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Colorectal Cancer Hannah Allegretto University of Pittsburgh School of Pharmacy Pharm D. Candidate 2013 Epidemiology • Lifetime risk: 1/20 • Slightly lower in women than in men • 3rd leading cause of cancer-related deaths in the US • Responsible for over 51,500 deaths in 2012 • Median age of diagnosis: 45 years old • Survival dependent on extent of disease at diagnosis • 5 year survival: • 90% for localized • 66% of regional • 9% for distant Risk Factors • Genetic predisposition • Hereditary nonpolyposis colon cancer (HNPCC) – “Lynch Syndrome” • Familial adenomatosis polyposis (FAP) • Lifetime risk ~100% without intervention • Inflammatory Bowel Disease • Polyps • Diet • Red and processed meat consumption • Smoking • Alcohol consumption • Obesity • Diabetes Prevention Strategies • Diet • • • • High fiber, low fat Decrease consumption of red and processed meat Increase fruit and vegetable consumption Increase milk and calcium consumption • Abstain from smoking • Limit alcohol consumption • Physically active lifestyle • NSAID use Signs and Symptoms • Change in bowel habits • Rectal bleeding/bloody stools • Abdominal discomfort • Persistent cramps, gas, or pain • Weakness and fatigue • Unexplained weight loss Screening Recommendations Average Risk Screening • Beginning at age 50, both men and women at average risk should use one of the following tests: • • • • • Flexible sigmoidoscopy every 5 years Colonoscopy every 10 years (preferred) Double-contrast barium enema every 5 years CT colonography every 5 years Digital Rectal Exam (DRE) • Family History • Screening at 35-40 years old • HNPCC • Screening at age 30 • FAP • Screening at age 10-12 Staging Stage Description 0 No growth beyond the inner layer of colon or rectum I Cancer has grown through muscularis into the submucosa or into the propria II Growth through wall of colon/rectum but not into other tissues or organs III Lymph node involvement IV Metastatic disease TNM Staging T = primary tumor Tx No description of tumor’s extent possible Tis Earliest stage (in situ). Mucosal involvement only T1 Extending into the submucosa T2 Cancer extends into thick outer muscle layer T3 Cancer extends into outermost layers of colon/rectum but not through them T4a Cancer has grown through the outermost lining of intestines T4b Cancer has grown through wall of colon/rectum and is attached to or invades nearby tissues or organs TNM Staging N = Regional Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1a Metastasis in one regional lymph node N1b Metastasis in 2-3 regional lymph nodes N2a Metastasis in 4-6 regional lymph nodes N2b Metastasis in 7+ lymph nodes TNM Staging M = distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1a Distant metastasis to 1 site M1b Distant metastasis to more than one site Treatment Options • Surgery – curative intent for stage I and II • Local Excision • Resection • Anastomosis • Colostomy • Radiation • External vs internal • Pharmacological Therapy • Chemotherapy • Monoclonal antibodies Treatment by Stage • Stage 0 and I • Local excision (stage 0) • Resection and anastomosis • Stage II and III • Resection and anastomosis followed by chemotherapy • Chemotherapy (often clinical trials) – Controversial in Stage II • Stage IV and Recurrent • • • • Resection and anastomosis Surgery to remove metastasis Radiation or chemotherapy (palliative) Monoclonal antibodies Pharmaceutical Options • FOLFOX • FOLFIRI • CapeOX • 5-FU and leucovorin, with or without bevacizumab • Capecitabine, with or without bevacizumab • FOLFOXIRI • Irinotecan, with or without cetuximab • Cetuximab alone • Panitumumab alone FOLFOX • FOLFOX 4 and modified FOLFOX 6 most widely used • Combination of 5-FU, leucovorin, and oxaliplatin • Repeated every 14 days for approximately 12 cycles FOLFOX 4 vs 6 FOLFOX 4 FOLFOX 6 Leucovorin 200mg/m2/day given as 2 hour infusion day on day 1 400mg/m2/day given as 2 hour infusion on day 1 5-Fluorouracil Bolus: 400mg/m2 and a 22 hour continuous infusion of 600mg/m2 repeated for 2 consecutive days Bolus: 400mg/m2 and a 22 hour continuous infusion of 1200mg/m2 repeated for 2 consecutive days Oxaliplatin 85mg/m2/day on day 1 85mg/m2/day on day 1 5-Fluorouracil • Mechanism of Action: • Inhibits thymidylate synthase (TS), which converts uracil to thymidine • Combination with leucovorin enhances toxicity of 5-FU • Toxicities: • • • • • Myelosuppression Diarrhea Photosensitivity Mucositis Hand-Foot Syndrome Leucovorin • Enhances the effects of 5-FU by stabilizing the binding to thymidylate synthase (TS) • TS important for DNA repair and replication • Advanced colorectal cancer meta-analysis project showed that 5-FU with leucovorin generated statistically significant response rates when compared to 5-FU monotherapy (23% vs 11%) • Adverse reactions: • D/N/V • Fatigue Oxaliplatin • Mechanism of Action: • Forms cross-linking-adducts, thus blocking DNA replication and transcription • Combination with leucovorin + 5-FU significantly improves response rates • Approved for both second-line and first-line treatment of colorectal cancer • Adverse effects: • • • • Sensitivity to cold Numbness/tingling in hands and feet Myelosuppression Nausea/vomiting FOLFIRI • Leucovorin + Irinotecan + 5-FU repeated every 14 days Agent Dose Leucovorin 200mg/m2 IV on day 1 5-FU 400mg/m2 IV push on day 1, followed by 2400mg/m2 CI over 46 hours 180mg/m2 IV on day 1 Irinotecan Irinotecan • Mechanism of Action: • Inhibits topoisomerase I impedes DNA uncoiling leading to double stranded DNA breaks • Adverse Reactions: • • • • • Alopecia Diarrhea – both early and late onset Loss of appetite Myelosuppression (neutropenia) Nausea/vomiting Other Agents • Capecitabine • MOA: pro-drug of 5-FU, inhibits DNA synthesis and slows growth of tumor tissue • Dose: Initial 2500mg/m2/day in two divided doses • 2 weeks on, 1 week off cycle • Oral administration • Adverse effects: • • • • Hand-foot syndrome Mucositis Myelosuppression Skin discoloration/nail changes Monoclonal Antibodies • Bevacizumab • Mechanism of action: • Monoclonal antibody against vascular endothelial growth factor (VEGF) • VEGF most potent proangiogenic factor • Indicated for use in 1st or 2nd line therapy in combination with 5-FU therapy for metastatic colorectal cancer • Dosing: 5mg/kg IV q 14 days Monoclonal Antibodies • Epidermal Growth Factor Receptor (EGFR) • Binding of a monoclonal antibody to extracellular domain of EGFR • Inhibits cell growth • Induces apoptosis • Decreases production of growth factors • Anti-EGFR Agents: • Cetuximab • Panitumumab Cetuximab • Indicated for metastatic colorectal cancer (k-ras mutation negative) EGFR expressing, as monotherapy for pts failing irinotecan/oxaliplatin, or in combination with FOLFIRI • Dosage: • 400mg/m2 IV loading dose of 120 minutes followed by 250mg/m2 IV over 60 minutes. • Complete dose 1 hour before starting chemotherapy regimen • Requires premedication with diphenhydramine 50mg IV 30 to 60 minutes before dose • Adverse reactions: • Skin reactions • Acne-like rash • Cracking on fingers and toes • Allergic Reaction • Diarrhea • Malaise Panitumumab • Indicated for EGFR-expressing metastatic colorectal cancer in patients progressing on or following 5-FU, oxaliplatin, and irinotecan-containing regimens • Dosing: • 6mg/kg IV over 1 hour every 14 days • Adverse Reactions: • • • • Acne-form rash Decreased magnesium Diarrhea Malaise The case • RB is a 56yo male referred to Chartwell Pharmacy to receive 5-FU therapy • PMH: • Colorectal cancer • Underwent resection and anastomosis • GERD • Family History: noncontributatory • Allergies: Penicillin, aspirin • Immunization History Unknown • Current Medications: • Omeprazole 20mg PO 30 minutes before breakfast The Case • Measurements: • Height: 71.5in • Weight: 78.2kg • BMI: 23.7 • Vitals: • BP: 138/86 HR: 82 RR: 16 • Patient reported pain scale: 0/10 • RB’s risk factors: • Previous smoker • Previous alcohol abuser The Case • Plan: • Colorectal Cancer Management • Initiate FOLFOX6 q14 days x 12 cycles • Oxaliplatin: 168mg IV over 2 hours on day 1 • Leucovorin: 792mg IV over 2 hours on day 1 • 5-FU: 792mg IV bolus day 1 followed by 4752mg IV continuous infusion over 46 hours • Pain Management: • Currently, no pain. Reassess at each subsequent visit. • If moderate pain develops, initiate hydrocodone/acetaminophen 5mg/325mg PO every 4 to 6 hours as needed. The Case • Chemotherapy-induced Nausea/Vomiting • FOLFOX6 = level 4 emetogenicity • Acute nausea/vomiting prevention • Dexamethasone 20mg IV over 20 minutes day 1 • Delayed nausea/vomiting treatment • Prochlorperazine 10mg PO q4h PRN • GERD Management • Continue omeprazole 20mg PO 30 minutes before breakfast • Unknown Immunization Status • Give Fluzone 0.5mL IM yearly • Discuss with PCP status of required immunizations References Boyle P, Leon ME. Epidemiology of colorectal cancer. British Medical Bulletin. 2002;64:1-25. Cunningham D, Atkin W, Lenz HJ et al. Colorectal cancer. Lancet. 2010; 375:1030-47. National Cancer Institute. Colon Cancer Treatment. Treatment Options for Colon Cancer. http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient/page5 (accessed 2012 Nov 29). Mayo Clinic. Colon Cancer. Symptoms. http://www.mayoclinic.com/health/coloncancer/DS00035/DSECTION=symptoms (accessed 2012 Nov 30). American Cancer Society. Colorectal Cancer. Treatment by stage of colon cancer. http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectalcancer-treating-by-stage-colon (accessed 2012 Nov 30). Jeon HJ, Woo JH, Lee HY et al. Adjuvant chemotherapy using the FOLFOX regimen in colon cancer. J Korean Soc Coloproctol. 2011;27: 140-6. References Longley DB, Harkin DP Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3: 330-38. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004; 350:2343-51. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350: 2335-42. Saltz LB, Meropol NJ, Loehrer PJ et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004; 22:120108. Douillard JY, Siena S, Cassidy J et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as firstline treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010; 28:4697-705.