This document discusses advances in colorectal cancer treatment over the past century. In the early 1900s, surgery was the only option. In the 1960s, chemotherapy was introduced with 5-Fluorouracil being the first drug. Screening became important in the 1970s. Between 1995-present, prevention strategies improved along with adjuvant therapy using multiple chemotherapy drugs. Personalized medicine is now allowing for targeted drugs and precision treatment based on a patient's genetic profile. Continued research promises new immunotherapies and genetically engineered treatments that could further improve outcomes.

1. Creating Survivors:
A Century of Treatment Advances in
Colorectal Cancer
Edward Greeno, MD
Associate Professor of Medicine, University of Minnesota
Medical Director, Masonic Cancer Clinic
Executive Medical Director, UMPhysicians Cancer Care

2. 1900’s to 1960’s
Surgery
2

3. 1965 to 1995
One Chemotherapy drug: 5-Fluorouracil
Screening
3

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 kindergarden
From:
Lancet
7/29/00

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. 1995 to Present
Prevention
Adjuvant Therapy
Multiple new chemotherapies
Personalized Medicine
6

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. Prevention in high risk
populations
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. 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. 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. NeoAdjuvant Therapy
Using regimens prior to surgery
Dramatic response rates allow curative-
intent resection of previously inoperable
patients.
11

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. 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. Capecitabine vs Bolus IV 5FU
 Van Cutsem et
al, JCO 2001

15. Irinotecan vs
Best Supportive Care
100% Irinotecan
Best Supportive Care
Survival
After
50%
failing 5FU
0%
6.5mo 11.5mo 18mo
Cunningham, Lancet 1998

16. Oxaliplatin
 Survival with Frontline Oxaliplatin/5FU
100% Oxaliplatin plus 5FU
5FU alone
50%
From: 0%
JCO 6 12 18 24 30 36 mo
8/15/00

17. Cytotoxic chemotherapy of
Colorectal Cancer: Summary
Percent
Survival 0 Drugs
(but well enough for a study)
1 Drug
2 Drugs
50% 3 Drugs
Time (mo) 12 14 16 18

18. New targeted agents
Angiogenesis inhibitors
EGFR Inhibitors

19. Angiogenesis Inhibitors
The
concept: A
tumor
must grow
a blood
supply
Berger, Nature Reviews 2003

20. VEGF Inhibition in Colon Ca

21. 4 months better
The results Median Survival
Hurwitz, NEJM 2004

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. Epidermal Growth Factor Receptor
Inhibition Ciardiello, Clin
Can Res, 2001

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
0.8
Overall CETUXIMAB
survival 0.6 BEST SUPPORTIVE CARE
P=0.0046
0.4
0.2
0 6 12 18 24
Months

25. Epidermal Growth Factor Receptor
Inhibition Ciardiello, Clin
Can Res, 2001

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. Aflibercept
Complex molecule to block multiple
pathways--1 month survival benefit
27
J Clin Oncol 30:3499-3506.

28. Drug Therapy of Advanced
Colorectal Cancer:
Impact of new agents
Percent 0 Drugs 4 Drugs
Survival 1 Drug 5 Drugs
2 Drugs 6 Drugs
3 Drugs 7 Drugs
50%
Time (mo) 12 14 16 18
>30 months median

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. Selecting patients for adjuvant
therapy
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. Cetuximab-importance of KRAS
If KRAS is mutated:
Cetuximab never works
 NCI CTG CO.17
 Karepetis et al, NEJM 2008
31

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. 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. Salmonella-pIL2
Colorectal 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

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. Adenovirus
Developed by Masato Yamamoto Controls
Effective in
mouse xenograft
model
Modified
virus
First in human trial awaiting toxicity
studies and funding