The Latest in Colorectal Cancer Research

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The Latest in Colorectal Cancer
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Fight Colorectal Cancer
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Dr. Richard Goldberg, MD
Physician-in-Chief
Professor of Medicine
The Klotz Family Chair in Cancer Research
Associate Director of Outreach
The Ohio State University Comprehensive Cancer Center
877-427-2111

Cancer of the Colon and Rectum:
A Decade of Progress
Richard M Goldberg M.D.
Klotz Family Chair in Cancer Research
Professor and James Cancer Hospital Physician-in-Chief
The Ohio State University

Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012

Trends in Incidence Rates: 1975-2008

The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 8

Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012

US Death Rates in Men & Women:1975-2008
57,100 in 2003 & 51,690 in 2012


The Genetics of Colorectal Cancer:
Henry Lynch


Colorectal Cancer: Genetics

15% 85%
MIN (MSI+) CIN
(Microsatellite Instability) (Chromosome Instability)

2-3% 13% <1% 85%
FAP Sporadic
Lynch Sx Sporadic MSI(+)
Germline Acquired
Germline Mutation Mutation APC, p53,
MMR genes •Epigenetic silencing of
APC DCC, kras,
MLH1, MSH2, MLH1 by hypermethylation
LOH,...
MSH6 & PMS2 of its promoter region


Revised Lynch Syndrome Screening Criteria
(Amsterdam criteria II)
 > 3 relatives with an HNPCC-associated cancer
 (CRC, cancer of the endometrium, small
bowel, ureter, or renal pelvis)
 One should be a first-degree relative of the other 2
 At least 2 successive generations should be affected
 At least 1 should be diagnosed before age 50
 Familial adenomatous polyposis should be excluded
in the CRC case(s) if any
 Tumors should be verified by pathological exam
Vasen, Gastroenterology, 116: 1453-6, 1999

Patient & Family Implications: Lynch Syndrome

MLH1
MSH2 MSH6

PMS2


Screening for the Lynch Syndrome
(Hereditary Nonpolyposis Colorectal Cancer)

Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa
H, Sotamaa K, Prior T, Westman J, Panescu J, Fix D, Lockman J, Comeras I, and
de la Chapelle A.

Heather Hampel Albert de la Chapelle

N Engl J MedMed
Volume 352:1851-1860, 2005


Potential Impact

 Columbus Project:
 44 of 1600 screened had Lynch Syndrome
 50% diagnosed over age 50
 25% met neither Amsterdam or Bethesda criteria
 Ohio Colorectal Cancer Prevention Initiative
 Nationally
 143,460 new cases of CRC in the US in 2013
 4,016 have Lynch syndrome (2.8%)
 12,050 of their relatives have LS (~3 per proband)
 Total of 15,816 individuals who could be diagnosed
with Lynch Syndrome with universal screening
American Cancer Society Facts & Figures

Genomics:
Comprehensive Molecular
Characterization of Human Colon
and Rectal Cancer
The Cancer Genome Atlas Network
Nature 487: 330-337, 2012
Raju Kucherlapati


Methods and Key Findings
 Methods: Whole genome sequencing of 276
colorectal tumors
 Exome sequence, DNA copy number, promotor
methylation, messenger and micro RNA expression
 Key Findings
 16% hypermutated; 75% MSI-H
 Colon and rectal cancers share similar patterns of
genomic alteration
 24 genes significantly mutated:
 Expected: APC, TP53, SMAD4, PIK3CA, KRAS
 Unexpected: ARID1A, SOX9, FAM123B, ERBB2
 Potential new targets: ERBB2, IGF2


Genomics: Cancer Genome Atlas


Significance

 “While it may take years to translate this
foundational genetic data on colorectal cancers into
new therapeutic strategies and surveillance
methods, this genetic information unquestionably will
be the springboard for determining what will be
useful clinically against colorectal cancers,” said
Harold Varmus, NCI director.


Abstract 3511. Identification and validation
of gene expression subtypes in a large set
of colorectal cancer samples
PETACC3 + public datasets
E Budinska, V Popovici, S Tejpar, N Lapique, K Otylia Sikora, AF Di Narzo, JG Hodgson, S
6 8
Weinrich, F Bosman, A Roth , M Delorenzi

J Clin Oncol 30, 2012 (suppl; abstr 3511)

Sabine Tejpar


Novel Subtypes are Characterized by Distinct Biological
Components that Predict Patient Survival


Subtypes are Validated in Independent Datasets

Based on the set of
gene modules derived
, we performed subtype
derivation in the
validation set.

While subtypes A, C, D
and E appeared in the
Larger datasets are
needed to confirm and
further study additional
subtypes.


Subtype Summary
A – normal -like epithelial: KRAS, differentiated, no CSC markers, Wnt
down, good OS and RFS

B – proliferative epithelial: differentiated, but lost secretory
cells, proliferative, 20q genes up, Wnt active, MSS, nonBRAF, non-
mucinous, good OS, RFS, SAR

C – CIMP-H like: undifferentiated
carcinomas, MSI, BRAF, mucinous, right, less frequently p53
mutated, enriched in females, proliferative, immune, CIMP+, the shortest
SAR, poor OS

D – mesenchymal: no proliferation, high CSC markers, Wnt
inactive, active EMT, the shortest RFS, poor OS and SAR

E – intermediate: MSS, nonBRAF, non mucinous, left, CSC
markers, EMT, proliferation, differentiation, p53 enriched

Prevention

Charles Fuchs Robert Sandler

Jeff Mayerhardt John Baron


Colorectal Cancer:
Risk Factors Overview
Decrease Risk Increase Risk Uncertain Impact
Screening Family history Statins
Exercise Ulcerative colitis/ Fiber
Aspirin / NSAIDs Crohn’s Disease Glycemic load
Vitamin D Diabetes Fruits/Vegetables
Post-menopausal Obesity Folic Acid
estrogen Red meat
Calcium Western diet
Alcohol
Smoking

Data from Observational
Studies for Stage I-III Disease
 Decrease risk of recurrence
 Physical activity
 Avoidance of Western pattern diet
 Avoidance of class II/ III obesity (BMI > 35 kg/m2)
 Aspirin or COX-2 inhibitor
 Higher vitamin D levels Credits:
Charles Fuchs
Jeffrey Meyerhardt
 No association with recurrence to date Brian Wolpin
Kimmie Ng
 Weight change (gain or loss)
Andrew Chan
 Smoking status or history Nadine McCleary
Donna Niedzwiecki
 Multivitamin Donna Hollis
CALGB

Physical Activity and
Colorectal Cancer
 Cohort study from Australia of 526 colorectal cancer patients
with pre-diagnosis physical activity assessment

Van Loon K, Wigler D, Niedzwiecki D, Venook AP, Fuchs C, Blanke C, Saltz L,
Goldberg RM, Meyerhardt JA, Clin Colorectal Cancer. Epub ahead of print 1/11/ 2013
Colorectal cancer specific survival
Haydon Gut. 2006 Jan;55(1):62-7

89803 and Exercise: Disease-Free Survival
in Stage III Colon Cancer Survivors

1.2
Hazard Ratio Recurrence or Death

1

0.8

0.6

0.4

0.2

0
<3 3-8.9 9-17.9 18.0-26.9 >27
Regular Physical Activity (met-hours per week)
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

NSABP and Body Mass Index

Disease-free and overall survival by body mass index (BMI) category in 4288 patients
from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for
Dukes B and C colon cancer

Research Institute
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654
29

Glycemic Load
Hazard Ratio for Cancer Recurrence or Death
in Colon Cancer Patients
2.5
2.26

2
1.7

1.5

1 1.07
0.99
1
1 1
0.91
0.81
0.5 0.65
BMI <
25
0
1 2 3 4 5
Quintiles of Glycemic Load
Meyerhardt JA Dietary glycemic load and cancer recurrence and survival in patients with
stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst.104:1702-11, 2012.
Research Institute Meyerhardt, J. et al JNCI 2012 30

Mortality among Patients with Colorectal Cancer, According to
Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA
Mutation Status.

Liao X et al. N Engl J Med 367:1596-1606, 2012.

Screening


Colonoscopic Polypectomy and Long-
Term Prevention of Colorectal-Cancer
Deaths
Zauber A, Winawer SJ, O’Brien MJ, Lansdorp-Vogelaar
I, van Ballegooijen M, Hankey BF, Shi W, Bond JH, Schapiro
M, Panish JF, Stewart ET, and Waye JD.
N Engl J Med 366:687-96, 2012.

Ann Zauber


National Polyp Study

 2602 patients with adenomas removed between
1980-90.
 CRC deaths expected: 25.4
 CRC deaths observed: 12
 53% reduction in mortality

 These findings support the hypothesis that
colonoscopic removal of adenomatous polyps
prevents death from colorectal cancer.


DNA Stool Tests and CT Colonography
Perry Pickhardt

Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML,
Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard
NC, Laurberg S, Sørensen HT, Berger BM, Lidgard GP. Next-generation
stool DNA test accurately detects colorectal cancer and large adenomas.
Gastroenterology. 142:248-56, 2012

Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA,
Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic
virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults.
N Engl J Med. 349:2191-200, 2003.


Stool DNA Testing
 Biologically rational
Mucus at Cancer Surface
 Noninvasive
 No cathartic preparation
 No diet or med restriction
 Off-site collection
Normal
 Widely accessible
 Not affected by lesion site Adenoma

 High sensitivity for both CRC & precancer


Detection Rates
at 90% Specificity Cutoffs
100

88.8
90
85.3
Covariate
80 78.1
analysis
70
63.9 63.6 63.8

60

50 CRC
Adenoma >1cm
40

30

20

10

0

Training Set Test Set Ohio State University Comprehensive Cancer Center –
The
Combined Set
Research Institute 37 37

CT Colonography:
Advanced Adenoma
Polyp size 10 mm or >. Prevalence c.5 -7 %


CT Colonography: Issues

 Sensitivity: Detection of patients with
adenomas >9mm:

Sensitivity Specificity
Pickhardt 94% 96%
Cotton 55% 96%
Rockey 59% 96%

NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11


Surgical Techniques

Laparoscopic Robotic


Laparoscopically Assisted
Versus Open Colectomy For
Colon Cancer
790 patients accrued
Conventional Colectomy
R
Laparoscopic Colectomy (LAC)

Heidi Nelson
N Engl J Med 351:933-934, 2004


COST Outcomes

Conversion Incision Time LOS IV narcs PO narcs
rate Cm Minutes Days Days days
LAC 21% 6 150 5 3 1
Open NA 18 95 6 4 2
P-value <.001 <.001 <.001 <.001 <.02


LAC vs Open Colectomy

 No difference in
 Complication rate
 Wound recurrences
 30 day mortality (4 open, 2 LAC)
 Disease free survival
 Overall survival
 Equivalent cancer procedures

Weeks, JAMA 2002
Nelson, NEJM 2004


Other Effects


Rectal Cancer
Z6051: Lap Rectal Cancer Trial
Eligible pt with stage II-III
primary rectal adenocarcinoma
by ERUS or MRI staging

Randomization

Open Laparoscopic
rectal resection rectal resection


TME: a comparison of oncological and
functional outcomes between robotic and
laparoscopic surgery for rectal cancer.

# Pts Time Med # Margin Efficacy
min nodes < 2 mm
Robotic 50 270 16.5 0 ?
Laparoscopic 50 275 13.8 6 ?

D'Annibale A, Pernazza G, Monsellato I, Pende V, Lucandri G, Mazzocchi P,
Alfano G. Surg Endosc. Epub ahead of print, Jan 5, 2013


Liver Resection
Gross Anatomy Eight Segments

Rene Adam


Survival After Liver Resection In Metastatic Colorectal
Cancer: Review And Meta-analysis Of Prognostic Factors
3-yr survival 5-yr survival Median
(%) (%) survival
years
All 58% 40% 3.6 years
Solitary 61 47 3.6
Extrahepatic 40 24 3.6
Isolated 54 39 3.2
Periop chemo 55 37 3.3
Resectable at Dx 55 41 3.3
Synchronous 46 37 3.2
Metachronous 58 43 3.3

Kanas GP, Taylor A, Primrose JN, Langeberg W, Kelsh MA, Mowat FS,
Alexander DD, Choti MA, and Poston G. Clin Epidemiol. 4: 283–301, 2012.

Types of Chemotherapy-Induced Hepatic Injury

Sinusoidal Steatosis Steatohepatitis
Dilatation (NASH)

Stereotactic body radiotherapy for
colorectal liver metastases

Chang AT, Swaminath A, Kozak M, Weintraub J,Koong AC, John Kim J, Dinniwell R,
Brierley J, Kavanagh BD, Dawson LA, Schefter TE. Cancer 117:4060–4069, 2011


Steriotactic Radiosurgery

 47 patients
 Median dose: 42 Gray
 3 fraction model
 1 year local control 92%

Daniel Chang


Preoperative versus Postoperative
Chemoradiotherapy for Rectal Cancer
Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus
P, Tschmelitsch J, Hager E, Hess CF, Karstens J-H, Liersch T, Schmidberger
H, and Raab R for the German Rectal Cancer Study Group

 Locally advanced rectal cancer
 Radiation pre vs post operatively
 5-FU chemotherapy
 TME
 823 pts randomized
 Median follow up now 10 years
N Engl J Med 351:1731-174, 2004.
J Clin Oncol. 30:1926-33, 2012

Cumulative Incidence of Local Relapse
Median Follow-up: 40 months

.14
Locoregional Recurrences

.12

.10 12%
Post-op CRT
.08

.06

.04 6%
.02
Pre-op CRT p = 0.006
0.00
0 10 20 30 40 50 60
Months

German Rectal Cancer Trial

Preop Post op P-value
Pelvic recur 6% 12% 0.006
Distant
29.8% 29.6% 0.90
recur
Survival 59.6% 59.9% 0.9
Gr 3-4 tox 29% 32% N.S.
Anastomotic
2.7% 8.5% 0.001
stenosis
APR 39% 19% 0.004

Advances in the Drug Treatment of CRC
1980 1985 1990 1995 2000 2005 2013

5-FU
Hanna Kelly Sanoff Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Aflibercept
Regorafinib

Therapeutic concepts
Palliative chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Updated from Kelly and Goldberg. J Clin Oncol. 2005;23:4553

Oxaliplatin Vs 5-FU/LV In
Adjuvant Therapy
MOSAIC & NSABP C-07

Aimery de Gramont Thierry Andre Greg Yothers Norman Wolmark

André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant
treatment for colon cancer: MOSAIC Investigators. N Engl J Med 350: 2343–51, 2004.

Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer:
Updated results of NSABP C-07, including survival and subset analyses. J Clin Oncol 29:3768–
74, 2011.

MOSAIC Phase III Trial

R
A
N N=1100 FOLFOX4
D
O
M
I • 40% Stage II
Z • 60% Stage III
A
T
I
O N=1100 LV5FU2
N


Disease-free Survival:
1.0
Stage II and III Patients
0.9
p=0.258
0.8
3.8%
0.7 p=0.005
Probability

0.6

0.5
7.5%
0.4

0.3 FOLFOX4 stage II
LV5FU2 stage II
0.2
FOLFOX4 stage III
0.1
LV5FU2 stage III
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Months

MOSAIC OS with >6 Years Follow-up
1.0
p=0.996
0.9

0.8 p=0.029 0.1%
0.7
Probability

0.6 4.4%
0.5

0.4

0.3 FOLFOX4 stage II
0.2 LV5FU2 stage II
0.1 FOLFOX4 stage III
0 LV5FU2 stage III
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Overall survival (months)

NSABP C-07
Stage ll + lll
Stratify: # positive nodes

Randomize

FU/LV FLOX

Oxaliplatin as adjuvant therapy for colon cancer: updated results of
NSABP C-07 trial, including survival and subset analyses.


3-year DFS (stage III)
Study treatment 3-year DFS
Moertel Observation 52%
no
RX IMPACT Observation 44%
IMPACT 5FU/LV 62%
monotherapy

Punt 5FU/LV 65%
Fields 5FU/LV 67%
André 5FU/LV 61%
MOSAIC 5FU/LV 65%
X-Act Capecitabine 64%
2 drugs MOSAIC FOLFOX4 73%
C-07 FLOX 76%

Advances In Treatment Of
Advanced Disease Since 2013

Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanthan RK, Williamson SK,
Findlay BP, Pitot HC, Alberts SA. A randomized controlled trial of fluorouracil plus
leucovorin, irinotecan, and oxaliplatin combinations in patients with previously
untreated metastatic colorectal cancer. J Clin Oncol 22: 23-30, 2004.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J,
Baron A, Griffing S., Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F.
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal
Cancer, N Engl J Med 350:2335-2342, 2004.


Intergroup Study N9741:
A Combination Chemotherapy Comparison
IFL (median 15.0 mo)
FOLFOX4 (median 19.5 mo)
100 IROX (median 17.4 mo)

R n=267 90
FOLFOX4: oxaliplatin
A + infusional 5-FU/LV 80
N

% of patients
D 70
O
IFL: irinotecan + 60
M n=264
I bolus 50
Z 5-FU/LV
A 40
T
30
I
n=264 IROX: oxaliplatin +
O 20 FOLFOX4 vs IFL P=0.0001; HR=0.66
N irinotecan
10 IROX vs IFL P=0.04; HR=0.81
FOLFOX4 vs IROX P=0.09; HR=0.83
0
0 1 2
Years

Phase III Trial of Bevacizumab in
First-Line MCRC
Median Survival (mo)
R 1.0 IFL + placebo = 15.1
A IFL + placebo IFL + bevacizumab = 20.5
N (n=411) 5-FU/LV + bevacizumab =
D
O 0.8 18.3

Proportion surviving
M IFL + bevacizumab
I
Z
(5 mg/kg, q2w) (n=402)
A
0.6
T
I 5-FU/LV + bevacizumab*
O (5 mg/kg, q2w) (n=110)
N
0.4
Treatment Group
IFL + placebo (n=101)*
0.2 IFL + bevacizumab
(n=103)*
5-FU/LV + bevacizumab
(n=110)
0
0 10 25 30 40
Months

Cetuximab and
Panitumumab
Cetuximab for the Treatment of Colorectal Cancer
Jonker DJ, O'Callaghan CJ, Karapetis C, Zalcberg JR, Tu D, Au H-J,
Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R,
Langer C, and Moore MJ. N Engl J Med 2007; 357:2040-2048

Van Cutsem E, Peeters M, Salvatore Siena S, Humble Y, Hendlisz A, Neyns B,
Canon J-L, Van Laethem J-L, Maurel J, Richardson G, Wolf M, and Amado RG.
Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared
With Best Supportive Care Alone in Patients With Chemotherapy-Refractory
Metastatic Colorectal Cancer, J Clin Oncol. 25:1658-1664, 2007.

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T,
Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS
is required for panitumumab efficacy in patients with metastatic colorectal cancer.
J Clin Oncol. 2008;26:1626-1634.


Single Agent Cetuximab

R
A
N Cetuximab* + BSC
D
O
M
I BSC alone
Z
E


Kaplan–Meier Curves for Progression-freewith Cetuximab alone
Progression Free Survival Survival According to Treatment.
Correlated with K-ras Status

Karapetis CS et al. N Engl J Med 2008;359:1757-
1765.

Single Agent Panitumumab

R
A
N Panitumumab +
D BSC
O
M
I BSC alone
Z
E


Single Agent Panitumumab:
N=208
K-Ras Mutation Wild-Type K-Ras

Panitumumab registration trial


Aflibercept and Regorafinib

Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P,
van Hazel GA, Moiseyenko V, Ferry, McKendrick J, Polikoff J, Tellier A, Castan R,
Allegra C. Addition Of Aflibercept To Fluorouracil, Leucovorin, And Irinotecan
Improves Survival In A Phase III Randomized Trial In Patients With Metastatic
Colorectal Cancer Previously Treated With An Oxaliplatin-based Regimen.
J Clin Oncol. 30:3499-506, 2012.

Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché
O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM,
Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; for the CORRECT Study Group.
Regorafenib monotherapy for previously treatedmetastatic colorectal cancer
(CORRECT): an international, multicentre, randomised, placebo-controlled,
phase 3 trial. Lancet. Epub Nov 21 2012.


FOLFIRI +/- Aflibercept

Aflibercept
600 pts
4 mg/kg IV
+ FOLFIRI

R
Placebo + FOLFIRI
600 pts


Regorafinib

505 pts Regorafinib po
+ BSC

R
Placebo
255 pts
+ BSC


Progression-Free Survival

Regorafenib Cetuximab Panitumumab


Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005 2010 2015

BSC
35
5-FU
Irinotecan
30
Capecitabine
25 Oxaliplatin
Cetuximab
OS (months)

20 Bevacizumab
Panitumumab
15
Aflibercept
10 Regorafenib
median overall survival BBP
5

0 Arthur G. James Cancer Hospital and Richard J. Solove
1980 1985 1990 1995 2000 2005 2010 2015

Guidelines:
Association Between Adherence To
National Comprehensive Cancer
Network Treatment Guidelines And
Improved Survival In Patients With
Colon Cancer.
Boland GM, Chang GJ, Haynes AB, Chiang YJ, Chagpar R, Xing Y, Hu CY,
Feig BW, You YN, Cormier JN. Cancer. Epub ahead of print Dec 21, 2012

Janice Cormier

Research Institute

Guidelines


Adjuvant Therapy of Colon Cancer

 National Cancer Database 1998-2002
 High risk Stage II and Stage III
 167,434 patients
 Rates of guideline adherence
 36% for high-risk stage II
 74% Stage III
 5-year survival versus adherence to guidelines
 Yes: 67.7%
 No: 54.5%


A Decade of Progress
 Declining mortality by > 10%
 Potential for universal Lynch Syndrome screening
 Unraveling the mysteries of the genome
 Prevention & prevention of recurrence
 New screening tools: fecal DNA, CT colonography
 Laparoscopic, robotic and hepatic surgery
 Preoperative rectal radiation and Cyberknife
 Oxaliplatin, bevacizumab, cetuximab, panitumumab,
aflibercept, regorafinib



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