Colorectal Cancer Therapy and Associated Toxicity
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1 Colorectal Cancer Therapy and Associated Toxicity Mountain States Cancer Conference November 6, 2010 Colin D. Weekes, M.D., Ph.D Assistant Professor University of Colorado
2 GI Cancers Are Common 2009 Estimated U.S. Cancer Deaths Available at: Lung and bronchus 30% Prostate 9% Colon and rectum 10% Pancreas 6% Leukemia 4% Liver/bile duct 4% Esophagus 4% Urinary bladder 3% Non-Hodgkin Lymphoma 3% Kidney 3% All other sites 24% Men 292,540 Women 269,800 Colorectal cancer represents 2 nd leading cause of death Available at: 26% Lung and bronchus 15% Breast 9% Colon and rectum 6% Pancreas 5% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Brain/other nervous system 2% Liver/bile duct 23% All other sites
3 Goals Define TherapeuHc Groups Discuss Treatment OpHons Discuss Treatment Related Toxicity & Management Discuss Cancer Surveillance OpHons
4 Colon Cancer Staging
5 Prognosis
6 Treatment OpHons Adjuvant Therapy Stage II High Risk and III High Risk Features Grade 3 or 4 Lymphovascular invasion Bowel obstruchon < 12 lymph nodes disected indeterminant or posihve margins peroforahon Systemic Therapy MetastaHc Disease
7 Colorectal Cancer Treatment Options Cytotoxics Mechanism 1. 5-Fluorouracil (5-FU) -> pyrimidine analog 2. Capecitabine (Xeloda) -> oral 5-FU pro-drug 3. Irinotecan (Camptosar) -> topoisomerase I inhibitor 4. Oxaliplatin (Eloxatin) -> 3 rd generation platinum Biologics Mechanism 1. Cetuximab (Erbitux) -> antibody against EGFR Epidermal Growth Factor Receptor 2. Panitumumab (Vectibix)-> antibody against EGFR 3. Bevacizumab (Avastin) -> antibody against VEGF Vascular Endothelial Growth Factor
8 Proposed Mechanism of Action of Cetuximab (Erbitux) ERBITUX package insert, February 2004
9 Blood Vessels and Tumor Growth Solid tumors cannot grow beyond 1 to 2 mm 3 without an increase in blood supply via new vessel formation 1 Angiogenesis is thus required for tumor growth and metastasis 1 Inhibition of tumor angiogenesis leads to tumor cell growth arrest, death of tumor cells, and in some cases, tumor regression 2 Tumor angiogenesis is stimulated Courtesy of Novartis Oncology New vessels then facilitate tumor growth.
10 VEGF: A Central Mediator of Angiogenesis Environmental factors 1 (hypoxia, ph) Growth factors, hormones 1 (EGF, bfgf, PDGF, IGF-1, IL-1α, IL-6, estrogen) VEGF Binding and activation of VEGF receptor 2 Genes involved in tumorigenesis 1,3 (p53, p73, src, ras, vhl, bcr-abl) Endothelial cell activation 2 P P P P Survival Proliferation Migration 1. Dvorak. J Clin Oncol. 2002;20: Ferrara et al. Nat Med. 2003;9: Ebos et al. Mol Cancer Res. 2002;1:89. ANGIOGENESIS
11 Role of K ras in CRC Therapy
12 EGFR Ras Signal Transduction
13 NEJM 2008
14 Therapy for Advanced Colorectal Cancer: Response rates and survival First Line Second Line Third Line - FOLFOX or - FOLFOX or - Irinotecan + - CAPOX or - FOLIRI or Cetuximab - FOLFIRI - Irinotecan alone - Cetuximab +/- Bevacizumab - Irinotecan/Cetuximab - Panitumumab +/- Bevacizumab Response Rates in Randomized Trials: 30-60% 5-15% 10-20% Survival Benefit in Randomized Trials: Yes Yes Yes
15 Incremental Survival Advantage in First Line Metasta>c Colorectal Cancer No active drug ~4-6 mo 5-FU/LV IFL FOLFOX4 IFL + bevacizumab FOLFOX/FOLFIRI FOLFOX/FOLFIRI + biologics mo ~ mo ~ 20 mo 20.3 mo Median OS (mo) 21.5 mo?
16 Chemotherapy Toxicity 5 FU Bone Marrow Suppression GI Toxicity Hand and Foot Syndrome Cardiovasospasm Ocular Toxicity Irinotecan Bone Marrow Suppression Diarrhea Alopecia OxaliplaHn Bone Marrow Suppression Neuropathy Acute Chronic
17 Bevacizumab Toxicity Hypertension Impaired Wound Healing RPLS Reversible Posterior Leukoencephalopathy Syndrome NEJM 354:980, 2006
18 EGFR Toxicity Skin Rash Kidney Hypomagnesemia GI Diarrhea
19 Early Stage Surveillance J Clin Oncol 27:3671,2009
20 Surveillance J Clin Oncol 27:3671,2009
21 Surveillance J Clin Oncol 27:3671,2009
22 Summary Colon cancer outcomes have improved with addihon of biologic therapies Chemotherapy side effects are managable Aggressive surveillance does impact survival
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