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Creating Survivors:A Century of Treatment Advances inColorectal Cancer                  Edward Greeno, MD   Associate Prof...
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 surviva...
Screening Fecal Occult Blood testing    randomized trials   MN:   48,000 annual 10%+ tests           33% lower CRC morta...
1995 to Present Prevention Adjuvant  Therapy Multiple new chemotherapies Personalized Medicine                        ...
Prevention Diet   Populations  with low fat, high fiber diets rich in    fruits and vegetables = lower risk   Patients ...
Prevention in high riskpopulations  Identification   of high risk patients    Geneticscreening    Inflammatory bowel di...
Adjuvant Therapy Definition:Treatment added to primary  curative therapy to improve cure rates Frequent    recurrences a...
Adjuvant Therapy Chemotherapy   can cure microscopic  metastatic disease Studies in early 90’s show 20-30% risk  reducti...
NeoAdjuvant Therapy Using   regimens prior to surgery Dramatic  response rates allow curative-  intent resection of prev...
New Drugs Oral agents allow easier adminstration New cytoxic agents improve control of  metastatic disease Better under...
Oral 5-FU  5-FU    poor, highly variable bioavalibility    To   work best needs long IV infusion  UFT:     5FU congene...
Capecitabine vs Bolus IV 5FU   Van Cutsem et   al, JCO 2001
Irinotecan vs  Best Supportive Care                          100%           Irinotecan                                    ...
Oxaliplatin      Survival with Frontline Oxaliplatin/5FU                100%                  Oxaliplatin plus 5FU       ...
Cytotoxic chemotherapy ofColorectal Cancer: SummaryPercentSurvival                    0 Drugs                            (...
New targeted agents Angiogenesis inhibitors EGFR Inhibitors
Angiogenesis Inhibitors        The           concept: A           tumor           must grow           a blood           s...
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...
Epidermal Growth Factor ReceptorInhibition                     Ciardiello, Clin                               Can Res, 2001
Cetuximab-current dataSurvival          benefit vs. BSC     After          failure of conventional therapy     QOL of l...
Epidermal Growth Factor ReceptorInhibition                     Ciardiello, Clin                               Can Res, 2001
Regorafenib Randomized     study in colon cancer  patients failing all other therapies   Survival   improved 2 months   ...
Aflibercept Complex molecule to block multiple  pathways--1 month survival benefit                                       ...
Drug Therapy of AdvancedColorectal Cancer:Impact of new agentsPercent                     0 Drugs    4 DrugsSurvival      ...
Personalized Medicine New  tools create much more detailed  information about individual patient tumors Allow   more pre...
Selecting patients for adjuvanttherapy  Microsatellite   instability (MSI)    Genetic alteration in some tumors    Pred...
Cetuximab-importance of KRASIf KRAS is mutated:Cetuximab never works                         NCI    CTG CO.17            ...
New Therapies for Colon Cancer For   60 years all we had was surgery Inthe next 30 we learned to do screening  and devel...
Advances In the Pipeline Genetically      Engineered Salmonella    Infects           tumor cells    Induces immune dest...
Salmonella-pIL2Colorectal livermetastases reduced inmice orally administeredSalmonella-IL2 vs.saline (control) orSalmonell...
Minnelide vs. Pancreas Cancer  Science Translational Medicine, 17 October 2012 Vol 4 Issue 156  Effective in mice even wi...
AdenovirusDeveloped by Masato Yamamoto               ControlsEffective inmouse xenograftmodel                             ...
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Edward Greeno, M.D.

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Creating Survivors: A century of treatment advances in colorectal cancer

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  1. 1. 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
  2. 2. 1900’s to 1960’s Surgery 2
  3. 3. 1965 to 1995 One Chemotherapy drug: 5-Fluorouracil Screening 3
  4. 4. 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
  5. 5. 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
  6. 6. 1995 to Present Prevention Adjuvant Therapy Multiple new chemotherapies Personalized Medicine 6
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. NeoAdjuvant Therapy Using regimens prior to surgery Dramatic response rates allow curative- intent resection of previously inoperable patients. 11
  12. 12. 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
  13. 13. 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
  14. 14. Capecitabine vs Bolus IV 5FU  Van Cutsem et al, JCO 2001
  15. 15. Irinotecan vs Best Supportive Care 100% Irinotecan Best Supportive Care Survival After 50% failing 5FU 0% 6.5mo 11.5mo 18moCunningham, Lancet 1998
  16. 16. 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
  17. 17. 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
  18. 18. New targeted agents Angiogenesis inhibitors EGFR Inhibitors
  19. 19. Angiogenesis Inhibitors The concept: A tumor must grow a blood supplyBerger, Nature Reviews 2003
  20. 20. VEGF Inhibition in Colon Ca
  21. 21. 4 months better The results Median SurvivalHurwitz, NEJM 2004
  22. 22. 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
  23. 23. Epidermal Growth Factor ReceptorInhibition Ciardiello, Clin Can Res, 2001
  24. 24. 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
  25. 25. Epidermal Growth Factor ReceptorInhibition Ciardiello, Clin Can Res, 2001
  26. 26. Regorafenib Randomized study in colon cancer patients failing all other therapies  Survival improved 2 months 26 www.thelancet.com Vol 381 January 26, 2013
  27. 27. Aflibercept Complex molecule to block multiple pathways--1 month survival benefit 27 J Clin Oncol 30:3499-3506.
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. Cetuximab-importance of KRASIf KRAS is mutated:Cetuximab never works  NCI CTG CO.17  Karepetis et al, NEJM 2008 31
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. AdenovirusDeveloped by Masato Yamamoto ControlsEffective inmouse xenograftmodel Modified virus First in human trial awaiting toxicity studies and funding
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