Richard M Goldberg M.D. Klotz Family Chair in Cancer Research
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Transcript of Richard M Goldberg M.D. Klotz Family Chair in Cancer Research
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
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Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Trends in Incidence Rates: 1975-2008Seigel, 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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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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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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Patient & Family Implications: Lynch Syndrome
MLH1
PMS2
MSH2 MSH6
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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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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 Cancer Genome Atlas NetworkNature 487: 330-337, 2012
Genomics:Comprehensive Molecular
Characterization of Human Colon and Rectal Cancer
Raju Kucherlapati
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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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Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Genomics: Cancer Genome Atlas
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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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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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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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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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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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Prevention
Charles Fuchs
Jeff Mayerhardt
Robert Sandler
John Baron
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Colorectal Cancer: Risk Factors Overview
Decrease Risk Increase Risk Uncertain ImpactScreening Family history StatinsExercise Aspirin / NSAIDs
Ulcerative colitis/ Crohn’s Disease
Fiber Glycemic load
Vitamin D Diabetes Fruits/VegetablesPost-menopausal estrogen
Obesity Red meat
Folic Acid
Calcium Western dietAlcoholSmoking
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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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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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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
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Rat
io R
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Dea
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<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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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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Glycemic Loadin Colon Cancer Patients
Quintiles of Glycemic Load
Haz
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Rat
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r Can
cer R
ecur
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Dea
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Meyerhardt, J. et al JNCI 2012
1 2 3 4 50
0.5
1
1.5
2
2.5
1
0.650.81
1 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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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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Screening
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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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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.
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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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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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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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CT Colonography:Advanced Adenoma
Polyp size 10 mm or >. Prevalence c.5 -7 %
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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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Surgical Techniques
Laparoscopic Robotic
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Laparoscopically Assisted Versus Open Colectomy For
Colon Cancer
Conventional ColectomyR Laparoscopic Colectomy (LAC)
790 patients accrued
Heidi NelsonN Engl J Med 351:933-934, 2004
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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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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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Other Effects
s
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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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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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Liver ResectionGross Anatomy Eight Segments
Rene Adam
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Survival After Liver Resection In Metastatic Colorectal Cancer: Review And Meta-analysis Of Prognostic Factors
3-yr survival (%)
5-yr survival (%)
Median survival
yearsAll 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.
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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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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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Steriotactic Radiosurgery
47 patients Median dose: 42 Gray 3 fraction model 1 year local control 92%
Daniel Chang
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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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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
Loco
regi
onal
Rec
urre
nces
p = 0.006
Post-op CRT
Pre-op CRT
12%
6%
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Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
German Rectal Cancer Trial
Preop Post op P-valuePelvic recur 6% 12% 0.006
Distant recur 29.8% 29.6% 0.90Survival 59.6% 59.9% 0.9Gr 3-4 tox 29% 32% N.S.Anastomotic stenosis 2.7% 8.5% 0.001
APR 39% 19% 0.004
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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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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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MOSAIC Phase III Trial
RANDOMI
Z ATION
LV5FU2
FOLFOX4N=1100
N=1100
• 40% Stage II• 60% Stage III
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Disease-free Survival: Stage II and III Patients
FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III
Months
Prob
abili
ty
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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MOSAIC OS with >6 Years Follow-up
FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III
Overall survival (months)
Prob
abili
ty1.0
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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NSABP C-07
Stage ll + lll
FLOXFU/LV
Randomize
Stratify: # positive nodes
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Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.
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Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
3-year DFS (stage III)Study treatment 3-year
DFSMoertel 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
mon
othe
rapy
2 drugs
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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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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 pat
ient
s
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=0.66IROX vs IFL P=0.04; HR=0.81FOLFOX4 vs IROX P=0.09; HR=0.830
102030405060708090
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
Prop
ortio
n su
rviv
ing
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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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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Single Agent Cetuximab
RANDOMI ZE
Cetuximab* + BSC
BSC alone
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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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Single Agent Panitumumab
RANDOMI ZE
Panitumumab + BSC
BSC alone
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Single Agent Panitumumab: N=208
K-Ras Mutation Wild-Type K-Ras
Panitumumab registration trial
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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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R
600 ptsAflibercept 4 mg/kg IV+ FOLFIRI
600 ptsPlacebo + FOLFIRI
FOLFIRI +/- Aflibercept
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Regorafinib
R
505 pts Regorafinib po+ BSC
255 pts Placebo + BSC
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Regorafenib Cetuximab Panitumumab
Progression-Free Survival
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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
AfliberceptRegorafenibBBP
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
72
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 colonograpy Laparoscopic, robotic and hepatic surgery Preoperative rectal radiation and Cyberknife Oxaliplatin, bevacizumab, cetuximab, panitumumab,
aflibercept, regorafinib