Edward Greeno, M.D.
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Edward Greeno, M.D.



Creating Survivors: A century of treatment advances in colorectal cancer

Creating Survivors: A century of treatment advances in colorectal cancer



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    Edward Greeno, M.D. Edward Greeno, M.D. Presentation Transcript

    • Creating Survivors:A Century of Treatment Advances inColorectal Cancer Edward Greeno, MD Associate Professor of Medicine, University of Minnesota Medical Director, Masonic Cancer Clinic Executive Medical Director, UMPhysicians Cancer Care
    • 1900’s to 1960’s Surgery 2
    • 1965 to 1995 One Chemotherapy drug: 5-Fluorouracil Screening 3
    • Outcomes with 5-FU 30 years of progress Survival 6-12 months  Probable 1-2 mo improvement in survival (Fancy 5FU) (5FU) Ed finished fellowship Ed started kindergardenFrom:Lancet7/29/00
    • Screening Fecal Occult Blood testing randomized trials  MN: 48,000 annual 10%+ tests 33% lower CRC mortality  UK: 150,00 biennial 2%+ tests 15% lower CRC mortality  DN: 62,000 biennial 1%+ 18% lower CRC mortality 5
    • 1995 to Present Prevention Adjuvant Therapy Multiple new chemotherapies Personalized Medicine 6
    • Prevention Diet  Populations with low fat, high fiber diets rich in fruits and vegetables = lower risk  Patients after resection of colon cancer who follow good diet => lower risk of recurrence Exercise  Patientsafter resection of colon cancer who exercise regularly => lower risk of recurrence 7
    • Prevention in high riskpopulations Identification of high risk patients  Geneticscreening  Inflammatory bowel disease  Frequent polyps Regular colonscopy with resection of polyps => 50% risk reduction Resection of the colon => 90% reduction 8
    • Adjuvant Therapy Definition:Treatment added to primary curative therapy to improve cure rates Frequent recurrences after surgery  10-80% depending on stage Due to occult (tiny & not visible) spread 9
    • Adjuvant Therapy Chemotherapy can cure microscopic metastatic disease Studies in early 90’s show 20-30% risk reduction with 5FU Additionof Oxaliplatin improved reduction to 40-50% 10
    • NeoAdjuvant Therapy Using regimens prior to surgery Dramatic response rates allow curative- intent resection of previously inoperable patients. 11
    • New Drugs Oral agents allow easier adminstration New cytoxic agents improve control of metastatic disease Better understanding of cancer biology allows better identification of targets 12
    • Oral 5-FU 5-FU poor, highly variable bioavalibility  To work best needs long IV infusion UFT:  5FU congener plus Uracil  comparable to IV 5FU Ralitrexed  Probably less effective than IV 5FU Capecitabine (Xeloda) 13
    • Capecitabine vs Bolus IV 5FU  Van Cutsem et al, JCO 2001
    • Irinotecan vs Best Supportive Care 100% Irinotecan Best Supportive Care Survival After 50% failing 5FU 0% 6.5mo 11.5mo 18moCunningham, Lancet 1998
    • Oxaliplatin  Survival with Frontline Oxaliplatin/5FU 100% Oxaliplatin plus 5FU 5FU alone 50%From: 0%JCO 6 12 18 24 30 36 mo8/15/00
    • Cytotoxic chemotherapy ofColorectal Cancer: SummaryPercentSurvival 0 Drugs (but well enough for a study) 1 Drug 2 Drugs 50% 3 Drugs Time (mo) 12 14 16 18
    • New targeted agents Angiogenesis inhibitors EGFR Inhibitors
    • Angiogenesis Inhibitors The concept: A tumor must grow a blood supplyBerger, Nature Reviews 2003
    • VEGF Inhibition in Colon Ca
    • 4 months better The results Median SurvivalHurwitz, NEJM 2004
    • Epidermal Growth Factor Receptor Subfamily of growth receptors  EGFR, HER2/neu, HER3, HER4 Activation leads to:  Ras/MAPK/Cyclin-D1 activation  Cellproliferation  Angiogenesis, Inhibition of apoptosis, metastases Autocrine growth pathway frequently activated in human tumors
    • Epidermal Growth Factor ReceptorInhibition Ciardiello, Clin Can Res, 2001
    • Cetuximab-current dataSurvival benefit vs. BSC  After failure of conventional therapy  QOL of life also better NCI CTG CO.17 1.0 Jonker et al, NEJM 2007 0.8Overall CETUXIMABsurvival 0.6 BEST SUPPORTIVE CARE P=0.0046 0.4 0.2 0 6 12 18 24 Months
    • Epidermal Growth Factor ReceptorInhibition Ciardiello, Clin Can Res, 2001
    • Regorafenib Randomized study in colon cancer patients failing all other therapies  Survival improved 2 months 26 www.thelancet.com Vol 381 January 26, 2013
    • Aflibercept Complex molecule to block multiple pathways--1 month survival benefit 27 J Clin Oncol 30:3499-3506.
    • Drug Therapy of AdvancedColorectal Cancer:Impact of new agentsPercent 0 Drugs 4 DrugsSurvival 1 Drug 5 Drugs 2 Drugs 6 Drugs 3 Drugs 7 Drugs 50% Time (mo) 12 14 16 18 >30 months median
    • Personalized Medicine New tools create much more detailed information about individual patient tumors Allow more precise selection of therapy Most of the promise just beginning to be realized 29
    • Selecting patients for adjuvanttherapy Microsatellite instability (MSI)  Genetic alteration in some tumors  Predicts lower recurrence risk  Predicts less effect of chemotherapy Avoid chemotherapy in low risk patients with MSI Molecular predictors being developed for multiple cancers 30
    • Cetuximab-importance of KRASIf KRAS is mutated:Cetuximab never works  NCI CTG CO.17  Karepetis et al, NEJM 2008 31
    • New Therapies for Colon Cancer For 60 years all we had was surgery Inthe next 30 we learned to do screening and developed one chemotherapy drug Inthe past 15 we dramatically improved outcomes The next 5 years will eclipse all of that 32
    • Advances In the Pipeline Genetically Engineered Salmonella  Infects tumor cells  Induces immune destruction Minnelide—Plant derived drug  downregulates protective mechanisms in cancer cells Genetically engineered Adenovirus  Infect and destroy tumor cells 33
    • Salmonella-pIL2Colorectal livermetastases reduced inmice orally administeredSalmonella-IL2 vs.saline (control) orSalmonella-no-IL2.Developed By DanSaltzmanFirst in human Phase Istudy nearly completewith no significant ttoxicity
    • Minnelide vs. Pancreas Cancer Science Translational Medicine, 17 October 2012 Vol 4 Issue 156  Effective in mice even with Developed by Ashok fresh patient xenograft rather Saluja than cell line  Effective even when tumor First in human trial allowed to grow to massive to begin in June volume
    • AdenovirusDeveloped by Masato Yamamoto ControlsEffective inmouse xenograftmodel Modified virus First in human trial awaiting toxicity studies and funding