Εταιρεία Ογκολόγων Παθολόγων Ελλάδας - ΕΟΠΕ



20111314450964565Androulakis N, Boutis A, Golfinopoulos V, Katopodi O,Liakakos T, Vini L, Makatsoris T, Nasioulas G,Pentheroudakis G, Sgouros J, Spiliotis J, Triantopoulou C,Tzardi M, Vasileiadis K, Xynos E.00Androulakis N, Boutis A, Golfinopoulos V, Katopodi O,Liakakos T, Vini L, Makatsoris T, Nasioulas G,Pentheroudakis G, Sgouros J, Spiliotis J, Triantopoulou C,Tzardi M, Vasileiadis K, Xynos E.Hellenic Society of Medical Oncology Consensus Meeting on Gastric Cancer Suggestions, Opinions & Recommendationsfor the Diagnosis, Management, Treatment and Surveillance of Gastric Cancer LEGAL DISCLAIMERHeSMO considers adherence to these guidelines to be voluntary. The ultimate determination regarding their application is to be made by the physician in light of each patient’s individual circumstances. In view of the consultory and non-binding nature, these guidelines cannot form the basis for legal action or litigation for compliance or absence of compliance in the clinical practice setting but can only be considered as general guidelines based on best available evidence for assistance in decision-making.Any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. HESMO makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.In addition, these guidelines describe evaluations and administration of therapies in clinical practice; they cannot be assumed to apply to interventions performed in the context of clinical trials, given that such clinical studies are designed to test innovative management strategies in a disease for which better treatment is sorely needed. However, by reviewing and synthesizing the latest literature, this practice guideline serves to identify questions for further research and the settings in which investigational therapy should be considered.Evidence Level and Recommendation GradeLevel of EvidenceIEvidence from at least one large randomized control trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted RCTs without heterogeneityIISmall RCTs or large RCTs with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneityIIIProspective cohort studiesIVRetrospective cohort studies or case-control studiesVStudies without control group, case reports, experts opinionsStrength of RecommendationAStrong evidence for efficacy with a substantial clinical benefit, strongly recommendedBStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommendedCInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs,..) optionalDModerate evidence against efficacy or for adverse outcome, generally not recommendedEStrong evidence against efficacy or for adverse outcome, never recommendedContents TOC \o "1-3" \h \z \u LEGAL DISCLAIMER PAGEREF _Toc388491435 \h 2Evidence Level and Recommendation Grade PAGEREF _Toc388491436 \h 31. GENERAL CONSIDERATIONS PAGEREF _Toc388491437 \h 61.1 MOLECULAR BASIS PAGEREF _Toc388491438 \h 71.2 PROGNOSTIC AND PREDICTIVE FACTORS PAGEREF _Toc388491439 \h 72. DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS PAGEREF _Toc388491440 \h 92.1 CLINICAL PRESENTATION, DIAGNOSIS AND STAGING PAGEREF _Toc388491441 \h 92.1.1Clinical features PAGEREF _Toc388491442 \h 92.1.2Diagnosis PAGEREF _Toc388491443 \h 102.1.3Endoscopic Staging PAGEREF _Toc388491444 \h 112.1.4Endoscopic Surveillance PAGEREF _Toc388491445 \h 122.2 GASTRIC POLYPS PAGEREF _Toc388491446 \h 132.2.1Fundic gland polyps PAGEREF _Toc388491447 \h 132.2.2Hyperplastic polyps PAGEREF _Toc388491448 \h 142.2.3Adenomatous polyps PAGEREF _Toc388491449 \h 142.2.4Hamartomatous polyps PAGEREF _Toc388491450 \h 142.2.5Familial adenomatous polyposis PAGEREF _Toc388491451 \h 153. HEREDITARY GASTRIC CANCER PAGEREF _Toc388491452 \h 163.1 INTRODUCTION AND DIAGNOSIS PAGEREF _Toc388491453 \h 163.2 MANAGEMENT PAGEREF _Toc388491454 \h 173.3 SURVEILLANCE PAGEREF _Toc388491455 \h 174. IMAGING WORK UP AT STAGING PAGEREF _Toc388491456 \h 204.1 CROSS SECTIONAL IMAGING MODALITIES PAGEREF _Toc388491457 \h 204.2 HISTOPATHOLOGICAL FEATURES PAGEREF _Toc388491458 \h 214.2.1Specimen Preparation PAGEREF _Toc388491459 \h 214.2.2Gross Description PAGEREF _Toc388491460 \h 214.2.3Microscopic Description PAGEREF _Toc388491461 \h 224.2.4Gastric endoscopic mucosal resection specimen PAGEREF _Toc388491462 \h 255. NEO-ADJUVANT, PERI-OPERATIVE AND ADJUVANT CHEMOTHERAPY PAGEREF _Toc388491463 \h 265.1 NEO-ADJUVANT CHEMORADIOTHERAPY PAGEREF _Toc388491464 \h 265.2 ADJUVANT CHEMORADIOTHERAPY PAGEREF _Toc388491465 \h 285.3 PERIOPERATIVE AND ADJUVANT CHEMOTHERAPY PAGEREF _Toc388491466 \h 306. SURGICAL TREATMENT PAGEREF _Toc388491467 \h 357. LOCALLY ADVANCED DISEASE PAGEREF _Toc388491468 \h 407.1 DEFINITION SELECTION CRITERIA PAGEREF _Toc388491469 \h 407.2 MANAGEMENT OF LOCALLY ADVANCED GASTRIC CANCER PAGEREF _Toc388491470 \h 427.2.1Radiotherapy PAGEREF _Toc388491471 \h 427.2.2Chemotherapy PAGEREF _Toc388491472 \h 437.2.3Management of Peritoneal Disease PAGEREF _Toc388491473 \h 44 PAGEREF _Toc388491474 \h 458. TREATMENT OF METASTATIC DISEASE AND PALLIATIVE CARE PAGEREF _Toc388491475 \h 468.1 IMAGING PAGEREF _Toc388491476 \h 468.2 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE PAGEREF _Toc388491477 \h 478.2.1First-line therapy PAGEREF _Toc388491478 \h 488.2.2Second-line therapy PAGEREF _Toc388491479 \h 518.2.3Targeted Therapies PAGEREF _Toc388491480 \h 518.3 PALLIATIVE AND SUPPORTIVE CARE PAGEREF _Toc388491481 \h 548.3.1Chemoradiotherapy PAGEREF _Toc388491482 \h 558.3.2Surgery PAGEREF _Toc388491483 \h 558.4 TUMOR-RELATED SYMPTOMS PAGEREF _Toc388491484 \h 569. REFERENCES PAGEREF _Toc388491485 \h 59POSITION STATEMENT PAGEREF _Toc388491486 \h 711. GENERAL CONSIDERATIONSThe worldwide incidence of gastric cancer has declined rapidly over the recent few decades, the reasons for which are incompletely understood. Part of the decline may be due to the recognition of certain risk factors such as H. pylori and other dietary and environmental risks. Refrigerators also improved the storage of food, thereby reducing salt-based preservation, preventing bacterial and fungal contamination, whilst they also allowed for fresh food and vegetables to be more readily available, which may be a valuable source of antioxidants important for cancer prevention.However, the rate of decline has been variable in different regions. In the United States, the incidence rate for non-cardia gastric cancer declined among all race and age groups except for whites aged 29 to 39 years for whom it increased [Anderson et al, 2010]. Despite the general decline, the absolute number of new cases per year is increasing, mainly due to aging in the world population. Thus, gastric cancer will continue to represent an important cause of cancer and cancer-related mortality for the foreseeable future.Despite the decline in gastric cancer overall, there has been an explosive increase in incidence of cancer of the gastric cardia [Powell and McConkey, 1990]. The shift from distal to proximal stomach may in part be due to the decrease in the distal cancers. However, it has also been proposed that carcinoma at the cardia is a different entity from that of the rest of the gastric carcinoma. The histologic pattern of gastric cancer is also changing with a decline in the intestinal-type compared with the diffuse type [Henson et al., 2004]. 1.1 MOLECULAR BASIS Gastric cancer is the second cause of cancer-related death worldwide. The etiology of it is likely to be multifactorial. Factors that predispose patients to develop gastric cancer are among others, obesity, gastroesophageal reflux disease and helicobacter pylori infection. Some of these factors are more important for the development of tumors of the proximal stomach while others for the development of tumors of the body and antrum of the stomach. The above mentioned factors are related to the development of gastric cancer by causing mutation in tumor suppressor genes or by activating oncogenes. Despite the fact that many studies are underway trying to identify these genes, so far we have important data only for a few genes. Two of them are E-cadherin, in diffuse type of gastric adenocarcinoma, and the tumor suppressor gene p-53 [Tamura et al., 2006].1.2 PROGNOSTIC AND PREDICTIVE FACTORS Prognostic factorsAdvanced stage by the 7th edition of the staging system developed jointly by the AJCC and the IUCC confers a worse prognosis. In patients presenting with resectable early gastric cancer, the prognosis depends on the surgical staging. The more the number of lymph nodes are involved the worse the prognosis. Also, both poor performance status and alkaline phosphatase’s level 100IU, or more, are poor prognostic factors. Kattan et al. developed a nomogram that uses various clinicopathologic factors in patients who had R0 tumor resection, to predict the risk of recurrence. These factors are age and gender of the patient, primary tumor site, Lauren classification, tumor size and depth, and number of positive lymph nodes [Kattan et al., 2003]Also, in patients with localized disease and receiving pre-operative chemotherapy, the type of response to chemotherapy is correlated to survival. Residual tumor less than 10% was related to better overall survival in one study [Becker et al, 2003] while in another the number of positive lymph nodes and the presence of perineural or perivascular invasion were related to worse prognosis.There are no conclusive data regarding the prognostic significance of HER2 protein expression.Predictive factorsMany predictive factors have been proposed but none of them has been adequately validated. Overexpression of the receptor HER2 in patients with locally advanced, recurrent or metastatic gastric cancer is related to response to treatment with Trastuzumab [Bang et al, 2010].RecommendationsHER2 overexpression should be tested in all patients with locally advanced or metastatic gastric cancer as it is a predictive factor for response to chemotherapy combined with trastuzumab. (LOE I, SOR A)2. DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS2.1 CLINICAL PRESENTATION, DIAGNOSIS AND STAGINGClinical featuresWeight loss and persistent abdominal pain are the most common symptoms at initial diagnosis. Weight loss usually results from insufficient caloric intake rather than increased catabolism, and may be attributable to anorexia, nausea, abdominal pain, early satiety, and/or dysphagia. When present, abdominal pain tends to be epigastric, vague and mild early in the disease but more severe and constant as the disease progresses. Cancers arising from the proximal stomach may present with dysphagia, and advanced distal tumors may cause gastric outlet obstruction. A pseudoachalasia syndrome may occur as the result of involvement of Auerbach's plexus due to local extension or to malignant obstruction near the gastroesophageal junction. Nausea or early satiety from poor distensibility of the stomach have been noted in cases of an aggressive form of diffuse-type gastric cancer called “linitis plastica". Occult gastrointestinal bleeding with or without iron deficiency anemia is not uncommon, while overt bleeding (i.e., melena or hematemesis) is seen in less than 20% of cases. The presence of a palpable abdominal mass is the most common physical finding and generally indicates long-standing, advanced disease. Patients may also present with signs or symptoms of distant metastatic disease. The most common metastatic distribution is to the liver, peritoneal surfaces, and nonregional or distant lymph nodes. Less commonly, ovaries, central nervous system, bone, pulmonary or soft tissue metastases occur. Since gastric cancer can spread via lymphatics, the physical examination may reveal a left supraclavicular lymphadenopathy (Virchow's node), which is the most common physical examination finding of metastatic disease, a periumbilical nodule (Sister Mary Joseph's node), or a left axillary node (Irish node). Peritoneal spread can present with an enlarged ovary (Krukenberg's tumor), or a mass in the cul-de-sac on rectal examination (Blumer's shelf). However, there are patients with ovarian metastasis without other peritoneal disease. Ascites can also be the first indication of peritoneal carcinomatosis. A palpable liver mass can indicate metastases, although metastatic disease to the liver is often multifocal or diffuse. Jaundice or clinical evidence of liver failure is seen in the preterminal stages of metastatic disease.DiagnosisEven though a delay in diagnosis has not been associated with a poorer prognosis, a prompt diagnostic evaluation should be commenced when gastric cancer is suspected or when new-onset of dyspepsia in older age is noticed (Talley NJ, Vakil N, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia Am J Gastroenterol 2005;100:2324-37). The early use of upper endoscopy in patients presenting with gastrointestinal complaints may be associated with a higher rate of early gastric cancer detection. Approximately 25% of patients have a history of gastric ulcer. All gastric ulcers should be followed to complete healing, and benign-appearing gastric ulcers should be evaluated by biopsy and histologic assessment, since the diagnosis of early gastric cancer offers the greatest opportunity for surgical cure and long-term survival. A single biopsy has 70% sensitivity for diagnosing an existing gastric cancer, while performing seven biopsies from the ulcer margin and base increases the sensitivity to greater than 98%. The diagnosis of a particularly aggressive form of diffuse-type gastric cancer, so called "linitis plastica", can be difficult by endoscopy. Poor distensibility of the stomach or the classic appearance on barium?swallow (described as a leather-flask appearance) may suggest the presence of this disease. Because these tumors tend to infiltrate the submucosa and muscularis propria, superficial mucosal biopsies may be falsely negative. For this reason, the combination of strip and bite biopsy techniques should be used when there is a suspicion of a diffuse type of gastric cancer [Tsendsuren et al., 2006]. Endoscopic StagingEndoscopy with multiple (>7) biopsies providing adequate material for histologic interpretation have become an important tool to assist with diagnosis, treatment planning and follow up examinations. Endoscopic mucosal resection (EMR) of 1.5 cm focal nodules can be performed in the setting of early stage disease to provide accurate T-staging, with the potential of being therapeutic. En bloc excision by endoscopic submucosal dissection (ESD) has been shown to be more effective than EMR in curing early gastric cancer, but requires greater skills and instrumentation to perform and has a significant risk of complications, including perforation [Karita and Tada, 1994; Yahagi et al., 2004].Endoscopic ultrasound (EUS) could be used in the initial clinical staging of gastric cancer, since it provides evidence of depth of tumor invasion (T-stage) and presence of abnormal or enlarged lymph nodes likely to harbor cancer (N-assessment). This is especially important in patients who are being considered for EMR [Botet et al., 1991; Bentrem et al., 2007; Okada et al., 2010] and could be coupled to FNA. Sometimes, it is difficult to distinguish T2 from T3 lesions, and most errors in staging are due to understaging nodal involvement and the depth of primary tumor invasion; however, overstaging can also occur, and is attributed to inflammation around the tumor or to lymph nodes [Tsendsuren et al., 2006]. EUS staging is perhaps of greatest utility for patients with early gastric cancer because accurate assessment of submucosal invasion is essential before considering the option of endoscopic mucosal resection. EUS findings alone rarely affect decisions regarding the need for laparotomy, except when considering patients for a neo-adjuvant therapy clinical trial, because individuals with T1 disease are generally excluded from such studies. However, even patients with locoregionally advanced tumors may still be candidates for surgery, particularly if a palliative resection would be considered. EUS is not recommended for pretreatment evaluation of gastric cancer. Endoscopic SurveillanceEndoscopic surveillance following definitive treatment of gastric cancer requires careful attention to detail for mucosal surface changes, and multiple (4-6) biopsies of any visualized abnormalities. Strictures should be biopsied to rule-out neoplastic cause. EUS performed in conjunction with endoscopy exams has a high sensitivity for recurrent disease. EUS-guided FNA should be performed if suspicious lymph nodes or areas of wall thickening are seen [Lightdale et al., 1989].Endoscopic tumor ablation can be performed for the short-term control of bleeding. Endoscopic insertion of expandable metal stents is effective in long-term relief of tumor obstruction at the EGJ or the gastric outlet, though surgical gastro-jejunostomy may be more efficacious for those with longer-term survival [Schmidt et al., 2009; Vakil et al., 2001].Long-term palliation of anorexia, dysphagia or malnutrition may be achieved with endoscopic or radiographic assisted placement of feeding jejunostomy (PEJ) or gastrostomy (PEG) in selected cases where the distal stomach is uninvolved by tumor, or the placement of a feeding jejunostomy (PEJ) [Shike et al., 1996].RecommendationsUpper GI dyspeptic symptoms in patients aged more than 55 years old must be an indication for upper GI endoscopy. (LOE III, SOR A) Endoscopic staging with multiple (>7) biopsies is the most sensitive diagnostic modality of gastric cancer. Strip and bite biopsies are required to detect carcinoma infiltrating the submucosa and muscularis propria (linitis plastica). (LOE III, SOR A)Endoscopic ultrasound gives information of T and N stage of the disease. EUS findings may guide treatment strategy in case of neo-adjuvant treatment planning, and for confirmation of an early lesion suitable for EMR. (LOE III, SOR B)Endoscopic surveillance involves careful inspection of the gastrojejunal mucosa and multiple biopsies of any suspicious lesion. EUS-guided FNA is recommended in case of suspicious lymph nodes or areas of wall thickening. (LOE III, SOR B)2.2 GASTRIC POLYPSThe widespread use of endoscopic examinations has resulted in increased detection of gastric polyps. Depending on histological type, some polyps have malignant potential or require further investigation, especially if they appear as an expression of a genetic disease or if they indicate an increased risk of intestinal and extra-intestinal malignancy [Goddard et al., 2010]. The comprehension of the nature of gastric polyps provides guidance for endoscopists who encounter these lesions. Fundic gland polypsFundic gland polyps are the most common type of benign gastric polyps found on upper endoscopy. They usually occur as sporadic, almost always in the absence of Helicobacter pylori. They are usually multiple, sessile polyps, less than 10 mm in diameter, located in the body and fundus. Histopathologically, they show cystically dilated fundic glands lined by normal gastric corpus type mucosa, and the frequency of dysplasia is low (<1% of sporadic FGPs). Since the malignant potential of these polyps is very weak, if biopsy confirms the nature of the polyp, no follow-up is needed. Their association with long-term proton pump inhibitors intake has been studied, and the results are controversial. It seems that even there is an increase in the risk of fundic gland polyps in subjects on PPI therapy, the risk of dysplasia is small [Jalving et al., 2006]. Fundic gland polyps are also common in patients with familial adenomatous polyposis and they develop dysplasia in 30-50% of cases. Since the presence of numerous fundic gland polyps may be a manifestation of FAP, colonic investigation maybe is needed to exclude FAP. If biopsy confirms the nature of the polyp, OGD needs to be repeated every 2 years. Hyperplastic polypsHyperplastic polyps occur as solitary usually in the antrum or as multiple throughout the stomach. Histopathologically, they consist of elongated tortuous glands lined by hyperplastic foveolar type epithelium and may contain varying degrees of chronic or active inflammation. Hyperplastic polyps’ formation may be associated with HP infection and high serum gastrin level and up to 80% have been found to regress after eradication of H pylori [Hongo et al., 2010]. Polypectomy has been suggested due to the chance of causing blood loss, gastric obstruction, or because of the risk of neoplasia especially if polyps exceed 2 cm in size. Adenomatous polypsAdenomatous polyps occur sporadically or in association with familial adenomatous polyposis. They are usually solitary and located in the antrum on a background of atrophic gastritis and intestinal metaplasia. Their histology consists of dysplastic epithelium hence they are strong associated with gastric adenocarcinoma progression. The larger the polyp, the greater the probability that the polyp contains foci of adenocarcinoma, and in polyps larger than 2 cm the risk for focus of adenocarcinoma is as high as 50% [Carmack et al., 2009]. All adenomatous polyps should be removed and endoscopic follow up is required at 6 months. Hamartomatous polypsHamartomatous polyps include juvenile polyps, polyps of Peutz-Jeghers’ syndrome, and Cowden’s disease. Juvenile polyps are solitary and histologically have inflammatory infiltrate without neoplastic potential. Multiple polyps are associated with juvenile polyposis and gastric malignancy in over 50% of cases. OGD every 3 years after age 18 is recommended [Goddard et al., 2010]. Peutz-Jeghers’ syndrome is characterized by mucocutaneous pigmented lesions and polyps histologically easily recognized by the presence of hyperplastic glands and a unique smooth muscle core that arborizes throughout the polyp. Peutz-Jeghers’ syndrome increases the risk of gastrointestinal cancer and extra-intestinal malignancies such as breast, colon, stomach, small intestine, ovaries, endometrial, pancreatic and lung cancers. Removal of polyps in order to prevent polyp-related complications and annual screening of other susceptible organs is recommended [Beggs et al., 2010]. Cowden’s syndrome is characterized by orocutaneous hamartomatous tumors, gastrointestinal polyps, abnormalities of the breast, thyroid gland and genitourinary system. Gastrointestinal polyps are generally benign and histologically indistinguishable from gastric hyperplastic polyps. Since there is no association with gastric malignancy in cases of Cowden’s syndrome, no further OGD is recommended. Familial adenomatous polyposisMost polyps found in the stomach are usually benign fundic gland polyps and gastric adenomatous polyps occur in only 10% of gastric polyps, usually in the antrum. Duodenal and periampullary polyps occurring in 50-90% of patients are usually adenomas and require frequent surveillance. Surveillance should be guided according to the number and the size of polyps, the histological type and presence of dysplasia and could be varied from 6 months to 4 years intervals. Endoscopic treatment of duodenal dysplasia is associated with high recurrence rates and complications. Partial gastrectomy, local duodenal resection or pancreaticoduodenectomy may be justified in some patients [Brosens et al., 2005]. 3. HEREDITARY GASTRIC CANCER3.1 INTRODUCTION AND DIAGNOSIS1-3% of gastric cancers arise as a result of inherited gastric cancer predisposition syndromes. Most cases represent diffuse type adenocarcinomas and are referred to as hereditary diffuse gastric cancer (HDGC). Other syndromes include familial intestinal gastric cancer, hereditary non-polyposis colorectal cancer (HNPCC), Li-Fraumeni syndrome, familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS) [Caldas, 1999; Pharoah, 2001].HDGC diagnostic criteria include [Park, 2000; Kaurah, 2007]: At least two documented cases of diffuse gastric cancer in first or second degree relatives, at least one diagnosed before the age of 50 years. At least three documented cases of diffuse gastric cancer in first or second degree relatives regardless of age.A single documented case of diffuse gastric cancer before the age of 40 years.Personal or family history of diffuse gastric cancer and lobular breast cancer, at least one before the age of 50 years.Between 25-50% of HDGC cases carry inactivating germline mutations of the tumor suppressor gene E-cadherin (CDH1), which are inherited in an autosomal dominant pattern. Mutation carriers have a 60-80% lifetime risk of developing gastric cancer and 40-60% of lobular breast cancer in women. Median age at diagnosis of gastric cancer is 38 years [Fitzgerald, 2010].Diagnostic approach of hereditary gastric cancerObtain family pedigree at least for 3 generations.Confirm pathological diagnosis of identified cases.Discuss lifetime risk.Obtain informed consent for genetic testing.Perform DNA analysis (sequencing and MLPA) in blood sample.3.2 MANAGEMENTFor all individuals with suspected familial predisposition of gastric cancer, a baseline upper GI endoscopy should be performed. Helicobacter pylori screening should be done routinely and eradicated if identified.All CDH1 mutation carriers should be referred for total D0 gastrectomy in early adult life (>18) in specialized centers after appropriate counseling about the morbidity of the operation [Norton, 2007; Fitzgerald, 2010]. Individuals who decline gastrectomy and those who do not carry a mutation or carry mutations of undetermined significance, are offered active surveillance at least 10 years earlier from the age of the youngest affected relative. In the absence of mutation and positive family history for HDGC, according to the criteria defined above, active surveillance is indicated [Lynch, 2008].3.3 SURVEILLANCEThe proper use of terminology is screening for high-risk individuals vs surveillance for identified mutation carriers.Offer prophylactic gastrectomy in mutation carriers. If individual declines, consider annual endoscopy with random biopsies, ideally under a research protocol.Endoscopy protocolRefer to specialized center.Use of white light high definition endoscope and take multiple biopsies.Screen for Helicobacter pylori and eradicate if identified. Individuals should also be screened for breast and colorectal cancer if an identified mutation carrier in the family suffered from CRC.Screen for breast cancerBreast self-exam monthly, starting at age 35.Annual mammogram and MRI.Insufficient date to recommend prophylactic mastectomy or chemoprevention with tamoxifen.Screen for CRCConsider annual colonoscopy beginning at age 40, or 10 years younger than the youngest diagnosis of colon cancer in the family.RecommendationsDiagnosisIdentify individuals with suspected familial predisposition of gastric cancer. Search for E-cadherin mutations and HNPCC if diagnostic criteria of either are met. (LOE V, SOR B)ManagementPerform baseline endoscopy. (LOE III, SOR A)Screen for Helicobacter pylori and eradicate if present. (LOE III, SOR A)Offer prophylactic gastrectomy in early adult life to CDH1 mutation carriers. (LOE III, SOR A) SurveillancePerform annual endoscopy in persons with absence of mutation (LOE IV, SOR B) or mutation-carriers that decline gastrectomy (LOE IV, SOR A).4. IMAGING WORK UP AT STAGING4.1 CROSS SECTIONAL IMAGING MODALITIES The accurate staging of gastric cancer is the most important prognostic factor for patient management. Presently, endoscopic ultrasonography (EUS) is the most reliable method for assessing the primary tumor and evaluating T and N stage with high diagnostic rates. The accuracy of EUS for gastric cancer staging varies among different authors with ranges between 64.8% and 92% for T staging and 50% and 90% for N staging, with a few incidences of overstaging and understaging [Tsendsuren et al., 2006]. Multidetector CT provides relatively valuable results of T and N staging, including differentiation between T1a, T1b, and T2 gastric cancers [Lee et al., 2010]. The use of the combination of virtual gastroscopy and dynamic contrast-enhanced MPR images obtained at multi–detector row CT after air and water distention of the stomach can improve tumor detection rates as well as accuracy rates in T and N staging of gastric cancers [Chen et al., 2007]. Virtual gastroscopy from images obtained in air-distended stomach provides an excellent overview of abnormal mucosal lesions within the stomach lumen [Lee, 2000]. The technique is most helpful in the detection of type IIa, IIc, and III early gastric cancer mucosal lesions. These lesions are usually missed at CT due to absence of thickening of the gastric wall.At CT, positive lymph nodes are identified on the basis of size, shape, and enhancement pattern. CT in general is relatively insensitive and also nonspecific for detecting nodal metastases due to its inability to detect microscopic nodal invasion, which is common in gastric cancer, and the presence of reactive nodes that may be greater than 10 mm [Monig et al., 1999]. The role of FDG PET in the preoperative staging of gastric cancer is considered to be still uncertain but it is most useful in detecting advanced disease [Podoloff et al., 2007]. PET is not yet accepted because it cannot provide the exact T stage and N stage of the disease. PET is not helpful in T staging because it is a functional imaging modality. In primary tumor detection, variable levels of FDG uptake have been found. Gastric adenocarcinomas, such as mucinous carcinoma, signet ring cell carcinoma, and poorly differentiated adenocarcinomas, tend to show significantly lower FDG uptake than other histologic types of gastric cancer do.RecommendationsMultidetector CT with a dedicated protocol is the imaging modality of choice in the initial assessment of gastric cancer. (LOE II, SOR B) EUS should be considered as a complementary technique for the evaluation of T stage and N stage (with the addition of EUS-guided biospies). (LOE II, SOR B) FDG PET is not recommended for the initial preoperative staging of gastric cancer, specifically in early disease. (LOE II, SOR B) 4.2 HISTOPATHOLOGICAL FEATURESSpecimen PreparationThe surgical specimen is preferably sent to the pathology department immediately after removal from the patient. The specimen should be received fresh or fixed and opened along the anterior margin of the greater curve. Gross DescriptionThe gross description report must contain at least: a) the nature of the specimen (partial, total gastrectomy), b) length of greater and lesser curvatures of the stomach, length of duodenum and length of esophagus, c) site of the tumor, d) distance from the proximal and distal margin, e) tumor size at three dimensions (tumor size as a prognostic index is contradictory) and f) macroscopic appearance according to Bormann types (polypoid: type 1, fungating: type 2, ulcerated: type 3 and diffuse infiltrating: type 4). Several studies have shown that infiltrating type has a poor prognosis. Microscopic DescriptionA pathology report of gastric cancer specimen should include:Histological Type and GradeThe Lauren classification is the most in use. According to this classification, gastric adenocarcinoma is classified as intestinal, diffuse and mixed type [Allum et al., 2002; Burroughs et al., 1999; Novelli, 2007; Stanley et al., 2000]. According to the WHO classification, gastric carcinomas are divided in adenocarcinoma of intestinal and diffuse type, papillary, tubular, mucinous adenocarcinoma, signet-ring carcinoma, adenosquamous carcinoma, squamous carcinoma, small cell carcinoma, undifferentiated carcinoma and others [Novelli, 2007; Stanley et al., 2000].Grade of differentiation of gastric adenocarcinoma is considered a major prognostic factor. Well and moderately differentiated lesions show a better prognosis than poorly differentiated tumors [Burroughs et al., 1999; Novelli, 2007; Stanley et al., 2000].Depth of InvasionDepth of invasion (T stage) is assessed according to TNM staging system as follow:T1: tumor in the lamina propria or/and submucosaT1a: tumor invades lamina propria or muscularis mucosaeT1b: tumor invades submucosaT2: tumor invading the muscularis propria T3: tumor penetrating the subserosa connective tissue without invasion of visceral peritoneum or adjacent structuresT4: tumor invading serosa (visceral peritoneum) or adjacent structuresT4a: tumor invading serosa (visceral peritoneum)T4b: tumor invading adjacent structuresLymphatic, Vascular, Perineural InvasionThere is evidence that lymphatic, extramural-vascular, or perineural invasion are associated with poor prognosis.Distal and Proximal Resection and Circumferential MarginsStatus of the proximal and distal resection margin is of great prognostic value. There is evidence that R0 resection (no residual tumor at the distal and proximal margins) is a significant and independent prognostic factor of outcome.For tumors located at the cardia, the status of circumferential resection margin of the esophagus should be reported [Burroughs et al., 1999; Novelli, 2007].Lymph NodesAt least 12 lymph nodes should be identified in the resected specimen for an adequate N staging according to 6th UICC classification. The number of the involved over the total number of lymph nodes should be reported. According to the 7th UICC TNM system, N staging depends on the positive lymph nodes as follow:N0: negative lymph nodesN1: 1-2 positive regional lymph nodes N2: 3-6 positive regional lymph nodes N3: seven or more positive regional lymph nodesN3a: 7-15 positive regional lymph nodesN3b: 16 or more positive regional lymph nodesThe minimum number of the lymph nodes that should be identified in a surgical specimen is not clarified in the 7th UICC classification.Other Prognostic FactorsThere is increasing evidence [Chiaravalli et al., 2001; Solcia et al., 2007] that other histopathological features such as T- lymphocytes peri-tumoral, intra-tumoral infiltration and macro-satellite instability (MSI) and specific histologic subtypes (medullary carcinoma) should be assessed. Also, most recently, evaluation of the Her-2 gene status by immune-histo-chemistry, or FISH (fluorescence in situ hybridization), or real-time quantitative polymerase chain reaction (PCR), or CISH (chromogenic in situ hybridization) is proposed as significant predictive factors. It has been shown that overexpression of the HER-2 gene is associated with intestinal type adenocarcinomas and well to moderate differentiated carcinomas, according to WHO classification [Min et al., 2007; Washington, 2010]. No reactivity or membranous staining in < 10% of tumor cells score 0 (negative)Reactivity only in part of the membrane in >10% of cells score 1 ( negative) Weak to moderate complete or basolateral membranous reactivity score 2( equivocal)Moderate to strong complete or basolateral membranous reactivity in >10 of cells score 3 ( positive) For biopsies, the cut off is 5 positive tumor cells. Some investigators consider that biopsies with cohesive IHC score 3 focally or FISH positivity <10% of cells are positive. RecommendationsThe macroscopic pathological evaluation of a gastric cancer specimen should include the maximum tumor diameter, and the site and the macroscopic appearance of the tumor. (LOE III, SOR A)The microscopic histopathological evaluation of a gastric cancer specimen should include the depth of invasion (anatomical layer), the histological type and grade, the status of resection margins (proximal, distal and circumferential), any presence of vascular or/and perineural invasion and ratio of number of involved to total number of lymph nodes. (LOE III, SOR A)Maximum tumor diameterSite of tumorMacroscopic appearance of the tumorDepth of invasion (anatomical layer)Histological typeHistological grade Resection margins (proximal, distal and circumferential)Vascular, perineural invasionLymph node statusHER-2Gastric endoscopic mucosal resection specimen The specimen must be stretching and pinning on firm surface (wax). The margins should be inking as well the deep margin. At the gross description, the size of the specimen, appearance and the dimension of the lesion must be included. Blocks should be taken at 2mm interval.In the histological report, the histological type, histological grade, depth of invasion and the status of the margins must be described. Clearance of the depth margin is important for the local recurrence risk. Some authors showed that patients with a clearance of minimum 2mm do not recur. In the cases with extension of the carcinoma at the margin, the recurrence rate is 37-50%. Another important finding is the lymphatic or vascular invasion.The histological grade, depth of invasion and the lymphovascular invasion play an important role for the lymph node or/and distant metastasis. 5. NEO-ADJUVANT, PERI-OPERATIVE AND ADJUVANT CHEMOTHERAPY5.1 NEO-ADJUVANT CHEMORADIOTHERAPY The rationale for neo-adjuvant radiochemotherapy in gastric cancer is that tumor response and downstaging might facilitate R0 resection. Several single arm prospective studies and retrospective analyses have suggested efficacy of preoperative chemoradiotherapy. An early pilot study assessing the feasibility of preoperative chemoradiotherapy showed significant pathological response in over 60% of patients with complete response in about 10% [Lowy et al., 2001]. In the RTOG 9904 phase II study of preoperative chemotherapy (5FU/cisplatin/leucovorin) followed by chemo-RT (45Gy and 5FU infusion and weekly paclitaxel) [Ajani et al., 2006], pathological complete response was achieved in 26% of patients, R0 resection in 77% and D2 lymphadenectomy in 50%. Median survival was 23 months, and 1 year survival was 72%; however, for complete responders, 1-year OS was 82% compared to 69% of those who achieved less than PR. In addition, neoadjuvant radiotherapy has been evaluated in a few randomized trials. Zhang et al. randomized 370 patients with cancer of the gastric cardia to 40Gy preoperative RT followed by surgery versus surgery alone [Zhang 1998]. They reported improved local control (61% vs 48%), statistically significantly improved in 5 and 10 year survival (overall survival at 10 years 20% versus 13% in the surgery group) and also higher resection rates while operative morbidity and mortality did not differ between arms. In another trial, a trend for improved survival was reported with a short course RT (20Gy in one week) delivered immediately before surgery with 10 year survival of 32% versus 18% in the surgery group [Skoropad, 2002]. In the meta-analysis published by Fiorica in 2007, which included 4 trials of preoperative radiotherapy, 3 and 5-year mortality was significantly reduced by preoperative radiotherapy.In a recent phase III study [Stahl et al., 2009], 119 patients with adenocarcinomas of the gastroesophageal junction were randomized to preoperative chemotherapy or chemoradiotherapy. Although the trial was closed early, the combined treatment increased the pathological complete response rate and also the 3-year survival (27% vs 47%). In all the above studies, patients with locally advanced disease (T3-T4, N+) were included. Despite a significant amount of accumulating data on this issue [Oscar Matzinger et al., 2009], the value of preoperative chemoradiation remains uncertain and needs to be evaluated in prospective randomized studies. Acute toxicity of radiotherapy to the stomach is generally moderate, including mainly nausea, anorexia, pain, fatigue and myelosuppression with concurrent chemotherapy. Preoperative chemoradiotherapy is generally better tolerated than postoperative treatment, and patients are more likely to receive the prescribed doses of both chemotherapy and radiotherapy. While there is a potential for increased surgical morbidity and mortality, trials of preoperative chemoRT have yielded conflicting results. The RTOG study reported a 21% grade 4 toxicity but no treatment related deaths. In general, neoadjuvant chemoradiotherapy is associated with acceptable toxicity.RecommendationPreoperative chemoradiotherapy could be considered for patients with resectable T3-4, LN+ disease. (LOE II, SOR C)5.2 ADJUVANT CHEMORADIOTHERAPY A number of retrospective series and prospective studies suggested significant benefit from adjuvant chemoradiotherapy in reducing locoregional recurrences after radical resection of gastric cancer. An early randomized trial by the British Stomach Cancer Group showed a significant reduction in locoregional recurrence rates with postoperative radiotherapy compared to surgery alone but no difference in survival (10% vs 29%) [Hallisey et al., 1994]. The INT0116 study randomized 556 patients with resected stage IB-IV M0 tumors to observation or postoperative chemoradiotherapy (5FU/Leucovorin before, during and after RT of 45Gy in 25 fractions). With a follow-up over 10 years, this trial showed that postoperative chemoradiotherapy significantly decreased local failure (29% vs 19%) while improved median survival (27 vs 36 months), RFS (31% vs 48%) and OS (41% vs 50%) for all patient groups except those with diffuse histology [Macdonald et al., 2001, 2003]. Given that no differences were noted in rates of distant metastatic disease, the overall survival benefit has been attributed to improvements in locoregional control, suggesting that chemotherapy is exerting its maximum effect as a radiosensitizer. The trial was criticized because of the suboptimal extent of surgery; the beneficial effect of chemoradiation appeared greatest in patients who had a D1 or less than D1 resection. Although D2 lymph node dissection was recommended, it was only performed in 10% of cases and 54% did not even have clearance of the D1 nodal regions. Nevertheless, the results of this study have established postoperative chemoradiotherapy as the standard of care in the USA. A large non-randomized observational study suggested a clinical benefit from postoperative chemoradiation after optimal D2 dissection [Kim et al., 2005]. Mature results of two recent phase III trials (CALGB 80101, CRITICS) are pending. Alternative chemoradiation regimens with newer agents and RT techniques have been evaluated in small phase II studies with promising results [Leong et al 2001]. A meta-analysis of the randomized trials in which radiotherapy (postoperative, preoperative, and intraoperative) was compared to surgery alone or surgery plus chemotherapy in resectable gastric cancer showed a statistically significant 5-year survival benefit with the addition of radiotherapy [Valentini et al., 2009].Radiotherapy should be planned following CT simulation with 3-dimensional treatment planning and should be delivered with high energy linear accelerator using a 3 or 4-field technique. The target volume should include the tumor/gastric bed, the anastomosis of stumps and pertinel lymph nodes, being based on the detailed surgical report and the quality assessment of the fresh specimen. A dose of 45-50.4Gy in 25-28 daily fractions (1.8Gy per fraction) is recommended depending on margin status and presence of residual micro- or macroscopic disease. Every effort should be made to reduce radiation doses to vital organs (liver, kidneys, spinal cord, lungs, heart) below tolerance levels. The use of IMRT may be appropriate in selected cases to reduce dose to normal structures, however, the use of this technique in gastric cancer remains investigational. RecommendationsPostoperative chemo-RT could be considered for patients with IB-IV stage disease, especially in the occurrence of D0 and D1 dissection. (LOE II, SOR B)Postoperative chemo-RT should be considered after R1 and R2 resection, if reoperation is not feasible. (LOE III, SOR C)Radiotherapy should be planned following CT simulation with 3-dimensional treatment planning and should be delivered with high energy linear accelerator using a 3 or 4-field technique, at a dose of 45-50.4Gy in 25-28 daily fractions (1.8Gy per fraction).5.3 PERIOPERATIVE AND ADJUVANT CHEMOTHERAPYFollowing radical resection of gastric cancer, adjuvant treatment with chemotherapy or chemoradiotherapy has been tested in many randomized control trials (RCT) in various countries. The use of perioperative chemotherapy as a combined modality therapy in the setting of locally-confined disease appears to confer a clinically and statistically significant improvement in progression-free and overall survival. This approach has become standard of care in most European and Australasian countries. By contrast, most patients in North America are routinely treated with primary resection followed by post-operative 5FU-based adjuvant chemoradiation. Nevertheless, the two approaches have never been compared in a randomized fashion and cross-trial comparison cannot establish superiority for either strategy due to important differences in the populations of the trials conducted so far. At the moment, level A evidence exists only for perioperative chemotherapy (MRC MAGIC trial, NEJM 2006, UK), post-operative chemoradiotherapy (Intergroup Study 0116, NEJM 2001, US), and post-operative chemotherapy (CLASSIC trial, ASCO 2011, Korea), (S-1 trial, NEJM 2007, Japan). There are important differences in these four studies regarding the studied population, type and quality of surgery, timing of studies etc. The peri-operative chemotherapy, as tested in the MAGIC study, consisted of three cycles of Epirubicin, Cisplatin and 5-fluorouracil (ECF) before and after surgery, demonstrated a 13% improvement in overall survival (from 23% to 36,3%) [Cunningham et al., 2006] (For treatment details, see APPENDIX I) Similar findings regarding the benefit of peri-operative chemotherapy were recently reported in another phase III study by Ychou et al. (LOE I, SOR A) [Ychou et al., 2011]. Because of the non-inferiority of capecitabine (X) with 5-fluorouracil (5-FU) in advanced disease and because it obviates the need for an indwelling central venous access device, many centers use ECX in the perioperative setting [LOE IV, SOR A] The post-operative chemoradiotherapy approach is supported by the North American Intergroup randomized study 0116, which demonstrated a 15% improvement in 5-year overall survival (OS) [LOE I, SOR A]. (For treatment details, see APPENDIX I) Two other phase III studies on Asian patients have been recently published and showed that adjuvant chemotherapy, with S-1 (an oral fluoropyrimidine) for 12 months or capecitabine plus oxaliplatin for six months, resulted in a significant improvement of survival. [Sakuramoto et al., 2007; Bang et al., 2011] (For treatment details, see APPENDIX I) Two meta-analyses of RCTs on adjuvant chemotherapy in gastric cancer have been published over the last few years. The first meta-analysis demonstrated a small survival benefit for adjuvant chemotherapy, with an apparently greater benefit noted in the five studies from Asia [relative risk 0.74, 95% confidence interval (CI) 0.64–0.85] compared with the 14 studies conducted outside Asia (relative risk 0.90, 95% CI 0.85–0.96) [LOE I, SOR A] [Liu et al., 2008]. The second meta-analysis from the GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group analyzed data from 17 RCTs (3838 patients) and confirmed the survival benefit from the addition of adjuvant chemotherapy over surgery alone [HR, 0.82; CI, 0.76-0.90; p<0.001]. Though there was heterogeneity of the chemotherapy regimens used in all these trials, it was reported that fluoropyrimidine-based regimens were active and associated with reduced risk of death in resected gastric cancer compared to surgery alone. [GASTRIC Group, Paoletti et al., 2010]Targeted therapiesThere is no evidence, so far, regarding potential benefit from the addition of a targeted agent in the adjuvant setting GC. Therefore, use of any targeted agent should be considered only in the context of a clinical trial.RecommendationsPatients with gastric cancer should be discussed in the context of a multidisciplinary team meeting prior to any radical treatment, in order to achieve the most appropriate management from diagnosis to staging and treatment. Patients with clinical and pathological stage IA and IB (only T2,N0) do not derive additional benefit from adjuvant therapy. In patients with proper pre-operative staging and D2 surgery, adjuvant treatment options include chemotherapy with fluoropyrimidine and platinum agent for 6-8 cycles (LOE I, SOR A) or chemoradiotherapy according to Intergroup 0116 study regimen (LOE II, SOR B).If peri-operative chemotherapy is opted for, this should comprise 3 cycles of platinum-5FU based chemotherapy before and 3 cycles of the same regimen after surgery. (LOE I, SOR A)If no proper pre-operative management or adequate surgery (D0, no peritoneal biopsies) was performed, the adjuvant treatment should be individualized. GC PROPOSED TREATMENT ALGORITHMAPPENDIX IPhase III Randomized controlled trials of perioperative or adjuvant treatment in gastric and gastro-esophageal junction cancerStudyDisease stage and study designTreatment detailsPrimary endpointCommentsMAGIC study(perioperative chemotherapy)Stage Ib-III Arm 1: Surgery Arm 2: 3 cycles ECF Surgery 3 cycles ECFEpirubicin 50mg/m2Cisplatin 60mg/m25-FU 1000mg/m2 d1-21(3 weeks cycles)3DFSArm1: 23%Arm2: 35%mOS Arm1: 20moArm2: 24moD resection at surgeons’ discretionOnly 65% received postoperative chemotherapyINT 0116(postoperative chemoradiotherapy)Stage Ib-IV(M0)Arm 1: Surgery Arm 2: Surgery 1 cycle 5FU/L + 5FU/L/RT for 5 weeks + 2 cycles 5FU/L5FU 425 mg/m2 + L 20mg/m2 (d1-5)RT 4500cGy (25#, 5d/week x 5weeks) with 5FU 400 mg/m2 + L 20mg/m2 (with #1-4 and #23-25)mOSArm1: 27 moArm2: 36 mo36% D0 resection54% D1 resection10% D2 resectionS-1Postoperative chemotherapyStage II-IIIArm 1: Surgery Arm 2: Surgery S-1 S-1 orally 80 mg/m2 for 4 weeks on- 2 weeks off (for 1 year)3 years OSArm1: 70,1%Arm2: 81.1%≥ D2 resection Japanese only PtsCLASSIC Postoperative chemotherapyStage II-IIIbArm 1: Surgery Arm 2: Surgery Capecitabine + OxaliplatinCapecitabine 1000 mg/m2?BID d1-14 Oxaliplatin 130 mg/m2?d1Every 3 weeks for 6 months (8 cycles)3 years DFSArm1: 74%Arm2: 59%D2 resection Korean, Chinese and Taiwanese PtsAbbreviations: 5FU; 5-fluorouracil, BID; twice a day, DFS; disease free survival, L; leucovorin, mOS; median overall survival; Pts; patients, RT; radiotherapy6. SURGICAL TREATMENTFor patients with early stage gastric cancer (Tis- T1a), the use of endoscopic mucosal resection (EMR) [Soetikno et al., 2005] and endoscopic submucosal dissection (ESD) [Yahagi et al., 2004] is indicated [Ono et al., 2001]. The endoscopic approach offers a residual and recurrence- free survival rate of 98% and 93% [Oda et al., 2006]. This stands true, in particular after en bloc ESD resection of lesions less than 5mm in diameter [Cao et al., 2009; Hoteya et al., 2009; Nakamoto et al., 2009; Watanabe et al., 2010]. However, the success of these methods depends on the experience of the individual center, and is more technically demanding in case of ESD. In centers lacking such experience, patients with early gastric cancer should be treated by surgical local excision.For gastric cancers invading the submucosa, there is an increased risk for lymph node metastasis in comparison with that of mucosal invasion alone (21% vs 3.4%) [Hyung et al., 2004]. This is the reason for which these patients cannot be offered a local excision (endoscopic or surgical). A type of gastrectomy is recommended (distal, subtotal or total), depending on the location of the tumor, and requires a surgical margin greater than 4cm [Ito et al., 2004]. D1 lymph node dissection is also recommended. For tumors invading the muscularis propria (T2), the standard procedure for patients fit for surgery should be gastrectomy with extended lymph node dissection (D2). This procedure has been proven to be the most beneficial, regarding the long term survival of patients, as it has been shown in a long term follow up in the Dutch trial [Songun et al., 2010]. Also, an American trial of 1377 patients, regarding the influence of the extended lymphadenectomy in advanced gastric cancer patients, underlines the need for resection of a large number of lymph nodes and highlights the impact in survival, depending on the number of resected negative lymph nodes (more than 15 for N2 or more than 20 for N3) [Schwarz et al., 2007]. Resection of the spleen and pancreas should be performed only when there is a direct invasion of these organs. A prophylactic splenectomy for the removal of negative lymph nodes near the spleen is not recommended, according to a randomized clinical trial [Yu et al., 2006]. This is a modification of D2 lymph node dissection (mD2) which is often described as D1.5 or D1+ (figures 1,2). On the other hand, surgery alone is not recommended for fit patients of these stages. Results published by the British Medical Research Council, showed a survival rate of 36% after preoperative chemotherapy as compared to 23% after surgery alone, in 503 patients [Cunningham et al., 2006]. The results of this study have established preoperative chemotherapy as another option to the standard of care for patients with resectable gastric cancer. When neoadjuvant therapy is performed, the time to surgery is traditionally 6 to 8 weeks after the end of radiotherapy. There are, though, retrospective reports showing that this time interval can be longer, without any additional technical problems [Kim, 2012; Ruol, 2010]. Another treatment option for patients fit for surgery with resectable disease has been evaluated in a large randomized trial from Japan (ACTS GC), regarding the adjuvant use of chemotherapy after gastrectomy with D2 lymph node dissection. The study showed a clear benefit for these patients undergoing adjuvant chemotherapy as compared to those treated with surgery alone (80,1% versus 70,1% respectively) [Sakuramoto et al., 2007].Despite the advancements in staging of the disease, there is a group of patients who unexpectedly present with advanced disease at laparotomy. For this reason, exploratory laparoscopy and even peritoneal lavage cytology is proposed in order to avoid unnecessary resections [Mezhir et al., 2010]. Table. Treatment of Gastric Cancer According to StageTis, T1a EMR or ESD or surgery [local excision] (if EMR or ESD not available) T1b Surgery (+ D1 lymphadenectomy)117030512509500 Surgery (mD2) + chemo 11696701581150011785601670050117877217504900T2- 4 , N0-3, M0 OR Chemotherapy + surgery (mD2) + chemotherapy OR Chemotherapy + surgery (D0-1) + chemoradiation OR Surgery (D0-1) + chemoradiation RecommendationsTis and T1a cancers can be treated by EMR in centers of excellence (LOE III, SOR B). Alternatively local excision is recommended.T1b should have surgery with D1 lymph node dissection (LOE III, SOR B).For T2- T4 N0- 3 M0, preoperative chemotherapy improves survival over surgery alone (LOE I, SOR A). For T2-T4 N0-3 M0, surgery with extended lymph node dissection followed by either adjuvant chemotherapy or chemoradiation are alternative strategies (LOE I, SOR A). Staging laparoscopy and peritoneal fluid cytology should be considered prior to surgery or perioperative chemotherapy for T4 or bulky tumors, in order to identify M1 patients and modify the treatment plan (LOE III, SOR B).FIGURE 1Definition of the extent of lymph node dissection in gastric cancer (total gastrectomy) Japanese gastric cancer treatment guidelines 2010 (ver. 3) Japanese Gastric Cancer AssociationFigure 2Definition of the extent of lymph node dissection in gastric cancer (distal gastrectomy) Japanese gastric cancer treatment guidelines 2010 (ver. 3) Japanese Gastric Cancer Association7. LOCALLY ADVANCED DISEASE (Initially not amenable to R0 resection, T3-4 N1-3 M0)7.1 DEFINITION SELECTION CRITERIAThe purpose of the preoperative evaluation is to initially stratify patients into two clinical groups: those with locoregional, potentially resectable (stage I to III) disease and those with locally advanced unresectable disease or with systemic (stage IV) involvement. Although staging is most accurately determined through surgical pathology, clinical staging directs the initial approach to therapy: Gastric cancer often presents with incurable disease with serosal invasion, peritoneal dissemination, and or lymph node metastases. Also, in about 40% of patients in whom the preoperative intention was a curative resection subsequently had a palliative operation according to the surgeon’s opinion postoperatively. As a result there were many incomplete resections and recurrence of tumor within 12 months and a one-year postoperative survival of only 53%. Careful staging allows the clinician to select the most appropriate therapy, minimizes unnecessary surgery, and maximizes the likelihood of benefit from the selected treatment. The only widely accepted criteria of unresectability for gastric cancer are the presence of distant metastases, and invasion of a major vascular structure, such as the aorta, or disease encasement or occlusion of the hepatic artery or celiac axis/proximal splenic artery. Distal splenic artery involvement is not an indicator of unresectability; the vessel can be resected en bloc with a left upper quadrant exenteration: stomach, spleen and distal pancreas. In addition, the presence of locoregional lymph node metastases that are located topographically distant from the tumor (e.g., celiac nodes with a primary tumor on the greater curvature of the stomach) may not necessarily be considered an indicator of unresectability. However patients who have bulky lymph nodes involvement fixed to the pancreatic head that might indicate the need for a Whipple procedure are at a high risk for occult metastatic disease. In these cases, it is probably best to consider staging laparoscopy or upfront chemotherapy rather than upfront surgery. Also, evidence of unresectability is the metastasis in lymph nodes, which are considered outside of the surgical field such as those behind or inferior to the pancreas, aortocaval region or in the porta hepatis (these nodes would fall into areas that would be defined as third or fourth echelon nodes in the Japanese nomenclature). Finally, linitis plastica is considered to be a contraindication to potentially curative resection from many surgeons since its present is associated with an extremely poor prognosis.Patients with locally advanced gastric cancer that is deemed inoperable initially should be treated with palliative chemotherapy and may be reassessed for surgery if a response is achieved. Treatments for palliation of advanced-inoperable gastric cancer can be either local or systemic. While cytotoxic chemotherapy is the most effective treatment modality for patients with metastatic disease and it may adequately palliate dysphagia, other symptoms such as nausea, pain, obstruction, perforation, or bleeding from a locally advanced or locally recurrent primary tumor often require multidisciplinary management using endoscopic, surgical, radiotherapeutic or other approaches. The survival benefit from combined modality therapy has become clearer over time, although there is no consensus as to the optimal approach. The treatment strategy should be decided in the context of a multidisciplinary team. RecommendationsIn patients with locally advanced gastric cancer, after completion of initial treatment, restaging is recommended and if the disease has become resectable, medically fit patients should be offered surgical resection (LOE II, SOR B).7.2 MANAGEMENT OF LOCALLY ADVANCED GASTRIC CANCERRadiotherapyExternal-beam RT (45-50.4Gy) as a single modality has minimal value in patients with locally advanced unresectable or inoperable gastric cancer and does not improve survival. However when used concurrently with 5FU, improves survival. Moerel et al. assessed 5FU plus RT compared with RT alone in the treatment of locally advanced unresectable gastric cancer. Patients receiving combined modality treatment had a significantly better median survival (13 vs 6 months) and 5-year OS (12% vs 0). In another study by the Gastrointestinal Tumor Study Group (GITSG), patients with unresectable gastric cancer received either combination chemotherapy (5FU-methl-CCNU) or split-course RT with intravenous bolus 5FU followed by maintenance 5FU and methyl-CCNU, showed that a small fraction of patient with unresectable cancer can be cured with combined modality treatment. Several ongoing studies with newer agents, including cisplatin, taxanes and irinotecan, initially followed by radiotherapy concurrently with 5-FU or capecitabine report promising preliminary results [Saikawa et al., 2008]. A phase II study of paclitaxel based chemoradiotherapy in gastric carcinomas reported a 20% pathological complete response and R0 resection in 78% of patients with acceptable toxicity [Ajani, 2005]. Neoadjuvant chemoradiation with cisplatin-etoposide after induction chemotherapy with cisplatin/5FU is also feasible for locally advanced EGJ carcinomas. The German POET study showed higher rates of complete response and a trend towards survival benefit with chemoradiation [Stahl, 2009].In patients with symptomatic locally advanced or recurrent disease, radiotherapy is recommended for locoregional control. Hypo-fractionated radiotherapy (45-50Gy) is an effective and well-tolerated modality to manage bleeding, pain and occasionally obstruction [Kim et al., 2005]. RecommendationsRadiotherapy (a dose of 45-50Gy) concurrently with fluoropyrimidine or taxane based chemotherapy is recommended to medically fit patients with unresectable loco-regional disease as well as to medically unfit patients with loco-regional disease.After completion of initial treatment, patients should be restaged and if the disease has become resectable, medically fit patients should be offered surgical resection.Chemotherapy Chemotherapy significantly improves survival comparing with BSC in patients with advanced disease, [Wagner et al., 2005; Wagner et al., 2006]. A randomized trial showed that the administration of ECF or FAMTX in patients with locally advanced disease achieved objective responses that allowed curative surgery [Webb et al., 1997]. The current standard of care for these patients is chemotherapy as neo-adjuvant, based on the extrapolation of the results of the MAGIC trial [Cunningham, 2006], and, following that, re-assessment of the status of the disease with intent to surgery. Chemotherapy regimens that have been used in this disease setting are ECF and ECF-like (EOX, ECX, e.tc), while FAMTX, CF and TCF are considering reasonable alternatives. Trastuzumab in combination with cisplatin/fluoropyrimidine should be considered for patients with HER2-positive gastric tumors based on the results achieved in the metastatic setting. Adjuvant chemotherapy or chemoradiotherapy should be offered in case of curative resection as in patients with initially resectable disease [Macdonald, 2001; Sakuramoto, 2007]. The use of other targeted agents should be confined to the context of clinical trials (grade B). RecommendationsSystemic chemotherapy followed by disease re-assessment with intent to surgery is the treatment of choice for medically fit patients with locally advanced, initially inoperable, gastric cancer (LOE II, SOR B).Chemotherapy with palliative intent should be offered in inoperable patients with locally advanced disease (LOE II, SOR B)Management of Peritoneal DiseasePeritoneal carcinomatosis (PC) from gastric cancer is characterized by the presence of tumor nodules of various sizes, number and distribution on parietal or/and visceral peritoneal surfaces. Prognosis is very poor and a median survival of less than 6 months is expected. To tackle this problem, a more aggressive treatment strategy in the form of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed, over the past three decades references. Cohort studies suggest that CRS plus HIPEC could improve outcome of patients with PC from gastric cancer [Glehen et al., 2010]. Non-randomized comparative studies also suggest the superior efficacy of CRS plus HIPEC over CRS alone for the treatment of gastric PC [Spiliotis et al., 2011]. Most recently, a phase III randomized trial has demonstrated that, for synchronous gastric PC, CRS plus HIPEC with mitomycin and cis-platinum versus CRS alone improves survival (11months versus 6.5months, p<0.04) with acceptable morbidity [Yang et al., 2011).RecommendationsIn locally advanced unresectable gastric cancer, palliative interventions, by means either of endoscopy or of surgery, are recommended to alleviate symptoms form obstruction and bleeding. (LOE III, SOR C)In advanced gastric cancer patients with peritoneal spread of the disease, there is some evidence that cyto-reductive surgery plus hyperthermic peritoneal chemotherapy (HIPEC) may be occasionally offered to patients who also respond to systemic treatment. (LOE IV, SOR D)FLOW CHARTLocally advanced unresectable Good PS (0-1)Poor PS (≥2)Neoadjuvant chemotherapyChemo-Radiotherapypalliative surgerychemotherapypalliative carePalliative surgery as necessary -5736219685Re – evaluate for surgery00Re – evaluate for surgery8. TREATMENT OF METASTATIC DISEASE AND PALLIATIVE CARE8.1 IMAGINGFor the evaluation of distant metastasis, multidetector CT is currently the method of choice [Habermann et al., 2004]. MRI has an additional role only in the assessment of indeterminate liver lesions. PET/CT is complementary to CT in detecting distant metastasis at advanced stage of the disease. Peritoneal dissemination is a poor prognostic factor. Detection of peritoneal metastases may change the surgical strategy from curative to palliative or deter the surgeon from laparotomy altogether. Increasingly sophisticated CT scans facilitate diagnosis of peritoneal metastases prior to visual inspection during surgery. PET may give additional sensitivity to CT. Diffuse uptake of tracer that obscures the serpiginous outline of the bowel may be an indicator of peritoneal metastases, as well as discrete areas of local uptake along areas within the peritoneal cavity that are otherwise anatomically unexplained [Lim et al., 2006].PET/CT could also be considered for the evaluation of therapeutic response and to help making the decision of continuing the ongoing therapy or redirecting the patient to other salvage therapies. A 35% decrease in uptake between pre-chemotherapy and PET scan taken 2 weeks after initiation of therapy predicts response with accuracy of 85% [Hopkins and Young, 2011]. The value of PET/CT in the evaluation or recurrent gastric cancer has also been proven in many studies [Yoshioka et al., 2003]. Some studies have revealed that there is a significant discordance between the two techniques (CT and PET/CT). This situation is mainly contributed to the sclerotic bone lesions and the millimetric lung nodules that PET/CT fails to show. The clinical significance of this discordance is uncertain as the millimetric nodules are sometimes proved to be non-malignant in the clinical course. Lung nodules that do not show FDG uptake and no change in size or characteristics in consecutive CT examinations should be clinically accepted as nonmetastatic [Ozkan et al., 2011]. Concerning skeletal metastases, not sclerotic but lytic lesions can be apparently diagnosed by PET/CT [Fogelman et al., 2005]. RecommendationsMultidetector CT is currently the method of choice in the assessment of metastatic disease (LOE II, SOR B) MRI is indicated only for the differential diagnosis of equivocal liver lesions (LOE III, SOR B)PET/CT is complementary to CT in detecting distant metastasis at locally advanced gastric cancer (LOE III, SOR B)PET/CT could be considered for the evaluation of tumor response to therapy and in clinical suspicion of tumor recurrence non depicted on CT (LOE II, SOR B)8.2 CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASEPalliative treatment options include chemotherapy, or clinical trial or best supportive care. Patients with a Karnofsky performance score of 60 or less or an ECOG performance score of 3 or more should probably be offered best supportive care only. Patients with better performance status may be offered chemotherapy, if possible within a clinical trial. Chemotherapy can provide palliation and improved survival in patients with advanced and metastatic disease. Older agents such as mitomycin, 5-fluorouracil, cisplatin, and etoposide have demonstrated activity. Newer agents such as irinotecan, oxaliplatin, docetaxel, and capecitabine have also shown activity as single agent as well as in combination regimens. The basic two classes of drugs include a fluoropyrimidine and a platinum compound. Based on the patient’s performance status and organ function, a third agent may be added.In a randomized comparison between chemotherapy and best supportive care vs. best supportive care alone for advanced gastric cancer, OS (8 months vs. 5 months, though not statistically significant) and time to progression (5 months vs. 2 months, P = 0.03) were longer in patients receiving chemotherapy [Glimelius et al., 1997]. A meta-analysis of randomized trials that compared chemotherapy and supportive care in patients with advanced gastric cancer also showed that chemotherapy increased the one-year survival rate and improved the quality of life [Casaretto et al., 2006]. First-line therapyIn a large phase III RCT, patients with histologically confirmed adenocarcinoma, squamous or undifferentiated cancer of the oesophagus, GE junction or stomach were randomized to receive one of the four epirubicin-based regimens (epirubicin, cisplatin, 5-fluorouracil [ECF]; epirubicin, oxaliplatin, 5-fluorouracil [EOF]; epirubicin, cisplatin and capecitabine [ECX]; and epirubicin, oxaliplatin and capecitabine [EOX]) in the REAL2 phase III trial [Cunningham et al., 2008]. Results from this study suggest that capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin respectively, in patients with previously untreated oesophagogastric cancer. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidences of grade 3 or 4 diarrhoea and neuropathy. The toxic effects from 5-fluorouracil and capecitabine were not different. ML 17032, another phase III randomized trial, evaluated the combination of capecitabine and cisplatin (XP) versus the combination of 5-fluorouracil and cisplatin (FP) as first-line treatment in patients with advanced gastric cancer [Kang et al., 2006]. Overall response rate (41% for XP vs. 29% for FP, P = 0.03) and non-inferior for PFS (5.6 for XP vs. 5.0 for FP, P = 0.003). No difference was seen for OS between the two arms. The results of this study suggest that capecitabine is as effective as 5-fluorouracil in the treatment of patients with advanced gastroesophageal cancers. An individual-patient data meta-analysis of the REAL-2 and ML17032 trials suggested that OS was superior in the 654 patients treated with capecitabine-based combinations compared with the 664 patients treated with 5-fluorouracil-based combinations (HR 0.87, 95% CI 0.77-0.98, P = 0.02) although no significant difference in PFS between treatment groups was seen [Okines et al., 2009].The V325 study compared Cisplatin infusional 5FU chemotherapy to a three-drug regimen (docetaxel, cisplatin, infusional 5FU) [Van Cutsem, 2006]. DCF was superior in terms of RR (37% vs. 25%, P = 0.01), TTP (HR 1.47, 95% CI 1.19-1.82), OS (HR 1.29, 95% CI 1.0-1.6), though at a cost of enhanced toxicity, including a 29% rate of febrile neutropenia. Several attempts have been made to decrease the toxicity of the DCF combination by testing modified regimens [Ajani, 2008] and most new trials use one of these regimens for advanced gastric cancer. 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. In a randomized phase III trial conducted in Japan (SPIRITS trial), 298 patients with advanced gastric cancer were randomized to S-1 plus cisplatin versus S-1 alone [Koizumi et al., 2008]. Median OS (13 vs. 11 months; HR 0.77, 95% CI 0.61-0.98) and PFS (6.0 vs. 4 months, P < 0.0001) were significantly longer for the combination of S-1 and cisplatin compared with S-1 alone.Results of First Line Advanced Gastric Cancer Study (FLAGS) comparing the combination of cisplatin and S-1 (CS) with cisplatin and 5-fluorouracil (CF) in patients with advanced gastric/gastroesophageal adenocarcinoma were recently presented [Ajani et al., 2009]. In this study, 1053 patients were randomized to either CS or CF. The investigational CS regimen had similar efficacy compared to CF with improved safety. Additional studies are needed to confirm the activity of S-1 in the US and western hemisphere.Irinotecan as a single agent or in combination has been explored in single arm and randomized clinical trials. The results of a randomized phase III study comparing weekly irinotecan with infusional 5-FU and folinic acid to cisplatin with infusional 5-FU in patients with advanced adenocarcinoma of the stomach or GE junction showed non-inferiority for PFS but not for OS and improved tolerance of the irinotecan containing regimen; it can therefore be an alternative when platinum-based therapy cannot be delivered [Dank et al., 2008]. In another randomized multicenter phase II study, Moehler et al. compared capecitabine combined with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or GE junction [Moehler et al., 2010]. There were no significant differences in overall response rates (37.7% and 42.0% respectively), and median PFS (4.2 months and 4.8 months respectively, P = 0.56), although there was a trend towards better median OS in the irinotecan arm (10.2 vs. 7.9 months, P = 0.13). The results of this study need to be validated further in larger studies. Irinotecan has not produced level 1 evidence for prolongation of survival in patients with advanced gastric cancer; therefore, its use is preferred in the second or third line setting. Oxaliplatin has also being tested for advanced gastric cancer, mostly as part of the FOLFOX regimen. In a randomized clinical trial, FOLFOX-4 regimen was tested against the paclitaxel with cisplatin and 5-FU regimen in 94 patients with advanced gastric cancer [Li et al., 2011]. No significant difference was observed between the two arms in RR, disease control rate, median survival and one-year survival. Several single-arm phase II trials have also tested the FOLFOX regimen and its modifications in elderly patients, providing an option when more toxic chemotherapy cannot be tolerated.Second-line therapyA randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO) comparing irinotecan to best supportive care in the second-line setting showed that irinotecan significantly prolonged OS compared to best supportive care [Thuss-Patience et al., 2009]. Median survival was 123 days in the irinotecan arm compared to 72.5 days in the best supportive care only arm (HR 2.85, 95% CI 1.41-5.79). Second-line chemotherapy with irinotecan, fluorouracil and leucovorin (FOLFIRI) was also active and well tolerated in patients with metastatic gastric cancer not previously treated with fluoropyrimidines [Di Lauro et al., 2009]. Targeted TherapiesThe overexpression of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and HER2-neu has been associated with poor prognosis in patients with gastric and esophageal cancers. In clinical trials, trastuzumab (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 GE junction adenocarcinoma. The ToGA study is the first randomized, prospective, multicenter, phase III trial to evaluate the efficacy and safety of trastuzumab in patients with HER2-neu-positive gastric and EGJ adenocarcinoma in combination with cisplatin and a fluoropyrimidine [Bang et al., 2010]. The results of this study confirmed that trastuzumab plus standard chemotherapy is superior to chemotherapy alone in patients with HER2-neu-positive advanced gastric cancer. 594 patients with HER2-neu-positive gastroesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were randomized to receive trastuzumab plus chemotherapy (5-fluorouracil or capecitabine and cisplatin) or chemotherapy alone. HER2 positivity was defined as HER2 IHC 3+ or FISH+. There was a significant improvement in the median OS with the addition of trastuzumab to chemotherapy compared to chemotherapy alone (13.5 vs. 11.1 months; HR 0.74, 95% CI 0.60-0.91). The most striking survival advantage (16.5 vs 11 months) was seen in patients harbouring tumor IHC HER2 3+ and IHC 2+ with FISH+. Safety profiles were similar, with no unexpected adverse events in the trastuzumab. There was also no difference in symptomatic congestive heart failure between arms. This establishes that trastuzumab plus chemotherapy as a new standard of care for the treatment of patients with a HER2-neu-expressing advanced gastric and EGJ adenocarcinoma. The use of trastuzumab in combination with an anthracycline is not recommended. Although no randomized trials have been reported as yet, it is reasonable to administer a trastuzumab-containing regimen for second-line treatment for trastuzumab-naive patients. There is no evidence currently to support continuation of trastuzumab with different chemotherapy agents beyond first-line treatment, as is the case for advanced breast cancer.The safety and efficacy of lapatinib, bevacizumab, erlotinib, sorafenib, and cetuximab, has been evaluated in multiple phase II studies. The AVAGAST phase III trial randomized patients with advanced gastric cancer to cisplatin and a fluoropyrimidine with or without bevacizumab and failed to show improvement of its primary endpoint, OS (HR 0.87, 95% CI 0.73-1.03) [Ohtsu et al., 2011]. However, response rates (46.0% vs. 37.4%, P = 0.0315) and median PFS (HR 0.80, 95% CI 0.68-0.93) were improved with the addition of bevacizumab. Ongoing phase III trials are underway to confirm the efficacy and safety of the above mentioned agents in combination with standard chemotherapy in patients with advanced gastric and EGJ adenocarcinoma.ConclusionsFirst-line therapyDCF or its modifications ECF or its modifications Regimens incorporating platinum salts (cisplatin or oxaliplatin) with a fluoropyrimidine Trastuzumab with active chemotherapy for patients who are HER2-neu-positive, as determined by a standardized method (IHC 3+ or IHC 2+ and FISH+).Second-line therapyTrastuzumab with active chemotherapy for patients who are HER2-neu-positive, if not used as first-line therapyDocetaxel Irinotecan-based single agent or combination therapy RecommendationsRegimens should be chosen in the context of performance status, medical comorbidities, toxicity profile, and HER2-neu expression.The backbone of a modern chemotherapy regimen for advanced gastric cancer consists of a platinum compound with a fluoropyrimidine (LOE I, SOR A). An alternative regimen for patients intolerant to platinum is a fluoropyrimidine/irinotecan combination (LOE II, SOR C).Two-drug regimens are preferred. The use of three-drug regimens for advanced disease should be reserved for patients who are medically fit, with a good performance status (ECOG performance status of 0 or 1), and with access to frequent toxicity assessment. Infusional 5-FU and capecitabine may be used interchangeably (except as indicated). Infusion is the preferred route compared with bolus 5-FU (LOE I, SOR A).Cisplatin and oxaliplatin may be used interchangeably depending on toxicity profile (LOE I, SOR A).Trastuzumab with chemotherapy for HER2-neu overexpressing adenocarcinoma according to TOGA trial (LOE I, SOR A) for combination with cisplatin and fluoropyrimidine (not recommended for use with anthracyclines) is standard treatment approach.Recent phase III data support the administration of second line therapy (irinotecan or docetaxel) in selected fit patients. Administration of second-line trastuzumab in combination with non-anthracycline cytotoxic compounds in cases of patients with HER2-overexpressing gastric cancers not treated with trastuzumab in the first-line setting could be considered (LOE V, SOR C).8.3 PALLIATIVE AND SUPPORTIVE CAREThe goal of best supportive care is to prevent, reduce, and relieve suffering, and improve the 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 also result in prolongation of life. 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.ChemoradiotherapyIn patients with symptomatic locally advanced or recurrent disease radiotherapy is an effective and well tolerated modality to palliate persistent symptoms [Tey et al., 2006]. With moderate doses, 30-40Gy, 50-75% patients experience improvement of symptoms such as bleeding, outlet obstruction or pain with palliation lasting the majority of patients’ lives. Bleeding can often be stopped with radiation doses of 20Gy in 5 fractions in one week. There is some evidence that patients receiving combined chemotherapy and higher dose radiotherapy have better local tumor control and longer duration of response [Kim et al., 2008]. Currently, there is increasing interest in the use of Strereotactic Body RadioTherapy (SBRT) in the treatment of small liver metastases, by delivering high doses of radiation (21Gy in 7 fractions).RecommendationsRadiotherapy with or without chemotherapy could be considered for palliation in metastatic gastric cancer (LOE II, SOR B).SurgeryThere is no important role for surgery in patients with liver metastasis from gastric cancer. There are sporadic reports in the literature with limited number of patients included, and therefore of limited scientific value. Liver metastasis from gastric cancer is usually associated with extra-hepatic disease including peritoneal dissemination, lymph nodes metastasis etc references. In the published series, resection rate is reported to around 20%, and survival is rather unsatisfactory, as patients develop intra-hepatic as well as distant recurrence. Prognostic factors of liver metastases resectability are the stage of the primary tumor, the number of liver metastasis, the timing of diagnosis in case of metachronous lesions, and status of surgical margins after resection. It has been suggested that patients with metastatic liver disease from gastric cancer are candidates for resection when there is no serosa, venous or lymphatic invasion of the primary tumor, metastatic lesions are unilobar and show a maximum diameter of <4cm. Radiofrequency ablation can be used in combination with chemotherapy when the tumor is <3cm in diameter, but the level of evidence is very low references. RecommendationsThe role of surgery in liver metastasis form gastric cancer is limited, and recommended when primary gastric lesion is limited to the gastric muscular wall, and metastases are unilobar and <4cm in diameter (LOE III, SOR C)Evidence of radiofrequency ablation of liver metastases is of very low level (LOE IV, SOR C)8.4 TUMOR-RELATED SYMPTOMSIn patients with unresectable or locally advanced cancer, palliative interventions provide relief of symptoms and improve the nutritional status and overall quality of life. The optimal management is debated and the choice of palliative methods should be based upon anatomical features, patient preferences, and available expertise so, multimodality interdisciplinary approach is encouraged. Methods for palliation of dysphagia include endoscopic therapies, radiation therapy, brachytherapy, chemotherapy or surgery. In a study from Homs et al, single dose brachytherapy was associated with fewer complications and better long-term relief of dysphagia compared with metal stents (Homs, 2004). For patients with complete esophageal obstruction, endoscopic lumen restoration, external beam RT and chemotherapy are recommended. There are several endoscopic approaches providing palliation from malignant dysphagia such as dilation, laser and photodynamic therapy and stent placement. Esophageal dilation can be performed with the use of dilating balloons or bougies to temporarily relieve obstruction from tumors or treatment related strictures. Long-term palliation of dysphagia can be achieved with endoscopic tumor ablation by Nd:YAG laser and PDT, or endoscopic and radiographic assisted insertion of expandable metal or plastic stents [Lightdale et al., 1995; Vakil et al., 2001]. Placement of self-expanding metal stents is the preferred treatment for patients with tracheoesophageal fistula and those who are not candidates for chemoradiation or those who failed to achieve adequate palliation with such therapy [Ross, 2007]. Surgical or radiographic assisted placement of feeding jejunostomy or gastrostomy tubes may be necessary to provide adequate hydration and nutrition and long-term palliation of anorexia and dysphagia. Percutaneous endoscopic gastrostomy in the preoperative setting may compromise the gastric vasculature, thereby interfering with the creation of the gastric conduit in the reconstruction during esophagectomy and should be avoided.External beam RT and/or endoscopic therapy may be indicated in patients with brisk bleeding from the cancer. Bleeding that occurs primarily from the tumor surface may be controlled with endoscopic coagulation techniques such as argon plasma coagulation but bleeding could also be secondary to tumor related aorto-esophageal fistulization. RecommendationsPatients with acute severe bleeding should undergo prompt endoscopic assessment. Endoscopic hemostatic interventions appropriate to the findings should be carried out. 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Randomised trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methrotrexate in advanced oesophagogastric cancer. J Clin Oncol 1997;15:261e7. Yahagi N, Fujishiro M, Kakushima N, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electrosurgical snare (thin type). Dig Endosc. 2004;16:34-8.Yang X, Huang C, Suo T, et al. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: Final results of phase III randomized trial. Ann Surg Oncol 2011;18:1575-81. Ychou M, Boige V, Pignon JP et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: a FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29:1715-21Yoshioka T, Yamaguchi K, Kubota K, et al. Evaluation of 18F-FDG PET in patients with advanced, metastatic, or recurrent gastric cancer.J Nucl Med 2003; 44(5):690-9.Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg 2006;93:559-63.Zhang ZX, Gu XZ, Yin WB, et al. Randomised clinical trial of the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of the gastric cardia – report on 370 patients. Int J Rad Oncol Biol Phys 1998;42:929-934.POSITION STATEMENTAccording to current evidence and practice, patients with “esophageal cancer” and “gastric cancer” should be referred for care to highly specialized centers with adequate case volume, as this ensures better outcomes in terms of morbidity, mortality, local recurrence and survival. At those centers, a multidisciplinary team of surgeons, oncologists, pathologists, radiotherapists and radiologists should be on charge, caring for the patients at any stage of the treatment from the initial evaluation to the follow-up, according to the recommendations listed above.Audit and quality control of therapeutic services require compulsory patient’s full data collection and registration according to regional or national programs. Registered data should include all preoperative characteristics, intraoperative outcomes and quality of surgery parameters, postoperative morbidity and mortality, follow-up details and oncological outcomes, as also defined above. A case-mixed adjusted feedback is crucial in the whole process of the “quality assurance” concept. If suboptimal performance is encountered, the responsible treating team should be instructed to improve results by further and more intensive training or to cease treating such cases. ................
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