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

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1 Table of Contents Clinical in Oncology V Continue Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

2 Table of Contents Panel Members * Paul F. Engstrom, MD/Chair Marwan G. Fakih, MD David P. Ryan, MD Fox Chase Cancer Center Roswell Park Cancer Institute Massachusetts General Hospital Cancer Center Juan Pablo Arnoletti, MD University of Alabama at Birmingham Comprehensive Cancer Center * Al B. Benson, III, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Jdan D. Berlin, MD Vanderbilt-Ingram Cancer Center Yi-Jen Chen, MD, PhD City of Hope Comprehensive Cancer Center Michael A. Choti, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Harry S. Cooper, MD Fox Chase Cancer Center Raza A. Dilawari, MD St. Jude Children's Research Hospital/University of Tennessee Cancer Institute Dayna S. Early, MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Peter C. Enzinger, MD Dana-Farber/Brigham and Women s Cancer Center Guidelines Panel Disclosures James Fleshman, Jr., MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Charles Fuchs, MD Dana-Farber/Brigham and Women's Cancer Center Massachusetts General Hospital Cancer Center Jean L. Grem, MD UNMC Eppley Cancer Center at The Nebraska Medical Center James A. Knol, MD University of Michigan Comprehensive Cancer Center Lucille A. Leong, MD City of Hope Cancer Center Edward Lin, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Mary F. Mulcahy, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Eric Rohren, MD, PhD ф The University of Texas M. D. Anderson Cancer Center Continue * Leonard Saltz, MD Þ Memial Sloan-Kettering Cancer Center David Shibata, MD H. Lee Moffitt Cancer Center and Research Institute at the University of South Flida John M. Skibber, MD The University of Texas M. D. Anderson Cancer Center William Small, Jr., MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Constantinos T. Sofocleous, MD, PhD ф Memial Sloan-Kettering Cancer Center James Thomas, MD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Alan P. Venook, MD UCSF Comprehensive Cancer Center Christopher Willett, MD Duke Comprehensive Cancer Center Medical Oncology Radiotherapy/Radiation oncology Surgery/Surgical oncology Pathology Hematology/Hematology Oncology Þ Internal medicine Gastroenterology ф Diagnostic/Interventional Radiology * Writing Committee Member Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

3 Table of Contents Table of Contents Panel Members Summary of the Guidelines Updates Clinical Presentations and Primary Treatment: Pedunculated polyp (adenoma [tubular, tubulovillous, villous]) with invasive cancer (COL-1) Sessile polyp (adenoma [tubular, tubulovillous, villous]) with invasive cancer (COL-1) Colon cancer appropriate f resection (COL-2) Suspected proven metastatic adenocarcinoma from the large bowel (COL-5) Pathologic Stage, Adjuvant Therapy and Surveillance (COL-3) Recurrence and Wkup (COL-9) Principles of Pathologic Review (COL-A) Principles of Surgery (COL-B) Chemotherapy f Advanced Metastatic Disease (COL-C) Principles of Risk Assessment f Stage II Disease (COL-D) Principles of Adjuvant Therapy (COL-E) Principles of Radiation Therapy (COL-F) Principles of Survivship (COL-G) Print the Guideline F help using these documents, please click here Staging Discussion References Clinical Trials: The believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.g/clinical_trials/physician.html Categies of Evidence and Consensus: All recommendations are Categy 2A unless otherwise specified. See Categies of Evidence and Consensus These guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk makes no representations warranties of any kind, regarding their content use application and disclaims any responsibility f their application use in any way. These guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of.

4 Summary of the Guidelines updates Table of Contents Summary changes in the version of the Colon Guidelines from the version include: COL-6 The chemotherapy was clarified as 2-3 months in the treatment option. Under adjuvant therapy, this was clarified as 6 mo perioperative treatment preferred. Footnote x is new to the page, FOLFOXIRI is not recommended in this setting. COL-7 Under adjuvant therapy, this was clarified as 6 mo perioperative treatment preferred. COL-9 Serial CEA elevation, add Consider PET scan to initial wkup. COL-10 Unresectable patients with previous adjuvant FOLFOX within past 12 months, FOLFIRI ± cetuximab (KRAS WT gene only) was added as a treatment recommendation. COL-11 Resectable patients with no previous chemotherapy, treatment after resection changed from FOLFOX ± bevacizumab to Active chemotherapy regimen (See COL-C). Unresectable patients with previous adjuvant FOLFOX within past 12 months, FOLFIRI ± cetuximab (KRAS WT gene only) was added as a treatment recommendation. COL-C 1 of 6 FOLFOXIRI recommendation: Therapy after first progression changed from 5-FU/leucovin + bevacizuamb to Cetuximab (KRAS WT gene only) + irinotecan, patients not able to tolerate combination, consider single agent cetuximab (KRAS WT gene only) panitumumab (KRAS WT gene only) (not as combination). COL-C 3 of 6 Footnote 5 was changed from Combination therapy involving me than one biologic agent is not recommended to Combination therapy involving cytotoxics, anti-egfrs, and anti-vegfs is not recommended. COL-G 2 of 3 Oxaliplatin-induced neuropathy: Recommendation f gabapentin and tricyclic antidepressants deleted and replaced with Consider the use of analgesics referral to a pain specialist. The section fo Sexual Dysfunction after Pelvic Radiation was removed. MS-1 The updated discussion section was added that cresponds with the algithm. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UPDATES

5 Summary of the Guidelines updates Table of Contents Summary changes in the version of the Colon Guidelines from the version include: Footnote 6 was added to page COL-C 1 of 6 and COL-C 3 of 6 clarifying that if cetuximab is used as initial therapy, then neither cetuximab n panitumumab should be used in second subsequent lines of therapy. The ASCO abstract reference in footnote 5 was updated to the published version from the January NEJM. Summary changes in the version of the Colon Guidelines from the version include: COL-3 COL-7 The option of 5-FU/leucovin/oxaliplatin was deleted from the The following primary treatment options were added f recommended adjuvant therapy options f T3,N0,M0 (no high risk unresectable metastases: FOLFOX FOLFIRI CapeOX ± features). cetuximab (KRAS wild-type gene only). Link added to new Principles of Survivship section (COL-G). The regimen FOLFOXIRI was added to the primary treatment COL-4 options with a categy 2B designation. Link added to new Principles of Survivship section (COL-G). The recommendation f re-evaluation f conversion to COL-5 resectable every 2 mo was added after primary treatment. Multidisciplinary team evaluation, including a surgeon with The recommendation f hepatic artery infusion was moved from expertise in the resection of hepatobiliary and lung metastases the body of the algithm to footnote x. was added to the wkup section. COL-9 The recommendation f MRI was deleted and footnote t added, Footnote z was added with the recommendation of KRAS gene describing that MRI should only be considered if the CT with testing and referral to the Principles of Pathology section. contrast is inadequate. COL-10 Unresectable disease was defined as including potentially The recommendation f re-evaluation f conversion to convertible and unconvertible. Further guidance and a resectable every 2 mo was added after primary treatment. description of these categies was added to the Principles of Footnote z was added with the recommendation of KRAS gene Surgery section (COL-B 2 of 3). testing and referral to the Principles of Pathology section. COL-6 The recommendation f hepatic artery infusion was moved from The following primary treatment options were added f the body of the algithm to footnote x. resectable metastases: FOLFOX FOLFIRI CapeOX ± The treatment option of observation was moved from the cetuximab (KRAS wild-type gene only). footnote into the body of the algithm after primary treatment. The clarification of 2-3 months was added f neoadjuvant There is a new footnote aa specifying that therapy should be chemotherapy. considered f a maximum of 6 months. The recommendation f hepatic artery infusion was moved from COL-11 the body of the algithm to footnote x. The clarification of 2-3 months was added f neoadjuvant chemotherapy. The recommendation f hepatic artery infusion was moved from the body of the algithm to footnote x. The treatment option of observation was moved from the footnote into the body of the algithm after primary treatment. There is a new footnote aa specifying that therapy should be considered f a maximum of 6 months. Continued Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UPDATES

6 Summary of the Guidelines updates Table of Contents Summary changes in the version of the Colon Guidelines from the version include: COL-A 3 of 4 The KRAS Mutation testing section was added to provide further definition and direction f testing and use of results. COL-A 4 of 4 References were added to suppt KRAS infmation. COL-B 2 of 3 Liver - the following bullets were added to the page: Patients with resectable metastatic disease and primary tum in place should have both sites resected with curative intent. These can be resected in one operation as a staged approach, depending on the complexity of the hepatectomy colectomy, combid diseases, surgical exposure, and surgeon expertise. When hepatic metastatic disease is not optimally resectable based on insufficient remnant liver volume, approaches utilizing preoperative ptal vein embolization staged liver resection can be considered. Some institutions use intra-arterial embolization in select patients with chemotherapy resistant/refracty disease, without obvious systemic disease, with predominant hepatic metastases (categy 3). Confmal external beam radiation therapy should not be used unless the patient is symptomatic in the setting of a clinical trial. Lung - the following bullets were added to the page: Ablative techniques can be considered when unresectable and amenable to complete ablation. Patients with resectable synchronous metastases can be resected synchronously using a staged approach. NEW SECTION - There is a new section with recommendations f evaluating a patient f conversion to resectable disease. COL-B 3 of 3 References 6, 10-13, and were added to suppt the recommendations on COL-B 2 of 3. COL-C 1 of 6 Patients appropriate f therapy - the following options were added f initial therapy: FOLFOX FOLFIRI CapeOX ± cetuximab (KRAS wild-type gene only), FOLFOXIRI with a categy 2B designation. 5FU/leucovin + bevacizumab was added as a treatment option f patients progressing after FOLFOXIRI. If patients progress on 5FU/leucovin + bevacizumab, the recommended therapy options are cetuximab panitumumab. COL-C 2 of 6 Cetuximab was added as a treatment option f patients not appropriate f intensive therapy with a categy 2B designation. COL-C 3 of 6 Footnote 5 is new to the page: Combination therapy involving me than one biologic agent is not recommended. Footnote 10 is new to the page: Data are not mature f the addition of biologic agents to FOLFOXIRI. COL-F The following bullet was modified: Intensity modulated radiotherapy (IMRT) tomotherapy should only be used in the setting of a clinical trial. The last 2 bullets are new to the page: Some institutions use intra-arterial embolization in select patients with chemotherapy resistant/refracty disease, without obvious systemic disease, and with predominant hepatic metastases (categy 3). Confmal external beam radiation therapy should not be used unless the patient is symptomatic in the setting of a clinical trial. COL-G Principles of Survivship is a new section to the Guidelines. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. UPDATES

7 Table of Contents CLINICAL PRESENTATION a WORKUP FINDINGS SURGERY Pedunculated polyp (adenoma [tubular, tubulovillous, villous]) with invasive cancer Pathology reviewb,c Colonoscopy Marking of cancerous polyp site (at time of colonoscopy within 2 wks) Single specimen, completely removed with favable histological featuresd and clear margins Fragmented specimen margin cannot be assessed unfavable histological features d Observe Colectomye with en bloc removal of regional lymph nodes See Pathologic Stage, Adjuvant Therapy, and Surveillance (COL-3) Sessile polyp (adenoma [tubular, tubulovillous, villous]) with invasive cancer Pathology reviewb,c Colonoscopy Marking of cancerous polyp site (at time of colonoscopy within 2 wks) Single specimen, completely removed with favable histological featuresd and clear margins Fragmented specimen margin cannot be assessed unfavable histological features d Observef Colectomy e with en bloc removal of regional lymph nodes Colectomye with en bloc removal of regional lymph nodes See Pathologic Stage, Adjuvant Therapy, and Surveillance (COL-3) a All patients with colon cancer should be counseled f family histy. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP, see the Colectal Cancer Screening Guidelines. bconfirm the presence of invasive cancer (pt1). ptis has no biological potential to metastasize. cit has not been established if molecular markers are useful in treatment determination (predictive markers) and prognosis. College of American Pathologists Consensus Statement Prognostic facts in colectal cancer. Arch Pathol Lab Med 2000;124: dsee Principles of Pathologic Review (COL-A) - Endoscopically removed malignant polyp. esee Principles of Surgery (COL-B 1 of 3). fobservation may be considered, with the understanding that there is an added 10-15% risk of lymph node metastases. Nivatvongs S, Back to Other Clinical Rojanasakul A, Reiman HM, et al. The risk of lymph node metastasis in colectal polyps with invasive adenocarcinoma. Dis Colon Rectum Presentations 1991;34(4): (Table of Contents) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-1

8 Table of Contents CLINICAL WORKUP FINDINGS SURGERY PRESENTATION a Resectable, nonobstructing Colectomye with en bloc removal of regional lymph nodes Colon cancer appropriate f resection (non metastatic) Pathology reviewd Colonoscopy CBC, platelets, chemistry profile, CEA Chest/abdominal/ pelvic CT PET scan is not routinely indicated Resectable, obstructing (unprepped) Locally unresectable medically inoperable One-stage colectomy with en bloc removal of regional lymph nodes Resection with diversion Stent Diversion Palliative therapy g e Colectomye with en bloc removal of regional lymph nodes See Pathologic Stage, Adjuvant Therapy, and Surveillance (COL-3) See Chemotherapy f Advanced Metastatic Disease (COL-C) Suspected proven metastatic adenocarcinoma from large bowel See Management of suspected proven metastases (COL-5) a All patients with colon cancer should be counseled f family histy. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP, see the Colectal Cancer Screening Guidelines. dsee Principles of Pathologic Review (COL-A) - Colon cancer appropriate f resection, pathological stage, and lymph node evaluation. Back to Other Clinical esee Principles of Surgery (COL-B 1 of 3). Presentations gpalliative therapy may include RT f uncontrolled bleeding, stent f obstruction, supptive care. (Table of Contents) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-2

9 Table of Contents PATHOLOGIC STAGE d Tis; T1, N0, M0; T2, N0, M0 T3, N0, M0i (no high risk features) T3, N0, M0 at high risk f systemic recurrence (grade 3-4, lymphatic/vascular invasion, bowel obstruction, < 12 lymph nodes examined) T4, N0, M0; T3 with localized perfation close, indeterminate positive margins ADJUVANT THERAPY h,j None Consider capecitabinek,l 5-FU/leucovink,l Clinical trial Observation k 5-FU/leucovin/oxaliplatink,l,m,n capecitabinek,l,n 5-FU/leucovink,l,n Clinical trial Observationk SURVEILLANCE o Histy and physical every 3-6 mo f 2 y, then every 6 mo f a total of 5 y CEAp every 3-6 mo f 2 y, then every 6 mo f a total of 5 y f T2 greater lesions Chest/abdominal/pelvic CT annually x 3 y f patients at high risk f recurrenceo,q Colonoscopya in 1 y except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 3-6 mo If advanced adenoma, repeat in 1 y If no advanced adenoma, r repeat in 3 y, then every 5 ys PET scan is not routinely recommended See Principles of Survivship (COL-G) Node positive disease, see page COL-4 aall patients with colon cancer should be counseled f family histy. Patients with mtreatment options include FOLFOX (infusional 5-FU, leucovin, oxaliplatin) suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous FLOX (bolus 5-FU, leucovin, oxaliplatin). Grade 3-4 diarrhea is considerably polyposis (FAP) and attenuated FAP see the Colectal Cancer Screening higher with FLOX than FOLFOX in cross study comparison. Guidelines. nconsider RT f T4 with penetration to a fixed structure. See Principles of dsee Principles of Pathologic Review (COL-A) - Pathological stage. Radiation Therapy COL-F. hthere are no data to suppt adjuvant therapy in Stage I disease, however certain odesch CE, Benson III AB, Somerfield MR, et al. Colectal cancer surveillance: high risk Stage II patients (lymphovascular invasion, poly differentiated 2005 update of the American Society of Clinical Oncology Practice Guideline. J histology, inadequate lymph node sampling) may be considered at higher risk and Clin Oncol 2005;23: a discussion of chemotherapy may be warranted. pif patient is a potential candidate f further intervention. ipatients considered to be N0 but who have < 12 nodes examined are suboptimally qct scan may be useful f patients at high risk f recurrence (eg, lymphatic staged and should be considered in the high risk group. See Principles of venous invasion by tum, poly differentiated tums). Pathologic Review (COL-A) - Lymph node evaluation. rvillous polyp, polyp > 1 cm, high grade dysplasia. jthere are insufficient data to recommend the use of molecular markers to srex DK, Kahi CJ, Levin B, et al. Guidelines f colonoscopy surveillance after determine adjuvant therapy. cancer resection: a consensus update by the American Cancer Society and the ksee Principles of Risk Assessment f Stage II Disease (COL-D). US Multi-Society Task Fce on Colectal Cancer. Gastroenterology lsee Principles of Adjuvant Therapy (COL-E). 2006;130: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. See Recurrence and Wkup (COL-9) Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-3

10 Table of Contents PATHOLOGIC STAGE d ADJUVANT THERAPY j SURVEILLANCE o T1-3, N1-2, M0 T4, N1-2, M0 5-FU/leucovin/oxaliplatin (categy1) l,m,n Capecitabinel,n 5-FU/leucovinl,n Histy and physical every 3-6 mo f 2 y, then every 6 mo f a total of 5 y CEAp every 3-6 mo f 2 y, then every 6 mo f a total of 5 y f T2 greater lesions Chest/abdominal/pelvic CT annually x 3 y f patients at high risk f recurrenceo,q Colonoscopya in 1 y except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 3-6 mo If advanced adenoma, repeat in 1 y If no advanced adenoma, r repeat in 3 y, then every 5 ys PET scan is not routinely recommended See Principles of Survivship (COL-G) See Recurrence and Wkup (COL-9) a All patients with colon cancer should be counseled f family histy. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP see the Colectal Cancer Screening Guidelines. dsee Principles of Pathologic Review (COL-A) - Pathological stage. jthere are insufficient data to recommend the use of molecular markers to determine adjuvant therapy. lsee Principles of Adjuvant Therapy (COL-E). mtreatment options include FOLFOX (infusional 5-FU, leucovin, oxaliplatin) FLOX (bolus 5-FU, leucovin, oxaliplatin). Grade 3-4 diarrhea is considerably higher with FLOX than FOLFOX in cross study comparison. nconsider RT f T4 with penetration to a fixed structure. See Principles of Radiation Therapy COL-F. o p q Desch CE, Benson III AB, Somerfield MR, et al. Colectal cancer surveillance: 2005 update of the American Society of Clinical Oncology Practice Guideline. J Clin Oncol 2005;23: If patient is a potential candidate f further intervention. CT scan may be useful f patients at high risk f recurrence (eg, lymphatic venous invasion of tum poly differentiated tums). rvillous polyp, polyp > 1 cm, high grade dysplasia. srex DK, Kahi CJ, Levin B, et al. Guidelines f colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Fce on Colectal Cancer. Gastroenterology 2006;130: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-4

11 Table of Contents CLINICAL PRESENTATION WORKUP FINDINGS Resectable e See Treatment and Adjuvant Therapy (COL-6) Suspected proven metastatic synchronous adenocarcinoma from large bowel (Any T, any N, M1) Colonoscopy Chest/abdominal/pelvic CTt CBC, platelets, chemistry profile CEA Determination of tum KRAS gene statusd Needle biopsy, if clinically indicated PET scan only if potentially surgically curable M1 disease Multidisciplinary team evaluation, including a surgeon experienced in the resection of hepatobiliary and lung metastases Synchronous liver only lung only metastases Synchronous abdominal/peritoneal metastases Unresectable (potentially convertiblee unconvertible) See Treatment and Adjuvant Therapy (COL-7) See Primary Treatment and Adjuvant Therapy (COL-8) d e t See Principles of Pathologic Review (COL-A 3 of 4) - KRAS Mutation Testing. See Principles of Surgery (COL-B 2 of 3). CT should be with contrast. Consider MRI with contrast if CT is inadequate. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-5

12 Table of Contents TREATMENT Resectablee synchronous liver only lung only metastases Colectomy, with synchronous staged liver lung resection Neoadjuvant therapy (f 2-3 months) FOLFIRI FOLFOX CapeOX u± bevacizumabv FOLFIRI FOLFOX CapeOX u ± cetuximab (KRAS wild-type gene only) d followed by synchronous staged colectomy and resection of metastatic disease Colectomy, followed by chemotherapy (f 2-3 months) FOLFIRI FOLFOX CapeOXu ± bevacizumabv FOLFIRI FOLFOX CapeOX u ± cetuximab (KRAS wild-type gene only) d and staged resection of metastatic disease ADJUVANT THERAPY SURVEILLANCE (resected metastatic disease) (6 mo perioperative treatment preferred) Active chemotherapy regimen f advanced disease ( See Chemotherapy f Advanced Metastatic Disease (COL-C) w,x (categy 2B) Consider observation shtened course of chemotherapy, if patient received neoadjuvant therapy If patient stage IV, NED: CEA every 3 mo x 2 y, then every 6 mo x 3-5 y Chest/abdominal/pelvic CT scan every 3-6 mo x 2 y, then every 6-12 mo up to a total of 5 y Colonoscopya in 1 y except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 3-6 mo If advanced adenoma, repeat in 1 y If no advanced adenoma, r repeat in 3 y, then every 5 ys Recurrence (See COL-9) a All patients with colon cancer should be counseled f family histy. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP see the Colectal Cancer Screening Guidelines. dsee Principles of Pathologic Review (COL-A 3 of 4) - KRAS Mutation Testing. esee Principles of Surgery (COL-B 2 of 3). rvillous polyp, polyp > 1 cm, high grade dysplasia. srex DK, Kahi CJ, Levin B, et al. Guidelines f colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi- Society Task Fce on Colectal Cancer. Gastroenterology 2006;130(6): uthe majity of safety and efficacy data f this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m2 twice daily f 14 days, repeated every 21 days, is standard. Evidence suggests that Nth American patients may experience greater toxicity with capecitabine (as well as with other fluopyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large scale randomized trials. vthe safety of administering bevacizumab pre postoperatively, in combination with 5-FU-based regimens, has not been adequately evaluated. There should be at least a 6 wk interval between the last dose of bevacizumab and elective surgery and re-initiation of bevacizumab at least 6-8 weeks postoperatively. There is an increased risk of stroke and other arterial events especially in age 65. The use of bevacizumab may interfere with wound healing. whepatic artery infusion ± systemic 5-FU/leucovin (categy 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of this procedure. xfolfoxiri is not recommended in this setting. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-6

13 Table of Contents TREATMENT Unresectable synchronous liver only lung only metastases Systemic therapy (FOLFIRI FOLFOX CapeOX u± bevacizumabv FOLFIRI FOLFOX CapeOX u ± cetuximab [KRAS wild-type gene only] d FOLFOXIRI [categy 2B] ) Consider colon resectione only if imminent risk of obstruction significant bleeding Re-evaluate f conversion to resectablee every 2 mo Converted to resectable e Remains unresectable See Chemotherapy f Advanced Metastatic Disease (COL-C) Synchronized staged resection e of colon and metastatic cancer ADJUVANT THERAPY (6 mo perioperative treatment preferred) Active chemotherapy regimen f advanced disease ( See Chemotherapy f Advanced Metastatic Disease (COL-C) w (categy 2B) Consider observation shtened course of chemotherapy, if patient received neoadjuvant therapy SURVEILLANCE If patient stage IV, NED: CEA every 3 mo x 2 y, then every 6 mo x 3-5 y Chest/abdominal/pelvic CT scan every 3-6 mo x 2 y, then every 6-12 mo up to a total of 5 y Colonoscopya in 1 y except if no preoperative colonoscopy due to obstructing lesion, colonoscopy in 3-6 mo If advanced adenoma, repeat in 1 y If no advanced adenoma, r repeat in 3 y, then every 5 ys Recurrence (See COL-9) a All patients with colon cancer should be counseled f family histy. Patients with suspected hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP) and attenuated FAP see the Colectal Cancer Screening Guidelines. dsee Principles of Pathologic Review (COL-A 3 of 4) - KRAS Mutation Testing. esee Principles of Surgery (COL-B 2 of 3). rvillous polyp, polyp > 1 cm, high grade dysplasia. srex DK, Kahi CJ, Levin B, et al. Guidelines f colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi- Society Task Fce on Colectal Cancer. Gastroenterology 2006;130(6): uthe majity of safety and efficacy data f this regimen have been developed in Europe, where a capecitabine starting dose of 1000 mg/m2 twice daily f 14 days, repeated every 21 days, is standard. Evidence suggests that Nth American patients may experience greater toxicity with capecitabine (as well as with other fluopyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large scale randomized trials. vthe safety of administering bevacizumab pre postoperatively, in combination with 5-FU-based regimens, has not been adequately evaluated. There should be at least a 6 wk interval between the last dose of bevacizumab and elective surgery and re-initiation of bevacizumab at least 6-8 weeks postoperatively. There is an increased risk of stroke and other arterial events especially in age 65. The use of bevacizumab may interfere with wound healing. whepatic artery infusion ± systemic 5-FU/leucovin (categy 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of this procedure. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-7

14 Table of Contents FINDINGS PRIMARY TREATMENT Nonobstructing See Chemotherapy f Advanced Metastatic Disease (COL-C) Synchronous abdominal/ peritoneal metastases y Obstructed imminent obstruction Colon resectione Diverting colostomy Bypass of impending obstruction Stenting See Chemotherapy f Advanced Metastatic Disease (COL-C) e See Principles of Surgery (COL-B 2 of 3). y Aggressive cyteductive debulking and/ intraperitoneal chemotherapy are not recommended outside the setting of a clinical trial. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-8

15 Table of Contents RECURRENCE WORKUP Serial CEA elevation Physical exam Colonoscopy Chest/abdominal/ pelvic CT Consider PET scan Negative findings Positive findings PET scan Reevaluate chest/ abdominal/pelvic CT in 3 mo See treatment f Documented metachronous metastases COL-10 Negative findings Positive findings See treatment f Documented metachronous metastases COL-10 Documented metachronous metastasesz by CT, MRI and/ biopsy See treatment f Documented metachronous metastases COL-10 z Determination of tum KRAS gene status. See Principles of Pathologic Review (COL-A 3 of 4) - KRAS Mutation Testing. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-9

16 Table of Contents PRIMARY TREATMENT Resectable e See Primary Treatment COL-11 Documented metachronous metastases by CT, MRI and/ biopsy z,aa Unresectable (potentially convertiblee unconvertible) Previous adjuvant FOLFOX within past 12 months Previous adjuvant FOLFOX > 12 months Previous 5-FU/LV capecitabine No previous chemotherapy FOLFIRI ± bevacizumab FOLFIRI ± cetuximab (KRAS WT gene only) Active chemotherapy regimen ( See COL-C) Re-evaluate f conversion to resectablee every 2 mo Converted to resectable e Remains unresectable Resection w Active chemotherapy regimen ( See COL-C) Observation Active chemotherapy regimenbb ( See COL-C) Observation e See Principles of Surgery (COL-B 2 of 3). w Hepatic artery infusion ± systemic 5-FU/leucovin (categy 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of this procedure. zdetermination of tum KRAS gene status. See Principles of Pathologic Review (COL-A 3 of 4) - KRAS Mutation Testing. aapatients should be evaluated by a multidisciplinary team including surgical consultation f potentially resectable patients. bbtotal perioperative therapy should be considered f a maximum of 6 months. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-10

17 Table of Contents Resectable e,aa metachronous metastases PET scan Resectable e Unresectable No previous chemotherapy Previous chemotherapy Previous adjuvant FOLFOX within past 12 months Previous adjuvant FOLFOX > 12 months Previous 5-FU/LV capecitabine No previous chemotherapy PRIMARY TREATMENT Resection w Active chemotherapy regimen ( See COL-C) Neoadjuvant Response chemotherapy Resection (2-3 mo) w ( See COL-C) No response Resection w Neoadjuvant chemotherapy (2-3 mo) ( See COL-C) FOLFIRI ± bevacizumab FOLFIRI ± cetuximab (KRAS WT gene only) Active chemotherapy regimen ( See COL-C) Converted to resectable e Remains unresectable esee Principles of Surgery (COL-B 2 of 3). whepatic artery infusion ± systemic 5-FU/leucovin (categy 2B) is also an option at institutions with experience in both the surgical and medical oncologic aspects of this procedure. aapatients should be evaluated by a multidisciplinary team including surgical consultation f potentially resectable patients. bbtotal perioperative therapy should be considered f a maximum of 6 months. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Active chemotherapy regimen bb ( See COL-C) Observation Resection w Response No response bb Repeat initial chemotherapy bb Active chemotherapy regimen bb ( See COL-C) Observation Repeat initial chemotherapy bb Active chemotherapy regimen bb ( See COL-C) Observation Active chemotherapy regimen ( See COL-C) Observation Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-11

18 PRINCIPLES OF PATHOLOGIC REVIEW (1 of 4) Table of Contents Endoscopically removed malignant polyps A malignant polyp is defined as one with cancer invading through the muscularis mucosae and into the submucosa (pt1). ptis is not considered a malignant polyp. Favable histological features: grade 1 2, no angiolymphatic invasion and negative margin of resection. There is no consensus as to the definition of what constitutes a positive margin of resection. A positive margin has been defined as 1) tum < 1 mm from the transected margin, 2) tum < 2 mm from the transected margin, 3) tum cells present within the diathermy of the transected margin. 1-4 Unfavable histological features: grade 3 4, angiolymphatic invasion, a positive margin. - see positive margin definition above. There is controversy as to whether malignant colectal polyps with a sessile configuration can be successfully treated by endoscopic removal. The literature seems to indicate that endoscopically removed sessile malignant polyps have a significantly greater incidence of adverse outcomes (residual disease, recurrent disease, mtality, hematogenous metastasis, but not lymph node metastasis) than do polypoid malignant polyps. However, when one closely looks at the data, configuration by itself is not a significant variable f adverse outcome and endoscopically removed malignant sessile polyps with grade I II histology, negative margin, and no lymphovascular invasion can be successfully treated with endoscopic polypectomy. 3-7 Colon cancer appropriate f resection Histological confirmation of primary colonic malignant neoplasm Pathological stage The following parameters should be repted. Grade of the cancer Depth of penetration, (T) Number of lymph nodes evaluated and number positive (N) Status of proximal, distal, and peritoneal margins (radial) 8-9 See Staging (ST-1) See Lymph node evaluation and sentinel lymph node on page 2 of 4 COL-A See KRAS Mutation Testing page 3 of 4 COL-A See footnotes on page 4 of 4 COL-A Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-A 1 of 4

19 PRINCIPLES OF PATHOLOGIC REVIEW (2 of 4) Table of Contents Lymph node evaluation The AJCC and College of American Pathologists recommend examination of a minimum of 12 lymph nodes to accurately identify stage II colectal cancers The literature lacks consensus as to what is the minimal number of lymph nodes to accurately identify stage II cancer. The minimal number of nodes has been repted as >7, >9, >13, >20, > The number of lymph nodes retrieved can vary with age of the patient, gender, tum grade and tum site. 12 F stage II (pn0) colon cancer, if less than 12 lymph nodes are initially identified, it is recommended that the pathologist go back to the specimen and resubmit me tissue of potential lymph nodes. If 12 lymph nodes are still not identified, a comment in the rept should indicate that an extensive search f lymph nodes was undertaken. The pathologist should attempt to retrieve as many lymph nodes as possible. It has been shown that the number of negative lymph nodes is an independent prognostic fact f patients with stage IIIB and IIIC colon cancer. 20 Sentinel lymph node and detection of micrometastasis by immunohistochemistry Examination of the sentinal lymph node allows an intense histological and/ immunohistochemical investigation to detect the presence of metastatic carcinoma. Studies in the literature have been repted using multiple H & E sections and/ immunohistochemistry (IHC) to detect cytokeratin positive cells. While studies to date seem promising, there is no unifmity in the definition of what constitutes "true metastatic carcinoma." Confusion arises when isolated tums cells (ITC) have been considered micrometastatic disease in contraindication to true micrometastasis (tum aggregates > 0.2 mm to < 2 mm in size). The significance of detection of single cells by IHC alone is controversial. Some studies have considered these to be micrometastasis, however, consensus recommends these to be considered ITC and not micrometastatic disease While the 6th edition of the AJCC Cancer Staging26 manual considers "tum clusters" < 0.2 mm as isolated tum cells (pn0) and not metastatic carcinoma, some have challenged this. Some investigats believe that size should not effect the diagnosis of metastatic cancer. They believe that tum foci that show evidence of growth (eg, glandular differentiation, distension of sinus, stromal reaction) should be diagnosed as a lymph node metastasis regardless of size. 27 Hermanek et al28 proposed isolated tum cells to be defined as single tum cells small clusters (never me than a few cells clumped together) without evidence of extrasinusoidal stromal proliferation reaction and no contact with invasion of the vessel (lymphatic) wall. Some studies have shown that the detection of IHC cytokeratin positive cells in stage II (N0) colon cancer (defined by H & E) has a wse prognosis while others have failed to show this survival difference. In these studies, ITC were considered micrometastasis At the present time the use of sentinel lymph nodes and detection of cancer cells by IHC alone should be considered investigational and results used with caution in clinical management decisions ,29-33 See Malignant polyp, colon cancer appropriate f resection, and pathological stage on page 1 of 4 COL-A See KRAS Mutation Testing page 3 of 4 COL-A See footnotes on page 4 of 4 COL-A Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-A 2 of 4

20 PRINCIPLES OF PATHOLOGIC REVIEW (3 of 4) Table of Contents KRAS Mutation Testing Mutations in codons 12 and 13 in exon 2 of the coding region of the KRAS gene predict lack of response to therapy with antibodies targeted to the epidermal growth fact recept. 34,35 Testing f mutations in codons 12 and 13 should be perfmed only in labaties that are certified under the clinical labaty improvement amendments of 1988 (CLIA 88) as qualified to perfm high complex clinical labaty (molecular pathology) testing. No specific methodology is recommended (sequencing, hybridization, etc.). The testing can be perfmed on fmalin fixed paraffin embedded tissue. The testing can be perfmed on the primary colectal cancers and/ the metastasis as literature has shown that the KRAS mutations are similar in both specimen types. 36 Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. See footnotes on page 4 of 4 COL-A Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-A 3 of 4

21 Volk EE, Goldblum JR, Petras RE, et al. Management and outcome of patients with invasive carcinoma arising in colectal polyps. Gastroenterology 1995;109: Cooper HS, Deppisch LM, Gourley WK, et al. Endoscopically removed malignant colectal polyps: clinical pathological crelations. Gastroenterology 1995;108: Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk facts f an adverse outcome in early invasive colectal carcinoma. Gastroenterology 2004;127: Seitz U, Bohnacker S, Seewald S, et al. Is endoscopic polypectomy an adequate therapy f malignant colectal polyps? Presentation of 114 patients and review of the literature. Dis Colon Rectum 2004;47: Mson BC, Whiteway JE, Jones EA, et al. Histopathology and prognosis of malignant colectal polyps treated by endoscopic polypectomy. Gut 1984;25: Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic facts in colectal carcinomas arising in adenomas: implications f lesions removed by endoscopic polypectomy. Gastroenterology 1985;89: Netzer P, Binck J, Hammer B, et al. Significance of histological criteria f the management of patients with malignant colectal polyps. Scand J Gastroenterol 1997;323: Compton CC and Greene FL. The staging of colectal cancer: 2004 and beyond. Ca Cancer J Clin 2004;54: Compton CC, Fielding LP, Burgardt LJ, et al. Prognostic facts in colectal cancer. College of American pathologists consensus statement. Arch Pathol Lab Med 2000;124: Sobin HL, and Greene FL. TNM classification. Clarification of number of regional lymph node f pn0. Cancer 2001;92(2): Le Voyer TE, Sigurdson ER, Hamlin AL, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survery of intergroup trial INT J Clin Oncol 2003;21: Sarli L, Bader G, Lusco D, et al. Number of lymph nodes examined and prognosis of TNM stage II colectal cancer. European Journal of Cancer 2005;41: Swanson RS, Compton CC, Stewart AK, and Bland KI. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10: Chaplin S, Scerottini G-P, Bosman FT, Konstanda MT, Givel J PRINCIPLES OF PATHOLOGIC REVIEW (4 of 4) References C. F patients with Duke's B (TNM stage II) colectal carcinoma, examination of six fewer lymph nodes is related to po prognosis. Cancer 1998;83: Maurel J, Launoy G, Grosclaude P, et al. Lymph node harvest repting in patients with carcinoma of the large bowel. A French population-based study. Cancer 1998;82: Procard M, Panis Y, Malassagane B, et al. Assessing the effectiveness of mesectal excision in rectal cancer. Dis Colon Rectum 1998;41: Joseph NE, Sigurdson ER, Hamlin AL, et al. Accuracy of determining nodal negativity in colectal cancer on the basis of number of nodes retrieved on resection. Ann of Surg Oncol 2003;10: Goldstein NS. Lymph node recurrences from 2427 pt3 colectal resection specimens spanning 45 years. Recommendations f a minimum number of recovered lymph nodes based on predictive probabilities. Am J Surg Pathol 2002;26: Scott KWM and Grace RH. Detection of lymph node metastasis and colectal carcinoma befe and after fat clearance. Br J Surg 1989;76: Johnson PM, Pter GA, Ricciardi R and Baxter NN. Increasing negative lymph node count is independently associated with improved long term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 2006;24: Turner RR, Na DT, Trochas D, and Bilchik AJ. Colectal carcinoma in nodal staging. Frequency and nature of cytokeratin positive cells in sentinal and nonsentinal lymph nodes. Arch Pathol Lab Med 2003;127: Saha S, Van AG, Beutler T, et al. Sentinal lymph mapping techniques in colectal cancer. Sem Oncol 2004;31: Wood TF, Na DT, Mton DL, et al. One hundred consecutive cases of sentinal node mapping in early colectal carcinoma. Detection of missed micrometastasis. J Gastrointest Surg 2002;6: Wiese DA, Sha S, Badin J, et al. Pathological evaluation of sentinel lymph nodes in colectal carcinoma. Arch Pathol Lab Med 2000;124: Bertagnolli M, Miedema B, Redstone M, et al. Sentinal node staging of resectable colon cancer. Results of a multicenter study. Ann Surg 2004;240: Table of Contents AJCC Cancer Staging Manual, 6th ed. Greene FL, Page D, Balch C, et al (edits) Springer, New Yk, 2002:227. Jass JB, O'Brien MJ, Riddell RH, Snover DC, on behalf of the Association of Directs of Anatomic and Surgical Pathology. Recommendations f the repting of surgically resected specimens of colectal carcinoma. Hum Pathol 2007;38: Hermanek P, Hutter RVP, Sobin LH, Wittekind CH. Classification of isolated tum cells and micrometastasis. Cancer 1999;86: Noura S, Yamamoto H, Ohnishi T, et al. Comparative detection of lymph node micrometastasis of stage II colectal cancer by reverse transcriptase polymerase chain reaction in immunohistochemistry. J Clin Oncol 2002;20: Yasuda K, Adachi Y, Shiraishi N, et al. Pattern of lymph node micrometastasis and prognosis of patients with colectal cancer. Ann Surg Oncol 2001;8: Noura S, Yamamoto H, Miyake Y, et al. Immunohistochemical assessment of localization of frequency of micrometastasis in lymph nodes of colectal cancer. Clin Cancer Research 2002;8: Oberg A, Stenling R, Tavelin B, Lindmark G. Are lymph node micrometastasis of any clinical significance in Duke stages A and B colectal cancer? Dis Colon Rectum 1998;41: Greenson JK, Isenhart TCE, Rice R, et al. Identification of occult micrometastasis in pericolonic lymph nodes of Duke's B colectal cancer. Patient's using monoclonal antibodies against cytokeratin and CC49. Crelation with long term survival. Cancer 1994;73: Lievre A, Bachatte J-B, Blige V, et al. KRAS mutations as an independent prognostic fact in patients with advanced colectal cancer treated with Cetuximab. J Clin Oncol 2008;26: Amado IG, Wolf M, Peters M, et al. Wild-type KRAS is required f panitunumab efficacy in patients with metastatic colectal cancer. J Clin Oncol 2008;26: Etienne-Gimeldi M-C, Fmenta J-L, Francoual M, et al. KRAS mutations in treatment outcome in colectal cancer in patients receiving exclusive fluopyrimidine. Clin Cancer Research 2008;14: Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 08/12/ National Comprehensive Cancer Netwk, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any fm without the express written permission of. COL-A 4 of 4