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

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

Capecitabine vs Bolus IV 5FU

Van Cutsem et al, JCO 2001

Irinotecan vs Best Supportive Care

Cunningham, Lancet 1998

Survival After failing 5FU

100%

50%

0%

6.5mo 11.5mo 18mo

IrinotecanBest Supportive Care

Oxaliplatin

Survival with Frontline Oxaliplatin/5FU

From:JCO8/15/00

Oxaliplatin plus 5FU5FU alone

100%

50%

0%6 12 18 24 30 36 mo

Cytotoxic chemotherapy of Colorectal Cancer: Summary

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50%

PercentSurvival

Time (mo)

0 Drugs (but well enough for a study)

1 Drug2 Drugs3 Drugs

14 16 18

New targeted agents

Angiogenesis inhibitorsEGFR Inhibitors

Angiogenesis Inhibitors

The concept: A tumor must grow a blood supply

Berger, Nature Reviews 2003

VEGF Inhibition in Colon Ca

The results

Hurwitz, NEJM 2004

4 months betterMedian Survival

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

Epidermal Growth Factor Receptor Inhibition Ciardiello, Clin

Can Res, 2001

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

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.

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

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

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

AdenovirusDeveloped by Masato Yamamoto

Effective in mouse xenograft model

Controls

Modified virus

First in human trial awaiting toxicity studies and funding