Transcript Best of ASCO 2006: Colorectal Cancer

Translating Clinical Trial Data into the
Community Setting: A Case-Based
Approach to Metastatic Colorectal
Cancer—Overview
Axel Grothey, MD
Professor of Oncology
Department of Oncology
Mayo Clinic, College of Medicine
Rochester, Minnesota
New Agents Have Significantly Improved
Treatment and Patient Outcomes
Regimen
First
Line
Second
Line
FDA Approval Year
5-FU
√
√
1962
√
1996
Irinotecan (monotherapy)
IFLa
√
2000
Capecitabine (monotherapy)
√
2001
Oxaliplatin + infusional 5-FU/LVb
√
Cetuximab (with or without irinotecan)
Bevacizumab + IV 5-FU-based regimensc
Panitumumab (single agent)
√
√
Second line 2002
First line 2004
√
2004
√
First line 2004
Second line 2006
Salvage 2006
FOLFIRI
More regimens provide more options for
FOLFOX
multiple lines of therapy to extend survival
c IFL, FOLFIRI, FOLFOX, and FU/LV
5-FU = 5-fluorouracil; IFL = irinotecan+5-FU+leucovorin; LV = leucovorin.
a
b
Venook A. Oncologist. 2005;10:250.
NCCTG/Intergroup Trial N9741
Efficacy
25
Median Months
19.5
(P = .0001)
20
15
15
8.7
10
6.9
(P = .0014)
IFL
FOLFOX
5
0
IFL
FOLFOX
Overall Survival
Progression-Free Survival
Response rate: IFL 31%, FOLFOX 45% (P = .002)
NCCTG = North Central Cancer Treatment Group; IFL = irinotecan + 5-FU + leucovorin;
FOLFOX = leucovorin + 5-FU + oxaliplatin.
Goldberg RM, et al. J Clin Oncol. 2004;22:23.
Tournigand Trial (N = 220)
FOLFOX
FOLFIRI
FOLFIRI
FOLFOX
(1st line
2nd line)
(1st line
2nd line)
No. Patients
111
69
109
81
RR
54%
4%
56%
Resection of
hepatic metastases
21%
2nd line
62%
PFS (mo)
8.0
2.5
Median OS (mo)
20.6
FOLFOX = leucovorin + 5-FU + oxaliplatin; FOLFIRI = leucovorin + 5-FU + irinotecan;
RR = response rate; PFC = progression-free survival; OS = overall survival.
Tournigand C, et al. J Clin Oncol. 2004;22:229.
15%
2nd line
74%
9%
8.5
4.2
21.5
Different Philosophies…
Piling up
FOLFOXIRI
PACCE
Sequencing
FOCUS
CAIRO
Courtesy of Dr. A. Grothey.
CAIRO—Trial Design
Randomize
Arm A
Arm B
1st line
Capecitabine
N = 397
Capecitabine +
irinotecan
N = 398
2nd line
Irinotecan
N = 251 (62%)
Capecitabine +
oxaliplatin
N = 213 (53%)
3rd line
Capecitabine +
oxaliplatin
N = 143 (36%)
Courtesy of Dr. C.J. Punt.
CAIRO—Overall Survival
Median OS
17.4 vs 16.3 mo
Reprinted from Koopman M, et al. Lancet. 2007;370:135, with permission from Elsevier.
Phase III Trial of FOLFOXIRI vs FOLFIRI as
First-Line Therapy of Advanced Colorectal Cancer
FOLFIRI
N = 122
FOLFOXIRI
N = 122
P-value
RRa (%)
34
60
<.0001
CR+PR+SDa (%)
68
81
N/A
R0 resection
(%) (all patients)
6
15
.033
R0 resection (%)
(liver limited)
12
36
.017
PFS (mo)
6.9
9.8
.0006
OS (mo)
16.7b
22.6
.032
aExternally
reviewed; b67% 2nd line FOLFOX
RR= Response Rate; CR= Completed Response; PR= Partial Response; SD= Stable Disease
Falcone A, et al. J Clin Oncol. 2007;25:1670.
Concept of “All 3 Drugs”—Update 2005
11 Phase III Trials, 5768 Patients
Multivariate analysis:
Effect on OS
P
First-line doublet
.69
All 3 drugs
.005
22
Median OS (mo)
21
20
First-Line Therapy
Infusional 5-FU/LV
+ irinotecan
Infusional 5-FU/LV
+ oxaliplatin
Bolus 5-FU/LV
+ irinotecan
Irinotecan
+ oxaliplatin
Bolus 5-FU/LV
LV5FU2
19
18
17
16
15
14
P = .0001
13
12
0
10
20
30
40
50
60
70
80
FOLFOXIRI
Patients with 3 Drugs (%)
OS (mo) = 13.2 + (% 3 drugs x 0.1), R^2 = .85
Grothey A, Sargent D. J Clin Oncol. 2005;23:9441.
CAIRO
2007
mAbs Target Tumor Cell-Bound EGFR
Ligand
Extracellular
EGF-R
Ras
PI3K
Raf
Akt
Intracellular
MEK
MAPK
Cell survival
DNA
Proliferation
Courtesy of Dr. A. Grothey.
Angiogenesis
Cell motility
Metastasis
NCIC CTG CO.17—Cetuximab vs BSC
Proportion Progression-Free
Progression-Free Survival
1.0
Study Arm
Med PFS
95% CI
0.9
Cetuximab + BSC
1.9
1.8–2.1
0.8
BSC alone
1.8
1.8–1.9
0.7
HR 0.68 (95% CI = 0.57–0.80)
0.6
P-value < .0001
0.5
0.4
OS 6.1 vs 4.6 mo
HR 0.77, P = .0046
(NO cross-over)
0.3
0.2
0.1
0.0
0
3
6
9
12
15
Months
CETUXIMAB + BSC
CENSORED
BSC
CENSORED
Reprinted from Jonker DJ, et al. N Engl J Med. 2007;357(20):2040-2048, with permission from the Massachusetts Medical Society.
CRYSTAL Study—First-Line
Patients with EFGR+ mCRCa
Randomized to
FOLFIRI
(n = 599)
FOLFIRI+ Cetuximab
(n = 599)
Primary endpoint: PFS (independent review)
Secondary endpoints: RR, DCR, OS, safety, QOL
a Stratified
by region, ECOG PS
Van Cutsem E, et al. ASCO; June 1-5, 2007. Abstract 4000. Courtesy of Dr. E. Van Cutsem.
CRYSTAL Trial—Primary Endpoint=PFS
ITT Population Independent Review
1.0
Progression-Free Survival Estimate
RR
0.9
0.8
FOLFIRI + cetuximab
46.9%
FOLFIRI
38.7%
0.7
P = .0038
0.6
8.9 mo
0.5
1- y PFS rate
23% vs 34%
8.0 mo
0.4
0.3
HR = 0.851
P = .0479
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
Progression-Free Survival Time (months)
Van Cutsem E, et al. ASCO; June 1-5, 2007. Abstract 4000. Courtesy of Dr. A. Grothey.
20
mAbs Target Tumor Cell-Bound EGFR
Ligand
Extracellular
EGF-R
Ras
PI3K
Raf
Akt
Intracellular
MEK
MAPK
Cell survival
DNA
Proliferation
Courtesy of Dr. A. Grothey.
Angiogenesis
Cell motility
Metastasis
K-ras as Biomarker for Panitumumab
Response in Metastatic CRC
• PFS log HR significantly different depending on K-ras status (P <.0001)
• Percentage decrease in target lesion greater in patients with wild-type K-ras receiving panitumumab
Patients with Wild-Type K-ras
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pmab + BSC
BSC alone
Events/No. (%)
Median
(Wk)
Mean
(Wk)
115/124 (93)
114/119 (96)
12.3
7.3
19.0
9.3
HR: 0.45 (95% CI: 0.34–0.59)
Stratified log rank test: P < .0001
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
1.0
Proportion with PFS
Proportion with PFS
1.0
Patients with Mutant K-ras
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pmab + BSC
Median
BSC alone
Events/No. (%) (Wks)
76/84 (90)
95/100 (95)
7.4
7.3
Mean
(Wks)
9.9
10.2
HR: 0.99 (95% CI: 0.73–1.36)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
Weeks
Amado RG, et al. ECCO; December 8-11, 2007. Abstract 0007. Courtesy of Dr. RG Amado.
Weeks
Anti-VEGF Approaches and
Agents—Summary
Bevacizumab
VEGF-trap
VEGFR-1
IMC-1121b
VEGFR-2
IMC-18F1
Sunitinib
Vatalanib
Sorafenib
Vandetanib
Motesanib
Axitinib
AZD2171
Pazopanib
Sunitinib
Vatalanib
Motesanib
Axitinib
AZD2171
Pazopanib
VEGFR-3
Sunitinib
Sorafenib
Vandetanib
Motesanib
Axitinib
AZD2171
Pazopanib
Src
PI3-K
PKC
Akt
Akt/PKB
MEK
EPC recruitment
Migration
Invasion
MAPK
Proliferation Survival
eNOS
Lymphangiogenesis
Vasculogenesis
Migration Permeability
Reprinted from Kowanetz M, et al. Clin Cancer Res. 2006;12:5018-5022, with permission from the American Association for
Cancer Research.
Phase III Trial of IFL +/Bevacizumab in MCRC—Survival
Proportion surviving
1.0
HR = 0.66, P = .00004
Median survival: 15.6 vs 20.3 mo
0.8
0.6
0.4
Treatment Group
0.2
IFL + placebo
IFL + bevacizumab
0
0
10
20
30
40
Duration of survival (mo)
Reprinted from Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342, with permission from the Massachusetts Medical Society.
BICC-C—Summary
Period 1 (No BEV)
Period 2 (+ BEV)
Efficacy
FOLFIRI
N = 144
mIFL
N = 141
CapIri
N = 145
FOLFIRI
N = 57
mIFL
N = 60
RR (%)
46.6
41.9
38
57.9
53.3
PFS (mo)
7.6
5.9
5.8
11.2
8.3
OS
23.1
17.6
18.9
NR
19.2
Diarrhea
14
19
48
11
12
Dehydr.
6
7
19
5
2
MI/stroke
0.7
4.4
0
1.8
0
60-d mort.
3.4
5.1
3.5
1.8
6.8
G 3/4 (%)
NR = not reached.
Fuchs CS, et al. J Clin Oncol. 2007;25:4779.
XELOX vs FOLFOX +/- Bevacizumab
Roche NO16966—Study Design
Recruitment
June 2003–May 2004
Recruitment
Feb 2004–Feb 2005
XELOX
n = 317
XELOX + placebo
n = 350
XELOX +
bevacizumab
n = 350
FOLFOX4
n = 317
FOLFOX4 + placebo
n = 351
FOLFOX4 +
bevacizumab
n = 350
Initial 2-arm
open-label study
(n = 634)
Protocol amended to 2x2 placebocontrolled design after bevacizumab
phase III data became available
(n = 1401)
Cassidy J, et al. ASCO; June 1-5, 2007. Abstract 4026. Courtesy of Dr. J. Cassidy.
PFS Chemotherapy + Bevacizumab
Progression-Free Survival Estimate
Primary Objective Met
FOLFOX+placebo/XELOX+placebo
(n = 701; 547 events)
FOLFOX+bevacizumab/XELOX+bevacizumab (n = 699; 513 events)
1.0
0.8
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
P =.0023
0.6
0.4
0.2
8.0
9.4
0
0
5
10
15
Months
Saltz L, et al. ASCO. June 1-5, 2007. Abstract 4028. Courtesy of Dr. L. Saltz.
20
25
NO16966 Study Drug Exposure
Median Months of Treatment
FOLFOX
+ Placebo
FOLFOX
+ Bev
XELOX
+ Placebo
XELOX
+ Bev
(n = 336)
(n = 341)
(n = 339)
(n = 353)
Oxaliplatin
6.0
6.0
5.5
5.8
Fluoropyrimidine
6.3
6.7
5.6
6.3
Placebo or bev
6.3
6.0
5.5
6.0
Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine
alone or placebo or bevacizumab alone but not oxaliplatin alone.
Saltz L, et al, Proc Am Soc Clin Oncol. 2007; Abstract 4028. Courtesy of Dr. L. Saltz.
OPTIMOX Studies
FOLFOX 4 until TF
OPTIMOX-1
n = 620
FOLFOX 7
FOLFOX 7
sLV5FU2
Tournigand C, et al. J Clin Oncol. 2006; 22:229.
mFOLFOX 7
OPTIMOX-2
n = 202
mFOLFOX 7
sLV5FU2
mFOLFOX 7
mFOLFOX 7
CFI
Maindrault-Goebel F, et al. ASCO. June 1-5, 2007. Abstract 4013. Courtesy of Dr. A. Grothey.
OPTIMOX-2—Overall Survival
1.0
Maintenance
26 months
0.8
P = .0549
19 months
0.6
CFI
0.4
Lesson from OPTIMOX-2—Don’t stop
treatment before progression
0.2
0.0
0
10
Courtesy of Dr. A. Grothey.
20
30
Months
40
50
PACCE Study
Randomized, Open-Label, Controlled Phase 3b Trial
S
C
R
E
E
N
I
N
G
Ox-based CT
(eg, FOLFOX)
N = 800
Inv choice
Iri-basedCT
(eg, FOLFIRI)
N = 200
1:1
R
A
N
D
O
M
I
Z
E
Inv choice
Panitumumab
6 mg/kg q2wk
Ox-CT
Bevacizumab
Ox-CT
Bevacizumab
1:1
Panitumumab
6 mg/kg q2wk
Iri-CT
Bevacizumab
Iri-CT
Bevacizumab
Stratification factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs.
Tumor assessments: q12wk until disease progression or intolerability.
PACCE = Panitumumab Advanced Colorectal Cancer Evaluation.
Courtesy of Dr. J. Hecht.
Proportion Progression-Free
Limited Update of PFS—Ox-CT Cohort
(Central Review, Apr 2007 Data Cutoff)
100%
# PFS
Events (%)
Median
95% CI (mo)
Pmab+bev/Ox-CT
206 (50)
9.0 (8.5–10.4)
Bev/Ox-CT
172 (42)
10.5 (9.7–11.6)
HR = 1.29 (95% CI, 1.05–1.58)
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
5
10
413
410
267
298
92
96
Months
15
20
21
21
3
1
Patients at risk:
Pmab+bev/Ox-CT N
bev/Ox-CT N
ITT set
Courtesy of Dr. J. Hecht.
PACCE—Grade 3/4 AEs of Interest
Ox-CT Cohort
Pmab+bev/
Ox-CT, %
(n = 401)
bev/Ox-CT, %
(n = 392)
Adverse Effects
Gr 3
Gr 4
Gr 3
Gr 4
Skin toxicity
33
<1
1
0
Diarrhea
21
2
12
1
Dehydration
14
2
4
1
Hypokalemia
8
2
3
1
Hypomagnesemia
3
1
0
0
Neutropenia
12
10
17
7
Neuropathy
9
<1
10
<1
Nausea
10
0
4
<1
Infectionsa
16
2
7
2
Deep venous thrombosis
6
0
7
0
Pulmonary embolismb
0
6
0
4
MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0
aGrade 5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT pts.
bGrade 5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts.
Courtesy of Dr. J. Hecht.
CALGB/SWOG Intergroup Trial 80405
(n = 2289)
“Dealer’s Choice”
FOLFOX or FOLFIRI
Randomize to
Bevacizumab
Cetuximab
Primary endpoint: overall survival
HR 1.25 (22 vs 27.5 months)
http://www.cancer.gov protocol ID CALGB-80405
Bevacizumab+
Cetuximab
BRiTE Registry—Patients with
Bevacizumab Beyond Progression (BBP)
BRiTE
N = 1953
1445 pts with 1st progression
932 deaths (1/21/07 cut-off)
Median follow-up 19.6 mo
Evaluable
patients
(n = 1953)
1st progression
(n = 1445)
Physician decision—no randomization
No Postprogression
treatment
(n = 253)
Grothey A, et al. J Clin Oncol. 2008 (in press).
No BBP
(n = 531)
BBP
(n = 642)
BRiTE—Patient Outcome Based on
Treatment Post 1st PD
No Post-PD
Treatment
(n = 253)
No BBP
(n = 531)
BBP
(n = 642)
Number of
deaths (%)
168
(66%)
306
(58%)
260
(41%)
Median OS (mo)
12.6
19.9
31.8
1-year OS rate
(%)
52.5
77.3
87.7
OS after 1st PD
(mo)
3.6
9.5
19.2
PD = progression; BBP = bevacizumab beyond progression; OS = overall survival.
Grothey A, et al. J Clin Oncol. 2008 (in press).
Multivariate Analysis of Pre- and PostTreatment Variables on Survival
Hazard Ratio (HR) (95% Cl)
P value
Age at 1st PD (per 10 years)
1.04 (0.98, 1.11)
.235
ECOG PS
0 (n = 632)
1 (n = 598)
≥2 (n = 87)
1.0 (reference)
1.29 (1.09, 1.52)
1.58 (1.20, 2.09)
.003
.001
Albumin, (per g/dL)
0.73 (0.64, 0.32)
<.001
Alkaline phosphatase, per (100 U/L)
1.18 (1.12, 1.23)
<.001
Site of primary tumor, %
Colon (n = 1137)
Rectum (n = 293)
1.0 (reference)
0.79 (0.66, 0.97)
.024
Exposure to EGFR inhibitors (cetuximab
and/or other EGFR monoclonal antibodies)
No (n = 884)
Yes (n = 542)
1.0 (reference)
0.97 (0.81, 1.16)
.724
Exposure to all 3 active CT agentsb
No (n = 681)
Yes (n = 745)
1.0 (reference)
0.93 (0.77, 1.12)
.447
Time-To-1st PD, per month
0.91 (0.89, 0.93)
<.001
Best 1st-line response
CR (n = 156)
PR (n = 468)
SD (n = 488)
PD (n = 314)
1.0 (reference)
1.64 (1.14, 2.35)
1.62 (1.13, 2.33)
1.32 (0.88, 1.97)
.007
.008
.173
Post-1st progression therapy
No BBP (n = 531)
BBP (n = 642)
No Post-PD treatment (n = 253)
1.0 (reference)
0.48 (0.41, 0.57)
2.01 (1.61, 2.51)
<.001
<.001
Grothey A, et al. J Clin Oncol. 2008 (in press).
SWOG/NCCTG/NCIC 2nd-Line Trial
S0600/iBET (Intergroup BEV Continuation Trial)
Open since June 2007
(FOLF)IRI/C225
MCRC pretreated with
FOLFOX + BEV or
CAPOX + BEV or
OPTIMOX + BEV
(FOLF)IRI/C225
+ BEV 5 mg/kg
(FOLF)IRI/C225
+ BEV 10 mg/kg
n = 1260
Primary endpoint: OS (HR 1.30; 12  15.6 mo)
Principal Investigators: Gold P, Grothey A
Courtesy of Dr. A. Grothey.
Patient Potentially Curable?
Yes
No
Time, QOL
Induction Ctx (3–4 mo)
Induction Ctx (3–4 mo)
Eg, FOLF?? + BEV/C225
eg, FOLF?? + BEV
Re-evaluation
of resectability
Evaluation of
tumor biology
Yes
Surgery
with curative intent
Maintenance
CFI ??
Yes
“Adjuvant” Ctx
Re-induction Ctx
Observation
“All 5 drugs”
Courtesy of Dr. A. Grothey.
Treatment Continuum
Curative Approach
RR
Case Study: Stage IV Metastatic
Colon Cancer in a Patient with
Ulcerative Colitis
J. Philip Kuebler, MD, PhD
Principal Investigator
Columbus Community Clinical Oncology Program
Columbus, Ohio
Martin
• A 71-year-old man presented with chronic
abdominal pain and recent blood in his stool
• There were no changes in bowel habits
• He had a history of ulcerative colitis and
associated symptoms
• There was no family history of cancer
• He was moderately overweight but has no other
medical problems
• Physical exam revealed abdominal tenderness
Martin
• An abdominal CT scan showed a large mass in the
ascending colon
• The CT scan also showed bilateral masses in his liver
• Abdominal and retroperitoneal lymph nodes, as well as
pulmonary nodules, were also present
• A liver biopsy was positive for metastatic adenocarcinoma
consistent with a colon primary
• After being told surgery was not an option due to the extent
of his disease, he was referred to a medical oncologist
Advances in the Treatment
of Colorectal Cancer
1980
1985
1990
1995
2000
2005
5-FU
Therapeutic concepts
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Targeted therapies
Panitumumab
{
Palliative CT
Adjuvant CT
Neoadjuvant CT
5-FU
=
Courtesy of Dr. J. Kuebler.
5-fluorouracil;
CT
=
chemotherapy.
First-Line Chemotherapy in MCRC
Phase III Trials—Progression-Free Survival
PFS or TTP (mo)
de Gramont
12
11
10
9
8
7
6
5
4
3
2
1
0
Douillard
N9741a
Saltz
d
9.0 c
Tournigandb
c
8.7
8.0
7.0 d
6.7 c
6.2
4.4
6.9
8.5
6.5
4.3
X
O
4
4
I
IR
LF
FO X 6
O
X
LF
FO
O
LF
FO
IR
L
IF
L
IF V
L
U/
F
5-
I
IR
LF
FO V
L
U/
F
5-
X
O
LF
FO V
L
U/
F
5-
aUpdate:
After a median follow-up of 4.3 years, median TTP was significantly longer in the FOLFOX arm,
9.2 mo vs 6.5 mo for IROX (P≤.001) and 6.0 mo for IFL (P≤.001); bIn first-line therapy; cP≤.001; dP≤.01.
MCRC = metastatic colorectal cancer; PFS = progression-free survival; TTP = time to progression.
de Gramont A, et al. J Clin Oncol. 2000;18:2938; Douillard JY, et al. Lancet. 2000;355:1041; Goldberg RM, et al. J Clin Oncol. 2004;22:23;
Saltz LB, et al. N Engl J Med. 2000;343:905; Sanoff HKK, et al. 43rd ASCO; June 1–5, 2007. Abstract 4067; Tournigand C, et al. J Clin
Oncol. 2004;22:229.
Courtesy of Dr. J. Kuebler.
First-Line Bevacizumab in MCRC
Progression-Free Survival
Phase III
AVF2107g
PFS or TTP (mo)
12
BICC-C
NO16966
11.2
a
10.6
b
9.4
10
8.0
8
8.3
c
7.6
6.2
5.9
6
4
2
0
IF
L
aP<.001; bP<.005; cP=.004
IF
L
+
B
FO
LF
ev
O
X
FO
LF
/C
O
X
ap
eO
x
FO
LF
/C
IR
ap
eO
x
FO
LF
I
m
IR
I+
IF
L
B
ev
m
IF
L
+
B
ev
vs mIFL.
Fuchs CS, et al. J Clin Oncol. 2007;25:4779; Hochster HS, et al. ASCO; June 1–5, 2006. Abstract 3510; Hurwitz H, et
al. N Engl J Med. 2004;350:2335; Saltz LB, et al. ASCO GI; January 17–21, 2007. Abstract 238.
Courtesy of Dr. J. Kuebler.
First-Line Cetuximab in MCRC
Phase III Trials—Progression-Free Survival
CALGB 80203a
PFS or TTP (mo)
12
10
CRYSTAL
10.6
9.8
8.9 b
8.4
8.2
b
8.0
8
6
4
2
0
FO
FO
I+
IR
LF
I
IR
LF
+
I+
IR
LF
X
X
I
IR
LF
O
LF
O
LF
FO
FO
FO
FO
C
et
et
et
C
C
a16
months’ follow-up; bP<.05.
Conclusions on overall survival await further follow-up.
Van Cutsem E, et al. 43rd ASCO; June 1–5, 2007. Abstract 4000; Venook A, et al. 42nd ASCO; June 2–6, 2006. Abstract 3509.
Courtesy of Dr. J. Kuebler.
Correlation Between Survival and
Percentage of Patients Receiving 3 Drugs*
in Phase III Trials
22
21
Median OS (mo)
20
19
18
17
16
15
14
13
12
0
10
20
30
40
50
60
70
80
Patients receiving 3 drugs (%)
*3 drugs: 5-FU/LV, irinotecan, oxaliplatin.
Reprinted from Grothey A, et al. J Clin Oncol. 2005;23:9441,with permission from the American Society of Clinical Oncology.
Managing Side Effects of
Chemotherapy—Diarrhea
• Treat diarrhea aggressively and promptly with
antidiarrheals
• Fluid/electrolyte replacement for grade >3 diarrhea
• Hospitalization/antibiotics for diarrhea with febrile
neutropenia
• Delay chemotherapy until bowel function back to
grade 0–1 with no antidiarrheals
• Consider dose reduction if diarrhea grade >3
• Anticholinergic therapy for diarrhea due to irinotecan
Kuebler JP, et al. Cancer. 2007;110:1945.
Managing Side Effects of
Chemotherapy—Neurotoxicity
• Distal paresthesias/dysethesias triggered by cold
• Educate patients to breathe in warm air, drink warm fluids
• Acute paresthesias tend to last longer with each cycle and may
increase as duration of infusion increases
• Efficacy of calcium and magnesium still being evaluated
• Evaluate neurotoxicity prior to each treatment
– Stop oxaliplatin when paresthesias begin to interfere with activities of daily
living
– Residual paresthesias can last up to 2 years
Land SR, et al. J Clin Oncol. 2007;24:2205.
Managing Side Effects of
Chemotherapy—Bevacizumab
• Treat hypertension (blood pressure persistently >140/90)
with oral agents
• Stop chemotherapy if blood pressure uncontrolled on oral
agents
• Monitor dipstick urine assays
• Interrupt treatment if proteinuria >2 gm/24 hours
• Risk for arterial thrombotic events greater in patients
aged >65 years or with arteriosclerosis
• Mild epistaxis common, major bleeding rare
• Avoid surgery 1 month prior to and 6–8 weeks after
bevacizumab
• GI perforation in ~1.5% of patients
Gordon MS, Cunningham D. Oncology. 2005;69(suppl 3):25; Kozloff M, et al. ASCO GI; January 17–21, 2007. Abstract 364;
Rosiak J, Sadowski L. Clin J Oncol Nurs. 2005;9:407; Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:232;
Ellis LM, et al. J Clin Oncol. 2005;23:4853; Sugrue M, et al. 42nd ASCO; June 2–6, 2006. Abstract 3535.
Managing Side Effects of
Chemotherapy—Cetuximab
• Treat grade 1 acneiform skin rash with topical
anti-inflammatory agents
• Treat pruritis with oral antihistamines
• Treat grade >2 skin rash with oral tetracycline (minocycline
at 100 mg/day)
• Treat paronychia with topical antiseptics/antibiotics
• Due to severe infusion reactions in ~3% of patients,
premedicate with antihistamines
• Monitor patients for 1 hour posttreatment
Segaert S, Van Cutsem E. Ann Oncol. 2005;16:1425.
Martin
• The patient had a marked initial response to
FOLFOX + bevacizumab, documented by CT scan
and drop in CEA
• After 11 cycles of chemotherapy, he was still in
response, but he was beginning to have problems
with fine motor control
• His wife had to help button his shirts and he had
difficulty holding a pen to write his name
• He discussed options for further therapy
(maintenance vs observation) with his medical
oncologist
OPTIMOX Studies
FOLFOX4 until progression
OPTIMOX-1:
maintenance therapy1
(N = 620)
FOLFOX7
FOLFOX7
sLV5FU2
mFOLFOX7
OPTIMOX-2:
CT-free interval2
(N = 202)
mFOLFOX7
sLV5FU2
mFOLFOX7
mFOLFOX7
CT-free interval
1. Tournigand C, et al. J Clin Oncol. 2004;22:229. 2. Maindrault-Goebel F, et al. 43rd ASCO; June 1–5, 2007. Abstract 4013.
Courtesy of Dr. A. Grothey.
Chemotherapy-Free Intervals of mFOLFOX
in Patients With MCRC (OPTIMOX-2)—OS
OS
1.0
OPTIMOX-1 (median 26 mo)
OPTIMOX-2 (median 19 mo)
Probability
0.8
0.6
P = .0549
0.4
0.2
0
0
10
20
30
40
50
Months
MCRC = metastatic colorectal cancer; OS = overall survival.
Maindrault-Goebel F, et al. 43rd ASCO; June 1–5, 2007. Abstract 4013. Courtesy of Dr. F. Maindrault-Goebel.
Martin
• The patient was placed on maintenance
treatment with infusional 5-FU + leucovorin
• The neurotoxicity improved quickly but did not
resolve entirely
• After 4 months, his CEA began to rise and a
follow-up CT scan confirmed progressive
disease
• Options for second-line chemotherapy were
discussed as the patient’s performance status
had not changed
Second/Third-Line Therapy
Options in MCRC
• If FOLFOX + bevacizumab used as first-line, consider FOLFIRI or
irinotecan, +/- cetuximab, as second-line treatment
• IF FOLFIRI + bevacizumab used as first-line, consider FOLFOX,
CAPOX or cetuximab + irinotecan as second-line
• If 5-FU/LV + bevacizumab used as first-line (not preferred), consider
FOLFOX, CAPOX, FOLFIRI, or irinotecan as second-line
• For third-line therapy, consider cetuximab, panitumumab, or cetuximab
+ irinotecan
• Avoid single-agent bevacizumab or oxaliplatin
• Consider going back to FOLFOX or FOLFIRI
FOLFIRI + Cetuximab ± Bevacizumab
in Patients with Relapsed MCRC
(S0600/iBET)—Phase III Trial Design
Previously treated
patients with MCRCa
N = 1250
R
A
N
D
O
M
I
Z
A
T
I
O
N
FOLFIRI + cetuximab
+
placebo
(q2w)
FOLFIRI + cetuximab
+
bevacizumab
(5 mg/kg q2w)
FOLFIRI + cetuximab
+
bevacizumab
(10 mg/kg q2w)
Primary end point: Overall Survival (OS)
Secondary end point: Progression-Free Survival (PFS)
MCRC = metastatic colorectal cancer; iBET = Intergroup Bevacizumab Continuation Trial.
aPatients progressed on FOLFOX, OPTIMOX, or CAPEOX + bevacizumab as first-line regimen.
http://clinicaltrials.gov/ct/show/NCT00499369?order=1. Accessed August 27, 2007.
Summary
• First-line treatment regimen should be based on the disease and
patient situation
• mFOLFOX, FOLFIRI, CAPOX, or 5-FU/LV with bevacizumab or
cetuximab are all reasonable choices for first-line therapy
• Maintenance therapy after response is reasonable but there are no
randomized data
• Bevacizumab is an option for maintenance and with second-line
therapy
• Cetuximab plus irinotecan is an option for second- or third-line
therapy
• Overall survival of patients with metastatic unresectable disease has
been steadily increasing with the use of regimens in sequence or in
combination (FOLFOXIRI)
Case Study: Surgically Resectable
Metastatic Colorectal Cancer
Cathy Eng, MD
Assistant Professor
Department of Gastrointestinal Medical Oncology
The University of Texas M. D. Anderson Cancer Center
Houston, Texas
Case Presentation—Ann
• Ann is a 49-year-old female with newly diagnosed metastatic
colorectal cancer who presents for treatment recommendations
• Six weeks earlier, she presented to the ER with weakness,
nausea and vomiting, and abdominal pain
• She denies any prior constitutional symptoms or change in
bowel habits until the past month
• Physical exam revealed a young, thin female in moderate
distress with 8/10 right-sided abdominal pain
• Her ECOG PS was 1
• Diagnostic studies included blood work, obstruction series, and
CT scan of the chest, abdomen, and pelvis
– Findings: Hb = 10.1 g/dL, MCV = 73 fL, LFTs = WNL
– Obstruction series of the abdomen demonstrated air fluid levels and
dilated small bowel loops consistent with small bowel obstruction
ER = Emergency Room; ECOG PS = Eastern Cooperative Group performance status;
CT = computed tomography; Hb = hemoglobin; MCV = mean corpuscular volume;
LFTs = liver function tests; WNL = within normal limits.
CT Scan at Baseline
Carcinoma of the cecum
Courtesy of Dr. C. Eng.
2 coalescent lesions 4.8 cm in
greatest diameter
Case Presentation
• Preoperative carcinoembryonic antigen (CEA) =
38 ng/mL (normal, <5 ng/mL)
• No known family history of colon cancer
• Emergent right hemicolectomy performed due to bowel obstruction
• Palpation of the liver revealed no additional hepatic lesions, a
finding confirmed by intraoperative ultrasound
• The surgeon elected to resect the hepatic lesions at a later date
• Postoperative pathology revealed a moderately differentiated
adenocarcinoma of the colon penetrating through the muscularis
propria, with 5 of 22 lymph nodes positive
• AJCC staging: T3N2M1 right-sided colon cancer
Case Presentation
Postoperative state
• Ann has recovered fully
• ECOG PS = 0
–
–
–
–
–
She has only lost 5 lbs since the surgery
She has 1–2 bowel movements daily
Postoperative CEA = 16 ng/mL
LFTs: within normal limits
Postoperative CT scan reveals no new lesions
• She is anxious to initiate therapy
• She desires to know what her options are to be “cancer-free” in the
future
• What is the best approach to address her metastatic disease in the
liver?
Options in Management of Hepatic
Metastasis from Colorectal Cancer
•
Prioritize multidisciplinary discussion with the liver
surgeon
Options
•
–
–
–
–
Surgical resection
Neoadjuvant systemic chemotherapy
Conversion chemotherapy
Hepatic arterial infusion therapy–fallen out of favor
Immediate Hepatic Resection
•
•
•
•
Resectable disease
Role of adjuvant chemotherapy is unknown
Duration of adjuvant chemotherapy is unknown
To date, no randomized trial of surgical resection
followed by observation vs adjuvant chemotherapy has
been completed
Neoadjuvant Systemic Chemotherapy
• Majority of prior studies have been retrospective
• Ideal for surgically resectable or borderline resectable
disease
• Allows indirect measure of chemotherapy
responsiveness
• Be wary of chemotherapy-induced hepatic toxicities
– Do not treat until best response
– Radiologic complete response ≠ pathologic complete response
Phase III EORTC 40983
Perioperative FOLFOX for Resectable
Hepatic Metastases*
Randomize
N = 364
Surgery
FOLFOX4
6 cycles
(3 months)
Surgery
• Primary endpoint: progression-free survival
• Eligibility criteria: < 4 liver lesions
(metachronous or synchronous),
FOLFOX4
6 cycles
(3 months)
surgically resectable, no extrahepatic disease
*Only prospective trial to date.
Nordlinger B, et al. 43rd ASCO; June 1-5, 2007. Abstract LBA5.
Complications of Surgery
Postoperative complications*
Peri-op CT
Surgery
40 /159 (25.2%)
27 / 170 (15.9%)
Cardiopulmonary failure
3
2
Bleeding
3
3
Biliary fistula
122
5
(9)
(2)
Includes output >100 mL/d, >10 d
Hepatic failure
11
8
(10)
(5)
Wound infection
4
4
Intra-abdominal infection
8
2
Needed to re-operate
5
3
Other
25
16
Includes postoperative death
1 patient
Includes bilirubin >10 mg/dL, >3 d
*P = .04
Courtesy of Dr. B. Nordlinger.
2 patients
Final Results of EORTC 40983
No. Pts
CT
N Pts
Surgery
Absolute
Difference
in 3-Year PFS
(95.66%
Confidence
Interval)
Hazard
Ratio
(95.66%
Confidence
Interval)
P-value
All patients
(ITT)
182
182
+7.3%
(28.1%–35.4%)
0.79
(0.62–1.02)
P = .058
All eligible
patients
171
171
+8.1%
(28.1%–36.2%)
0.77
(0.60–1.00)
P = .041
All resected
patients
151
152
+9.2%
(33.2%–42.4%)
0.73
(0.55–0.97)
P = .025*
*Statistically significant only in those patients surgically resected.
Courtesy of Dr. B. Nordlinger.
Conversion Chemotherapy
• Defined as systemic chemotherapy
provided to decrease tumor burden and
improve likelihood of surgical resection
• Previously conducted studies
– FOLFOXIRI
– CRYSTAL
– NO16966
FOLFIRI vs FOLFOXIRI
Phase III
(Gruppo Oncologico Nord Ovest)
Randomize
untreated MCRC
N=244
FOLFIRI
X 12
Falcone A, et al. J Clin Oncol. 2007;25:1670.
FOLFOXIRI
x 12
FOLFOXIRI vs FOLFIRI
Results
FOLFIRI
(n = 122)
FOLFOXIRI
(n = 122)
CR*
6%
8%
PR*
35%
58%
RR*
41%
66%
[95%: 0.32-0.50]
[95%: 0.56-0.74]
12% (n = 42)
36% (n = 39)
P = .017
R0 (hepatic
resection)†
* Investigators assessment
† Patients with liver metastases only
Falcone A, et al. J Clin Oncol. 2007;25:1670.
Role of Biologics in Hepatic
Resection?
CRYSTAL Trial
Liver Resection with Cetuximab
FOLFIRI Alone
Cetuximab + FOLFIRI
ITT Population
7
6
Liver-Metastases–Only Population
P = .0034*
9
8
5
4.3
4
2.5
1.5
2
Percentage (%)
Percentage (%)
6
3
9.8
10
7
6
5
4.5
4
3
2
1
1
0
0
Surgery with
Curative Intent
n = 599/Group
No Residual Tumor
After Resection
n = 599/Group
Courtesy of Dr. E. Van Cutsem.
No Residual Tumor in Patients
with Liver Metastases
n = 134/n = 122
Lucrative Points in the
Management of Hepatic
Resection
Duration of Chemotherapy
• Chemotherapy may induce hepatic toxicities
• At a median of 4 months of chemotherapy with fluoruracil
and irinotecan or oxaliplatin, many patients developed
– Sinusoidal dilatation
– Steatosis
– Steatohepatitis
 Associated with increased 90-day postoperative mortality
• Shorter duration of chemotherapy (e.g. 2-3 months may
be optimal)
• Biologic therapy
– Bevacizumab recommended to be held 4-8 weeks prior to
surgical resection
Vauthey JN, et al. J Clin Oncol. 2006;24:2065.
Radiologic CR = Pathologic Cure?
• 1998–2004
– 586 consecutive patients treated for up to 10 hepatic
metastases
 38 patients had radiologic CR of >1 hepatic lesion
 Surgery was conducted 4 weeks after start of neoadjuvant
treatment
• Number of neoadjuvant cycles: 9 + 5
• Types of chemotherapy
– 5-FU/LV = 9
– FOLFOX = 17
– FOLFIRI = 12
Nordlinger B, et al. 42nd ASCO; June 2-6, 2006. Abstract 3501.
Radiological CR = Cure?
• 66 liver lesions had a radiologic CR
 20 (9 pts) had macroscopic residual disease
– Mean size 12 + 7 mm
– Viable cancer cells at biopsy
 15 (15 pts) had microscopic disease
– No visible tumor was seen surgically or by IOUS
– Site was resected
– Viable cancer cells were seen in 12 of 15 liver mets
 31 lesions in 14 pts showed no evidence of disease
surgically or by IOUS
– Site was not resected
– One year follow-up: 23 of 31 mets had in situ recurrences
• Findings: 55 of 66 (83%) of the lesions were not
pathologically cured
• Conclusions: Consider pursuing surgical resection
regardless of no radiographic evidence of disease.
Nordlinger B, et al. 42nd ASCO; June 2-6, 2006. Abstract 3501.
Case Presentation
• Ann received 5 cycles of FOLFOX + bevacizumab,
followed by 1 cycle of FOLFOX without bevacizumab
• Except for mild cold hypersensitivity, she tolerated her
chemotherapy well
• In the interim, genetics counseling showed that she is
microsatellite-stable
• Her CEA concentration is now 7.2 ng/mL
• CT of her chest, abdomen, and pelvis all showed
response to therapy
• Her PET/CT scan is negative for extrahepatic disease
Postchemotherapy CT Scan
• The patient undergoes
right hepatic resection
without complications
• Minimal <5% steatosis
was noted
• Due to her excellent
response to
chemotherapy, the
patient opted for an
additional 4–6 months of
adjuvant FOLFOX +
bevacizumab
Courtesy of Dr. C. Eng.
Conclusions
• Multidisciplinary management is crucial for a patient with
resectable hepatic metastases
• Resection of the primary tumor is patient dependent
based on presenting symptoms
• Be wary of duration of neoadjuvant therapy—Do not
treat a patient to cure for hepatic metastases but treat
until surgically resectable
• Radiolologic CR is not equivalent to pathologic CR and
must still be evaluated if possible
– Challenge: identifying the original site of disease
intraoperatively
• To date, the role of biologic therapy in conjunction with
chemotherapy as neoadjuvant treatment has not been
defined in a large randomized phase II or phase III trial