Intermittent versus Continuous Systemic Therapy for Metastatic Colorectal Cancer
PRO: Continue Systemic Therapy
Deb Schrag, MD, MPHPresentation in “Great Debates” Symposium
March 28th, 2014Attending Physician, Dana-Farber Cancer Institute
Professor of Medicine, Harvard Medical School Boston MA, USA
Overview
• Brief review of stop versus go trials– COIN– OPTIMOX1 and 2– DREAM– CAIRO-3
• Challenges to interpretation of these studies
• Strategies for clinical decision making
Common Clinical Decisions• What is optimal management of mCRC post-induction chemo?
• How long to continue induction systemic rx?
• Should maintenance therapy:– Be identical to induction?– Drop oxaliplatin?– Include 5FU/Bev?– Bev alone, Bev/erlotinib?– No maintenance?
• How long is it reasonable to continue chemo breaks?
Strategy for post-induction systemic treatment for mCRC patients who do not have PD
Example trial that uses this strategy
Plan to alternate intense/light phases of treatment..eg 2 months on 2 months off systematically
GISCAD
Eliminate the most toxic ingredient eg oxaliplatin or irinotecan but restart the more intense regimen at progression
OPTIMOX-1
Eliminate cytotoxics and continue biologics
DREAM/OPTIMOX-3, SAKK
Eliminate all therapy….true “holiday” OPTIMOX 2, CAIRO-3
Stop and Go Strategies for Post-Induction Systemic Therapy Are Not
All Created Equal
Stop and Go Trials’ Heterogeneity Makes them Challenging to Compare
• Different induction regimens/durations
• Different maintenance regimens/durations
• Various endpoints• 1st PFS interval, 2nd PFS interval• Duration of disease control• OS
• Monitoring strategy influences PFS assessment• CEA frequency• Scan frequency
Continuous v Intermittent Therapy: The MRC Coin Trial
Maughan et al The Lancet. 2003. 361: 457-64.
Responding or stable disease after 12 weeks
Continuous v Intermittent Therapy: MRC COIN Trial
• CAPOX or FOLFOX until PD vs. CAPOX/FOLFOX for 12 weeks with re-initiation of same chemo at progression for another 12 weeks
• Median off-treatment duration with intermittent therapy was 4.3 months• Significantly fewer adverse events • Overall survival was similar in both groups• Intermittent strategy didn’t meet non-inferiority threshold
Maughan et al The Lancet. 2003. 361: 457-64.
PFS HR1.20 (0.96-1.49) favors continuous
OPTIMOX Studies
OPTIMOX-1N = 620
FOLFOX4 until TF
FOLFOX7 FOLFOX7
sLV5-FU2
OPTIMOX-2N = 202
mFOLFOX7 mFOLFOX7
sLV5-FU2
mFOLFOX7 mFOLFOX7
CFI
Tournigand et al, JCO 2006
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
OPTIMOX 1: Hold the oxaliplatin post-induction
Tournigand et al. JCO 2006;24:394-400
FOLFOX7 x 6 cyclessLV5FU2 x up to 12 cycles
FOLFOX7 x 6 cycles
FOLFOX4 until Progression N=311
N=309
RANDOMI
Z e
Only 40%reintroduced oxaliplatin
18.5% early progression/death18.4% toxicity (including neuropathy)5.5% surgery17.5% unknown
OPTIMOX 1: Maintenance 5FU Alone
Tournigand et al. JCO 2006;24:394-400
PFS OS
No meaningful benefit is clearly evident from continuation of oxaliplatin without a break
Caveat: most of us don’t use FOLFOX4 or 7
OPTIMOX 1: Maintenance 5FU alone
Tournigand et al. JCO 2006;24:394-400
Grade 3 / 4 Toxicity
Grade 3 Neurotoxicity
Continuous therapy has:
•higher overall toxicity
•substantially higher late neurotoxicity
OPTIMOX 2: Go and Full Stop
Chibaudel B et al. JCO 2009;27:5727-5733
OPTIMOX 2: Go and Full Stop
Chibaudel B et al. JCO 2009;27:5727-5733
HR= 0.71 (95% CI, 0.51 to 0.99; P = .046
Median duration of maintenance therapy = 4.8 months in the arm 1Median duration of chemotherapy free interval = 3.9 months in arm 2.
OPTIMOX 2: Go and Full Stop
Chibaudel B et al. JCO 2009;27:5727-5733
PFSHR = 0.61; P = .0017
OSHR = 0.88; P = 0.42
A chemotherapy holiday with no maintenance therapy has significantly worse PFS compared to maintenance therapy (allowing for attenuating oxaliplatin). Overall survival trend also favors maintenance therapy but is not significant
MACRO Trial
ProgressionRCapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
Bevacizumabuntil progression
N=480
N=239
N=241
CapecitabineOxaliplatin
Bevacizumabx6 cycles q3w
CapecitabineOxaliplatin
Bevacizumabuntil progression
Taberno et al ASCO 2010
Non-inferiority design
Assuming 10 months as median PFS Non-inferiority limit of 7.6 m (HR=1.32)One sided alpha = 0.025, one side; Power = 80%
LNI: 1.32
Patients at risk
MACRO Trial: Non-significant PFS trend favors continuation of XELOX
Taberno et al ASCO 2010
Patients at risk
MACRO TrialNo difference in overall survival
Taberno et al ASCO 2010
The GERCOR DREAM phase III trial: Bevacizumab with or without erlotinib maintenance
following induction 1st-line chemotherapy plus bevacizumab, in patients with metastatic CRC
CC. Tournigand et al ASCO 2012
• 6-12 cycles of Induction Chemotherapy– EITHER FOLFOX-7 or XELOX or FOLFIRI all with Bev
• If no Disease Progression then randomize 1:1 to
• Maintenance Bev and Erlotinib or • Maintenance Bev alone
DREAM ResultsBev vs. Bev/Erlotinib maintenance
B222
B+E223
HR P value
PFS from randomization
4.6 5.8 0.73 P=.005
PFS from registration
9.2 10.2 0.75 P=.005
Grade 3 skin toxicity
0% 20% - -
Overall survival no difference: 25.4 months [95% CI 22.9–28.2]
TAKE HOME: Marginal survival benefit and excess toxicity for Bev/Erlotinib
SAKK: Induction +/- Maintenance Bev
First-line chemo-therapy + BEVfor 4-6 months
No PD
Randomization1: 1
BEV continuation(7.5 mg/kg q 3 w)
until PD
No antitumor treatment(no BEV) until PDStratification factors:
• Best response during first-line chemotherapy + BEV (CR/PR vs SD)• Duration of first-line chemotherapy + BEV (16-20 vs 21-24 weeks)• Type of chemotherapy (Irinotecan + 5-FU vs Oxalipaltin + 5-FU vs Fluoropyrimidine mono)• Disease burden (metastases in one organ vs multiple organs)
Study conducted in 26 sites in Switzerland (accrual period 2007-2012)
SAKK: Induction +/- Maintenance-BTTP
(from randomization)
/
/ / / /
/ /
/ / / / / /
0 6 12 18 24 30 36 42 480.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
porti
on w
ithou
t pro
gres
sion
BEVno BEV
No. at riskBEV 131 40 14 8 6 5 3 2 1no BEV 131 22 10 7 5 1 1 1 0
BEV no BEV
No. of events 124 123
Median(95%CI)
4.1 months(3.1-5.4)
2.9 months(2.8-3.8)
HR 95% CI
0.74 (0.57-0.95)
Non-inferiority p = 0.47
Koeberle ASCO 2013
TTP Trend favors continued Bev
SAKK: Induction +/- Maintenance-B PFS
(from start of first-line therapy)
/
/
/ / / /
/
/ / / / / /
0 6 12 18 24 30 36 42 48 540.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
porti
on w
ithou
t pro
gres
sion
/dea
th BEVno BEV
No. at riskBEV 131 122 40 13 6 6 5 3 2 1no BEV 131 116 18 8 7 4 1 1 0 0
BEV no BEV
No. of events 125 124
Median(95%CI)
9.5 months(8.6.-10.2)
8.5 months(8-8.9)
HR 95% CI
0.75 (0.58-0.96)
Difference p = 0.021
Koeberle ASCO 2013
PFSTrend favors continued Bev
SAKK: Induction +/- Maintenance-B Overall Survival
(from start of first-line therapy)/ /
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0 6 12 18 24 30 36 42 48 54 600.0
0.2
0.4
0.6
0.8
1.0
Time (months)
Pro
porti
on s
urvi
ving
BEVno BEV
No. at riskBEV 131 130 115 86 52 33 22 10 3 1 0no BEV 131 131 107 76 44 25 13 6 1 1 1
BEV no BEV
No. of events 84 84
Median(95%CI)
25.1 months(22-28.9)
22.8 months (20.3-26.1)
HR 95% CI
0.83(0.61-1.12)
Difference p = 0.218
OS Trend favors continued Bev
Koeberle ASCO 2013
CAIRO-3: Study design
SD/PR/CR post CAPOX-B x 6
observation
R
capecitabine + bevacizumab
PDRe-introduction
CAPOX-B
PFS1 PFS2
Koopman: ASCO 2013 for Dutch Colorectal Study Group
Primary endpoint: PFS2 •time from randomization to progression upon re-introduction of CAPOX- B•PFS2 is considered to be equal to PFS1 for patients in whom CAPOX- B is not reintroduced after PFS1 for any reason
CAIRO-3: Study design
SD/PR/CR post CAPOX-B x 6
observation
R
capecitabine + bevacizumab
PDAny further RxIncluding CAPOX-B
PFS1 TT2PD
Koopman: ASCO 2013 for Dutch Colorectal Study Group
• TT2PD = time to second progression of disease• = time from randomization to progression after any post PFS1 Rx
including CAPOX-B
Time (mths)
PFS
2 P
roba
bilit
y
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 207 111 42 16 11 4 Observation
279 207 130 66 38 23 12 Maintenance
Observation
Maintenance
median PFS2 - Observation : 10.5 (95% CI: 9.3 - 12.3 )
median PFS2 - Maintenance : 11.8 (95% CI: 10.2 - 13.3 )
ITT, events/n ( 246 / 279 - 243 / 279 )
HR= 0.81 ( 95% CI: 0.67 - 0.98 )
stratified log-rank p-value 0.028
CAIRO-3Primary endpoint PFS2
Median PFS2Observation 10.5 m [95%CI: 9.3-12.3]Maintenance 11.8 m [95%CI: 10.2-13.3]Stratified HR 0.81 [95%CI: 0.67-0.98]p value 0.028
adjusted HR 0.77, p 0.007
Time (mths)
TT2P
D P
roba
bilit
y
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 247 174 97 52 36 13 Observation
279 251 187 134 87 52 31 Maintenance
Observation
Maintenance
median TT2PD - Observation : 15.0 (95% CI: 13.6 - 16.4 )
median TT2PD - Maintenance : 19.8 (95% CI: 18.0 - 21.9 )
ITT, events/n ( 223 / 279 - 251 / 279 )
HR= 0.67 ( 95% CI: 0.55 - 0.81 )
stratified log-rank p-value 0
CAIRO-3 TT2PDMedian TT2PD
Observation 15.0 m [95%CI:13.6-16.4]Maintenance 19.8 m [95%CI: 18.0-21.9]Stratified HR 0.67 [95%CI: 0.55-0.81]p value < 0.00001
adjusted HR 0.63, p <0.001
Time (mths)
OS
Pro
babi
lity
0 6 12 18 24 30 36
0.0
0.2
0.4
0.6
0.8
1.0
279 248 184 122 78 53 28 Observation
279 252 192 143 95 58 33 Maintenance
Observation
Maintenance
median OS - Observation : 18.2 (95% CI: 16.3 - 20.8 )
median OS - Maintenance : 21.7 (95% CI: 19.4 - 24.0 )
ITT, events/n ( 204 / 279 - 217 / 279 )
HR= 0.87 ( 95% CI: 0.71 - 1.06 )
stratified log-rank p-value 0.156
CAIRO-3 Overall SurvivalMedian OS
Observation 18.2 m [95%CI: 16.3-20.8]Maintenance 21.7 m [95%CI: 19.4-24.0]Stratified HR 0.87 [95%CI: 0.71-1.06]p value 0.156
adjusted HR 0.80, p 0.035
preliminary survival analysis
Cancer Care Ontario Metanalysis
• Includes 10 trials, but not CAIRO3• Notes heterogeneity of stop/go strategies• Variation in maintenance regimens• Inconclusive as to benefits
Evidence Summary from Trials• No strategy is clearly superior
• The preponderance of evidence favors some form of maintenance therapy
• Reasonable to drop the oxaliplatin (OPTIMOX-1)—low threshold to do so
• Reasonable to continue 5FU-B (CAIRO)
Gompertzian Model of Tumor Growth and Norton–Simon hypothesis
Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493
The Norton-Simon hypothesis states that the rate of cancer cell death in response to treatment is directly proportional to the tumor growth rate at the time of treatment.
Factors to Consider in Counseling mCRC patients about “Chemo Holidays”
Tilt towards maintenance:• Continued response could result
in candidacy for R0 resection• Major/brisk/ongoing response • More symptoms from cancer
than from chemotherapy• Easy to track disease status—
CEA or measurable disease• mCRC is primary threat to
survival• Tolerates chemotherapy well• Prefers intensive management
Tilt towards true holiday• Will never be a candidate for
R0 resection• Stable disease/slow response• Minimal disease burden• Tolerates therapy poorly• Major comorbidity• Prefers less
intensive/interventionist management
Viewpoint• We are saturated on maintenance regimen trials
• Time to tailor strategies to disease biology
• If biology doesn’t provide a clear cut signal-- patient preference is the key issue
• Better understanding of resistance mechanisms and genomics should enable us to distinguish low vs. high grade tumors with greater accuracy
Are further trials of continuous versus intermittent treatment important?
• With current agents, seems unlikely that additional trials will provide greater clarity
• May yield some insight from subgroup analyses based on genomic charachteristics of mCRC
• genomic analyses of olecular subtypes by continuous vs. intermittent strategy neede
