Optimizing Conventional Chemotherapy in Advanced
Colorectal Cancer
Optimizing Conventional Chemotherapy in Advanced
Colorectal Cancer
Axel Grothey
Mayo Clinic College of Medicine
Rochester, MN
Axel Grothey
Mayo Clinic College of Medicine
Rochester, MN
Pertinent Questions in Advanced CRCPertinent Questions in Advanced CRC
• Multiple effective agents and regimens available• What is the best strategic use of options?
• Patients routinely live >2 years• Can and should we keep treating patients with
same intensity until PD?
• FOLFOX has become one of the standards of care• How can we prevent or delay the onset of sensory
neurotoxicity?
• Can capecitabine be a substitute for infusional 5-FU?
• (Can celecoxib enhance the efficacy and/or reduce the toxicity of chemotherapy?)
• Multiple effective agents and regimens available• What is the best strategic use of options?
• Patients routinely live >2 years• Can and should we keep treating patients with
same intensity until PD?
• FOLFOX has become one of the standards of care• How can we prevent or delay the onset of sensory
neurotoxicity?
• Can capecitabine be a substitute for infusional 5-FU?
• (Can celecoxib enhance the efficacy and/or reduce the toxicity of chemotherapy?)
BICC-C, OPTIMOX, GISCAD
OPTIMOX, GISCAD
OPTIMOX, XENOX
BICC-C, (TREE)
BICC-C
BICC-C: DesignBICC-C: Design
• First head-to-head comparison between FOLFIRI, mIFL, and CapIri (similar design as TREE-trials)
• 3x2 design to address effect of celecoxib vs placebo on efficacy and toxicity
• Planned sample size N=1000, when BEV approved accrual adjusted to N=430 (Period 1)
• BEV then added to FOLFIRI and mIFL arm (N=117)(Period 2, similar to TREE-2)
• Primary endpoint PFS for FOLFIRI vs mIFL
• First head-to-head comparison between FOLFIRI, mIFL, and CapIri (similar design as TREE-trials)
• 3x2 design to address effect of celecoxib vs placebo on efficacy and toxicity
• Planned sample size N=1000, when BEV approved accrual adjusted to N=430 (Period 1)
• BEV then added to FOLFIRI and mIFL arm (N=117)(Period 2, similar to TREE-2)
• Primary endpoint PFS for FOLFIRI vs mIFL
Cape 1000 mg/m2 BID d1-14 Irino 250 mg/m2, q3wks
2/3 wks, not 4/6 wks
BICC-C: SummaryBICC-C: SummaryPeriod 1, no BEV Period 2, + BEV
Efficacy FOLFIRIN=144
mIFLN=141
CapIriN=145
FOLFIRIN=57
mIFLN=60
RR (%) 46.6 41.9 38 54.4 53.3
PFS (mo) 7.6 5.8 5.5 9.9 8.3
OS 23.1 17.6 18.9 NR 18.7
G 3/4 (%)
Diarrhea 13 19 48 11 12
Dehydr. 6 7 19 5 2
MI/stroke 0.7 4.4 0 1.8 0
60d mort. 2.9 5.8 3.5 1.8 6.8
NR = not reached
What have we learned from BICC-C?What have we learned from BICC-C?
• Celecoxib is a non-issue in advanced CRC
• IFL, even in its modified form, is obsolete
• CAPIRI (XELIRI) is problematic
• Overlapping toxicities
• What is the best capecitabine dose/schedule?
• Did toxicity issues affect efficacy?
• Similar effect in TREE-2?
• FOLFIRI is the clear winner of the head-to-head comparison
• Celecoxib is a non-issue in advanced CRC
• IFL, even in its modified form, is obsolete
• CAPIRI (XELIRI) is problematic
• Overlapping toxicities
• What is the best capecitabine dose/schedule?
• Did toxicity issues affect efficacy?
• Similar effect in TREE-2?
• FOLFIRI is the clear winner of the head-to-head comparison
Capecitabine US vs RoW: RelRiskGrade 3/4 tox. 1.77Dose reductions 1.72Discontinuation 1.83
Haller ASCO 2006 #3514
EORTC 40015 (d/c-ed for toxicity)N=85 G3/4 Diarrhea PFSCapIri 37% 5.9 moFOLFIRI 13% 9.6 mo
Greve ASCO 2006 #3072
What have we learned from BICC-C?What have we learned from BICC-C?
• Celecoxib is a non-issue in advanced CRC
• IFL, even in its modified form, is obsolete
• CAPIRI (XELIRI) is problematic
• Overlapping toxicities
• What is the best capecitabine dose/schedule?
• Did toxicity issues affect efficacy?
• Similar effect in TREE-2?
• FOLFIRI is the clear winner of the head-to-head comparison
• Celecoxib is a non-issue in advanced CRC
• IFL, even in its modified form, is obsolete
• CAPIRI (XELIRI) is problematic
• Overlapping toxicities
• What is the best capecitabine dose/schedule?
• Did toxicity issues affect efficacy?
• Similar effect in TREE-2?
• FOLFIRI is the clear winner of the head-to-head comparison
• On phase II trial level and cross-trial comparison, bevacizumab increases efficacy of FOLFIRI and IFL
• PFS for FOLFIRI + BEV (BICC-C) and FOLFOX + BEV (TREE-2) are both 9.9 mos*
• PFS is a better parameter to appreciate differences between first-line therapies than OS
• FOLFIRI + bevacizumab is one of the standard-of-care regimens in palliative first-line therapy of CRC
• On phase II trial level and cross-trial comparison, bevacizumab increases efficacy of FOLFIRI and IFL
• PFS for FOLFIRI + BEV (BICC-C) and FOLFOX + BEV (TREE-2) are both 9.9 mos*
• PFS is a better parameter to appreciate differences between first-line therapies than OS
• FOLFIRI + bevacizumab is one of the standard-of-care regimens in palliative first-line therapy of CRC
What have we learned from BICC-C?What have we learned from BICC-C?
*Hochster GI ASCO 2006
Oxaliplatin-induced NeurotoxicityOxaliplatin-induced Neurotoxicity
• Acute neuropathy:
• Transient, cold-triggered paresthesia/dysesthesia
• Frequent (85-95%)
• Not dose-limiting
• Chronic, cumulative neurotoxicity:
• Predictable phenomenon, correlated with cumulative dose of oxaliplatin
• Frequency of grade 3 15-20% in phase III trials
• Dose-limiting toxicity of oxaliplatin
• Delayed neurotoxicity
• Acute neuropathy:
• Transient, cold-triggered paresthesia/dysesthesia
• Frequent (85-95%)
• Not dose-limiting
• Chronic, cumulative neurotoxicity:
• Predictable phenomenon, correlated with cumulative dose of oxaliplatin
• Frequency of grade 3 15-20% in phase III trials
• Dose-limiting toxicity of oxaliplatin
• Delayed neurotoxicity
N9741: FOLFOX4 - TTP and TTFN9741: FOLFOX4 - TTP and TTF
0
10
20
30
40
50
60
70
80
90
100
0 12 18 24
% E
ven
t-F
ree
TTP TTF
6
Time (mos)
9.3 mos
5.8 mos
Green et al, GI ASCO 2005
63% of pts d/c-edFOLFOX for otherreasons than PD
XENOX: Rationale and DesignXENOX: Rationale and Design
• Xaliproden: Interesting agent as potential neuroprotectant
• Large, placebo-controlled trial
• Problems:• Xaliproden d/c-ed 15 days after last oxaliplatin
• Effect on recovery not assessable• Endpoint: Focus on grade 3/4 neurotoxicity
• But grade 2 is also clinically relevant!
• Xaliproden: Interesting agent as potential neuroprotectant
• Large, placebo-controlled trial
• Problems:• Xaliproden d/c-ed 15 days after last oxaliplatin
• Effect on recovery not assessable• Endpoint: Focus on grade 3/4 neurotoxicity
• But grade 2 is also clinically relevant!
Xaliproden: EfficacyXaliproden: Efficacy
Logrank test, p = 0.0203HR [95% CI] = 0.61 [0.40, 0.93]
Placebo
Xaliproden
0 200 400 600 800 1000 1200 1400 1600 1800 2000Oxaliplatin cumulative dose (mg/m2)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ilit
y G
rad
e 3
Neu
roto
x
PlaceboXaliproden
Patients at risk:
Placebo 324 303 275 240 199 104 34 23 6 3 1
Xaliproden 325 308 281 248 200 119 50 23 16 5 2
% of patients
Placebon = 324
Xaliprodenn = 325
All Grades 73.5 73.2
G1 38.0 38.5
G2 18.8 23.7
G3 16.7 11.1
What should we expect from an oxaliplatin neuroprotectant?
What should we expect from an oxaliplatin neuroprotectant?
• No interference with efficacy
• Tolerable side-effects/ toxicity profile
• Reduced overall neurotoxicity
• Reduced severe neurotoxicity (grade 2/3)
• Longer time on therapy
• Higher cumulative dose of oxaliplatin
• More rapid recovery from neurotoxicity
• Reduced acute excitatory and cold-triggered phenomena
• No interference with efficacy
• Tolerable side-effects/ toxicity profile
• Reduced overall neurotoxicity
• Reduced severe neurotoxicity (grade 2/3)
• Longer time on therapy
• Higher cumulative dose of oxaliplatin
• More rapid recovery from neurotoxicity
• Reduced acute excitatory and cold-triggered phenomena
yesyes
no
?
nono
?
no
Stop and Go concept - OPTIMOX1
Tournigand et al, JCO 2006
6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7
FOLFOX4
620 pts
R
Cum. Oxali 780 1560
(%) FOLFOX4 FOLFOX7
RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4 NTox 17.9 13.3
Primary endpoint
Maughan et al., Lancet 2003
“Our findings provided no clear evidence of a benefit in continuing therapy indefinitely
until disease progression”
Continuous vs Intermittent Therapy?- MRC Trial -
Continuous vs Intermittent Therapy?- MRC Trial -
OPTIMOX StudiesOPTIMOX Studies
OPTIMOX-1
FOLFOX 4 until TF
FOLFOX 7 FOLFOX 7
sLV5FU2
OPTIMOX-2
mFOLFOX 7 mFOLFOX 7
sLV5FU2
mFOLFOX 7 mFOLFOX 7
CFI
OPTIMOX-2: DesignOPTIMOX-2: Design
• mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin
• Comparison: maintenance therapy vs chemotherapy-free intervals (CFI)
• Primary endpoint DDC
• Planned trial size N=600, after bevacizumab approved downsized to a randomized phase II trial (N=200)
• « no formal hypotheses between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%) »
• mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin
• Comparison: maintenance therapy vs chemotherapy-free intervals (CFI)
• Primary endpoint DDC
• Planned trial size N=600, after bevacizumab approved downsized to a randomized phase II trial (N=200)
• « no formal hypotheses between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%) »
OPTIMOX-2: Why DDC?OPTIMOX-2: Why DDC?
• OPTIMOX-1/-2 tested sequences of regimens (or CFI)
• Time-related endpoint most appropriate, not RR
• OS too much influenced by subsequent lines of treatment to reliably reflect differences in initial phase
• PFS captures efficacy of continuous first-line therapy very well, but not of an induction-maintenance/CFI-reintroduction strategy
• Is DDC the answer?
• OPTIMOX-1/-2 tested sequences of regimens (or CFI)
• Time-related endpoint most appropriate, not RR
• OS too much influenced by subsequent lines of treatment to reliably reflect differences in initial phase
• PFS captures efficacy of continuous first-line therapy very well, but not of an induction-maintenance/CFI-reintroduction strategy
• Is DDC the answer?
OPTIMOX-Trials: DDCOPTIMOX-Trials: DDC
t
T size
FOLFOX FOLFOX
PFS 1
PD Baseline progression
PFS 2
Progressionat reintroduction
DDC=PFS1+PFS2Tournigand JCO 2006
?
OPTIMOX-2: EfficacyOPTIMOX-2: Efficacy
OPTIMOX
Maintenance CFI P-value
RR (%) 61 61 n.s.
PFS (mo) 8.7 6.9 .009
DDC (mo) 12.9 11.7 n.s.
OS ? ?
How valid is DCC as endpoint without data on OS?
OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors
0 10 20 30 400.00
0.25
0.50
0.75
1.00
Good Prog. n=30 med. 35 weeks
Poor Prog. n=57 med. 20 weeks
p=.005
weeks
probability
8.0 months
4.6 months
PS 2LDH ↑Alk Ph >3x ULN>1 site
GISCAD-Trial: DesignGISCAD-Trial: Design
• Primary endpoint: OS
• Non-inferiority: 4 months difference accepted!
• Primary endpoint: OS
• Non-inferiority: 4 months difference accepted!
R
FOLFIRIFOLFIRIFOLFIRIFOLFIRI
Evaluation
4 mos
N=336
GISCAD: SummaryGISCAD: Summary
GISCAD BICC-C
Efficacy FOLFIRICont N=163
FOLFIRIInt N=168
FOLFIRIN=144
RR (%) 33.6 36.5 46.6
PFS (mo) 6.5 6.2 7.6
OS 17.6 16.9 23.1
G 3/4 (%)
Diarrhea 3.6 3.2 13
• No difference in efficacy• No difference in toxicity (surprisingly!)
How does all this translate into clinical practice?
How does all this translate into clinical practice?
• Stop-and-Go with maintenance• Oxaliplatin: mandatory - stop before
tox!• Irinotecan: can be done
• Stop-and-Go with maintenance• Oxaliplatin: mandatory - stop before
tox!• Irinotecan: can be done
• Chemotherapy-free intervals• Intriguing, consistent results from MRC,
OPTIMOX2 and GISCAD trials• Applicable for patients with “good” tumor biology • But not standard of care yet
• Endpoint validation (DDC)• Role of biologics in maintenance strategy
needs to be explored in phase III trial
• Chemotherapy-free intervals• Intriguing, consistent results from MRC,
OPTIMOX2 and GISCAD trials• Applicable for patients with “good” tumor biology • But not standard of care yet
• Endpoint validation (DDC)• Role of biologics in maintenance strategy
needs to be explored in phase III trial
From OPTIMOX to DREAMFrom OPTIMOX to DREAM
OPTIMOX-1
OPTIMOX-2
Efficacy =Toxicity
Efficacy = ?Toxicity =
DREAMBevacizumab
ErlotinibBevacizumab
No More “Lines” of TherapyNo More “Lines” of Therapy
• Chemotherapy regimens and agents get recycled in the course of therapy in the palliative setting
• We should not think in terms of “1st-2nd-3rd line” therapy anymore, but
• rather develop a treatment strategy
• with emphasis on different “phases” of therapy
• Defining the overall goal of therapy upfront sets the stage for treatment strategy
• Chemotherapy regimens and agents get recycled in the course of therapy in the palliative setting
• We should not think in terms of “1st-2nd-3rd line” therapy anymore, but
• rather develop a treatment strategy
• with emphasis on different “phases” of therapy
• Defining the overall goal of therapy upfront sets the stage for treatment strategy
Patient potentially curable?
Induction Ctx (3-4 mos)e.g. FOLF?? + BV/C225
Surgery with curative intent
“Adjuvant” Ctx
yes
yes
yes
Re-evaluation of resectability
Observation
RRInduction Ctx (3-4 mos)
e.g. FOLF?? + BV
Maintenance
Re-Induction Ctx
“All 5 drugs”
no
Evaluation oftumor biology
CFI
Time, QOL