Grupo COI - Colon and Rectal Cancer Guideline by Carlos Felipe Braga Pinto

Medical Oncology Guidelines

COI Colon and Rectal Cancer Guideline

COI Colon and Rectal Cancer Guideline TNM DEFINITION AJCC 7th edition, 2010 Tx

Primary tumor cannot be assessed

No evidence of primary tumor

Tis

Carcinoma in situ: intraepithelial or invasion of lamina propria¹

Tumor invades submucosa

Tumor invades muscularis propria

Tumor invades through the muscularis propria into pericolorectal tissues

T4a

Tumor penetrates to the surface of the visceral peritoneum²

T4b

Tumor directly invades or is adherent to orther organs or structures² ³

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Metastasis in 1-3 regional lymph nodes

N1a

Metastasis in one regional lymph node

N1b

Metastasis in 2-3 regional lymph nodes

N1c

Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis

Metastasis in 4 or more regional lymph nodes

N2a

Metastasis in 4-6 regional lymph nodes

N2b

Metastasis in 7 or more regional lymph nodes

No distant metastasis

Distant metastasis

M1a

Metastasis confined to one organ or site (for example, liver, lung, ovary, nonregional node)

M1b

Metastases in more than one organ/site or the peritoneum

! TNM CATEGORIES

Tis

T1 T2

N0 N0

M0 M0

IIA

IIB

T4a

IIC

T4b

IIIA

T1-T2 T1

N1/N1c N2a

M0 M0

IIIB

T3-T4a T2-T3 T1-T2

N1/N1c N2a N2b

M0 M0 M0

IIIC

T4a T3-T4a T4b

N2a N2b N1-N2

M0 M0 M0

IVA

Any T

Any N

M1a

IVB

Any T

Any N

M1b

NOTE: cTNM is the clinical classification, pTNM is the pathologic classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (for example, ypTNM). Patients who have a complete pathologic response are ypTONOcMO that may be similar to Stage Group 0 or 1. The r prefix is to be used for those cancers that have recurred after a disease-free interval (rTNM). *Dukes B is a composite of better (T3 NO MO) and worse (T4 N0 M0) prognostic groups, as is Dukes C (any TN1 M0 and Any T N2 M0). MAC is the modified Astler-Coller classification

RECTAL CANCER MID AND LOW RECTAL CANCER Location of rectal tumors: Low rectal cancer: up until 5 cm of the anal verge Mid rectal cancer: 5 to 10 cm of the anal verge High rectal cancer: 10 to 15 cm of the anal verge – peritonization on the anterior and lateral portions. High rectal cancer will be treated as colon cancer. In this situation radiotherapy will not be recommended.

INITIAL DISEASE STAGING I Initial Evaluation: - Colonoscopy - Rectal NMR - Thorax, upper abdomen and pelvic CT - Laboratory tests including CBC, liver and kidney functions, LDH and CEA - PET-CT – in patients with potentially resectable metastasis - Endorectal ultrasound, if available, if it is a N0 radiological disease TREATMENT ALGORITHM T1Nx, negative margins

Follow-up

Transanal Resection *

T1Nx

T1Nx, high risk² T2Nx

T2Nx

T1/2N0

Follow-up

T3/4 or N+

chemotherapy and radiotherapy4

Transabdominal resection***

1 Criteria for transanal excision: <3cm in the greater diameter, margin >3mm, mobile, nonfixed, within 8cm distant from anal verge, T1 only, endoscopically removed polyp with cancer or indeterminate pathology, absence of lymphovascular or perineural invasion, well or moderately differentiated and with no evidence of lymphadenopathy at staging 2 High risk criteria: lymphovascular invasion, poorly differentiated, positive margins or invasion of the third layer of submucosa 3 Abdominoperineal resection or lower anterior resection or coloanal anastomosis, with total mesorectum excision is recommended 4 Adjuvant treatment duration: 6 months

CHEMOTHERAPY AND RADIOTHERAPY (RT) REGIMENS:

mFOLFOX6 or

XELOX or

5FU/leucovorin or

Infusional 5 FU/RT or 5FU bolus/RT or

capecitabine

capecitabine/RT

mFOLFOX6 or XELOX or 5FU/leucovorin or capecitabine

Infusional 5 FU/RT or 5 FU bolus/ RT or capecitabine/RT

mFOLFOX6 or XELOX or 5FU/leucovorin or capecitabine 1- Adjuvant chemotherapy regimens containing oxaliplatin are based on the extrapolation of adjuvant chemotherapy regimens for colon cancer. 2- Discuss with multidisciplinary team the best moment to start chemotherapy and radiotherapy combination during adjuvant treatment.

CHEMOTHERAPY REGIMENS

1- mFOLFOX6 Oxaliplatin 85 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 day 1 and 5FU 2400 mg/m2 for 46 hours in continuous infusion by infusion pump, every two weeks. *Check CBC on D1 ** Check neuropathy on D1 *** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion 2- XELOX Oxaliplatin 130 mg/m2 day 1 and Capecitabine 1000 mg/m2 twice a day, D1-D14 every 3 weeks *Check CBC on D1 ** Check neuropathy on D1 *** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion 3- 5FU/leucovorin 5FU 370mg/m2 and leucovorin 50mg (fixed dose), every week Or 5FU 500 mg/m², Leucovorin 500 mg/ m², once a week, for 6 weeks, every 8 weeks *Check CBC every 21 days

4- Capecitabine Capecitabine 1000 mg/m2 twice a day, D1-D14 every 3 weeks * Check CBC on D1 ** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet 5- Infusional 5FU/RT 5FU 225 mg/m²/day, in continuous infusion, concomitant with radiotherapy * Check CBC weekly **Check for radiotherapy cutaneous toxicity every week. 6- Bolus 5FU/RT Bolus 5-FU 350 mg/m²/day, Leucovorin 500 mg/m², for 5 days, on RT weeks 1 and 5 * Check CBC prior to weeks 1 and 5 ** Check for radiotherapy cutaneous toxicity every week 7- Capecitabine/RT Capecitabine 825 mg/m2 twice a day, on RT days * Check CBC weekly ** Check for radiotherapy cutaneous toxicity every week *** Check for hand-foot syndrome – prophylactic recommendation of moisturizing hands and feet

LOCALLY ADVANCED DISEASE STAGE II/III Initial Evaluation: - Colonoscopy - Rectal NMR - Thorax, upper abdomen and pelvic CT - Laboratory tests including CBC, liver and kidney functions, LDH and CEA - PET-CT – in patients with potentially resectable metastasis - Endorectal ultrasound, if available, if it is a N0 radiological disease

TREATMENT ALGORITHM

¹ Total duration of perioperative treatment is 6 months (adjuvant treatment is about 4 months) ² The wait and see strategy in case of total clinical response after chemotherapy and radiotherapy is not recommended as a routine procedure because of the lack of proper prospective control studies.

CHEMOTHERAPY AND RADIOTHERAPY (RT) REGIMENS

Infusional 5 FU/RT or 5 FU bolus/ RT or capecitabine/RT

SURGERY

mFOLFOX6 or

XELOX or

5FU/leucovorin or

capecitabine

CHEMOTHERAPY REGIMENS 1- mFOLFOX6 Oxaliplatin 85 mg/m2 day 1 IV, Leucovorin 400 mg/m2 day 1 IV, 5FU 400 mg/m2 day 1 IV and 5FU 2400 mg/m2 IV for 46 hours, every two weeks *Check CBC before D1 ** Check neuropathy before D1 *** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: N Engl J Med 2004;350:2343-2351 Br J Cancer 2002;87:393-399

2- XELOX Oxaliplatin 130 mg/m2 day 1 IV and Capecitabine 1000 mg/m2 PO twice a day D1-D14, every 3 weeks *Check CBC before D1 ** Check neuropathy before D1 *** Check for hand-foot syndrome before D1– prophylactic recommendation of moisturizing hands and feet **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2011;29:1465-1471

3- 5FU/leucovorin 5FU 370mg/m2 day 1 IV and Leucovorin 50mg (fixed dose) day 1 IV, once a week Ref: Lancet 2007;370:2020-2029

4- Capecitabine Capecitabine 1000 mg/m2 PO twice a day, D1-D14 every 3 weeks * Check CBC before D1 ** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet Ref: N Engl J Med 2005;352:2696-2704

5- Infusional 5FU/RT 5FU 225 mg/m²/day, IV, concomitant with radiotherapy * Check CBC weekly **Check for radiotherapy cutaneous toxicity every week. Ref: N Engl J Med 1994; 331:502-507

6- Bolus 5FU/RT Bolus 5-FU 350 mg/m²/day IV, Leucovorin 500 mg/m² IV, for 5 days, on RT weeks 1 and 5 * Check CBC before weeks 1 and 5 ** Check for radiotherapy cutaneous toxicity every week Ref: J Clin Oncol 2002;20:1744-1750

7- Capecitabine/RT Capecitabine 825 mg/m2 PO twice a day, on RT days * Check CBC weekly ** Check for radiotherapy cutaneous toxicity every week *** Check for hand-foot syndrome – prophylactic recommendation of moisturizing hands and feet Ref: Lancet Oncol 2012;13:579-588

ADVANCED DISEASE STAGE IVA/IVB Initial Evaluation: - Colonoscopy - Rectal MRI - Thorax, upper abdomen and pelvic CT - Laboratory tests including CBC, liver and kidney functions, LDH and CEA - PET-CT – in patients with potentially resectable metastasis - NRAS mutation (exon 2, 3 and 4) and KRAS mutation (exon 2, 3 and 4) testing TREATMENT ALGORITHM

Symptomatic rectum disease

Local treatment/colostomy²

chemotherapy ± antibody³,4

Unresectable metastasis¹ Asymptomatic rectum disease

Potentially resectable metastasis5

Resectable metastasis5

chemotherapy ± antibody³,4

metastasis / rectum surgery

chemotherapy and radiotherapy

chemotherapy and radiotherapy6

metastasis / rectum surgery

Chemotherapy and radiotherapy6

metastasis / rectum surgery

Chemotherapy8

metastasis / rectum surgery

Chemotherapy2 and radiotherapy

Chemotherapy8

metastasis / rectum surgery

Chemotherapy ± Antibody3,4

Chemotherapy7 and radiotherapy

Chemotherapy8

1 Case discussion with multidisciplinary team to adjust treatment sequence. 2 Consider radiotherapy, chemotherapy and radiotherapy, surgery and stent 3 Antibody selection based on status NRAS and KRAS mutation status. 4 Reassess response to determine the possibility of ressecability every 2-3 months. Sequencing of the treatment for persistent non resectable metastasis is described in colon cancer routine (check NRAS and KRAS mutation status) 5 Case discussion with multidisciplinary team to adjust treatment sequence. Assess the need for initial local treatment of primary tumor according to symptomatology 6 Isolated short course radiotherapy should be considered 7 Oxaliplatin-based chemotherapy is an option except during radiotherapy 8 Oxaliplatin-based chemotherapy – 6 month perioperative treatment

CHEMOTHERAPY ± ANTIBODY REGIMENS - FOLFIRI or mFOLFOX6 or XELOX ± bevacizumab - FOLFOXIRI ± bevacizumab - FOLFIRI or FOLFOX ± cetuximab or panitumumab (only if KRAS/NRAS wild-type)³ 1 Reassess response every 2 to 3 months 2 In case of unresectable disease the patient should be treated until maximum response or toxicity. Following this, maintenance should be carried out with fluoropyrimidine and antibody. 3 Panitumumab is a completely human anti-EGFR monoclonal antibody, with lower incidence of severe allergic reactions. Also consider cases of allergic reaction to cetuximab. In treatments with panitumumab, associate it to chemotherapy with FOLFOX. 4 Sequencing of the treatment for persistent non resectable metastasis is described in colon cancer routine

POSTOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY (RT) REGIMENS

mFOLFOX6 or XELOX

Infusional 5FU/RT or Bolus 5FU/RT or capecitabine/RT

mFOLFOX6 or XELOX Infusional 5FU/RT or Bolus 5FU/RT or capecitabine/RT

mFOLFOX6 or XELOX

Infusional 5FU/RT or Bolus 5FU/RT or capecitabine/RT

1 Perioperative chemotherapy for 6 months. 2 Postoperative chemotherapy regimens are based on the extrapolation of adjuvant chemotherapy regimens for colon cancer 3 Discuss with multidisciplinary team the best moment to start chemotherapy and radiotherapy combination during treatment.

POSTOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY (RT) REGIMENS

Infusional 5FU /RT or Bolus 5FU/RT or capecitabine/RTยน POSTOPERATIVE CHEMOTHERAPY REGIMEN FOLFOX or XELOX 1 The chemotherapy regimen prior to surgery can be considered based on metastasis sensitivity

CHEMOTHERAPY AND ANTIBODY REGIMENS 1- FOLFIRI Irinotecan 180 mg/m² IV, leucovorin 400 mg/m² IV and 5-FU 400 mg/m² IV, on day 1 and 5-FU 2400 mg/m² IV for 46 h, every 2 weeks *Check CBC and bilirubin before D1 ** Premedication with atropine 0.25 to 1.0 mg to avoid acute cholinergic symptoms or diarrhea. Ref: J Clin Oncol 2004;22:229-237and Lancet Oncol 2014;10:1065-1075 2- mFOLFOX6 Oxaliplatin 85 mg/m2 day 1 IV, leucovorin 400 mg/m2 day 1 IV, 5FU 400 mg/m2 day 1 IV and 5FU 2400 mg/m2 IV for 46 hours, every two weeks *Check CBC before D1 ** Check neuropathy before D1 *** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2008;26:3523-3529, J Clin Oncol 2014;32(Suppl 5): Abstract LBA3 and Lancet 2008; 371: 1007–1016 3- XELOX Oxaliplatin 130 mg/m2 day 1 IV and Capecitabine 1000 mg/m2 PO twice a day, D1-D14 every 3 weeks *Check CBC before D1 ** Check neuropathy before D1 *** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2008; 26:2013-2019 4- Bevacizumab Bevacizumab 5 mg/kg IV every 2 weeks Bevacizumab 7.5 mg/kg IV, every 3 weeks – when administered with XELOX *Monitor blood pressure before D1 **Urine dipstick analysis before D1 – protein presence ≥ 2+ - colect 24-hour urine – if there is protein presence, no restriction to release from treatment ≤ 2+ ***Stop 42 days prior to major surgery. Start only 28 days after major surgery. Ref: Lancet Oncol 2014;10:1065-1075, J Clin Oncol 2014;32:5s (abstr LBA3) and J Clin Oncol 2008;26:2013-2019 5- Cetuximab Cetuximab 500 mg/m² IV every 2 weeks * Premedication with diphenhydramine 50mg and dexamethasone 20mg **Check magnesium every 2 cycles ***Check for cutaneous rash before D1 **** Recommendation for the use of sunscreen and skin moisturizing. Consider primary prophylaxys of cutaneous rash. Ref: Lancet Oncol 2014;10:1065-1075, J Clin Oncol 2014;32:5s (abstr LBA3) and J Clin Oncol 2011; 29:2011-2019 6- Panitumumab Panitumumab 6 mg/kg IV every 2 weeks In case of first line treatment – only with FOLFOX *Check magnesium every 2 cycles **Check for cutaneous rash before D1 ***Recommendation for the use of sunscreen and skin moisturizing. Consider primary prophylaxys of cutaneous rash. Ref: N Engl J Med 2013;369:1023-1034

7- FOLFOXIRI Irinotecan 165 mg/m² IV, oxaliplatin 85 mg/m² IV, 5-FU 400 mg/m² IV and leucovorin 200 mg/m² IV, on day 1 and 5-FU 3.200 mg/m² IV for 46h, every 2 weeks *Check CBC and bilirubin before D1 ** Premedication with atropine 0.25 to 1.0 mg to avoid acute cholinergic symptoms or diarrhea. *** Check neuropathy before D1 **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2007;25(13):1670-1676 and J Clin Oncol 2013;31(Suppl 4): Abstract 336 8- Infusional 5FU/RT 5FU 225 mg/m²/day IV, in continuous infusion, concomitant with radiotherapy * Check CBC weekly **Check for radiotherapy cutaneous toxicity every week. Ref: N Engl J Med 1994; 331:502-507 9- Bolus 5FU/RT Bolus 5-FU 350 mg/m²/day IV, Leucovorin 500 mg/m² IV, for 5 days, on RT weeks 1 and 5 * Check CBC prior to weeks 1 and 5 ** Check for radiotherapy cutaneous toxicity every week Ref: J Clin Oncol 2002;20:1744-1750 10- Capecitabine/RT Capecitabine 825 mg/m2 PO twice a day, on RT days * Check CBC weekly ** Check for radiotherapy cutaneous toxicity every week *** Check for hand-foot syndrome – prophylactic recommendation of moisturizing hands and feet Ref: Lancet Oncol 2012;13:579-588

COLON CANCER High rectal cancer treatment will be the same as colon cancer treatment. MANAGEMENT OF ADENOMA WITH INVASIVE CARCINOMA (POLYP) Non-fragmented, completely removed polyp, with negative margins and absence of unfavorable histologic Features¹

Pedunculated polyp

Follow up

Sessile polyp Fragmented polyp, positive margins or unfavorable histologic features¹

Colectomy

Pathologic staging

1 Unfavorable histologic features: grade 3, lymphovascular invasion and positive margins

INITIAL DISEASE STAGE I, II AND III Initial Evaluation: - Colonoscopy - Thorax, upper abdomen and pelvic CT - Laboratory tests including CBC, liver and kidney functions, LDH and CEA TREATMENT ALGORITHM Stage I

Surgery¹

Follow up

Low risk stage II² Stage II

Surgery High risk stage II²

Stage III

Follow up

Surgery

Adjuvant chemotherapy5,6

Adjuvant chemotherapy3,4,5

1 At least 12 assessed negative lymph nodes 2 High risk criteria: grade 3, less than 12 assessed lymph nodes, lymphatic, vascular or perineural invasion, T4 disease, obstruction, positive margins and perforation 3 Whenever possible assess microsatellite instability (MSI). Patients with high microsatellite instability (MSI – H) may not have the benefit of adjuvant chemotherapy. 4 Adjuvante chemotherapy without oxaliplatin (fluoropyrimidine alone) 5 Adjuvant treatment should be started preferably 4 weeks after surgery. Delay in starting treatment is directly related to lower survival rates. 6 Adjuvante chemotherapy with fluoropyrimidine and oxaliplatin. A benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients age 70 and older has not been proven – consider comorbidities and performance status

CHEMOTHERAPY REGIMENS

5FU/leucovorin or capecitabine¹ mFOLFOX6 ou XELOX ou mFLOX2,3 1 Adjuvante therapy for stage II disease 2 Adjuvante therapy for stage III disease 3 More diarrhea with FLOX than with FOLFOX 4 Total duration of adjuvant treatment is 6 months

CHEMOTHERAPY REGIMENS 1- 5FU/leucovorin 5FU 370mg/m2 IV and leucovorin 50mg (fixed dose) IV, every week, 30 weeks *Check CBC every 21 days Ref: Lancet 2007; 370:2020-2029 2- Capecitabine Capecitabine 1000 mg/m2 PO twice a day, D1-D14 every 3 weeks, 8 cycles * Check CBC before D1 ** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet Ref: N Engl J Med 2005;352:2696-2704 3- mFOLFOX6 Oxaliplatin 85 mg/m2 day 1 IV, Leucovorin 400 mg/m2 day 1 IV, 5FU 400 mg/m2 day 1 IV and 5FU 2400 mg/m2 IV for 46 hours, every two weeks, 12 cycles *Check CBC before D1 ** Check neuropathy before D1 *** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: N Engl J Med 2004;350:2343-2351 Br J Cancer 2002;87:393-399

4- XELOX Oxaliplatin 130 mg/m2 day 1 IV and Capecitabine 1000 mg/m2 PO twice a day D1-D14, every 3 weeks, 8 cycles *Check CBC before D1 ** Check neuropathy before D1 *** Check for hand-foot syndrome before D1– prophylactic recommendation of moisturizing hands and feet **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2011;29:1465-1471 3 – mFLOX Oxaliplatin 85 mg/m²IV, on weeks 1, 3 and 5, every 8 weeks, 5-FU 500 mg/m² IV and leucovorin 20 mg/m² IV on weeks 2,4 and 6, every 8 weeks, 3 cycles *Check CBC before D1, D3 and D15 ** Check neuropathy on D1, D15 and D29 ***Recommendation for oxaliplatin treatments - patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2007;25:2198-2204

ADVANCED DISEASE STAGE IVA/IVB Initial Evaluation: - Colonoscopy - Rectal NMR - Thorax, upper abdomen and pelvic CT - Laboratory tests including CBC, liver and kidney functions, LDH and CEA - PET-CT – in patients with potentially resectable metastasis - NRAS mutation (exon 2, 3 and 4) and KRAS mutation (exon 2, 3 and 4) testing TREATMENT ALGORITHM Symptomatic primary tumor¹

Surgery or local procedures²

Asymptomatic primary tumor

Chemotherapy ±antibody

Surgery

Postoperative chemotherapy

Preoperative chemotherapy3

Surgery

Synchronous metastasis

Resectable metastasis Preoperative chemotherapy3

Potentially resectable metastasis

Resectable

Surgery

Non-resectable

Chemotherapy ±antibody

Postoperative chemotherapy

Chemotherapy ±antibody4,5

1 Obstructed or imminent obstruction 2 Resection, ostomy or stent 3 It is not recommended to use monoclonal antibodies in perioperative chemotherapy 4 Antibody selection based on status NRAS and KRAS mutation status 5 Reassess response to determine the possibility of ressecability every 2-3 months

TREATMENT ALGORITHM

Non-resectable metastasis NRAS/KRAS wild-type

Non-resectable metastasis NRAS/KRAS mutation

Chemotherapy + bevacizumab

Chemotherapy + cetuximab or panitumumab

Chemotherapy + bevacizumab

Panitumumab or Cetuximab ± Irinotecan

1 In selected case, consider capecitabine and bevacizumab as first line treatment, for elderly patients 2, 4 Reassess response every 2-3 months.

PREOPERATIVE AND POSTOPERATIVE CHEMOTHERAPY REGIMEN FOLFOX or XELOX 1 Total duration of perioperative treatment should be 6 months (for 2 to 3 months prior to surgery and for 3 to 4 months after surgery, until the completion of 12 cycles)

CHEMOTHERAPY ± ANTIBODY REGIMENS FOLFIRI or mFOLFOX6 or XELOX ± bevacizumab FOLFOXIRI ± bevacizumab 3 FOLFIRI or FOLFOX ± cetuximab or panitumumab (only if KRAS/NRAS wild-type) 1 Reassess response every 2 to 3 months 2 In case of unresectable disease the patient should be treated until maximum response or toxicity. Following this, maintenance should be carried out with fluoropyrimidine and antibody. 3 Panitumumab is a completely human anti-EGFR monoclonal antibody, with lower incidence of severe allergic reactions. Also consider cases of allergic reaction to cetuximab. In treatments with panitumumab, associate it to chemotherapy with FOLFOX.

CHEMOTHERAPY AND ANTIBODY REGIMENS 1- FOLFIRI Irinotecan 180 mg/m² IV, leucovorin 400 mg/m² IV and 5-FU 400 mg/m² IV, on day 1 and 5-FU 2400 mg/m² IV for 46 h, every 2 weeks *Check CBC and bilirubin before D1 ** Premedication with atropine 0.25 to 1.0 mg to avoid acute cholinergic symptoms or diarrhea. Ref: J Clin Oncol 2004;22:229-237and Lancet Oncol 2014;10:1065-1075 2- mFOLFOX6 Oxaliplatin 85 mg/m2 day 1 IV, leucovorin 400 mg/m2 day 1 IV, 5FU 400 mg/m2 day 1 IV and 5FU 2400 mg/m2 IV for 46 hours, every two weeks *Check CBC before D1 ** Check neuropathy before D1 *** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2008;26:3523-3529, J Clin Oncol 2014;32(Suppl 5): Abstract LBA3 and Lancet 2008; 371: 1007–1016 3- XELOX Oxaliplatin 130 mg/m2 day 1 IV and Capecitabine 1000 mg/m2 PO twice a day, D1-D14 every 3 weeks *Check CBC before D1 ** Check neuropathy before D1 *** Check for hand-foot syndrome on D1– prophylactic recommendation of moisturizing hands and feet **** Patients should not drink cold beverages or touch cool surfaces for the week following the infusion Ref: J Clin Oncol 2008; 26:2013-2019 4- Bevacizumab Bevacizumab 5 mg/kg IV every 2 weeks Bevacizumab 7.5 mg/kg IV, every 3 weeks – when administered with XELOX *Monitor blood pressure before D1 **Urine dipstick analysis before D1 – protein presence ≥ 2+ - colect 24-hour urine – if there is protein presence, no restriction to release from treatment ≤ 2+ ***Stop 42 days prior to major surgery. Start only 28 days after major surgery. Ref: Lancet Oncol 2014;10:1065-1075, J Clin Oncol 2014;32:5s (abstr LBA3) and J Clin Oncol 2008;26:2013-2019 5- Cetuximab Cetuximab 500 mg/m² IV every 2 weeks * Premedication with diphenhydramine 50mg and dexamethasone 20mg **Check magnesium every 2 cycles ***Check for cutaneous rash before D1 **** Recommendation for the use of sunscreen and skin moisturizing. Consider primary prophylaxys of cutaneous rash. Ref: Lancet Oncol 2014;10:1065-1075, J Clin Oncol 2014;32:5s (abstr LBA3), J Clin Oncol 2011; 29:20112019 and N Engl J Med 2004;351:337-345 6- Panitumumab Panitumumab 6 mg/kg IV every 2 weeks In case of first line treatment – only with FOLFOX *Check magnesium every 2 cycles **Check for cutaneous rash before D1 ***Recommendation for the use of sunscreen and skin moisturizing. Consider primary prophylaxys of cutaneous rash. Ref: N Engl J Med 2013;369:1023-1034 J Clin Oncol 2007;25:1658-1664

SURVEILLANCE (CÓLON E RETO) INITIAL/LOCALLY DISEASE Clinical examination: - Every 3-6 months from the 1st to the 3rd year - Every 6 months from the 4th to the 5th year CEA: - Every 3 months from the 1st to the 3rd year - Every 6 months from the 4th to the 5th year Thorax CT and abdomen/pelvic CT or abdomen/pelvic NMR: - Every 6 months from the 1st to the 3rd year - Once a year until the 5th year Colonoscopy: - On the first year. If it was not done pre-surgery, do it as soon as possible. - On the third year and after that, every 5 years

ADVANCED DISEASE Clinical examination: - Every 15-30 days CEA: - Every 15-30 days Thorax CT and abdomen/pelvic CT or abdomen/pelvic NMR: - Every 2-3 months PET CT: - Not indicated as a routine (exceptions: 1 – High CEA, no evidence of disease by conventional imaging methods, evaluation of metastasis resection and detection of recurrences when radiological findings are inconclusive, even without CEA increased (in nonsecretor tumors)