NCCN Clinical Practice Guidelines in Oncology. Gastric Cancer V Continue.

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1 Clinical in Oncology V Continue

2 Panel Members * Jaffer Ajani, MD/Chair The University of Texas M. D. Anderson Cancer Center * Tanios Bekaii-Saab, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University * Thomas A. D Amico, MD Duke Comprehensive Cancer Center Charles Fuchs, MD Dana-Farber/Brigham and Women s Cancer Center Massachusetts General Hospital Cancer Center Michael K. Gibson, MD Þ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Melvyn Goldberg, MD Fox Chase Cancer Center James A. Hayman, MD, MBA University of Michigan Comprehensive Cancer Center Medical oncology Gastroenterology Surgery/Surgical oncology Þ Internal medicine Radiotherapy/Radiation oncology Hematology/Hematology oncology * Writing committee member David H. Ilson, MD, PhD Þ Memorial Sloan-Kettering Cancer Center Milind Javle, MD Roswell Park Cancer Institute Scott T. Kelley, MD H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida Robert C. Kurtz, MD Þ Memorial Sloan-Kettering Cancer Center Gershon Yehuda Locker, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Neal J. Meropol, MD Fox Chase Cancer Center Bruce D. Minsky, MD Memorial Sloan-Kettering Cancer Center Mark B. Orringer, MD University of Michigan Comprehensive Cancer Center Continue Raymond U. Osarogiagbon, MD Þ St. Jude Children s Research Hospital/University of Tennessee Cancer Institute James A. Posey, MD University of Alabama at Birmingham Comprehensive Cancer Center Jack Roth, MD The University of Texas M.D. Anderson Cancer Center * Aaron R. Sasson, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Stephen G. Swisher, MD The University of Texas M. D. Anderson Cancer Center Douglas E. Wood, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Gary Yang, MD Roswell Park Cancer Institute Yun Yen, MD, PhD City of Hope Cancer Center Version , 03/09/ 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.

3 Table of Contents Panel Members Workup and Evaluation (GAST-1) Postlaparoscopy Staging and Treatment (GAST-2) Adjunctive Treatment (GAST-3) Follow-up and Salvage Therapy (GAST-4) Principles of Surgery (GAST-A) Principles of Systemic Therapy (GAST-B) Print the Guideline For help using these documents, please click here Staging References This manuscript is being updated to correspond with the newly updated algorithm. Clinical Trials: The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.org/clinical_trials/physician.html Categories of Consensus: All recommendations are Category 2A unless otherwise specified. See Categories of Consensus Summary of Guidelines Updates 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 representations nor warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrighted by 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 Version , 03/09/ 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.

4 Summary of the Guidelines Updates Summary of major changes in the version of the guidelines from the 2006 version include: ( GAST-1): Additional Evaluation: Laparoscopic recommendations were condensed and changed to Consider laparoscopy (category 2B) Added new footnote a regarding the appropriateness of PET/CT scans for T1 or M1 patients ( GAST-2): Medically fit, potentially resectable: M0 pathway revised to include T1 and T2 tumors Added new footnote d about surgery as primary treatment for treatment for T1 cancer ( GAST-A) A new page entitled, Principles of Surgery was added to outline recommended guidelines for gastric surgery ( GAST-B): All category of consensus recommendations for systemic therapies were revised to reflect current data Preoperative Chemotherapy: Added ECF Postoperative Chemotherapy: Added ECF 5-FU was changed to fluoropyrimidine throughout page Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. UPDATES

5 WORKUP CLINICAL PRESENTATION ADDITIONAL EVALUATION Medically fit, b potentially resectable Multidisciplinary evaluation H&P CBC, platelets, SMA-12 Abdominal CT CT/ultrasound pelvis (females) Chest x-ray Esophagogastroduodenoscopy PET/CT scan a Locoregional (M0) Stage IV (M1) Medically fit, b unresectable Medically unfit Cosider Laparoscopyc (category 2B) Postlaparoscopy Staging (see GAST-2) Salvage Therapy (see GAST-4) a b c May not be appropriate for T1 or M1 patients. Medically able to tolerate major abdominal surgery. Laparoscopy is performed to evaluate for peritoneal spread when considering chemotherapy/rt or surgery. Laparoscopy is not indicated if a palliative resection is planned. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-1

6 POSTLAPAROSCOPY STAGING PRIMARY TREATMENT Medically fit, b potentially resectable M0 T1 or less (by clinical staging) T2 or higher (by clinical staging or N+) Surgery d,e Surgery or e Preoperative chemotherapyf Surgery e Surgical Outcomes (see GAST-3) M1 Salvage Therapy (see GAST-4) Medically fit, b unresectable M0 M1 RT, Gy + concurrent 5-FU-based radiosensitization (category 1) or Chemotherapy f Salvage Therapy (see GAST-4) Adjunctive Treatment Postchemotherapy ± RT (see GAST-3) Medically unfit M0 RT, Gy + concurrent 5-FU-based radiosensitization (category 1) or Salvage Therapy (see GAST-4) Adjunctive Treatment Postchemotherapy ± RT (see GAST-3) M1 Salvage Therapy (see GAST-4) bmedically able to tolerate major abdominal surgery. d Surgery as primary therapy is appropriate for T1 cancer or actively bleeding cancer, or when postoperative adjuvant therapy is preferred. esee Principles of Surgery (GAST-A). fsee Principles of Systemic Therapy (GAST-B). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-2

7 SURGICAL RESECTION ADJUNCTIVE TREATMENT T1, N0 Observe Follow-up (see GAST-4) R0 resection T2, N0 Observe or Chemotherapy ( 5-FU-based)/RT for selected patientsg f Surgical outcomes R1 resection R2 resection T3, T4 or Any T, N+ RT, Gy + concurrent 5-FU-based radiosensitization (preferred) + 5-FU ± leucovorin RT, Gy + concurrent 5-FU-based radiosensitization or Chemotherapyf or Best supportive care (poor performance status) RT, Gy + concurrent 5-FU-based radiosensitization (preferred) + 5-FU ± leucovorin Follow-up (see GAST-4) Salvage Therapy (see GAST-4) M1 Salvage Therapy (see GAST-4) Follow-up Restaging (preferred): Complete response (see GAST-4) Chest x-ray Adjunctive or or major response Abdominal CT Surgery, e if treatment, Pelvic imaging appropriate postchemotherapy ± RT locoregional Residual, (females) CBC, SMA-12 Salvage Therapy (see GAST-4) and/or PET/CT scan distant metastases esee Principles of Surgery (GAST-A). fsee Principles of Systemic Therapy (GAST-B). g High risk features such as poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion, or < 50 years of age. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-3

8 FOLLOW-UP SALVAGE THERAPY H&P every 4-6mofor3y, then annually CBC, platelets, SMA-12, as indicated Radiologic imaging or endoscopy, as clinically indicated Monitor vitamin B12 for proximal or total gastrectomy patientsh Karnofsky performance score > 60 or ECOG performance score 2 Karnofsky performance score 60 or ECOG performance score 3 Chemotherapy or Clinical trial or Best supportive care Best supportive care f Supportive Care Modalities Obstruction: Stent, laser, photodynamic therapy, RT, surgery Nutrition: Enteral feeding, nutritional counseling Pain control: RT and/or medications Bleeding: RT, surgery or endoscopic therapy fsee Principles of Systemic Therapy (GAST-B). h Patients should be monitored for vitamin B12 deficiency and treated as indicated. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-4

9 PRINCIPLES OF SURGERY Surgery Type: Distal (body + antrum): prefer subtotal gastrectomy Proximal (cardia): total or proximal gastrectomy, as indicated Splenectomy: avoid if possible Consider placing a feeding jejunostomy tube Prefer > 5cmproximal and distal margins from gross tumor Criteria for unresectability for cure: Peritoneal seeding or distant metastases Inability to perform a complete resection Invasion or encasement of major vascular structure Extent of lymph node dissection recommended: D0: unacceptable Minimum of 15 lymph nodes should be evaluated Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-A

10 PRINCIPLES OF SYSTEMIC THERAPY For resected gastric carcinoma, only f luoropyrimidine/leucovorin has been studied in conjunction with radiation therapy in a phase III setting (Intergroup 116). 1 However, many participating institutions have developed chemotherapy variations in the context of phase II studies. Thus, many regimens indicated below represent institutional preferences but they may not be superior to f luoropyrimidine/leucovorin. For metastatic gastric carcinoma: there have been only a few phase III trials (experimental arms being: ECF (Epirubicin/cisplatin/5-FU), DCF (Docetaxel/cisplatin/5-FU), and FOLFIRI (AIO regimen Infusional 5-FU/leucovorin/irinotecan). The regimens indicated below include institutional preferences in the context of phase II trials. The regimens not studied in the phase III setting may not be superior to DCF or ECF. It should be noted that there is no established second-line therapy for advanced gastric cancer. Moreover, many regimens may be considered as reference regimens in the first-line setting. Preoperative Chemotherapy: ECF (category 1) Preoperative Chemoradiation (Recommended in localized unresectable case) : Fluoropyrimidine/leucovorin (category 2B) Fluoropyrimidine-based (category 2B) Cisplatin-based (category 2B) Taxane-based (category 2B) Irinotecan-based (category 2B) Postoperative Chemoradiation: Fluoropyrimidine/leucovorin (category 1) Fluoropyrimidine-based (category 1) Fluoropyrimidine/cisplatin (category 2B) ECF (category 2B) Taxane-based (category 2B) Postoperative Chemotherapy: ECF (Only when preoperative ECF has been administered) (category 1) Metastatic Cancer: Fluoropyrimidine/leucovorin (category 2B) Fluoropyrimidine-based (category 2B) Cisplatin-based (category 2B) Oxaliplatin-based (category 2B) Taxane-based (category 1) Irinotecan-based (category 2B) ECF (category 1) 1 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. Sep 6;345(10):725-30, Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/09/ 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. GAST-B

11 Staging Table 1 American Joint Committee on Cancer (AJCC) TNM Staging Classification for Carcinoma of the Stomach* Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria T1 Tumor invades lamina propria or submucosa T2 Tumor invades muscularis propria or subserosa T2a Tumor invades muscularis propria T2b Tumor invades subserosa T3 Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures T4 Tumor invades adjacent structures Regional Lymph Nodes (N) NX Regional lymph node(s) cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in 1 to 6 regional lymph nodes N2 Metastasis in 7 to 15 regional lymph nodes N3 Metastasis in more than 15 regional lymph nodes Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Histologic Grade (G) GX Grade cannot be assessed G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Undifferentiated Stage Grouping Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T1 N1 M0 T2a/b N0 M0 Stage II T1 N2 M0 T2a/b N1 M0 T3 N0 M0 Stage IIIA T2a/b N2 M0 T3 N1 M0 T4 N0 M0 Stage IIIB T3 N2 M0 Stage IV T4 N1-3 M0 T1-3 N3 M0 Any T Any N M1 *Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York. (For more information, visit Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed written permission of Springer-Verlag New York on behalf of the AJCC. A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified as T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum, the tumor should be classified as T3. The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum. Intramural extension to the duodenum or esophagus is classified by the depth of the greatest invasion in any of these sites, including the stomach. A designation of pn0 should be used if all examined lymph nodes are negative, regardless of the total number removed and examined. Version , 03/09/ 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. ST-1

12 Categories of Consensus This manuscript is being updated to correspond with the newly updated algorithm. Category 1: There is uniform consensus, based on high-level evidence, that the recommendation is appropriate. Category 2A: There is uniform consensus, based on lowerlevel evidence including clinical experience, that the recommendation is appropriate. Category 2B: There is nonuniform consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate. Category 3: There is major disagreement that the recommendation is appropriate. All recommendations are category 2A unless otherwise noted. Overview Carcinomas originating in the upper gastrointestinal (GI) tract (esophagus, gastroesophageal junction, and stomach) constitute a major health problem around the world. It is estimated that approximately 36,830 new cases of upper GI carcinomas and 25,200 deaths will 1 occur in the United States in There has been a dramatic shift in 2 the location of upper GI tumors in the United States. Changes in histology as well as location of upper GI tumors have also been 3-5 observed in some parts of Europe. In countries in the Western Hemisphere, gastric carcinoma has migrated proximally; it occurs most frequently along the proximal lesser curvature, in the cardia, and in the 2 gastroesophageal junction. It is possible that in the coming decades these changing trends will also occur in South America and Asia. Epidemiology of Gastric Carcinoma Gastric carcinoma is rampant in many countries around the world. By some estimates, it is the second most common malignant disorder worldwide. Its incidence, however, has been declining globally since World War II. Gastric carcinoma is one of the least common cancers in North America. Nevertheless, it remains the eighth leading cause of cancer death in the United States. In 2006, more than 22,280 new cases of gastric cancer are estimated to occur in the United States and 11,430 deaths are expected as a 1 result. In developed countries, the incidence of gastric cancer localized to the cardia follows the distribution of esophageal cancer; however, unlike the latter, the rates of gastric cancer have stabilized 6-8 since Noncardia gastric adenocarcinoma also shows marked geographic variation; thus, countries such as Japan, Costa Rica, Peru, Brazil, China, Korea, Chile, Taiwan, and the former 9,10 Soviet Union show a high incidence of the cancer. In Japan, gastric cancer remains the most common type of cancer among men. In contrast to the increasing incidence of proximal tumors in the West, non-proximal tumors continue to predominate in Japan 11,12 and other parts of the world. The cause of this shift remains elusive and may be multifactorial. Gastric carcinoma is often diagnosed at an advanced stage, because screening for gastric carcinoma is not performed in most of the world, except in Japan (and in a limited fashion in Korea) where early detection of gastric carcinoma is often done. Thus, gastric carcinoma continues to pose a major challenge for healthcare professionals. Risk factors include Helicobacter pylori infection, smoking, high salt intake, and other dietary factors. A few gastric cancers (1%-3%) are associated with inherited gastric cancer predisposition syndromes. E-cadherin mutations occur in an Version , 03/09/ 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. MS-1

13 estimated 25% of families with an autosomal dominant predisposition to diffuse type gastric cancers; this subset of gastric highly penetrant hereditary diffuse gastric cancer. Staging Two major classification systems are currently in use for gastric carcinoma. The most elaborate of these, the Japanese classification, is based on refined anatomic involvement, particularly the lymph node stations. The other staging system for gastric carcinoma, developed jointly by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), is based on a gastric cancer database and demonstrates that the prognosis of node-positive patients depends on the number of lymph nodes involved. The modern staging of gastric carcinoma is based on this tumor/node/metastasis (TNM) classification, rather than on the size of the cancer. The AJCC/UICC classification (see Table 1) is the system used in countries in the Western Hemisphere. Patient outcome depends on the initial stage of the cancer at diagnosis. However, at diagnosis, approximately 50% of patients have gastric carcinoma that extends beyond the locoregional confines. In addition, approximately 50% of patients with locoregional gastric carcinoma cannot undergo a curative resection (R0). Note that the R classification refers to the amount of residual cancer remaining after tumor resection: R0 indicates no macroscopic or microscopic cancer at resection margins (ie, negative margins); R1 indicates microscopic residual cancer (ie, update Surgeryin positive margins); and R2 indicates gross (macroscopic) residual cancer (ie, positive margins) but not distant disease. Although cancer has been termed hereditary diffuse gastric cancer. 13 Data surgical pathology yields the most accurate stage, clinical staging suggest it may be useful to provide genetic counseling and to has been greatly improved by advancements in imaging techniques, consider prophylactic gastrectomy in young, asymptomatic carriers including laparoscopic evaluation of the peritoneal cavity and liver of germ-line truncating CDH1 mutations who belong to families with as well as endoscopic ultrasonography to assess the primary tumor 17, and regional lymph nodes. 20 Nearly 70% to 80% of resected gastric carcinoma specimens have metastases in the regional lymph nodes. Thus, it is common to encounter patients with advanced gastric carcinoma at presentation. Poor prognostic factors in patients with locally advanced and metastatic esophago-gastric cancer include: poor performance status (2 or more), liver metastases, peritoneal metastases, and alkaline phosphatase of 100 U/L or more. Surgical therapy is the primary treatment for gastric carcinoma. Widely agreed on surgical principles for the management of gastric cancer include complete resection with adequate margins (5 cm). The type of resection (subtotal versus total gastrectomy) and the role of extensive lymphadenectomy have been the subjects of international debate. For distal gastric cancers, subtotal gastrectomy has been shown to have an equivalent oncologic result with significantly fewer complications when compared with total gastrectomy. The surgical procedure of choice for proximal gastric cancers is more controversial, because both procedures (proximal gastrectomy and total gastrectomy) are associated with postoperative nutritional impairments. Currently, most authorities advocate total gastrectomy for proximal (cardia) tumors Version , 03/09/ 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. MS-2

14 Even more controversial is the extent of lymphatic dissection that is underwent surgical resection with curative intent were randomly required. The Japanese Research Society for the Study of Gastric assigned to either a D1 or D2 lymphadenectomy. When compared Cancer has established guidelines for pathologic examination and with the D1 dissection, both the morbidity (25% versus 43%, P < evaluation of lymph node stations that surround the stomach. 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. A D1 dissection entails the removal of the involved distal part of the stomach or the entire stomach (distal or total resection), including the greater and lesser omenta. For a D2 dissection, the omental bursa is removed, along with the front leaf of the transverse mesocolon, and the mentioned arteries are cleared completely. A splenectomy (to remove stations 10 and 11) is required for a D2 Japanese investigators have often emphasized the value of extensive lymphadenectomy (D2 and above); however, Western investigators have not found a survival advantage when extensive lymphadenectomy is compared with a D1 resection. The Dutch Group Trial recently published long-term survival data comparing D1 versus D2 resection. A total of 711 patients who ) and mortality (4% versus 10%, P =.004) were higher for the D2 dissection, with no difference in overall survival (30% versus 35%, P =.53). The authors identified splenectomy, pancreatectomy, and age older than 70 years as contributing risk factors for increased morbidity and mortality. In a subset analysis, a trend to improved survival appeared to occur in patients with N2 cancer undergoing a D2 lymphadenectomy. Unfortunately, N2 cancer can only be detected after microscopic examination of the surgical specimen. A similar study conducted by the Medical Research Council failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy. In addition, the D2 dissection was associated with increased morbidity and mortality. A meta-analysis did not show any survival benefit from extended lymph node dissections but did show increased mortality. dissection for proximal gastric tumors. If N1 lymph nodes are not Despite these results, interest in extended lymphatic dissections (D2 28 removed, then this is defined as a D0 dissection. The technical and greater) has not waned. Investigators have argued that if the aspects of performing a D2 dissection require a significant degree of complication rate after a D2 operation could be decreased then training and expertise. In an Intergroup trial examining the role of there may be a benefit in selected patients. A recent phase II study adjuvant therapy for gastric cancer, 54% of the patients had a D0 of D2 dissection by the Italian Study Group (IGCSG) lymphadenectomy, whereas only 10% of patients had the has demonstrated a morbidity of 20.9% and a postoperative recommended D2 lymphadenectomy. mortality rate of 3%. These rates are comparable to the rates for D1 dissections in the Dutch and United Kingdom trial. The difference in the IGCSG trial was the lack of routine pancreatectomy in patients with proximal gastric tumors (except when warranted for direct invasion). Japanese investigators comparing D2 versus extended D2 (including para-aortic lymph nodes) have recently reported a postoperative morality rate of 0.8% in each arm Survival data from Version , 03/09/ 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. MS-3

15 Radiotherapy and Chemoradiation this study are currently not available. A surgical option that may decrease morbidity and mortality is an over-d1 (ie, D1+) Locally Unresectable Cancer lymphadenectomy with preservation of the pancreatic tail and 31, 32 Moderate-dose external-beam radiation ( Gy) as a single without splenectomy. modality has minimal value in palliating locally unresectable gastric 39 With improvements in endoscopic techniques (endoscopic mucosal carcinoma and does not improve survival. However, when used resection [EMR]) and minimal access surgery (laparoscopic wedge concurrently with 5-fluorouracil (5-FU), moderate-dose external-beam 40 resection), there has been interest in applying these modalities to radiation does improve survival. Moertel and colleagues assessed early gastric cancer (T1, mucosal and submucosal). Node-negative 5-FU plus 35 to 40 Gy of radiotherapy compared with radiotherapy 33 T1 tumors are associated with a 5-year survival of more than 90%. alone in the treatment of locally unresectable gastric carcinoma. They As such, there is interest in performing more limited resection for observed a 6-month survival advantage in the group receiving combined modality therapy. In another study by the Gastrointestinal these tumors. Proper patient selection is paramount when employing endoscopic or limited gastric resections (wedge). The Tumor Study Group, 90 patients with locally advanced gastric carcinoma were randomly assigned to receive either combination chemo- probability of lymph node metastasis in early gastric cancer is influenced by tumor factors and is increased with increasing tumor therapy (5-FU plus methyl-ccnu [lomustine]) or split-course radiation therapy (RT) with a concurrent intravenous bolus of 5-FU given size, submucosal invasion, poorly differentiated tumors, and 34 lymphatic and vascular invasion. Indications for EMR include welldifferentiated or moderately differentiated histology, tumor size less break, and followed by maintenance 5-FU plus methyl-ccnu. In the during the first 3 days of 2 sessions of 25 Gy, separated by a 2-week 41 than 30 mm, absence of ulceration, and no evidence of invasive first 26 weeks, mortality was higher in the combined modality group. 35 findings. Regardless of the technique used for resecting early At 3 years, however, the survival curve reached a plateau in the gastric tumors, complete excision with negative margins is required. combined modality arm, but tumor-related deaths continued to occur Endoscopic ultrasound may be useful in assessing the depth of in the chemotherapy-alone arm, suggesting that a small fraction of 36,37 tumor invasion and may aid in appropriate patient selection. Most patients can be cured with combined modality therapy. of the experience with EMR for early gastric cancer has been gained This approach needs to be further developed in light of newly by countries with a high incidence of gastric cancer and an active 38 available radioenhancers. New agents---such as taxanes, screening program. The applicability of these techniques in the epirubicin, and irinotecan---have been used in combination with United States is limited because of the low incidence of early gastric RT. Results of the comparative trials are pending. cancer. Furthermore, long-term follow-up and survival data are lacking therefore, the routine use of endoscopic techniques is not Preoperative or Postoperative Chemotherapy recommended outside a clinical trial and should be limited to Recent studies suggest that preoperative induction chemotherapy medical centers with extensive experience. followed by chemoradiotherapy yields a substantial pathologic Version , 03/09/ 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. MS-4

16 45,46 response that results in durable survival time. However, the value These data suggest that preoperative radiation improves local of such approaches needs to be determined in comparative trials. control and survival. However, randomized trials are needed to confirm these results in patients from the Western Hemisphere. 47 Nonrandomized trials from Baeza and colleagues have reported encouraging results for patients with R0 resections who receive The seminal trial examining the role of postoperative combined adjunctive treatment. Limited reports from randomized trials of modality therapy in gastric cancer was reported by Moertel and 40 postoperative RT with or without chemotherapy after a complete colleagues in 1969 (40 Gy versus 40 Gy plus 5-FU). This trial resection with negative margins did not reveal a clear survival revealed a significant improvement in survival. The remaining 48,49 advantage. randomized trials include patients with unresectable or residual cancer. None have shown a survival advantage. The use of 23,50 The landmark trial is the Intergroup trial INT Eligibility intraoperative RT remains investigational. included patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction. After a resection with negative For resected gastric carcinoma, only 5-FU/leucovorin (category 1) margins, 603 patients were randomly assigned to either observation has been studied in conjunction with RT in a phase III setting 23 alone or postoperative combined modality therapy consisting of 5 (Intergroup 116). However, many participating institutions have monthly cycles of bolus chemotherapy with 45 Gy concurrent with developed other chemotherapy regimens in the context of phase II cycles 2 and 3. There was a significant decrease in local failure as studies. Thus, these regimens represent institutional preferences, the first site of failure (19% versus 29%) as well as an increase in but they may not be superior to 5-FU/leucovorin. In the median survival (36 versus 27 months), 3-year relapse-free survival algorithm, preoperative chemoradiation options for localized, (48% versus 31%), and overall survival (50% versus 41%, P =.005) unresectable disease include 5-FU/leucovorin (category 1) as well with combined modality therapy. The CALGB phase III trial is as the following category 3 options such as 5-FU--based, cisplatinbased, taxane-based, and irinotecan-based regimens. Postoperative currently assessing postoperative standard therapy with 5- FU/leucovorin/radiation versus ECF (epirubicin, cisplatin, and 5- chemoradiation options include 5-FU/leucovorin (category 1) as well FU)/radiation as the following category 3 options such as 5-FU/cisplatin, 5-FU-- ( based, taxane-based, and ECF regimens. 7&version=patient&protocolsearchid= ). Smalley and colleagues 51 reviewed gastric anatomy and patterns of failure after surgery, and they offer detailed radiation treatment planning recommendations. A randomized trial by Zhang and associates from Beijing revealed a significant improvement in survival with preoperative radiation (30% versus 20%, P =.0094). 52 Chemotherapy Advanced gastric carcinoma is incurable, but chemotherapy can have a palliative effect in symptomatic patients. In four studies, combination chemotherapy resulted in better quality of life and overall survival when compared with best supportive care in patients with advanced gastric carcinoma However, all four studies only Version , 03/09/ 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. MS-5

17 had a small number of patients. Only a few single agents have interest, including vaccines, antireceptor agents, and antiangiogenic established activity against advanced gastric carcinoma; these agents. A number of chemotherapy combinations are currently in agents include 5-FU, mitomycin, etoposide, and cisplatin. In the early 1980s, the FAM (5-FU, doxorubicin, and mitomycin) regimen was the gold standard therapy for patients with advanced gastric carcinoma. In a pivotal study performed by the North Central Cancer Treatment Group (NCCTG), the FAM regimen was compared with 5-FU as a single agent and 5-FU plus doxorubicin. No significant survival difference was detected among patients treated with these three regimens. However, response rates were higher with combination chemotherapy than with 5-FU alone. Thus, combination chemotherapy is preferable to single-agent therapy for palliation. Several randomized studies comparing FAM versus FAMTX (5-FU, adriamycin, and methotrexate [with leucovorin rescue]), FAMTX 62 versus ECF, and FAMTX versus ELF (etoposide, leucovorin, and 5- FU) versus 5-FU plus cisplatin have been reported in the past several years. No one standard therapy has emerged from these trials. Outside of clinical trials, the recommended chemotherapy for advanced gastric carcinoma is either cisplatin-based or 5-FU--based combination chemotherapy. Several drugs and their combinations have shown activity against gastric carcinoma. The agents include paclitaxel, docetaxel, irinotecan, UFT (a combination of uracil and tegafur), oral etoposide, and S-1. In addition, combination chemotherapy regimens have also been assessed. 59 hold promise in the treatment of gastric carcinoma. 63 A number of oral agents also Agents that have not been extensively studied include capecitabine, oxaliplatin, and rubitecan. In addition, several new categories of agents are of ,82 phase III trials, and we anticipate that a widely accepted front-line standard for patients with advanced gastric carcinoma might emerge in the near future. For metastatic gastric carcinoma, there have been only a few phase III trials, which have assessed ECF, DCF (docetaxel/cisplatin/5-fu), and FOLFIRI-AIO (infusional 5- FU/leucovorin/irinotecan). However, participating institutions have developed chemotherapy regimens in the context of phase II studies. The regimens that have not been studied in the phase III setting may not be superior to DCF or ECF. In the algorithm, options for metastatic cancer include 5-FU/leucovorin (category 1) as well as the following category 3 options such as 5-FU--based (capecitabine), cisplatin-based, oxaliplatin-based, taxane-based, irinotecan-based, and ECF regimens. Moreover, many regimens may be considered as reference regimens in the first-line setting. There is no established second-line therapy for advanced gastric cancer. Workup 90,91 In patients with gastric cancer, presenting symptoms can include anemia, early satiety, weight loss, and/or bleeding. Newly diagnosed patients should undergo a complete history, physical examination, chest x-ray, and endoscopy of the entire upper GI tract. A complete blood count (CBC), platelets, multichannel serum chemistry analysis (ie, SMA-12), coagulation studies, and a computed tomography (CT) scan of the abdomen should be performed; a positron emission tomography (PET) scan may also be useful, although there may be false-positive results with PET. 92 Combined PET/CT imaging is more useful than either imaging alone for preoperative staging In Version , 03/09/ 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. MS-6

18 women, a pelvic CT scan or ultrasound is also recommended. discovered to have an M1 carcinoma after laparoscopy may be offered salvage therapy. The goal of surgery is to accomplish a The workup permits classification of patients into 1 of 2 groups: (1) curative resection (R0) with negative margins, and 5 cm or greater patients with apparent locoregional carcinoma (stages I to III or M0), proximal and distal margins are desirable. A D0 lymphadenectomy is and (2) those with obvious metastatic carcinoma (stage IV or M1). unacceptable. It is recommended that at least 15 lymph nodes be Patients with apparent locoregional cancer can be further classified: removed and examined. For carcinomas located in the distal (1) those who are medically fit (ie, able to tolerate major abdominal stomach (body and antrum), a subtotal gastrectomy is preferred. For surgery) and whose cancer is potentially resectable, (2) those who carcinomas located proximally (in the cardia), total gastrectomy is are medically fit but whose cancer is unresectable, and (3) those recommended; however, proximal gastrectomy may also be who are medically unfit. appropriate. Splenectomy should be avoided, if possible. Placement Additional Evaluation For the group of medically fit patients with apparent locoregional carcinoma, the guidelines address the role of laparoscopy before definitive surgery or combined chemotherapy and radiation. The use of this staging procedure differs among the institutions, with several centers preferring laparoscopic staging of the peritoneal cavity for medically fit patients, whether in the potentially resectable or unresectable category (category 2B). For medically unfit patients with apparent locoregional carcinoma, laparoscopic staging of the peritoneal cavity can be done when considering chemotherapy/rt or surgery. If a palliative resection is planned, laparoscopy is not indicated. Postlaparoscopic Staging If a laparoscopic examination is performed, there are two possibilities for both medically fit and unfit patients with apparent locoregional carcinoma. Patients will either have apparent locoregional carcinoma or will have metastatic carcinoma (M1). Primary Therapy Surgery is recommended for medically fit patients with a potentially resectable (stages I to III) carcinoma. Medically fit patients of a jejunostomy feeding tube should be considered. Carcinomas are unresectable if there is evidence of peritoneal involvement, distant metastases, or invasion or encasement of major blood vessels. For medically fit patients found to have an unresectable locoregional cancer, the recommended therapy (category 1) is combined RT (45 to 50.4 Gy) with concurrent 5-FU-- based radiosensitization. Medically unfit patients with locoregional carcinoma may be offered one of the following choices: (1) RT (45 to 50.4 Gy) with concurrent 5-FU--based radiosensitization (category 1); or (2) salvage chemotherapy with 5-FU/leucovorin (category 1) or other agents which are category 3 (such as ECF, 5-FU--based [capecitabine], cisplatin-based, oxaliplatin-based, taxane-based, or irinotecan-based chemotherapy). Medically unfit patients discovered to have M1 carcinoma after laparoscopy may also be offered salvage therapy. Adjunctive Therapy 40,41 40,41 As previously discussed, select patients with negative margins (R0 resection) and no evidence of metastatic carcinoma after gastrectomy may receive adjuvant chemoradiation based on the Version , 03/09/ 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. MS-7

19 results of the Intergroup trial (INT-0116). However, a patient whose surgical pathologic stage is T1, N0, M0 may be observed and not treated with adjuvant therapy. All patients with an R0 resection who have T2, N0 along with high-risk features (ie, poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion, or age younger than 50 years) should receive adjuvant chemoradiotherapy (5-FU--based/RT); those patients without highrisk features may be observed. The panel recommends that all patients with an R0 resection who have T3, T4, or any T, N+ cancer should be offered radiotherapy (45 to 50.4 Gy) plus concurrent 5-FU--based radiosensitization (preferred) plus 5-FU with or without leucovorin. 23,40 It should also be noted that 20% of patients in the Intergroup-0116 trial had cancers that involved the gastroesophageal junction; therefore, adjuvant chemoradiotherapy should also be recommended for patients with similar cancers (again, patients with T1, N0, M0 tumors may be observed as can patients with T2, N0 without high-risk features). Patients with R1 resections should be offered radiotherapy (45 to 50.4 Gy) plus concurrent 5-FU--based radiosensitization (preferred) plus 5-FU with or without leucovorin. In the absence of M1 carcinoma, patients with R2 resections may be offered (1) RT (45 to 50.4 Gy) with concurrent 5-FU--based radiosensitization; (2) salvage chemotherapy; or (3) best supportive care, if performance status is poor. Medically unfit patients should undergo restaging (including chest x-ray, abdominal CT, CBC, SMA-12, pelvic imaging [women], PET/CT scan) after completion of chemoradiotherapy. 95 If a complete response of the carcinoma is determined, these patients should be observed or have surgery if it is deemed appropriate. If there is evidence of residual or M1 cancer, patients may be offered salvage therapy. Follow-up and Surveillance All patients should be followed up systematically. This follow-up should include a complete history and physical examination every 4 to 6 months for 3 years, then annually thereafter. Complete blood count, platelets, SMA-12 tests, and other investigations (such as endoscopy and other radiologic studies) should be done if clinically 96 indicated. Vitamin B levels should be monitored for patients who have had proximal or total gastrectomy. Salvage Therapy Salvage therapy consists of either best supportive care, chemotherapy, or clinical trial depending on the patient's performance scores on the Karnofsky or Eastern Cooperative Group (ECOG) scales. The constituents of best supportive care depend on the patient's symptoms. In the case of luminal obstruction, a patient may be offered a stent placement, laser surgery, photodynamic therapy, radiotherapy, surgery, or a combination of these methods, as appropriate. For patients requiring nutritional support, placement of a percutaneous endoscopic gastronomy (PEG) tube may be warranted; nutritional counseling may also be valuable. Version , 03/09/ 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. 12 Pain control may be achieved with the use of radiotherapy plus pain medications. Similarly, surgery, endoscopic therapy, or radiotherapy may be indicated in patients with brisk bleeding from the carcinoma. Whenever possible, patients should be enrolled in clinical trials. Outside of a clinical trial, patients may be treated with 5- FU/leucovorin (category 1) or other agents, which are category 3 (such as ECF, 5-FU based [capecitabine], cisplatin-based, oxaliplatin-based, taxane-based, or irinotecan-based chemotherapy). The decision of whether to offer best supportive care alone or with chemotherapy should be based on the patient's 97 MS-8

20 performance status. Patients should be offered only best supportive care if they have a Karnofsky performance score of 60 or less, or an ECOG (Eastern Cooperative Oncology Group) performance score of 3 or greater. Patients with a better performance status may be offered best supportive care alone, chemotherapy, or a clinical trial. Summary Gastric cancer is rampant in several countries around the world. Its incidence in the Western Hemisphere has been on the decline for more than 40 years; however, the location of gastric cancer has shifted proximally in the past 15 years. The reason for this shift is not clear. Diffuse histology is also more common now than intestinal type of histology. Advances have been made in staging procedures, such as laparoscopy and endoscopic ultrasonography, and in possible functional imaging techniques. The current TNM classification requires an examination of at least 15 lymph nodes; a D0 dissection is unacceptable. Patients with locoregional gastric carcinoma should also be referred to high-volume treatment centers. Combination chemotherapy and radiotherapy in the adjuvant setting for a select group of patients is the new standard in the United States. The Guidelines provide a uniform systematic approach to gastric cancer in the United States. We look forward to the results of investigations of new chemotherapeutic agents, including antireceptor agents, vaccines, gene therapy, and antiangiogenic agents. The panel anticipates many advances in the treatment of gastric carcinoma in the future. Disclosures for the Guidelines Panel At the beginning of each panel meeting to develop guidelines, panel members disclosed the names of companies, foundations, and/or funding agencies from which they received research support; for which they participate in speakers' bureau, advisory boards; and/or in which they have equity interest or patents. Members of the panel indicated that they have received support from the following: AstraZeneca; Berlex; Bristol Myers- Squibb; Discovery Laboratories, Inc; Exelixis; Genentech Inc; ImClone; Introgen Therapeutics, Inc; National Cancer Institute; OSI Pharmaceuticals, Inc; Pfizer Inc; Sanofi-Aventis; and U.S. Surgical. Some panel members do not accept any support from industry. The panel did not regard any potential conflicts of interest as sufficient reason to disallow participation in panel deliberations by any member. Version , 03/09/ 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. MS-9