detectable metastases. Combined treatment with radiation therapy and chemotherapy appears to prolong survival but rarely results in long-term cure.108 Although only a modest effect on survival is seen, these studies have established, importantly, the foundation of contemporary combined modality therapy and have served as a stimulus to further clinical investigation in gastric cancer as well as other gastrointestinal disease sites. The results of these phase III studies have had a significant impact on clinical trial development in gastrointestinal malignancies (Table 58.11).
In a historical trial from 1969, Moertel et al.108 reported the results of a prospective, controlled double-blind study of patients with locally advanced unresectable gastric cancer. In this study, 48 patients were randomized to 35 to 40 Gy of radiation therapy over 4 weeks with and without 5-FU. Mean survival was 13 months in patients receiving radiation therapy and 5-FU versus 5.9 months for the radiation therapy patients (p <.01). These results demonstrated for the first time the clinical benefit of combining concurrent 5-FU with radiation therapy and encouraged further investigation of combination therapy in gastric cancer and other gastrointestinal disease sites (esophageal, pancreatic, rectal, and anal carcinomas).
As a follow-up to this study, the Gastrointestinal Tumor Study Group (GITSG) examined the combination of 5-FU/MeCCNU, or 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1 nitrosourea, and radiotherapy (RT; 50 Gy/split course/8 weeks) versus the same chemotherapy alone in locally advanced gastric cancer.109 Patients were eligible if the tumor involved regional lymph nodes or adjacent structures that could be completely resected en bloc. Of the 90 patients entered, 66 patients had a resection of the primary tumor. Of these, 23 patients had gross residual disease, 36 patients had microscopic residual, and 7 patients had no documented residual disease. The study was closed prematurely because of an excess of early deaths in the combined chemotherapy–RT arm. The excessive early mortality of the combined-modality arm was attributed to early tumor progression and poor tolerance of the combined-modality regime. However, further follow-up beyond 3 years indicated continuing mortality among the chemotherapy-alone arm, whereas the combined chemoradiotherapy arm exhibited a plateau with 18% of patients surviving 5 years. Thus, despite an excess of early mortality, the combined-modality arm exhibited an overall superiority in 5-year survival. It is important to note that patients who had had their primary tumor resected experienced superior survival to those without resection. All of the survival benefit in patients receiving combined modality was in patients whose primary tumor had been resected. This trial showed that combined chemoradiation therapy is capable of rendering a substantial percentage of patients with microscopic residual gastric cancer free from disease. It furthermore supported the rationale of exploring chemoradiation adjuvant trials in completely resected patients at high risk for locoregional relapse because control of microscopic disease was able to cure a significant number of these patients.
Resectable Gastric Cancer
The recognition of the high rates of local and regional failure following surgery in patterns of failure analyses has served as the basis for clinical trials assessing the value of radiation therapy both with and without chemotherapy as an adjuvant treatment (Table 58.5). Although these studies have all addressed the important question of whether clinical outcome is enhanced by adjuvant radiation therapy, there has been marked variability in radiation dose and schedule, sequence with surgery (preoperatively, intraoperatively, or postoperatively), and the use of concurrent and maintenance chemotherapy (Table 58.12). These differences in study design may explain in part the conflicting results observed in phase III studies.
TABLE 58.12 ADJUVANT IRRADIATION WITH AND WITHOUT CHEMOTHERAPY FOR RESECTED GASTRIC CANCER: TREATMENT RESULTS OF RANDOMIZED TRIALS
Adjuvant Radiation Therapy
Two randomized phase III studies have studied the use of external-beam radiation therapy alone (EBRT) with surgery.66,110,111 Although both studies used similar radiation dose and schedule, sequence with surgery differed. In the British Stomach Cancer Group study, 436 patients were randomized to surgery alone; postoperative radiation therapy (45 to 50 Gy in 25 to 28 fractions); or cytotoxic chemotherapy with mitomycin, doxorubicin, and fluorouracil (FAM).66,110 The 5-year survival for surgery alone was 20%, for surgery plus radiation therapy 12%, and for surgery plus chemotherapy 19%. In this study, no survival advantage was observed for patients who received postoperative EBRT, although there was an apparent improvement in local control, demonstrating that local disease could be affected by adjuvant radiation therapy. Locoregional failure was documented in only 15 of 153 patients (10%) in the irradiation arm versus 39 of 145 patients (27%) in the surgery-alone arm and 26 of 138 patients (19%) in the FAM group. Interpretation of the results is complicated by the inclusion of 171 patients undergoing resection with gross or microscopic residual carcinoma. These patients would not be candidates for contemporary gastric surgical adjuvant trials in the United States. In addition, approximately one-third of patients randomized to receive adjuvant treatment did not receive the assigned therapy. Of 153 patients randomized to the irradiation arm, only 104 (68%) received a dose ≥40.5 Gy, and 36 (24%) received none.
Neoadjuvant Radiation Therapy
In contrast, the results of a phase III study from Beijing demonstrated a survival benefit for patients with gastric cardia carcinoma receiving preoperative irradiation and surgery versus surgery only.111 In this study, 370 patients with gastric cardia carcinoma were randomized to 40 Gy in 20 fractions over 4 weeks of preoperative irradiation and surgery or surgery only. The 5-year survival rates of preoperative irradiation and surgery and the surgery-alone group were 30% and 20%, respectively (10-year, 20% and 13%, respectively). These differences were statistically significant (p = .009). Further, local and regional nodal control was improved in patients undergoing preoperative irradiation and surgery (61% and 61%) versus surgery (48% and 45%) only. Morbidity and mortality rates were not increased in patients receiving preoperative irradiation and surgery.
Intraoperative Radiation Therapy
An alternative approach to postoperative or preoperative irradiation is intraoperative radiation therapy (IORT).112,113 The advantage of this technique is the ability to deliver a single large fraction (10 to 35 Gy) of radiation to the tumor or tumor bed while excluding or protecting surrounding normal tissue from the high-dose field. This approach permits high-dose irradiation with minimal normal tissue treatment. Two randomized trials have examined the efficacy of IORT in combination with surgery for patients with gastric carcinoma. Abe et al.113 from Kyoto University performed a randomized trial of 211 patients with gastric cancer comparing surgery alone with surgery and intraoperative radiation (28 to 35 Gy). Patients were randomized based on hospital day of admission for surgery. For patients with tumor confined to the gastric wall, 5-year survival rates were similar for IORT and for resection alone. However, patients with Japanese stages II to IV disease who received IORT in conjunction with resection showed improved survival over patients who underwent resection without irradiation. Among patients with stage IV disease (who usually had local residual disease after maximal resection), there were no 5-year survivors who received surgery alone; however, 15% of the patients who received IORT were alive at 5 years. The experience with IORT in gastric cancer at Kyoto University suggested that IORT may be beneficial in the treatment for locally advanced malignancies of the stomach.
To further evaluate this approach, Sindelar et al.114 at the National Cancer Institute conducted a prospectively randomized controlled trial comparing surgical resection and IORT with conventional therapy in gastric carcinoma. Patients in the experimental group underwent gastrectomy, and IORT was administered to the gastric bed (20 Gy). Patients in the control group underwent resection and postoperative EBRT to the upper abdomen (50 Gy in 25 fractions) for advanced-stage lesions extending beyond the gastric wall. Of the 100 patients screened for the study, 60 patients were randomized and underwent exploratory surgery. Nineteen patients were excluded intraoperatively because of unresectability or metastases, leaving 41 patients in the study. The median survival for patients with tumors of all stages was 25 months for the IORT group and 21 months for the control group (p = not significant [NS]). Locoregional disease relapse occurred in 7 of 16 IORT patients (44%) and in 23 of 25 control patients (92%) (p <.001). Complication rates were similar between IORT and control patients. Although IORT failed to afford a significant advantage over conventional therapy in overall survival, IORT significantly improved control of locoregional disease. The use of IORT in gastric cancer remains a topic of investigation.
Adjuvant Chemotherapy
A randomized trial from Japan evaluated 579 patients undergoing resection to receive adjuvant chemotherapy alone versus observation alone. Primarily, early T-stage patients in the treatment group received a combination of mitomycin and fluorouracil twice weekly for 3 weeks following surgery, followed by delivery of UFT (uracil + tegafur [an oral 5-FU prodrug]). No survival benefit was seen with adjuvant chemotherapy.115 However, a more recent follow-up study from Japan evaluated the efficacy of adjuvant chemotherapy in patients with stage II/III gastric cancer undergoing R0, D2 dissection (excluding T1 patients). This study randomized 1,059 patients to surgery alone versus treatment with S-1, an oral fluoropyrimidine combining tegafur and oxonic acid. Three-year survival was significantly improved in patients receiving adjuvant chemotherapy (80%) versus surgery alone (70%).116 Whether the impact of S-1 in the Asian population can be extrapolated to Western patients remains less clear and the subject of investigation, including potential biologic differences among populations regarding how this drug is metabolized.
A meta-analysis of 17 randomized controlled trials using individual patient data comparing surgery alone to surgery with adjuvant chemotherapy in patients with resectable gastric cancer was performed. In this study, adjuvant chemotherapy was associated with a significant survival benefit in terms of overall survival (hazard ratio [HR] 0.82, confidence interval [CI] 0.76 to 0.90, p <.001) and disease-free survival. Estimated 5-year overall survival was increased from approximately 50% to 55% with the use of chemotherapy. The authors117 concluded that adjuvant chemotherapy with fluorouracil-containing regimens reduce the risk of death in gastric cancer compared to surgery alone. As discussed previously, how these varying studies apply to Western patients remains unclear.
Adjuvant Chemoradiation Therapy
Because of the promising results in the early studies of combined-modality therapy for locally advanced unresectable or subtotally resected gastric cancer, investigators also have studied this combination in resectable gastric carcinoma. A small study from South Africa randomized 66 patients with resected gastric cancer (T1 to T3, N1 or N2, M0) to low-dose postoperative irradiation (20 Gy in eight fractions over 10 days) and 5-FU or no further therapy.86 No difference in survival was observed between the patients undergoing surgery and adjuvant therapy and those undergoing surgery alone. Given the subtherapeutic doses of radiation used in this study, it is difficult to draw any conclusions as to the efficacy of adjuvant radiation therapy and 5-FU.
In 1984, Moertel et al.95 reported the results of a prospective randomized trial conducted at the Mayo Clinic of 62 patients with poor prognosis but completely resected gastric cancers who were randomized to either surgery alone or surgery followed by irradiation (37.5 Gy in 24 fractions over 4 to 5 weeks) with concurrent 5-FU. A nonstratified, prerandomization scheme was used with a 2:3 ratio favoring treatment. Informed consent was requested of only the 39 patients randomized to treatment. Ten of the 39 patients 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 (overall 5-year survival 23% vs. 4%, p <.05). When patient outcome was compared with actual treatment received (29 adjuvant treatment, 33 surgery alone), 5-year survival still favored the adjuvant group (20% vs. 12%), although the differences were not statistically significant in view of the small patient numbers. 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 overall survival was 20% versus 4%, with an advantage to those receiving adjuvant treatment. When analyzed by treatment delivered, locoregional relapse was decreased with adjuvant treatments (54% incidence with surgery alone vs. 39% with irradiation and 5-FU).
Because of these conflicting results, an Intergroup 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 following resection of gastric cancer.99 Eligibility included patients with stage group IB through IV nonmetastatic adenocarcinoma of the stomach or GE junction. After an en bloc resection, 556 patients were randomized to either observation alone or postoperative 5-FU/leucovorin for one cycle followed by combined-modality therapy consisting of 45 Gy in 25 fractions plus concurrent 5-FU and leucovorin (4 days in week 1, 3 days in week 5) followed by two monthly 5-day cycles of 5-FU and leucovorin. Minor or major errors in field design were discovered in 35% during preirradiation quality assurance review, allowing most deviations to be corrected prior to radiation therapy initiation, resulting in a 6.5% final major deviation rate. Nodal metastases were present in 85% of the cases. With 5 years of median follow-up, 3-year relapse-free survival was 48% for adjuvant treatment and 31% for observation (p = .001); 3-year overall survival was 50% for treatment and 41% for observation (p = .005). The median overall survival in the surgery-only group was 27 months, compared with 36 months in the chemoradiotherapy group; the HR for death was 1.35 (95% CI 1.09 to 1.66, p = .005). The HR for relapse in the surgery-only group as compared with the chemoradiotherapy group was 1.52 (95% CI 1.23 to 1.86, p<.001). The median duration of relapse-free survival was 30 months in the chemoradiotherapy group and 19 months in the surgery-only group. Patterns of failure were based on the site of first relapse only and were categorized as local, regional, or distant. Local recurrence occurred in 29% of patients who relapsed in the surgery-only group and 19% of those who relapsed in the chemoradiotherapy 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 chemoradiotherapy group. Extra-abdominal distant metastases were diagnosed in 18% of those who relapsed in the surgery-only group and 33% of those who relapsed in the chemoradiotherapy group. Treatment was tolerable, with three (1%) toxic deaths. Grades 3 and 4 toxicity occurred in 41% and 32% of cases, respectively, and 17% of patients assigned to the chemoradiotherapy group stopped treatment owing to toxicity from therapy. Long-term results at >10-year median follow-up continued to show significant improvement in overall and disease-free survival in the chemoradiation group, benefiting all T- and N-stage patients included in the trial.118 The results of this large study demonstrate a clear survival advantage for the use of postoperative chemoradiation and strongly support its integration into the routine care of patients with curatively resected high-risk carcinoma of the stomach and GE junction.119
The follow up Intergroup trial CALGB 80101 randomized patients with resected gastric or GE junction adenocarcinoma to receive either (a) one cycle of 5-FU/leucovorin, followed by 45 Gy with concurrent continuous infusion 5-FU, followed by two additional cycles of 5-FU/leucovorin; or (b) one cycle of ECF (epirubicin, cisplatin, 5-FU), followed by 45 Gy with concurrent, continuous infusional 5-FU, followed by two additional cycles of reduced dose ECF. Preliminary trial results showed that grade 4 toxicity was significant higher in arm 1 at 40% versus 26% (p <.001), including higher rates of neutropenia, diarrhea, and mucositis. Median overall survival was 37 months versus 38 months (p = .8), 3-year overall survival 50% versus 52%, and 3-year disease-free survival 46% versus 47%. The conclusions from these preliminary results were that following curative resection of gastric or GE junction adenocarcinoma, postoperative chemoradiotherapy using ECF before and after 5-FU–based radiation does not improve survival compared to bolus 5-FU/leucovorin given in the same manner.120
A large retrospective study from Korea evaluated the role of adjuvant chemoradiation in patients undergoing D2 gastric cancer resection, a group that was not adequately represented in the aforementioned Intergroup trial. In the Korean study, 544 patients treated with D2 dissection and postoperative chemoradiation therapy were compared to 446 patients with similar characteristics treated with D2 dissection alone. Overall survival was significantly higher in patients treated with adjuvant chemoradiation (median survival 95 vs. 63 months, p = .02) as well as significant improvement in relapse-free survival.81 Additionally, a recent collective review of nine randomized trials incorporating radiation therapy approaches with surgery alone also demonstrated a significant 5-year survival benefit with the addition of radiation therapy in resectable gastric cancer patients.121
A Korean phase III trial (the Adjuvant Chemoradiation Therapy in Stomach Cancer [ARTIST] study) compared the effects of adjuvant chemoradiation (capecitabine/cisplatin [XP] + RT) to adjuvant chemotherapy alone (capecitabine/cisplatin) following D2 resection of gastric cancer in 458 patients.121a Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/RT/XP arm. The addition of radiation to XP chemotherapy did not significantly prolong disease-free survival (p = .086). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/RT/XP arm experienced superior disease-free survival when compared with those who received XP alone (p = .0365), and the statistical significance was retained at multivariate analysis (estimated HR 0.69, p = .047). The authors121a concluded that the addition of RT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer, although a subsequent trial (ARTIST-II) in patients with lymph node–positive gastric cancer is planned. Additionally, a study by the Dutch Colorectal Cancer Group (the Chemoradiotherapy after Induction Chemotherapy in Cancer of the Stomach [CRITICS] trial) is randomizing patients to receive preoperative chemotherapy (epirubicin, cisplatin, capecitabine) for three cycles followed by D1+ resection, followed by a similar postoperative chemotherapy regimen, with or without radiotherapy concurrent with cisplatin/capecitabine.
Preoperative Chemoradiation Therapy
Because preoperative radiation therapy and chemotherapy have improved the surgical outcome in patients with rectal and esophageal cancer, this treatment is a logical approach to explore in gastric cancer as well. Although no phase III trials have tested the value of preoperative radiation plus chemotherapy for patients with gastric cancer, two phase III trials for patients with esophagus cancer have included either lesions of the gastric cardia122 or the esophagogastric junction.123 In both trials, the trimodality arm demonstrated an improvement in survival when compared with the control arm of surgery alone. The series by Walsh et al.122 (adenocarcinoma of the esophagus or gastric cardia) demonstrated a median survival of 16 versus 11 months and 3-year survival of 32% versus 6% (p = .01), with the advantage to trimodality treatment. The U.S. Gastrointestinal Intergroup phase III trial (adenocarcinoma or squamous cell of the esophagus or GE junction), which closed prematurely owing to low accrual, resulted in a median survival of 54 months versus 21.6 months and 5-year survival of 39% versus 16% (p = .008), with an advantage to the trimodality arm.
Preoperative chemoradiation data for patients with gastric cancer is limited to phase II studies from single institutions and cooperative groups. MD Anderson Cancer Center has reported a study in which 33 patients completed a preoperative protocol that started with induction chemotherapy of 5-FU, leucovorin, and cisplatin, followed by 45 Gy of radiation therapy in 25 fractions over 5 weeks. Infusional 5-FU was administered concurrently with radiation therapy. In 28 patients (85%), a gastrectomy was performed and D2 lymph node dissection was attempted. Pathologic complete and partial response was found in 64% of all operated patients. These patients showed a significantly longer median survival of 64 months in comparison with 13 months in patients with tumors not pathologically responding.124a In a study from the same institution, 41 patients with operable gastric cancer received two cycles of continuous 5-FU, paclitaxel, and cisplatin followed by 45 Gy of radiation therapy with concurrent 5-FU and paclitaxel. An R0 resection was achieved in 78% of patients, pathologic complete response in 25%, and pathologic partial response in 15%. Pathologic response, R0 resection, and postoperative T- and N-stage were correlated with overall and disease-free survival.124b The Radiation Therapy Oncology Group reported the results of a phase II study of 49 patients undergoing induction 5-FU, leucovorin, and cisplatin followed by concurrent radiation therapy and infusional 5-FU and paclitaxel.124c Resection was attempted 5 to 6 weeks after radiation therapy and chemotherapy. The pathologic complete response and R0 resection rates were 26% and 77%, respectively. At 1 year, more patients with tumors exhibiting a pathologic complete response (89%) were living than patients with tumors exhibiting a less favorable response (66%). Grade 4 toxicity occurred in 21% of patients. These data appear to support a randomized phase III study evaluating preoperative versus postoperative radiation therapy and chemotherapy.124c
Preoperative Chemoradiation Versus Preoperative Chemotherapy
A randomized trial comparing neoadjuvant chemotherapy alone versus neoadjuvant combined modality therapy was conducted by German investigators (the Preoperative Chemotherapy or Radiochemotherapy in Esophago-gastric Adenocarcinoma Trial [POET]).125 Patients with advanced esophagogastric adenocarcinoma were randomized to receive (a) cisplatin/5-FU–based chemotherapy alone versus (b) a similar induction chemotherapy followed by concurrent cisplatin/etoposide with 30 Gy of radiation therapy. Both groups went on to receive surgery. Although this study closed early owing to poor accrual, patients receiving preoperative chemoradiotherapy had significantly higher N0 rates (37 vs. 64%, p = .04) and pathologic complete response rates (2% vs. 16%, p = .03), as well as statistical trends toward improved local control (59% vs. 76%, p = .06) and overall survival (3-year survival 28% vs. 47%, p = .07, HR 0.67). The authors concluded that preoperative combined modality improves overall survival as compared to chemotherapy alone in patients with locally advanced esophagogastric adenocarcinoma.125 Along these lines, a randomized phase II/III trial of preoperative chemoradiotherapy versus preoperative chemotherapy alone for resectable gastric and GE junction cancer (the TOPGEAR study) was recently initiated in Australia.
Perioperative Chemotherapy
Various combinations of active drugs have been reported to improve the response rate among patients with metastatic or locally unresectable gastric carcinoma.9 A combination of FAM has been associated with a 30% to 40% response rate and was the most widely prescribed regimen for patients with advanced disease in the 1980s.9 Despite an initial response rate of 64% when a combination of etoposide, doxorubicin, and cisplatin (EAP) was used by German investigators, in subsequent trials this regimen was considerably less effective and extremely toxic.126,127–128 A combination of fluorouracil, doxorubicin, and high-dose methotrexate (FAMTX) was associated with a significant improvement in response rate compared with either EAP or FAM. As a result of these studies, FAMTX became standard therapy for metastatic disease.
In a British study of patients with unresectable or metastatic gastric and esophageal adenocarcinoma, 274 patients were randomized to either 5-FU, doxorubicin, and methotrexate (FAMTX) or epirubicin, cisplatin, and continuous infusion 5-FU (ECF).129,130 ECF was associated with a superior response rate (45% vs. 21%, p = .0002), median survival (8.7 months vs. 5.7 months, p = .0006 vs. .006), and 1-year survival (36% vs. 21%). Moreover, ECF was associated with a superior quality of life and less toxicity.
The Medical Research Council (MRC) subsequently initiated a trial (the Medical Research Council Adjuvant Gastric Infusional Chemotherapy [MAGIC] trial) to address the question of perioperative chemotherapy (pre- and post-) in operable gastric cancer patients. Patients with resectable adenocarcinoma of the stomach, GE junction, or lower esophagus were randomized to preoperative and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU (ECF) versus surgery alone. Although originally designed to include patients with only tumors of the stomach, eligibility was later expanded to include tumors of the lower third of the esophagus, with approximately one-fourth of patients having adenocarcinoma involving the lower esophagus or GE junction. The resected tumors were significantly smaller and less advanced in the perioperative chemotherapy group. With a median follow-up of 4 years, 149 patients in the perioperative chemotherapy group and 170 patients in the surgery group had died. As compared with the surgery group, the perioperative chemotherapy group had statistically improved progression-free and overall survival rates. No patient achieved pathologic complete response. However, patients receiving perioperative chemotherapy had a HR for death of 0.75, which was highly significant, with 5-year survival in patients receiving chemotherapy 36% versus 23% in patients undergoing surgery alone (p = .009).131 A follow-up MRC study is evaluating the role of the vascular endothelial growth factor inhibitor bevacizumab with this regimen (MAGIC B).
French investigators reported the results of a similar randomized trial of 224 patients assigned to perioperative chemotherapy (cisplatin and 5-FU) versus surgery alone. Although originally designed to include only patients with tumors of the lower third of the esophagus or GE junction, eligibility was later expanded to include gastric cancers, although most (75%) of patients had disease of the lower esophagus or GE junction. Chemotherapy consisted of a planned two to three preoperative and three to four postoperative cycles. This study was prematurely terminated because of low accrual. Nonetheless, patients receiving chemotherapy had improved overall survival (5-year 38% vs. 24%, p = .02), disease-free survival (5-year 34% vs. 19%, p = .003), and R0 resection rates (84% vs. 73%, p = .04). Only 50% of patients received postoperative chemotherapy. T0 disease (complete pathologic response at the primary site) disease was seen in 3% of neoadjuvantly treated patients. Total locoregional recurrence rates were 24% and 26%, respectively, in the chemotherapy versus surgery group, with distant recurrence rates of 42% versus 56%, respectively.132
Palliative Radiation Therapy
Radiation therapy is capable of providing substantial palliation of local gastric cancer symptoms.133–135,136,137,138 It appears that 50% to 75% of patients can expect improvement of symptoms such as gastric outlet obstruction, pain from local tumor extension, bleeding, or biliary obstruction.136 The likelihood of benefit may increase with concomitant 5-FU administration, with less tumor bulk, and if the patient’s performance score is better before therapy.105,134,139,140 The median duration of palliation varies from 4 to 18 months in reports addressing this issue.134,139–141
SEQUELAE OF THERAPY
Anorexia, nausea, and fatigue are very common complaints during gastric radiation therapy; however, the understanding of these problems is quite limited.122,142–144,145 Although visceral afferents may play some role in the acute emetogenic effects of radiation, other unknown factors, possibly chemical in nature and mediated by the chemoreceptor trigger zone, appear to be more important. Although selective serotonin (5-HT3) antagonists effectively treat radiation-induced emesis, it is not clear whether the mechanism of action is directed at the 5-HT3 receptor alone or has an effect on inhibition of serotonin release.146 Other compounding factors may include the altered gastric motility and prolonged gastric emptying time observed in animal experiments as a response to irradiation.93,142,143,147 Chemotherapy-related leukopenia and thrombocytopenia may occur. If chemotherapy is used with irradiation, blood counts are generally obtained once to twice weekly. Additional acute toxicities of radiation therapy include esophagitis, epidermitis, fatigue, and weight loss in most patients. Nausea, vomiting, dehydration, and anorexia are relatively common, particularly in patients with lower esophageal and GE junction tumors. During therapy, patient tolerance, weight, and blood counts are checked at least weekly. Many symptoms resolve within 1 to 2 weeks of treatment completion. Because of potential toxicities in the treatment for gastric cancer patients (dehydration, weight loss, anorexia, etc.), aggressive supportive measurements and symptom management are indicated in efforts to avoid treatment-related interruptions, hospitalizations, or failure to complete the intended treatment course. Varying antiemetics should be used liberally, including on a prophylactic basis. Antacids including proton pump inhibitors are frequently implemented, and antidiarrheal medications may be appropriate. Additionally, nutritional supportive measurements are paramount and, when appropriate, the use of enteral methods implemented. In selected cases, the use of feeding jejunostomy may be appropriate. Patients may require intermittent hydration both during and shortly following the treatment course. Postoperatively, B12, iron, and calcium levels should be monitored and supplemented as appropriate.
Nutritional complications of treatment and myelosuppression, if concurrent chemotherapy is used during irradiation, can carry substantial morbidity and even occasional mortality from therapy. The GITSG reported a minimum 13% treatment-related mortality from nutritional problems or septic events on their concurrent chemoradiation arm,109 and almost 20% of the patients of Caudry et al.148 were unable to complete therapy because of nutritional problems. However, others reported no severe or life-threatening nutritional compromise with aggressive chemoradiation.104,105,149 Toxic gastrointestinal effects usually are managed with careful nutritional support and antiemetic therapy. It may be prudent to proactively prescribe antiemetics at the initiation of therapy in patients undergoing aggressive upper abdominal irradiation.
Myelosuppression causing serious or, rarely, lethal toxicity also is reported in many of the combined-modality trials.104,105,112,149 If blood counts are monitored weekly during combined-modality therapy, serious problems with sepsis or bleeding should be uncommon.104,105,112
Moderate doses of 16 to 36 Gy reduce secretion of pepsin and hydrochloric acid.1,13,93,150 For this reason, radiation therapy was once a common and successful therapy for peptic ulcer disease. Most of the gastric ulcers healed, although they recurred in approximately 40% of patients.1,93,150 Gastric acid secretion decreased in almost all cases, with achlorhydria in 25% to 40%.61 The gastric acid decrease usually persisted from 1 to 6 months; however, 25% showed persistent decrease in acid production for 1 to 5 years or more.
Gastric late effects were categorized by the Walter Reed Group as dyspepsia, radiation gastritis, uncomplicated gastric ulcer, or gastric ulcer with perforation or obstruction.151–153 The associations between dose and these late effects are described in Table 58.13. These data suggest a 20% to 30% incidence of ulceration with doses of 45 to 59 Gy, with complications of these ulcers in 30% to 50% of the treated patients. Some caution is necessary in interpreting this experience because the Walter Reed cohort was treated with 200-keV photons or 1-MV photons using a 70-cm target-skin distance, usually using only one field each day with daily fraction sizes of 3 Gy to midline, which sometimes produced daily given doses of 4 to 6 Gy.152,153
Most data suggest that gastric late effects are rare with doses of 40 to 52 Gy using conventional fractionation of 1.8 to 2 Gy. The relatively low risk of gastric late effects with doses <50 Gy is corroborated by many series using radiation therapy with or without chemotherapy for locally advanced gastric cancer.36,42,56,64,71,122 However, doses in the range of 50 to 55 Gy may produce variable gastric late effects, which have been reported to reach 9% in some series. Doses of 60 Gy carried a 5% to 15% risk of gastric late effects.1–3,46,56,61,90,106,122,134,135,140,148,150–156,157,158
The ability of histamine (H2) blockers and sucralfate to prevent the later development of radiation-induced gastric ulcerations is unproven. It may be reasonable to administer H2 blockers or proton pump inhibitors prophylactically to patients receiving >45 Gy to any significant volume of the stomach or proximal duodenum.
Several series have described a gradual decline in renal function occurring ≥18 to 24 months following postoperative radiation therapy for gastric cancer. However, it is unclear that this is of clinical significance, and long-term renal function among gastric cancer survivors has not been reliably reported. Nonetheless, advanced techniques may enhance renal sparing and also allow potential dose escalation as well as integration of novel (and potentially nephrotoxic) systemic agents.98 Radiation-induced cardiac toxicity is a broad term describing potential radiation injury to a number of cardiac structures, including pericardium (as manifested by effusion, pericarditis), coronary arteries, the heart muscle itself, and cardiac valves as well as nerve/conduction injury. Radiation injury primarily consists of fibrosis and/or small vessel injury. The mechanism of radiation-induced cardiac injury is relatively poorly defined, particularly in the context of gastric cancer. Historical data from the treatment for Hodgkin’s disease patients have suggested that dose >40 Gy may increase the risk of cardiac death as well as pericarditis.159,160 Several studies of cardiac toxicity and esophageal cancer patients have demonstrated that an increasing V30 predicted for a significant increase in pericardial effusion, and increasing fraction size (particularly ≥3.5 Gy) also predicted for the same. Additionally, some authors have shown a possible trend for decrease in ejection fraction in patients with increasing V20 of the left ventricle.161 A more detailed discussion on potential long-term cardiac sequelae of radiation therapy can be found in Chapter 53.
TABLE 58.13 RADIATION DOSE COMPARED WITH LATE EFFECTS IN THE WALTER REED EXPERIENCE151–153
CONCLUSIONS AND RECOMMENDATIONS
Radiation therapy, usually administered with concomitant 5-FU–based chemotherapy, is indicated for locally confined gastric cancer that either is not technically resectable or occurs in medically inoperable patients. In this setting, therapy can be administered with curative or palliative intent, depending on the clinical situation. Those who undergo gastric resection with incomplete tumor resection or have truly positive margins of resection are also appropriately managed by combined-modality therapy. Preferably, patients with locally advanced disease that is unresectable with negative margins would be identified preoperatively with endoscopic ultrasonography and CT staging. Preoperative chemoradiation then could precede an attempt at gross total resection, alone or in combination with IORT, and maintenance chemotherapy.
The results of the U.S. Gastrointestinal Intergroup Gastric Adjuvant Trial have changed the standard of care in the United States to the use of both chemotherapy and radiation therapy in the postoperative setting for patients with disease extension through the gastric wall and/or with nodes positive for tumor. Postoperative irradiation and concurrent and maintenance 5-FU–based chemotherapy are recommended for patients with stage IB, II, IIIA, IIIB, or IV and M0 gastric cancer. The role of postoperative chemoradiation in patients with T2N0 tumors remains more controversial. In patients with high-risk features (i.e., poorly differentiated or higher-grade cancers, lymph vascular invasion, perineural invasion, age <50 years, or suboptimal resection including lymph node resection), postoperative chemoradiotherapy may be indicated.
Because extended node dissections were not commonly performed as a component of surgery in the Intergroup trial, some have questioned whether postoperative chemoradiation would give added benefit following a D2 nodal resection. Similarly, given the survival benefit from the use of perioperative chemotherapy alone in European esophagogastric patients, ongoing trials are examining the role of adjuvant chemoradiation in both the settings of perioperative chemotherapy as well as D2 lymph node dissection. Additionally, further trials are investigating new systemic agents with radiation therapy to establish efficacy compared with 5-FU and leucovorin. Given the poor prognosis with patients receiving either perioperative chemotherapy or adjuvant chemoradiotherapy, integration of the approaches has the potential to improve disease-related outcomes compared to either alone. Similarly, on the basis of encouraging outcomes with phase II preoperative chemoradiation trials in patients with gastric cancer and phase III esophagus cancer trials, it would be appropriate to continue to evaluate this approach in patients with both potentially resectable and unresectable lesions.
The irradiation field design from the current phase III U.S. Gastrointestinal Intergroup trial was based on optimized field design related to both site of the primary lesion and T- and N-stage of disease.103 With the wide availability of 3D conformal treatment-planning systems, it may be possible to more accurately target the high-risk volume and to use unconventional field arrangements and/or IMRT to produce superior dose distributions. To accomplish this without marginal misses, however, it will be necessary to both carefully define and encompass the various target volumes (tumor bed, nodal sites at risk) because target volumes that would be included in AP/PA fields may be missed with other field arrangements (oblique, lateral, noncoplanar).
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