Practice Guidelines in Oncology - Gastric Cancer

NCCN Clinical Practice Guidelines in Oncology 

Gastric Cancer 

V.1.2007 

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www.nccn.org

® 

Practice Guidelines 

NCCN in Oncology – v.1.2007 

* 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 


† Medical oncology 

¤ Gastroenterology 

Surgery/Surgical oncology 

Þ Internal medicine 

§ Radiotherapy/Radiation oncology 

‡ Hematology/Hematology oncology 

*Writing committee member 


NCCN Gastric Cancer Panel Members 

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 


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 § 


Mark B. Orringer, MD 

University of Michigan Comprehensive 


Continue 

Version 1.2007, 03/09/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. 

Guidelines Index 

Gastric Table of Contents 

Staging, MS, References 

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 


* Aaron R. Sasson, MD 

UNMC Eppley Cancer Center at The 

Nebraska Medical Center 

Stephen G. Swisher, MD 

The University of Texas M. D. Anderson 


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

® 



Table of Contents 

NCCN Gastric Cancer 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) 


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documents, please click here 

Staging 

Manuscript 

References 

This manuscript is being 

updated to correspond 

with the newly updated 

algorithm. 

Clinical Trials: The NCCN 

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 NCCN 

member institutions, click here: 

nccn.org/clinical_trials/physician.html 

NCCN Categories of Consensus: 

All recommendations are Category 

2A unless otherwise specified. 

See NCCN 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 NCCN. ©2007.

® 



Summary of the Guidelines Updates 


Summary of major changes in the 1.2007 version of the Gastric Cancer 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: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. 





UPDATES

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WORKUP 

� Multidisciplinary 

evaluation 

� H&P 

� CBC, platelets, SMA-12 

� Abdominal CT 

� CT/ultrasound pelvis 

(females) 

� Chest x-ray 

� Esophagogastroduodenoscopy 

� PET/CT scana a 

b 

c 

CLINICAL 

PRESENTATION 

Locoregional 

(M0) 

Stage IV 

(M1) 


Medically fit, b 

potentially 

resectable 


unresectable 

Medically unfit 

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. 

ADDITIONAL 

EVALUATION 

Cosider 

Laparoscopyc 

(category 2B) 







Postlaparoscopy 

Staging (see GAST-2) 

Salvage Therapy 

(see GAST-4) 

GAST-1

® 




potentially 

resectable 


unresectable 

Medically 

unfit 

b 

d 

POSTLAPAROSCOPY 

STAGING 

M0 

M1 

M0 

M1 

M0 

M1 

T1 or less 

(by clinical staging) 

T2 or higher 

(by clinical 

staging or N+) 


PRIMARY 

TREATMENT 

Surgery d,e 

Surgery 

RT, 45-50.4 Gy + concurrent 

5-FU-based radiosensitization (category 1) 

or Chemotherapy f 


(see GAST-4) 

RT, 45–50.4 Gy + concurrent 

5-FU-based radiosensitization 

(category 1) 

or 


(see GAST-4) 


(see GAST-4) 

Medically able to tolerate major abdominal surgery. 

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) . 



or 


e 

Preoperative 

chemotherapyf 


(see GAST-4) 

Surgery e 




Surgical Outcomes 

(see GAST-3) 

Adjunctive Treatment 

Postchemotherapy ± RT 

(see GAST-3) 

Adjunctive Treatment 

Postchemotherapy ± RT 

(see GAST-3) 

GAST-2

® 



Surgical 

outcomes 

SURGICAL RESECTION 

R0 resection 

R1 resection 

R2 resection 

T1, N0 

T2, N0 


T3, T4 or 

Any T, N+ 

ADJUNCTIVE TREATMENT 


5-FU-based radiosensitization (preferred) 

+ 5-FU ± leucovorin 


5-FU-based radiosensitization 



or 

Chemotherapy 

or 

Best supportive care 

(poor performance status) 


f 

Observe 




Follow-up (see GAST-4) 

Observe or Chemotherapy 

( 5-FU-based)/RT 

for selected patientsg 


5-FU-based 

radiosensitization (preferred) 

+ 5-FU ± leucovorin 

Follow-up (see GAST-4) 

Salvage Therapy (see GAST-4) 

M1 Salvage Therapy (see GAST-4) 

Restaging (preferred): 

� Chest x-ray 

Adjunctive 

� Abdominal CT 

treatment, 

� Pelvic imaging 

postchemo- 

(females) 

therapy ± RT 

� CBC, SMA-12 

� PET/CT scan 

eSee 

Principles of Surgery (GAST-A) . 

fSee 

Principles of Systemic Therapy (GAST-B) . 

Complete response 

or major response 

Residual, 

locoregional 

and/or 

distant metastases 

Follow-up 

(see GAST-4) 

or 

Surgery, e if 

appropriate 

Salvage Therapy (see GAST-4) 

gHigh risk features such as poorly differentiated or higher grade cancer, lymphovascular invasion, neural invasion, or < 50 years of age. 

f 

GAST-3

® 



FOLLOW-UP 

� 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 

SALVAGE THERAPY 

Karnofsky performance 

score > 60 

or 

ECOG performance 

score � 2 

Karnofsky performance 

score � 60 

or 

ECOG performance 

score � 3 

fSee 

Principles of Systemic Therapy (GAST-B). 

hPatients should be monitored for vitamin B12 deficiency and treated as indicated. 


Chemotherapy 

or 

Clinical trial 

Best 

supportive 

care 




or 

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 

GAST-4

® 



Surgery 


PRINCIPLES OF 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 







GAST-A

® 



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) 


PRINCIPLES OF SYSTEMIC THERAPY 

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) 





� 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. 

1Macdonald 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, 2001. 



GAST-B

® 




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 

www.cancerstaging.net.) 

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. 

ST-1

® 



Manuscript 

NCCN Categories of Consensus 

This manuscript is being updated to correspond 

with the newly updated algorithm. 

Category 1: 

There is uniform NCCN consensus, based on high-level 

evidence, that the recommendation is appropriate. 

Category 2A: 

There is uniform NCCN consensus, based on lowerlevel 

evidence including clinical experience, that the 

recommendation is appropriate. 

Category 2B: 

There is nonuniform NCCN consensus (but no major 

disagreement), based on lower-level evidence including clinical 

experience, that the recommendation is appropriate. 

Category 3: 

There is major NCCN 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 2006. 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. 


Manuscript 

update in 

progress 





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 1998. 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 

MS-1

® 



estimated 25% of families with an autosomal dominant 

predisposition to diffuse type gastric cancers; this subset of gastric 

cancer has been termed hereditary diffuse gastric cancer. Data 

suggest it may be useful to provide genetic counseling and to 

consider prophylactic gastrectomy in young, asymptomatic carriers 

of germ-line truncating CDH1 mutations who belong to families with 

highly penetrant hereditary diffuse gastric cancer. 

13 

14 


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 

15 

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 

16 

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 

17,18 

(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, 


Manuscript 

update Surgeryin 

progress 





positive margins); and R2 indicates gross (macroscopic) residual 

19 

cancer (ie, positive margins) but not distant disease. Although 

surgical pathology yields the most accurate stage, clinical staging 

has been greatly improved by advancements in imaging techniques, 

including laparoscopic evaluation of the peritoneal cavity and liver 

as well as endoscopic ultrasonography to assess the primary tumor 

20 

and regional lymph nodes. 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 

21 

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 

22 

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. 

MS-2

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Even more controversial is the extent of lymphatic dissection that is 

required. The Japanese Research Society for the Study of Gastric 

Cancer has established guidelines for pathologic examination and 

12 

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 

dissection for proximal gastric tumors. If N1 lymph nodes are not 

removed, then this is defined as a D0 dissection. The technical 

aspects of performing a D2 dissection require a significant degree of 

training and expertise. In an Intergroup trial examining the role of 

adjuvant therapy for gastric cancer, 54% of the patients had a D0 

lymphadenectomy, whereas only 10% of patients had the 

23 

recommended D2 lymphadenectomy. 

Japanese investigators have often emphasized the value of 

extensive lymphadenectomy (D2 and above); however, Western 

investigators have not found a survival advantage when extensive 

24 

lymphadenectomy is compared with a D1 resection. The Dutch 

Gastric Cancer Group Trial recently published long-term survival 

25 

data comparing D1 versus D2 resection. A total of 711 patients who 


Manuscript 


progress 





underwent surgical resection with curative intent were randomly 

assigned to either a D1 or D2 lymphadenectomy. When compared 

with the D1 dissection, both the morbidity (25% versus 43%, P < 

.001) 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 

26 

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 

27 

show increased mortality. 

Despite these results, interest in extended lymphatic dissections (D2 

28 

and greater) has not waned. Investigators have argued that if the 

complication rate after a D2 operation could be decreased then 

there may be a benefit in selected patients. A recent phase II study 

of D2 dissection by the Italian Gastric Cancer Study Group (IGCSG) 

has demonstrated a morbidity of 20.9% and a postoperative 

29 

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 

30 

postoperative morality rate of 0.8% in each arm. Survival data from 

MS-3

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this study are currently not available. A surgical option that may 

decrease morbidity and mortality is an “over-D1” (ie, D1+) 

lymphadenectomy with preservation of the pancreatic tail and 

31, 32 

without splenectomy. 

With improvements in endoscopic techniques (endoscopic mucosal 

resection [EMR]) and minimal access surgery (laparoscopic wedge 

resection), there has been interest in applying these modalities to 

early gastric cancer (T1, mucosal and submucosal). Node-negative 

33 

T1 tumors are associated with a 5-year survival of more than 90%. 

As such, there is interest in performing more limited resection for 

these tumors. Proper patient selection is paramount when 

employing endoscopic or limited gastric resections (wedge). The 

probability of lymph node metastasis in early gastric cancer is 

influenced by tumor factors and is increased with increasing tumor 

size, submucosal invasion, poorly differentiated tumors, and 

34 

lymphatic and vascular invasion. Indications for EMR include welldifferentiated 

or moderately differentiated histology, tumor size less 

than 30 mm, absence of ulceration, and no evidence of invasive 

35 

findings. Regardless of the technique used for resecting early 

gastric tumors, complete excision with negative margins is required. 

Endoscopic ultrasound may be useful in assessing the depth of 

36,37 

tumor invasion and may aid in appropriate patient selection. Most 

of the experience with EMR for early gastric cancer has been gained 

by countries with a high incidence of gastric cancer and an active 

38 

screening program. The applicability of these techniques in the 

United States is limited because of the low incidence of early gastric 

cancer. Furthermore, long-term follow-up and survival data are 

lacking therefore, the routine use of endoscopic techniques is not 

recommended outside a clinical trial and should be limited to 

medical centers with extensive experience. 


Radiotherapy and Chemoradiation 

Manuscript 


progress 





Locally Unresectable Cancer 

Moderate-dose external-beam radiation (45-50.4 Gy) as a single 

modality has minimal value in palliating locally unresectable gastric 

39 

carcinoma and does not improve survival. However, when used 

concurrently with 5-fluorouracil (5-FU), moderate-dose external-beam 

40 

radiation does improve survival. Moertel and colleagues assessed 

5-FU plus 35 to 40 Gy of radiotherapy compared with radiotherapy 

alone in the treatment of locally unresectable gastric carcinoma. They 

observed a 6-month survival advantage in the group receiving combined 

modality therapy. In another study by the Gastrointestinal 

Tumor Study Group, 90 patients with locally advanced gastric carcinoma 

were randomly assigned to receive either combination chemotherapy 

(5-FU plus methyl-CCNU [lomustine]) or split-course radiation 

therapy (RT) with a concurrent intravenous bolus of 5-FU given 

during the first 3 days of 2 sessions of 25 Gy, separated by a 2-week 

41 

break, and followed by maintenance 5-FU plus methyl-CCNU. In the 

first 26 weeks, mortality was higher in the combined modality group. 

At 3 years, however, the survival curve reached a plateau in the 

combined modality arm, but tumor-related deaths continued to occur 

in the chemotherapy-alone arm, suggesting that a small fraction of 

patients can be cured with combined modality therapy. 

This approach needs to be further developed in light of newly 

available radioenhancers. New agents---such as taxanes, 

epirubicin, and irinotecan---have been used in combination with 

42-44 

RT. Results of the comparative trials are pending. 

Preoperative or Postoperative Chemotherapy 

Recent studies suggest that preoperative induction chemotherapy 

followed by chemoradiotherapy yields a substantial pathologic 

MS-4

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45,46 

response that results in durable survival time. However, the value 

of such approaches needs to be determined in comparative trials. 

47 

Nonrandomized trials from Baeza and colleagues have reported 

encouraging results for patients with R0 resections who receive 

adjunctive treatment. Limited reports from randomized trials of 

postoperative RT with or without chemotherapy after a complete 

resection with negative margins did not reveal a clear survival 

48,49 

advantage. 

23,50 

The landmark trial is the Intergroup trial INT-0116. Eligibility 

included patients with T3 and/or N+ adenocarcinoma of the stomach 

or gastroesophageal junction. After a resection with negative 

margins, 603 patients were randomly assigned to either observation 

alone or postoperative combined modality therapy consisting of 5 

monthly cycles of bolus chemotherapy with 45 Gy concurrent with 

cycles 2 and 3. There was a significant decrease in local failure as 

the first site of failure (19% versus 29%) as well as an increase in 

median survival (36 versus 27 months), 3-year relapse-free survival 

(48% versus 31%), and overall survival (50% versus 41%, P = .005) 

with combined modality therapy. The CALGB 80101 phase III trial is 

currently assessing postoperative standard therapy with 5- 

FU/leucovorin/radiation versus ECF (epirubicin, cisplatin, and 5- 

FU)/radiation 

( http://www.nci.nih.gov/search/ViewClinicalTrials.aspx?cdrid=25878 

7&version=patient&protocolsearchid=1575831). 

51 

Smalley and colleagues 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 

52 

survival with preoperative radiation (30% versus 20%, P = .0094). 


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These data suggest that preoperative radiation improves local 

control and survival. However, randomized trials are needed to 

confirm these results in patients from the Western Hemisphere. 

The seminal trial examining the role of postoperative combined 

modality therapy in gastric cancer was reported by Moertel and 

40 

colleagues in 1969 (40 Gy versus 40 Gy plus 5-FU). This trial 

revealed a significant improvement in survival. The remaining 

randomized trials include patients with unresectable or residual 

cancer. None have shown a survival advantage. The use of 

intraoperative RT remains investigational. 

For resected gastric carcinoma, only 5-FU/leucovorin (category 1) 

has been studied in conjunction with RT in a phase III setting 

23 

(Intergroup 116). However, many participating institutions have 

developed other chemotherapy regimens in the context of phase II 

studies. Thus, these regimens represent institutional preferences, 

but they may not be superior to 5-FU/leucovorin. In the NCCN 

algorithm, preoperative chemoradiation options for localized, 

unresectable disease include 5-FU/leucovorin (category 1) as well 

as the following category 3 options such as 5-FU--based, cisplatinbased, 

taxane-based, and irinotecan-based regimens. Postoperative 

chemoradiation options include 5-FU/leucovorin (category 1) as well 

as the following category 3 options such as 5-FU/cisplatin, 5-FUbased, 

taxane-based, and ECF regimens. 

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 

53-56 

with advanced gastric carcinoma. However, all four studies only 

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had a small number of patients. Only a few single agents have 

established activity against advanced gastric carcinoma; these 

57 58 

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 

59 

gastric carcinoma. In a pivotal study performed by the North 

60 

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, 

61 

adriamycin, and methotrexate [with leucovorin rescue]), FAMTX 

62 

versus ECF, and FAMTX versus ELF (etoposide, leucovorin, and 5- 

63 

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 

64-66 67-69 

gastric carcinoma. The agents include paclitaxel, docetaxel, 

70 71 

irinotecan, UFT (a combination of uracil and tegafur), oral 

72 73-77 

etoposide, and S-1. In addition, combination chemotherapy 

78-89 

regimens have also been assessed. A number of oral agents also 

81,82 

hold promise in the treatment of gastric carcinoma. Agents that 

have not been extensively studied include capecitabine, oxaliplatin, 

and rubitecan. In addition, several new categories of agents are of 


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interest, including vaccines, antireceptor agents, and antiangiogenic 

agents. A number of chemotherapy combinations are currently in 

90,91 

phase III trials, and we anticipate that a widely accepted front-line 

standard for patients with advanced gastric carcinoma might emerge 

92 

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 NCCN 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 

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 

93 

false-positive results with PET. Combined PET/CT imaging is more 

94 

useful than either imaging alone for preoperative staging. In 

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women, a pelvic CT scan or ultrasound is also recommended. 

The workup permits classification of patients into 1 of 2 groups: (1) 

patients with apparent locoregional carcinoma (stages I to III or M0), 

and (2) those with obvious metastatic carcinoma (stage IV or M1). 

Patients with apparent locoregional cancer can be further classified: 

(1) those who are medically fit (ie, able to tolerate major abdominal 

surgery) and whose cancer is potentially resectable, (2) those who 

are medically fit but whose cancer is unresectable, and (3) those 

who are medically unfit. 

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 NCCN 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 


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discovered to have an M1 carcinoma after laparoscopy may be 

offered salvage therapy. The goal of surgery is to accomplish a 

curative resection (R0) with negative margins, and 5 cm or greater 

proximal and distal margins are desirable. A D0 lymphadenectomy is 

unacceptable. It is recommended that at least 15 lymph nodes be 

removed and examined. For carcinomas located in the distal 

stomach (body and antrum), a subtotal gastrectomy is preferred. For 

carcinomas located proximally (in the cardia), total gastrectomy is 

recommended; however, proximal gastrectomy may also be 

appropriate. Splenectomy should be avoided, if possible. Placement 

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-- 

40,41 

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 

40,41 

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 

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 

MS-7

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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 

23,40 

leucovorin. 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 

95 

chemoradiotherapy. 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 

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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 B12 levels should be monitored for patients who 

have had proximal or total gastrectomy. 


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 

97 

warranted; nutritional counseling may also be valuable. 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 

MS-8

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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 NCCN Gastric Cancer 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. 


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Disclosures for the NCCN Gastric Cancer Guidelines 

Panel 

At the beginning of each panel meeting to develop NCCN 

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. 

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REF-7

Practice Guidelines in Oncology - Gastric Cancer

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