Colorectal Cancer Learning Materials

15 Cancer ColonColon Cancer Colorectal Cancer Dr. Leiva Colon CA Screening Recommendations Average Risk Recommendation Interval Fecal occult blood test (FOBT) OR Fecal immunochemical test (FIT) Annually ACS: Age ≥45 years Exam The decision to screen between ages 76-85 years should be individualized FIT-DNA test weBetter Flexible sigmoidoscopy Colonoscopy Every 1 or 3 years# tes s Every 5-10 years* Every 10 years CT colonography (virtual colonoscopy) Every 5 years Any one of the above options is appropriate NCCN=National Comprehensive Cancer Network. USMSTF=U.S. Multi-Society Task Force on Colorectal Cancer ACS=American Cancer Society. USPSTF=United States Preventative Services Task Force *NCCN and USMSTF allow a range of 5-10 years, whereas ACS recommends every 5 years # NCCN®, ACS, & USMSTF recommend every 3 years, whereas USPSTF recommends every 1 or 3 years Eons A Colonoscopy • Colonoscopy advantages: • Views entire colon • Provides information on the mucosa of the entire colon • Can be used for biopsy or excision of e Is polyps • Highly sensitive diagnostic tool • Disadvantages: • Full bowel preparation • Expensive • Sedation needed • Risk of bowel tears or infection Rog At Staging of disease (T) is based on the depth of tumor involvement, not size of the mass TNM Staging of Colorectal CA Colon and rectal cancers metastasize to liver, lung, peritoneum, bone, and brain e Transition of normal mucosa to adenomatous polyps (adenoma) to colorectal cancer 5% of adenomatous polyps are estimated to become malignant after 5-10 years • Adenoma < 1 cm has 1% chance of developing into cancer • Adenoma > 2 cm has 40% chance of developing into cancer tamormakerto we CEA (Carcinoembryonic Antigen) • CEA is a glycoprotein normally found in embryonic entodermal epithelium • Increased levels of CEA may be found in colorectal cancer • May be useful in monitoring colorectal cancer response to treatment Monitoring CEA is not recommended for colorectal cancer screening • Most healthy subjects (97%) have values ≤ 3 ng/mL – smokers can have higher CEA levels • Serial monitoring of CEA should begin prior to therapy to verify post therapy decrease in concentration and to establish a baseline for evaluating possible recurrence • Grossly elevated CEA concentrations (>20 ng/mL) in a patient with compatible symptoms are strongly suggestive of the presence of cancer and also suggest metastasis Genetic Mutations and Aberrations • Test for these mutations if the patient is metastatic • KRAS/NRAS/BRAF Signaling pathway– Predictive response to Anti-EGFR drug if Wild Type • KRAS – Mutation associated with Right sided tumors • NRAS - Mutation associated with Right sided tumors • BRAF – Mutation associated with Right sided tumors • If patient has the BRAF V600E mutation, we can add a TKI to make the Anti-EGFR drugs work for some patients) dMMR and MSI-High • Test ALL colon cancer patients regardless of stage • Predictive Response to Checkpoint Inhibitors and no benefit to 5FU in early stage disease (Stage II) Gay • Mismatch Repair Deficient (dMMR) • Microsatellite Instability High (MSI-H) • Lynch Syndrome – Autosomal dominant Germline mutation that increases risk of colorectal cancer related to dMMR • Checkpoint inhibitors often effective for metastatic disease if not appropriate for aggressive therapy Workup and Treatment Algorithm Resectable Disease – Adjuvant Therapy if Appropriate • MMR/MSI testing Then Resection?? Stages 0 - III Stages 0-IIC Stage II w/high risk for recurrence Stage IIIA-IIIB (Low Risk Stage III) Stage IIIA-IIIC (High Risk Stage III) Surveillance Frequency and method depend on Stage and Risk of Recurrence Fluorouracil/5-FU • Administration: • CIVI usually dosed 1200 mg/m2/day x 2 days • CIVI during radiation therapy 300-1000mg/m2/day x 5 days • Bolus dose given over 10 minutes – more mucositis • Drug Interactions: Allopurinol interferes w/ activation of 5-FU • Monitoring: • • CBC w/ diff, LFTs, neuro checks • Nadir Day 9-14, recovery Day 30 • Antidotes to 5-FU – Uridine Triacetate (Vistoguard) - 10 grams orally every 6 hours for 20 doses AT ADRs: Stomatitis, diarrhea, hand-foot syndrome, photosensitivity, alopecia, cardiac events – vasospasm/angina/cardiac failure, neutropenia, neurotoxicity – acute cerebellar syndrome (confusion, ataxia, visual disturbances) 5-FU Adverse Effects • Patients with dihydropyrimidine dehydrogenase deficiency (DPD) should not receive 5-FU. • Creates an inability or impaired ability in some patients to detoxify fluorouracil in the liver. • Increases risk for acute early-onset toxicity • Severe, life-threatening and fatal adverse reactions • Routine screening is not universally performed Leucovorin • MOA: Increases the efficacy of 5-FU by stabilizes the complex between FdUMP and thymidylate synthase • Administration: • When given in FOLFOX run over 2 hours w/ Oxaliplatin • When given in FOLFIRI run over 90 minutes w/ Irinotecan • Had a Critical Shortage in the US • Dosing Modifications: • None • Drug Interactions: Potentiates 5-FU activity • ADRs: Related to concurrent chemotherapy; N/V, diarrhea, and dehydration Capecitabine (Xeloda) • PO prodrug of 5-FU • Administration: • Multiple doses depending on regimen • Often given on Days 1-14 of 21 day cycle • Taken with food • Drug Interactions: Strong CYP2C9 Inhibitor  Avoid Warfarin • Dosing Modifications: • CrCl <30 mL/min contraindicated • Monitoring: • CBC w/diff, LFTs, SrCr, BUN DLT e • ADRs: paresthesias, HA, peripheral neuropathy, Hand-foot syndrome (~60%), cardiac events, BMS, diarrhea – median time to first occurrence was 34 days L Capecitabine (Xeloda®) Adverse Effects • Adverse effects are similar to continuous-infusion regimens of 5-FU • Constant blood level is maintained through oral administration • Diarrhea • Mucositis • Hand-foot syndrome • Minimal myelosuppression Oxaliplatin (Eloxatin) Administration: • Only compatible w/ D5W • Infused over 2 hours • Do NOT let patient drink cold beverages or eat very cold food during their infusion and 5-7 days after • Wear a scarf and avoid fans or Air Conditioning Exposure to prevent laryngospasm • 6-8th Dose reactions are more common • Irritant if extravasated Dosing Modifications: • Reduce in Renal impairment Monitoring: • CBC w/ diff, LFTs, SrCr ADRs: Alopecia, moderately emetogenic, acute and persistent neuropathy, BM suppression, HSR The Regimens FOLFOX (Given every 2 weeks x 6 months) • Oxaliplatin • Leucovorin • Fluorouracil (Continuous IV infusion + bolus) CapeOX (Given every 3 weeks for 3 months) • Capecitabine • Oxaliplatin Stage IV - M1 Disease Chemotherapy +/- Biotherapy Start with either an Oxaliplatin OR Irinotecan containing regimen Stage IV - M1 Disease • First line Therapy Combinations For Patients • First line Therapy For Patients who CAN’T who CAN tolerate aggressive therapy tolerate aggressive therapy • FOLFIRINOX • 5FU + Leucovorin +/- Bevacizumab • Addition of Bevacizumab • FOLFOX • Capecitabine +/- Bevacizumab • Addition of Bevacizumab • EFGR inhibitor ONLY FOR KRAS/NRAS/BRAF • EFGR inhibitor ONLY FOR WT LEFT SIDED TUMORS KRAS/NRAS/BRAF WT LEFT SIDED TUMORS • Nivolumab or Pembrolizumab (dMMR, MSI• FOLFIRI H only) • Addition of VEGF Inhibitor OR EGFR inhibitor • Trastuzumab + Pertuzumab or Lapatinib • EFGR inhibitor ONLY FOR (HER2 + and RAS/BRAF WT) KRAS/NRAS/BRAF WT LEFT SIDED TUMORS • Nivolumab + Ipilimumab OR pembrolizumab (dMMR, MSI-H only) Stage IV - M1 Disease • First Line  Second Line  Subsequent Lines • Principles are to continue to use the regimen that is most effective and least toxic for as long as possible. • If progression on therapy or <12 months after finishing, then switch up regimen and agents • If progressed on Oxaliplatin  Switch to Irinotecan  Switch to or add biologic or small molecule inhibitors as appropriate for the patient. • Regorafenib is the last ditch effort. Final drug in the arsenal. • Must have failed 5FU/Capecitabine, Oxaliplatin, Irinotecan, anti-VEGF, and antiEGFR (if appropriate) Stage IV - M1 Disease • Irinotecan (Camptosar) ”I ran to the can” • Administration: • Given over 90 minutes • Give Atropine IVPush as premed and PRN cramping/diarrhea – can happen within 30 min of administration • Dosing Modifications: • Hepatic impairment • Caution: UGT1A1*28 polymorphism • 10% of North Americans are homozygous for UGT1A1*28 allele • Decreased glucuronidation of SN38, thus increased toxicity of irinotecan • Moderately emetogenic • Monitoring: • CBC w/ diff, LFTs • ADRs: Severe diarrhea!!! Alopecia, BM suppression, other cholinergic ADRs Irinotecan Adverse Effects • Diarrhea (“I ran to the can”) • Two phases of irinotecan-induced diarrhea: • Early-onset diarrhea (≤ 24 hrs): Atropine 0.25 – 0.4 mg IV is given prophylactically • Cholinergic surge from inhibition of acetylcholinesterase • Late-onset diarrhea (> 24 hrs): Treated with intensive loperamide • 4 mg po at 1st onset, then 2 mg p.o. q2h until diarrhea-free for 12 hours; max dose of 16 mg/day doesn’t apply • Incidence • Chemotherapy-induced diarrhea (CID) ~ 50-80% • Regimens containing 5-FU and irinotecan ~80% EGFR Inhibitors • Indications: • KRAS/NRAS/BRAF WT Left sided Tumors or In combination with encorafenib for patients with BRAF V600E mutations. • Cetuximab • Panitumumab • Class ADRs • Acineform rash, infusion reactions, pt electrolyte abnormalities, cardiac sabpplemented arrest WINE next Cetuximab (Erbitux) IngeRosh • Only efficacious in KRAS/NRAS WT/BRAF WT patients with Left-sided tumors UNLESS it’s given with encorafenib if they have a BRAF V600E Mutation • Administration: • • • • Premed w/ Diphenhydramine First dose higher (LD); if concurrent w/radiation, loading dose must be given 7 days prior to XRT. Use in-line filter to administer NTE 10 mg/min infusion rate • Loading Dose given over 2 hours • Subsequent doses given over 1 hour • Monitoring: • Mg, K+, Ca2+ • ADRs: 88% of patients get acneiform rash w/in first 2 weeks of therapy, diarrhea, bone pain, and fatigue; Severe ALL reactions in the Southeast due to alpha-galactose cross-reactivity from tick bites (Alpha-gal syndrome) and other potential antigen exposures Panitumumab (Vectibix)) • Only efficacious in KRAS/NRAS WT/BRAF WT patients with Left-sided tumors UNLESS it’s given with either Dabrafenib + Trametinib OR Vemurafenib because they have a BRAF V600E mutation • Administration: • In-line filter for administration • Infuse over 60-90 min • Monitoring: • Mg, K+, Ca2+ • ADRs: 74% of patients get acneiform rash, fatal infusion reactions, eye toxicities, pulmonary fibrosis, and fatigue Nivolumab (Opdivo) • MOA: PD-1 receptor inhibitor, immune checkpoint inhibitor NiveBefePI thecombinationsBetter survival do consistlychedited moretoxict • Dosing: • 240 mg with ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks OR • 240 mg every 2 weeks or 480 mg every 4 weeks • Administration: • In-line filter for administration • Run over 30 minutes; always give first when giving in combo • Monitoring: • CBC w/diff and CMP prior to every dose • Full thyroid panel (every 6 weeks or every cycle if given with ipi), Free random cortisol every 8 weeks • No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune -mediated adverse reactions. Permanently discontinue OPDIVO for lifethreatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids • ADRs: • As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection • In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness Ipilimumab (Yervoy) • MOA: CTLA4 inhibitor • Dosing: 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses ONLY in combo with Nivolumab. Not used as a single agent in CRC • Administration: • In-line filter for administration • Run over 30 minutes • Monitoring: • CBC w/diff, CMP prior to every dose, full thyroid panel • Free random cortisol every 6-9 weeks • ADRs: • Most common adverse reactions (≥20%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. (6.1) Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness Small Molecule Inhibitors • BRAF Inhibitors: For use ONLY IN PATIENTS WITH BRAF V600E Mutation • Encorafenib • Multi-kinase Inhibitor – Given as single agent – Last drug before we stop • Regorafenib Regorafenib (Stivarga) • Indicated for metastatic CRC that has failed all the standard therapies • Multi-kinase Inhibitor – Targets: EGFR, VEGFR, BRAF, RAF-1, BRAF V600E, etc • Administration: • PO w/ low fat breakfast Days 1-21 every 28 Days • Dosing Modifications: • Hepatic impairment • Drug Interactions: CYP3A4 substrate • Monitoring: • LFTs baseline and every 2 weeks x 2 months, then monthly • ADRs: Muscle stiffness, GI perforation, hypertension, delayed wound healing, hepatoxicity, bleeding, hand-foot syndrome, diarrhea, the “penias” VEGF Inhibitors • Indication: Metastatic CRC with Chemo (5FU, Oxaliplatin, Irinotecan) • Bevacizumab • Ramucirumab • Ziv-alfibercept • Class ADRS: • GI Perforation, Hypertension, Proteinuria, Nephrotic syndrome, thrombotic events Bevacizumab (Avastin) • Administration: • Held for 28 days prior to surgery and 28 days after surgery • BP >160/90 (Hold) • Initial infusion 90 min • 2nd infusion 60 min • Remaining 30 min • Monitoring: • Urinalysis for proteinuria (do 24 hour collection for >2+), BP Q 2 weeks, CBC w/diff • ADRs: Hypertension, proteinuria, severe bleeding, GI perforations, VTE, DVT, POOR WOUND HEALING Ziv-alfibercept (Zaltrap) • MOA: Similar to the others but the fusion protein acts as a decoy receptor for VEGF-A, VEGF-B, and Placental growth factor to prevent activation of VEGFR. • Administration: • Held for 4 weeks prior to surgery and 4 weeks after surgery • HOLD FOR <1500 • Monitoring: • Urinalysis for proteinuria (do 24 hour collection for >2+), BP Q 2 weeks, CBC w/diff • ADRs: Hypertension, proteinuria, severe bleeding, Diarrhea, GI perforations, VTE, DVT, POOR WOUND HEALING, neutropenia/febrile neutropenia Ramucirumab (Cyramza) • Administration: • Held for prior to surgery and until proper wound healing per clinical judgement • BP >160/90 (Hold) – No firm number but may providers use the same numbers as Bevacizumab • Premedicate with Dexamethasone and acetaminophen; should add H1 blocker if patient previously had a mild reaction. • Monitoring: • Urinalysis for proteinuria (do 24 hour collection for >2+), BP q 2 weeks, CBC w/diff • ADRs: Hypertension, proteinuria, severe bleeding, GI perforations, VTE, DVT, POOR WOUND HEALING Stage IV - M1 Disease • First Line  Second Line  Subsequent Lines • Principles are to continue to use the regimen that is most effective and least toxic for as long as possible. • If progression on therapy or <12 months after finishing, then switch up regimen and agents • If progressed on Oxaliplatin  Switch to Irinotecan  Switch to or add biologic or small molecule inhibitors as appropriate for the patient. • Regorafenib is the last ditch effort. Final drug in the arsenal. • Must have failed 5FU/Capecitabine, Oxaliplatin, Irinotecan, anti-VEGF, and anti-EGFR (if appropriate) Advanced or metastaticdisease t I PIcantakeaggressivetherapy Screening 2 EGFR IKRIsNRIs • ACS screening guidelines ptcan'ttakeaggressivetherapy CEA and Genetic Mutations pond • Genetic Mutations If pthaveRIamoreno Noses • Screening or symptomatic to EIB Wrap Up inhibitor Treatment for Stages 0-III • Adjuvant • Neoadjuvant  Surgery  Adjuvant if inoperable Treatment for Metastatic Disease • Neoadjuvant  Surgery  Adjuvant if inoperable (Depending on Metastatic Sites like Liver or Lung • First Line  Second Line  Subsequent  Clinical Trial or Best Supportive Care