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Gastric Cancer

Version 1.2006, 03/03/06 2006 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.

NCCN Practice Guidelines

in Oncology v.1.2006

Guidelines Index

Gastric Table of Contents

Staging, MS, References

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NCCN Clinical Practice Guidelines in Oncology

Gastric CancerV.1.2006

www.nccn.org

Gastric Cancer




Guidelines Index



*

NCCN Gastric Cancer 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. DAmico, MD

Duke Comprehensive Cancer Center

Charles Fuchs, MD

Dana-Farber/Partners CancerCare

Michael K. Gibson, MD

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

David H. Ilson, MD, PhD

Memorial Sloan-Kettering Cancer Center

Milind Javle, MD

Roswell Park Cancer Institute

Bruce D. Minsky, MD


Mark B. Orringer, MD

University of Michigan Comprehensive

Cancer Center

Scott Kelley, MD

H. Lee Moffitt Cancer Center and Research

Institute at the University of South Florida

Robert C. Kurtz, MD


Gershon Yehuda Locker, MD

Robert H. Lurie Comprehensive Cancer

Center at Northwestern University

Neal J. Meropol, MD

Fox Chase Cancer Center

Raymond U. Osarogiagbon, MD

St. Jude Childrens Research

Hospital/University of Tennessee Cancer

Institute

Stephen G. Swisher, MD

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

The University of Texas M. D. Anderson

Cancer Center

Douglas E. Wood, MD

Fred Hutchinson Cancer Research

Center/Seattle Cancer Care Alliance

Yun Yen, MD, PhD

City of Hope Cancer Center

Medical oncology

Gastroenterology

Surgery/Surgical oncology

Internal medicine

Radiotherapy/Radiation oncology

Hematology/Hematology oncology

*Writing committee member

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Gastric Cancer




Guidelines Index



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 Systemic Therapy (GAST-A)

Guidelines Index

Print the Gastric Cancer Guideline

These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. 2006.

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Staging

Manuscript

References

Clinical Trials:

Categories of Consensus:NCCN

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

To find clinical trials online at NCCNmember institutions,

All recommendations are Category2A unless otherwise specified.

See

NCCN

click here:nccn.org/clinical_trials/physician.html

NCCN Categories of Consensus

Summary of Guidelines Updates

Gastric Cancer




Guidelines Index



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.

CLINICAL

PRESENTATION

ADDITIONAL

EVALUATION

WORKUP

Multidisciplinary

evaluation

H&P

CBC, platelets, SMA-12

Abdominal CT

CT/ultrasound pelvis

(females)

Chest x-ray

Esophagogastro-

duodenoscopy

PET/CT scan

Locoregional

(M0)

Stage IV

(M1)

Medically fit,

potentially

resectable

a

Consider

laparoscopyb

Salvage Therapy(see GAST-4)

Medically fit,

unresectable

a

Medically unfit

aMedically 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.

b

PostlaparoscopyStaging (see GAST-2)



Laparoscopy

(preferred)

b

(category 2B)

Laparoscopy

(preferred)

b

(category 2B)

GAST-1

Gastric Cancer




Guidelines Index





POSTLAPAROSCOPY

STAGING

PRIMARY

TREATMENT

Medically fit ,

potentially

resectable

aM0

M1

Surgery


Surgical Outcomes(see GAST-3)

RT, 4550.4 Gy + concurrent

5-FU-based radiosensitization

(category 1)orSalvage Therapy

(see GAST-4)

RT, 45-50.4 Gy + concurrent

5-FU-based radiosensitization (category 1)

or Chemotherapyc

Adjunctive TreatmentPostchemotherapy RT(see GAST-3)

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 > 5 cm proximal and distal margins from gross tumor

Extent of lymph node dissection:

D0: unacceptable

Minimum of 15 lymph nodes should be evaluated

Criteria for unresectability for cure:

Peritoneal seeding or distant metastases

Inability to perform a complete resection

Invasion or encasement of major vascular structure

Medically fit ,

unresectable

a

Medically

unfit



Adjunctive TreatmentPostchemotherapy RT(see GAST-3)

M0

M1

M0

M1

GAST-2

aMedically able to tolerate major abdominal surgery.cSee Principles of Systemic Therapy (GAST-A).

Gastric Cancer




Guidelines Index





Surgical

outcomes

Adjunctive

treatment,

postchemo-

therapy RT

ADJUNCTIVE TREATMENT


5-FU-based radiosensitization (preferred)

+ 5-FU leucovorin


5-FU-based radiosensitization

or

Chemotherapy

or

Best supportive care

(poor performance status)

c Salvage Therapy (see GAST-4)

Restaging (preferred):

Chest x-ray

Abdominal CT

Pelvic imaging

(females)

CBC, SMA-12

PET/CT scan

Complete response

or major response

Follow-up(see GAST-4)orSurgery, ifappropriate

Residual,

locoregional

and/or

distant metastases

Follow-up (see GAST-4)

Follow-up (see GAST-4)

T1, N0

T3, T4 or

Any T, N+


5-FU-based

radiosensitization (preferred)

+ 5-FU leucovorin

M1 Salvage Therapy (see GAST-4)

Salvage Therapy (see GAST-4)

R0 resection

R1 resection

R2 resection

GAST-3

T2, N0

Observe

Observe or Chemotherapy

(

for selected patients

c

d5-FU-based)/RT

SURGICAL RESECTION

c

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

See Principles of Systemic Therapy (GAST-A).

Gastric Cancer




Guidelines Index





FOLLOW-UP

Best

supportive

care

Chemotherapy

or

Clinical trialor

c

Best supportive

care

SALVAGE THERAPY

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

Karnofsky performance

score 60

or

ECOG performance

score 3

Karnofsky performance

score > 60

or

ECOG performance

score 2

H&P every 4 - 6 mo for 3 y,

then annually

CBC, platelets, SMA-12, as

indicated

or

endoscopy, as clinically

indicated

Monitor vitamin B for

proximal or total

gastrectomy patients

Radiologic imaging

12

e

GAST-4

c

ePatients should be monitored for vitamin B deficiency and treated as indicated.12

See Principles of Systemic Therapy (GAST-A).

Gastric Cancer




Guidelines Index



Postoperative Chemotherapy

Metastatic Cancer

:

None recommended

:

5-FU/leucovorin (category 1)

5-FU-based (Capecitabine) (category 3)

Cisplatin-based (category 3)

Oxaliplatin-based (category 3)

Taxane-based (category 3)

Irinotecan-based (category 3)

ECF (category 3)

Preoperative Chemotherapy

Preoperative Chemoradiation

(Recommended in localized unresectable case)

Postoperative Chemoradiation

:

None recommended. Awaiting more data

:


5-FU-based

Cisplatin-based

Taxane-based

Irinotecan-based

:

5-FU-based (category 3)

5-FU/cisplatin

ECF

Taxane-based

(category 3)

(category 3)

(category 3)

(category 3)


(category 3)

(category 3)

(category 3)

PRINCIPLES OF SYSTEMIC THERAPY

For resected gastric carcinoma, only 5-FU/leucovorin has been studied in conjunction with radiation therapy in a phase III setting

(Intergroup 116). 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 5-FU/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

1



GAST-A

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. 2001 Sep 6;345(10):725-30.

Gastric Cancer




Guidelines Index



Summary of the Guidelines Updates

UPDATES

Highlights of major changes in the 2006 version of the Gastric Cancer guidelines from the 1.2005 version include:

Under Workup, PET/CT scan was added ( ).

After T3, T4 or Any T, N+, the RT and chemotherapy recommendations were revised ( ).

PET/CT scan was added for Restaging after Adjunctive treatment, postchemotherapy RT ( ).

Under Supportive Care Modalities: Surgery was added to Obstruction and Nutritional counseling was added

to Nutrition ( ).

The panel added a new page entitled, Principles of Systemic Therapy ( ).

GAST-1

GAST-3

GAST-3

GAST-4

GAST-A

Gastric Cancer




Guidelines Index



Staging

Table 1

American Joint Committee on Cancer (AJCC) TNM Staging

Classification for Carcinoma of the Stomach*

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastasis (M)

Histologic Grade (G)

Stage Grouping

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situ: intraepithelial tumor without invasion of the

lamina propriaT1 Tumor invades lamina propria or submucosaT2 Tumor invades muscularis propria or subserosaT2a Tumor invades muscularis propriaT2b Tumor invades subserosaT3 Tumor penetrates serosa (visceral peritoneum) without

invasion of adjacent structuresT4 Tumor invades adjacent structures

NX Regional lymph node(s) cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in 1 to 6 regional lymph nodesN2 Metastasis in 7 to 15 regional lymph nodesN3 Metastasis in more than 15 regional lymph nodes

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

GX Grade cannot be assessedG1 Well differentiatedG2 Moderately differentiatedG3 Poorly differentiatedG4 Undifferentiated

Stage 0 Tis N0 M0Stage IA T1 N0 M0Stage IB T1 N1 M0

T2a/b N0 M0Stage II T1 N2 M0

T2a/b N1 M0T3 N0 M0

Stage IIIA T2a/b N2 M0T3 N1 M0T4 N0 M0

Stage IIIB T3 N2 M0Stage IV T4 N1-3 M0

T1-3 N3 M0Any T Any N M1

*Used with permission of the American Joint Committee on Cancer(AJCC), Chicago, Illinois. The original and primary source for thisinformation is the (2002)published by Springer-Verlag New York. (For more information, visit

.) Any citation or quotation of this material must becredited to the AJCC as its primary source. The inclusion of thisinformation herein does not authorize any reuse or further distributionwithout the expressed written permission of Springer-Verlag New York onbehalf of the AJCC.

A tumor may penetrate the muscularis propria with extension into thegastrocolic or gastrohepatic ligaments, or into the greater or lesseromentum, without perforation of the visceral peritoneum covering thesestructures. In this case, the tumor is classified as T2. If there is perforationof 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, transversecolon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney,small intestine, and retroperitoneum. Intramural extension to theduodenum or esophagus is classified by the depth of the greatest invasionin any of these sites, including the stomach.

A designation of pN0 should be used if all examined lymph nodes arenegative, regardless of the total number removed and examined.

AJCC Cancer Staging Manual, Sixth Edition

www.cancerstaging.net

ST-1

Gastric Cancer




Guidelines Index



Manuscript

NCCN Categories of Consensus

Category 1

Category 2A

Category 2B

Category 3

All recommendations are category 2A unless otherwise noted.

: There is uniform NCCN consensus, based on high-level

evidence, that the recommendation is appropriate.

: There is uniform NCCN consensus, based on lower-

level evidence including clinical experience, that the

recommendation is appropriate.

: There is nonuniform NCCN consensus (but no major

disagreement), based on lower-level evidence including clinical

experience, that the recommendation is appropriate.

: There is major NCCN disagreement that the

recommendation is appropriate.

Overview

Carcinomas originating in the upper gastrointestinal (GI) tract (esopha-

gus, 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

occur in the United States in 2006. There has been a dramatic shift in

the location of upper GI tumors in the United States. Changes in

histology as well as location of upper GI tumors have also been

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

gastroesophageal junction. It is possible that in the coming decades

these changing trends will also occur in South America and Asia.

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

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

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

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

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 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

1

2

3-5

2

1

6-8

9,10

11,12

Epidemiology of Gastric Carcinoma

Helicobacter pylori

MS-1

Gastric Cancer




Guidelines Index



estimated 25% of families with an autosomal dominant

predisposition to diffuse type gastric cancers; this subset of gastric

cancer has been termed . 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.

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 ) 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,

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

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

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

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.

hereditary diffuse gastric cancer13

14

15

16

17,18

19

20

21

22

Staging

Table 1

Surgery

MS-2

Gastric Cancer




Guidelines Index



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

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

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

lymphadenectomy is compared with a D1 resection. The Dutch

Gastric Cancer Group Trial recently published long-term survival

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

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%,

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[Ghiduri][Cancer]Gastric Cancer