Download Colon Cancer: Rate of Liver Resections/RR

Mario Scartozzi
Clinica di Oncologia Medica
Ancona
HIGHLIGHTS IN COLORECTAL CANCER
MANAGEMENT
TREATMENT OF METASTATIC DISEASE
Bittoni, Giampieri et al, CROH 2012
Colon Cancer: what we already know
– Chemotherapy has determined a relevant
improvement in survival in the last 15 years:
from 6 to 18 months
– Probably FOLFOX = FOLFIRI and
XELOX=FOLFOX
(XELIRI has PHYLOSOPHICAL problems with
toxicity)
– Concept of all three drugs
– Some patients with stage IV disease can be
cured by an interdisciplinary approach
Colon Cancer: what we already know
– Chemotherapy has determined a relevant
improvement in survival in the last 15 years:
from 6 to 18 months
– Probably FOLFOX = FOLFIRI and
XELOX=FOLFOX
(XELIRI has PHYLOSOPHICAL problems with
toxicity)
– Concept of all three drugs
– Some patients with stage IV disease can be
cured by an interdisciplinary approach
Not all liver metastases are created equal
Bittoni, Giampieri et al, CROH 2012
Multimodality Management of CRC Liver
Metastases
– Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
• Hepatic arterial infusion (HAI)
• Systemic treatment
Colon Cancer: NOT all liver metastases are created equal
BIOLOGICALLY
CHALLANGING
Colon Cancer: MULTIMODALITY management
– Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
Colon Cancer: MULTIMODALITY management
– Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
Colon Cancer: EORTC 40983 (the EPOC trial)
FOLFOX4
for 6 cycles (12 wks)
(n = 182)
•
•
•
•
R
•
•
for 6 cycles (12 wks)
364 patients randomized
Potentially resectable (≤ 4 liver
metastases)
Goal: Improve PFS
Interim objective: Evaluate tumor
response to perioperative CT
Perioperative CT (n = 182)
–
–
Surgery
FOLFOX4
Surgery
159 (87.3%) underwent surgery
151 (83.0%) resected
Surgery (n=182)
–
–
170 (93.4%) underwent surgery
152 (83.0%) resected
(n = 182)
Nordlinger B, et al. Lancet 2008
Efficacy Results
No. pts
CT
No. pts
Surgery
% absolute difference
in 3-year PFS
Hazard ratio
(confidence interval)
All patients
182
182
+7.2%
(28.1% to 35.4%)
0.79
(0.62-1.02)
0.058
All eligible
patients
171
171
+8.1%
(28.1% to 36.2%)
0.77
(0.60-1.00)
0.041
All resected
patients
151
152
+9.2%
(33.2% to 42.4%)
0.73
(0.55-0.97)
0.025
p Value
MOSAIC: 3-yr DFS for stage III: +7.2%
Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.
2012
Nordlinger et al
Surgery
Chemotherapy
Biologicals: How Do They Fit Into This Strategy?
Colon Cancer: PFS in BEVACIZUMAB trials
Wagner et al. Cochrane Review ‘09
Colon Cancer: PFS in anti-EGFR trials
Loupakis, Bria E et al. Cancer 2011
BEVACIZUMAB: PFS on TREATMENT!
Saltz, et al. ASCO GI 2007
Colon Cancer: NOT all liver metastases are created equal
TECHNICALLY
CHALLANGING
Colon Cancer: MULTIMODALITY management
– Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
Colon Cancer: MULTIMODALITY management
– Neoadjuvant chemotherapy
• Resectable liver metastases:
– Facilitate surgery
– Obtain predictive and prognostic information
– Early systemic therapy for poor-prognosis pts
– Conversion chemotherapy
• Unresectable liver metastases:
– Allow R0 resection via downsizing
– Postoperative (adjuvant) chemotherapy
What Do We Expect from Ideal Conversion Chemo?
•High (anatomical) response rate
– RR = goal of therapy in stage IV CRC only
for
• Conversion therapy
• Patients with significant tumor-related
symptoms
•Good toxicity profile
– No hepatotoxicity
– No interference with surgery
– No interference with liver regeneration
Conversion Therapy: Liver Toxicities
– 5-FU: hepatic steatosis, associated with increased
postoperative morbidity - yellow liver
– Irinotecan: non-alcoholic steatohepatitis (especially in
obese patients), can affect hepatic reserve and increase
morbidity and mortality after hepatectomy - orange liver
– Oxaliplatin: hepatic sinusoidal obstruction syndrome,
does not appear to be associated with increased risk of
perioperative death - blue liver
– Both response rate and toxicity should be considered when
selecting preoperative CT in patients with colorectal liver
metastases
Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86.
Colon Cancer: Rate of Liver Resections/RR
Rate of liver resection
following CT
Data from studies/retrospective
analyses with “selected pts”, only liver
MTS (r=0.96) (p=0.002)
Selected pts
(liver mets)
△
▲
Not selected pts
Data from studies/retrospective
analyses with “non selected pts”
(r=0.74) (p<0.001), solid line
Not selected pts: only phase III trials
(r=0,67) (p=0.024), dashed line
Folprecht et al. Ann Oncol ‘05
FOLFIRI vs FOLFOXIRI: RESULTS
FOLFIRI
FOLFOXIRI
122 pts
122 pts
Confirmed RR
34%
60%
<0.0001
R0 surgery (all pts)
6%
15%
0.033
R0 surgery (liver only)
12%
36%
0.017
mPFS (months)
6.8
9.8
<0.001
mOS (months)
16.7
23.4
0.026
P value
Falcone A, JCO ‘07 & Masi JNCI’10
Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
Colon Cancer: Rate of Liver Resections/RR
Rate of liver resection
following CT
Data from studies/retrospective
analyses with “selected pts”, only liver
MTS (r=0.96) (p=0.002)
K-RAS wt
△
▲
Not selected pts
Data from studies/retrospective
analyses with “non selected pts”
(r=0.74) (p<0.001), solid line
Not selected pts: only phase III trials
(r=0,67) (p=0.024), dashed line
Folprecht et al. Ann Oncol ‘05
Colon Cancer: Rate of Liver Resections/RR
Rate of liver resection
following CT
Selected pts
(liver mets)
Data from studies/retrospective
analyses with “selected pts”, only liver
MTS (r=0.96) (p=0.002)
K-RAS wt
△
K-RAS mt
Not selected pts
▲
Data from studies/retrospective
analyses with “non selected pts”
(r=0.74) (p<0.001), solid line
Not selected pts: only phase III trials
(r=0,67) (p=0.024), dashed line
Folprecht et al. Ann Oncol ‘05
Cetuximab: CELIM & RR & R0 resection (LLD)
Folprecht et al. Lancet Oncology 2010
Colon Cancer: Rate of Liver Resections/RR
Rate of liver resection
following CT
Selected pts
(liver mets)
Data from studies/retrospective
analyses with “selected pts”, only liver
MTS (r=0.96) (p=0.002)
K-RAS wt
K-RAS mt
△
▲
Not selected pts
Data from studies/retrospective
analyses with “non selected pts”
(r=0.74) (p<0.001), solid line
Not selected pts: only phase III trials
(r=0,67) (p=0.024), dashed line
Folprecht et al. Ann Oncol ‘05
Response Rate in anti-EGFR trials
Loupakis F, Bria E et al. Cancer 2011
Response Rate in BEVACIZUMAB trials
Wagner et al. Cochrane Review ‘09
CT Morphology vs RECIST
A - Pretreatment
B - Posttreatment
C - Pretreatment
D - Posttreatment
CT Morphology vs
Response on BEV

RECIST
to
Determine
234 pts with CRC liver mets treated with chemo + BEV
− 50 pts underwent hepatic resection

Three blinded radiologists evaluated response of liver
mets according to
− Standard RECIST criteria
− Novel CT morphology criteria
Computer Tomographic Tumor Characteristics
Morphology
group
Overall Attenuation
Tumor-Liver Interface
Pheripheral Rim of Enhancement
3
Heterogeneous
III defined
May be present
2
Mixed
Variable
If initially present, partially resolved
1
Homogeneous and
hypoattenuating
Sharp
If initially present, completely resolved
Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
Response Evaluation: Morphology vs. RECIST
Patients with unresectable tumor
Morphologic
response criteria
RECIST
1.0
0.8
Proportion surviving
Proportion surviving
1.0
0.6
0.4
0.2
0.8
0.6
0.4
0.2
Log-rank p=0.009
Log-rank p=0.45
0.0
0.0
0
10
20
30
40
50
60
0
10
20
Months
30
40
50
60
Months
No. at risk
Responders
30
30
26
16
6
2
35
34
25
14
3
0
Ronresponder
52
49
25
14
4
1
47
45
26
16
7
3
Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.
Colon Cancer: NEVER (NEVER!) resectable
Bad, Bad luck…..
Phase III randomized trials: gains in activity and
efficacy in 1st line therapy
N° of patients
RR
PFS
OS
Hurwitz
402
45 vs 35
10.6 vs 6.2
20.3 vs 15.6
No16966
700
38 vs 38
9.4 vs 8
nr
Crystal
599
58 vs 40
9.9 vs 8.7
23.5 vs 20
COIN
2445
64 vs 57
8.6 vs 8.6
17 vs 17.9
Nordic
566
47 vs 46
7.9 vs 8.7
19.7 vs 20.3
656
55 vs 48
9.6 vs 8
Ne vs 18.8
Bevacizumab
Cetuximab
Panitumumab
Prime
Overall Survival in BEVACIZUMAB trials
Wagner et al. Cochrane Review ‘09
Overall Survival in anti-EGFRs trials
Loupakis, Bria E et al. Cancer 2011
Phase III randomized trials: gains in
activity and efficacy in 2nd line therapy
N° of patients
RR
PFS
OS
829
22.7 vs 8.6
7.3 vs 4.7
12.9 vs 10.8
1298
16.4 vs 4.2
4 vs 2.6
10.7 vs 10
597
35 vs 15
5.9 vs 3.9
14.5 vs 12.5
Bevacizumab
Giantonio
Cetuximab
EPIC
Panitumumab
Peeters
Amado JCO 2008
Amado JCO 2008
PFS/DFS for EGFR inhibitors improves across
lines of therapy in KRAS wild-type patients
1.2
0.8
Slide Courtesy
of A Grothey
Adjuvant
First line
Second line
CO.179
Amado8
Study 1817
EPIC6
CRYSTAL5
0
PRIME4
0.2
COIN3
0.4
NORDIC VII2
0.6
N01471
Hazard ratio
1.0
Salvage
(single agent)
1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011
4. Douillard, et al. ASCO 2011; 5. Van Cutsem, et al. JCO 2011; 6. Langer, et al. ESMO 2008
7. Sobrero, et al. ASCO GI 2012; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008
2012
Arnold D, et Al
2012
Arnold D, et Al
2012
Arnold D, et Al
2012
Arnold D, et Al
AFLIBERCEPT
2012
Allegra C, et Al
2012
Allegra C, et Al
2012
Allegra C, et Al
GI 2009
Kopetz S et AL
2012
Van Cutsem E, et al
2012
Van Cutsem E, et al
2012
Van Cutsem E, et al
2012
Van Cutsem E, et al
2012
Van Cutsem E, et al
CT Response on REGORAFENIB
Baseline
After 2 cycles
Bittoni, Giampieri et al, CROH 2012
Bittoni, Giampieri et al, CROH 2012