Transcript Diapositiva 1

ASCO highlights: Colorectal cancer
Mark Kozloff
The University of Chicago
Chicago, USA
Chemotherapy ± biologics in
the adjuvant setting
● Phase III study
Centralized
KRAS
analysis
KRAS
mutant
● Primary endpoint: DFS at 3 years
REGISTRATION
Stage III
colon
cancer
(n=3768)
PREREGISTRATION
KRAS
wild-type
RANDOMIZATION
N0147: adjuvant therapy of stage III colon cancer
Arm A
mFOLFOX6
Arm D
mFOLFOX6 +
cetuximab
Arm G
• Adjuvant
therapy per
primary
oncologist
• Report therapy
given
• Annual status
through year 8
● Secondary endpoint: OS
Alberts, et al. ASCO 2010
N0147: no DFS benefit with cetuximab + FOLFOX
in resected KRAS wild-type stage III colon cancer
1.0
DFS estimate
0.8
FOLFOX
FOLOX + cetuximab
0.6
0.4
0.2
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
(n=902)
75.8
(72.1–79.6)
1.2
(0.96–1.5)
FOLFOX + C
(n=945)
72.3
(68.5–76.4)
6
12
p value
0.22
0
0
18
24
30
36
Months
C = cetuximab
Alberts, et al. ASCO 2010
N0147: no OS benefit with cetuximab + FOLFOX
in resected KRAS wild-type stage III colon cancer
1.0
OS estimate
0.8
FOLFOX
FOLOX + cetuximab
0.6
0.4
0.2
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
n=902
87.8
(84.7–90.9)
1.3
(0.96–1.8)
FOLFOX + C
n=945
83.9
(80.3–87.6)
p value
0.13
0
0
6
12
18
24
30
36
Months
Alberts, et al. ASCO 2010
N0147: does cetuximab treatment of KRAS mutated
tumors drive chemotherapy resistance?
KRAS mutant
1.0
1.0
0.8
0.8
0.6
0.4
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
n=902
75.8
(72.1–79.6)
1.2
(0.96–1.5)
FOLFOX +C
n=945
72.3
(68.5–76.4)
p value
0.22
0.2
DFS estimate
DFS estimate
KRAS wild-type
0.6
0.4
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
n=374
67.2
(61.4–73.5)
1.2
(0.9–1.6)
FOLFOX +C
n=343
64.2%
(58.7–70.2)
p value
0.13
0.2
FOLFOX
FOLFOX + cetuximab
FOLFOX
FOLFOX + cetuximab
0
0
0
6
12
18
24
Months
30
36
0
6
12
18
24
Months
30
36
Goldberg, et al. ASCO 2010
N0147: does cetuximab treatment of KRAS mutated
tumors drive chemotherapy resistance?
KRAS mutant
1.0
1.0
0.8
0.8
0.6
0.4
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
n=902
87.8
(84.7–90.9)
1.3
(0.96–1.8)
FOLFOX +C
n=945
83.9
(80.3–87.6)
p value
0.13
0.2
OS estimate
OS estimate
KRAS wild-type
0.6
0.4
Arm
3 year rates
(95% CI)
HR
(95% CI)
FOLFOX
n=374
88.8
(83.8–92.5)
1.5
(0.9–2.3)
FOLFOX +C
n=343
80.4
(74.8–86.4)
p value
0.12
0.2
FOLFOX
FOLFOX + cetuximab
FOLFOX
FOLOX + cetuximab
0
0
0
6
12
18
24
Months
30
36
0
6
12
18
24
Months
30
36
Goldberg, et al. ASCO 2010
N0147: conclusions
● No benefit to adding cetuximab to FOLFOX6 in patients with
resected KRAS wild-type stage III colon cancer1
– Decreased tolerance with cetuximab?
– Differences in dose intensity?
– Interaction with age?
● Patients with resected KRAS mutant stage III colon cancer did
worse with cetuximab2
– Hypothesis: cetuximab treatment of KRAS mutated tumors
drives chemotherapy resistance
The outcomes are surprising2
– Understanding the interactions of tumor genotype and patient
biology challenge us
– The key to individualizing care lies in that understanding
– We hope to find the answers in the tumor blocks
1. Alberts, et al. ASCO 2010
2. Goldberg, et al. ASCO 2010
Chemotherapy ± biologics in
the metastatic setting
Untreated mCRC
• (Neo)adjuvant
therapy ≥6 months
prior to study entry
• If adjuvant therapy
administered, no
disease progression
during treatment or
<6 months of its
completion
• No prior radiotherapy
to target lesions
(n=480)
RANDOMIZATION
MACRO: bevacizumab until progression
Bevacizumab + XELOX
until PD
Bevacizumab + XELOX
6 cycles
Bevacizumab
until PD
● Prospective, randomized, phase III study
● Primary endpoint: PFS
● Secondary endpoints: OS, ORR, time to response, duration of
response, number of treatment cycles, safety
Tabernero, et al. ASCO 2010
MACRO: non-inferiority of single-agent
bevacizumab in maintenance therapy for mCRC
OS
PFS
XELOX-BEV
BEV
No. of patients
239
241
Event
131 (55)
130 (54)
Censored
108 (45)
111 (46)
Median (95% CI)
23.4 (20.0–26.0) 21.7 (18.3–25.1)
HR=1.04 (0.81–1.32)
1.0
0.4
XELOX-BEV
BEV
0.8
PFS estimate
0.6
0.2
BEV
241
174 (72)
67 (28)
9.7 (8.5–10.6)
Follow-up median
months (range)
21.1 (0–40)
20.4 (0–38)
0.6
0.4
0.2
0
0
0
6
12
18
24
Months
30
36
0
No. of patients at risk:
XELOX-BEV
BEV
1.0
Follow-up median
months (range)
XELOX-BEV
21.1 (0–40)
BEV
20.4 (0–38)
0.8
OS estimate
XELOX-BEV
No. of patients
239
Event
161 (67)
Censored
78 (33)
Median (95% CI)
10.4 (9.3–11.9)
HR=1.11 (0.89–1.37)
239 227 208 191 170 146 120 85 60 40 23 13
241 226 210 193 159 132 101 77 54 39 26 19
BEV = bevacizumab
6
12
18
24
Months
30
36
No. of patients at risk:
6
8
2
0
XELOX-BEV 239 204 158 108 71 49 27 13 7
BEV
241 199 160 102 58 40 27 17 11
4
8
2
6
1
4
0
1
Tabernero, et al. ASCO 2010
MACRO: conclusions
● This data indicate that a priori specified non-inferiority
cannot be still confirmed, but we can reliably exclude a
detriment of larger than 3 weeks in PFS
● This study suggests that maintenance therapy with
single-agent bevacizumab is an appropriate option
following induction XELOX-bevacizumab in patients with
mCRC
● Further studies evaluating single-agent bevacizumab after
standard chemotherapy in mCRC are warranted
Tabernero, et al. ASCO 2010
ARIES: post-progression observation of
bevacizumab treatment
● ARIES
– total n=1,548
– prospective,
non-randomized,
observational phase III study
– primary endpoint: SBP
– secondary endpoint:
OS, time to first PD,
OS, safety
Unresectable mCRC treated with
first-line chemotherapy +
bevacizumab (n=1,548)
First progression
(n=1,113*)
Physician decision
(no randomization)
No post-PD
treatment‡
(n=282)
No bevacizumab
post-PD
(n=336)
*1,026 patients were alive 2 months after first PD
‡No treatment ever or bevacizumab and/or chemotherapy ≥2 months after PD
Bevacizumab
post-PD
(n=408)
Cohn, et al. ASCO 2010
ARIES: potential survival benefit from bevacizumab
beyond progression
No bevacizumab
post-PD*
(n=336)
Bevacizumab
post-PD‡
(n=408)
Median OS, months
(95% CI)
18.7
(17.5–20.4)
27.5
(25.6–29.9)
Median SBP, months
(95% CI)§
7.5
(6.2–8.7)
14.1
(12.6–16.1)
1.0
(reference)
0.52
(0.42–0.63)
Adjusted HR (95% CI)¶
*Patients
alive 2 months post-PD and starting chemotherapy/biologics <2 months post-PD; no
bevacizumab ever post-PD
‡Patients alive 2 months post-PD and starting chemotherapy/biologics + bevacizumab <2 months post-PD
§For SBP, t =PD+2 months
0
¶Multivariate model adjusted for patient characteristics
Cohn, et al. ASCO 2010
ARIES*: does bevacizumab beyond progression
extend survival?
1.0
Bevacizumab post-PD (n=408)
No bevacizumab post-PD (n=336)
SBP estimate
0.8
HR=0.52 (95% CI: 0.42–0.63)
p<0.001‡
0.6
0.4
0.2
7.5
0
0
5
14.1
10
15
Months
*Non-randomized, observational study
‡Bevacizumab post-PD versus no bevacizumab post-PD
20
25
30
Cohn, et al. ASCO 2010
ARIES: conclusions
● Patients receiving bevacizumab who continued or initiated
early after disease progression had a longer median SBP
than patients who received only chemotherapy/biologics
early post-PD
● The ARIES bevacizumab beyond progression preliminary
analysis results are generally consistent with the earlier
findings in the BRiTE study and support the hypothesis that
sustained VEGF suppression improves the clinical outcomes
for patients with mCRC
Cohn, et al. ASCO 2010
COIN: cetuximab + oxaliplatin-based chemotherapy
in first-line mCRC therapy
Inclusion
Advanced
colorectal cancer,
first-line therapy
No prior
chemotherapy
for metastatic
disease
No prior EGFR
IHC
PS0-2
5-FU or capecitabine
oxaliplatin
Arm A
815
CONTINUOUS CT until progression, toxicity or patient choice
Second-line
chemotherapy
5-FU or capecitabine
oxaliplatin
cetuximab
Arm B
815
Irinotecanbased
CONTINUOUS CT until progression, toxicity or patient choice
Good organ
function
Arm C
815
FU or cap
FU or cap
FU or cap
oxaliplatin
oxaliplatin
oxaliplatin
INTERMITTENT CT Treat for 12 weeks then stop and monitor.
Restart on progression for a further 12 weeks
OxMdG: 2 weekly IV l-folinic acid 175mg, oxaliplatin 85mg/m2 over 2 h, IV bolus 5-FU 400mg/m2,
5-FU 2400mg/m2 inf. 46 h via ambulatory pump (mFOLFOX)
XELOX: 3 weekly IV oxaliplatin 130mg/m2 over 2 h, capecitabine 1000mg/m2 p.o. bd for 2 weeks
(reduced to 850mg/m2 in Arm B from July 07 for toxicity)
Patients/clinicians chose OxMdG or XELOX before randomization
Maughan, et al. ASCO 2010
COIN: distribution and prognostic significance
of KRAS, NRAS and BRAF mutations
Prognostic effect of mutational
status
BRAF-mutant
n=102 (8%)
102
554
Total
n=1316 (81%)
Population
n
Arm A
Arm B
ITT
1630
815
815
Assessed for mutations
1316
648
668
of which:
- KRAS mutation
- NRAS mutation
- BRAF mutation
565 (43%)
50 (4%)
102 (8%)
268
18
57
297
32
45
KRAS wild-type
729 (55%)
367
362
KRAS/NRAS/BRAF-wild-type
“All wild-type”
581 (44%)
289
815
815
Median OS
(months)
6 12 18
39
11
Arm B
292
0 10 20 30 40 0
“All-wild-type”
n=581 (44%)
Arm A
Median PFS
(months)
0
6 12
NRAS-mutant
n=50 (4%)
2-year OS (%)
KRAS-mutant
n=565 (43%)
N:
Mutation status:
BRAF mutantation
Any mutation
KRAS mutation
All patients
KRAS wild-type
All wild-type
Maughan, et al. ASCO 2010
COIN: no OS or PFS benefit with cetuximab +
FOLFOX in KRAS wild-type mCRC
PFS
Arm A
Arm B
Diff.
Median OS: months
17.9
17.0
-0.92
2-year survival rates (%)
36.1
34.4
-1.66
1.0
1.0
0.8
0.8
0.6
HR=1.038
(95% CI: 0.90–1.20)
p=0.68
0.4
0.2
PFS estimate
OS estimate
OS
Arm A
Arm B
Diff.
Median PFS: months
8.6
8.6
+0.07
2-year survival rates (%)
8.83
9.55
+0.72
0.6
HR=0.959
(95% CI: 0.84–1.09)
p=0.60
0.4
Arm A (OxFp)
Arm B (OxFp + C)
0.2
Arm A (OxFp)
Arm B (OxFp + C
0
0
0
6
12
18
24
30
36
42
48
0
6
12
18
Months
No. of patients at risk:
A
367 316 250
B
362 306 238
154
149
83
80
24
30
36
42
11
9
6
6
1
0
48
Months
44
42
19
17
1
3
367
361
245
249
92
103
41
42
18
22
Maughan, et al. ASCO 2010
COIN: no OS benefit with cetuximab + FOLFOX in
KRAS, NRAS, BRAF wild-type or mutant mCRC
All wild-type
Any mutation
Arm A
Arm B
Diff.
Median OS: months
20.1
19.9
-0.20
2-year survival rates (%)
40.0
38.8
-1.24
Arm B
Diff.
Median OS: months
14.4
12.7
-1.64
2-year survival rates (%)
21.2
25.5
+4.29
1.0
1.0
0.8
HR=1.019
(95% CI: 0.86–1.20)
p=0.86
0.6
0.4
0.2
OS estimate
0.8
OS estimate
Arm A
HR=1.004
(95% CI: 0.87–1.15)
p=0.96
0.6
Arm A (OxFp)
Arm B (OxFp + C)
0.4
0.2
Arm A (OxFp)
Arm B (OxFp + C)
0
0
0
6
12
18
24
30
36
42
48
0
6
12
18
Months
No. of patients at risk:
A
289 256 208
B
292 258 211
133
136
76
70
24
30
36
42
19
27
7
13
1
0
48
Months
41
37
19
15
1
3
340
366
285
290
198
187
108
108
46
65
Maughan, et al. ASCO 2010
COIN: no PFS benefit with cetuximab + FOLFOX in
KRAS, NRAS, BRAF wild-type or mutant mCRC
All wild-type
Any mutation
Arm A
Arm B
Diff.
Median PFS: months
8.8
9.2
+0.43
2-year PFS rates (%)
10.2
10.8
+0.55
Arm B
Diff.
Median PFS: months
6.6
6.3
-0.33
2-year PFS rates (%)
3.45
3.19
-0.26
1.0
1.0
0.8
HR=0.922
(95% CI: 0.80–1.07)
(97% Cl: 0.78–1.09) p=0.36
0.6
Arm A (OxFp)
Arm B (OxFp + C)
0.4
PFS estimate
0.8
PFS estimate
Arm A
0.6
0.2
0
0
6
12
18
24
30
36
42
48
Arm A (OxFp)
Arm B (OxFp + C)
0.4
0.2
0
HR=1.079
(95% CI: 0.95–1.23)
(97% Cl: 0.93–1.25) p=0.33
0
6
12
18
Months
No. of patients at risk:
Arm A 289 200
75
Arm B 292 220
94
35
37
18
19
24
30
36
42
2
4
1
2
0
0
48
Months
11
8
6
5
1
0
340
366
204
200
61
59
24
21
7
8
Maughan, et al. ASCO 2010
COIN: improved response rate in patients with KRAS
wild-type mCRC overall and at 12 weeks
All patients
KRAS wild-type
KRAS mutant
Arm A
Arm B
Arm A
Arm B
Arm A
Arm B
Patients randomized, n
815
815
367
362
268
297
ORR at 12 weeks, %
45
49
50
59
41
40
Odds ratio
Best ORR, %
Odds ratio
1.17 (p=0.124)
51
53
1.08 (p=0.428)
1.44 (p=0.015)
57
64
0.97 (p=0.877)
46
43
OR=1.35 (p=0.049) OR=0.88 (p=0.449)
Maughan, et al. ASCO 2010
COIN: conclusions
● In this negative study, subgroup analyses suggest that there
may be a benefit for cetuximab in combination with
oxaliplatin chemotherapy in:
– patients with KRAS wild-type tumors
– patients with limited metastatic disease (0/1 metastatic
sites)
– combination with infusional 5-FU and oxaliplatin
● The differential benefit for choice of fluoropyrimidine and
distribution of disease requires validation from other
datasets
● Strong prognostic effect of KRAS, BRAF and NRAS mutation
status independent of the use of cetuximab
Maughan, et al. ASCO 2010
Perifosine
● Oral alkylphospholipid
● Inhibition of multiple signal transduction pathways
– AKT inhibition
– NF-kB inhibition
– Activation of apoptotic pathway via JNK
● Selective tumor cell accumulation and potential disruption of
membrane asymmetry
Potential mechanisms of action of
perifosine + capecitabine
● NF-kB inhibition
– Fluorouracil resistance associated with upregulation of
NF-kB1
– Inhibition of NF-kB pathway (proteasome inhibitors,
mTOR inhibitors) augments fluorouracil anti-tumor effect2
– Perifosine shown to inhibit NF-kB nuclear translocation
and pathway activation3
● Anti-angiogenic effects
– Downstream inhibition of VEGF receptor signaling
pathway
– Anti-VEGF therapy potentially augments chemotherapy
1. Voboril, et al. J Surg Res 2004; 2. Nakanishi, Toi. Nat Rev Cancer 2005
3. Leleu, et al. Blood 2008
Patients with secondor third-line mCRC
No prior radiotherapy
with CAP in metastatic
setting
Prior Rx with 5-FU or 5FU based regimen
RANDOMIZATION
P-CAP vs CAP: perifosine + capecitabine in
second- or third-line mCRC therapy
Perifosine 50mg PO QD
Capecitabine 825mg/m2
b.i.d days 1–14
Cycle = 21 days
Placebo PO QD
Capecitabine 825mg/m2
b.i.d days 1–14
● Prospective, randomized, phase II study
● Primary objective: to compare TTP of P-CAP vs CAP as second- or
third-line treatment
● Secondary objectives:
– to compare overall response rate (CR + PR) and overall survival
– to evaluate the safety of P-CAP vs CAP
Richards, et al. ASCO 2010
P-CAP vs CAP: significant TTP benefit with
perifosine + capecitabine in second- or third-line mCRC
All evaluable patients
5-FU refractory patients
Capecitabine + perifosine
1.0
1.0
Median TTP: P-CAP:
28 weeks (95% CI: 12– 48)
Median TTP: CAP:
11 weeks (95% CI: 9–15.9)
0.6
Median TTP: P-CAP:
18 weeks (95% CI: 12–36)
Median TTP: CAP:
10 weeks (95% CI: 6.6–11)
0.8
TTP estimate
0.8
TTP estimate
Capecitabine + placebo
HR=0.284 (0.127–0.636)
p=0.0012
0.4
0.6
HR=0.186 (0.066–0.521)
p=0.0004
0.4
0.2
0.2
0
0
0
24
48
72
96
Weeks
120
144
168
0
24
48
72
96
120
144
168
Weeks
Richards, et al. ASCO 2010
P-CAP vs CAP: significant OS benefit with
perifosine + capecitabine in second- or third-line mCRC
All evaluable patients
5-FU refractory patients
Capecitabine + perifosine
OS estimate
0.8
0.6
HR=0.410
(0.193–0.868)
0.4
Median OS: P-CAP:
15.1 months (95% CI: 7.3–22.3)
Median OS: CAP:
6.6 months (95% CI: 4.7–11.7)
p=0.0112
1.0
0.8
OS estimate
Median OS: P-CAP:
17.7 months (95% CI: 8.5– 24.6)
Median OS: CAP:
10.9 months (95% CI: 5–16.9)
p=0.0161
1.0
Capecitabine + placebo
0.6
HR=0.313
(0.122–0.802)
0.4
0.2
0.2
0
0
0
12
24
Months
36
0
12
24
Months
36
Richards, et al. ASCO 2010
P-CAP vs CAP: increase in grade 3–4 hand-foot
syndrome and anemia
Capecitabine +
perifosine
(n=20)
Capecitabine +
placebo
(n=18)
Hand and foot
6 (30)
0
Anemia
3 (15)
0
Abdominal pain
1 (5)
2 (11)
Fatigue
0
2 (11)
Bowl obstruction
0
2 (11)
Grade 3–4 adverse
events >10%, n (%)
● Median time to onset of grade 3–4 hand-foot syndrome for patients
in perifosine arm: 19 weeks
● Median time to onset of hand-foot syndrome for patients in
capecitabine arm: 11 weeks
Richards, et al. ASCO 2010
Role of biomarkers in colorectal cancer
First-line mCRC,
unresectable
(n=1198)
RANDOMIZATION
CRYSTAL: cetuximab + FOLFIRI in first-line mCRC
therapy
FOLFIRI
FOLFIRI + cetuximab
● Prospective, randomized, phase III study
● Primary endpoint: PFS
● Secondary endpoints: OS, ORR, safety
● Additional tumor samples analyzed retrospectively (n=1,063 in total)
Van Cutsem, et al. NEJM 2009
CRYSTAL: efficacy in patients with KRAS wild-type
tumors according to BRAF mutation status
Cetuximab
+ FOLFIRI
vs FOLFIRI
KRAS wt
(n=666)
Cetuximab
+ FOLFIRI
vs FOLFIRI
KRAS wt/BRAF wt
(n=566)
Cetuximab
+ FOLFIRI
vs FOLFIRI
KRAS wt/BRAF mt
(n=59)
OS, months
23.5 vs 20.0
(HR=0.796; p=0.0093)
25.1 vs 21.6
(HR=0.83; p=0.0549)
14.1 vs 10.3
(HR=0.908; p=0.744)
PFS, months
9.9 vs 8.4
(HR=0.696; p=0.0012)
10.9 vs 8.8
(HR=0.679; p=0.0016)
8.0 vs 5.6
(HR=0.934; p=0.866)
57.3 vs 39.7
(OR=2.0693; p<0.0001)
61.0 vs 42.6
(OR=2.175; p<0.0001)
19.2 vs 15.2
(OR=1.0842; p<0.9136)
Outcome
ORR, %
mt = mutant
wt = wild-type
Van Cutsem, et al. ASCO 2010
CRYSTAL NRAS and BRAF – 2 results
● ASCO GI
Prognostic and predictive biomarkers in mCRC
Prognostic biomarker
Predictive biomarker
Provides information about
patient outcome,
regardless of therapy
Used in advance of therapy
to estimate the response
to a specific treatment
KRAS
Prognostic
Predictive
BRAF
Prognostic
NRAS
Prognostic
Summary: how will the ASCO data impact
your clinical practice?
NCCN guidelines for the first-line treatment of mCRC
FOLFOX ± bevacizumab
XELOX ± bevacizumab
FOLFOX ± cetuximab* or panitumumab*
Patients appropriate
for intensive therapy
FOLFIRI + bevacizumab
FOLFIRI ± cetuximab* or panitumumab*
5-FU/LV + bevacizumab
Previously
untreated
mCRC
FOLFOXIRI‡
Capecitabine ± bevacizumab
Patients not appropriate
for intensive therapy
Infusional 5-FU/LV ± bevacizumab
Cetuximab*‡
Panitumumab*‡
*KRAS wild-type only
‡Category 2B recommendation
National Comprehensive Cancer Network.
NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010.
NCCN guidelines for the first- and second-line
treatment of mCRC
Therapy after first progression
FOLFOX ± bevacizumab
FOLFIRI
XELOX ± bevacizumab
Irinotecan
FOLFOX ± cetuximab* or panitumumab*
Patients
appropriate
for intensive
therapy
FOLFIRI + bevacizumab
FOLFIRI ± cetuximab* or panitumumab*
5-FU/LV + bevacizumab
Previously
untreated
mCRC
FOLFOXIRI‡
Patients not
appropriate
for intensive
therapy
FOLFIRI ± cetuximab* or
panitumumab*
Irinotecan + cetuximab*‡
FOLFOX or XELOX or cetuximab*
+ irinotecan, patients not able
to tolerate combination, consider
single-agent cetuximab*
or panitumumab*
Capecitabine ± bevacizumab
FOLFOX or XELOX
Infusional 5-FU/LV ± bevacizumab
Irinotecan
Cetuximab*‡
FOLFIRI
Panitumumab*‡
*KRAS wild-type only
‡Category 2B recommendation
National Comprehensive Cancer Network.
NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010.
NCCN guidelines for adjuvant therapy of
colorectal cancer*
Pathologic stage Adjuvant therapy
Tis; T1, N0, M0;
T2, N0, M0
T3, N0, M0‡
(no high risk features)
T3, N0, M0
(high risk of systemic
recurrence);
T4, N0, M0;
T3 with localized
perforation, or
close, indeterminate
positive margins
Surveillance
None
Consider capecitabine
or 5-FU/leucovorin
or clinical trial
or observation
5-FU/leucovorin/
oxaliplatin§¶
or capecitabine§ or
5-FU/leucovorin§
or clinical trial
or observation
History and physical every 3–6 months for 2
years, then every 6 months for a total of 5 years
CEA** every 3–6 months for 2 years then every
6 months for a total of 5 years for T2 or greater
lesions
Chest/abdominal/pelvic CT annually 3 years
for patients at high risk of recurrence
Colonoscopy in 1 year except if no preoperative due to obstructing lesion,
colonoscopy in 3–6 months
if advanced adenoma, repeat in 1 year
if no advanced adenoma, repeat in 3 years,
then every 5 years
PET-CT scan is not routinely recommended
*No data to support adjuvant therapy in Stage I disease, although some high-risk Stage II patients may be
considered at higher risk and discussion of chemotherapy may be warranted. Bevacizumab, cetuximab,
panitumumab and irinotecan should not be used in the adjuvant setting for Stage II or III patients outside of a
clinical trial; ‡Patients considered to be N0 but who have <12 nodes examined are suboptimally staged and
should be considered high risk; §Consider RT for T4 with penetration to a fixed structure; ¶Treatment options
include FOLFOX or FLOX; **If a patient is a candidate for further intervention
National Comprehensive Cancer Network.
NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010.
NCCN guidelines for adjuvant therapy of
colorectal cancer* (high-risk patients)
Pathologic stage
T1–3, N1–2, M0
or T4, N1–2, M0
Adjuvant therapy
Surveillance
5-FU/leucovorin/oxaliplatin
(category 1)‡§
or
capecitabine§
or
5-FU/leucovorin§
• History and physical every 3–6 months for 2
years, then every 6 months for a total of 5
years
• CEA¶ every 3–6 months for 2 years then
every 6 months for a total of 5 years for T2 or
greater lesions
• Chest/abdominal/pelvic CT annually 3 years
for patients at high risk of recurrence
• Colonoscopy in 1 year except if no preoperative due to obstructing lesion,
colonoscopy in 3–6 months
– if advanced adenoma, repeat in 1 year
– if no advanced adenoma, repeat in 3
years, then every 5 years
• PET-CT scan is not routinely recommended
*No data to support adjuvant therapy in Stage I disease, although some high-risk Stage II patients may be
considered at higher risk and discussion of chemotherapy may be warranted. Bevacizumab, cetuximab,
panitumumab and irinotecan should not be used in the adjuvant setting for Stage II or III patients outside
of a clinical trial
‡Treatment options include FOLFOX or FLOX
§Consider RT for T4 with penetration to a fixed structure
¶If a patient is a candidate for further intervention
National Comprehensive Cancer Network.
NCCN clinical practice guidelines in oncology: colon cancer. V.2.2010.
Backup
NO16968 (XELOXA): significant improvement in DFS
with adjuvant XELOX in ITT population
1.0
XELOX
(n=944)
3-year
DFS
70.9%
5-FU/LV
(n=942)
66.5%
4-year
DFS
68.4%
62.3%
5-year
DFS
66.1%
59.8%
HR=0.80 (95% CI: 0.69–0.93)
DFS estimate
0.8
0.6
Absolute difference
at 3 years: 4.5%
(p=0.0045)
4.0
Absolute difference
at 4 years: 6.1%
Absolute difference
at 5 years: 6.3%
2.0
0
0
1
2
3
Years
4
5
6
Haller, et al. ASCO 2010
NO16968 (XELOXA): trend to superior OS with
adjuvant XELOX in ITT population
5-year OS
XELOX
(n=944)
77.6%
5-FU/LV
(n=942)
74.2%
1.0
OS estimate
0.8
0.6
Absolute difference
at 5 years: 3.4%
4.0
HR=0.87 (95% CI: 0.72–1.05)
p=0.1486
2.0
0
0
1
2
3
Years
4
5
6
Haller, et al. ASCO 2010
NO16968 (XELOXA): subgroup analysis of DFS by age
3-year DFS
XELOX (%)
5-FU/LV (%)
HR
(95% CI)
<65 years (n=1142)
72
69
0.80 (0.65–0.98)
≥65 years (n=744)
68
62
0.81 (0.64–1.03)
<70 years (n=1477)
72
69
0.79 (0.66–0.94)
≥70 years (n=409)
66
60
0.87 (0.63–1.18)
Age group
<65 vs ≥65 years
<70 vs ≥70 years
Interaction of age
by treatment*
p=0.6222
This non-significant p value indicates that
XELOX efficacy is positive, irrespective of age
*Multiple Cox regression
ITT population
Haller, et al. ASCO 2010
NO16968 (XELOXA): subgroup analysis of OS by age
5-year OS
XELOX (%)
5-FU/LV (%)
HR
(95% CI)
<65 years (n=1142)
80
77
0.87 (0.67–1.13)
≥65 years (n=744)
73
70
0.90 (0.68–1.19)
<70 vs ≥70 years
80
76
0.86 (0.69–1.08)
≥70 years (n=409)
69
67
0.94 (0.66–1.34)
Age group
<65 vs ≥65 years
<70 vs ≥70 years
Interaction of age
by treatment*
p=0.7065
This non-significant p value indicates that
XELOX efficacy is positive, irrespective of age
*Multiple Cox regression
Haller, et al. ASCO 2010
AVAGAST: first phase III randomized trial with
bevacizumab in gastric cancer
XP + bevacizumab (n=387)
1.0
HR=0.87
(95% CI: 0.73–1.03)
p=0.1002
0.6
0.4
HR=0.80
(95% CI: 0.68–0.93)
p=0.0037
0.8
PFS estimate
0.8
OS estimate
XP + placebo (n=387)
1.0
0.2
0.6
XP +
placebo
(n=387)
XP +
bevacizu
mab
(n=387)
37%
46%
ORR
0.4
p=0.0315
0.2
10.1
0
0
12.1
12
Months
5.3
0
24
0
6.7
12
Months
24
Kang, et al. ASCO 2010
AVAGAST: regional differences in efficacy
OS
PFS
Median survival (months)
30
25
20
XP + bevacizumab
XP + placebo
0.97
0.85
(0.75–1.25) (0.63–1.14)
0.63
(0.34–0.94)
15
10
0.92
(0.74–1.14)
0.71
(0.54–0.93)
0.65
(0.46–0.93)
Asia
Europe
Pan-America
5
0
Asia
Europe
Pan-America
Note: HR (95% CI) are shown above data bars
Kang, et al. ASCO 2010
ToGA: trastuzumab significantly improves OS in
gastric cancer
OS
(primary endpoint)
1.0
Events
Median OS
FC + T
167
13.8
FC
182
11.1
1.0
 2.7
0.8
HR=0.74
95% CI (0.60–0.91)
p=0.0046
0.6
Events
Median OS
FC + T
120
16.0
FC
136
11.8
0.8
OS estimate
OS estimate
OS in IHC2+/FISH+ or IHC3+
(exploratory analysis)
0.4
0.2
HR=0.65
95% CI (0.51–0.83)
0.6
0.4
0.2
11.1
0
0
6
13.8
12
18
24
Months
FC = fluoropyrimidine + cisplatin
T = trastuzumab
11.8
0
30
36
0
6
16.0
12
18
24
Months
30
36
Van Cutsem, et al. ASCO GI 2010
ToGA: OS gain in HER2-positive advanced gastric
or GEJ cancer patients translates into longer PFS
without disease symptoms or treatment toxicity
Mean time in each health
state by treatment arm,
months (95% CI)
XP/FP
(n=290)
T-XP/FP
(n=294)
Mean
difference
PFS
7.07
(6.24–7.89)
9.36
(8.27–10.45)
2.29
OS
13.01
(11.79–14.24)
15.54
(14.24–16.84)
2.52
TOX
2.52
(2.13–2.9)
2.54
(2.10–2.98)
0.02
TWiST
4.55
6.82
2.27
REL
5.95
6.18
0.23
Chung, et al. ASCO 2010