Title: Colorectal Cancer Update: 2004
1Colorectal Cancer Update 2004
Shannon B. Holloway MHS RPA-C New York
Presbyterian-Weill Cornell Solid Tumor
Service The Jay Monahan Center for
Gastrointestinal Health
2Overview of Presentation
- Statistics
- Prevention Screening
- Overview of the Major Therapeutic Agents
- Evolution of Colorectal Cancer Treatments
- What the Future Holds
3Colorectal 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..
4US Mortality, 2001
No. of deaths
of all deaths
Rank
Cause of Death
- 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
5.1 -
- 5. Accidents (Unintentional injuries) 101,537
4.2 -
- 6. Diabetes mellitus 71,372 3.0
-
- 7. Influenza and Pneumonia 62,034 2.6
-
- 8. Alzheimers disease 53,852 2.2
-
Source US Mortality Public Use Data Tape 2001,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2003.
52004 Estimated US Cancer Deaths
Men290,890
Women272,810
- 25 Lung bronchus
- 15 Breast
- 10 Colon rectum
- 6 Ovary
- 6 Pancreas
- 4 Leukemia
- 3 Non-Hodgkin lymphoma
- 3 Uterine corpus
- 2 Multiple myeloma
- 2 Brain/ONS
- 24 All other sites
Lung bronchus 32 Prostate 10 Colon
rectum 10 Pancreas 5 Leukemia 5 Non-Hodgkin 4
lymphoma Esophagus 4 Liver intrahepatic 3bil
e duct Urinary bladder 3 Kidney 3 All other
sites 21
ONSOther nervous system. Source American Cancer
Society, 2004.
6Change in the US Death Rates by Cause, 1950
2001
Rate Per 100,000
1950 2001
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
Age-adjusted to 2000 US standard
population. Sources 1950 Mortality Data -
CDC/NCHS, NVSS, Mortality Revised. 2001 Mortality
DataNVSR-Death Final Data 2001Volume 52, No. 3.
http//www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03
.pdf
7Colorectal CancerBreakdown of Stage of
Diagnosis and Survival Times
8American Cancer SocietyScreening Recommendations
for Colorectal Cancer, 2003
9Overview of Potential Risk FactorsColorectal
Cancer
- Dietary Lifestyle
- Obesity ??
- Smoking ?
- Red Meat ?
- Alcohol ?
- Fruits Vegetables ?
-
10Overview of Risk FactorsColorectal Cancer
- Inherited Disorders
- Familial Adenomatous Polyposis (FAP)
- Hereditary Nonpolyposis Colorectal Cancer
(HNPCC) -
-
11Colorectal Cancer TNM Dukes Staging Guidelines
American Joint Committee on Cancer TNM Staging System Duke American Joint Committee on Cancer TNM Staging System
Stage I (T1-2N0M0) A T1 Tumor invades submucosa T2 Tumor invades muscularis propria
Stage II A (T3N0M0) B (T4N0M0) B T3 Tumor invades through muscularis propria or into pericolic and perirectal tissues. T4 Invasion into adjacent organs/tissues /- visceral invasion
Stage III A (T1-2N1M0) B (T3-4N1M0) C (TanyN2M0) c N1 Metastatis in 1-3 regional lymph nodes N2 Metastatis into 4 regional lymph nodes
Stage IV(TanyNanyM1) Presence of Metastatic Disease
12Current Anti-Cancer Approaches
13CRC Treatment by Stage
14Natural History of Cancer
Cellular Dedifferentiation
Growth Dysregulation
Loss of Apoptosis
Invasion and Metastasis
Unlimited Cell Division
Angiogenesis
15Molecular Events in Cancer
Dysregulation of Growth Factors or Receptors
Aberrant Signal Transduction
Secretion of Autocrine Growth Factors
Secretion of Angiogenic Growth Factors
Secretion of Matrix Metalloproteinases
Expression of Oncogenes Loss of Tumor Suppressor
Genes
161994
Fluorouracil (5FU)
172000
Irinotecan (Camptosar)
Fluorouracil (5FU)
18Irinotecan (Camptosar)
Oxaliplatin (Eloxatin)
Cetuximab (Erbitux)
2004
Fluorouracil (5FU)
Capecitabine (Xeloda)
Bevacizumab (Avastin)
191994 Overall Survival Metastatic Disease
10 months
202004 Overall Survival Metastatic Disease
25 months
21Cytotoxic Chemotherapy
22Fluorouracil (5-FU)
23Fluorouracil (5FU)
- Indication for Use
- In neo-adjuvant, adjuvant therapy and as a
component in therapy for metastatic colorectal
cancer
24Fluorouracil (5FU)
- Administration
- IV Bolus
- Continuous Infusion
- Target
- Thymidylate Synthase (TS)
- Mechanism of Action
- Prevents DNA replication, causes RNA/DNA strand
breaks
25Fluorouracil (5FU)
- IV Bolus Side Effects
- Diarrhea
- N/V
- Stomatitis
- Continuous Infusion Side effects
- Stomatitis
- Diarrhea
- Hand-Foot Syndrome
26The Meta-Analysis Group in Cancer
27Meta-Analysis of 5FU Bolus vs Infusional
6 Trials (N1219) Bolus Infusional
Response Rate 14 22
Median Survival 11.3 12.1
Neutropenia 31 4
Hand-Foot Syndrome 13 34
28Irinotecan (Camptosar)
29Irinotecan (Camptosar)
- Indications for use
- First or second-line therapy in combination with
5FU for metastatic colorectal cancer
30Irinotecan Pro-drug Topoisomerase-1 Inhibitor
C
H
3
C
H
O
2
N
N
O
N
O
C
O
O
N
O
H
C
H
C
H
2
3
Irinotecan hydrochloride
Carboxylesterases
C
O
2
C
H
3
C
H
O
2
HO
N
N-H
N
O
O
N
O
H
C
H
C
H
2
3
SN-38
Piperidinopiperidine
31Irintotecan (Camptosar)
- Administration
- IV
- Target
- Topoisomerase 1
- Mechanism of Action
- Prevents religation and single-strand DNA breaks
32Irinotecan (Camtosar)
- Side Effects
- Late-Onset Diarrhea
- Neutropenia
- Nausea/Vomiting
33Doulliard Saltz
34Pharmacia 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 Irinotecan 125 mg/m2 over 90
minutes Leucovorin 20 mg/m2 IV bolus Fluorouracil
500 mg/m2 IV bolus Weekly 4 0f 6 weeks
N226
N226
5-FU/LV (Mayo) Leucovorin 20 mg/m2 IV
bolus Fluorouracil 425 mg/m2 IV bolus d 1-5 q4wk
Single-agent irinotecan Irinotecan 125 mg/m2
over 90 minutes Weekly 4 0f 6 weeks
N231
Saltz LB et al. N Engl J Med. 2000343905.
35Median SurvivalIrinotecan plus bolus 5-FU/LV
14.8 mo
plt0.042
12.6 mo
Saltz et al. N Engl J Med 343905, 2000.
360038 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. 2000343905.
37Capecitabine (Xeloda)
38Capecitabine (Xeloda)
- Indication for use
- First-line treatment for metastatic colorectal
cancer when treatment with fluoropyrimidine
therapy alone is preferred
39XELODA (capecitabine) Chemical Structure
NH-CO-O-C5H11
F
O
N
F
HN
O
N
O
H3C
O
N H
HO
OH
XELODA
5-FU
40Capecitabine (Xeloda)
- Administration
- Oral
- Target
- Thymidylate Synthase
- Mechanism of Action
- Prevents DNA Replication
41Capecitabine (Xeloda)
- Side Effects
- Palmar-Plantar Erythrodysesthesia (PPE) or
Hand-Foot Syndrome - Diarrhea
- Nausea Vomiting
- Interaction with warfarin
42Van Cutsem and Hoff
43Phase II Study1 Results
- Response rates of 2124 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.
2000181337-1345.
44Phase 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 114 followed by a 7-day
rest period - Mayo Clinic regimen leucovorin (LV) 20 mg/m2
5-FU 425 mg/m2 (IV bolus), days 15 every 4 weeks
45Efficacy of XELODA (capecitabine) vs 5-FU/LV in
Metastatic Colorectal Cancer
Phase III Study 1
XELODA 5-FU/LV (n302) (n303)
Overall Response Rate (, 95 C.I.) 21
(1626) 11 (815) (P-value) 0.0014 Time to
Progression (median, days, 95 C.I.) 128
(120136) 131 (105153) Hazard Ratio
(XELODA/5-FU/LV) 0.99 95 C.I. for Hazard
Ratio (0.841.17) Survival (median, days, 95
C.I.) 380 (321434) 407 (366446) Hazard Ratio
(XELODA/5-FU/LV) 1.00 95 C.I. for Hazard
Ratio (0.841.18)
46Phase III Studies in First-line Treatment of
MCRC Overall Survival, Integrated Analysis1
1.0 0.8 0.6 0.4 0.2 0
XELODA (n603) 5-FU/LV (n604)
Median (CI) XELODA 12.9 (12.014.0) 5-FU/LV 12
.8 (11.814.0) Hazard ratio 0.96(0.851.08) Log
-rankP0.48
Estimated Probability
5-FU/LV 12.8
XELODA 12.9
0 5 10 15 20 25 30 35 40 45
Time (months)
1. Twelves C. Eur J Cancer. 200238(suppl)S15-S20
.
47Phase III Studies in First-line Treatment of
MCRC Most Common Treatment-Related Adverse
Events ?20, Integrated Analysis1 (Total)
XELODA (n596) 5-FU/LV (n593)
Plt0.001
Patients ()
Diarrhea Stomatitis Hand-foot Nausea Vomiting Alo
pecia Fatigue syndrome
1. Twelves C, et al. Eur J Cancer. 200238
(suppl)S15-S2.
48CapeOX regimen (Tabernero, ASCO 02)
1 8 15 21
Day
oxaliplatin 130 mg/m2(2-hour infusion)
capecitabine 1,000 mg/m2 twice daily
Days 114
Rest
repeated every 3 weeks
49Capecitabine/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 (N96 pts)
- RR 45
- PFS 7.6 months
- Overall Survival 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. 200322 (abstr
1023).
50Oxaliplatin (Eloxatin)
51Oxaliplatin (Eloxatin)
- Indications for use
- Treatment of metastatic colorectal cancer in
combination with infusional 5FU
52OxaliplatinMolecular Structure
53Oxaliplatin (Eloxatin)
- Administration
- IV
- Target
- DNA
- Mechanism of Action
- Prevents Replication and Transcription of DNA
54Oxaliplatin (Eloxatin)
- Side Effects
- Acute Neuropathy
- Cumulative Neuropathy
- Nausea
- Diarrhea
55N9741
56N9741 Schema
IFL
(n264) Irinotecan 125 mg/m2 over 90
minutes Leucovorin 20 mg/m2 IV bolus Fluorouracil
500 mg/m2 IV bolus Weekly 4 0f 6 weeks
RANDOMI ZAT ION
FOLFOX4 (n269) 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
(n265) ELOXATIN 85 mg/m2 d 1 CPT-11
200 mg/m2 d 1 q3w
57N9741Overall Survival
FOLFOX vs IFL p0.0001 Hazard ratio 0.66
IROX vs IFL p0.04 Hazard ratio 0.80
19.5
20
17.4
14.8
15
Median survival (months)
10
5
0
IFL
FOLFOX
IROX
58N9741One Year Survival
72
80
67
59
60
40
20
IFL
FOLFOX
IROX
59N9741Confirmed Response Rates
FOLFOX vs IFL p0.002
FOLFOX vs IROX p0.03
50
45
40
34
31
30
20
10
0
IFL
FOLFOX
IROX
60N9741 Time to Progression
FOLFOX vs IFL p0.0014 Hazard ratio 0.72
IROX vs IFL pgt 0.50 Hazard ratio 1.02
10
8.7
8
6.9
6.5
Median TTP(months)
6
4
2
0
IROX
IFL
FOLFOX
2-sided p values
61N9741 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. 200322 (abstr
1009).
62Tournigand
63Tournigand Study DesignRandomized, Multicentric,
Open-label, Prospective, Phase III Trial
Until progression
Arm A (n113)
FOLFIRI
FOLFOX6
Until progression
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
FOLFOX6
FOLFIRI
Until progression
Arm B (n113)
Eloxatin 100 mg/m2 IV LV 200 mg mg/m2 over 2
hours d1, 5FU 2400-3000 mg/m2 over 46 hours
64Tournigand 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
0.65
Median TTP, mos
14.4
11.5
0.9
Median OS, mos
20.4
21.5
2-year Survival,
41
45
65Tournigand StudyTime to Progression
1.0
FOLFIRI / FOLFOX
0.8
FOLFOX/FOLFIRI
FOLFIRI/FOLFOX
Median (months) Events/patients Median follow-up
11.5 9.2-14.6
14.4 12.5-17.0
0.6
Probability
85/109
86/111
18.6 months
0.4
FOLFOX/FOLFIRI
0.2
Log-rank p.065
0.0
6
12
18
24
30
36
0
Months
66Median OS Correlates With Availability of All
Effective Drugs
- Patients OS
- Author Study With 3 Drugs (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
67Monoclonal Antibodies Targeted TherapyIn
Oncology
68Goals 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. 199926(suppl 12)41-50
Breedveld FC. Lancet. 2000355735-740 Reff ME,
Hariharan K, Braslawsky G. Cancer Control.
20029152-166 Herbst RS, Shin DM. Cancer 2002
941593-1611 Carter P. Nat Rev Cancer.
20011118-129. Review.
69Antibody 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. Kubys
Immunology. New York, NYWH Freeman and Company
2003.
70Bevacizumab (Avastin)
71Bevacizumab (Avastin)
- Indication for use
- In combination with 5FU for first-line therapy
for metastatic colorectal cancer
72Bevacizumab (Avastin)
- Side Effects
- Hypertension
- GI Bleeds Perforation
- Thrombotic Events
73(No Transcript)
74VEGF Activates Angiogenic Pathways
VEGF
VEGF
VEGF
Endothelial Cell
KDR-Flt 1
KDR-KDR
Flt 1-Flt 1
Actin cytoskeleton reorganization
FAK phosphorylation Paxillin phosphorylation Vincu
lin assembly
Gene induction
MMPs Flt 1
Growth mitosis
Cell modify migration
ANGIOGENESIS
75Role of Anti-Angiogenic Agents
76(No Transcript)
77Hurwitz
78Avastin Phase III study regimens1
Reference 1. Avastin Prescribing Information.
Genentech, Inc. February 2004.
79Avastin significantly extended median survival1
- 30 increase in median survival in combination
with IFL vs IFL alone (N813) - The survival benefit associated with Avastin was
observed early in treatment and persisted
throughout the course of the trial
Reference 1. Avastin Prescribing Information.
Genentech, Inc. February 2004.
80Avastin significantly extended median
progression-free survival1
- 66 increase in median progression-free survival
in combination with IFL vs IFL alone (N813)
References 1. Avastin Prescribing Information.
Genentech, Inc. February 2004. 2. Data on file
(SR1). Genentech, Inc.
81Avastin 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.
82Clinical 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.
83Cetuximab (Erbitux)
84Cetuximab (Erbitux)
- Indications for use
- In combination with irinotecan for
EGFR-expressing metastatic colorectal cancer that
is refractory to irinotecan-based therapy or as a
single agent in patients who are intolerant to
irinotecan
85Role 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
86(No Transcript)
87(No Transcript)
88Cetuximab (Erbitux)
- Side Effects
- Acneform Rash
- Asthenia
- Hypersensitivity reactions
89Bond
90Bond Trial
Irinotecan Cetuximab
EGRF Patients with advanced CRC progressed on
or within 3 months of Irinotecan-based therapy
Randomization
Cetuximab
Irinotecan Cetuximab
91BOND Trial Study with Cetuximab and Irinotecan
Cetuximab Monotherapy Cetuximab Irinotecan P Value
RR 10.8 22.9 0.007
Median TTP (Months) 1.5 4.1 lt0.001
Median Survival (Months) 6.9 8.6 0.48
92Summary
- 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. 20029152-166 Herbst RS, Shin DM.
Cancer 20021941593-1611 Goldsby RA, Kindt
TJ, Osborne BA et al. Kubys Immunology. New
York, NYWH Freeman and Company 2003 Breedveld
FC. Lancet. 2000355735-740 Weiner LM. Semin
Oncol. 199926(suppl 12)41-50.
93What the future holdsIncorporation of
targeted therapies into standard cytotoxic
regimens.Microarray AnalysisInnovative
Screening Techniques
94Thank You