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.
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Century of Treatment Advances in Colorectal Cancer
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
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
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
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
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
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
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
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