Colon cancer. Sriwatree Chawsamtong, B.Sc.Pharm, BCOP Grad.Dip. In Pharmacotherapy Faculty of Medicine Vajira Hospital, Navamindradhiraj University

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1 Colon cancer Sriwatree Chawsamtong, B.Sc.Pharm, BCOP Grad.Dip. In Pharmacotherapy Faculty of Medicine Vajira Hospital, Navamindradhiraj University

2 World Cancer Burden 2012 Incidence Cancer is a leading cause of disease worldwide. An estimated 14.1 million new cancer cases occurred in Lung cancer 2. Female breast cancer 3. Colorectal cancer 4. Stomach cancer Mortality Cancer is a leading cause of death worldwide, with 8.2 million deaths in More than half of all cancer deaths each year are due to 1.Lung cancer 2.Stomach cancer 3. Liver cancer 4. Colorectal cancer 5. Female breast cancers Estimated age-standardized rates (World) per 100,000 2

3 Epidemiology: USA 2017 (estimated) Estimated New cases Prostate 161,360 19% 7% Lung & bronchus 116,990 14% Colon & rectum 71,420 9% Urinary bladder 60,490 7% Melanoma of the skin 52,170 6% Kidney & renal pelvis 40,610 5% Non-Hodgkin lymphoma 40,080 5% Leukemia 36,290 4% Oral cavity & Pharynx 35,720 4% Liver & intrahepatic bile duct 29,200 3% All Sites 836, % Estimated Males Females Males Females Breast 252,710 30% 1% Lung & bronchus 105,510 12% Colon & rectum 64,010 8% Uterine corpus 61,380 7% Thyroid 42,470 5% Melanoma of the skin 34,940 4% Non-Hodgkin lymphoma 32,160 4% Leukemia 25,840 3% Pancreas 25,700 3% Kidney & renal pelvis 23,380 3% All Sites 852, % Lung Deaths & bronchus 84,590 27% Lung & bronchus 71,280 25% Colon & rectum 27,150 9% 1% Breast 40,610 14% Prostate 26,730 8% 1% Colon & rectum 23,110 8% Pancreas 22,300 7% Pancreas 20,790 7% Liver & intrahepatic bile duct 19,610 6% Ovary 14,080 5% Leukemia 14,300 4% Uterine corpus 10,920 4% Esophagus 12,720 4% Leukemia 10,200 4% Urinary bladder 12,240 4% Liver & intrahepatic bile duct 9,310 3% Non-Hodgkin lymphoma 11,450 4% Non-Hodgkin lymphoma 8,690 3% Brain & Other nervous system 9,620 3% Brain & Other nervous system 7,080 3% All Sites 318, % All Sites 282, % Siegel, R. L., Miller, K. D. and Jemal, A. (2017), Cancer Statistics, CA: A Cancer Journal for Clinicians, 67:

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5 Rectal Cancer 1. The rectum is located cm from the anal verge 2. Early stage Rectal Cancer (stages I, II, and III) a. Clinical staging upon diagnosis is determined by rectal endoscopic ultrasound (EUS) or MRI of pelvis and is used to determine whether patients should receive neoadjuvant chemoradiation or proceed with surgery first for early stage rectal cancer (non-metastatic disease) b. Post-operative therapy (adjuvant therapy) is indicated in all patients who receive preoperative (neoadjuvant therapy) regardless of surgical pathology results for non-metastatic disease

6 Rectal Cancer The rectum is located cm from the anal verge Early stage Rectal Cancer (stages I, II, and III) Risk of local recurrence for early stage rectal cancer 1) Stage I % 2) Stage II 15-30% 3) Stage III greater than 50%

7 Genomics Genetic alterations Hereditary nonpolyposis colorectal cancer (HNPCC), AKA Lynch Syndrome Familial adenomatous polyposis (FAP) Other genetic entities include Muir-Torre, Turcot, Gardner, Cowden, Bannayan-Riley-Ruvalcaba, Peutz-Jeghers, juvenile polyposis, and serrated polyposis syndromes (SPS)

8 Genomics Defective DNA mismatch repair (dmmr) Tumor is tested for microsatellite instability (MSI) or testing for loss of genes involved in DNA mismatch repair (MLH1, MSH2, MSH6, and PMS2) Patients with stage II MSI-H tumors may have a good prognosis and do not benefit from adjuvant 5-FU therapy predicts increased benefit from programmed cell death protein 1 (PD-1) inhibitors in patients with progressive metastatic disease

9 Genomics Enzymatic deficiencies Dihydropyridine dehydrogenase (DPD) Deficiency and 5-FU Genetic abnormality in the DPD enzyme; partial deficiency occurs in 3-5% and complete deficiency occurs in 0.2% of general population Low concentration of DPD = increased levels of 5-FU that may result in severe GI toxicities (mucositis, diarrhea), myelosuppression, neurologic toxicity, and possibly death Screening for DPD deficiency prior to 5-FU exposure is not routinely performed no formal recommendations for dose adjustments of 5-FU based on presence of DPD deficiency

10 Genomics Enzymatic deficiencies Uridine diphosphate glycosyltransferase 1 family polypeptide A1 (UGT1A1) and irinotecan Reduced activity of UGT1A1 leads to significant toxicities 1) Patients with a UGT1A1*28 polymorphism, especially a homozygous mutation, are at much higher risk to develop significant neutropenia and diarrhea 2) Approximately 10% of US population is homozygous for UGT1A1*28 allele 3) Irinotecan dose reductions are recommended for patients who are UGT1A1*28 homozygous a) The precise dose reduction is not known and modifications should also consider individual patient characteristics 4) FDA-approved test is available to evaluate for UGT1A1 polymorphisms, however there are no official guidelines for the use of this test in clinical practice

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12 Genomics Predictive biomarkers EGFR testing does not demonstrate predictive value for response to anti-egfr monoclonal antibody (MAB) therapy RAS mutation status RAS status impacts response to anti-egfr MAB therapy (cetuximab, panitumumab). Several trials have demonstrated these agents only work in RAS-wild type (WT) disease 1) KRAS exon 2 mutations at codons 12 and 13 2) KRAS non-exon 2 mutations 3) NRAS mutation

13 Genomics BRAF mutation status V600E BRAF mutation occurs in 5-15% of colorectal cancers and results in poorer prognosis Data suggest lack of activity for anti-egfr MAB therapy in the presence of V600E mutations in the second-line setting

14 Risk Factors Age Genetic predisposition Hereditary nonpolyposis colon cancer (HNPCC) or Lynch Syndrome (5-10%) Familial adenomatosis polyposis (FAP) 0.5% Other genetic disorders: Turcot syndrome Inflamatory bowel disease Ulcerative colitis ;5X Crohn s Disease ;10X Tobacco; 35 pack-year increase risk Sedentary lifestyle Obesity; 2X Diabetes

15 Risk Factors Diet High Fat/Low fiber, Red meat, process meat Alcohol Family history 3X if 2 nd first degree relatives or 1 st degree relative < 50 yrs of age with colorectal cancer

16 Prevention Diet Vitamin supplementation High fiber Cyclooxygenase inhibition COX-2 expression is enhanced in up to 90% of colorectal carcinomas NSAIDs ; Women who regularly used aspirin ( 2 325mg tablets per week) had a multivariate RR for colorectal cancer of 0.77 (95% CI, ) U.S. Preventive Services Task Force (USPSTF) recommendation in April 2016 Initiate low- dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.

17 Prevention; Cyclooxygenase inhibition COX-2 inhibitions in familial adenomatous polyposis (FAP) Celecoxib 100 mg BID, 400 mg BID, or placebo BID for 6 months COX-2 inhibition in FAP results in reduction of the number of colorectal polyps, decreases risk of developing colorectal adenocarcinoma, and may also delay need for a prophylactic colectomy

18 Screening

19 CRC = colorectal cancer; IBS = inflammatory bowel disease; FAP = familial adenomatous polyposis; *IBS considered as Increased risk per NCCN Guidelines and High risk per ACS

20 CRC = colorectal cancer; IBS = inflammatory bowel disease; FAP = familial adenomatous polyposis; *IBS considered as Increased risk per NCCN Guidelines and High risk per ACS

21 Screening modalities for colorectal cancer

22 Test Advantage Disadvantage Fecal occult blood testing (FOBT) - Inexpensive - Easy to use - No bowel preparation - Low risk to the patient a. > 50% of colorectal cancers go undetected due to no bleeding at the time of examination b. Associated with false positive results 1) Rare red meat, uncooked fruits, vegetables (avoid 3 days prior to testing) 2) Iron supplementation, rectal medications, NSAIDs c. Associated with false negative results 1) Ascorbic acid ingestion >250mg per day 2) Dehydrated samples d. Positive results require further workup

23 Test Advantage Disadvantage Fecal immunochemical test (FIT) - No drug or food interactions - Can be used in place of FOBT - Positive results require further workup and testing with colonoscopy, etc. Stool DNA test: A value > 183 indicated a positive result Cologuard - For precancerous lesions, sensitivity of the DNA test was higher for distal lesions than for proximal lesions - DNA test was more sensitive than FIT for detection of lesions with high-grade dysplasia - No bowel preparation - No pre-test dietary restrictions - Sampling is done at home - May miss diagnosis of polyps - May produce false positive results - Colonoscopy needed if abnormal results

24 Test Advantage Disadvantage Flexible sigmoidoscopy Double contrast barium enemas - Useful in examining the lower 35-60% of the bowel - Visualizes the distal portion of the colon and rectum - Can be used for biopsy or excision of polyps - Minimal bowel preparation, done every 5 years - Does not require a specialist - Least expensive method in evaluation entire colon - View entire colon using barium enema and abdominal x-ray, done every 5 years, - No sedation needed - Views only lower 1/3 of colon and can miss ~ 50% of lesions if do not go past the sigmoid colon - Can miss small polyps and can not remove (inferior to colonoscopy) - Full bowel preparation - False positive and False negative result (rates range 2-20%) - Misinterpretation if poor preparation

25 Test Advantage Disadvantage Colonoscopy - Views entire colon - Provides information on the mucosa of the entire colon - Can be used for biopsy or excision of polyps - Highly sensitive diagnostic tool - Involves greater risk and inconvenience to patients - Preferred due to its superior ability to detect lesion in proximal or right side of the colon - Best follow-up for a guaiac positive test - Best method for screening high-risk patients - Inability to detect small lesions because of mucosa folds, blind corners, and cecum may not be reached - Full bowel preparation - Expensive - Sedation needed - Risk of bowel tears or infection

26 CT Colonography Advantage - Views entire colon - Does not require sedation Disadvantage - Can miss small polyps, some false positive results - Requires full bowel preparation - If polyps or other suspicious lesions are detected, a colonoscopy is needed for biopsy and/or excision - Expensive

27 Tumor markers Carcinoembryonic antigen (CEA) level Maybe useful in monitoring colorectal cancer response to treatment Monitoring CEA is not recommended for colorectal cancer screening Normal < 3 ng/ml Normal in smokers 0-6 ng/ml CEA can be higher with elevated serum creatinine, hepatic dysfunction or chemo (5-FU) so may see an increase in CEA and then a decrease after a few months of treatment T ½ is ~ 7 days Monitoring recommendations in the adjuvant setting2 1) Only monitor if patient is a potential candidate for further intervention 2) At baseline, then every 3-6 months for 2 years, then every 6 months for a total of 5 years

28 Signs and Symptoms Depends on the site and extent of tumour involvement -Right colon 1. Vague abdominal pain 2. Anaemia secondary to chronic blood loss, blood will be mixed in w/ stool so harder to detect 3. Weakness 4. Weight loss 5. No obstruction, secondary to stool is liquid here so more diarrhoea

29 Signs and Symptoms Left colon 1. Constipation alternating with diarrhea secondary to obstruction 2. Secondary to pressure against the obstruction that causes stool to liquefy 3. Blood will be on the stool (coating) 4. Abdominal pain 5. Obstructive symptoms (nausea/vomiting)

30 Signs and Symptoms Rectum 1. Changes in bowel movements 2. Rectal fullness 3. Urgency, 4. Bleeding (bright red blood)

31 Diagnosis A. Medical and family history for: 1. Signs/symptoms 2. Inflammatory bowel disease 3. Colorectal cancer or polyps B. Physical examination for: 1. Lymphadenopathy 2. Hepatomegaly 3. Masses or ascites 4. Women should undergo appropriate evaluations to rule out breast, ovarian, endometrial cancers

32 Diagnosis C. Colonoscopy D. Biopsy of any detected lesions E. CT scan of chest/abdomen/pelvis F. PET scan only if potential surgically curable metastatic disease G. CBC with platelets, LFTs, creatinine

33 Diagnosis H. Carcinoembryonic antigen (CEA) level 1. May be useful in monitoring colorectal cancer response to treatment 2. Normal < 3 3. Normal in smokers CEA can be higher with SrCr, hepatic dysfunction or chemo (5-FU) so may see an increase in CEA and then a decrease after a few months of treatment 5. T ½ is ~ 7 days a. Check baseline level b. 4 to 6 weeks after surgery c. Check every 3 months

34 Diagnosis I. Anatomy 1. Proximal (Ascending and Transverse Colon)-35-45% of cancers diagnosed 2. Descending colon-5% of cancers diagnosed 3. Distal (Sigmoid colon and Rectum)-45-55% of cancers diagnosed J. Pathology 1. Adenocarcinomas make up 90-95% of large bowel neoplasms 2. Mucinous adenocarcinomas characterized by large amount of extracellular mucus within the tumor 3. Signet ring cell carcinoma a. Characterized by large amount of intracellular mucus b. Make up 1% of adenocarcinomas c. Involve the submucosa so detection is difficult with imaging

35 Diagnosis J. Pathology (Cont.) 4. Pathology review for KRAS, BRAF and MMR 5. Microsatellite Instability (MSI) testing a. MMR protein testing should be performed for all patients < 50 years old with colon cancer, based on increased likelihood of Lynch syndrome. MMR should also be considered for all patients with stage II disease because stage II MSI high patients may have a good prognosis and do not benefit from 5-FU adjuvant therapy

36 TNM Staging

37 Prognostic Factors

38 Treatment and symptom management Principles of Surgery Generally involves partial colectomy (potentially curable disease) Removal of isolated pulmonary or hepatic metastases Palliation or symptom management in metastatic disease 12 lymph nodes necessary for adequate sampling to determine node positive or negative disease

39 Surgical approach for rectal cancer Transanal excision may be performed for superficial rectal tumors meeting specific criteria Transabdominal resection 1) Abdominoperineal resection (APR) performed for tumors located in the lower one-third of the rectum involving the anal sphincter or the levator muscles, and in cases where negative margin resection of primary tumor results in loss of anal sphincter function and incontinence a) APR generally removes distal sigmoid colon, rectum, and anus, requiring creation of a permanent colostomy 2) Low anterior resection (LAR) used for tumors located in the mid to upper rectum, leaves the anal sphincter intact. Generally removes primary tumor and 4-5 cm below distal edge of the tumor using TME (see below) and creation of colorectal anastomosis. 3) Total mesorectal excision (TME) removal of the mesorectum including vascular and lymphatic structures, fatty tissue, and mesorectal fascia, sparing autonomic nerves

40 Treatment and symptom management Principles of radiation therapy 1. Colon cancer - minimal role as rates of distant recurrences are higher than local recurrences a. May use radiation for a T4 lesion, perforation, incomplete resection or palliative therapy if unresectable or inoperable - bleeding, obstruction 2. Rectal cancer Administered prior to or following surgery in patients with curable disease 1) Neoadjuvant for stage II and III disease a) Utilized to improve resectability of primary tumor (decrease risk for positive margins and increase opportunity for LAR resection) and to decrease risk of local recurrence 2) Adjuvant for stage II and III disease a) Used to decrease risk of local recurrence b) Radiation alone after surgery has been found to be inferior to concurrent radiation and chemotherapy in rectal cancer 3) Metastatic disease a) Utilized for symptom reduction (pain, bleeding)

41 Treatment and symptom management Complications of radiation to the rectum a. Acute toxicity Thrombocytopenia/leukopenia, dysuria, diarrhea, abdominal cramping, proctitis b. Chronic toxicity Can persist for months following discontinuation of XRT Diarrhea, small bowel disease, proctitis, enteritis

42 Principles of chemotherapy; Neoadjuvant For localized disease, regimens usually contains a fluoropyrimidine with or without oxaliplatin a) Regimen should be based on patient chemotherapy history and safety and toxicity issues Can be used for metastatic patients for conversion to resectability a) Multiple trials have shown successful conversion with fluoropyrimidine-based regimens, adding bevacizumab, or adding cetuximab b) Optimal sequencing of neoadjuvant/adjuvant chemotherapy unknown c) NCCN panel recommends to limit neoadjuvant chemotherapy for potentially resectable metastatic disease to 2-3 months, with adjuvant chemotherapy limited to maximum of 3 month (for a total of perioperative chemotherapy of 6 month) Consider use for clinical T4b tumors NCCN Guidelines

43 Principles of chemotherapy; Neoadjuvant Rectal cancer Used in combination with radiation to increase radiation sensitization and improve systemic control of disease Fluoropyrimidine-based chemotherapy should be delivered concurrently with neoadjuvant radiation

44 Principles of chemotherapy; Adjuvant Decreases risk of disease recurrence by eradicating micrometastatic disease and improving disease-free survival after surgical resection for curative intent Results in a 2-5 % absolute risk reduction for recurrence of stage II Results in a % absolute risk reduction for recurrence of stage III Adjuvant therapy begins 4 to 8 weeks after surgery and lasts for 6 months

45 Principles of chemotherapy; Metastatic disease Used for palliation of symptoms and to prolong life in patients with unresectable, uncurable disease Includes either a combination of chemotherapy or single agents: 5-FU/leucovorin or capecitabine Irinotecan Oxaliplatin (No indication as a single agent and should be used in appropriate combination therapy) Bevacizumab, ziv-aflibercept, or ramucirumab a) No indication as single agents and should be used in appropriate combination therapy Cetuximab or panitumumab a) For RAS wild-type tumors only Regorafenib Trifluridine-tipiracil Nivolumab or pembrolizumab ;For dmmr/msi-h tumors only

46 Treatment of early stage colon cancer 1.Stage I (T1-2 N0 M0) a. Surgical excision of primary tumor and removal of regional lymph nodes b. Surveillance (no adjuvant chemotherapy) 2.Stage II a. Surgical excision of primary tumor and removal of regional lymph nodes b. Role of adjuvant chemotherapy still unclear for stage II - Reduces risk of recurrence, 3% survival benefit - Stage II disease to be evaluated for MMR. Adjuvant therapy is not recommended for stage II MSI-H tumors.

47 Treatment of early stage colon cancer 2.Stage II - T3 N0 M0 (IIA) - No high risk features: Consider adjuvant chemotherapy with capecitabine, 5-fluorouracil/Leucovorin (5-FU/LV), clinical trial or surveillance. - T3 N0 M0 (IIA) with high risk features for recurrence - FOLFOX, CapeOx, FLOX, capecitabine, 5-FU/LV, clinical trial, or surveillance. - T4 N0 M0 (IIB, IIC) - FOLFOX, CapeOx, FLOX, capecitabine, 5-FU/LV, clinical trial, or surveillance

48 High Risk Features of Recurrence Inadequate lymph node sampling Obstruction Tumor perforation Poorly or undifferentiated Histology Lymph-vascular invasion Perineural invasion T4-level invasion Perineural invasion: Illustrated is a tumor enveloping a peripheral nerve in cross section revealing tumor cell spread. Molecules expressed by tumors interact with surrounding stroma as well as receptors associated with peripheral nerves. 1. Engstrom PF, Arnoletti JP, Benson AB III, Chen YJ, Choti MA, Cooper HS et al. NCCN clinical practice guidelines in oncology: colon carcinoma. J Natl Compr Canc Netw 2009; 7(8): Benson AB III, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16): Labianca R, Nordlinger B, Beretta GD, Brouquet A, Cervantes A. Primary colon cancer: ESMO clinical practice guidelines for diagnosis, adjuvant treatment and follow-up. Ann Oncol 2010;21(suppl 5): J Gastrointest Surg Jun;19(6): doi: /s z. Epub 2015 Feb 7

49 Treatment of early stage colon cancer 3. Stage III a. Surgical excision of primary tumor and removal of regional lymph nodes b. Adjuvant therapy FOLFOX and CapeOx preferred, FLOX, Capecitabine, 5- FU/LV

50 Treatment by Stage Adjuvant Therapy for Colon Cancer (NCCN guidelines V ) IA (T1, N0, M0) IB (T2, N0, M0) IIA (T3, N0, M0) MSI-H or dmmr IIA* (T3, N0, M0 MSI-L or MSS and no high risk features) IIA (T3, N0, M0 with high risk features) IIB (T4a, N0, M0) IIC (T4b, N0, M0) IIIA (T3, N1, M0) IIIB (T4, N1, M0) IIIC (T1-4, N2, M0) Surveillance (no adjuvant therapy) Clinical trial, Observation, or Consider Capecitabine or 5-FU/LV FOLFOX, CapeOx, FLOX, Capecitabine, 5-FU/LV, Clinical trial or Observation FOLFOX or CapeOx preferred (category 1) Other options: FLOX (category 1), Capecitabine, 5-FU/LV

51 Adjuvant Regimens for Colon and Rectal Cancer Regimen 5 fluorouracil + HDLV (Roswell Park) Dosing Leucovorin 500 mg/m 2 IV over 2 hours + 5 fluorouracil 500 mg/m 2 IV over 1 hour post Leucovorin every week x 6 weeks followed by 2 week rest 5 fluorouracil + LDLV (Mayo Clinic) Leucovorin 20 mg/m 2 IVP + 5 fluorouracil 450 mg/m 2 IVP x 5 days and Repeat every 4 weeks Capecitabine Capecitabine mg/m 2 BID PO days 1-14 Repeat every 21 days FLOX Leucovorin 500 mg/m 2 IV over 2 hours and One hour after starting Leucovorin administer: 5-Fluorouracil 500 mg/m 2 IV bolus Administered on days1, 8, 15, 22, 29, and 36 Oxaliplatin 85 mg/m 2 IV on days 1, 15, and 29

52 Adjuvant Regimens for Colon and Rectal Cancer Regimen Dosing mfolfox6 Oxaliplatin 85 mg/m 2 IV over 2 hours day 1 Leucovorin 400 mg/m 2 IV over 2 hours on day 1 Followed by:5-fluorouracil 400 mg/m 2 IV bolus on day 1, then 5-Fluorouracil 1200 mg/m 2 /day IVCI x 2 days (Total 2400 mg/m 2 IVCI over 46 hours) Repeat every 14 days for a total of 12 cycles CapeOx (Xelox) Capecitabine mg/m 2 BID PO days 1-14 Oxaliplatin 130 mg/m 2 IV over 2 hours day 1 Repeat every 21 days for a total of 8 cycles

53 NCCN Treatment Pathways for Early Stage Rectal Cancer Clinical Stage Treatment Pathologic Stage Adjuvant Treatment pt1 N0 M0 pt2 N0 M0 Surveillance ct1 N0 Transanal Excision: - <50 % circumference of bowel - <3 cm in size - Margin clear (>3 mm) - Mobile, not fixed - Within 8 cm of anal verge - No Lymphovascular invasion or PNI - Well to moderate diff. pt3 N0 M0 pt1-3 N1-2 M0 Adjuvant Therapy (Chemotherapy + ChemoRT = 6 months total therapy) Option 1 FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin 5-FU* or Capecitabine (preferred) + RT FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin Option 2 5-FU* or Capecitabine (preferred) + RT FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin

54 NCCN Treatment Pathways for Early Stage Rectal Cancer Clinical Stage Treatment Pathologic Stage Adjuvant Treatment ct1-2 N0 Trans-abdominal Resection: - Low anterior resection - Coloanal anastomosis by Total mesorectal excision - Remove primary tumor with adequate margins - Restore organ integrity pt1-2 N0 M0 pt3 N0 M0 pt1-3 N1-2 M0 Surveillance Adjuvant Therapy (Chemotherapy + ChemoRT = 6 months total therapy) Option 1 FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin 5-FU* or Capecitabine (preferred) + RT FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin Option 2 5-FU* or Capecitabine (preferred) + RT FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin

55 NCCN Treatment Pathways for Early Stage Rectal Cancer Clinical Stage Treatment Pathologic Stage Adjuvant Treatment Stage IIA(cT3 N0) Stage III (ct any N1-2) Neoadjuvant Therapy with 5-FU* or Capecitabine + RT Followed by Trans-abdominal Resection Plan does not change based on pathologic stage Adjuvant Therapy (Neoadjuvant ChemoRT+ Chemotherapy = 6 months total therapy) FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin 5-Fluorouracil 255 mg/m 2 IVCI over 24 hours 5-7 days/week during RT (preferred) Capecitabine 825 mg/m 2 BID 5 days/week during RT (preferred) 5-fluorouracil 400 mg/m 2 IV bolus + Leucovorin 20 mg/m 2 for 4 days during weeks 1 and 5 of RT

56 NCCN Treatment Pathways for Early Stage Rectal Cancer Clinical Stage Treatment Pathologic Stage Adjuvant Treatment ct4 Neoadjuvant Therapy with 5-FU* or Capecitabine + RT Followed by resection if possible If resection contraindicated, give active chemotherapy for advanced disease Plan does not change based on pathologic stage Adjuvant Therapy (Neoadjuvant ChemoRT+ Chemotherapy = 6 months total therapy) FOLFOX, 5-FU/LV, or Capecitabine ± Oxaliplatin 5-Fluorouracil 255 mg/m 2 IVCI over 24 hours 5-7 days/week during RT (preferred) Capecitabine 825 mg/m 2 BID 5 days/week during RT (preferred) 5-fluorouracil 400 mg/m 2 IV bolus + Leucovorin 20 mg/m 2 for 4 days during weeks 1 and 5 of RT

57 Chemoradiation in Rectal Cancer Author Comparative Regimens PFS, Mos OS, Mos Hofheinz RD et al. Lancet Oncol Jun;13(6): Bolus 5-FU x 2 cycles Infusional 5-FU + RT Bolus 5-FU x 2 cycles (n = 195) Capecitabine x 2 cycles Capecitabine + RT Capecitabine x 3 cycles (n = 197) 3-Year: 67 % 5-Year: 67 % 3-Year: 75 % P = HR 1.4 (CI ) 5-Year: 76 % P = HR 1.5 (CI ) - Capecitabine was associated with more fatigue, proctitis, HFS. - Diarrhea was significantly higher during capecitabine + RT 45% vs. 32% (p = 0.009) - Capecitabine was noninferior to 5-FU and demonstrated an improvement in DFS and OS. Randomized, phase II, open- label study in Locally advanced (ct3, resectable ct4, any ct3n+) rectal cancer Fernandez-Martos C et al. Arm A (n = 52): chemort (Capecitabine + Oxaliplatin) followed by surgical resection and adjuvant CapeOx for 4 cycles Arm B (n = 56): chemotherapy (CapeOx) for 4 cycles followed by chemort (Capecitabine + Oxaliplatin) followed by surgical resection pathologic complete response rate (pcr) 13% pathologic complete response rate (pcr) 14% 89% 97% - Downstaging (lower pathologic T stage than with clinical T stage) occurred in 58% of patients in arm A and 43% in arm B (p=0.13).

58 Chemoradiation in Rectal Cancer Author Comparative Regimens RR SD Retrospective review of 61 patients with clinical stage II and III rectal cancer (T3 N0, T4 N1-2) Cercek A et al. Neoadjuvant FOLFOX 4-6 cycles ChemoRT (Capecitabine/5-FU) Surgical resection pcr 36% clinical CR (ccr) 14% pn0 75% cases developed metastatic disease NSABP R-04 Patients with clinical stage II (T3,4 N0) or III (1-4 N1-2) rectal cancer 1 Endpoint: time to first locoregional failure at 3 years (not yet reached) 2 Endpoints: pcr, sphincter-sparing surgery, surgical downstaging, and toxicity O Connell MJ et al. 5-FU + chemort (n=308) Capecitabine + chemort (n=304) 5-FU and Oxaliplatin + chemort (n=309) Capecitabine and Oxaliplatin + chemort (n=309) pcr 17.8% pcr 19.5% SSS 61% SD 23.5% SSS 57.8% SD 17.9% - The addition of oxaliplatin to fluoropyrimidine chemort did not improve surgical outcomes and resulted in patients experiencing more diarrhea - Patients who received oxaliplatin experienced significantly more grade 3, 4 diarrhea 16.5% vs. 6.9% (p <0.001)

59 Stage IV Colon cancer Chemotherapy is used for palliation of symptoms and to prolong life Surgical resection of the primary tumor may be performed or symptom management in patients with bleeding, obstruction, or localized abdominal pain due to large or bulky primary tumor Removal of isolated pulmonary or hepatic metastases may be performed in select patients

60 Stage IV Colon cancer Resectable synchronous liver and/or lung only metastases 1) Synchronous or staged colectomy with liver or lung resection, followed by adjuvant chemotherapy 2) Neoadjuvant chemotherapy for 2-3 months, followed by synchronous or staged colectomy with liver or lung resection 3) Colectomy followed by adjuvant chemotherapy and a staged resection of metastatic disease

61 Stage IV Colon cancer Perioperative chemotherapy 1) Combined neoadjuvant and adjuvant treatment should not exceed 6 months 2) Chemotherapy used in preoperative setting to increase curative resection rates and to convert patients from unresectable to resectable disease 3) Pre-operative chemotherapy with oxaliplatin and irinotecan has been associated with steatosis, steatohepatitis, portal hypertension, and sinusoidal injury, which may affect outcomes after liver resection

62 Stage IV Colon cancer Neoadjuvant chemotherapy options a) FOLFIRI, FOLFOX, or CapeOx alone or with bevacizumab i. Discontinue bevacizumab at least 6 weeks prior to surgery ii. Wait 6-8 weeks after surgery b) FOLFIRI or FOLFOX with panitumumab c) FOLFIRI with cetuximab Adjuvant chemotherapy options a) FOLFOX or CapeOx (preferred) b) FOLFIRI, FOLFOX, or CapeOx alone or with bevacizumab c) FOLFIRI or FOLFOX with panitumumab d) FOLFIRI with cetuximab i. There is currently conflicting data regarding the use of FOLFOX + cetuximab in patients with potentially resectable liver metastases

63 Select Neoadjuvant Trials for Metastatic Colon and Rectal Cancer

64 Chemotherapy Regimen Results FOLFOX, IROX, IFL Delaunoit T et al. FOLFIRI Barone C et al. FOLFOX pre- and postsurgery Nordlinger B et al. Patients received FOLFOX, IROX, or IFL Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection Response rate for FOLFOX was significantly better than with IFL or IROX Median TTP was 18.4 mo Median OS was 42.4 mo Median OS in resected patients is 42.4 months, and median TTP is 18.4 mo 5 patients received chemo post-operatively and 4 of 5 remained disease free at 32 mo 40 patients received FOLFIRI x 6 cycles, then reassess for liver met resection 47.5% achieved an objective overall response 33% underwent resection of liver metastases after a median of 8 cycles (range 6-12) Patients received 6 cycles of adjuvant therapy Median DFS was 52.5 mo for resected patients Median survival for all patients was 31.5 mo For non-resected patients median survival was 24 mo; not reached for resected patients Median time to progression was 14.3 and 5.2 mo for all and non-resected patients, respectively Patients randomized to receive either 6 cycles of FOLFOX before and after surgery or surgery alone 151 (83%) patients were resected after a median of 6 (range 1-6) preoperative cycles and 115 (63%) patients received a median 6 (range 1-8) postoperative cycles. The absolute increase in rate of progression-free survival at 3 years was 7.3% (from 28.1% to 35.4%; p=0.058)

65 Chemotherapy Regimen Results CapeOx + Bevacizumab Gruenberger B et al. CapeOx + Bevacizumab Wong R et al. FOLFIRI + Bevacizumab Nasti G et al. Phase II trial with 56 patients Resection performed in 52/56 patients 73% response rate to chemotherapy Bevacizumab discontinued 5 weeks prior to liver resection No increase in bleeding complications ostoperative liver function and regeneration were normal in all but one patient Phase II of 46 patients with poor risk disease not suitable for upfront resection of liver metastases Patients received CapeOx + bevacizumab and reassessed for resection every 4 cycles Objective response rate 78%, median # of cycles was 4 for patients that went on to resection Converted 40% to resectable liver metastases Patients received 4 cycles of chemotherapy after surgical resection At median follow-up of 12.5 months, PFS was 50% and OS was 86% Phase II trial of 39 patients that received FOLFIRI + bevacizumab x 7 cycles (bevacizumab stopped at cycle 6 to reduce the risk of surgical bleeding) Primary endpoint was 1 year progression free survival Objective response rate was 66.7% 37 patients (95%) underwent surgical resection Patients received 4 cycles post-operatively At 1 year, 61.6% were alive without disease progression Median PFS was 14 months, median OS 38 months

66 Chemotherapy Regimen FOLFOX or FOLFIRI + Cetuximab vs. chemotherapy alone Ye LC et al. FOLFOX + Cetuximab vs. FOLFIRI + Cetuximab (CELIM study) Taieb J et al. Folprecht G et al. Results Chinese patients with unresectable liver metastases were randomized to receive FOLFOX or FOLFIRI plus cetuximab (arm A, n=70) vs. chemotherapy alone (arm B,n=68) after resection of KRAS WT primary colon or rectal cancer Patients received 4 cycles and were evaluated to determine if liver metastases became resectable. Patients were re-evaluated every 2 cycles up to 12 cycles 18 patients in arm A and 5 patients in arm B achieved an R0 resection (p < 0.01) Objective response rate for arm A was 57% vs. 29.5% for arm B (p < 0.01) 3-year PFS was 10.2 months for arm A vs. 5.8 months for arm B (p=0.004) 3 -year OS was 31 months for arm A vs. 21 months for arm B (p = 0.013) Patients in arm A that received resection of liver metastases had significantly longer MST compared to patients that did not receive resection (46.4 vs months, p <0.01 months) Cetuximab plus chemotherapy improved resection rate of liver metastases and survival compared to chemotherapy alone Phase II trial of patients with unresectable and/or > 5 liver metastases were treated with FOLFOX + cetuximab (arm A, n=56) or FOLFIRI + cetuximab (arm B, n=55) Median number of treatment cycles was 8 Objective response rate was 68% in arm A vs. 57% in arm B (p=0.23) R0 resection was performed in 20 patients in arm A and 16 patients in arm B Resectability rates increased from 32% at baseline to 60% after chemotherapy (p<0.0001) Median PFS was 11.2 months for arm A vs months with arm B (p = 0.4) Median OS was 35.8 months for arm A vs.29 months with arm B (p = 0.9) Patients that received R0 resection had median OS of 54 months vs. 22 months in patients that did not undergo resection

67 Chemotherapy Regimen Results FOLFOX or Xelox + Cetuximab Primrose J et al. Patients with KRAS WT resectable or sub optimally resectable liver metastases were randomized to receive FOLFOX or Xelox with cetuximab (n=129) or chemotherapy alone (n=128) for 12 weeks before and after liver resection 100 patients in the chemotherapy alone group and 98 patients in the cetuximab group received resection PFS was significantly shorter in the chemotherapy + cetuximab group compared to chemotherapy alone (14.1 months vs months, p = 0.030) Median OS in the chemotherapy + cetuximab arm was 39 months and not yet reached for the chemotherapy alone group Further investigation with the combination of cetuximab and oxaliplatin in patients with resectable liver metastases is needed

68 Stage IV Colon cancer Unresectable liver or lung only lesions are treated with chemotherapy and evaluated every 2 months to assess resectability of liver and/or lung metastases. Consider colon resection if risk of obstruction or significant bleeding 1) FOLFIRI, CapeOx, or FOLFOX + bevacizumab 2) FOLFIRI or FOLFOX + panitumumab or cetuximab if KRAS/NRAS WT 3) FOLFOXIRI + bevacizumab 4) For patients that are able to undergo resection of metastatic disease, they should receive 6 months of adjuvant therapy with an active regimen for advanced disease, observation, or shortened course of chemotherapy

69 Rectal Cancer Metastatic Rectal Cancer (Stage IV) a. Resectable synchronous liver only or lung only metastases 1) Combination chemotherapy for 2-3 months followed by resection of metastases and rectal primary and consideration for chemoradiation with 5-FU or capecitabine 2) Combination chemotherapy for 2-3 months followed by chemoradiation with 5-FU or capecitabine and then resection of metastases and rectal primary

70 Rectal Cancer Metastatic Rectal Cancer (Stage IV) Cont. a. Resectable synchronous liver only or lung only metastases 3) Chemoradiation with 5-FU or Capecitabine followed by resection of metastases and rectal primary and the chemotherapy with a regimen for advanced disease (FOLFOXIRI is not recommended in this setting) b. Unresectable Stage IV Rectal Cancer 1) Chemotherapy as above for metastatic colon cancer 2) Patients with rectal pain, bleeding may receive palliative chemoradiation, resection of involved rectal segment, diverting colostomy, stenting, or laser recanalization

71 Summary of NCCN guidelines for Unresectable Metastatic Colon and Rectal Cancer

72 LV = leucovorin Bevacizumab preferred anti-angiogenic agent based on toxicity and cost *KRAS/NRAS wild-type only #Trifluridine/tipiracil can be given before or after regorafenib, but must be after all other standard therapies dmmr/msi-h and if neither given previously

73 LV = leucovorin Bevacizumab preferred anti-angiogenic agent based on toxicity and cost *KRAS/NRAS wild-type only #Trifluridine/tipiracil can be given before or after regorafenib, but must be after all other standard therapies dmmr/msi-h and if neither given previously

74 LV = leucovorin Bevacizumab preferred anti-angiogenic agent based on toxicity and cost *KRAS/NRAS wild-type only #Trifluridine/tipiracil can be given before or after regorafenib, but must be after all other standard therapies dmmr/msi-h and if neither given previously

75 LV = leucovorin Bevacizumab preferred anti-angiogenic agent based on toxicity and cost *KRAS/NRAS wild-type only #Trifluridine/tipiracil can be given before or after regorafenib, but must be after all other standard therapies dmmr/msi-h and if neither given previously

76 Select Chemotherapy Regimens for Metastatic Colon and Rectal Cancer Dose scheduled

77

78

79 mcrc: First Line 5-Fluorouracil-based regimens Trial (Regimen) Chemotherapy RR (%) Median Progression (months) Continuous Infusion vs. Bolus 5- FU/LV Piedbois P et al Capecitabine Van Cutsem E. Median OS (months) Conclusions / Comments Bolus 5-FU/LV 14 NR Grade 3, 4 hematologic Continuous 22 NR 12.1 toxicity Bolus > Continuous Infusion 5-FU/LV P=0.002 P= Hand-foot syndrome HR 0.55 HR 0.88 Continuous > Bolus ( ) ( ) - No difference in incidence - of diarrhea, mucositis, - nausea/vomiting Mayo clinic 15 TTP 4.7 Capecitabine 18.9 (CI %) Capecitabine has equivalent efficacy when compared to 5-FU/LV TTP 5.2 HR 0.96 (CI ) 12.1 Capecitabine had significantly less stomatitis 13.2 P=0.33 HR 0.92 (CI ) alopecia, neutropenia Capecitabine had higher incidence of hand-foot syndrome and grade 3/4 hyperbilirubinemia 79

80 mcrc: First Line 5-Fluorouracil-based regimens Trial (Regimen) Chemotherapy RR (%) Median Progression (months) FOLFOX De Gramont A et al FOLFIRI Douillard JY et al. Infusional 5-FU/LV (n = 210) FOLFOX4 (n = 210) 5-FU/LV (n=187) FOLFIRI (n=198) 22.3 PFS P = PFS 8.2 P = TTP P < TTP 6.7 P < Median OS (months) Conclusions / Comments Neutropenia, mucositis, diarrhea, and peripheral neuropathy: 16.2 P=0.12 (NS) FOLFOX > INF 5-FU/LV - FOLFOX = 1st line Tx of metastatic colon and rectal cancer Diarrhea, neutropenia, Asthenia: Irinotecan > P=0.031 FU/LV - Irinotecan = 1st line Tx of metastatic colon and rectal cancer 80

81 mcrc: First Line 5-Fluorouracil-based regimens Trial (Regimen) Chemotherapy RR (%) Median Progression (months) FOLFIRI or FOLFOX 1ST Line Tournigand C et al. Arm A FOLFIRI 1st line 56 PFS 8.5 FOLFOX 2nd line 15 PFS 4.2 Arm B FOLFOX 1st line 54 PFS 8.0 FOLFIRI 2nd line 4 PFS 2.5 Median OS (months) (p=0.99) Conclusions / Comments - No difference in PFS for 1 st line, 2 nd PFS, OS - More patients experienced grade 3 / 4 toxicities with FOLFOX than FOLFIRI (74 vs.53% P = 0.001) - FOLFOX ;significantly more neurotoxicity, grade 3 / 4 neutropenia and thrombocytopenia - FOLFIRI ; significantly more grade 3 / 4 febrile neutropenia,nausea/vomit ing, mucositis, fatigue - Either FOLFOX or FOLFIRI may be used 1st line. 81

82 mcrc: First Line 5-Fluorouracil-based regimens Trial (Regimen) Chemotherapy RR (%) Median Progression (months) CapeOx (Xelox) Cassidy J et al. FOLFOXIRI Falcone A et al. Median OS (months) Conclusions / Comments FOLFOX4 48 PFS Neutropenia, FN: FOLFOX > CapeOx - Diarrhea & HFS: CapeOx > FOLFOX CapeOx 47 PFS 8.0 HR 1.04 (CI ) FOLFIRI (n = 122) FOLFOXIRI (n = 122) 19.8 HR 0.99 (CI ) - CapeOx is non-inferior to FOLFOX4 for 1st line Tx of mcrc 34 PFS Neurotoxicity & neutropenia: FOLFOXIRI > FOLFIRI 66 (P < 0.001) PFS 9.8 P=0.006 HR 0.63 (CI ) 22.6 P=0.032 HR 0.70 (CI ) - Patients in FOLFOXIRI arm were able to undergo R0 resection of metastatic disease 82

83 First-line Chemotherapy ± Bevacizumab in mcrc: Efficacy Author Comparative Regimens RR (%) PFS, Mos OS, Mos Comments Bevacizumab + 5- FU/LV Kabbinavar F et al. Bevacizumab + FOLFOX/CapeOx (NO16996) Saltz LB et al. 5-FU/LV (n = 36) 17 TTP Bevacizumab 5 mg/kg 5-FU/LV + Bevacizumab 5 mg/kg (n = 35) 5-FU/LV + Bevacizumab 10 mg/kg (n = 33) Oxaliplatin-based regimen (FOLFOX4 or CapeOx) (n = 701) Bevacizumab + Oxaliplatin-based regimen (FOLFOX4 or CapeOx) (n = 699) 40 P= NS NS PFS 8.0 TTP 9.0 P=0.005 HR 0.46 TTP 7.2 PFS 9.4 P= HR 0.83 (CI ) NS resulted in 62 % reduction in risk of disease progression ADRs: headache, epistaxis, HTN,thromboembolic events, proteinuria Grade 3/4 toxicities associated with bevacizumab included thromboembolic events, hypertension, bleeding Bevacizumab + oxaliplatinbased regimen of FOLFOX or CapeOx improved PFS 83

84 First-line Chemotherapy ± Bevacizumab in mcrc: Efficacy Author Comparative Regimens RR (%) PFS, Mos OS, Mos Tree 1 and Tree 2 Hochster HS et al. mfolfox6 FLOX CapeOx mfolfox6 +Bevacizumab FLOX + Bevacizumab CapeOx + Bevacizumab NS NS TTP NS TTP NS NS NS - Neutropenia and thrombocytopenia more common with FOLFOX and FLOX - Diarrhea, nausea, dehydration more common with CapeOx - Bevacizumab did not significantly increase AEs - Similar efficacy with the 3 oxaliplatin-based regimens Median OS for all 3 arms was 23.7 months with addition of bevacizumab vs months without Hurwitz H, et al. N Engl J Med. 2004;350:

85 First-line Chemotherapy ± Bevacizumab in mcrc: Efficacy Author Comparative Regimens RR (%) PFS, Mos OS, Mos FOLFIRI (n = 144) 47.2 NS PFS NS mifl (n = 141) 43.3 NS PFS NS - CapeIRI associated with highest rates of N/V, diarrhea, dehydration, HFS BICC-C - Fuchs CS et al. - Sobrero A et al CapeIRI (n = 145) 38.6 NS PFS NS FOLFIRI + Bevacizumab (n = 57), (n = 209) 57.9 NS 53.1 PFS 11.2 NS 11.1 NR P= mifl + Bevacizumab (n = 60) 53.3 PFS CapeIRI + Bevacizumab arm discontinued NR NR NR FOLFIRI + bevacizumab significantly improved OS over mifl + bevacizumab mifl and CapeIRI are no longer recommended in NCCN Guidelines 85

86 First-line Chemotherapy ± Bevacizumab in mcrc: Efficacy Author Comparative Regimens RR (%) PFS, Mos OS, Mos Bevacizumab + FOLFIRI Sobrero A et al. FOLFIRI + Bevacizumab (n = 209) 53.1 PFS Bevacizumab was associated with bleeding (epistaxis most common),htn, VTE FOLFIRI was associated with neutropenia, diarrhea, and fatigue Results were similar to previous studies combining bevacizumab with irinotecan and oxaliplatinbased regimens FOLFIRI + bevacizumab is listed in the NCCN Guidelines as 1st line regimen for colorectal Cancer 86

87 First-line Chemotherapy ± Bevacizumab in mcrc: Efficacy Author Comparative Regimens RR (%) PFS, Mos OS, Mos Bevacizumab + FOLFOXIRI (TRIBE) FOLFIRI + Bevacizumab FOLFOXIRI + Bevacizumab 65 P = P = HR 0.77 (CI ) Bevacizumab Summary Bevacizumab has demonstrated Loupakis F et al. improved response rates and survival when added to Cremolini C et al. Fluoropyrimidine (5-FU or capecitabine) based regimens. Bevacizumab is recommended in combination with 5-FU, capecitabine, FOLFOX, CapeOx,FOLFIRI, and FOLFOXIRI for 1st line therapy of metastatic colon and rectal cancer 29.8 p=0.03 HR 0.80 (CI ) Patients received a maximum of 12 cycles followed by maintenance bevacizumab + 5-FU Patients in the FOLFOXIRI arm experienced more neutropenia (49% vs. 20%), diarrhea, stomatitis, andneurotoxicity FOLFOXIRI + bevacizumab improved OS and PFS compared to FOLFIRI + bevacizumab and its use for metastatic colon and rectal cancer is supported by NCCN Guidelines 87

88 First Line EGFR Inhibitor Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Cetuximab + FOLFIRI (Crystal) Van Cutsem E et al. Panitumumab + FOLFOX (PRIME) Douillard JY et al. Panitumumab + FOLFIRI Kohne CH et al. FOLFIRI (n = 599) 38.7 PFS More benefit from cetuximab in KRAS WT FOLFIRI + Cetuximab (n = 599) 46.9 P=0.004 HR 1.40 (CI ) PFS 8.9 P=0.048 HR 0.85 (CI ) 19.9 NS Cetuximab was associated with rash, infusion reactions, and diarrhea FOLFOX4 (n = 590) 48 PFS Panitumumab was FOLFOX4 + Panitumumab (n = 593) FOLFIRI + Panitumumab 57 p= (KRAS WT) PFS 10 p=0.01 HR 0.80 (CI ) 8.9 (KRAS WT) 23.9 p=0.17 HR 0.88 (CI ) NR associated with rash, diarrhea, paronychia, low magnesium, and mucositis More benefit in KRAS WT Median TTP was 11.2 months for KRAS WT Cetuximab + FOLFOX (CALGB/SWOG 80405) Venook AP et al. Chemotherapy + Bevacizumab (n=559) Chemotherapy + Cetuximab (n=568) NR Chemotherapy in combination with either NR bevacizumab or cetuximab demonstrated equivalent OS (p=0.34)

89 Second Line and Beyond Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Cont. of Bevacizumab after 1 st Progression (ML18147) Bennouna J et al. Aflibercept + FOLFIRI (Previous FOLFOX/Beva) Van Cutsem E et al. Cetuximab + Irinotecan after FOLFOX (EPIC) After FOLFOX Sobrero A et al. Chemotherapy (Oxaliplatin or Irinotecan-based) VS Chemotherapy + Beva FOLFIRI (n = 614) VS FOLFIRI + Aflibercept (n = 612) Irinotecan (n = 650) VS Irinotecan + Cetuximab (n = 648 ) NR 11.1 vs 19.8 P = vs 16.4 P < PFS 4.1 vs 5.7 P < HR 0.68 (CI ) 4.67 vs 6.9 P < HR 0.76 (CI ) 2.6 vs 4.0 P = HR (CI ) KRAS mutation status was not taken into consideration in this study 9.8 vs 11.2 P = HR 0.81 (CI ) vs 13.5 P = HR 0.82 (CI ) 10.0 vs 10.7 NS Continuation of bevacizumab with 2nd line chemotherapy significantly improved PFS and OS and is supported in NCCN Guidelines Aflibercept + FOLFIRI More diarrhea, stomatitis, and neutropenia were higher with Aflibercept was associated with hypertension, thromboembolic events, proteinuria 47% of patients that received Irinotecan went on to receive Cetuximab, which may have contributed to NS outcomes in OS

90 Second Line and Beyond Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Panitumumab + FOLFIRI Peeters M et al. Cetuximab 500 mg/m 2 every 14 days Pfeiffer P et al. Cetuximab + Irinotecan (was refractory to irinotecan therapy) (BOND) Cunningham D et al. FOLFIRI (n = 595) VS FOLFIRI + Panitumumab (n = 591 ) Cetuximab 500 mg/m 2 every 14 days + Irinotecan (n = 40) Cetuximab (n = 111 ) VS Cetuximab + Irinotecan (n = 218 ) KRAS WT 10 vs 35 P < vs 22.9 P = KRAS WT 3.9 vs 5.9 P = HR 0.73 (CI ) TTP vs 4.1 P < HR 0.54 (CI ) KRAS WT 12.5 vs 14.5 NS vs 8.6 NS Patients could not have received prior Irinotecan therapy Panitumumab + FOLFIRI ; skin toxicities, low magnesium, diarrhea, mucositis Cetuximab 500 mg/m 2 every 2 weeks provides an alternative dosing schedule Cetuximab may be given in combination with FOLFOX, FOLIRI, and irinotecan as above, or used as monotherapy in KRAS WT mcrc 90

91 Second Line and Beyond Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Ramucirumab + FOLFIRI (progressed on 1st line FOLFOX + bevacizumab) (RAISE) Tabernero J et al. FOLFIRI +Placebo (n = 536) VS FOLFIRI + Ramucirumab (n = 536) 12.5 vs 13.4 (P = ) 4.5 vs 5.7 P < HR (CI ) 11.7 vs 13.3 P = HR 0.84 (CI Ramucirumab + FOLFIRI significantly improved PFS and OS Ramucirumab + FOFLIRI neutropenia, hypertension, diarrhea, stomatitis, and Fatigue

92 Second Line and Beyond Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Cetuximab vs. BSC Jonker DJ et al. Panitumumab vs. BSC Van Cutsem E et al. Regorafenib (CORRECT) Grothey A et al. BSC (n = 285) VS Cetuximab + BSC (n =287) BSC (n = 232) VS Panitumumab + BSC (n =231) BSC (placebo) (n = 255) VS Regorafenib + BSC (n = 505) NR 0 vs vs 1 NS 1.9 vs 3.7 P < HR 0.4 (CI ) 7.3 weeks vs 8 weeks P < HR 0.54 (CI ) 1.7 vs 1.9 P < HR 0.49 (CI ) 4.8 vs 9.5 P < HR 0.55 (CI ) HR 1.00 (CI ) P = vs 6.4 P= HR 0.77 (CI ) KRAS mutation status was not taken into consideration in this study KRAS mutation status was not taken into consideration in this study - Dose modifications required in 76% of patients of which 70% required more than 1 dose interruption due to AEs - Grade 3/4 AEs associated with regorafenib included HFS reaction, fatigue, diarrhea, HTN, and rash 92

93 Second Line and Beyond Regimens Author Comparative Regimens RR (%) PFS, Mos OS, Mos Patients had to receive >2 prior standard chemo Regimens Trifluridine and tipiracil (TAS-102) trifluridine and tipiracil vs. placebo for previously treated mcrc (RECOURSE) Mayer RJ et al. Placebo (n-266) Vs Trifluridine and tipiracil (n=534) 0.4 vs vs 2.0 P < HR 0.48 (CI ) 5.3 vs 7.1 P < HR 0.68 (CI Disease control rate was 44% in TAS-102 group and 16% for placebo Grade 3/4 adverse events: neutropenia (38%), anemia (18%), thrombocytopenia (5%) 53% of pts had a delay in beginning of next cycle by > 4 days due to toxicity. 14% of pts required dose reductions.

94 Salvage Therapy Choice of salvage therapy depends on initial treatment regimen Initial Therapy FOLFOX or CapeOx based FOLFIRI based 5-FU/LV or capecitabine FOLFOXIRI Salvage Therapy FOLFIRI or irinotecan ± EGFR-targeted agent (KRAS wild-type tumor only) FOLFOX/CapeOx; EGFR-targeted agent (KRAS WT tumor only) ± irinotecan FOLFOX; CapeOx; FOLFIRI; irinotecan ± oxaliplatin EGFR-targeted agent (KRAS wild-type tumor only) ± Irinotecan NCCN. Clinical practice guidelines in oncology: colon cancer. v Goodwin RA, et al. Clin Colon Rectal Surg. 2009;22:

95 Targeted Agents Improve Outcomes in the Salvage Setting Trial/ Author E3200 [1] Pretreated Population Design PFS, Mos HR OS, Mos HR 5-FU/irinotecan refractory (n = 829) FOLFOX/Bev vs FOLFOX vs Bev 7.3 vs 4.7 vs vs 10.8 vs EPIC [2] 5-FU/oxaliplatin refractory (n = 1298) Cetux/Iri vs Cetux 4.0 vs vs [3] One 5-FU based regimen, KRAS WT (n = 597) FOLFIRI/Pmab vs FOLFIRI 5.9 vs vs VELOUR [4] FOLFOX (n = 1226) FOLFIRI/aflibercept vs FOLFIRI NCIC CO.17 [5] Amado [6] CT refractory, KRAS WT (n = 230) CT refractory, KRAS WT (n = 243) 6.9 vs vs Cetux/BSC vs BSC 3.7 vs vs Pmab/BSC vs BSC 12.3 wks vs 7.3 wks All survival outcome differences significant except OS in EPIC, 181, and Amado vs Giantonio BJ, et al. J Clin Oncol. 2007;25: Sobrero AF, et al. J Clin Oncol. 2008;26: Peeters M, et al. J Clin Oncol. 2010;28: Tabernero J, et al. ECCO-ESMO Abstract LBA6. 5. Karapetis CS, et al. N Engl J Med. 2008;359: Amado RG, et al. J Clin Oncol. 2008;26:

96 Grade 3/4 Chemotherapy-Associated Toxicities in mcrc: Phase III Experience Regimen Neutropenia,% Diarrhea, % Neurosensory, % HFS, % Capecitabine CapeOx FU/LV (infusional) FOLFIRI FOLFOX IFL mfolfox Grenon NN, et al. Clin J Oncol Nurs. 2009;13:

97 Organ Function and Treatment Liver dysfunction can significantly alter pharmacokinetics of drugs metabolized by the liver Irinotecan should be used with caution in patients with elevated serum bilirubin levels (> 2 mg/dl) Renal dysfunction Oxaliplatin contraindicated in patients with CrCl < 20 ml/min Capecitabine may result in increased toxicity for patients with reduced creatinine clearance Dose reduction of 25% indicated with CrCl ml/min 99

98 Bevacizumab Associated Toxicity Adverse Event Incidence With Bev Across Indications, [1] % Comments Grade 3 ATE 2.6 Risk of ATE increased in pts 65 yrs of age or older or with ATE history Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed GI perforations Grade 3 hemorrhagic event Bevacizumab not recommended for pts with serious hemorrhage or recent hemoptysis Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors Wound complications 15 Discontinue 4-8 wks before surgery, resume 6-8 wks postsurgery *Predominantly grade 3. May apply more to NSCLC. When surgery conducted during bevacizumab therapy. Potential for increased VTE risk controversial, increased risk noted in 1 study, but not in others [2,3] 1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; Nalluri SR, et al. JAMA. 2008;300; Hurwitz H, et al. J Clin Oncol. 2011;29:

99 Surveillance A. NCCN Guidelines 1. Stage I, II, III Colon and Rectal Cancer a. Colonoscopy at 1 year, if normal repeat in 3 years, then every 5 years b. History and physical exam every 3-6 months x 2 years, then every 6 months for a total of 5 years c. CEA every 3-6 months x 2 years, then every 6 months for a total of 5 years d. CT of the chest, abdomen, and pelvis annually for up to 5 years

100 Surveillance A. NCCN Guidelines (Cont.) 2. Stage IV Colon and Rectal Cancer a. Colonoscopy at 1 year, if normal repeat in 3 years, then every 5 years b. History and physical exam every 3-6 months x 2 years, then every 6 months for a total of 5 years c. CEA every 3-6 months x 2 years, then every 6 months for 3-5 years d. CT of the chest, abdomen, and pelvis every 3-6 months x 2 years, then every 6-12 months for a total of 5 years

101 Surveillance B. ASCO guidelines 1. Colonoscopy 1 year after initial surgery and then every 5 years, dictated by the findings of the previous one. If not performed before diagnosis, a colonoscopy should be performed after completion of adjuvant therapy before 1 year 2. History and physical examination every 3 to 6 months for 5 years 3. Carcinoembryonic antigen (CEA) every 3 to 6 months postoperatively for 5 years 4. Annual CT of the chest, abdomen, pelvis for 3 years after primary therapy

102 Supportive care for colorectal cancer patients a. Dermatologic toxicities b. Hypersensitivity reactions c. Oxaliplatin neurotoxicity d. Irinotecan-induced diarrhea

103 EGFR inhibitor papulopustular (acneiform) rash 75 to 90% of patients receiving EGFR inh. 32% of providers will discontinue therapy and up to 76% hold therapy Onset; within the first 2 weeks of treatment

104 EGFR inhibitor papulopustular (acneiform) rash Rash is characterized by papules and pustules coupled with pruritus and pain 1) Distributed in seborrheic areas, such as the face and scalp but is not acne as no comedones are seen and histopathology differs 2) Changes in the appearance of the skin lesions, oozing of fluid, yellow and/or brown crusting may be symptoms of superinfection and should be treated promptly a) Superinfection can occur in up to 38% of patients d. Positive correlation between rash severity and occurrence with overall survival and tumor response has been proven, therefore it is important to manage the rash so therapy can continue

105 EGFR inhibitor papulopustular (acneiform) rash EGFRs play an important role in the development, integrity and physiology of normal skin via the regulation of keratinocyte proliferation, differentiation and survival Positive correlation between rash severity and occurrence with overall survival and tumor response has been proven, therefore it is important to manage the rash so therapy can continue

106 Management of EGFR inhibitor-associated papulopustular rash Skin and subcutaneous tissue disorders Grade ADRs Rash acneiform : Papules and/or pustules covering <10% BSA, which ± with symptoms of pruritus or tenderness covering 10-30% BSA, which ± with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL covering >30% BSA, which ± with symptoms of pruritus or tenderness; limiting self care ADL; associated with local superinfection with oral antibiotics indicated covering any % BSA, which ± with symptoms of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; life threatening consequences Death

107 Management of EGFR inhibitor-associated papulopustular rash 1. Multinational Association for Supportive Care (MASCC) in Cancer Skin Toxicity Study Group clinical practice guidelines for prevention and treatment of EGFR inhibitor-associated dermatologic toxicities a) Pre-emptive management should be used in all patients due to the high frequency of rash and the fact that it consistently presents in the first 2 to 4 weeks of therapy a) i. Hydrocortisone 1% combined with a moisturizer, sunscreen and doxycycline 100 mg BID for the 1st 6 weeks is recommended based on trial data b) ii. Another study showed that prophylactic minocycline 100 mg QD is also effective c) iii. Note: doxycycline seems to be better tolerated than minocycline, especially in patients with renal dysfunction. Minocycline is less photosensitizing; therefore, preferred in areas with a high UV index.

108 Management of EGFR inhibitor-associated papulopustular rash 1.) Multinational Association for Supportive Care (MASCC) in Cancer Skin Toxicity Study Group clinical practice guidelines for prevention and treatment of EGFR inhibitor-associated dermatologic toxicities a. Reactive management consists of the use of medium- to high-potency topical corticosteroids (alclometasone 0.05% cream or fluocinonide 0.05% cream BID), topical clindamycin 1%, and/or oral antibiotics (doxycycline or minocycline) 2) Other guidelines and recommendations exist, all espousing similar approach 3) Standard acne therapies should be avoided as they will worsen rash

109 Summary of recommendations for treatment 1) Pre-emptive management a) Hydrocortisone 1% with a moisturizer, sunscreen, and doxycycline 100 mg BID i. For at least 1st 6 weeks 2) Reactive management a) Grade 1: topical hydrocortisone and clindamycin b) Grade 2: topical hydrocortisone, oral doxycycline or minocycline c) Grade 3/4: Modify chemotherapy dose per PI; topical hydrocortisone, oral doxycycline or minocycline, oral prednisone

110 Hand-foot syndrome vs hand foot reaction Dose dependency, pain, and a palm plantar distribution can be seen with both hand foot syndrome (HFS) and hand foot skin reaction (HFSR), however they differ in both histopathological and clinical features

111 Hand-foot syndrome vs hand foot skin reaction HFSR multikinase inhibitors, including sorafenib, sunitinib, and regorafenib Onset; 2 to 4 weeks after therapy is initiated Loss of repair mechanisms by endothelial cells and fibroblasts, when combined with daily trauma may result in the characteristic palmoplantar symptoms HFS (palmar-plantar erythrodysesthesia) conventional cytotoxic chemotherapies, including capecitabine and 5-FU few days to up to 10 months after therapy initiation More diffuse regions of edema and erythema than seen with HFSR Longer exposure to drug appears to increase incidence

112 Hand foot skin reaction Presents with dysesthesias, erythema or paresthesias involving the palms and soles with blisters which are followed by thick hyperkeratotic, tender lesions Lesions arise in areas of friction and / or trauma including the flexural surface of interphalangeal joints, distal phalanges or heels and may significantly impact weight-bearing ability and mobility of patients May manifest as loss of finger prints

113 Hand foot skin reaction Preemptive strategies are crucial in the management of HFSR123: a) Perform full body exam to locate hyperkeratotic regions on palms / soles and removal of all calluses b) Wear thick cotton gloves and/or slippers or socks c) Avoid: i. Exposing skin to hot water ii. Friction or trauma for the first 2-4 weeks of therapy iii. Rigorous exercise (especially during first 4 weeks of therapy) iv. Tight fitting shoes v. Excessive pressure when applying lotions

114 Hand foot skin reaction Data emerging supporting topical urea prior to and during treatment i. Randomized, open-label trial of 871 patients with hepatocellular cancer receiving sorafenib received 10% urea-based cream versus placebo124 (a) 12-week incidence of any grade HFSR was 56% vs. 73.6% with significantly longer time to first occurrence of HFSR (84 days vs 34 days)

115 Hand-foot syndrome Longer exposure to drug appears to increase incidence; e.g. continuous infusion 5-FU has higher incidence versus bolus administration Initial symptom is paresthesias followed by symmetrical painful erythema and edema of the palms and soles after 3 to 4 days; if not managed the lesions may blister, desquamate, form crusts, ulcerate or progress to epidermal necrosis

116 Hand-foot syndrome Conflicting data regarding use of pyridoxine (vitamin B6) for prevention and / or treatment of HFS but a randomized controlled trial to prevent capecitabine-induced HFS was negative so not recommended Use of corticosteroids is also conflicting and cannot be recommended Regional cooling strategies also lack adequate evidence to support its use

117 Grading Skin and subcutaneous tissue disorders Grade ADRs Palmar-plantar erythrodysesthesia syndrome Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self care ADL - -

118 Management of HFS and HFSR Grade 0 a) Prophylaxis with ammonium lactate 12% cream BID or heavy moisturizer (petroleum- or lanolin-based ointments) BID Grade 1 a) Continue antineoplastic treatment at current dose and monitor for change in severity b) Urea 20% cream BID AND clobetasol 0.05% cream daily c) Reassess in 2 weeks; if reaction is worse or not improved proceed to treatment of next grade

119 Management of HFS and HFSR Grade 2 a) Continue antineoplastic treatment at current dose and monitor for change in severity b) Urea 20% cream BID AND clobetasol 0.05% cream daily to BID AND pain control with NSAIDs / GABA agonists or opioids c) Reassess in 2 weeks; if reaction is worse or not improved proceed to treatment of next grade

120 Management of HFS and HFSR Grade 3 a) Hold antineoplastic therapy until severity decreases to grade 0 or 1 b) Clobetasol 0.05% cream BID AND pain control with NSAIDs / GABA agonists or opioids c) Reassess in 2 weeks and if reaction is worse or not improved then dose interruption or discontinuation per PI may be necessary

121 HFS Skin and subcutaneous tissue disorders Grade ADRs Palmar-plantar erythrodysesthesia syndrome Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting instrumental ADL Severe skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting self care ADL

122 Oxaliplatin-induced neurotoxicity Dose-limiting toxicity that is a persistent sensory peripheral neuropathy ;all dose levels and schedules of administration Up to 97% of patients receiving oxaliplatin will have neurologic symptoms and abnormalities during treatment stocking-glove distribution

123 Oxaliplatin-induced neurotoxicity Acute neurotoxicity sensory disturbance paresthesia, dysesthesia, and hypoesthesia Pharyngolaryngeal dysesthesias Hours to days following treatment Chronic neurotoxicity Persistent sensory chemotherapyinduced peripheral neuropathy that is gradually progressive in onset Pain and paresthesias can completely resolve in some cases and may only be partially reversible or permanent in others Associated with cumulative doses between >540 to 850 mg/m2

124 Oxaliplatin-induced neurotoxicity Prevention (Acute) Prevention of acute oxaliplatin-induced neuropathy Dose reduction

125 Oxaliplatin-induced neurotoxicity Stop-and-Go Approach (OPTIMOX1) Arm A = FOLFOX4 every 14 days until disease progression or toxicity Arm B = FOLFOX7 for 6 cycles, followed by 12 cycles of maintenance 5-FU and leucovorin, and reintroduction of FOLFOX7 for an additional 6 cycles Primary endpoint was duration of disease control (DDC), progression free survival (PFS)

126 Oxaliplatin-induced neurotoxicity Grade 3 sensory neuropathy in 18% of patients in Arm A and 13% in Arm B (p=0.12) Discontinuing oxaliplatin after 6 cycles followed by 5-FU maintenance achieved similar PFS, OS, and response rates compared to continuing oxaliplatin until disease progression or toxicity. Patients that received maintenance therapy experienced less grade 3 and 4 toxicities compared to those that received continuous therapy with FOLFOX, including less neuropathy This approach may be considered for preventing and/or delaying the development of sensory neuropathy in patients receiving oxaliplatin-based chemotherapy

127 Oxaliplatin-induced neurotoxicity Ca/Mg infusions NCCN Guidelines recommendation there is no data to support the routine use of Ca/Mg infusions to prevent oxaliplatin-related neurotoxicity and therefore should not be used The American Society of Clinical Oncology (ASCO) guideline for prevention and management of chemotherapy-induced neuropathy also does not recommend the use of Ca/Mg infusions for patients receiving oxaliplatinbased chemotherapy. The guideline does support a moderate recommendation for the use of duloxetine for the treatment of chemotherapy induced peripheral neuropathy.

128 Chemotherapy-Induced Diarrhea Any chemotherapeutic agent may cause diarrhea Higher rates in irinotecan, 5-FU, methotrexate, cytarabine, tyrosine kinase inhibitors, immune checkpoint inhibitors and stem cell transplant conditioning 50-80% of patients receiving modulated 5-FU regimens, single-agent irinotecan, and combination regimens of irinotecan and 5-FU experience diarrhea and greater than 30% of these patients may experience grade 3 to 5 diarrhea Underlying malignancy, infectious diseases, radiation, dietary changes and many supportive care drugs can contribute to chemotherapy-associated diarrhea

129 Diarrhea Grade ADRs Diarrhea Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to baseline Increase of 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living Lifethreatening consequenc es; urgent intervention indicated Death

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