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Colorectal Cancer Update: 2004
Shannon B. Holloway MHS RPA-C
New York Presbyterian-Weill Cornell – Solid Tumor Service
The Jay Monahan Center for Gastrointestinal Health
Overview of Presentation
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Statistics
Prevention & Screening
Overview of the Major Therapeutic Agents
Evolution of Colorectal Cancer Treatments
What the Future Holds
Colorectal Cancer Overview
• 148,000 new cases annually in United States
• Third-leading cause of cancer death (57,100 per
year)
• Unresectable disease is generally fatal
• Until recently, chemotherapy has been perceived
by some as affording only modest clinical benefit
Cancer Facts & Figures, 2003. American Cancer Society..
US Mortality, 2001
Rank
Cause of Death
No. of
deaths
% of all
deaths
•
•
•
1.
Heart Diseases
700,142 29.0
2.
Cancer
553,768 22.9
•
•
•
•
•
•
•
•
•
•
•
•
3.
Cerebrovascular diseases
163,538 6.8
4.
Chronic lower respiratory diseases 123,013
5.
Accidents (Unintentional injuries)
101,537 4.2
6.
Diabetes mellitus
71,372
3.0
7.
Influenza and Pneumonia
62,034
2.6
8.
Alzheimer’s disease
53,852
2.2
5.1
Source: US Mortality Public Use Data Tape 2001, National Center for Health Statistics, Centers for Disease Control
and Prevention, 2003.
2004 Estimated US Cancer Deaths*
Lung & bronchus
32%
Prostate
10%
Colon & rectum
10%
Pancreas
5%
Leukemia
5%
Non-Hodgkin
lymphoma
4%
Esophagus
4%
Liver & intrahepatic
bile duct
3%
Urinary bladder
3%
Kidney
3%
All other sites
Men
290,890
Women
272,810
•25% Lung & bronchus
•15% Breast
•10% Colon & rectum
• 6% Ovary
• 6% Pancreas
• 4% Leukemia
21%
• 3% Non-Hodgkin
lymphoma
• 3% Uterine corpus
• 2% Multiple myeloma
• 2% Brain/ONS
•24%
ONS=Other nervous system.
Source: American Cancer Society, 2004.
All other sites
Change in the US Death Rates* by Cause,
1950 & 2001
Rate Per 100,000
600
586.8
1950
2001
500
400
300
245.8
200
193.9
180.7
194.4
100
57.5
48.1
21.8
0
Heart
Diseases
Cerebrovascular
Diseases
Pneumonia/
Influenza
* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3.
http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf
Cancer
Colorectal Cancer:
Breakdown of Stage of Diagnosis and
Survival Times
100
90
80
70
60
50
40
30
20
10
0
CRC Stage at
Diagnosis
Five-Year Survival
by Stage
Stage 1 Stage 2 Stage 3 Stage 4
American Cancer Society
Screening Recommendations for Colorectal Cancer, 2003
Women and Men
> Age 50
Should follow one of these testing regimens
Fecal Occult Blood Test and Flexible Sigmoidoscopy
Flexible Sigmoidoscopy
Every 5 years
Annually and Every 5 years
Respectively
Fecal Occult Blood Test
(FOBT)
Annually
Colonoscopy
Every 10 years
Double Contrast Barium Enema
(DCBE)
Every 5 Years
Overview of Potential Risk Factors
Colorectal Cancer
Dietary & Lifestyle
• Obesity 
• Smoking 
• Red Meat 
• Alcohol 
• Fruits & Vegetables 
Overview of Risk Factors
Colorectal Cancer
Inherited Disorders
- Familial Adenomatous Polyposis (FAP)
- Hereditary Nonpolyposis Colorectal
Cancer (HNPCC)
Colorectal Cancer :TNM & Duke’s Staging Guidelines
American Joint Committee on
Cancer TNM Staging System
Stage I
Duke
American Joint Committee on
Cancer TNM Staging System
(T1-2N0M0) A T1
T2
Stage II A (T3N0M0)
B (T4N0M0)
Tumor invades muscularis propria
B T3
Tumor invades through muscularis propria or into
pericolic and perirectal tissues.
T4
Stage III A (T1-2N1M0) c N1
B (T3-4N1M0)
N2
C (TanyN2M0)
Stage IV(TanyNanyM1)
Tumor invades submucosa
Invasion into adjacent organs/tissues +/- visceral invasion
Metastatis in 1-3 regional lymph nodes
Metastatis into 4+ regional lymph nodes
Presence of Metastatic Disease
Current Anti-Cancer Approaches
Surgery
Remove known tumor masses
Radiation
Kill rapidly dividing tumor cells,
including tumor cells in adjacent tissues
Chemotherapy
Kill rapidly dividing tumor cells
Hormonal
therapy
Inhibit the growth and survival of
hormone-dependent tumor cells
Targeted
therapy
Specifically inhibit processes
required for tumor cell growth
CRC Treatment by Stage
Colon Cancer
Treatment Modality
Stage I
Surgery
Stage II
Surgery
(Chemotherapy Controversial)
Stage III
Surgery and Chemotherapy
Stage IV
Primary Chemotherapy,
Resection and Radiation
when possible/indicated
Rectal Cancer
Treatment Modality
Stage I
Surgery
Stage II
Surgery and Chemotherapy
Plus Radiation
Stage III
Surgery and Chemotherapy
Plus Radiation
Stage IV
Primary Chemotherapy,
Resection and Radiation
when possible/indicated
Natural History of Cancer
Cellular
Dedifferentiation
Growth
Dysregulation
Loss of
Apoptosis
Invasion and
Metastasis
Unlimited
Cell Division
Angiogenesis
Molecular Events in Cancer
Aberrant
Signal Transduction
Dysregulation of
Growth Factors
or Receptors
Secretion of
Autocrine
Growth Factors
Secretion of
Angiogenic
Growth Factors
Secretion of
Matrix Metalloproteinases
Expression of Oncogenes
Loss of Tumor Suppressor Genes
1994
Fluorouracil
(5FU)
2000
Irinotecan
(Camptosar)
Fluorouracil
(5FU)
Irinotecan
(Camptosar)
Oxaliplatin
(Eloxatin)
Cetuximab
(Erbitux)
2004
Fluorouracil
(5FU)
Capecitabine
(Xeloda)
Bevacizumab
(Avastin)
1994
Overall Survival
Metastatic Disease
10 months
2004
Overall Survival
Metastatic Disease
25 months
Henrick et al. Proc Am Soc Clin
Oncol.2004;23:249 Absract 3517
Cytotoxic Chemotherapy
Fluorouracil
(5-FU)
Fluorouracil (5FU)
Indication for Use:
In neo-adjuvant, adjuvant therapy and as a
component in therapy for metastatic
colorectal cancer
Fluorouracil (5FU)
• Administration
– IV Bolus
– Continuous Infusion
• Target
– Thymidylate Synthase (TS)
• Mechanism of Action
– Prevents DNA replication, causes RNA/DNA
strand breaks
Fluorouracil (5FU)
• IV Bolus Side Effects
– Diarrhea
– N/V
– Stomatitis
• Continuous Infusion Side effects
– Stomatitis
– Diarrhea
– Hand-Foot Syndrome
The Meta-Analysis Group
in Cancer
Meta-Analysis of 5FU Bolus vs Infusional
6 Trials (N=1219)
Bolus
Infusional
Response Rate
14%
22%
Median Survival
11.3
12.1
Neutropenia
31%
4%
Hand-Foot Syndrome 13%
The Meta-Analysis Group. J Clinical
Oncol.1998;16:301-308
34%
Irinotecan
(Camptosar)
Irinotecan (Camptosar)
Indications for use:
First or second-line therapy in combination
with 5FU for metastatic colorectal cancer
Irinotecan –
Pro-drug Topoisomerase-1 Inhibitor
CH3
CH2
N
O
O
N
N
C
O
N
HO
Irinotecan hydrochloride
CO2
O
O
CH2CH3
Carboxylesterases
CH3
CH2
N
N-H
O
HO
N
+
N
O
HO
Piperidinopiperidine + SN-38
O
CH2CH3
Irintotecan (Camptosar)
• Administration
– IV
• Target
– Topoisomerase 1
• Mechanism of Action
– Prevents religation and single-strand DNA breaks
Irinotecan (Camtosar)
• Side Effects
– Late-Onset Diarrhea
– Neutropenia
– Nausea/Vomiting
Doulliard
&
Saltz
Pharmacia 0038 Phase III Trial of
First-line Irinotecan + 5-FU/LV
Schema
R
A
N
D
O
M
I
Z
A
T
I
O
N
IFL
N=226
N=226
Irinotecan 125 mg/m2 over 90 minutes
Leucovorin 20 mg/m2 IV bolus
Fluorouracil 500 mg/m2 IV bolus
Weekly 4 0f 6 weeks
5-FU/LV (Mayo)
Leucovorin 20 mg/m2 IV bolus
Fluorouracil 425 mg/m2 IV bolus
d 1-5 q4wk
N=231
Single-agent irinotecan
Irinotecan 125 mg/m2 over 90 minutes
Weekly 4 0f 6 weeks
Saltz LB et al. N Engl J Med. 2000;343:905.
Median Survival
Probability
Irinotecan plus bolus 5-FU/LV
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Irinotecan/5-FU/LV (N=231)
5-FU/LV (N=226)
14.8 mo
p<0.042
12.6 mo
0
6
12
18
Months
Saltz et al. N Engl J Med 343:905, 2000.
24
30
0038 Phase III Trial of
First-line Irinotecan + 5-FU/LV
Results
IFL
5-FU/LV
Irinotecan
RR
39%
21%
18%
TTP (mo)
7.0
4.3
4.2
Overall Survival (mo)
14.8
12.6
12.0
Saltz LB et al. N Engl J Med. 2000;343:905.
Capecitabine
(Xeloda)
Capecitabine (Xeloda)
Indication for use:
First-line treatment for metastatic colorectal
cancer when treatment with
fluoropyrimidine therapy alone is preferred
XELODA® (capecitabine) Chemical
Structure
NH-CO-O-C5H11
F
N
O
N
O
HO
F
HN
O
H3C
O
N
H
OH
XELODA
5-FU
Capecitabine (Xeloda)
• Administration
– Oral
• Target
– Thymidylate Synthase
• Mechanism of Action
– Prevents DNA Replication
Capecitabine (Xeloda)
• Side Effects
– Palmar-Plantar Erythrodysesthesia (PPE) or
Hand-Foot Syndrome
– Diarrhea
– Nausea & Vomiting
– Interaction with warfarin
Van Cutsem and Hoff
Phase II
1
Study :
Results
• Response rates of 21%–24% achieved with
all three XELODA regimens
• The intermittent monotherapy regimen was
chosen for phase III trials based on its
higher dose-intensity, lower potential for
toxicity, and the prospect of drug-free days
1. Van Cutsem E, et al. J Clin Oncol. 2000;18:1337-1345.
Phase III Studies: XELODA® (capecitabine)
vs 5-FU/LV in First-line Treatment of
Metastatic Colorectal Cancer
• Two phase III trials with identical protocols
– Study 1 was conducted in the Americas1
– Study 2 was conducted in Europe, Israel, Australia, New
Zealand, and Taiwan2
• Patients were randomized to:
– XELODA: 1,250 mg/m2 twice daily
(2,500 mg/m2 total daily dose), days 1–14 followed by a 7day rest period
– Mayo Clinic regimen: leucovorin (LV) 20 mg/m2 + 5-FU
425 mg/m2 (IV bolus), days 1–5 every 4 weeks
1. Hoff PM, et al. J Clin Oncol. 2001;19:2282-2292.
2. Van Cutsem E, et al. J Clin Oncol. 2001;19:4097-4106.
Efficacy of XELODA® (capecitabine) vs
5-FU/LV in Metastatic Colorectal Cancer
Phase III – Study 1
Overall Response Rate (%, 95% C.I.)
(P-value)
Time to Progression (median, days, 95% C.I.)
Hazard Ratio (XELODA/5-FU/LV)
95% C.I. for Hazard Ratio
Survival (median, days, 95% C.I.)
Hazard Ratio (XELODA/5-FU/LV)
95% C.I. for Hazard Ratio
XELODA
(n=302)
5-FU/LV
(n=303)
21 (16–26)
11 (8–15)
0.0014
128 (120–136)
131 (105–153)
0.99
(0.84–1.17)
380 (321–434)
407 (366–446)
1.00
(0.84–1.18)
Phase III Studies in First-line Treatment of
MCRC: Overall Survival, Integrated Analysis1
1.0
Estimated Probability
XELODA (n=603)
0.8
Median (CI)
XELODA: 12.9 (12.0–14.0)
5-FU/LV: 12.8 (11.8–14.0)
5-FU/LV (n=604)
0.6
Hazard ratio = 0.96
(0.85–1.08)
0.4
Log-rank
P=0.48
0.2
5-FU/LV
XELODA
12.8
12.9
0
0
5
10
15
20
25
Time (months)
1. Twelves C. Eur J Cancer. 2002;38(suppl):S15-S20.
30
35
40
45
Phase III Studies in First-line Treatment of MCRC:
Most Common Treatment-Related Adverse Events
20%, Integrated Analysis1 (Total)
70
XELODA (n=596)
5-FU/LV (n=593)
Patients (%)
60
50
*
40
*
30
*P<0.001
*
20
10
0
*
*
Diarrhea
Stomatitis
Hand-foot
syndrome
1. Twelves C, et al. Eur J Cancer. 2002;38 (suppl):S15-S2.
Nausea
Vomiting
Alopecia
Fatigue
CapeOX regimen
(Tabernero, ASCO 02)
Day
1
8
15
21
oxaliplatin
130 mg/m
(2-hour infusion)
2
capecitabine
1,000 mg/m twice daily
2
repeated every 3 weeks
Days 1–14
Rest
Capecitabine/Oxaliplatin Phase II
Trial in First-line Colorectal Cancer
Oxaliplatin 130 mg/m2 day 1 plus
Capecitabine 1000 mg/m2 b.i.d. every 3 wks
(N=96 pts)
RR
PFS
Overall Survival
45%*
7.6 months
19.5 months
Grade  3 toxicity: 7% neutropenia, 13%
nausea/vomiting, 16% diarrhea, 16% neuropathy
*Based on independent response review
Van Cutsem E et al. Proc ASCO. 2003;22 (abstr 1023).
Oxaliplatin
(Eloxatin)
Oxaliplatin (Eloxatin)
Indications for use:
Treatment of metastatic colorectal cancer in
combination with infusional 5FU
Oxaliplatin
Molecular Structure
Oxaliplatin (Eloxatin)
• Administration
– IV
• Target
– DNA
• Mechanism of Action
– Prevents Replication and Transcription of DNA
Oxaliplatin (Eloxatin)
• Side Effects
–
–
–
–
Acute Neuropathy
Cumulative Neuropathy
Nausea
Diarrhea
N9741
N9741: Schema
798 stage IV patients
IFL
R
A
N
D
O
M
I
Z
A
T
I
O
N
(n=264)
Irinotecan 125 mg/m2 over 90 minutes
Leucovorin 20 mg/m2 IV bolus
Fluorouracil 500 mg/m2 IV bolus
Weekly 4 0f 6 weeks
FOLFOX4
(n=269)
ELOXATIN 85 mg/m2 over 2 hours d 1
LV 200 mg/m2 IV over 2 hours d 1,2
5-FU 400-mg/m2 bolus for 2-4 minutes d 1,2
5-FU 600-mg/m2 continuous infusion over 22 hours d 1,2
q2wk
IROX
ELOXATIN 85 mg/m2 d 1
CPT-11 200 mg/m2 d 1
q3w
(n=265)
N9741
Overall Survival
FOLFOX vs IFL
p=0.0001
Hazard ratio= 0.66
IROX vs IFL
p=0.04
Hazard ratio= 0.80
19.5
20
15
17.4
14.8
Median
survival 10
(months)
5
0
IFL
FOLFOX
IROX
N9741
One Year Survival
80
72%
67%
59%
%
60
40
20
IFL
FOLFOX
IROX
N9741
Confirmed Response Rates
50
FOLFOX vs IFL
*p=0.002
FOLFOX vs IROX
*p=0.03
45%
40
34%
31%
%
30
20
10
0
IFL
FOLFOX
IROX
N9741: Time to Progression
FOLFOX vs IFL
*p=0.0014
Hazard ratio 0.72
IROX vs IFL *p> 0.50
Hazard ratio 1.02
10
8
Median
TTP
(months)
8.7
6.9
6.5
6
4
2
0
IFL
* 2-sided p values
FOLFOX
IROX
N9741 Phase III Trial of First-line IFL vs
FOLFOX vs IROX
Conclusions
• FOLFOX significantly more active than IFL and IROX in
first-line therapy
• Toxicity less with FOLFOX than IFL regimen except for
peripheral sensory neuropathy
• Many patients received irinotecan after FOLFOX
• IFL uses 5-FU bolus while FOLFOX uses 5-FU infusion
• A new standard of care for first-line therapy
Goldberg RN et al. Proc ASCO. 2003:22 (abstr 1009).
Tournigand
Tournigand Study Design
Randomized, Multicentric, Open-label,
Prospective, Phase III Trial
Until progression
Arm A
FOLFIRI
FOLFOX6
Until progression
(n=113)
CPT-11 180 mg/m2 IV + LV 200 mg mg/m2 over 2 hours d1, 5FU 2400-3000 mg/m2 over 46 hours
R
Until progression
Arm B
(n=113)
FOLFOX6
FOLFIRI
Until progression
Eloxatin 100 mg/m2 IV + LV 200 mg mg/m2 over 2 hours d1, 5FU 2400-3000 mg/m2 over 46 hours
Tournigand Study Results
Arm A
Arm B
FOLFIRI
FOLFOX6
FOLFOX6
FOLFIRI
P
Value
ORR (CR), %
56 (3)
15
54 (5)
4
0.68
ORR + SD, %
79
63
81
35
Median TTP, mos
Median OS, mos
2-year Survival, %
14.4
11.5
0.65
20.4
21.5
0.9
41
45
Tournigand Study
Time to Progression
1.0
FOLFIRI / FOLFOX
Probability
0.8
FOLFIRI/FOLFOX FOLFOX/FOLFIRI
Median (months)
0.6
14.4 [12.5-17.0]
11.5 [9.2-14.6]
85/109
86/111
Events/patients
18.6 months
Median follow-up
0.4
FOLFOX/FOLFIRI
0.2
Log-rank p=.065
0.0
0
6
12
18
24
Months
30
36
Median OS Correlates With Availability of
All Effective Drugs
Author
Study
% Patients
With 3 Drugs
OS
(mo)
Saltz
2000
5%
14.8
Douillard
2000
16%
17.4
de Gramont
2000
29%
16.2
Giacchetti
2000
60%
19.4
Tournigand
2001
68%
21.0
Goldberg
2003
70%
19.5
Grothey
2002
75%
21.4
Monoclonal Antibodies: Targeted
Therapy
In Oncology
Goals for Monoclonal Antibodies
– Activity
• High specificity for a target critical to tumor growth and survival
• Able to achieve meaningful clinical benefit
– Utility
• Can be used as single agent or in combination
• Minimal overlapping toxicities
• Potential targets present across tumor types and stages
of disease
Weiner LM. Semin Oncol. 1999;26(suppl 12):41-50; Breedveld FC. Lancet. 2000;355:735-740; Reff ME, Hariharan K, Braslawsky G.
Cancer Control. 2002;9:152-166; Herbst RS, Shin DM. Cancer; 2002; 94:1593-1611; Carter P. Nat Rev Cancer. 2001;1:118-129.
Review.
Antibody Function
Antibodies have two
major functions:
• Recognize and bind antigen
• Induce immune responses
after binding
Variable
region
Constant
region
Goldsby RA, Kindt TJ, Osborne BA, et al. Kuby’s Immunology. New York, NY:WH Freeman and Company; 2003.
Bevacizumab
(Avastin)
Bevacizumab (Avastin)
Indication for use:
In combination with 5FU for first-line therapy
for metastatic colorectal cancer
Bevacizumab (Avastin)
• Side Effects
– Hypertension
– GI Bleeds Perforation
– Thrombotic Events
VEGF Activates Angiogenic
Pathways
VEGF
VEGF
Endothelial
Cell
KDR-KDR
KDR-Flt 1
Flt 1-Flt 1
Actin cytoskeleton
FAK phosphorylation
Gene induction
reorganization
Paxillin phosphorylation
MMPs
Growth
Vinculin assembly
Flt 1
mitosis
Cell modify & migration
ANGIOGENESIS
Role of
Anti-Angiogenic Agents
Anti-angiogenesis
approaches
Starve tumors of blood supply
Prevent vascular metastasis
Hurwitz
Avastin Phase III study
Reference
1. Avastin Prescribing Information. Genentech, Inc. February 2004.
1
regimens
Avastin significantly extended
median survival1
• 30% increase in median survival in combination
with
IFL vs IFL alone (N=813)
Reference
1. Avastin Prescribing Information. Genentech, Inc. February 2004.
Avastin significantly extended median
progression-free survival1
• 66% increase in median
progression-free survival in
combination with IFL vs IFL alone
(N=813)
References
1. Avastin Prescribing Information. Genentech, Inc. February 2004.
2. Data on file (SR1). Genentech, Inc.
Avastin significantly increased
response rate1
• Although tumor shrinkage is not an expected outcome
of anti-angiogenic therapy, response rate was significantly higher with
Avastin plus IFL vs IFL alone
Reference
1. Avastin Prescribing Information. Genentech, Inc. February 2004.
Clinical benefits in combination
with 5-FU/LV1,2
•
Pivotal Phase III colorectal cancer study included a
group (Arm 3) receiving Avastin plus 5-FU/LV
References
1. Avastin Prescribing Information. Genentech, Inc. February 2004.
2. Data on file (SR1). Genentech, Inc.
Cetuximab
(Erbitux)
Cetuximab (Erbitux)
Indications for use:
In combination with irinotecan for EGFRexpressing metastatic colorectal cancer that
is refractory to irinotecan-based therapy or
as a single agent in patients who are
intolerant to irinotecan
Role of Epidermal Growth Factor Receptor
(EGFR) in Human Cancer
• EGFR critically regulates tumor cell division, repair,
and survival, and is involved in tumor metastasis
• Binding of specific ligands to EGFR (eg, EGF, TGF-a)
activates the receptor and triggers signal transduction
cascades that affect cell proliferation
• Many human cancers express EGFR on the cell
surface
• Inhibition of EGFR on tumor cells may inhibit the
growth or progression of EGFR-expressing tumors
Cetuximab (Erbitux)
• Side Effects
– Acneform Rash
– Asthenia
– Hypersensitivity reactions
Bond
Bond Trial
EGRF+ Patients
with advanced
CRC progressed
on or within 3
months of
Irinotecan-based
therapy
Irinotecan +
Cetuximab
Randomization
Cetuximab
Irinotecan +
Cetuximab
BOND Trial :
Study with Cetuximab and Irinotecan
RR
Cetuximab
Monotherapy
Cetuximab +
Irinotecan
P Value
10.8%
22.9%
0.007
4.1
<0.001
8.6
0.48
Median TTP
1.5
(Months)
Median Survival 6.9
(Months)
Cunningham et al. Proc Am Soc Clin
Oncol 2003;22:252 Absract 1012
Summary
• Monoclonal antibodies are excellent therapeutic
agents in oncology
• Monoclonal antibody engineering has evolved
over time
• Monoclonal antibodies with different isotypes
have differential properties
Reff ME, Hariharan K, Braslawsky G. Cancer Control. 2002;9:152-166; Herbst RS, Shin DM. Cancer; 2002;1:94:1593-1611;
Goldsby RA, Kindt TJ, Osborne BA et al. Kuby’s Immunology. New York, NY:WH Freeman and Company; 2003; Breedveld FC.
Lancet. 2000;355:735-740; Weiner LM. Semin Oncol. 1999;26(suppl 12):41-50.
What the future holds:
Incorporation of targeted therapies into standard cytotoxic
regimens.
Microarray Analysis
Innovative Screening Techniques
Thank You