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Clinical Practice Guidelines in Oncology v.1.2004

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ColonCancer

Version 1.2004

Version 1.2004, 01/06/04 2004 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.

Colon CancerNCCN Practice Guidelinesin Oncology v.1.2004Guidelines Index

Colon Cancer TOCStaging, MS, References

NCCN Colon Cancer Panel Members

Sujata Rao, MDFred Hutchinson Cancer ResearchCenter/Seattle Cancer Care Alliance

M. Wasif Saif, MDUniversity of Alabama at BirminghamComprehensive Cancer Center

Leonard Saltz, MDMemorial Sloan-Kettering CancerCenter

John M. Skibber, MDThe University of Texas M. D.Anderson Cancer Center

Alan P. Venook, MDUCSF Comprehensive Cancer Center

Timothy J. Yeatman, MDH. Lee Moffitt Cancer Center &Research Institute at the University ofSouth Florida

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Marwan Fakih, MDRoswell Park Cancer Institute

Charles Fuchs, MDDana-Farber/Partners CancerCare

Krystyna Kiel, MDRobert H. Lurie ComprehensiveCancer Center of NorthwesternUniversity

James Knol, MDUniversity of MichiganComprehensive Cancer Center

Kirk A. Ludwig, MDDuke Comprehensive Cancer Center

Edward W. Martin, Jr., MDArthur G. James Cancer Hospital &Richard J. Solove Research Instituteat The Ohio State University

*Writing Committee Member

*

* Paul F. Engstrom, MD/ChairFox Chase Cancer Center

ComprehensiveCancer Center at

Al B. Benson, III, MDRobert H. Lurie ComprehensiveCancer Center of NorthwesternUniversity

Michael A. Choti, MDThe Sidney Kimmel

Johns Hopkins

Raza A. Dilawari, MDSt. Jude Children's ResearchHospital/University of TennesseeCancer Institute

James H. Doroshow, MDCity of Hope Cancer Center

Charles A. Enke, MDUNMC Eppley Cancer Center at TheNebraska Medical Center




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 patients care or treatment. The National Comprehensive Cancer Network makes no representations or warranties of any kind,regarding their content use or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrightedby National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any formwithout the express written permission of NCCN. 2004.

Table of Contents

Clinical Presentations and Primary Treatment:NCCN Colon Cancer Panel Members

Pedunculated polyp with invasive cancer (COL-1)Sessile adenomatous polyp with invasive cancer or Villous adenoma withinvasive cancer or Villoglandular adenoma with invasive cancer (COL-1)Colon cancer appropriate for resection (COL-2)

Pathologic Stage, Adjuvant Therapy and Surveillance (COL-3)Recurrence and Workup (COL-8)

Guidelines IndexPrint the Colon Cancer GuidelineOrder the Patient Version of the Colon Cancer Guideline

Suspected or proven metastatic adenocarcinoma from the large bowel (COL-4)

For help using thesedocuments, please click here

StagingManuscriptReferences

Clinical Trials:

Categories of Consensus:NCCNAll recommendations are Category2A unless otherwise specified.See

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

NCCN

To find clinical trials online at NCCNmember institutions, click here:nccn.org/clinical_trials/physician.html

NCCN Categories of Consensus




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.

COL-1

Superficial,

completely removedNone

None

Pathology

review

Colonoscopy

Marking of

polyp site

CLINICAL

PRESENTATIONa

Pedunculated polyp

with invasive cancer

Sessile adenomatous

polyp with invasive

cancer or Villous

adenoma with invasive

cancer or Villoglandular

adenoma with invasive

cancer

WORKUP FINDINGS SURGERY

Deep invasion into stalk or

margins cannot be assessed

or adverse pathologic findings

(ie, Grade 3-4, angiolymphatic

invasion, positive margins)

b

Single-specimen, Tis,

margins negative

Fragmented specimen or

dverse pathology, T1 or

greater or margins positive

margins cannot be assessed

or a

See PathologicStage, AdjuvantTherapy, andSurveillance(COL-3)

Back to Other ClinicalPresentations(Table of Contents)

a llA patients with colon cancer should be counseled for family history. Patients with suspected hereditary non-polyposis colon cancer(HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP, see theCancer less than 1 mm from the resected margin regardless of the portion of the polyp under evaluation.Consider more extensive colectomy for patients with strong family history of colon cancer or young age (< 50 yr).A randomized trial demonstrates that a laparoscopic colectomy is more costly and time to recovery is equivalent to colectomy.Laparoscopic colectomy cannot be recommended as an alternative option at this time.

bc

d

NCCN Colorectal Screening Guidelines

See NCCN Colorectal Screening Guidelines.

.

Pathology

review

Colonoscopy

Marking of

polyp site Colectomy with en

bloc removal of

regional lymph nodes

c

d

Colectomy with en

bloc removal of


c

d






COL-2

Suspected or proven metastatic

adenocarcinoma from large bowel

SeePathologicStage,AdjuvantTherapy, andSurveillance(COL-3)

Pathology review

Colonoscopy

CBC, platelets,

chemistry profile,

CEA

bdominal/pelvic

CT scan

Chest x-ray

A

Resectable,

nonobstructing

See Management of suspected orproven metastases (COL-4)

CLINICAL

PRESENTATIONaWORKUP FINDINGS SURGERY

Colon cancer

appropriate

for resection

Resectable,

obstructing

(unprepped)

Unresectable

Colectomy with en

bloc removal of


c

d

One-stage colectomy

with en bloc removal of

regional lymph nodesorResection with diversion

orStentorDiversion

DiversionorStent

Colectomy

with en bloc

removal of

regional lymph

nodes

Palliative

resection

Back to Other ClinicalPresentations(Table of Contents)

See SalvageTherapy(COL-9)

a llA patients with colon cancer should be counseled for family history. Patients with suspected hereditary non-polyposis colon cancer(HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP, see theConsider more extensive colectomy for patients with strong family history of colon cancer or young age (< 50 y).A randomized trial demonstrates that a laparoscopic colectomy is more costly and time to recovery is equivalent to colectomy.Laparoscopic colectomy cannot be recommended as an alternative option at this time.

c

d


See NCCN Colorectal Screening Guidelines.

.






COL-3

ADJUVANT THERAPYg

SeeRecurrenceand Workup(COL-8)

PATHOLOGIC STAGEe

Tis; T1, N0, M0;

T2, N0, M0None

a llA patients with colon cancer should be counseled for family history. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatouspolyposis (FAP) and attenuated FAP see the .A minimum of 14 lymph nodes need to be examined to clearly establish stage II (T 3-4, N0) colon cancer.Patients considered to be N0 but who have < 14 nodes examined are suboptimally staged and may be considered in the high risk group.There are insufficient data to recommend the use of molecular markers to determine adjuvant therapy.At this time, combination regimens including irinotecan, oxaliplatin and capecitabine cannot be recommended as standard adjuvant therapy. Although early results fromthe MOSAIC trial report an improvement in disease-free survival in stage III patients treated with 5-FU/leucovorin/oxaliplatin (FOLFOX), these results are stillconsidered too early to consider this regimen in routine use.

There are no data supporting the routine use of CT scans of the abdomen or chest x-rays, but some institutions agree these are indicated in certain clinical situations.If patient a potential candidate for surgical resection of isolated metastases.The incidence of second primary colorectal cancers was found to be higher than the general population in patients with a history of adenomatous polyps. Green RJ,Metlay JP, Propert K, et al. Surveillance for second primary colorectal cancer after adjuvant chemotherapy: an analysis of intergroup 0089. Ann Intern Med2002;136:261-269.

e

fgh

ijk


T3, N0, M0fClinical trialorObservation

T3, N0, M0; high risk for

systemic recurrence:Grade 3-4, lymphatic/

vascular invasion,

bowel obstruction

Consider 5-FU/leucovorinorClinical trialorObservation

h

T4, N0, M0; or T3 with

localized perforation or

close, indeterminate or

positive margins

Consider 5-FU/leucovorin RT (category 2B for RT)orClinical trialorObservation

h

T1-3, N1-2, M0 5-FU/leucovorinh (category 1)

T4, N1-2, M0

5-FU/leucovorinh

h

(category 1)or5-FU/leucovorin + RT

(category 2B)

SURVEILLANCEi

History and physical every 3 mo

for 2 y, then every 6 mo for a total

of 5 y

CEA every 3 mo for 2 y, then

every 6 mo for y 2-5 for T2 or

greater lesions

Colonoscopy in 1 y, repeat in 1 y

if abnormal or at least every 2-3 y

if negative for polyps. If no

preoperative colonoscopy due to

obstructing lesion, colonoscopy

in 3-6 mo.

j

a

k






COL-4

Suspected or

proven metastatic

adenocarcinoma

from large bowel

(Any T, any N, M1)

Back to Colon CancerTable of Contents

CLINICAL

PRESENTATION

WORKUP FINDINGS

Colonoscopy

Chest x-ray

Chest/Abdominal/pelvic CT

CBC, platelets, chemistry profile

CEA

Needle biopsy, if clinically indicated

If potentially resectable M1 disease,

the following may be considered for

preoperative evaluation:Spiral CT with contrastMRI with IV contrastLaparoscopy (category 2B)AngiogramPET scan

See Surgery andAdjuvant Therapy(COL-5)



Liver

metastases

Lung

metastases

Abdominal/

peritoneal

metastases






COL-5

See SalvageTherapy (COL-9)

If patientstage IV, NED:

CEA every 3 mo (if

elevated preoperatively)

Chest x-ray or chest CT

scan every 3-6 mo x 2 y,

then every 6-12 mo up to a

total of 5 y (category 2B)

Abdominal/pelvic CT scan

every 3-6 mo x 2 y, then

every 6-12 mo up to a total

of 5 y

Colonoscopy in 1 y,

repeat in 1 y if abnormal

or at least every 2-3 y if

negative for polyps. If no

preoperative colonoscopy

due to obstructing lesion,

colonoscopy in 3-6 mo.

a

k

FINDINGS SURGERY ADJUVANT THERAPY

(6 mo preferred)

SURVEILLANCE

Liver

metastases

Resectable

Unresectable

Colectomy with en bloc removal

of regional lymph nodes,

intraoperative ultrasound (IOUS),

synchronous liver resectionorColectomy with en bloc removal

of lymph nodes with subsequent

liver resection, IOUSorColectomy with neoadjuvant

chemotherapy

(5-FU/leucovorin/irinotecan, or

5-FU/leucovorin/oxaliplatin

[category 2B]) and staged liver

resection

5-FU/leucovorinor5-FU/leucovorin/irinotecanl

m

or5-FU/leucovorin/oxaliplatinorContinuous IV 5-FUorCapecitabineorCapecitabine + irinotecan

(category 2B)orCapecitabine + oxaliplatin

(category 2B)orHepatic artery infusion therapy

5-FU/leucovorin (category 2B) or

continuous IV 5-FUorObserve (category 2B)

m

Consider limited colon resection

if substantial risk of obstruction

and/or if liver burden low

ablative therapy (category 2B)Recurrence(See COL-8)

aAll patients with colon cancer should be counseled for family history. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familialadenomatous polyposis (FAP) and attenuated FAP see the .The incidence of second primary colorectal cancers was found to be higher than the general population in patients with a history of adenomatous polyps. Green RJ,Metlay JP, Propert K, et al. Surveillance for second primary colorectal cancer after adjuvant chemotherapy: an analysis of intergroup 0089. Ann Intern Med2002;136:261-269.

k

lA recent trial demonstrated an increased early 60-day mortality of bolus 5-FU/leucovorin/irinotecan. Careful monitoring of all regimens is required. Rothenberg M,Meropol N, Poplin E et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol2001;19:3801-3807.This recommendation is based on data from advanced disease phase II trials. Data from phase III trials comparing these regimens to other regimens have notbeen reported.

m







COL-6


Unresectable

(multiple)

Resectable

(1-3 nodules)

Consider colectomy with

en bloc removal of nodes

followed by resection of

pulmonary nodules

Consider limited

colon resection

FINDINGS SURGERY ADJUVANT THERAPY SURVEILLANCE

Lung

metastases

5-FU/leucovorinor5-FU/leucovorin/irinotecanl

m

or5-FU/leucovorin/oxaliplatinorContinuous IV 5-FUorCapecitabineorCapecitabine + irinotecan

(category 2B)orCapecitabine + oxaliplatin

(category 2B)orObserve (category 2B)

m

If patientstage IV, NED:

CEA every 3 mo (if

elevated preoperatively)

Chest x-ray or chest CT

scan every 3-6 mo x 2 y,

then every 6-12 mo up to a

total of 5 y (category 2B)

Abdominal/pelvic CT scan

every 3-6 mo x 2 y, then

every 6-12 mo up to a total

of 5 y

Colonoscopy in 1 y,

repeat in 1 y if abnormal

or at least every 2-3 y if

negative for polyps. If no

preoperative colonoscopy

due to obstructing lesion,

colonoscopy in 3-6 mo.

a

k

Recurrence(See COL-8)

aAll patients with colon cancer should be counseled for family history. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familialadenomatous polyposis (FAP) and attenuated FAP see the .The incidence of second primary colorectal cancers was found to be higher than the general population in patients with a history of adenomatous polyps. GreenRJ, Metlay JP, Propert K, et al. Surveillance for second primary colorectal cancer after adjuvant chemotherapy: an analysis of intergroup 0089. Ann Intern Med2002;136:261-269.

k

lA recent trial demonstrated an increased early 60-day mortality of bolus 5-FU/leucovorin/irinotecan. Careful monitoring of all regimens is required. Rothenberg M,Meropol N, Poplin E et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol2001;19:3801-3807.This recommendation is based on data from advanced disease phase II trials. Data from phase III trials comparing these regimens to other regimens have notbeen reported.

m







Limited resection

or

Diverting colostomy

or

Bypass of impending

obstruction

Consider limited

colon resection

FINDINGS SURGERY ADJUVANT THERAPY

Nonobstructing

Impending

obstruction



COL-7

Abdominal/

peritoneal

metastases






COL-8

WORKUP

Not a

resection

candidate

RECURRENCE

Serial

CEA

elevation

Documented

metastases

Negative

findings

Positive

findings

Colonoscopy

Chest CT

Abdominal/

pelvic CT

Physical exam

Consider PET

Reevaluate chest/

abdominal/pelvic

CT in 3 mo

Consider PET, if

not previously

done

Local recurrence

or isolated

resectable organ-

confined lesion

Adjuvant

therapy,

approximately

6 mo, if not

previously

administered

Resection

Consider

PET, if not

previously done

Unresectable or

multiple lesions

No further

metastatic

disease

identified

Clinical

assessment

of

performance

status

PS 0-2

PS 3

Best

supportive

careIf PS

improves,

refer to above

See SalvageTherapy(COL-9)






COL-9

Regimen

Bolus 5-FU/leucovorin/irinotecanl,n

Primary therapy: patient can

tolerate intensive therapy

Primary therapy: patient cannot

tolerate intensive therapy

Secondary therapy: non-cross

resistant regimen to primary therapy

Bolus or infusional 5-FU/leucovorin Xp

Irinotecan Xq

SALVAGE THERAPYo :

Combinations of 5-FU/leucovorin therapy with either irinotecan or oxaliplatin should be strongly considered in optimal treatment

strategies. The exact sequence has not yet been defined.

l

o

A recent trial demonstrated an increased early 60-day mortality of bolus 5-FU/leucovorin/irinotecan. Careful monitoring of all regimens is required. Rothenberg M,Meropol N, Poplin E et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001;19:3801-3807.

h I s e5-FU/leucovorin/oxaliplatin has shown to be superior to bolus 5FU/leucovorin/irinotecan as first-line therapy. Goldberg R, Morton R, Sargent D, et al. N9741:oxaliplatinor CPT-11 + 5-fluorouracil/leucovorin or oxal + CPT-11 in advanced colorectal cancer. Initial toxicity and response data from a GI Intergroup study, Proc Am Soc ClinOncol, 2002; (abstract 511).For chemotherapy references,

m

nT is recommendation is based on data from phase I trials. Data from phase III trials comparing the e regimens to other regimens have not been report d.

pqOnly if patient received no prior adjuvant therapy or progressive > 6 mo after adjuvant therapy.If patient received 5-FU/leucovorin in primary regimen.

see Salvage Chemotherapy References (COL-A).

Infusional 5-FU/leucovorin/irinotecan X

Hepatic artery infusion (FUDR)

systemic therapy, for liver onlyX

Capecitabine X

Protracted 5-FU/leucovorin infusion X

5-FU/leucovorin/oxaliplatinn X X

Capecitabine/oxaliplatin (category 2B)m X X

Capecitabine/irinotecan (category 2B)m X X




COL-A



1

2

4

5

6

7

8

Poon M, OConnell M, Moertel C et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients withadvanced colorectal carcinoma. J Clin Oncol 1989;7:1407-1418.Petrelli N, Herrera L, Rustum Y et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil andmethotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987;5:1559-1565.deGramont A, Bosset C, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin andfluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997;15:808-815.Lokich J, Ahlgren J, Gullo J et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectalcarcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 1989;7:425-432.Saltz L, Cox J, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000;343:905-914.Douillard J, Cunningham D, Roth A et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: amulticentre randomised trial. The Lancet 2000;355:1041-1047.deGramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol2000;18:2938-2947.

VanCutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: resultsof a large phase III study. J Clin Oncol 2001;19:4097-4106.VanCustem E, Twelves C, Tabernero J et al. Capecitabine and oxaliplatin in combination (Xelox) as first line therapy for patients with metastatic colorectal cancer:results of an international multicenter phase II trial. Proceedings ASCO 2003; (abstract 1023).Patt Y, Lin E, Leibmann et al. Capecitabine plus irinotecan for chemotherapy-naive patients with metastatic colorectal cancer: US multicenter phase II trial. ProceedingsASCO 2003 (abstract 1130).Cunningham D, Glimelius B. A phase III study of irinotecan (CPT-11) versus best supportive care in patients with metastatic colorectal cancer who have failed 5-fluorouracil therapy. V301 Study Group. Semin Oncol 1999;26:6-12.Kemeny N, Ron I. Hepatic arterial chemotherapy in metastatic colorectal patients. Semin Oncol 1999;26:524-535.

3

9

10

Goldberg R, Morton R, Sargent D, et al. N9741 : oxaliplatin or CPT-11 + 5-fluorouracil/leucovorin or oxal + CPT-11 in advanced colorectal cancer. Initial toxicity andresponse data from a GI Intergroup study, Proc Am Soc Clin Oncol, 2002; (abstract 511).

SALVAGE CHEMOTHERAPY REFERENCES

Bolus or infusional 5-FU/leucovorin1

Protracted IV 5-FU2

Bolus 5-FU/leucovorin/irinotecan3

5-FU/leucovorin/oxaliplatin5

Capecitabine6

Liver only; HAI therapy (FUDR) systemic therapy10

Infusional 5-FU/leucovorin/irinotecan4 Irinotecan9

Capecitabine + oxaliplatin7

Capecitabine + irinotecan8




Staging

Table 1

American Joint Committee on Cancer (AJCC) TNM Staging

System for Colorectal Cancer*

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastasis (M)

Stage Grouping

Histologic Grade (G)

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma : intraepithelial or invasion of lamina propriaT1 Tumor invades submucosaT2 Tumor invades muscularis propriaT3 Tumor invades through the muscularis propria into the subserosa,

or into non-peritonealized pericolic or perirectal tissuesT4 Tumor directly invades other organs or structures, and/or

perforates visceral peritoneum

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in 1 to 3 regional lymph nodesN2 Metastasis in 4 or more regional lymph nodes

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage T N M Dukes MAC0 Tis N0 M0 - -I T1 N0 M0 A A

T2 N0 M0 A B1IIA T3 N0 M0 B B2IIB T4 N0 M0 B B3IIIA T1-T2 N1 M0 C C1IIIB T3-T4 N1 M0 C C2/C3IIIC Any T N2 M0 C C1/C2/C3IV Any T Any N M1 - D

GX Grade cannot be assessedG1 Well differentiatedG2 Moderately differentiatedG3 Poorly differentiatiedG4 Undifferentiated

in situ

*Used with the 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 mustbe credited 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,Inc., on behalf of the AJCC.Tis includes cancer cells confined within the glandular basement

membrane (intraepithelial) or lamina propria (intramucosal) with noextension through the muscularis mucosae into the submucosa.Direct invasion in T4 includes invasion of other segments of the

colorectum by way of the serosa; for example, invasion of the sigmoidcolon by a carcinoma of the cecum. Tumor that is adherent to otherorgans or structures macroscopically is classified T4. However, if notumor is present in the adhesion microscopically the classificationshould be pT3. The V and L substaging should be used to identify thepresence or absence of vascular or lymphatic invasion.A tumor nodule in the pericolorectal adipose tissue of a primary

carcinoma without histologic evidence of residual lymph node in thenodule is classified in the pN category as a regional lymph nodemetastasis if the nodule has the form and smooth contour of a lymphnode. If the nodule has an irregular contour, it should be classified in theT category and also coded as V1 (microscopic venous invasion) or asV2 (if it was grossly evident), because there is a strong likelihood that itrepresents venous invasion.Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0)

prognostic groups, as is Dukes C (Any TN1 M0 and Any T N2 M0). MACis the modified Astler-Coller classification.

The y prefix is to be used for those cancers that are classifiedafter pretreatment, whereas the r prefix is to be used for those cancersthat have recurred.

AJCC Cancer Staging Manual Sixth Edition

Note:

www.cancerstaging.net

ST-1




MS-1

Manuscript

NCCN Categories of Consensus

Overview

Staging

Category 1

Category 2A

Category 2B

Category 3

All recommendations are category 2A unless otherwise noted.

: There is uniform NCCN consensus, based on high-levelevidence, that the recommendation is appropriate.

: There is uniform NCCN consensus, based on lower-level evidence including clinical experience, that therecommendation is appropriate.

: There is nonuniform NCCN consensus (but no majordisagreement), based on lower-level evidence including clinicalexperience, that the recommendation is appropriate.

: There is major NCCN disagreement that therecommendation is appropriate.

Colorectal cancer is the third most frequently diagnosed cancer inmen and women in the United States. In 2003, an estimated 105,500new cases of colon cancer will occur. During the same year, it isestimated that 57,100 people will die from colon and rectal cancer.Despite these statistics, mortality from colon cancer has decreasedover the past 30 years, possibly because of earlier diagnosisthrough screening and better treatment modalities.

This article summarizes the NCCN clinical practice guidelines formanaging colon cancer. The guidelines begin with the clinicalpresentation of the patient to the primary care physician orgastroenterologist and address diagnosis, pathologic staging,surgical management, adjuvant treatment, management of recurrent

and metastatic disease, and patient surveillance. When reviewingthese guidelines, clinicians should be aware of several things. First,these guidelines adhere to the TNM (tumor/node/metastasis)staging system ( ). Furthermore, all recommendations areclassified as category 2A except where noted in the text or on thealgorithm (see Categories of Consensus). The panel unanimouslyendorses giving priority to treating patients in a clinical trial overstandard or accepted therapy. This is especially true for cases ofadvanced disease and for patients with locally aggressive colorectalcancer who are receiving combined modality treatment.

The sixth edition of the Americal Joint Committee on Cancer'sincludes several modifications to the colon

and rectum staging system. In this version of the staging system,smooth metastatic nodules in the pericolic or perirectal fat areconsidered lymph node metastases and should be included in Nstaging. Irregularly contoured metastatic nodules in the peritumoralfat are considered vascular invasion.

Stage II is now subdivided into IIA (if the primary tumor is T3) and IIB(for T4 lesions). Stage III is subdivided into IIIA (T1 to T2, N1, M0),IIIB (T3 to T4, N1, M0), and IIIC (any T, N2, M0). The differencebetween N1 and N2 disease is in the number of nodes involved: N1lesions have 1 to 3 positive nodes, whereas N2 tumors have four ormore positive nodes. The difference in five-year survival issubstantial: stage IIIA is 59.8%, stage IIIB is 42.0%, and stage IIIC is27.3%. In addition, the current staging suggests that the surgeonmark the area of the specimen with the deepest tumor penetrationso that the pathologist can directly evaluate the radial margin. Thesurgeon is encouraged to score the completeness of the resection

1

2

3

AJCC

Cancer Staging Manual

Table 1




as (1) R0 for complete tumor resection with all margins negative; (2)R1 for incomplete tumor resection with microscopic involvement of amargin; and (3) R2 for incomplete tumor resection with grossresidual tumor not resected.

First-degree relatives of patients with newly diagnosed adenomasor invasive carcinoma are at increased risk for colorectal cancer.Therefore, colon cancer patients, especially those 50 years oryounger and those with suspected hereditary nonpolyposis coloncancer (HNPCC), familial adenomatous polyposis (FAP), orattenuated FAP should be counseled regarding their family history,as detailed in the NCCN Colorectal Cancer Screening ClinicalPractice Guidelines.

Before making a decision about surgical resection for anendoscopically resected adenomatous polyp or villous adenoma,physicians should review pathology and consult with patients. Thepanel recommends marking the polyp site at the time of endoscopicresection. Polyps that contain carcinomatous changes that areconfined to the mucosa (carcinoma-in-situ or severe dysplasia) donot have metastatic potential and are adequately treated withcomplete polypectomy. If a polyp has been completely resected atpolypectomy and demonstrates invasive carcinoma (ie, cancer thathas penetrated the muscularis mucosae into the submucosa) and noadverse features are present, then no additional surgery isnecessary. If deep invasion into the stalk has occurred or if adversefeatures (such as grade 3 to 4 lesions, lymphatic invasion, or

positive margins) are present, then en bloc colectomy isindicated. Similarly, if the patient has a broad-based villous orvilloglandular adenoma, or if the specimen is fragmented, then acolectomy may be necessary. The panel does not recommendlaparoscopic surgery as an option at this time. All patients who haveresected polyps should undergo total colonoscopy to rule out othersynchronous polyps, as well as appropriate follow-up surveillanceendoscopy. No adjuvant chemotherapy is indicated for patientswith stage I lesions.

Patients who present with invasive colon cancer require a completestaging workup, including pathologic tissue review, totalcolonoscopy, a complete blood count, platelets, chemistry profile,carcinoembryonic antigen (CEA) determination, chest radiograph,and a computed tomographic (CT) scan of the abdomen andpelvis. For resectable colon cancer, the surgical procedure ofchoice is colectomy with en bloc removal of the regional lymphnodes. Recently, laparoscopic colectomy has been advanced as anapproach to the surgical management of colon cancer. A Europeantrial has shown some survival advantage to the laparoscopicapproach, but the number of patients enrolled was small.Preliminary results in a larger U.S. randomized trial demonstratedthat laparoscopic colectomy is more costly and that the patient'srecovery time is equivalent to a standard colectomy. Outcomeresults are still pending. For this reason, the panel does notrecommend laparoscopic approaches in the routine setting. Forresectable colon cancer that is causing obstruction, resection withdiversion followed by colectomy or stent insertion followed bycolectomy is also recommended. If the cancer is unresectable, adiverting colostomy followed by a palliative resection should be

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Managing Polypoid Cancer

Managing Invasive Colon Cancer

Risk Assessment

Clinical Presentation and Treatment

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considered.

The panel recommends 6 months of 5-FU (5-fluorouracil) plusleucovorin adjuvant chemotherapy for patients with stage III (node-positive) colon carcinoma (category 1). Adjuvant chemotherapy isnot considered standard for stage II colon cancer. The Intergroup Trial0035 demonstrated a trend toward a decreased recurrence rate withchemotherapy versus surgery alone, but no survival advantageresulted. The International Multicentre Pooled Analysis of B2 ColonCancer Trials included data on 1016 patients with stage II cancer whowere randomly assigned to receive either 5-FU plus leucovorin orobservation. The event-free survival rates were 76% and 73%,respectively (5-year hazard ratio, 0.83; 90% CI, 0.72 to 1.07).However, patients with T3 colon tumors with no metastases and withhigh-risk factors for systemic recurrence (including grade 3 or 4lesions, lymphatic/vascular invasion, or bowel obstruction) may beconsidered for adjuvant chemotherapy with 5-FU/leucovorin. Thesepatients should be entered in a clinical trial, if possible. These patientsmay also be observed. Postoperative chemotherapy with radiation(category 2B for radiation) might benefit patients who have T3 tumorswith localized perforation or close, indeterminate, or positive marginsor it might benefit patients with T4, N0 colon cancer.

The use of combination therapy with either irinotecan/5-FU/leucovorin or oxaliplatin /5-FU/leucovorin as adjuvant treatment forpatients with resected colon cancer has aroused considerableinterest. Because both combination regimens have demonstratedimproved response and survival in advanced colon cancer, it ishighly likely that combination therapy will show survival benefit forpatients receiving irinotecan or oxaliplatin in the adjuvant setting.The results of two U.S. adjuvant colon trials are pending: the US GI

Intergroup (irinotecan/5-FU/leucovorin) and the NSABP(oxaliplatin/5-FU/leucovorin) trials. In addition, the GI Intergroup'snew rectal adjuvant trial also will explore the benefits of irinotecanand oxaliplatin compared to FU/leucovorin. At the ASCO 2003meeting, the preliminary results of the European Mosaic trial werepresented. This trial compares infusional 5-FU/leucovorin tooxaliplatin /5-FU/leucovorin (FOLFOX4) for stage II and III resectedcolon cancer patients. After three years, a significant improvementin disease-free survival was noted with the FOLFOX4 regimen(77.8% vs. 72.9%; a 23% risk reduction for the FOLFOX4 arm).Subset analysis demonstrated a 24% risk reduction (disease-freesurvival) for stage III patients and an 18% risk reduction for stage IIpatients. Although these risk reductions are encouraging, it will beimportant to review the overall survival results from a series of theserecently completed adjuvant trials before recommending the routineuse of combination therapy for resected colon cancer patients. Atthis time, it is reasonable for patients to consider combinationtherapy for high-risk resected colon cancer patients such as thosewith multiple positive nodes or perforation.

Patients with stage IV colon cancer or recurrent disease can presentwith localized liver metastases as the only manifestation of theirdisseminated disease. If a patient is a candidate for surgery and theliver metastases are deemed resectable, the panel recommendscolectomy followed by liver resection or colectomy withneoadjuvant chemotherapy and a staged liver resection. Treatmentof liver metastases by resection has been demonstrated to result ina 38% five-year survival. If the liver disease is deemed to beunresectable, limited colon resection should be considered if thepatient has a substantial risk of obstruction or if the liver burden islow. Ablative therapy on the liver disease using radiofrequency

Adjuvant Chemotherapy for Resectable Colon Cancer

Management of Localized Metastatic Disease

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ablation or cryosurgery may be considered at the time of surgery(category 2B).Patients who have completely resected liver metastases should beoffered 4 to 6 months of adjuvant chemotherapy. A completed trialdemonstrated that the combination of fluorodeoxyuridine (FUDR) byhepatic artery infusion plus systemic chemotherapy was superior tosystemic chemotherapy alone after hepatic resection. Additionaloptions for adjuvant therapy may also consider using one of theregimens with activity in disseminated metastatic disease, includingsystemic 5-FU plus leucovorin, 5-FU plus leucovorin plusoxaliplatin, continuous-infusion 5-FU, 5-FU plus leucovorin plusirinotecan, or a capecitabine containing regimen.Intraperitoneal chemotherapy is considered investigational, giventhe absence of evidence that it prolongs life. Patients withunresectable liver metastases should receive salvage therapy.Patients may also be observed (category 2B).Metastatic disease can also occur in the lung. Patients with 1 to 3nodules in their lungs who can undergo resection should beconsidered for colectomy with en bloc removal of nodes followed byresection of pulmonary nodules. Combined pulmonary and hepaticresections of resectable metastatic disease have been used inselective cases. A biologic waiting period of up to 2 months candistinguish patients who would be more likely to benefit frommetastasectomy because of indolent disease. Adjuvant therapyrecommended for patients with lung metastases includes 5-FU plusleucovorin, 5-FU plus leucovorin plus irinotecan, continuous infusionof 5-FU, or observation. If a patient cannot undergo resection or hasmultiple lesions, a limited colon resection should be consideredfollowed by salvage therapy. For patients with other nonobstructingunresectable metastases, a limited colon resection should be

considered followed by salvage therapy. Recommended surgery forpatients with an impending obstruction includes limited resection, adiverting colostomy, or a bypass of impending obstruction. Surgeryshould be followed with salvage therapy.

The current management of disseminated metastatic colon canceruses various active drugs, both in combination and as single agents:5-FU/leucovorin, irinotecan, oxaliplatin, and capecitabine. Thechoice of therapy is based on consideration of the type and timing ofthe prior therapy that has been administered and the differingtoxicity profiles of the constituent drugs.

As primary therapy for metastatic disease in a patient with goodtolerance, the guideline recommends combination therapyconsisting of fluoropyrimidines (either 5-FU/leucovorin orcapecitabine) and either irinotecan or oxaliplatin. Theseagents should be used in a sequential manner, but the guidelinedoes not specify the exact sequence. The guideline references thepreliminary findings in the NCCTG/Intergroup N9741 trial whichfound that the oxaliplatin/FU/leucovorin arm showed an improvedoverall survival compared to the irinotecan/FU/leucovorincombination (18.6 vs. 14.1 months, = .002). These findings arenot considered definitive because there are complexities ininterpreting the findings due to the lack of oxaliplatin availability as across-over agent and to the use of infusional FU in the oxaliplatinarm compared to bolus 5-FU in the irinotecan combination. If theirinotecan/5-FU/leucovorin combination is used, the guideline doescaution about the possible toxicity that has been associated with thisregimen. If recurrence is confined to the liver, liver-directed therapymay be considered.

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For patients with impaired tolerance to aggressive first-linemanagement, the guideline recommends bolus or infusionalFU/leucovorin, single-agent capecitabine, or prolonged FUinfusion. In planning second-line therapy, it should be noted thatirinotecan can be used as a single agent if the patient has receivedprior 5-FU/leucovorin, whereas oxaliplatin should be given withthese agents because the single agent has little activity in thissetting. Metastatic cancer patients with performance status 3 or 4should receive best supportive care.

Post-treatment surveillance of colon cancer patients remainscontroversial. A recent meta-analysis suggests some benefit tomore aggressive screening, but methodologic issues related to theanalyzed trials make a definitive determination difficult. In addition,the meta-analysis does not afford any information about whichcomponent of the intensive surveillance provided the benefit.Oncologists perform surveillance in these patients to assesstherapeutic complications, discover a recurrence that is potentiallyresectable for cure, identify new metachronous neoplasms at apreinvasive stage, and reassure the patient. For successfully treatedpatients who have no known residual disease, the panelrecommends a history and physical examination every 3 months forthe first 2 years and then every 6 months for the next 5 years.

For T2 or greater lesions, a CEA test is recommended at baselineand every 3 months for 2 years, then every 6 months for the next2 to 5 years if the clinician determines that the patient is a potentialcandidate for aggressive curative surgery. Colonoscopy isindicated within 1 year of resection (or 3 to 6 monthspostoperatively) and is repeated annually if neoplastic polyps are

noted; if the colon is free of polyps, colonoscopic surveillance atleast every 3 years is recommended. Data show that patients witha history of colorectal cancer have an increased risk of developingsecond cancers, and the surveillance colonoscopies are aimed atremoving metachronous polyps.

Managing patients with an increased CEA level after resectionshould include colonoscopy; chest, abdominal, and pelvic CT scans;and a careful physical examination. If imaging study results arenormal in the face of an increasing CEA, repeat scans are indicatedevery 3 months if symptoms occur. In addition, a positron-emissiontomography scan may be used to see if isolated metastases can bedemonstrated. The panel does not recommend a so-called "blindabdominal exploration" for patients whose workup for an increasedCEA level is negative. The panel considered but does notrecommend, the use of anti-CEA--radiolabeled scintigraphy.Positron-emission tomography should be considered before surgicalresection for patients with a suspected recurrence or if an isolated,resectable, organ-confined lesion is detected. When recurrentdisease is identified at the site of the anastomosis in the bowel,curative surgery may be possible. Likewise, isolated lesions in theliver or lung may be resected for cure.

The NCCN Colon/Rectal/Anal Cancer Guidelines panel believes thata multidisciplinary approach is necessary for managing colorectalcancer. The panel endorses the concept that treating patients in aclinical trial has priority over standard or accepted therapy.

Post-Treatment Surveillance

Managing an Increasing Carcinoembryonic Antigen

Level

Summary

MS-5




MS-6

The recommended surgical procedure for resectable colon cancer isan en bloc resection. For patients with stage III disease, 5-FU--based adjuvant therapy is recommended. A patient who hasmetastatic disease in the liver or lung should be considered forsurgical resection if he or she is a candidate for surgery and ifsurgery can extend survival. Surgery should be followed by adjuvantchemotherapy. The panel advocates a conservative post-treatment

surveillance program for colon carcinoma patients. Serial CEAdeterminations are appropriate if the patient is a candidate foraggressive surgical resection, should recurrence be detected.Abdominal and pelvic CT scans should be used only when there areclinical indications of possible recurrence. Patients whose diseaseprogresses during 5-FU--based therapy should be treated withcombination chemotherapy consisting of 5-FU/leucovorin or




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