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

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1 Clinical in Oncology V Continue

2 Table of Contents Panel Members * Paul F. Engstrom, MD/Chair Peter C. Enzinger, MD David P. Ryan, MD Fox Chase Cancer Center Dana-Farber/Brigham and Women s Cancer Center 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 J. Michael Berry, MD UCSF Helen Diller Family Comprehensive 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 Guidelines Panel Disclosures Marwan G. Fakih, MD Roswell Park Cancer Institute 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 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 Comprehensive 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, PhD Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Alan P. Venook, MD UCSF Helen Diller Family 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 , 12/11/ 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 , 12/11/ 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: Global Changes PET scan changed to PET-CT scan throughout. COL-2 Footnote g is new to the page, PET-CT does not supplant a contrast-enhanced diagnostic CT scan. COL-3 Footnote l is new to the page, Bevacizumab, cetuximab, panitumumab, irinotecan should not be used in the adjuvant setting f stage II III patients outside the setting of a clinical trial. (also applies to COL-4) Footnote m is new to the page, Testing f mismatch repair proteins (MMR) should be considered f all patients < 50 years of age. (also applies to COL-4) COL-5 Consideration of BRAF gene status was added to the wkup recommendations as an option, if KRAS is non-mutated. Footnote w was clarified that IV contrast should be used f a CT MRI. COL-6 Footnote y is new to the page, Patients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. (also applies f COL-7, COL-10, and COL-11) COL-9 Footnote cc modified to include consideration of BRAF testing as an option, if KRAS is non-mutated. (also applies to COL-10) COL-10 If a patient remains unresectable after primary treatment, the recommendation of observation was removed. (also applies to COL-11) COL-A 3 of 4 New section added f BRAF testing. COL-B 2 of 3 Bullet 8 modified to Confmal external beam radiation therapy may be considered in highly selected cases in the setting of a clinical trial and should not be used indiscriminately in patients who are potentially surgically resectable. COL-C 1 of 6 Footnote 2 is new to the page, PET-CT should not be used to monit progress of therapy. CT with contrast MRI is recommended. (also applies to COL-C 2 of 6) Footnote 9 is new to the page, Patients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. COL-C 2 of 6 Panitumumab (KRAS WT gene only) was added as an option f patients not appropriate f intensive therapy with a categy 2B designation. COL-C 3 of 6 Footnotes 2 and 9 are new to the page as noted above. Hecht reference in footnote 6 updated. Version , 12/11/ 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: COL-C 4 of 6 Notation added Bevacizumab may be safely given at a rate of 0.5 mg/kg/minute (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes) FOLFOX 4 (Goldberg reference) and FOLFIRI (Douillard reference) regimens removed from the options f chemotherapy regimens. Footnote modified relating to levoleucovin, While used in Europe, levoleucovin is not approved f colectal cancer in the United States. Leucovin 400 mg/m2is the equivalent of levoleucovin 200 mg/m 2. (also applies f COL-C 5 of 6, and COL-E 1 of 3) COL-C 5 of 6 Bolus 5-FU/leucovin (de Gramont reference) regimen removed from the options f chemotherapy regimens. Irinotecan dosing regimen changed from 4 weeks on and 2 weeks off, to 2 weeks on and 1 week off. COL-D The following bullet was added to the Principles of Risk Assessment, If considering only fluopyrimidine therapy, MMR testing recommended. See Colectal Screening Guidelines. COL-E 1 of 3 FOLFOX 4 (Andre reference) and bolus 5-FU/leucovin (IMPACT reference) regimens removed from the options f chemotherapy regimens. Simplified LV5FU2 (Andre reference) added as a regimen option. COL-E 2 of 3 Cassidy reference in footnote 5 added. COL-E 3 of 3 Bullet 2 modified to note FOLFOX is superi to fluopyrimidine therapy alone f stage III patients. Bullet 4 added, Bevacizumab, cetuximab, panitumumab, irinotecan should not be used in the adjuvant setting f stage II III patients outside the setting of a clinical trial. COL-F Bullet 3 modified to note that confmal external beam radiation should be routinely used and IMRT reserved only f unique clinical situations. Bullet 4 - If IORT not available, additional Gy replaced low dose. Clarification added with the addition of to a limited volume. COL-G 2 of 3 References 4-6 added. Version , 12/11/ 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 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 , 12/11/ 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

7 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-CT scan is not routinely indicated g 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 h 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. esee Principles of Surgery (COL-B 1 of 3). Back to Other Clinical gpet-ct does not supplant a contrast-enhanced diagnostic CT scan. Presentations hpalliative 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 , 12/11/ 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

8 Table of Contents PATHOLOGIC STAGE d Tis; T1, N0, M0; T2, N0, M0 T3, N0, M0j (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 Node positive disease, see page COL-4 ADJUVANT THERAPY i,k,l,m None Consider capecitabinen,o 5-FU/leucovinn,o Clinical trial Observation n 5-FU/leucovin/oxaliplatinn,o,p,q capecitabinen,o,q 5-FU/leucovinn,o,q Clinical trial Observationn SURVEILLANCE r Histy and physical every 3-6 mo f 2 y, then every 6 mo f a total of 5 y CEAs 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 recurrencer,t 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, u repeat in 3 y, then every 5 yv PET-CT 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. ithere are no data to suppt adjuvant therapy in Stage I disease, however certain high risk Stage II patients (lymphovascular invasion, poly differentiated histology, inadequate lymph node sampling) may be considered at higher risk and a discussion of chemotherapy may be warranted. jpatients considered to be N0 but who have < 12 nodes examined are suboptimally staged and should be considered in the high risk group. See Principles of Pathologic Review (COL-A) - Lymph node evaluation. kthere are insufficient data to recommend the use of multi-gene assay panels to determine adjuvant therapy. lbevacizumab, cetuximab, panitumumab, irinotecan should not be used in the adjuvant setting f stage II III patients outside the setting of a clinical trial. mtesting f mismatch repair proteins (MMR) should be considered f all patients < 50 years of age. nsee Principles of Risk Assessment f Stage II Disease (COL-D). osee Principles of Adjuvant Therapy (COL-E). ptreatment 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. qconsider RT f T4 with penetration to a fixed structure. See Principles of Radiation Therapy COL-F. rdesch 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: sif patient is a potential candidate f further intervention. tct scan may be useful f patients at high risk f recurrence (eg, lymphatic venous invasion by tum, poly differentiated tums). uvillous polyp, polyp > 1 cm, high grade dysplasia. vrex 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 , 12/11/ 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

9 Table of Contents PATHOLOGIC STAGE d ADJUVANT THERAPY k,l,m SURVEILLANCE r T1-3, N1-2, M0 T4, N1-2, M0 5-FU/leucovin/oxaliplatin (categy1) o,p,q Capecitabineo,q 5-FU/leucovino,q Histy and physical every 3-6 mo f 2 y, then every 6 mo f a total of 5 y CEAs 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 recurrencer,t 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, u repeat in 3 y, then every 5 yv PET-CT 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. kthere are insufficient data to recommend the use of multi-gene assay panels to determine adjuvant therapy. lbevacizumab, cetuximab, panitumumab, irinotecan should not be used in the adjuvant setting f stage II III patients outside the setting of a clinical trial. mtesting f mismatch repair proteins (MMR) should be considered f all patients < 50 years of age. osee Principles of Adjuvant Therapy (COL-E). ptreatment 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. qconsider RT f T4 with penetration to a fixed structure. See Principles of Radiation Therapy COL-F. rdesch 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: sif patient is a potential candidate f further intervention. tct scan may be useful f patients at high risk f recurrence (eg, lymphatic venous invasion by tum, poly differentiated tums). uvillous polyp, polyp > 1 cm, high grade dysplasia. vrex 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 , 12/11/ 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

10 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 CTw CBC, platelets, chemistry profile CEA Determination of tum KRAS gene status (if KRAS non-mutated, consider BRAF testing) d Needle biopsy, if clinically indicated PET-CT 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 w See Principles of Pathologic Review (COL-A 3 of 4) - KRAS and BRAF Mutation Testing. See Principles of Surgery (COL-B 2 of 3). CT should be with IV contrast. Consider MRI with IV 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 , 12/11/ 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

11 Table of Contents TREATMENT Resectablee synchronous liver and/ lung metastases only ADJUVANT THERAPY SURVEILLANCE (resected metastatic disease) (6 mo perioperative treatment preferred) Colectomy, with synchronous staged liver lung resection Neoadjuvant therapy (f 2-3 months) FOLFIRI FOLFOX CapeOX w ± bevacizumabx FOLFIRI FOLFOX CapeOX w ± cetuximab (KRAS wild-type gene only) d,y followed by synchronous staged colectomy and resection of metastatic disease Colectomy, followed by chemotherapy (f 2-3 months) FOLFIRI FOLFOX CapeOXw ± bevacizumabx FOLFIRI FOLFOX CapeOX w ± cetuximab (KRAS wild-type gene only) d,y and staged resection of metastatic disease Active chemotherapy regimen f advanced disease ( See Chemotherapy f Advanced Metastatic Disease (COL-C) z,aa (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, u repeat in 3 y, then every 5 yv 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 and BRAF Mutation Testing. esee Principles of Surgery (COL-B 2 of 3). uvillous polyp, polyp > 1 cm, high grade dysplasia. vrex 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): wthe 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. xthe 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. ypatients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. zhepatic 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. aafolfoxiri 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 , 12/11/ 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

12 Table of Contents TREATMENT Unresectable synchronous liver and/ lung metastases only Systemic therapy (FOLFIRI FOLFOX CapeOX w± bevacizumabx FOLFIRI FOLFOX CapeOX w ± cetuximab [KRAS wild-type gene only] d,y FOLFOXIRI [categy 2B] ) Consider colon resectione only if imminent risk of obstruction significant bleeding a Re-evaluate f conversion to resectablee every 2 mo if conversion to resectability is a reasonable goal 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) z (categy 2B) Consider observation shtened course of chemotherapy, if patient received neoadjuvant therapy 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. 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, u repeat in 3 y, then every 5 yv Recurrence (See COL-9) 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 and BRAF Mutation Testing. esee Principles of Surgery (COL-B 2 of 3). uvillous polyp, polyp > 1 cm, high grade dysplasia. vrex 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): wthe 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. xthe 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. ypatients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. zhepatic 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. Version , 12/11/ 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

13 Table of Contents FINDINGS PRIMARY TREATMENT Nonobstructing See Chemotherapy f Advanced Metastatic Disease (COL-C) Synchronous abdominal/ peritoneal metastases bb 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). bb 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 , 12/11/ 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

14 Table of Contents RECURRENCE WORKUP Serial CEA elevation Physical exam Colonoscopy Chest/abdominal/ pelvic CT Consider PET-CT scan Negative findings Positive findings Consider PET-CT 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 metastasescc by CT, MRI and/ biopsy See treatment f Documented metachronous metastases COL-10 cc Determination of tum KRAS (if KRAS non-mutated, consider BRAF testing). See Principles of Pathologic Review (COL-A 3 of 4) - KRAS and BRAF 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 , 12/11/ 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

15 Table of Contents PRIMARY TREATMENT Resectable f See Primary Treatment COL-11 Documented metachronous metastases by CT, MRI and/ biopsy cc,dd 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) d,y Active chemotherapy regimen ( See COL-C) Re-evaluate f conversion to resectablee every 2 mo if conversion to resectability is a reasonable goal Converted to resectable e Remains unresectable Resection z Active chemotherapy regimen ( See COL-C) Active chemotherapy regimenee ( See COL-C) Observation d e y z See Principles of Pathologic Review (COL-A 3 of 4) - KRAS and BRAF Mutation Testing. See Principles of Surgery (COL-B 2 of 3). Patients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. 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. Determination of tum KRAS (if KRAS non-mutated, consider BRAF testing). See Principles of Pathologic Review (COL-A 3 of 4) - KRAS and BRAF Mutation Testing. Patients should be evaluated by a multidisciplinary team including surgical consultation f potentially resectable patients. Total perioperative therapy should be considered f a maximum of 6 months. cc dd ee 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 , 12/11/ 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

16 Table of Contents PRIMARY TREATMENT Resectable e,dd metachronous metastases Consider PET-CT 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 Resection z Neoadjuvant chemotherapy (2-3 mo) ( See COL-C) Resection z Neoadjuvant chemotherapy (2-3 mo) ( See COL-C) FOLFIRI ± bevacizumab FOLFIRI ± cetuximab (KRAS WT gene only) d,y Active chemotherapy regimen ( See COL-C) Active chemotherapy regimen ee ( See COL-C) Repeat initial Response chemotherapy Resection z No response Active chemotherapy regimen ee ( See COL-C) Observation Response Resection z Re-evaluate f conversion to resectablee every 2 mo if conversion to resectability is a reasonable goal No response Converted to resectable e Unresectable Active chemotherapy regimenee ( See COL-C) Observation Repeat initial chemotherapy Active chemotherapy regimenee ( See COL-C) Observation Active chemotherapy regimen ( See COL-C) d See Principles of Pathologic Review (COL-A 3 of 4) - KRAS and BRAF Mutation Testing. See Principles of Surgery (COL-B 2 of 3). Patients with a known V600E BRAF mutation appear to be unlikely to benefit from anti-egfr monoclonal antibodies. e y zhepatic 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. ddpatients should be evaluated by a multidisciplinary team including surgical consultation f potentially resectable patients. eetotal 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 , 12/11/ 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

17 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 radial margins8-9 See Staging (ST-1) See Lymph node evaluation and sentinel lymph node on page 2 of 4 COL-A See KRAS and BRAF 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 , 12/11/ 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

18 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 and BRAF 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 , 12/11/ 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

19 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 BRAF Mutation Testing Recent small studies suggest that patients with wt KRAS and a BRAF mutation are unlikely to respond to therapy with antibodies targeted to the epidermal growth fact recept. 37,38 Testing f the BRAF V600E mutation can be perfmed on fmalin fixed paraffin embedded tissues. This is usually perfmed by PCR amplification and direct DNA sequence analysis. This testing should be perfmed only in labaties that are certified under the clinical labaty improvement amendments of 1988 (CLIA-88) and qualified to perfm highly complex clinical labaty (molecular pathology) 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. See footnotes on page 4 of 4 COL-A Version , 12/11/ 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

20 PRINCIPLES OF PATHOLOGIC REVIEW (4 of 4) References 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;92:452. 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-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: Table of Contents 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: 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: Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required f response to panitumumab cetuximab in metastatic colectal cancer. J Clin Oncol 2008;26: Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colectal cancer. Br J Cancer 2009;101: 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 , 12/11/ 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