Download 3-year DFS (stage III)

Cancer of the Colon and Rectum:
A Decade of Progress
Richard M Goldberg M.D.
Klotz Family Chair in Cancer Research
Professor and James Cancer Hospital Physician-in-Chief
The Ohio State University
Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012
Trends in Incidence Rates: 1975-2008
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
2
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
3
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
4
Colorectal Cancer: Genetics
85%
15%
CIN
(Chromosome Instability)
MIN (MSI+)
(Microsatellite Instability)
2-3%
Lynch Sx
Germline Mutation
MMR genes
MLH1, MSH2,
MSH6 & PMS2
13%
<1%
Sporadic MSI(+)
•Epigenetic silencing of
MLH1 by hypermethylation
of its promoter region
FAP
Germline
Mutation
APC
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
85%
Sporadic
Acquired
APC, p53,
DCC, kras,
LOH,...
5
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
6
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
7
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.
Albert de la Chapelle
Heather Hampel
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
8
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
9
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
10
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
11
Genomics: Cancer Genome Atlas
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
12
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
13
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
14
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
15
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
16
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
17
Prevention
Charles Fuchs
Jeff Mayerhardt
Robert Sandler
John Baron
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
18
Colorectal Cancer:
Risk Factors Overview
Decrease Risk
Screening
Exercise
Aspirin / NSAIDs
Vitamin D
Post-menopausal
estrogen
Calcium
Increase Risk
Family history
Ulcerative colitis/
Crohn’s Disease
Diabetes
Obesity
Red meat
Western diet
Alcohol
Smoking
Uncertain Impact
Statins
Fiber
Glycemic load
Fruits/Vegetables
Folic Acid
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
19
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Credits:
Charles Fuchs
Jeffrey Meyerhardt
Brian Wolpin
Kimmie Ng
Andrew Chan
Nadine McCleary
Donna Niedzwiecki
Donna Hollis
CALGB
20
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
21
Haydon Gut. 2006 Jan;55(1):62-7
89803 and Exercise: Disease-Free Survival
in Stage III Colon Cancer Survivors
Hazard Ratio Recurrence or Death
1.2
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
22
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
NSABP and Body Mass Index
Disease-free and overall survival by body mass index (BMI) category in 4288 patients
from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for
Dukes B and C colon cancer
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
23
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654
Hazard Ratio for Cancer Recurrence or Death
Glycemic Load
in Colon Cancer Patients
2.5
2.26
2
1.7
1.5
1
1
0.99
1.07
1
1
0.81
0.5
0.65
0.91
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
Meyerhardt,
Research Institute
J. et al JNCI 2012
24
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
25
Screening
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
26
Colonoscopic Polypectomy and LongTerm 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
27
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
28
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
29
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
30
Detection Rates
at 90% Specificity Cutoffs
100
90
88.8
85.3
Covariate
analysis
78.1
80
70
63.9
63.6
63.8
60
CRC
50
Adenoma >1cm
40
30
20
10
0
Training Set
Test Set
Combined Set
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
31
31
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
32
CT Colonography: Issues
 Sensitivity: Detection of patients with
adenomas >9mm:
Pickhardt
Cotton
Rockey
Sensitivity
94%
55%
59%
Specificity
96%
96%
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
33
Surgical Techniques
Laparoscopic
Robotic
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
34
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
35
COST Outcomes
Conversion
rate
Incision
Cm
Time
Minutes
LOS
Days
IV narcs
Days
PO narcs
days
LAC
21%
6
150
5
3
1
Open
NA
18
95
6
4
2
<.001
<.001
<.001
<.001
<.02
P-value
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
36
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
37
Other Effects
s
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
38
Rectal Cancer
Z6051: Lap Rectal Cancer Trial
Eligible pt with stage II-III
primary rectal adenocarcinoma
by ERUS or MRI staging
Randomization
Open
rectal resection
Laparoscopic
rectal resection
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
39
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
40
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
41
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
42
Types of Chemotherapy-Induced Hepatic Injury
Sinusoidal
Dilatation
Steatosis
Steatohepatitis
(NASH)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
43
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
44
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
45
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
46
Cumulative Incidence of Local Relapse
Locoregional Recurrences
Median Follow-up: 40 months
.14
.12
.10
12%
Post-op CRT
.08
.06
6%
.04
.02
0.00
p = 0.006
Pre-op CRT
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
47
German Rectal Cancer Trial
Pelvic recur
Distant
recur
Survival
Gr 3-4 tox
Anastomotic
stenosis
APR
Preop
Post op
P-value
6%
12%
0.006
29.8%
29.6%
0.90
59.6%
59.9%
0.9
29%
32%
N.S.
2.7%
8.5%
0.001
39%
19%
0.004
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
48
Advances in the Drug Treatment of CRC
1980
1985
1990
5-FU
Hanna Kelly Sanoff
1995
2000
2005
2013
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
49
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 –
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Research Institute
50
MOSAIC Phase III Trial
R
A
N
D
O
M
I
Z
A
T
I
O
N
N=1100
FOLFOX4
• 40% Stage II
• 60% Stage III
N=1100
LV5FU2
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
51
Disease-free Survival:
Stage II and III Patients
1.0
0.9
p=0.258
0.8
Probability
3.8%
p=0.005
0.7
0.6
7.5%
0.5
0.4
FOLFOX4 stage II
0.3
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
52
MOSAIC OS with >6 Years Follow-up
1.0
p=0.996
0.9
Probability
0.8
p=0.029
0.1%
0.7
4.4%
0.6
0.5
0.4
0.3
FOLFOX4 stage II
0.2
LV5FU2 stage II
0.1
FOLFOX4 stage III
LV5FU2 stage III
0
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
53
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
54
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
55
3-year DFS (stage III)
monotherapy
no
RX
Study
treatment
3-year DFS
Moertel
Observation
52%
IMPACT
Observation
44%
IMPACT
Punt
5FU/LV
5FU/LV
62%
65%
Fields
5FU/LV
67%
André
5FU/LV
61%
MOSAIC
5FU/LV
65%
X-Act
Capecitabine
64%
FOLFOX4
FLOX
73%
76%
2 drugs MOSAIC
C-07
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
56
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
57
Intergroup Study N9741:
A Combination Chemotherapy Comparison
IFL (median 15.0 mo)
FOLFOX4 (median 19.5 mo)
IROX (median 17.4 mo)
100
n=267
n=264
n=264
90
FOLFOX4: oxaliplatin
+ infusional 5-FU/LV
IFL: irinotecan +
bolus
5-FU/LV
IROX: oxaliplatin +
irinotecan
80
% of patients
R
A
N
D
O
M
I
Z
A
T
I
O
N
70
60
50
40
30
20
FOLFOX4 vs IFL
P=0.0001; HR=0.66
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
58
Phase III Trial of Bevacizumab in
FirstLine MCRC
IFL + placebo
IFL + placebo = 15.1
IFL + bevacizumab = 20.5
5-FU/LV + bevacizumab =
18.3
(n=411)
0.8
IFL + bevacizumab
(5 mg/kg, q2w) (n=402)
5-FU/LV + bevacizumab*
(5 mg/kg, q2w) (n=110)
Proportion surviving
R
A
N
D
O
M
I
Z
A
T
I
O
N
Median Survival (mo)
1.0
0.6
0.4
Treatment Group
IFL + placebo (n=101)*
IFL + bevacizumab
(n=103)*
5-FU/LV + bevacizumab
(n=110)
0.2
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
59
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
60
Single Agent Cetuximab
R
A
N
D
O
M
I
Z
E
Cetuximab* + BSC
BSC alone
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
61
Kaplan–Meier
Curves for Progression-free
Survival
Accordingalone
to Treatment.
Progression
Free Survival with
Cetuximab
Correlated with K-ras Status
Karapetis CS et al. N Engl J Med 2008;359:17571765.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
62
Single Agent Panitumumab
R
A
N
D
O
M
I
Z
E
Panitumumab +
BSC
BSC alone
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
63
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
64
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
65
FOLFIRI +/- Aflibercept
600 pts
Aflibercept
4 mg/kg IV
+ FOLFIRI
R
600 pts
Placebo + FOLFIRI
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
66
Regorafinib
505 pts
Regorafinib po
+ BSC
R
255 pts
Placebo
+ BSC
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
67
Progression-Free Survival
Regorafenib
Cetuximab
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Panitumumab
68
Advances in the Treatment of Stage IV CRC
1980
1985
1990
1995
2000
2005
2010
2015
BSC
35
5-FU
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Panitumumab
30
OS (months)
25
20
15
Aflibercept
Regorafenib
BBP
10
median overall survival
5
0
1980
1985
1990
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
1995
2000
2005
2010
69
2015
Guidelines:
Association Between Adherence To
National Comprehensive Cancer
Network Treatment Guidelines And
Improved Survival In Patients With
Colon Cancer.
Boland GM, Chang GJ, Haynes AB, Chiang YJ, Chagpar R, Xing Y, Hu CY,
Feig BW, You YN, Cormier JN. Cancer. Epub ahead of print Dec 21, 2012
Janice Cormier
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Guidelines
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
71
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
72
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
73