Download - Edward Greeno, M.D
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Creating Survivors:A Century of Treatment Advances in Colorectal Cancer
Edward Greeno, MDAssociate Professor of Medicine, University of Minnesota
Medical Director, Masonic Cancer Clinic
Executive Medical Director, UMPhysicians Cancer Care
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1900’s to 1960’s
Surgery
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1965 to 1995
One Chemotherapy drug: 5-FluorouracilScreening
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Outcomes with 5-FU30 years of progress
Survival 6-12 monthsProbable 1-2 mo improvement in survival
From:Lancet7/29/00
(5FU)(Fancy 5FU)
Ed started kindergarden
Ed finished fellowship
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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
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1995 to Present
PreventionAdjuvant TherapyMultiple new chemotherapiesPersonalized Medicine
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Prevention
DietPopulations with low fat, high fiber diets rich in
fruits and vegetables = lower riskPatients after resection of colon cancer who
follow good diet => lower risk of recurrence
ExercisePatients after resection of colon cancer who
exercise regularly => lower risk of recurrence
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Prevention in high risk populations
Identification of high risk patientsGenetic screeningInflammatory bowel diseaseFrequent polyps
Regular colonscopy with resection of polyps => 50% risk reduction
Resection of the colon => 90% reduction
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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
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Adjuvant Therapy
Chemotherapy can cure microscopic metastatic disease
Studies in early 90’s show 20-30% risk reduction with 5FU
Addition of Oxaliplatin improved reduction to 40-50%
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NeoAdjuvant Therapy
Using regimens prior to surgery
Dramatic response rates allow curative-intent resection of previously inoperable patients.
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New Drugs
Oral agents allow easier adminstrationNew cytoxic agents improve control of
metastatic diseaseBetter understanding of cancer biology
allows better identification of targets
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Oral 5-FU
5-FU poor, highly variable bioavalibilityTo work best needs long IV infusion
UFT: 5FU congener plus Uracilcomparable to IV 5FU
RalitrexedProbably less effective than IV 5FU
Capecitabine (Xeloda)13
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Capecitabine vs Bolus IV 5FU
Van Cutsem et al, JCO 2001
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Irinotecan vs Best Supportive Care
Cunningham, Lancet 1998
Survival After failing 5FU
100%
50%
0%
6.5mo 11.5mo 18mo
IrinotecanBest Supportive Care
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Oxaliplatin
Survival with Frontline Oxaliplatin/5FU
From:JCO8/15/00
Oxaliplatin plus 5FU5FU alone
100%
50%
0%6 12 18 24 30 36 mo
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Cytotoxic chemotherapy of Colorectal Cancer: Summary
12
50%
PercentSurvival
Time (mo)
0 Drugs (but well enough for a study)
1 Drug2 Drugs3 Drugs
14 16 18
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New targeted agents
Angiogenesis inhibitorsEGFR Inhibitors
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Angiogenesis Inhibitors
The concept: A tumor must grow a blood supply
Berger, Nature Reviews 2003
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VEGF Inhibition in Colon Ca
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The results
Hurwitz, NEJM 2004
4 months betterMedian Survival
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Epidermal Growth Factor Receptor
Subfamily of growth receptorsEGFR, HER2/neu, HER3, HER4
Activation leads to:Ras/MAPK/Cyclin-D1 activationCell proliferationAngiogenesis, Inhibition of apoptosis,
metastasesAutocrine growth pathway frequently
activated in human tumors
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Epidermal Growth Factor Receptor Inhibition Ciardiello, Clin
Can Res, 2001
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Cetuximab-current dataSurvival benefit vs. BSC
After failure of conventional therapyQOL of life also better
1.0
0.8
0.6
0.4
0.2
0 6 12 18 24Months
CETUXIMABBEST SUPPORTIVE CAREP=0.0046
Overallsurvival
NCI CTG CO.17Jonker et al, NEJM 2007
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Epidermal Growth Factor Receptor Inhibition Ciardiello, Clin
Can Res, 2001
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RegorafenibRandomized study in colon cancer
patients failing all other therapiesSurvival improved 2 months
www.thelancet.com Vol 381 January 26, 2013
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AfliberceptComplex molecule to block multiple
pathways--1 month survival benefit
J Clin Oncol 30:3499-3506.
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Drug Therapy of Advanced Colorectal Cancer: Impact of new agents
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50%
PercentSurvival
Time (mo)
0 Drugs
1 Drug2 Drugs3 Drugs
4 Drugs5 Drugs6 Drugs7 Drugs
14 16 18 >30 months median
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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
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Selecting patients for adjuvant therapy
Microsatellite instability (MSI)Genetic alteration in some tumorsPredicts lower recurrence riskPredicts less effect of chemotherapy
Avoid chemotherapy in low risk patients with MSI
Molecular predictors being developed for multiple cancers
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Cetuximab-importance of KRAS
NCI CTG CO.17 Karepetis et al, NEJM 2008
NCI CTG CO.17 Karepetis et al, NEJM 2008
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If KRAS is mutated: Cetuximab never works
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New Therapies for Colon Cancer
For 60 years all we had was surgery
In the next 30 we learned to do screening and developed one chemotherapy drug
In the past 15 we dramatically improved outcomes
The next 5 years will eclipse all of that
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Advances In the Pipeline
Genetically Engineered SalmonellaInfects tumor cellsInduces immune destruction
Minnelide—Plant derived drug downregulates protective mechanisms in
cancer cells
Genetically engineered AdenovirusInfect and destroy tumor cells
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Salmonella-pIL2Colorectal liver metastases reduced in mice orally administered Salmonella-IL2 vs.
saline (control) or Salmonella-no-IL2.
Developed By Dan Saltzman
First in human Phase I study nearly complete with no significant t toxicity
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Effective in mice even with fresh patient xenograft rather than cell line
Effective even when tumor allowed to grow to massive volume
Science Translational Medicine, 17 October 2012 Vol 4 Issue 156
Minnelide vs. Pancreas Cancer
Developed by Ashok Saluja
First in human trial to begin in June
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AdenovirusDeveloped by Masato Yamamoto
Effective in mouse xenograft model
Controls
Modified virus
First in human trial awaiting toxicity studies and funding