Richard M Goldberg M.D. Klotz Family Chair in Cancer Research
Professor and James Cancer Hospital Physician-in-Chief The Ohio
State University Cancer of the Colon and Rectum: A Decade of
Progress
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2 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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3 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
US Death Rates in Men & Women:1975-2008 57,100 in 2003 &
51,690 in 2012 Seigel, Cancer Statistics, 2012, CA Cancer J
Clin.,62:10-29, 2012
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4 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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5 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
13%
6 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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7 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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8 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 MedMed Volume 352:1851-1860, 2005 Heather Hampel Albert de
la Chapelle
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9 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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10 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
The Cancer Genome Atlas Network Nature 487: 330-337, 2012 Genomics:
Comprehensive Molecular Characterization of Human Colon and Rectal
Cancer Raju Kucherlapati
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11 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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12 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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13 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. Harold Varmus, NCI director.
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14 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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15 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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16 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 the Larger
datasets are needed to confirm and further study additional
subtypes.
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17 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
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
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18 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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19 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Colorectal Cancer: Risk Factors Overview Decrease RiskIncrease
RiskUncertain Impact ScreeningFamily historyStatins Exercise
Aspirin / NSAIDs Ulcerative colitis/ Crohns Disease Fiber Glycemic
load Vitamin DDiabetesFruits/Vegetables Post-menopausal estrogen
Obesity Red meat Folic Acid CalciumWestern diet Alcohol
Smoking
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20 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 Fuchs Jeffrey Meyerhardt
Brian Wolpin Kimmie Ng Andrew Chan Nadine McCleary Donna
Niedzwiecki Donna Hollis CALGB
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21 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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22 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer
Survivors Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
Regular Physical Activity (met-hours per week) Hazard Ratio
Recurrence or Death
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23 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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24 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Glycemic Load in Colon Cancer Patients Quintiles of Glycemic Load
Hazard Ratio for Cancer Recurrence or Death Meyerhardt, J. et al
JNCI 2012 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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25 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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26 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Screening
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27 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 Deaths Zauber A, Winawer SJ, OBrien 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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28 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.
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29 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,
Bjerregaard NC, Laurberg S, Srensen 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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30 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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31 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
31 Detection Rates at 90% Specificity Cutoffs Covariate
analysis
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32 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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33 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 with
adenomas >9mm: SensitivitySpecificity Pickhardt94%96%
Cotton55%96% Rockey59%96% NEJM 2003; 349: 2191; JAMA 2004;
291:1713-9; Rockey: Lancet 2005;365: 305-11
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34 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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35 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) Conventional
Colectomy R Laparoscopic Colectomy (LAC) 790 patients accrued Heidi
Nelson N Engl J Med 351:933-934, 2004
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36 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
COST Outcomes Conversion rate Incision Cm Time Minutes LOS Days IV
narcs Days PO narcs days LAC21%6150531 OpenNA1895642 P-value6
">
53 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)
Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1
06121824603036424854669672788490 0.1% 4.4% p=0.996 p=0.029
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54 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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55 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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56 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
3-year DFS (stage III) Studytreatment 3-year DFS
MoertelObservation52% IMPACTObservation44% IMPACT5FU/LV62%
Punt5FU/LV65% Fields5FU/LV67% Andr5FU/LV61% MOSAIC5FU/LV65%
X-ActCapecitabine64% MOSAICC-07FOLFOX4FLOX73%76% no RX monotherapy
2 drugs
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57 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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58 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 RANDOMIZATIONRANDOMIZATION
n=267 n=264 Years % of patients IFL (median 15.0 mo) FOLFOX4
(median 19.5 mo) IROX (median 17.4 mo)
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59 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Phase III Trial of Bevacizumab in FirstLine MCRC IFL + placebo
(n=411) 5-FU/LV + bevacizumab* (5 mg/kg, q2w) (n=110) IFL +
bevacizumab (5 mg/kg, q2w) (n=402) RANDOMIZATIONRANDOMIZATION
Median Survival (mo) IFL + placebo = 15.1 IFL + bevacizumab = 20.5
5-FU/LV + bevacizumab = 18.3 Months Proportion surviving 0.2
250103040 0 0.8 1.0 0.4 0.6 Treatment Group IFL + placebo (n=101)*
IFL + bevacizumab (n=103)* 5-FU/LV + bevacizumab (n=110)
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60 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
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.
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61 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Single Agent Cetuximab RANDOMIZERANDOMIZERANDOMIZERANDOMIZE
Cetuximab* + BSC BSC alone
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62 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
KaplanMeier 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 alone Correlated with
K-ras Status
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63 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Single Agent Panitumumab RANDOMIZERANDOMIZERANDOMIZERANDOMIZE
Panitumumab + BSC BSC alone
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64 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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65 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, Bouch 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, Prausov 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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66 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute R
600 pts Aflibercept 4 mg/kg IV + FOLFIRI 600 pts Placebo + FOLFIRI
FOLFIRI +/- Aflibercept
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67 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 pts Placebo +
BSC
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68 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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69 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
198019851990199520002005 5-FU Irinotecan Capecitabine Oxaliplatin
Cetuximab Bevacizumab BSC Panitumumab 20152010 Aflibercept
Regorafenib BBP
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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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71 The Ohio State University Comprehensive Cancer Center Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute
Guidelines
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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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73 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