Practice Guidelines in Oncology - Gastric Cancer · 2009-01-22 · ® Practice Guidelines in Oncology – v.1.2007 Guidelines Index Gastric Table of Contents Staging, MS, References

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NCCN Clinical Practice Guidelines in Oncology™

Gastric CancerV.1.2007

www.nccn.org

Gastric Cancer

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.

NCCN® Practice Guidelines

in Oncology – v.1.2007

Guidelines Index

Gastric Table of Contents

Staging, MS, References

*

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. 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

The Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Melvyn Goldberg, MD

Fox Chase Cancer Center

† ¤

†

¶

†

† Þ

¶

§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

† Þ

†

¶

¤ Þ

†

†

§

¶

Scott T. 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 Children’s Research

Hospital/University of Tennessee Cancer

Institute

Stephen G. Swisher, MD

† Þ ‡

†

¶

¶

¶

¶

‡

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

Gary Yang, MD

Roswell Park Cancer Institute

Yun Yen, MD, PhD

City of Hope Cancer Center

§

† Medical oncology

¤ Gastroenterology

¶ Surgery/Surgical oncology

Þ Internal medicine

§ Radiotherapy/Radiation oncology

‡ Hematology/Hematology oncology

*Writing committee member

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Gastric Cancer




Guidelines Index



This manuscript is being

updated to correspond

with the newly updated

algorithm.

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)

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. ©2007.

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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

http://www.nccn.org/clinical_trials/physician.html

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.

Summary of the Guidelines Updates

UPDATES

Summary of major changes in the 1.2007 version of the Gastric Cancer guidelines from the 2006 version include:

( ):

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

( ):

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

A new page entitled, “Principles of Surgery” was added to outline recommended guidelines for gastric surgery

( ):

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

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GAST-1

GAST-2

GAST-B

GAST-A

Gastric Cancer




Guidelines Index





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 scana

Locoregional

(M0)

Stage IV

(M1)

Medically fit,

potentially

resectable

b

Salvage Therapy(see GAST-4)

Medically fit,

unresectable

b

Medically unfit

a

bMay 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.

c

PostlaparoscopyStaging (see GAST-2)

Cosider

Laparoscopy

(category 2B)

c

GAST-1

Gastric Cancer




Guidelines Index





POSTLAPAROSCOPY

STAGING

PRIMARY

TREATMENT

Medically fit,

potentially

resectable

b

Surgical Outcomes(see GAST-3)

RT, 45–50.4 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 Chemotherapyf

Adjunctive TreatmentPostchemotherapy ± RT(see GAST-3)Medically fit,

unresectable

b

Medically

unfit



Adjunctive TreatmentPostchemotherapy ± RT(see GAST-3)

M0

M1

M0

M1

GAST-2

b

e

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.d

fSee Principles of Surgery (GAST-A)

See Principles of Systemic Therapy (GAST-B)

.

.

T1 or less

(by clinical staging)Surgeryd,e

T2 or higher

(by clinical

staging or N+)

Surgery

or

Preoperative

chemotherapy

e

f

M0

M1

Surgerye


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)

f 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

e

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

f

g5-FU-based)/RT

SURGICAL RESECTION

e

f

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

See Principles of Surgery (GAST-A)

See Principles of Systemic Therapy (GAST-B)

.

.

Gastric Cancer




Guidelines Index





FOLLOW-UP

Best

supportive

care

Chemotherapy

or

Clinical trialor

f

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

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�

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

h

GAST-4

f

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

See Principles of Systemic Therapy (GAST-B).

Gastric Cancer




Guidelines Index



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 > 5 cm proximal 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

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GAST-A

Gastric Cancer




Guidelines Index



Postoperative Chemotherapy

Metastatic Cancer

:

ECF (Only when preoperative ECF has been administered)

(category 1)

:

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)

�

�

�

�

�

�

�

�

Preoperative Chemotherapy

Preoperative Chemoradiation

(Recommended in localized unresectable case)

Postoperative Chemoradiation

:

ECF (category 1)

:

Fluoropyrimidine/leucovorin (category 2B)

Cisplatin-based

Taxane-based

Irinotecan-based

:

ECF

Taxane-based

�

�

�

�

�

�

�

�

�

�

Fluoropyrimidine-based (category 2B)

(category 2B)

(category 2B)

(category 2B)

Fluoropyrimidine/leucovorin (category 1)

Fluoropyrimidine-based (category 1)

Fluoropyrimidine/cisplatin (category 2B)

(category 2B)

(category 2B)

�

PRINCIPLES OF SYSTEMIC THERAPY

�

�

�

For resected gastric carcinoma, only f /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

f /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.

luoropyrimidine

luoropyrimidine

1



GAST-B

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.

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 subserosa†T2a Tumor invades muscularis propriaT2b Tumor invades subserosaT3 Tumor penetrates serosa (visceral peritoneum) without

invasion of adjacent structures‡T4 Tumor invades adjacent structures‡

NX Regional lymph node(s) cannot be assessedN0 No regional lymph node metastasis§N1 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

http://www.cancerstaging.net

Gastric Cancer




Guidelines Index



Manuscriptupdate inprogress

This manuscript is being updated to correspondwith the newly updated algorithm.

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

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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

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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%, <

.001) and mortality (4% versus 10%, = .004) were higher for the

D2 dissection, with no difference in overall survival (30% versus

35%, = .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.

Despite these results, interest in extended lymphatic dissections (D2

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

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

12

23

24

25

26

27

28

29

30

P

P

P

MS-3

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Guidelines Index




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

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

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

lymphatic and vascular invasion. Indications for EMR include well-

differentiated or moderately differentiated histology, tumor size less

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

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

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

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.

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

modality has minimal value in palliating locally unresectable gastric

carcinoma and does not improve survival. However, when used

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

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 com-

bined modality therapy. In another study by the Gastrointestinal

Tumor Study Group, 90 patients with locally advanced gastric carci-

noma were randomly assigned to receive either combination chemo-

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

tion 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

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

RT. Results of the comparative trials are pending.

Recent studies suggest that preoperative induction chemotherapy

followed by chemoradiotherapy yields a substantial pathologic

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Locally Unresectable Cancer

Preoperative or Postoperative Chemotherapy

Radiotherapy and Chemoradiation

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

of such approaches needs to be determined in comparative trials.

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

advantage.

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%, = .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

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

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

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

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

(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, cisplatin-

based, 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-FU--

based, taxane-based, and ECF regimens.

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

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Chemotherapy

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

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

established activity against advanced gastric carcinoma; these

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

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. A number of oral agents also

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

interest, including vaccines, antireceptor agents, and antiangiogenic

agents. A number of chemotherapy combinations are currently in

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 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.

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. Combined PET/CT imaging is more

useful than either imaging alone for preoperative staging. In

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Workup

MS-6

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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.

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.

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).

Surgery is recommended for medically fit patients with a potentially

resectable (stages I to III) carcinoma. Medically fit patients

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--

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.

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

Additional Evaluation

Postlaparoscopic Staging

40,41

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Primary Therapy

Adjunctive Therapy

MS-7

Gastric Cancer




Guidelines Index




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 high-

risk 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. 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. 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.

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

indicated. Vitamin B 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

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

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97

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Follow-up and Surveillance

Salvage Therapy

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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.

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.

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.

Summary

Disclosures for the NCCN Gastric Cancer Guidelines

Panel

MS-9

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Documents

Practice Guidelines in Oncology - Gastric Cancer · 2009-01-22 · ® Practice Guidelines in Oncology – v.1.2007 Guidelines Index Gastric Table of Contents Staging, MS, References