Gastric Cancer Clinical Practice Guidelines in Oncology
NCCN Categories of Evidence and Consensus
Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.
Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.
Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).
Category 3: The recommendation is based on any level of evidence but reflects major disagreement.
Overview
Cancers originating in the esophagus, gastroesophageal junctions, and stomach constitute a major health problem worldwide. In the United States, 37,600 new diagnoses of and 25,150 deaths from upper gastrointestinal cancers were estimated in 2009.1 A dramatic shift in the location of upper gastrointestinal tumors has occurred in the United States,2 and changes in histology and location of them were observed in some parts of Europe.3,4 In countries in the Western Hemisphere, the most common sites of gastric cancer are the proximal lesser curvature, cardia, and gastroesophageal junction.2 These changing trends may also begin to occur in South America and Asia.
Epidemiology
Gastric cancer is rampant in many countries around the world. In Japan, it remains the most common type of cancer among men; in China, more new cases are diagnosed each year than in any other country. The incidence of gastric cancer, however, has been declining globally since World War II and it is one of the least common cancers in North America. By some estimates, it is the fourth most common cancer worldwide.5 In 2009, 21,130 new diagnoses of gastric cancer were estimated in the United States and 10,620 deaths expected.1 In developed countries, the incidence of gastric cancer originating from the cardia follows the distribution of esophageal cancer.6–8 Noncardia gastric adenocarcinoma has marked geographic variation, with countries such as Japan, Korea, China, Taiwan, Costa Rica, Peru, Brazil, Chile, and the former Soviet Union showing a high incidence.9 In contrast to the incidence trends in the West, nonproximal tumors continue to predominate in Japan and other parts of the world.10 The cause of this shift remains elusive and may be multifactorial.
Gastric cancer is often diagnosed at an advanced stage. In Japan (and in a limited fashion in Korea), where screening is performed widely, early detection is often possible. In other parts of the world, it continues to pose a major challenge for health care professionals. Environmental risk factors include Helicobacter pylori (H. pylori) infection, smoking, high salt intake, and other dietary factors. Patients with a family history of nonhereditary gastric cancer have a higher risk for developing gastric cancer. In a limited number of patients (1%–3%), its diagnosis is associated with inherited syndromes. E-cadherin mutations occur in approximately 25% of families with an autosomal-dominant hereditary form of diffuse gastric cancer.11 Genetic counseling is recommended, and prophylactic gastrectomy should be considered in young, asymptomatic individuals with germline truncating CDH1 mutations with a family history of highly penetrant hereditary diffuse gastric cancer.12
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer
Version 2.2010, 02-26-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 4; 10.6004/jnccn.2010.0030
Staging
Two major classifications are currently used. The Japanese classification is more elaborate and based on anatomic involvement, particularly in the lymph node stations.13 The other staging system developed jointly by the American Joint Committee on Cancer and the International Union against Cancer is used in the Western Hemisphere (see the staging table, available online, in these guidelines, at www.NCCN.org [ST-1]).14 A minimum of 15 examined lymph nodes are recommended for adequate staging.
Clinical baseline stage provides useful information for the development of an initial therapeutic strategy. Approximately 50% of patients will present with advanced disease at diagnosis and have a poor outcome. Other measures of poor outcome include poor performance status, presence of metastases, and alkaline phosphatase level of 100 U/L or more.15 In patients with localized resectable disease, outcome depends on the surgical stage of the disease. Nearly 70% to 80% of patients have involvement of the regional lymph nodes. The number of positive lymph nodes has a profound influence on survival.16
Preoperative Staging
Clinical staging has greatly improved with the availability of diagnostic modalities such as endoscopic ultrasound (EUS), CT, combined PET-CT, MRI, and laparoscopic staging.17–19
CT scan is routinely used for preoperative staging, and has an overall accuracy of 43% to 82% for T staging. PET-CT has a low detection rate because of the low tracer accumulation in diffuse and mucinous tumor types that are frequently in gastric cancer.20 It has a significantly lower sensitivity compared with CT for detecting local lymph node involvement (56% vs.78%), although it has an improved specificity (92% vs. 62%).21 Combined PET-CT imaging, however, has several potential advantages over PET scan alone.22 PET-CT has a significantly higher accuracy in preoperative staging (68%) than PET (47%) or CT (53%) alone. Recent reports have confirmed that PET alone is not an adequate diagnostic procedure for detecting and preoperative staging of gastric cancer but could be helpful when used in conjunction with CT.23,24
EUS is indicated for assessing the depth of tumor invasion.25 The accuracy of EUS for T staging ranges from 65% to 92% and 50% to 95% for N staging, and is operator-dependent. Distant lymph node evaluation with EUS is suboptimal given the limited depth and visualization of the transducer.26
Laparoscopic staging can detect occult metastases (page 386). In a study conducted by Memorial Sloan-Kettering Cancer Center, 657 patients with potentially resectable gastric adenocarcinoma underwent laparoscopic staging over 10 years.27 Distant metastatic disease (M1) was detected in 31% of the patients. Limitations of laparoscopic staging include 2-dimensional evaluation and limited use in the identification of hepatic metastases and perigastric lymph nodes.
Indications for using laparoscopic staging differ among various NCCN institutions. In some, laparoscopic staging is reserved for medically fit patients with potentially resectable disease, specifically when chemoradiotherapy or surgery is considered. In medically unfit patients, laparoscopy may still be considered, especially if the addition of radiation to chemotherapy is considered. The guidelines include laparoscopic staging as a category 2B recommendation (page 380).
Cytogenetic analysis of peritoneal fluid can help improve staging through identification of occult carcinomatosis.17 Reports in literature suggest that positive findings on peritoneal cytology is an independent predictor for identifying patients who are at higher risk for recurrence after curative resection.28,29
Surgery
Surgery is the primary treatment for early-stage gastric cancer. Complete resection with adequate margins (≥ 4 cm) is widely considered a standard goal, whereas the type of resection (subtotal vs. total gastrectomy) along with extent of lymphadenectomy remains a subject of controversy.
Principles of Surgery
The primary goal of surgery is to accomplish a complete resection with negative margins (R0 resection). Only 50% of patients will end up with an R0 resection of their primary.30,31 As a reminder, R1 indicates microscopic residual disease (positive margins), and R2 indicates gross (macroscopic) residual disease in the absence of distant metastasis.32
Subtotal gastrectomy is the preferred approach for distal gastric cancers. This procedure has a similar surgical outcome compared with total gastrectomy although with significantly fewer complications.33 Proximal and total gastrectomy are both indicated for proximal gastric cancers and are typically associated with postoperative nutritional impairment.
Clinical staging using CT scan with or without EUS should be performed before surgery to assess disease extent (page 386). Proximal and distal margins of 4 cm or greater from the gross tumor are preferred.34 The guidelines recommend distal, subtotal, or total gastrectomy of T1b to T3 tumors. T4 tumors require en bloc resection of involved structures. Routine or prophylactic splenectomy should be avoided if possible. In a randomized clinical study, patients who underwent total gastrectomy combined with splenectomy had slightly higher postoperative mortality and morbidity rates and marginally better survival, but no statistically significant differences were seen among the groups.35 The results of this study do not support prophylactic splenectomy to remove macroscopically negative lymph nodes near the spleen in patients undergoing total gastrectomy for proximal gastric cancer. A jejunostomy feeding tube may be considered for selected patients who will undergo postoperative chemoradiation.
Carcinomas are considered unresectable if evidence shows peritoneal involvement, distant metastases, or locally advanced disease, such as invasion or encasement of major blood vessels. Limited gastric resection, even with positive margins, is acceptable for symptomatic palliation of bleeding in unresectable tumors. Palliative gastric resection should not be performed unless the patient is symptomatic and lymph node dissection is not required (page 386). Gastric bypass with gastrojejunostomy to the proximal stomach may be useful for palliation of obstructive symptoms in symptomatic patients. Placement of a venting gastrotomy and/or feeding jejunostomy tube may be considered.
Lymph Node Dissection
Gastric resection may be classified by the extent of lymph node dissection at surgery. The extent of lymph node dissection remains controversial. The Japanese Research Society for the Study of Gastric Cancer established guidelines for pathologic examination and evaluation of lymph node stations surrounding the stomach.36 The perigastric lymph node stations along the lesser curvature (stations 1, 3, and 5) and greater curvature (stations 2, 4, and 6) of the stomach are grouped together as N1. The nodes along the left gastric artery (station 7), common hepatic artery (station 8), celiac artery (station 9), and splenic artery (stations 10 and 11) are grouped together as N2. More distant nodes, including para-aortic (N3 and N4), are regarded as distant metastases.
D0 dissection refers to incomplete resection of N1 lymph nodes. D1 dissection involves the removal of the involved proximal or distal part of the stomach or the entire stomach (distal or total resection), including the greater and lesser omental lymph nodes. In a D2 dissection, the omental bursa along with the front leaf of the transverse mesocolon is removed and the corresponding arteries cleared completely. A splenectomy (to remove stations 10 and 11) is required for a D2 dissection of proximal gastric tumors. The technical aspects of performing a D2 dissection require a significant degree of training and expertise.
A recent retrospective analysis has shown that more extensive lymph node dissection and analysis influences survival in patients with advanced gastric cancer. This analysis included 1377 patients diagnosed with advanced gastric cancer in the Surveillance, Epidemiology, and End Results (SEER) database. Patients who had more than 15 N2 nodes and more than 20 N3 nodes had the best long-term survival outcomes.37
Gastrectomy with D2 lymphadenectomy is the standard treatment for curable gastric cancer in eastern Asia. In a randomized controlled trial (JCOG9501), Japanese investigators comparing D2 lymphadenectomy alone with D2 lymphadenectomy with para-aortic nodal dissection (PAND) in patients undergoing gastrectomy for curable (T2b, T3, or T4) gastric cancer reported a postoperative morality rate of 0.8% in each arm.38 The final results of this study showed that D2 lymphadenectomy with PAND does not improve survival rates in curable gastric cancer compared with D2 lymphadenectomy alone. The 5-year overall survival rates were 70.3% and 69.2%, respectively, and no significant differences were seen in relapse-free survival rates.39
In a post hoc subgroup analysis, the survival rates were better among patients with pathologically negative nodes assigned to D2 lymphadenectomy plus PAND than those assigned to D2 lymphadenectomy alone, whereas in patients with metastatic nodes, the survival rates were worse for those assigned to D2 lymphadenectomy plus PAND. However, the investigators of this study caution that these results from post hoc analysis could be false-positive from multiple testing, and that the survival benefit of D2 lymphadenectomy plus PAND in node-negative patients must be clarified in further studies. The investigators concluded that D2 lymphadenectomy plus PAND should not be used to treat patients with curable (T2b, T3, or T4) gastric cancer.
Japanese investigators have often emphasized the value of extensive lymphadenectomy (≥ D2). However, Western investigators have not found a survival advantage when extensive lymphadenectomy is compared with a D1 resection.40–43
In the Dutch Gastric Cancer Group Trial, 711 patients who underwent surgical resection with curative intent were randomized to undergo either a D1 or D2 lymphadenectomy.42 Both the postoperative morbidity (25% vs. 43%; P < .001) and mortality (4% vs. 10%; P = .004) were higher for patients who underwent D2 dissection, with no difference in overall survival (30% vs. 35%; P = .53) between the groups. In a subset analysis, patients with N2 cancer undergoing a D2 lymphadenectomy showed a trend toward improved survival. Unfortunately, N2 cancer can only be detected after microscopic examination of the surgical specimen.
The British Cooperative Trial conducted by the Medical Research Council also failed to show a survival benefit for D2 over D1 lymphadenectomy.41 The 5-year overall survival rates were 35% for D1 and 33% for D2 dissection. In addition, the D2 dissection was associated with increased postoperative morbidity and mortality. Both trials found that splenectomy and pancreatectomy performed along with the D2 dissection significantly increased the mortality and morbidity.
Despite these results, interest in extended lymph node dissections (≥ D2) has not waned.44 Investigators have argued that if the complication rate after a D2 dissection could be decreased, then selected patients may experience benefit. A surgical option that may decrease morbidity and mortality is a modified D2 lymphadenectomy without pancreatectomy and splenectomy.45–48
The phase II study conducted by the Italian Gastric Cancer Study Group reported a survival benefit of pancreas-preserving D2 lymphadenectomy when performed in experienced cancer centers.49,50 The 5-year overall survival rate among all eligible patients was 55%. The overall 5-year morbidity rate was 20.9% and a postoperative in-hospital mortality rate was 3.1% for D2 dissection without pancreatectomy.50 These rates are comparable to the rates for D1 dissections in the Dutch and United Kingdom trials. The inclusion of pancreatectomy and splenectomy in D2 dissection resulted in increased morbidity and mortality.
Other reports from Western countries have also shown better outcomes for D2 lymphadenectomy when performed according to the recommendations of Japanese Research Society for Gastric Cancer. In an Austrian study, 5- and 10-year overall survival rates were 45.7% and 34.3%, respectively.51 For patients who underwent curative surgery, 5- and 10-year survival rates were 57.7% and 44.3%, respectively, which are comparable to those reported in Japanese trials. Postoperative mortality rates for R0, R1-R2, and palliative resections were 4.9%, 9%, and 13.4%, respectively, although cross-trial comparisons result in weak evidence and conclusions.
Sierra et al.52 from a single institution in Spain reported longer 5-year survival rates in the D2 group (50.6%) than the D1 group (41.4%), with no significant differences in morbidity (53.5% and 48.2%, respectively).Operative mortality was 2.3% for D1 and 0% for D2 dissection. Pancreatectomy, hepatic wedge resection, or partial colectomy was performed only for macroscopic invasion.
In a recent analysis involving patients from the INT-0116 adjuvant chemoradiation trial, Enzinger et al.53 assessed the impact of hospital volume on the outcome of patients who underwent lymphadenectomy. Patients were stratified into 2 groups: those who underwent D0 dissection (54%) and those who underwent D1 or D2 resection (46%). For patients who underwent D0 dissection, high-volume centers were not associated with any effect on overall or disease-free survival. However, a trend was seen toward improved overall survival among patients who underwent D1 or D2 dissection at moderate- to high-volume cancer centers.
In the West, D2 dissection is considered a recommended but not required operation. Modified D2 lymphadenectomy (without pancreatectomy and splenectomy) is associated with low mortality and reasonable survival times when performed in institutions that have sufficient experience with the operation and postoperative management.
The panel recommends that gastric cancer surgery be performed by experienced surgeons in high-volume cancer centers and include removal of perigastric lymph nodes (D1) and those along the named vessels of the celiac axis (D2), with a goal of examining 15 or more lymph nodes (page 386).
Endoscopic Mucosal Resection
Endoscopic mucosal resection (EMR) represents a major advance in minimally invasive surgery for gastric cancer. EMR has been used for patients with early gastric cancer (Tis or T1a tumors limited to mucosa).54,55 Node-negative T1 tumors require limited resection because the 5-year survival rate is more than 90%.56 Countries with high incidences of gastric cancer and active screening programs have the most experience with EMR for early gastric cancer.57 The applicability of these techniques in the United States is limited because of the low incidence of early gastric cancer. Indications for EMR include well- or moderately differentiated histology, tumors smaller than 30 mm, absence of ulceration, and no evidence of invasive findings.58 No randomized studies have compared EMR with other surgical techniques for gastrointestinal cancers. Nevertheless, EMR continues to evolve as a promising technology in the diagnosis and treatment of early esophageal and gastric cancers. Because long-term follow-up and survival data are lacking, the routine use of endoscopic techniques is not recommended outside a clinical trial and should be limited to medical centers with extensive experience.
Proper patient selection is essential when using endoscopic or limited gastric resections (wedge). The probability of lymph node metastasis in early gastric cancer is influenced by tumor factors and increases with increasing tumor size, submucosal invasion, poorly differentiated tumors, and lymphatic and vascular invasion.59 Tis or T1 tumors limited to mucosa (T1a) may be candidates for EMR in experienced centers.
Laparoscopic Resection
Laparoscopic resection is an emerging surgical approach that offers important advantages (less blood loss, reduced postoperative pain, accelerated recovery, early return to normal bowel function, and reduced hospital stay) over open surgical procedures for patients with gastric cancer.60 A prospective randomized study conducted by Huscher et al.61 compared early and 5-year clinical outcomes of laparoscopic and open subtotal gastrectomy in 59 patients with distal gastric cancer. The laparoscopic group showed better (though not significant) operative mortality (3.3% vs. 6.7%, respectively), 5-year overall survival (58.9% vs. 55.7%, respectively), and disease-free survival rates (57.3% vs. 54.8%, respectively). However, the role of this approach in the treatment of gastric cancer requires further investigation in larger randomized clinical trials.
Radiation Therapy
Randomized trials have assessed radiation therapy (RT) in both pre- and postoperative settings in patients with resectable gastric cancer. Smalley et al.62 reviewed clinical and anatomic issues related to RT and offer detailed recommendations for using RT in the management of patients with resected gastric cancer.
In a randomized trial conducted by Zhang et al.,63 preoperative RT was associated with a significant improvement in survival over surgery alone (30% vs. 20%; P = .0094), and higher resection rates (89.5% vs. 79%), suggesting that preoperative RT improves local control and survival. However, randomized trials are needed to confirm these results in patients from the Western Hemisphere.
The trial conducted by the British Cancer Stomach Group randomized 432 patients to undergo surgery alone or surgery followed by RT or chemotherapy.64 At 5-year follow-up, no survival benefit was seen for patients undergoing postoperative RT or chemotherapy compared with surgery alone. This trial also showed a significant reduction in locoregional relapse with the addition of RT to surgery (27% with surgery vs. 10% for adjuvant RT and 19% for adjuvant chemotherapy). The results from a recent systematic review and meta-analysis showed a statistically significant 5-year survival benefit with the addition of RT in patients with resectable gastric cancer.65
External-beam RT (45–50.4 Gy) as a single modality has minimal value in palliating locally unresectable gastric cancer and does not improve survival.66 However, when used concurrently with 5-fluorouracil (5-FU), it improves survival. Moertel et al.67 assessed 5-FU plus RT versus RT alone in the treatment of locally unresectable gastric cancer. Patients undergoing combined modality treatment had a significantly better median survival (13 vs. 6 months) and 5-year overall survival (12% vs. none).
In another study by the Gastrointestinal Tumor Study Group, 90 patients with locally advanced gastric cancer were randomized to receive either combination chemotherapy with 5-FU and methyl-CCNU (lomustine) or split-course RT with a concurrent intravenous bolus of 5-FU followed by maintenance 5-FU and methyl-CCNU.68 In the first 12 months, mortality was higher in the combined modality group. At 3 years, the survival curve reached a plateau in the combined modality arm, but tumor-related deaths continued to occur in the chemotherapy-alone arm, suggesting that a small fraction of patients can be cured with combined modality treatment. In most randomized trials, Hazard et al.66 noted that combined modality treatment showed advantage over RT alone in relatively few patients with unresectable cancer.
Intensity-modulated radiation therapy has a great potential to reduce radiation-related toxicity by delivering large doses of radiation to target tissues.69 The use of this technique in gastric cancer remains investigational and the impact of new conformal RT technologies must be assessed in randomized clinical trials.
Principles of RT
RT (preoperative, postoperative, or palliative) can be an integral part of treatment for gastric cancer. All patients should be simulated and treated in the supine position. The panel encourages use of CT simulation and 3-dimensional treatment planning. Intravenous and/or oral contrast may be used when appropriate for CT simulation to aid target localization. Use of an immobilization device is strongly recommended for reproducibility.
The panel recommends involvement of a multidisciplinary team, which should include medical, radiation, and surgical oncologists; radiologists; gastroenterologists; and pathologists to determine optimal diagnostic, staging, and treatment modalities. Pretreatment diagnostic studies, such as EUS, upper gastrointestinal endoscopy, and CT scans, should be used to identify tumor and pertinent nodal groups. The relative risk for nodal metastases at a specific location is dependent on the location of the primary tumor and the extent of gastric wall invasion (pages 389 and 390). It may be possible to accurately target high-risk areas and produce superior dose distributions using 3-dimensional treatment planning systems and unconventional field arrangements. To accomplish this, various target volumes must be carefully defined and encompassed. General guidelines for defining target volumes of pre- and postoperative RT for different locations of the tumor are described in detail on pages 389 and 390.
The panel recommends a dose range of 45 to 50.4 Gy delivered in fractions of 1.8 Gy per day. Every effort should be made to reduce unnecessary radiation doses to vital organs such as the liver, kidneys, spinal cord, heart (especially the left ventricle), and lungs. Optimal dose ranges for these vital organs are included on pages 389 and 390. Lung dose–volume histogram (DVH) parameters should be considered predictors of pulmonary complications in patients with gastric and gastroesophageal junction cancers treated with concurrent chemoradiation, although optimal criteria have not yet emerged. Optimal criteria for DVH parameters are currently being developed in NCCN institutions.
Close patient monitoring and aggressive supportive care are essential during RT. Management of acute toxicities is necessary to avoid treatment interruptions or dose reductions. Antiemetics should be given on a prophylactic basis when appropriate. Antacid and antidiarrheal medications may be prescribed when needed. If the caloric intake is inadequate, enteral and/or parenteral nutrition should be considered. Oral and/or intravenous hydration is often necessary throughout chemoradiation and early recovery. Feeding jejunostomies may be placed if clinically indicated. Levels of vitamin B12, iron, and calcium must be monitored in postoperative patients. Oral supplementation is recommended to maintain adequate levels.
Combined Modality Treatment: Concomitant Chemotherapy and RT
Preoperative Chemoradiation Therapy
In a pilot study, Lowy et al.70 assessed the feasibility of preoperative chemoradiation (45 Gy of external-beam RT with concurrent continuous infusion of 5-FU) followed by surgery and intraoperative RT (10 Gy) for treating patients with potentially resectable gastric cancer. Significant pathologic responses were seen in 63% of patients and complete pathologic response in 11% who underwent preoperative chemoradiation; 83% of patients who underwent chemoradiation therapy underwent D2 lymphadenectomy.
Recent studies have also shown that preoperative induction chemotherapy followed by chemoradiotherapy yields a substantial pathologic response that results in durable survival time.71–74 In the RTOG study, 26% of patients experienced pathologic complete response, and 50% and 77% underwent D2 lymphadenectomy and R0 resection, respectively.73
In a recent phase III study, Stahl et al.74 compared preoperative chemotherapy (cisplatin, FU, and leucovorin [FLP]) with chemoradiation therapy using the same regimen in 119 patients with locally advanced adenocarcinoma of the gastroesophageal junction. Patients with locally advanced adenocarcinoma of the lower esophagus or gastroesophageal junction were randomized to either chemotherapy followed by surgery (arm A) or chemotherapy followed by chemoradiotherapy followed by surgery (arm B). Patients in arm B had a significantly higher probability of showing pathologic complete response (15.6% vs. 2.0%) or tumor-free lymph nodes (64.4% vs. 37.7%) at resection. Preoperative chemoradiation therapy improved the 3-year survival rate from 27.7% to 47.4%.
Although the study closed prematurely because of low accrual, and statistical significance was not achieved, a trend was seen toward a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the gastroesophageal junction. The value of preoperative chemoradiation therapy remains uncertain and must be determined in larger prospective randomized trials.
Postoperative Chemoradiation Therapy
Nonrandomized trials from Baeza et al.75 reported encouraging results for patients with R0 resections who undergo adjunctive treatment. Limited reports from randomized trials of postoperative RT with or without chemotherapy after a complete resection with negative margins did not show a clear survival advantage.67,76,77
In a landmark trial, SWOG 9008/INT-0116,78 patients with T3, T4, and/or node-positive adenocarcinoma of the stomach or gastroesophageal junction were eligible for participation. After resection with negative margins, 603 patients were randomized to either observation alone or postoperative combined modality treatment consisting of 5 monthly cycles of bolus chemotherapy (5-FU and leucovorin), with RT (45 Gy) concurrent with cycles 2 and 3. A significant decrease in local failure as the first site of failure (19% vs. 29%) and an increase in median survival (36 vs. 27 months), 3-year relapse-free (48% vs. 31%), and overall survival rates (50% vs. 41%; P = .005) were seen with combined modality treatment. With more than 10 years of median follow-up, survival remains improved in patients with stage IB through IV (M0) gastric cancer treated with postoperative chemoradiation. No increases in late toxic effects were noted.79 Although gastric resection with extended lymph node dissection (D2) was recommended for all patients, only 10% of patients underwent D2 lymphadenectomy; 36% underwent D1 dissection and 54% underwent D0. It should be noted that surgery was not part of this protocol, and patients were eligible for participation only after recovering from surgery. Nevertheless, results of this study established postoperative chemoradiation therapy as a standard of care in patients with resected gastric cancer who have not undergone preoperative therapy.
An ongoing large phase III trial (ARTIST) is comparing the effects of adjuvant chemoradiation (capecitabine and cisplatin [XP] plus RT) compared with adjuvant chemotherapy (XP) after D2 resection of gastric cancer. The primary end point is 3-year disease-free survival.80
Chemotherapy
Perioperative Chemotherapy
The British Medical Research Council performed the first well-powered phase III trial (MAGIC trial) for perioperative chemotherapy.81 In this trial, 503 patients were randomized to undergo either perioperative chemotherapy (preoperative and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU [ECF]) and surgery or surgery alone. In each group, 74% of patients had stomach cancer, 14% had lower esophageal cancer, and 11% had cancer of the gastroesophageal junction. The perioperative chemotherapy group had a greater proportion of pathologic T1 and T2 tumors (51.7%) than the surgery group (36.8%). Five-year survival rates were 36% among those who received perioperative chemotherapy and 23% in the surgery group. Perioperative chemotherapy with the ECF regimen significantly improved progression-free and overall survival in patients with operable gastric and lower esophageal adenocarcinomas. The results of this study have established perioperative chemotherapy as another added option to the standard of care for patients with resectable gastric cancer.
Postoperative Chemotherapy
S-1 is a novel oral fluoropyrimidine that is a combination of tegafur (prodrug of 5-FU; 5-chloro-2,4-dihydropyridine) and oxonic acid.82 A large randomized phase III study (ACTS GC) in Japan evaluated the efficacy of adjuvant chemotherapy with S-1 in patients with stage II (excluding T1) or III gastric cancer who underwent R0 gastric resection with extensive lymph node dissection (D2).83 This study randomized 1059 patients to either surgery followed by adjuvant treatment with S-1 or surgery alone. Overall survival rates at 3 years were 80.1% and 70.1% for the S-1 and surgery alone groups, respectively. Hazard ratio for death in the S-1 group was 0.68.
These results represent the first time adjuvant chemotherapy was shown to be beneficial after D2 resection in the Japanese patient population. In an earlier randomized trial (579 patients) conducted by the Japan Clinical Oncology Group (JCOG 8801), no significant survival benefit for adjuvant chemotherapy was seen with S-1 after D2 resection.84 No data are available with S-1 in Western patients in this setting.
Chemotherapy for Advanced or Metastatic Disease
Chemotherapy can provide both palliation and improved survival in patients with advanced and metastatic disease. Single agents with activity in patients who have advanced gastric cancer include 5-FU, mitomycin, etoposide, and cisplatin, with reported response rates between 10% and 20%.85,86 Other agents, including irinotecan, paclitaxel, docetaxel, oral etoposide, oxaliplatin, and UFT (a combination of uracil and tegafur), have shown activity as single agents and in combination in patients with advanced gastric cancer.87–98
Irinotecan as a single agent or in combination has been explored extensively in single-arm and randomized clinical trials.99–108 The results of a phase III study, which randomized patients with advanced adenocarcinoma of the stomach or gastroesophageal junction to treatment with irinotecan in combination with 5-FU and folinic acid or cisplatin combined with infusional 5-FU, showed noninferiority for progression-free survival and improved tolerance of the irinotecan-containing regimen. Thus, irinotecan can be an alternative when platinum-based therapy cannot be delivered.102 However, it is best used after front-line therapy.
In another randomized multicenter phase II study, Moheler et al.105 compared capecitabine combined with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or gastroesophageal junction. No significant differences were seen in overall response rates (37.7% and 42.0%, respectively), or median progression-free survival (4.2 and 4.8 months, respectively), although a trend was seen toward better median overall survival in the irinotecan arm (10.2 vs. 7.9 months). The results of this study must be validated further in larger studies.
Chemotherapy resulted in improved quality of life and overall survival compared with best supportive care in patients with advanced gastric cancer.109,110 In the early 1980s, FAM (5-FU, doxorubicin, and mitomycin) was considered the gold standard for patients with advanced gastric cancer.111 The pivotal study performed by the North Central Cancer Treatment Group comparing FAM with 5-FU alone and 5-FU plus doxorubicin showed no significant survival difference among the arms.112 Higher response rates were observed in patients who underwent combination chemotherapy versus 5-FU alone.
In the past 3 decades, several randomized studies have compared FAM vs. FAMTX (5-FU, adriamycin, and methotrexate),113 FAMTX vs. ECF,114 FAMTX vs. ELF (etoposide, leucovorin, and 5-FU) vs. 5-FU plus cisplatin (FP),115 and ECF vs. MCF (mitomycin, cisplatin, 5-FU).116 ECF showed improvements in median survival and quality of life compared with FAMTX or MCF regimens.
In a recent phase III trial conducted by the German Study Group, the combination of FU, leucovorin, and oxaliplatin (FLO) showed a trend toward improved median progression-free survival compared with FLP (5.8 vs. 3.9 months).117 However, no significant differences were seen in median overall survival (10.7 vs. 8.8 months, respectively). FLO was associated with significantly less toxicity than FLP. In patients older than 65 years, FLO resulted in significantly superior response rates (41.3% vs.16.7%), time to treatment failure (5.4 vs. 2.3 months), progression-free survival (6.0 vs. 3.1 months), and an improved overall survival (13.9 vs. 7.2 months) compared with FLP.
In a randomized multinational phase III study (V325), 445 untreated patients with advanced gastric cancer were randomized to receive either the combination of docetaxel, cisplatin, and 5-FU (DCF) every 3 weeks or the combination of cisplatin and FU (CF).118 Time to progression for DCF was significantly longer than for CF (5.6 vs. 3.7 months). In 2006, based on the results of this study, the FDA approved DCF for treating advanced gastric cancer, including cancer of the gastroesophageal junction, in patients who have not undergone prior chemotherapy for advanced disease. Various modifications of DCF with the intent to improve tolerability are being evaluated in clinical trials for patients with advanced gastric cancer.119,120
Capecitabine is an orally administered fluoropyrimidine that is converted to 5-FU intracellularly. Several studies have evaluated capecitabine in combination with other agents in patients with advanced esophagogastric cancers.121 Two phase III trials (REAL-2 and ML 17032) have assessed the efficacy and safety of capecitabine in gastric cancer.122,123
The REAL-2 trial (with 30% of patients having an esophageal cancer) was a randomized multicenter phase III study comparing capecitabine with FU and oxaliplatin with cisplatin in 1003 patients with advanced esophagogastric cancer.122 Patients with histologically confirmed adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma of the esophagus, gastroesophageal junction, or stomach were randomized to undergo 1 of the 4 epirubicin-based regimens (ECF; epirubicin, oxaliplatin, and 5-FU [EOF]; epirubicin, cisplatin, and capecitabine [ECX]; and epirubicin, oxaliplatin, and capecitabine [EOX]). Median follow-up was 17.1 months. Results from this study suggest that capecitabine and oxaliplatin are as effective as FU and cisplatin, respectively, in patients with previously untreated esophagogastric cancer. Compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism, but slightly higher incidences of grade 3 or 4 diarrhea and neuropathy. The toxic effects from 5-FU and capecitabine were not different.
ML 17032, another phase III randomized trial, evaluated XP versus FP as first-line treatment in patients with previously untreated advanced gastric cancer.123 Overall response rate (41% vs. 29%) and overall survival (10.5 vs. 9.3 months) were superior for patients treated with the XP regimen. No difference in median progression-free survival was seen for both regimens (5.6 months for XP and 5.0 months for FP). The results of this study suggest that capecitabine is as effective as 5-FU for treating patients with advanced gastroesophageal cancers.
A meta-analysis of the REAL-2 and ML17032 trials suggested that overall survival was superior in the 654 patients treated with capecitabine-based combinations compared with the 664 patients treated with 5-FU–based combinations, although no significant difference was seen in progression-free survival.124
Another novel oral fluoropyrimidine, S-1, has shown promise in advanced gastric cancer, both as a single agent and in combination with cisplatin in early-phase studies.125–127 In a phase III trial (SPIR-ITS trial), 298 patients with advanced gastric cancer were randomized to S-1 plus cisplatin and S-1 alone. Median overall (13 vs. 11 months, respectively) and progression-free survival (6 vs. 4 months, respectively) were significantly longer for the combination of S-1 and cisplatin than for S-1 alone.128 A multicenter phase II trial conducted in the United States showed that combination S-1 and cisplatin in patients with untreated advanced gastric cancer and gastroesophageal junction adenocarcinoma was safe and active.129,130
The results of First Line Advanced Gastric Cancer Study (FLAGS) comparing combination cisplatin and S-1 with FP in patients with advanced gastric/gastroesophageal adenocarcinoma was recently presented. In this study 1053 patients were randomized to either cisplatin and S-1 or FP.131 Cisplatin and S-1 had similar efficacy as FP, with improved safety. In a subset analysis, cisplatin and S-1 produced statistically superior overall survival for patients with diffuse-type histology. Additional studies are needed in the United States and Western Hemisphere to confirm the activity of S-1.
Targeted Therapies
The overexpression of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and human epidermal growth factor receptor 2 (HER2) has been associated with poor prognosis in patients with gastric and esophageal cancers.132,133 In clinical trials, trastuzumab (an anti-HER2 antibody), bevacizumab (an anti-VEGFR antibody), and cetuximab (anti-EGFR antibody) have been evaluated in combination with chemotherapy in the treatment of patients with advanced gastric and gastroesophageal junction adenocarcinoma.
The ToGA study is the first randomized, prospective, multicenter, phase III trial to evaluate the efficacy and safety of trastuzumab in HER2-positive gastric cancer in combination with cisplatin and a fluoropyrimidine.134 Results of this study confirmed that trastuzumab plus standard chemotherapy is superior to chemotherapy alone in patients with HER2-positive advanced gastric cancer.
This study randomized 594 patients with HER2-positive gastroesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) to receive trastuzumab plus chemotherapy (5-FU or XP) or chemotherapy alone. A significant improvement in the median overall survival was seen with the addition of trastuzumab to chemotherapy compared with chemotherapy alone (13.5 vs. 11.1 months, respectively). Safety profiles were similar, with no unexpected adverse events occurring in the trastuzumab arm, and no difference was seen in symptomatic congestive heart failure. This establishes trastuzumab plus chemotherapy as a new standard of care for treating patients with a HER2-expressing advanced gastric and gastroesophageal cancers.
The safety and efficacy of bevacizumab,135–137 sorafenib,138 and cetuximab,139–144 have been evaluated in multiple phase II studies. Ongoing phase III trials are underway to confirm the efficacy and safety of these agents in combination with standard chemotherapy in patients with advanced gastric and gastroesophageal junction cancers.
Treatment Guidelines
The management of gastric cancer requires the expertise of several disciplines (radiation oncology, surgical oncology, medical oncology, nutritional support, and endoscopic expertise). Hence, the panel believes that multidisciplinary evaluation is preferred for the treatment of patients with esophagogastric cancer, particularly locoregionally confined tumors. The guidelines have now included a section on Principles of Multidisciplinary Team Approach for Gastroesophageal Cancers (page 385).
Workup
In patients with gastric cancer, symptoms can include anemia, early satiety, weight loss, nausea/vomiting, and/or bleeding. Newly diagnosed patients should undergo a complete history and physical examination, chest imaging, and endoscopy of the entire upper gastrointestinal tract. A CBC, chemistry profile, and abdominal CT with contrast should be performed. A pelvic CT scan or ultrasound is also recommended for women. EUS is recommended in patients with potentially resectable cancer. The panel also recommends H. pylori testing with appropriate treatment when clinically indicated.145
Use of PET-CT scans is optional; these are useful for predicting response to preoperative chemotherapy and in evaluating recurrent gastric cancer.146,147 They may also be useful in showing occult metastatic disease, although results may be false-positive. Therefore, histologic confirmation of occult PET-avid metastasis is recommended.148 Additional studies are needed to assess the efficacy of combined PET-CT scan in gastric cancer.
Initial workup enables patients to be classified into 3 groups with the following characteristics (page 380):
- • Localized (Tis or T1a) cancer
- • Locoregional cancer (stages I–III or M0)
- • Metastatic cancer (stage IV or M1)
Patients with apparent locoregional cancer are further classified into the following groups:
- • Medically fit patients (who are able to tolerate major abdominal surgery) with potentially resectable disease
- • Medically fit patients with unresectable disease
- • Medically unfit patients
Primary Treatment
EMR or surgery is the primary treatment option for medically fit patients with Tis or T1a tumors. Surgery is the primary treatment option for medically fit patients with potentially resectable locoregional cancer (T1b). For more advanced tumors, based on the results of the MAGIC trial, the guidelines included perioperative chemotherapy with ECF or its modifications with a category 1 recommendation for patients with T2 or higher tumors (pages 381 and 382). This strategy is feasible in institutions that have a multidisciplinary approach to localized gastric cancer already in place. The panel has also included preoperative chemoradiation (cisplatin or paclitaxel or docetaxel in combination with 5-FU or capecitabine)73,74 as an alternate treatment option with a category 2B recommendation (page 381).
RT (45–50.4 Gy) with concurrent 5-FU–based radiosensitization (category 1) is recommended for medically fit patients with unresectable locoregional cancer and medically unfit patients with locoregional cancer (page 381).67,68 Palliative chemotherapy with any one of the regimens listed on pages 387 and 388 for metastatic or locally advanced cancer is an alternate option for this group of patients.
All patients diagnosed with metastatic disease after laparoscopic staging should be treated with any one of the regimens listed on pages 387 and 388 for metastatic or locally advanced cancer. Medically unfit and fit patients with unresectable disease should undergo restaging, including CBC and chemistry profile, chest imaging, abdominal CT with contrast, pelvic imaging for women, and PET-CT scan after completion of primary treatment (page 383). Patients who experience a complete response should undergo observation or surgery, if appropriate. If evidence shows residual, unresectable, locoregional, and/or distant metastases, patients may be offered palliative treatment.
Postoperative Treatment
Postoperative treatment is based on the surgical margins and nodal status (page 382). Based on the results of INT-0116, selected patients with no residual disease at surgical margins (R0 resection) and no evidence of metastases after gastrectomy may undergo postoperative chemoradiation.78 However, after R0 resection, patients with Tis or T1, N0 or T2, N0 tumors may be observed. Fluoropyrimidine-based postoperative chemoradiation is recommended after R0 resection for selected patients with T2, N0 tumors along with high-risk features, such as poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion, or age younger than 50 years. INT-0116 also included patients (20%) with gastroesophageal junction adenocarcinoma. Therefore, fluoropyrimidine (5-FU or capecitabine)-based postperative chemoradiation may also be recommended (category 1) for patients with gastroesophageal junction adenocarcinoma.
The panel recommends that all patients with T3, T4, or any node-positive tumors with no residual disease at surgical margins (R0 resection) and all patients with microscopic residual disease at surgical margins (R1 resection) be treated with RT (45–50.4 Gy) plus concurrent 5-FU–based radiosensitization plus 5-FU with or without leucovorin (page 382). In the absence of metastases (M1), patients with macroscopic residual disease at surgical margins (R2 resections) may be treated with RT (45–50.4 Gy) and concurrent 5-FU–based radiosensitization or palliative chemotherapy. Best supportive care may be offered for patients with poor performance status (page 382).
Follow-Up and Surveillance
All patients should be followed up systematically. Follow-up should include a complete history and physical examination every 3 to 6 months for 1 to 3 years, every 6 months for 3 to 5 years, and annually thereafter (page 384). CBC, chemistry profile, imaging studies, or endoscopy should be performed if clinically indicated. Patients who have undergone surgical resection should be monitored and treated as indicated for vitamin B12 and iron deficiency.
Palliative Treatment for Recurrent or Metastatic Disease
In a randomized comparison between chemotherapy and best supportive care versus best supportive care alone for advanced gastric cancer, overall survival (8 vs. 5 months, although not statistically significant), and time to progression (5 vs. 2 months) were longer in patients undergoing chemotherapy.149 More patients in the chemotherapy group (45%) had an improved or prolonged high quality of life for a minimum of 4 months compared with those who received only best supportive care (20%). A recent meta-analysis of randomized trials compared chemotherapy and supportive care in patients with advanced gastric cancer showed that chemotherapy increased the 1-year survival rate and improved quality of life.150 A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie comparing irinotecan and best supportive care in the secondline setting showed that irinotecan significantly prolonged overall survival.151 Median survival was 123 days in the irinotecan arm compared with 72.5 days in the best supportive care–only arm.
Best supportive care is always indicated for patients with advanced gastric cancer. The decision to offer best supportive care alone or with chemotherapy is dependent on the patient's performance status. Several scales are available to measure performance status in patients with cancer. Karnofsky Performance Status (KPS) scale and Eastern Cooperative Oncology Group Performance Status (ECOG PS) are the 2 commonly used scales.152–154 KPS is an ordered scale with 11 levels (0–100), and the general functioning and survival of patients are assessed based on their health status (activity, work, and selfcare). Low Karnofsky scores are associated with poor survival and serious illnesses (http://www.hospicepatients.org/karnofsky.html). ECOG PS is a 5-point scale (0–4) based on the level of symptom interference with normal activity. Patients with higher levels are considered to have poor performance status (http://www.ecog.org/general/perf_stat.html).
Palliative treatment options include chemotherapy, clinical trial, or best supportive care. Patients with a KPS of 60 or less or an ECOG PS of 3 or more should probably be offered best supportive care only. Patients with better performance status (KPS ≥ 60, or ECOG PS ≤ 2) may be offered best supportive care with or without chemotherapy, or a clinical trial.
For metastatic gastric cancer, several phase III trials have assessed combinations such as ECF, DCF, and FOLFIRI. No second-line treatment has been established for advanced gastric cancer. Some regimens listed in the guidelines are based on institutional preferences supported by only phase II studies. The following regimens are listed in the guidelines for metastatic or locally advanced cancer (pages 387 and 388):
- • DCF or its modifications
- • ECF or its modifications
- • Irinotecan in combination with cisplatin or fluoropyrimidine (5-FU or capecitabine)
- • Oxaliplatin in combination with fluoropyrimidine (5-FU or capecitabine)
- • Paclitaxel-based regimens
- • Trastuzumab in combination with chemotherapy for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma that is HER2-positive as determined by a standardized method134
The ECF regimen or its modifications and DCF have a category 1 recommendation. DCF modifications and all other regimens have a category 2B recommendation. Leucovorin can be used with certain infusional 5-FU–based regimens.
Best Supportive Care
The goal of best supportive care is to prevent, reduce, and relieve suffering, and improve quality of life for patients and their caregivers, regardless of disease stage. In patients with unresectable or locally advanced cancer, palliative interventions undertaken to relieve major symptoms may result in prolongation of life. Palliative interventions for the management of bleeding, obstruction, pain, nausea, and vomiting are described in detail on page 391.
Bleeding: Bleeding is common in patients with gastric cancer and may be secondary to a tumor or tumor-related phenomenon, or may be a consequence of therapy. A multidisciplinary approach is required for the proper diagnosis and management of gastrointestinal bleeding in patients with cancer.155 Patients with acute bleeding (hematemesis or melena) should undergo prompt endoscopic assessment. Angiographic embolization techniques may be useful when endoscopy is not helpful. External-beam RT and/or endoscopic treatment may be indicated in patients experiencing bleeding.156
Obstruction: Gastrojejunostomy is the most commonly used palliative treatment modality for malignant gastric outlet obstruction. Endoscopic placement of self-expanding metal stents is a safe, effective, and minimally invasive palliative treatment for patients with luminal obstruction from advanced gastric cancer.157–159 The results of a systematic review suggest that stent placement may be associated with more favorable results in patients with a relatively short life expectancy, whereas gastrojejunostomy is preferable in patients with a more prolonged prognosis.160 Other palliative procedures, such as externalbeam RT or balloon dilation, may be used to alleviate symptoms of obstruction. The optimal palliative treatment for patients with malignant gastric outlet obstruction must be determined in large randomized clinical trials.
If endoscopic lumen restoration is not undertaken or unsuccessful, percutaneous endoscopic gastrotomy for gastric decompression may be performed if tumor location permits. Surgical placement of jejunal feeding tube may be necessary to provide adequate hydration and nutritional support. Nutritional counseling may also be valuable.
Pain: Pain control may be achieved with the use of RT and pain medications. Tumor-related pain should be assessed and treated according to the NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org). Severe uncontrolled pain after gastric stent placement should be treated emergently with endoscopic removal of the stent once uncontrollable nature of pain is established.
Nausea/Vomiting: Patients experiencing nausea and vomiting should be treated according to the NCCN Clinical Practice Guidelines in Oncology: Antiemesis (to view the most recent version of these guidelines, visit www.NCCN.org).
Summary
Gastric cancer is rampant in several countries. Its incidence in the Western Hemisphere has been declining for more than 40 years. In the past 15 years, the incidence of proximal gastric cancer has increased in Western countries compared with nonproximal gastric cancer, which is more prevalent in Japan and other parts of the world. Diffuse histology is also more common now than intestinal type of histology. H. pylori infection, smoking, and high salt intake are risk factors for gastric cancer. Few gastric cancers are associated with inherited gastric cancer predisposition syndromes.
Several advances have been made in therapeutic approaches, imaging techniques, and staging procedures. Multidisciplinary team management is essential for treating patients with gastric cancer. Patients with locoregional disease should be referred to high-volume treatment centers.
Surgery is the primary treatment option for medically fit patients with resectable gastric cancer. However, in the West, surgery alone is an insufficient therapy for most patients. Subtotal gastrectomy is preferred for distal gastric cancers, whereas proximal or total gastrectomy is recommended for proximal tumors. Based on the results of recent clinical trials, perioperative chemotherapy with ECF or its modifications is recommended for medically fit patients with resectable locoregional distal esophageal, gastroesophageal junction, and gastric adenocarcinoma (category 1). Preoperative chemoradiation may also be considered for these patients (category 2B). Postoperative treatment is based on surgical margins and nodal status. All patients with unresectable disease may be treated with 5-FU–based chemoradiation.
Targeted therapies in combination with chemotherapy have produced encouraging results in the treatment of patients with advanced gastric, esophageal, and gastroesophageal junction cancers. Based on the results of the ToGA trial, the NCCN panel included trastuzumab plus chemotherapy in the guidelines as a new treatment option for patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma. The efficacy of VEGFR and EGFR inhibitors in combination with chemotherapy for patients with advanced gastric and gastroesophageal junction cancers are being evaluated in ongoing randomized phase III trials.
Best supportive care is an integral part of treatment, especially in patients with metastatic and advanced gastric cancer. Patients with good performance status can be treated with chemotherapy or best supportive care, whereas best supportive care alone is the appropriate treatment for patients with poor performance status.
Assessment of disease severity and related symptoms is essential to initiate appropriate palliative interventions that will prevent and relieve suffering and improve quality of life for patients and their caregivers. Treatment options used for palliation of symptoms in patients with advanced gastric cancer include endoscopic placement of self-expanding metal stents, laser surgery, or RT.
The NCCN Gastric Cancer Guidelines provide an evidence-based systematic approach to the management of gastric cancer in the United States. Many new chemotherapeutic agents, targeted therapies, vaccines, gene therapy, and antiangiogenic agents are being studied in clinical trials. The panel encourages patients to participate in well-designed clinical trials to enable further advances.
Individual Disclosures for the NCCN Gastric Cancer Panel
These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.
These guidelines are copyrighted by the National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of the NCCN © 2010.
At the beginning of each NCCN guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.
Individual disclosures for the NCCN Gastric Cancer Guidelines Panel members can be found on page 409. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)
These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org.
References
- 2.↑
Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287–1289.
- 3.↑
Johnston BJ, Reed PI. Changing pattern of oesophageal cancer in a general hospital in the UK. Eur J Cancer Prev 1991;1:23–25.
- 4.↑
Powell J, McConkey CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer 1990;62:440–443.
- 5.↑
Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24:2137–2150.
- 6.↑
Crew KD, Neugut AI. Epidemiology of upper gastrointestinal malignancies. Semin Oncol 2004;31:450–464.
- 7.
Kubo A, Corley DA. Marked regional variation in adenocarcinomas of the esophagus and the gastric cardia in the United States. Cancer 2002;95:2096–2102.
- 8.↑
Powell J, McConkey CC, Gillison EW, Spychal RT. Continuing rising trend in oesophageal adenocarcinoma. Int J Cancer 2002;102:422–427.
- 9.↑
Corley DA, Buffler PA. Oesophageal and gastric cardia adenocarcinomas: analysis of regional variation using the Cancer Incidence in Five Continents database. Int J Epidemiol 2001;30:1415–1425.
- 10.↑
Parkin DM, Muir CS. Cancer Incidence in five continents. Comparability and quality of data. IARC Sci Publ 1992:45–173.
- 11.↑
Fitzgerald RC, Caldas C. Clinical implications of E-cadherin associated hereditary diffuse gastric cancer. Gut 2004;53:775–778.
- 12.↑
Huntsman DG, Carneiro F, Lewis FR et al.. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001;344:1904–1909.
- 13.↑
Japanese Research Society for Gastric Cancer. The General Rules for the Gastric Cancer Study in Surgery and Pathology, 12th ed. Tokyo: Kanahara Shuppan; 1993.
- 14.↑
Roder JD, Bottcher K, Busch R et al.. Classification of regional lymph node metastasis from gastric carcinoma. German Gastric Cancer Study Group. Cancer 1998;82:621–631.
- 15.↑
Chau I, Norman AR, Cunningham D et al.. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer--pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22:2395–2403.
- 16.↑
Karpeh MS, Leon L, Klimstra D, Brennan MF. Lymph node staging in gastric cancer: is location more important than number? An analysis of 1,038 patients. Ann Surg 2000;232:362–371.
- 17.↑
Abdalla EK, Pisters PW. Staging and preoperative evaluation of upper gastrointestinal malignancies. Semin Oncol 2004;31:513–529.
- 18.
Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol 2007;25:2107–2116.
- 20.↑
Stahl A, Ott K, Weber WA et al.. FDG PET imaging of locally advanced gastric carcinomas: correlation with endoscopic and histopathological findings. Eur J Nucl Med Mol Imaging 2003;30:288–295.
- 21.↑
Chen J, Cheong JH, Yun MJ et al.. Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography. Cancer 2005;103:2383–2390.
- 22.↑
Rosenbaum SJ, Stergar H, Antoch G et al.. Staging and follow-up of gastrointestinal tumors with PET/CT. Abdom Imaging 2006;31:25–35.
- 23.↑
Dassen AE, Lips DJ, Hoekstra CJ et al.. FDG-PET has no definite role in preoperative imaging in gastric cancer. Eur J Surg Oncol 2009;35:449–455.
- 24.↑
Lim JS, Yun MJ, Kim MJ et al.. CT and PET in stomach cancer: preoperative staging and monitoring of response to therapy. Radiographics 2006;26:143–156.
- 25.↑
Matsumoto Y, Yanai H, Tokiyama H et al.. Endoscopic ultrasonography for diagnosis of submucosal invasion in early gastric cancer. J Gastroenterol 2000;35:326–331.
- 26.↑
Tsendsuren T, Jun SM, Mian XH. Usefulness of endoscopic ultrasonography in preoperative TNM staging of gastric cancer. World J Gastroenterol 2006;12:43–47.
- 27.↑
Sarela AI, Lefkowitz R, Brennan MF, Karpeh MS. Selection of patients with gastric adenocarcinoma for laparoscopic staging. Am J Surg 2006;191:134–138.
- 28.↑
Bentrem D, Wilton A, Mazumdar M et al.. The value of peritoneal cytology as a preoperative predictor in patients with gastric carcinoma undergoing a curative resection. Ann Surg Oncol 2005;12:347–353.
- 29.↑
Burke EC, Karpeh MS Jr, Conlon KC, Brennan MF. Peritoneal lavage cytology in gastric cancer: an independent predictor of outcome. Ann Surg Oncol 1998;5:411–415.
- 30.↑
Ajani JA, Mayer RJ, Ota DM et al.. Preoperative and postoperative combination chemotherapy for potentially resectable gastric carcinoma. J Natl Cancer Inst 1993;85:1839–1844.
- 31.↑
Leichman L, Silberman H, Leichman CG et al.. Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program. J Clin Oncol 1992;10:1933–1942.
- 32.↑
Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol 1994;10:12–20.
- 33.↑
Bozzetti F, Marubini E, Bonfanti G et al.. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 1999;230:170–178.
- 34.↑
Ito H, Clancy TE, Osteen RT et al.. Adenocarcinoma of the gastric cardia: what is the optimal surgical approach? J Am Coll Surg 2004;199:880–886.
- 35.↑
Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg 2006;93:559–563.
- 36.↑
Kajitani T. The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg 1981;11:127–139.
- 37.↑
Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable gastric cancer of advanced stage. Ann Surg Oncol 2007;14:317–328.
- 38.↑
Sano T, Sasako M, Yamamoto S et al.. Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501. J Clin Oncol 2004;22:2767–2773.
- 39.↑
Sasako M, Sano T, Yamamoto S et al.. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 2008;359:453–462.
- 40.↑
Bonenkamp JJ, Hermans J, Sasako M et al.. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999;340:908–914.
- 41.↑
Cuschieri A, Weeden S, Fielding J et al.. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer 1999;79:1522–1530.
- 42.↑
Hartgrink HH, van de Velde CJH, Putter H et al.. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol 2004;22:2069–2077.
- 43.↑
McCulloch P, Nita ME, Kazi H, Gama-Rodrigues J. Extended versus limited lymph nodes dissection technique for adenocarcinoma of the stomach. Cochrane Database Syst Rev 2004:CD001964.
- 45.↑
Douglass HO Jr, Hundahl SA, Macdonald JS, Khatri VP. Gastric cancer: D2 dissection or low Maruyama Index-based surgery--a debate. Surg Oncol Clin N Am 2007;16:133–155.
- 46.
Jansen EPM, Boot H, Verheij M, van de Velde CJH. Optimal locoregional treatment in gastric cancer. J Clin Oncol 2005;23:4509–4517.
- 47.
Khatri VP, Douglass HO Jr. D2.5 dissection for gastric carcinoma. Arch Surg 2004;139:662–669; discussion 669.
- 48.↑
van de Velde CJ, Peeters KC. The gastric cancer treatment controversy. J Clin Oncol 2003;21:2234–2236.
- 49.↑
Degiuli M, Sasako M, Calgaro M et al.. Morbidity and mortality after D1 and D2 gastrectomy for cancer: interim analysis of the Italian Gastric Cancer Study Group (IGCSG) randomised surgical trial. Eur J Surg Oncol 2004;30:303–308.
- 50.↑
Degiuli M, Sasako M, Ponti A, Calvo F. Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer. Br J Cancer 2004;90:1727–1732.
- 51.↑
Jatzko GR, Lisborg PH, Denk H et al.. A 10-year experience with Japanese-type radical lymph node dissection for gastric cancer outside of Japan. Cancer 1995;76:1302–1312.
- 52.↑
Sierra A, Regueira FM, Hernandez-Lizoain JL et al.. Role of the extended lymphadenectomy in gastric cancer surgery: experience in a single institution. Ann Surg Oncol 2003;10:219–226.
- 53.↑
Enzinger PC, Benedetti JK, Meyerhardt JA et al.. Impact of hospital volume on recurrence and survival after surgery for gastric cancer. Ann Surg 2007;245:426–434.
- 54.↑
Hull MJ, Mino-Kenudson M, Nishioka NS et al.. Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms. Am J Surg Pathol 2006;30:114–118.
- 55.↑
Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol 2005;23:4490–4498.
- 56.↑
Kooby DA, Suriawinata A, Klimstra DS et al.. Biologic predictors of survival in node-negative gastric cancer. Ann Surg 2003;237:828–835.
- 57.↑
Bonenkamp JJ, van de Velde CJ, Kampschoer GH et al.. Comparison of factors influencing the prognosis of Japanese, German, and Dutch gastric cancer patients. World J Surg 1993;17:410–414.
- 58.↑
Ono H, Kondo H, Gotoda T et al.. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001;48:225–229.
- 59.↑
Hyung WJ, Cheong JH, Kim J et al.. Application of minimally invasive treatment for early gastric cancer. J Surg Oncol 2004;85:181–185.
- 60.↑
Reyes CD, Weber KJ, Gagner M, Divino CM. Laparoscopic vs open gastrectomy. A retrospective review. Surg Endosc 2001;15:928–931.
- 61.↑
Huscher CG, Mingoli A, Sgarzini G et al.. Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-year results of a randomized prospective trial. Ann Surg 2005;241:232–237.
- 62.↑
Smalley SR, 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.
- 63.↑
Zhang ZX, Gu XZ, Yin WB et al.. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)--report on 370 patients. Int J Radiat Oncol Biol Phys 1998;42:929–934.
- 64.↑
Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 1994;343:1309–1312.
- 65.↑
Valentini V, Cellini F, Minsky BD et al.. Survival after radiotherapy in gastric cancer: systematic review and meta-analysis. Radiother Oncol 2009;92:176–183.
- 66.↑
Hazard L, O' Connor J, Scaife C. Role of radiation therapy in gastric adenocarcinoma. World J Gastroenterol 2006;12:1511–1520.
- 67.↑
Moertel CG, Childs DS, Reitemeier RJ et al.. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969;2:865–867.
- 68.↑
The concept of locally advanced gastric cancer. Effect of treatment on outcome. The Gastrointestinal Tumor Study Group. Cancer 1990;66:2324–2330.
- 69.↑
Milano MT, Garofalo MC, Chmura SJ et al.. Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques. Br J Radiol 2006;79:497–503.
- 70.↑
Lowy AM, Feig BW, Janjan N et al.. A pilot study of preoperative chemoradiotherapy for resectable gastric cancer. Ann Surg Oncol 2001;8:519–524.
- 71.↑
Ajani JA, Mansfield PF, Crane CH et al.. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 2005;23:1237–1244.
- 72.
Ajani JA, Mansfield PF, Janjan N et al.. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 2004;22:2774–2780.
- 73.↑
Ajani JA, Winter K, Okawara GS et al.. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol 2006;24:3953–3958.
- 74.↑
Stahl M, Walz MK, Stuschke M et al.. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009;27:851–856.
- 75.↑
Baeza MR, Giannini TO, Rivera SR et al.. Adjuvant radiochemotherapy in the treatment of completely resected, locally advanced gastric cancer. Int J Radiat Oncol Biol Phys 2001;50:645–650.
- 76.↑
Dent DM, Werner ID, Novis B et al.. Prospective randomized trial of combined oncological therapy for gastric carcinoma. Cancer 1979;44:385–391.
- 77.↑
Moertel CG, Childs DS, O'Fallon JR et al.. Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. J Clin Oncol 1984;2:1249–1254.
- 78.↑
Macdonald JS, Smalley SR, Benedetti J et al.. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730.
- 79.↑
Macdonald JS, Benedetti J, Smalley S et al.. Chemoradiation of resected gastric cancer: a 10-year follow-up of the phase III trial INT0116 (SWOG 9008) [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4515.
- 80.↑
Lee J, Kang W, Lim D et al.. Phase III trial of adjuvant capecitabine/cisplatin (XP) versus capecitabine/cisplatin/RT (XPRT) in resected gastric cancer with D2 nodal dissection (ARTIST trial): safety analysis [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4537.
- 81.↑
Cunningham D, Allum WH, Stenning SP et al.. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.
- 83.↑
Sakuramoto S, Sasako M, Yamaguchi T et al.. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–1820.
- 84.↑
Nakajima T, Nashimoto A, Kitamura M et al.. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group. Lancet 1999;354:273–277.
- 86.↑
Shah MA, Schwartz GK. Treatment of metastatic esophagus and gastric cancer. Semin Oncol 2004;31:574–587.
- 88.
Einzig AI, Lipsitz S, Wiernik PH, Benson AB III. Phase II trial of taxol in patients with adenocarcinoma of the upper gastrointestinal tract (UGIT). The Eastern Cooperative Oncology group (ECOG) results. Invest New Drugs 1995;13:223–227.
- 89.
Ohtsu A, Boku N, Tamura F et al.. An early phase II study of a 3-hour infusion of paclitaxel for advanced gastric cancer. Am J Clin Oncol 1998;21:416–419.
- 90.
Ajani JA, Fairweather J, Dumas P et al.. Phase II study of Taxol in patients with advanced gastric carcinoma. Cancer J Sci Am 1998;4:269–274.
- 91.
Kim YH, Shin SW, Kim BS et al.. Paclitaxel, 5-fluorouracil, and cisplatin combination chemotherapy for the treatment of advanced gastric carcinoma. Cancer 1999;85:295–301.
- 92.
Ajani JA. Chemotherapy for advanced gastric or gastroesophageal cancer: defining the contributions of docetaxel. Expert Opin Pharmacother 2006;7:1627–1631.
- 93.
Sulkes A, Smyth J, Sessa C et al.. Docetaxel (Taxotere) in advanced gastric cancer: results of a phase II clinical trial. EORTC Early Clinical Trials group. Br J Cancer 1994;70:380–383.
- 94.
Roth AD, Maibach R, Martinelli G et al.. Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO). Ann Oncol 2000;11:301–306.
- 95.
Ajani JA, Mansfield PF, Dumas P. Oral etoposide for patients with metastatic gastric adenocarcinoma. Cancer J Sci Am 1999;5:112–114.
- 96.
Al-Batran SE, Atmaca A, Hegewisch-Becker S et al.. Phase II trial of biweekly infusional fluorouracil, folinic acid, and oxaliplatin in patients with advanced gastric cancer. J Clin Oncol 2004;22:658–663.
- 97.
Louvet C, Andre T, Tigaud JM et al.. Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients. J Clin Oncol 2002;20:4543–4548.
- 98.↑
Takiuchi H, Ajani JA. Uracil-tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol 1998;16:2877–2885.
- 99.↑
Bouche O, Raoul JL, Bonnetain F et al.. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol 2004;22:4319–4328.
- 100.
Boku N, Ohtsu A, Shimada Y et al.. Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 1999;17:319–323.
- 101.
Brell JM, Krishnamurthi SS, Javle M et al.. A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma. Cancer Chemother Pharmacol 2009;63:851–857.
- 102.↑
Dank M, Zaluski J, Barone C et al.. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol 2008;19:1450–1457.
- 103.
Enzinger PC, Ryan DP, Clark JW et al.. Weekly docetaxel, cisplatin, and irinotecan (TPC): results of a multicenter phase II trial in patients with metastatic esophagogastric cancer. Ann Oncol 2009;20:475–480.
- 104.
Moehler M, Eimermacher A, Siebler J et al.. Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer. Br J Cancer 2005;92:2122–2128.
- 105.↑
Moehler M, Kanzler S, Geissler M et al.. A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol 2010;21:71–77.
- 106.
Pozzo C, Barone C, Szanto J et al.. Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann Oncol 2004;15:1773–1781.
- 107.
Moehler M, Haas U, Siebler J et al.. Weekly treatment with irinotecan, folinic acid and infusional 5-fluorouracil (ILF) in patients with advanced gastric cancer. Anticancer Drugs 2003;14:645–650.
- 108.↑
Ajani JA, Baker J, Pisters PWT et al.. CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma. Cancer 2002;94:641–646.
- 109.↑
Glimelius B, Hoffman K, Haglund U et al.. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 1994;5:189–190.
- 110.↑
Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995;71:587–591.
- 111.↑
MacDonald JS, Schein PS, Woolley PV et al.. 5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 1980;93:533–536.
- 112.↑
Cullinan SA, Moertel CG, Fleming TR et al.. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061–2067.
- 113.↑
Wils JA, Klein HO, Wagener DJ et al.. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J Clin Oncol 1991;9:827–831.
- 114.↑
Webb A, Cunningham D, Scarffe JH et al.. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 1997;15:261–267.
- 115.↑
Vanhoefer U, Rougier P, Wilke H et al.. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 2000;18:2648–2657.
- 116.↑
Ross P, Nicolson M, Cunningham D et al.. Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 2002;20:1996–2004.
- 117.↑
Al-Batran SE, Hartmann JT, Probst S et al.. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26:1435–1442.
- 118.↑
Van Cutsem E, Moiseyenko VM, Tjulandin S et al.. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006;24:4991–4997.
- 119.↑
Moehler MH, Thuss-Patience P, Arnold D et al.. Docetaxel, oxaliplatin, and capecitabine (TEX regimen) for patients with metastatic gastric cancer: interim results from a phase II trial by the German AIO Group [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4554.
- 120.↑
Shankaran V, Mulcahy MF, Hochster HS et al.. Docetaxel, oxaliplatin, and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: preliminary results of a phase II study [abstract]. Presented at the 2009 ASCO Gastrointestinal Cancers Symposium; January 15–17, 2009; San Francisco, California>. Abstract 47.
- 121.↑
Ajani J. Review of capecitabine as oral treatment of gastric, gastroesophageal, and esophageal cancers. Cancer 2006;107:221–231.
- 122.↑
Cunningham D, Starling N, Rao S et al.. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 2008;358:36–46.
- 123.↑
Kang YK, Kang WK, Shin DB et al.. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol 2009;20:666–673.
- 124.↑
Okines AFC, Norman AR, McCloud P et al.. Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer. Ann Oncol 2009;20:1529–1534.
- 125.↑
Takahashi I, Kakeji Y, Emi Y et al.. S-1 in the treatment of advanced and recurrent gastric cancer: current state and future prospects. Gastric Cancer 2003;6(Suppl 1):28–33.
- 126.
Koizumi W, Tanabe S, Saigenji K et al.. Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer 2003;89:2207–2212.
- 127.↑
Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000;58:191–197.
- 128.↑
Koizumi W, Narahara H, Hara T et al.. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008;9:215–221.
- 129.↑
Ajani JA, Lee FC, Singh DA et al.. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24:663–667.
- 130.↑
Lenz HJ, Lee FC, Haller DG et al.. Extended safety and efficacy data on S-1 plus cisplatin in patients with untreated, advanced gastric carcinoma in a multicenter phase II study. Cancer 2007;109:33–40.
- 131.↑
Ajani JA, Rodriquez W, Bodoky G et al.. Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): secondary and subset analyses [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4511.
- 132.↑
Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 2008;19:1523–1529.
- 133.↑
Wagner AD, Moehler M. Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era. Curr Opin Oncol 2009;21:381–385.
- 134.↑
Van Cutsem E, Kang Y, Chung H et al.. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC) [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract LBA4509.
- 135.↑
Enzinger PC, Ryan DP, Regan EM et al.. Phase II trial of docetaxel, cisplatin, irinotecan, and bevacizumab in metastatic esophagogastric cancer [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 4552.
- 136.
Kelsen D, Jhawer M, Ilson D et al.. Analysis of survival with modified docetaxel, cisplatin, fluorouracil (mDCF), and bevacizumab (BEV) in patients with metastatic gastroesophageal (GE) adenocarcinoma: results of a phase II clinical trial [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4512.
- 137.↑
Shah MA, Ramanathan RK, Ilson DH et al.. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2006;24:5201–5206.
- 138.↑
Sun W, Powell ME, O'Dwyer P et al.. A phase II study: combination of sorafenib with docetaxel and cisplatin in the treatment of metastatic or advanced unresectable gastric and gastroesophageal junction (GEJ) adenocarcinoma (ECOG 5203) [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 4535.
- 139.↑
Pinto C, Di Fabio F, Siena S et al.. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510–517.
- 140.
Kanzler S, Trarbach T, Seufferlein T et al.. Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: a nonrandomized multicenter AIO phase II study [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4534.
- 141.
Kim C, Lee JL, Ryu MH et al.. A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Invest New Drugs 2010; in press.
- 142.
Pinto C, Di Fabio F, Barone C et al.. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer 2009;101:1261–1268.
- 143.
Woell E, Greil R, Eisterer W et al.. Oxaliplatin, irinotecan, and cetuximab in advanced gastric cancer. First efficacy results of a multicenter phase II trial (AGMT Gastric-2) of the Arbeitsgemeinschaft Medikamentoese Tumortherapie (AGMT) [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4538.
- 144.↑
Zhang X, Xu J, Shen l et al.. A phase II study of cetuximab with cisplatin and capecitabine as first-line treatment in advanced gastric cancer [abstract]. Presented at the 2009 ASCO Gastrointestinal Cancers Symposium; January 15–17, 2009; San Francisco, California. AbstractLBA39.
- 145.↑
Chey WD, Wong BCY. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808–1825.
- 146.↑
Jadvar H, Tatlidil R, Garcia AA, Conti PS. Evaluation of recurrent gastric malignancy with [F-18]-FDG positron emission tomography. Clin Radiol 2003;58:215–221.
- 147.↑
Ott K, Fink U, Becker K et al.. Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol 2003;21:4604–4610.
- 148.↑
Tian J, Chen L, Wei B et al.. The value of vesicant 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in gastric malignancies. Nucl Med Commun 2004;25:825–831.
- 149.↑
Glimelius B, Ekstrom K, Hoffman K et al.. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 1997;8:163–168.
- 150.↑
Casaretto L, Sousa PLR, Mari JJ. Chemotherapy versus support cancer treatment in advanced gastric cancer: a meta-analysis. Braz J Med Biol Res 2006;39:431–440.
- 151.↑
Thuss-Patience PC, Kretzschmar A, Deist T et al.. Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: a randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO) [abstract]. J Clin Oncol 2009;27(Suppl 1):Abstract 4540.
- 152.↑
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New York: Columbia University Press; 1949:199–205.
- 153.
Oken MM, Creech RH, Tormey DC et al.. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–655.
- 154.↑
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol 1984;2:187–193.
- 155.↑
Imbesi JJ, Kurtz RC. A multidisciplinary approach to gastrointestinal bleeding in cancer patients. J Support Oncol 2005;3:101–110.
- 156.↑
Kim MM, Rana V, Janjan NA et al.. Clinical benefit of palliative radiation therapy in advanced gastric cancer. Acta Oncol 2008;47:421–427.
- 157.↑
Holt AP, Patel M, Ahmed MM. Palliation of patients with malignant gastroduodenal obstruction with self-expanding metallic stents: the treatment of choice? Gastrointest Endosc 2004;60:1010–1017.
- 158.
Lindsay JO, Andreyev HJ, Vlavianos P, Westaby D. Self-expanding metal stents for the palliation of malignant gastroduodenal obstruction in patients unsuitable for surgical bypass. Aliment Pharmacol Ther 2004;19:901–905.
- 159.↑
Kim TO, Kang DH, Kim GH et al.. Self-expandable metallic stents for palliation of patients with malignant gastric outlet obstruction caused by stomach cancer. World J Gastroenterol 2007;13:916–920.
- 160.↑
Jeurnink SM, van Eijck CH, Steyerberg EW et al.. Stent versus gastrojejunostomy for the palliation of gastric outlet obstruction: a systematic review. BMC Gastroenterol 2007;7:18.
