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Colorectal Cancer: New Approaches Daniel G. Haller, MD Professor of Medicine Abramson Cancer Center at the University of Pennsylvania Philadelphia, PA USA St. Louis, MO 10/1/04

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Title: Colorectal Cancer: New Approaches Daniel G. Haller, MD Professor of Medicine Abramson Cancer Center at the University of Pennsylvania Philadelphia, PA USA St. Louis, MO 10/1/04


1
Colorectal CancerNew Approaches Daniel G.
Haller, MDProfessor of MedicineAbramson Cancer
Center at the University of PennsylvaniaPhiladel
phia, PA USASt. Louis, MO 10/1/04
2
Incidence of colorectal cancer in the U.S. and
Western Europe 2003 (n300,000)
Stage I 24
Stage II 26
Stage IV 22
Stage III 29
Initially eligible for systemic therapy n60,000
Eligible for adjuvant chemotherapy n160,000
(55)
3
Environmental Associates for Colorectal Cancer
  • Dietary Factors
  • Dietary Fiber
  • Dietary Fat
  • Red Meat
  • Alcohol
  • Folate
  • Methionine
  • Calcium and vitamin D
  • Non-Dietary Factors
  • Body Mass Index
  • Physical Activity
  • Smoking
  • Aspirin
  • Endoscopy Use

4
Old Paradigm for Colorectal Cancer Patients
Preclinical stage
Advanced disease
Localized disease
S
Adjuvant Rx
Early diagnosis
CT 1st-line
CT 2nd-line
Cure
S Surgery CT Chemotherapy
5
Key Therapeutic Agents in CRC Historical
Perspective
  • 1960 5-FU is the cornerstone of first-line
    therapy in MCRC
  • 1985 Addition of LV (biochemical modulator) to
    5-FU bolus regimens
  • 1998 Irinotecan as single agent approved as
    second-line in CRC
  • 2000 Irinotecan approved as first-line in CRC
    in bolus regimen (IFL)
  • 2001 Capecitabine approved as first-line in
    CRC
  • 2002 Oxaliplatin approved as second-line agent
  • 2004 Oxaliplatin approved as first-line agent
  • 2004 Introduction of biologics
  • bevacizumab
  • cetuximab

5-FU 5-fluorouracil MCRC metastatic CRC LV
leucovorin IFL irinotecan/5-FU/LV
6
5-Fluorouracil 5-FU
7
Irinotecan (CPT-11, Camptosar)
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
  • Topoisomerase I inhibitor

8
Phase III Trial of First-Line Irinotecan
5-FU/LV
R A N D O M I Z E
n231
IFL
n226
5-FU/LV
n226
Irinotecan monotherapy
End points PFS OS
PFS progression-free survival OS overall
survival. Saltz et al. N Engl J Med. 2000343905.
9
Phase III Trial of First-Line Irinotecan
5-FU/LV Efficacy
5-FU/LV IFL P Value Irinotecan
PFS (mo) 4.3 7.0 .004 4.2
ORR () 21 39 lt.001 18
OS (mo) 12.6 14.8 .04 12.0
P values comparing IFL with 5-FU/LV. ORR
objective response rate. Saltz et al. N Engl J
Med. 2000343905.
10
Chemical Structure of Platinum Analogues
Cl
NH3
Pt
Diaminocyclohexane (DACH) carrier ligand
Cl
NH3
NH2
O
C
CISPLATIN
OXALATE hydrolysable ligand
Pt
O
C
O
NH3
NH2
O
C
O
Pt
O
C
NH3
trans-l-diaminocyclohexane oxalatoplatinum OXALIPL
ATIN, Eloxatin
O
CARBOPLATIN
11
Preclinical Synergy of Oxaliplatin and 5-FU
300
Control
HT-29 colon tumor xenograft
250
5-FU 50 mg/kg
200
Oxali 10 mg/kg
Oxali 10 mg/kg 5-FU 50 mg/kg
150
D13 - Treatment
Tumor volume (mm3)
100
50
0
10
13
16
20
24
27
33
35
40
45
Days post tumor graft
Raymond et al. Anti Cancer Drugs. 1997.
12
Infusional 5-FU/LV Regimens
Oxaliplatin
Irinotecan
400
400
600
600
FOLFOX485
Douillard 180
x
LV5FU2 q2w
400
2400
FOLFOX6 100
FOLFIRI 180
x
sLV5FU2 q2w
400
2400
mFOLFOX6 85
x
sLV5FU2 q2w
2400
mFOLFOX7 130 (85)
x
vsLV5FU2 q2w
13
Oxaliplatin Second-Line Registrational Trial
n272
R A N D O M I Z E
Infusional LV5FU2
IFL Failures
n270
FOLFOX4
n274
Oxaliplatin
Primary end point OS Secondary end points TTP,
ORR, safety
Rothenberg et al. JCO 6/03.
14
Oxaliplatin Second-Line Registrational Trial
Efficacy
5-FU/LV FOLFOX4 P Value Oxaliplatin
TTP (mo) 2.6 5.6 lt.0001 1.9
OS (mo) 8.7 9.8 .07 8.1
ORR () Relief from tumor-related symptoms 0.7 15 9.6 28 lt.0001 lt.002 1.1 10
P values for FOLFOX4 vs 5-FU/LV. Rothenberg et
al. JCO 6/03
15
N9741 Phase III Trial of First-line IFL vs
FOLFOX4 vs IROX
Schema
R A N D O M I Z A T I O N
Bolus IFL (5-FU/LV Irinotecan)
N245
N246
FOLFOX4 (5-FU/LV Oxaliplatin)
IROX (Irinotecan/Oxaliplatin)
N250
Goldberg RN et al. JCO 1/1/04.
16
N9741 Safety Profile
Grade 3/4 Adverse Events
50
45
40
35
30
Percent
25
20
15
10
5
0
P?.002 for all comparisons of IFL and IROX vs
FOLFOX. Observed in gt10 of patients in any
treatment arm. Goldberg et al. J Clin Oncol.
20042223.
17
N9741 Phase III Trial of First-line IFL vs FOLFOX
Results
IFL FOLFOX p value
RR 31 45 0.002
Median Time to Progression (mo) 6.9 8.7 0.0014
Overall Survival (mo) 14.8 19.5 0.0001
FOLFOX Second-line approval in US 8/02 First
line approval 2/04
Goldberg RN et al. JCO 1/1/04 .
18
XELOX international phase II trial first-line
metastatic colorectal cancer
  • Regimen recommended from phase I trial1
  • Male/female 64/36 median age 64 years2
  • n96
  • Overall response rate 55

Oxaliplatin 130mg/m2 d1
1
8
15
21
Day
Capecitabine1,000mg/m2 twice daily
Day 1 (pm)15 (am)
Rest
Repeat cycle at day 22
1Díaz-Rubio E, et al. Ann Oncol
20021355865 2Van Cutsem E, et al. Proc Am Soc
Clin Oncol 200322255 (abst 1023)
19
Is There an Optimal Sequence in Therapy of
Metastatic CRC?
  • 5-FU, oxaliplatin, and irinotecan all have
    activity in first- and second-line settings
  • No compelling data exist to choose one sequence
    unless there is comorbid illness

20
The Evolution of Chemotherapy for CRC
21
Endothelial Cell
Pericyte
VEGFr-1
VEGFr-2
VEGFr-3
EGFr
PDGFr
PTK
PTK
PTK
Imatinib
Gefitinib/Erlotinib
COX-2
Bevacizumab
Trastuzumab
Cetuximab
Imatinib
Gefitinib/Erlotinib
EGFr
HER-2
PDGFr
Tumor Cell
22
Bevacizumab (Avastin)
  • A recombinant humanized anti-VEGF MAb
  • human IgG1 framework with antigen-binding regions
    from a murine MAb
  • Binds all forms of VEGF and prevents receptor
    binding
  • Effectively depletes circulating VEGF
  • Targets angiogenic components of tumor, stroma,
    and endothelial cells
  • Effect on drug delivery
  • Terminal half-life, 17-21 days

23
Phase III Study in Metastatic CRC
5-FU/LV/CPT-11 /- bevacizumab
  • Previously untreated metastatic colorectal cancer
  • n900

Previously untreated metastatic CRC
Randomization
5-FU/LV/CPT-11/ bevacizumab
5-FU/LV/CPT-11 (Saltz regimen)
5-FU/LV/ bevacizumab
Primary endpoint survival
24
Bevacizumab (anti-VEGF) in First-line Therapy
  • Phase III trial of irinotecan/5-FU/LV ?
    bevacizumab (BV) in 815 CRC patients
  • IFL/Placebo IFL/BV
  • N 412 403
  • ORR 35 45 (p0.0029)
  • Median Survival 15.6 mo 20.3 mo
    (p0.00003)
  • PFS 6.3 mo 10.6 mo (plt0.00001)

Hurwitz H et al. Proc ASCO. 200323 (abstr 3646).
25
Bevacizumab
  • Approved by FDA 2.26.04
  • 1st line therapy with any IV 5-FU-based
    chemotherapy
  • 5 mg/kg Q2W dose
  • Safety
  • Hypertension
  • Perforation
  • Cardiovascular events

26
Cetuximab (C225, Erbitux)
  • Chimeric monoclonal antibody to EGFR
  • ABX-EGF fully humanized
  • Inhibits EGFR function and downstream signal
    transduction pathways, promoting apoptosis
  • Synergistic with chemotherapy and radiation

ODwyer PJ, Benson AB III. Semin Oncol.
200229(suppl 14)10.
27
BOND Trial
  • Randomized Phase II trial in CPT-11-refractory
    CRC
  • CetuximabCPT-11 versus Cetuximab alone
  • 21 randomization, 300 pts
  • 1o endpoint response rate

28
Cetuximab in Irinotecan- Refractory EGFR
Patients
Cetuximab Cetuximab (n111)
Irinotecan
(n218) PR 11
23 TTP 1.5 mo
4.1 mo Overall Survival 6.9 mo 8.6
mo
Cunningham D et al. NEJM 7/04 Van Laethem JL et
al. Proc ASCO. 200323 (abstr 1058).
29
Cetuximab Approval
  • 2/04
  • For CPT-11 failures, in combination with CPT-11
  • Monotherapy, for CPT-11 intolerant patients
  • EGFR status known ???
  • Role in 1st line therapy?

30
Phase III TrialsFirst-line Metastatic Disease
? US TRIAL 2004
R A N D O M I Z A T I O N
Dealers choice Chemotherapy mFOLFOX6 FOLFIRI X
ELOX XELIRI
Cetuximab
Bevacizumab
Bevacizumab Cetuximab
31
The future of treatment of colon cancer
  • Cost Shrag, NEJM, 7/2004
  • Average patient with 1st line FOLFOX bevacizumab
    (8 months) followed by CPT-11 cetuximab (4
    months) 161,000 USD

32
Adjuvant Therapy of Colon Cancer
  • 1990 5-FU/lev better than surgery alone
  • 1994 5-FU/LV better than surgery alone
  • 1998 5-FU/LV better than 5-FU/lev
  • 1998 6 months 12 months
  • 1998 Levamisole unnecessary
  • 1998 HDLV LDLV
  • 1998 Weekly monthly
  • 2002 LV5FU2 monthly bolus

33
Adjuvant Therapy of Colon Cancer
  • 1990 5-FU/lev better than surgery alone
  • 1994 5-FU/LV better than surgery alone
  • 1998 5-FU/LV better than 5-FU/lev
  • 1998 6 months 12 months
  • 1998 Levamisole unnecessary
  • 1998 HDLV LDLV
  • 1998 Weekly monthly
  • 2002 LV5FU2 monthly bolus

34
CRC AJCC 6th Edition Staging Guidelines
  • The AJCC 6th edition staging manual refined
    stages II and III of the TNM system
  • Smooth nodules in fat are considered LNs
  • Stage II divided into IIA (T3) and IIB (T4)
  • Stage III divided into
  • IIIA (T1-2N1M0)
  • IIIB (T3-4N1M0)
  • IIIC (TAnyN2M0)
  • N2 denotes metastases to 4 or more regional lymph
    nodes

American Joint Committee on Cancer (AJCC) Cancer
Staging Manual, 6th Edition (2002).
35
Revised, node-positive TNM classification for
Stage III CRC (n50,042)
IIIA T1/2, N1
IIIB T3/4, N1
IIIC Any T, N2
Observed 5-year survival ()
plt0.0001
70
59.8
60
50
42.0
40
27.3
30
20
10
0
IIIA
IIIB
IIIC
Node-positive subgroups
Greene et al (2002)
36
Model-Derived Estimates of 5 year DFS () with
Surgery plus Adjuvant Therapy
37
Adjuvant Therapy for Stage IIColon Cancer
?
CPT-11, Oxalii
FU/LV
Surgery
38
Adjuvant Therapy for Stage II Colon
CancerCancer Care Ontario Metaanalysis
  • Data 62 randomized trials 11 metaanalysis
  • Primary analysis based on subset of 3586 pts in
    whom deaths in pts with stage II disease were
    provided
  • OR 0.82 (95 CI 0.67-1.01 p0.07)
  • ASCO Guidelines 8/15/04 JCO

39
Adjuvant Therapy for Stage III Colon Cancer
?
?
?
Surgery
CPT-11 OXALI
FU/LV
40
Extending Benefit in Stage II/III colon cancer
  • Do combination therapies offer advantages over
    5-FU alone?
  • oxaliplatin-based regimens MOSAIC, NSABP C0-7
  • irinotecan-based regimens CALGB,
    PETACC-3/V-307, FFCD/FNCLCC
  • Can convenience of administration be improved?
  • replace 5-FU with capecitabine
  • Can we further improve results? The role of
    biologics
  • anti-EGFR (cetuximab)
  • anti-VEGF (bevacizumab)

41
MOSAIC Treatment arms
Endpoints
  • Primary
  • 3-yr Disease Free Survival (DFS)
  • Secondary
  • Safety (including long-term)
  • Overall Survival (OS)

42
DFS by treatment arm (ITT)
3-year
Probability
FOLFOX4 (n1123) 77.8 LV5FU2
(n1123) 72.9
Hazard ratio 0.77 0.65 0.92 p lt 0.01
DFS (months)
23 risk reduction in the FOLFOX4 arm
43
Disease-Free Survival Stage III patients
3-year
Probability
FOLFOX4 (n672) 71.8 LV5FU2 (n675)
65.5
Hazard ratio 0.76 0.62-0.92
DFS (months)
24 risk reduction for stage III patients in
the FOLFOX4 arm
44
3 Year DFS vs 5 Year OS Approved by ODAC
5 yr OS 0.00020.9983 yr DFS
45
Adjuvant therapy for colon cancer
NO16968 (complete 10/04)
INT NO147 (open 2/04 151/4800 pts)
mFOLFOX6 vs. FOLFIRI vs. mFOLFOX6/FOLFIRI
cetuximab
NSABP C-07 (completed)
5-FU/LV (Roswell Park) oxaliplatin (FLOX)
NSABP C-08
mFOLFOX6 bevacizumab (12 mo?)
X-ACT Trial/C-06(ASCO 2004)
Capecitabine vs FU/LV (Mayo) UFT/LV vs RPMI
AVANT
MOSAIC (completed)
FOLFOX4 bevacizumab vs. XELOX bevacizumab
LV5FU2 vs. FOLFOX4
46
Surveillance
  • Chau, et. al. ECCO 2003
  • 550 pts with st II and III CRC treated with bolus
    or PVI median f/U
  • CEA each visit, CT C/A/P at 12 and 24 months
    non-randomized
  • 154 pts detected by
  • Sx (65), CEA (31), CT (49)
  • OS better in pts who had CT-detected tumor
  • 33 pts proceeded to potentially curative surgery

47
Salvage Surgery
INT-0035 (colon) INT-0114 (rectal)
Total patients 1247 1792
Recurred 548 (43) (42)
Salvage surgery 222 (41) ----
Curative intent surgery/ recurrences 109 (20) 173 (34)
5-yr DFS 23 (25 pts) OS 27 (46 pts)
therefore, 71 potential cures in 3039 patients
2.3
INT-0035 Goldberg, et al, Ann Intern Med
1998 INT-0114 Tepper, J Clin Oncol 2003
48
Liver metastases from colorectal cancer
  • Liver is the most common site of metastases from
    CRC
  • - 50 to 75 of patients with advanced CRC will
    develop liver metastases (1)
  • - 15 to 25 of patients have liver
    metastases at presentation (1, 2)
  • - 20 to 35 of patients will have metastatic
    disease confined to the liver (3)
  • Improving the outlook of advanced colorectal
    cancer necessitates better management of liver
    metastases
  • 1 - N. Kemeny, F. Fata, J. Hepatobiliary Pancreas
    Surg., 1999 6 39-492 - JK. Seifert, J. R.
    Coll. Surg. Edinb., 1998 43 141-54 3 - MM.
    Borner, Ann. Oncol., 1999 10, 6 623-26

49
Advances in surgery of liver metastases
Scheele, 1995 (1) Period 1960-1979 1980-1992 198
9-1992 N. of patients 52 382 114 Operative
mortality 11.5 3.4 1.8
Doci, 1995 (2) Period 1980-1986 1987-1992 N. of
patients 78 130 Operative mortality 5.1 0.8 Op
erative morbidity 53 24 Transfusions 450
ml 150 ml
1 - J. Scheele, et al., World J. Surg., 1995 19
59-712 - R. Doci, et al., Br. J. Surgery, 1995
82 377-81
50
Results of liver surgeryfor metastatic CRC (N gt
100)
N. of
patients Operative mort 5-yr survival Adson,
1984 (1) 141 2.8 23 Hughes, 1988 (2)
859 - 33 Doci, 1991 (3) 100 5 30 Scheele,
1991 (4) 219 6 39 Rosen, 1992 (5)
280 4 25 Nordlinger, 1992 (6)
1818 2.4 26 Gayowski, 1994 (7)
204 0 32 Rees, 1997 (8) 114 1 37
1 - MA. Adson et al., Arch. Surg., 1984 119
647-51 5 - CB. Rosen et al., Ann. Surg., 1992
216 493-5052 - KS. Hugues, Surgery, 1988 103
278-88 6 - B. Nordlinger et coll., Ed. Paris
Springer-Verlag, 1992 141-59 3 - R. Doci et
al., Br. J. Surg., 1991 78 797-801 7 - TJ.
Gayowski et al., Surgery, 1994 116 703-11 4 -
J. Scheele et al., Surgery, 1991 110 13-29 8 -
M. Rees et al., Br. J. Surg., 1997 84 1136-40
51
Ongoing Trials in Patients With Liver Metastases
  • EORTC Study 40983
  • FOLFOX surgery vs surgery alone
  • Primary endpoint 3-yr RFS also resectability
  • 350 patients, completed accrual (started 10/01)
  • CLOCC Trial
  • FOLFOX /- RFA for unresectable disease
  • NCCTG/NSABP
  • Is HAI necessary with optimal SYS therapy?
  • Adjuvant XELOX HAI FUdR

52
Rectal Cancer
Left upper valve of Houston
Portion of Rectum
Cm. from anal verge
Right middle valve of Houston
Upper 1/3 Middle 1/3 Lower 1/3
15
Peritoneum
11
Ampulla of Rectum
Left lower valve of Houston
7
2
Anal verge
Cohen AM, et al. Cancer Principles Practice of
Oncology. 5th ed. 1997, p. 1197
53
Rectal Cancer
  • OBJECTIVES OF TREATMENT
  • Cure
  • Quality of Life
  • sphincter preservation vs colostomy (distal
    lesions)
  • anorectal function
  • acute and late toxicity of treatment

54
Management of Early Rectal Cancer
  • SURGERY (TME)
  • RADIATION
  • reduce locoregional failure
  • reduce distant failure ( chemotherapy)
  • CHEMOTHERAPY
  • reduce distant failure
  • reduce locoregional failure ( radiation)

55
Local failure 1980s2000s
35 30 25 20 15 10 5 0
Local failure ()
Surgery only Surgery ? RT Surgery ? CTRT TME
RT/CTRT
56
Distant metastases 1980s2000s
40 35 30 25 20 15 10 5 0
Distant metastases ()
Surgery only Surgery ? RT Surgery ? CTRT
TME RT/CTRT
57
Adjuvant Therapy of Rectal Cancer
  • Preoperative
  • improved resectability
  • sphincter preservation
  • reduced damage to normal tissue
  • Only positive trial from Swedish study (2500
    cGy/5 fx)
  • Postoperative
  • pathologic staging
  • EUS, MRI
  • immediate surgery
  • patient bias
  • physician bias
  • referral patterns
  • Positive adjuvant trials in US in postoperative
    setting

58
Pre-operative adjuvant therapy in rectal cancer
recent advances
  • Emphasis on curative resection in addition to
    sphincter preservation
  • pre-operative staging (CRM unsafe)
  • pre-operative tumor down-staging
  • surgical technique (TME)
  • accurate pathological staging (R0)

CRM circumferential resection margin TME
total mesorectal excision
59
Preoperative vs Postoperative Chemoradiation
  • INT-0147
  • terminated prematurely secondary to low accrual
  • NSABP R-03
  • terminated prematurely secondary to low accrual
  • German Trial
  • completed accrual!

60
Sphincter Preserving Surgery ITT Analysis
Postoper. RCT Preoper. RCT n
394 n 405 85
109 17/85 (20) 43/109 (39)
Pre-randomization APR Necessary
Sphincter preserved
p 0.004
61
Cumulative Incidence of Local Relapses Intent-to-t
reat Analysis (Med. Follow-up 40 mts)
12
Postop CRT
Locoregional Recurrences
6
p 0.006
Preop CRT
62
The Univ. Of Pennsylvania Trial in Rectal Cancer
XELOX x2 cycles cetuximab
45 Gy 825 x 2/d (MonFri) 50/weekly
CORE
cetuximab
SURGERY
CT
63
A New Paradigm for Colorectal Cancer Patients
Preclinical stage
Advanced disease
Localized disease
S
S
S
CT 1st-line
Screening
CT 2nd-line
CT 3rd-line
Adjuvant Rx
CURE

Prevention
biological agents
S Surgery CT Chemotherapy
64
The future of treatment of colon cancer
  • Improve efficacy
  • Improve convenience
  • Reduce duration
  • Reduce toxicity
  • Individualize treatment
  • Patient selection (anatomic staging, prognostic
    markers)
  • Drug selection (proteinomics, pharmacogenomics,
    SNPs)
  • Cost/benefit
  • Confusion

65
Therapy for Colorectal Cancer
There are only two tragedies in life one is
not getting what one wants, and the other is
getting it.
Oscar Wilde
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