the latest in colorectal cancer research
DESCRIPTION
Each January, the best and brightest minds in colorectal cancer research meet at the Gastrointestinal Cancers Symposium. Fight Colorectal Cancer and the Colon Cancer Alliance are partnering to bring you the big news in colorectal cancer from the 2013 symposium. Join us to learn more about these topics: - Can aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) keep cancer from returning? - The relationship of body mass index (BMI) and exercise in colorectal cancer - What scientists are learning about how your immune system can fight cancer - The latest on what biomarkers can tell us about your cancer - Rectal cancer treatment that is based on your biological make-up The webinar will be led by Dr. Richard Goldberg, an internationally renowned gastrointestinal oncologist who specializes in colorectal cancer. He is a tenured professor in the Department of Internal Medicine at The Ohio State University and serves as physician-in-chief at Ohio State’s Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).TRANSCRIPT
Welcome!
The Latest in Colorectal Cancer Research
Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series
Our webinar will begin shortly
www.FightColorectalCancer.org877-427-2111
Fight Colorectal Cancer
1. Tonight’s speaker: Dr. Richard Goldberg, MD
2. Archived webinars: Link.FightCRC.org/Webinars
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4. Ask a question in the panel on the right side of your screen and look for hyperlinks during throughout the presentation.
5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111
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Fight Colorectal CancerDisclaimer
The information and services provided by Fight Colorectal Cancer are for general informational purposes only.
The information and services are not intended to be substitutes for professional medical advice, diagnosis, or treatment.
If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the nearest emergency room.
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Dr. Richard Goldberg, MDPhysician-in-Chief
Professor of MedicineThe Klotz Family Chair in Cancer Research
Associate Director of OutreachThe Ohio State University Comprehensive Cancer Center
Richard M Goldberg M.D.Klotz Family Chair in Cancer Research
Professor and James Cancer Hospital Physician-in-ChiefThe Ohio State University
Cancer of the Colon and Rectum: A Decade of Progress
8
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Trends in Incidence Rates: 1975-2008
Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
US Death Rates in Men & Women:1975-200857,100 in 2003 & 51,690 in 2012
Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The Genetics of Colorectal Cancer:Henry Lynch
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
13% <1% 85%
FAP Sporadic
MIN (MSI+)(Microsatellite Instability)
CIN (Chromosome Instability)
Lynch Sx Sporadic MSI(+)
Germline Mutation MMR genesMLH1, MSH2, MSH6 & PMS2
15%
2-3%
•Epigenetic silencing of MLH1 by hypermethylation of its promoter region
85%
Colorectal Cancer: Genetics
Acquired APC, p53, DCC, kras, LOH,...
Germline Mutation APC
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Patient & Family Implications: Lynch Syndrome
MLH1
PMS2
MSH2 MSH6
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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.
N Engl J MedMedVolume 352:1851-1860, 2005
Heather Hampel Albert de la Chapelle
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
The Cancer Genome Atlas NetworkNature 487: 330-337, 2012
Genomics:
Comprehensive Molecular Characterization of Human Colon
and Rectal Cancer
Raju Kucherlapati
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Genomics: Cancer Genome Atlas
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Abstract 3511. Identification and validation of gene expression subtypes in a large set
of colorectal cancer samples
J Clin Oncol 30, 2012 (suppl; abstr 3511)
PETACC3 + public datasets
Sabine Tejpar
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Novel Subtypes are Characterized by Distinct Biological Components that Predict Patient Survival
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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 theLarger datasets are needed to confirm and further study additional subtypes.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Subtype SummaryA – 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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Prevention
Charles Fuchs
Jeff Mayerhardt
Robert Sandler
John Baron
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Colorectal Cancer: Risk Factors Overview
Decrease Risk Increase Risk Uncertain Impact
Screening Family history Statins
Exercise Aspirin / NSAIDs
Ulcerative colitis/ Crohn’s Disease
Fiber Glycemic load
Vitamin D Diabetes Fruits/Vegetables
Post-menopausal estrogen
Obesity Red meat
Folic Acid
Calcium Western diet
Alcohol
Smoking
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
No association with recurrence to date Weight change (gain or loss) Smoking status or history Multivitamin
Credits:Charles FuchsJeffrey MeyerhardtBrian WolpinKimmie NgAndrew ChanNadine McClearyDonna NiedzwieckiDonna HollisCALGB
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Physical Activity and Colorectal Cancer
Cohort study from Australia of 526 colorectal cancer patients with pre-diagnosis physical activity assessment
Colorectal cancer specific survival
Haydon Gut. 2006 Jan;55(1):62-7
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
89803 and Exercise: Disease-Free Survivalin Stage III Colon Cancer Survivors
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
Regular Physical Activity (met-hours per week)
Haz
ard
Rat
io R
ecu
rren
ce o
r D
eath
<3 3-8.9 9-17.9 18.0-26.9 >270
0.2
0.4
0.6
0.8
1
1.2
Chart Title
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
NSABP and Body Mass Index
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Glycemic Loadin Colon Cancer Patients
Quintiles of Glycemic Load
Ha
zard
Ra
tio fo
r C
anc
er
Rec
urr
enc
e o
r D
eat
h
Meyerhardt, J. et al JNCI 2012
1 2 3 4 50
0.5
1
1.5
2
2.5
1
0.650000000000001
0.811
0.91
1 0.99 1.07
1.7
2.26
BMI < 25
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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Screening
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Colonoscopic Polypectomy and Long-Term Prevention of Colorectal-Cancer
DeathsZauber 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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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.
35
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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, BjerregaardNC, 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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Stool DNA Testing
Biologically rational Noninvasive No cathartic preparation No diet or med restriction Off-site collection Widely accessible Not affected by lesion site High sensitivity for both CRC & precancer
Adenoma
Normal
Mucus at Cancer Surface
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 37
Detection Rates at 90% Specificity Cutoffs
Training Set Test Set Combined Set0
10
20
30
40
50
60
70
80
90
100
88.8
78.1
85.3
63.9 63.6 63.8
CRCAdenoma >1cm
Covariateanalysis
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CT Colonography:Advanced Adenoma
Polyp size 10 mm or >. Prevalence c.5 -7 %
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
CT Colonography: Issues
Sensitivity: Detection of patients withadenomas >9mm:
Sensitivity SpecificityPickhardt 94% 96%Cotton 55% 96%Rockey 59% 96%
NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Surgical Techniques
Laparoscopic Robotic
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Laparoscopically Assisted Versus Open Colectomy For
Colon Cancer
Conventional Colectomy
R
Laparoscopic Colectomy (LAC)
790 patients accrued
Heidi NelsonN Engl J Med 351:933-934, 2004
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
COST Outcomes
Conversion rate
IncisionCm
TimeMinutes
LOSDays
IV narcsDays
PO narcsdays
LAC 21% 6 150 5 3 1
Open NA 18 95 6 4 2
P-value <.001 <.001 <.001 <.001 <.02
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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 2002Nelson, NEJM 2004
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Other Effects
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Eligible pt with stage II-IIIprimary rectal adenocarcinoma
by ERUS or MRI staging
Laparoscopicrectal resection
Openrectal resection
Randomization
Z6051: Lap Rectal Cancer TrialRectal Cancer
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
TME: a comparison of oncological and functional outcomes between robotic and
laparoscopic surgery for rectal cancer.
# Pts Time min
Med # nodes
Margin < 2 mm
Efficacy
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Liver ResectionGross Anatomy Eight Segments
Rene Adam
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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 yearsSolitary 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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
SteatosisSinusoidal Dilatation
Steatohepatitis(NASH)
Types of Chemotherapy-Induced Hepatic Injury
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Steriotactic Radiosurgery
47 patients Median dose: 42 Gray 3 fraction model 1 year local control 92%
Daniel Chang
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Preoperative versus PostoperativeChemoradiotherapy 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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Cumulative Incidence of Local RelapseMedian Follow-up: 40 months
6050403020100
.14
.12
.10
.08
.06
.04
.02
0.00
Months
Lo
core
gio
nal
Rec
urr
ence
s
p = 0.006
Post-op CRT
Pre-op CRT
12%
6%
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
German Rectal Cancer Trial
Preop Post op P-value
Pelvic recur 6% 12% 0.006
Distant recur 29.8% 29.6% 0.90
Survival 59.6% 59.9% 0.9
Gr 3-4 tox 29% 32% N.S.
Anastomotic stenosis 2.7% 8.5% 0.001
APR 39% 19% 0.004
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Advances in the Drug Treatment of CRC
1980 1985 1990 1995 2000 2005
Therapeutic conceptsPalliative chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
CapecitabineOxaliplatin
CetuximabBevacizumab
Irinotecan5-FU
Updated from Kelly and Goldberg. J Clin Oncol. 2005;23:4553
2013
AfliberceptRegorafinib
Hanna Kelly Sanoff
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
MOSAIC Phase III Trial
RANDOMI
Z ATION
LV5FU2LV5FU2
FOLFOX4FOLFOX4N=1100
N=1100
• 40% Stage II
• 60% Stage III
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Disease-free Survival: Stage II and III Patients
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Months
Pro
bab
ilit
y
1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 72
3.8%
7.5%
p=0.258
p=0.005
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
MOSAIC OS with >6 Years Follow-up
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Overall survival (months)
Pro
bab
ilit
y1.0
0.8
0.6
0.4
0.2
0
0.9
0.7
0.5
0.3
0.1
0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90
0.1%
4.4%
p=0.996
p=0.029
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
NSABP C-07
Stage ll + lll
FLOXFU/LV
Randomize
Stratify: # positive nodes
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
3-year DFS (stage III)Study treatment 3-year
DFS
Moertel Observation 52%
IMPACT Observation 44%
IMPACT 5FU/LV 62%
Punt 5FU/LV 65%
Fields 5FU/LV 67%
André 5FU/LV 61%
MOSAIC 5FU/LV 65%
X-Act Capecitabine 64%
MOSAICC-07
FOLFOX4FLOX
73%76%
no RX
mo
no
ther
apy
2 drugs
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Advances In Treatment Of Advanced Disease Since 2013
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.
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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
FOLFOX4: oxaliplatin + infusional 5-FU/LV
IFL: irinotecan + bolus
5-FU/LV
IROX: oxaliplatin + irinotecan
Intergroup Study N9741: A Combination Chemotherapy Comparison
RANDOMIZATION
n=267
n=264
n=264
Years
% o
f p
atie
nts
IFL (median 15.0 mo)FOLFOX4 (median 19.5 mo)IROX (median 17.4 mo)
0 1 2
FOLFOX4 vs IFL P=0.0001; HR=0.66
IROX vs IFL P=0.04; HR=0.81
FOLFOX4 vs IROX P=0.09; HR=0.830
10
20
30
40
50
60
70
80
90
100
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Phase III Trial of Bevacizumab in First Line MCRC
IFL + placebo (n=411)
5-FU/LV + bevacizumab*(5 mg/kg, q2w) (n=110)
IFL + bevacizumab (5 mg/kg, q2w) (n=402)
RANDOMIZATION
Median Survival (mo)
IFL + placebo = 15.1IFL + bevacizumab = 20.55-FU/LV + bevacizumab =
18.3
Months
Pro
po
rtio
n s
urv
ivin
g
0.2
250 10 30 400
0.8
1.0
0.4
0.6
Treatment GroupIFL + placebo (n=101)*IFL + bevacizumab (n=103)*5-FU/LV + bevacizumab (n=110)
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Cetuximab and Panitumumab
Cetuximab for the Treatment of Colorectal CancerJonker 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 ComparedWith Best Supportive Care Alone in Patients With Chemotherapy-RefractoryMetastatic 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.
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Single Agent Cetuximab
RANDOMI ZE
Cetuximab* + BSC
BSC alone
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Kaplan–Meier Curves for Progression-free Survival According to Treatment.
Karapetis CS et al. N Engl J Med 2008;359:1757-1765.
Progression Free Survival with Cetuximab aloneCorrelated with K-ras Status
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Single Agent Panitumumab
RANDOMI ZE
Panitumumab + BSC
BSC alone
70
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Single Agent Panitumumab: N=208
K-Ras Mutation Wild-Type K-Ras
Panitumumab registration trial
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Aflibercept and Regorafinib
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.
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.
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Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
R
600 ptsAflibercept 4 mg/kg IV+ FOLFIRI
600 ptsPlacebo + FOLFIRI
FOLFIRI +/- Aflibercept
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Regorafinib
R
505 pts Regorafinib po+ BSC
255 ptsPlacebo + BSC
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Regorafenib Cetuximab Panitumumab
Progression-Free Survival
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
median overall survival
Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005
5-FUIrinotecan
CapecitabineOxaliplatin
CetuximabBevacizumab
BSC
Panitumumab
20152010
Aflibercept
Regorafenib
BBP
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Guidelines
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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%
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
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
Fight Colorectal Cancer
www.FightColorectalCancer.org877-427-2111
Fight Colorectal CancerCONTACT US
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