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).
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The Latest in Colorectal Cancer Research
1. Welcome!
The Latest in Colorectal Cancer
Research
Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series
Our webinar will begin shortly
www.FightColorectalCancer.org
877-427-2111
2. Fight Colorectal Cancer
1. Tonight’s speaker: Dr. Richard Goldberg, MD
2. Archived webinars: Link.FightCRC.org/Webinars
3. Follow up survey to come via email. Get a free Blue Star of
Hope pin when you tell us how we did tonight.
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
www.FightColorectalCancer.org
877-427-2111
3. Fight Colorectal Cancer
Disclaimer
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.
Fight Colorectal Cancer never recommends or endorses any
specific physicians, products or treatments for any condition.
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877-427-2111
4. Fight Colorectal Cancer
March 2013 Events
March 1: Times Square Kick Off
March 18-20: Call-on Congress
Registration closes on Feb. 22nd!
www.FightColorectalCancer.org
March 20: Congressional Call-In
Unite behind a cure!
Join our one-day phone blitz to Congress
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6. Fight Colorectal Cancer
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
www.FightColorectalCancer.org
877-427-2111
7. 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
8. 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
9. 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 Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 9
10. The Genetics of Colorectal Cancer:
Henry Lynch
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 10
11. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 11
12. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 12
13. Patient & Family Implications: Lynch Syndrome
MLH1
MSH2 MSH6
PMS2
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 13
14. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 14
15. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 15
16. Genomics:
Comprehensive Molecular
Characterization of Human Colon
and Rectal Cancer
The Cancer Genome Atlas Network
Nature 487: 330-337, 2012
Raju Kucherlapati
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 16
17. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 17
18. Genomics: Cancer Genome Atlas
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 18
19. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 19
20. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 20
21. Novel Subtypes are Characterized by Distinct Biological
Components that Predict Patient Survival
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 21
22. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 22
23. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 23
24. Prevention
Charles Fuchs Robert Sandler
Jeff Mayerhardt John Baron
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 24
25. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 25
26. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 26
27. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 27
Haydon Gut. 2006 Jan;55(1):62-7
28. 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)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 28
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
29. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654
29
30. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute Meyerhardt, J. et al JNCI 2012 30
31. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 31
32. Screening
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 32
33. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 33
34. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 34
35. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 35
36. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 36
37. 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
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 37 37
38. CT Colonography:
Advanced Adenoma
Polyp size 10 mm or >. Prevalence c.5 -7 %
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 38
39. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 39
40. Surgical Techniques
Laparoscopic Robotic
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 40
41. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 41
42. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 42
43. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 43
44. Other Effects
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 44
45. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 45
46. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 46
47. Liver Resection
Gross Anatomy Eight Segments
Rene Adam
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 47
48. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 48
49. Types of Chemotherapy-Induced Hepatic Injury
Sinusoidal Steatosis Steatohepatitis
Dilatation (NASH)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 49
50. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 50
51. Steriotactic Radiosurgery
47 patients
Median dose: 42 Gray
3 fraction model
1 year local control 92%
Daniel Chang
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 51
52. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 52
53. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 53
54. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 54
55. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 55
56. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 56
57. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 57
58. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 58
59. 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)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 59
60. NSABP C-07
Stage ll + lll
Stratify: # positive nodes
Randomize
FU/LV FLOX
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 60
61. Oxaliplatin as adjuvant therapy for colon cancer: updated results of
NSABP C-07 trial, including survival and subset analyses.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 61
62. 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%
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 62
63. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 63
64. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 64
65. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 65
66. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 66
67. Single Agent Cetuximab
R
A
N Cetuximab* + BSC
D
O
M
I BSC alone
Z
E
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 67
68. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 68
69. Single Agent Panitumumab
R
A
N Panitumumab +
D BSC
O
M
I BSC alone
Z
E
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 69
70. Single Agent Panitumumab:
N=208
K-Ras Mutation Wild-Type K-Ras
Panitumumab registration trial
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 70
71. 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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 71
72. FOLFIRI +/- Aflibercept
Aflibercept
600 pts
4 mg/kg IV
+ FOLFIRI
R
Placebo + FOLFIRI
600 pts
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 72
73. Regorafinib
505 pts Regorafinib po
+ BSC
R
Placebo
255 pts
+ BSC
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 73
74. Progression-Free Survival
Regorafenib Cetuximab Panitumumab
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 74
75. 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
The Ohio State University Comprehensive Cancer Center –
0 Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 75
1980 1985 1990 1995 2000 2005 2010 2015
76. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
77. Guidelines
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 77
78. 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%
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 78
79. 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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute 79
81. Fight Colorectal Cancer
CONTACT US
Fight Colorectal Cancer
1414 Prince Street, Suite 204
Alexandria, VA 22314
(703) 548-1225
Toll-Free Answer Line: 1-877-427-2111
www.FightColorectalCancer.org
Email us: Info@FightColorectalCancer.org