standard management of stage iv colorectal cancer: start and stop, maintenance, chemotherapy...
Post on 13-Jan-2016
212 Views
Preview:
TRANSCRIPT
Standard Management of Stage IV Colorectal Cancer:
Start and Stop, Maintenance, Chemotherapy Holidays
Jeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
Disclosures
• Consultant: Sanofi-aventis
• Research funding (to DFCI or CALGB) – Pfizer, BMS, Astra Zeneca
• NCI research funding
Outline for this segment
• Continuous treatment for metastatic colorectal cancer – how we got here
• 3 strategies besides continuous– Full chemotherapy holiday– Maintenance – Start and stop (some twist of above 2)
5-Fluorouracil
• First introduced by Heidelberger & colleagues 1957 (J Am Chem Soc 1957; Nature 1957)
• While toxic, it does not have cumulative dose limiting toxicities– Rare patients with relative DPD deficiency have
severe bone marrow suppression – else, most do not bone marrow limitations
N
H
HN
O
O
F
Chemotherapy versus Best Supportive Care
Trial N Treatments Duration Result
NORDIC trial 133 Advanced, asymptomatic
Immediate v delayed MLF
Up to 6 months OS: 14 m v 9 m (p log rank 0.14; p Breslow-Gehan <0.02
Scheithauer
et al
40 Advanced, symptomatic
5-FU, LV, CDDP v BSC only
Up to 6 months OS: 11 v 5 months
Yorkshire GI Tumour Group
57 residual disease after palliative surgery
Methyl CCNU, 5-FU v BSC only
Up to 2 years 1 yr OS: 74 v 57%
RANDOMI
Z e
IrinotecanIrinotecan
IFL(bolus 5-FU/LV/Irinotecan)
IFL(bolus 5-FU/LV/Irinotecan)
5-FU/LV (Mayo Clinic)5-FU/LV (Mayo Clinic)
Saltz LB et al. N Engl J Med. 2000;343:905;
N=226
N=226
N=231
Irinotecan/5-FU/LV(AIO or de Gramont
regimen)
Irinotecan/5-FU/LV(AIO or de Gramont
regimen)
5-FU/LV(AIO or de Gramont
regimen)
5-FU/LV(AIO or de Gramont
regimen)
Douillard JY et al. Lancet. 2000;355:1041.
N=198
N=187
RANDOMI
Z e
First-Line Irinotecan
“Treatment was given until disease progressed, the patient developed unacceptable toxic effects, or consent was withdrawn. “
“Treatment was continued until one of the following occurred: disease progression, unacceptable adverse effects, or the withdrawal of consent by the patient. “
RANDOMI
Z E
De Gramont 5-FU/LVDe Gramont 5-FU/LV
FOLFOXFOLFOX
De Gramont et al. JCO. 2000; 18: 2938-47; Giacchetti et al. JCO. 2000; 18: 136-47;
N=210
N=210
First-Line Oxaliplatin
“Treatment was continued until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue treatment. “
RANDOMI
Z E
Chronomodulated 5-FU/LVChronomodulated 5-FU/LV
Oxaliplatin + Chrono 5-FU/LVOxaliplatin + Chrono 5-FU/LV
N=100
N=100
Treatment continued until toxicity limited, patient became surgical candidate, patient refusal, loss to f/u, death
RANDOMI
Z E
IFLIFL
Irinotecan/OxaliplatinIrinotecan/Oxaliplatin
FOLFOX (5-FU/LV/Oxali)FOLFOX (5-FU/LV/Oxali)
Goldberg JCO 2004.
N=245
N=246
N=250
Response rate
Time to Progress
Median Overall Survival
Grade 3/4 Neutropenia
Grade 3/4 Diarrhea
Grade 3/4
Neuropathy
IFL 33 % 6.9 m 14.8 m 40 % 28 % 3 %
FOLFOX 45 % 8.7 m 19.5 m 50 % 12 % 18 %
IROX 35 % 6.5 m 17.4 m 36 % 24 % 7 %
NCCTG 9741
Goldberg JCO 2004.
NCCTG 9741
IFL 67% ceased treatment due to disease progression or FOLFOX 42%IROX 55%
Log Kill Kinetics
Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493
Rate of tumor volume regression is proportional to the rate of growth.
Gompertzian Model of Tumor Growth and Norton–Simon hypothesis
Schmidt C JNCI J Natl Cancer Inst 2004;96:1492-1493
Rate of tumor volume regression is proportional to the rate of growth.
Lung Cancer Experience
• Continuation of 2 and 3 drug combinations beyond 4-6 cycles does not improve survival
Socinski M A et al. JCO 2002;20:1335-1343
Lung Cancer Experience
• Maintenance with non-cross resistant agents likely helpful– Docetaxel – PFS significant; OS trend– Pemetrexed – PFS and OS significant– EGFR TKIs – PFS significant; OS mixed data
Continuous v Intermittent Therapy: MRC Trial
Maughan et al The Lancet. 2003. 361: 457-64.
Responding or stable disease after 12 weeks
Continuous v Intermittent Therapy: MRC Trial
• Median off-treatment duration with intermittent therapy was 4.3 months– Significantly fewer adverse events
• Overall survival was similar in both groups
Maughan et al The Lancet. 2003. 361: 457-64.
PFS HR1.20 (0.96-1.49) favor continuous
Continuous v Intermittent Therapy: MRC Trial
• Selection bias – randomization after known disease control to therapy– Included and not included patients similar baseline
characteristics
• Only 37% in intermittent group resumed scheduled treatment at progression
Maughan et al The Lancet. 2003. 361: 457-64.
Continuous v Intermittent Therapy:2nd Line Irinotecan
Lal R et al. JCO 2004;22:3023-3031
Progressed on fluoropyrimidine therapy
Continuous v Intermittent Therapy:2nd Line Irinotecan
• No differences in failure-free survival (P = .999) or overall survival (P = .11)
• No difference in mean global health status QOL score
Lal R et al. JCO 2004;22:3023-3031
FOLFIRI x 2 m
EVALUATION
PD
STOPx 2 m
A
B
2nd Line(OHP)
CR, PR, SDRANDOM
FOLFIRI x 2 m
FOLFIRI x 2 m
FOLFIRI x 4 m
Every 4 m until PD
EVALUATION
Continuous v Intermittent Therapy:GISCAD Trial
Labiana ASCO 2006
Continuous v Intermittent Therapy:GISCAD Trial
Labianca R et al. Ann Oncol 2011;22:1236-1242
Continuous v Intermittent Therapy:GISCAD Trial
Labianca R et al. Ann Oncol 2011;22:1236-1242
Median OS17 v 18 monthsHR 0.88 (0.69–1.14)
Median PFS6 v 6 monthsHR 1.03 (0.81–1.29)
Median chemo-free interval 3.5 months
OPTIMOX 1: Trial of Maintenance
Tournigand et al. JCO 2006;24:394-400
FOLFOX7 x 6 cyclessLV5FU2 x up to 12 cycles
FOLFOX7 x 6 cycles
FOLFOX7 x 6 cyclessLV5FU2 x up to 12 cycles
FOLFOX7 x 6 cycles
FOLFOX4 until Progression
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: Trial of Maintenance
Tournigand et al. JCO 2006;24:394-400
OPTIMOX 1: Trial of Maintenance
Tournigand et al. JCO 2006;24:394-400
Duration of Disease Control
OPTIMOX 1: Trial of Maintenance
Tournigand et al. JCO 2006;24:394-400
PFS OS
OPTIMOX 1: Trial of Maintenance
Tournigand et al. JCO 2006;24:394-400
Grade 3 / 4 Toxicity
Grade 3 Neurotoxicity
OPTIMOX 2: Go and Full Stop
Chibaudel B et al. JCO 2009;27:5727-5733
OPTIMOX 2: Go and Full Stop
A
FOLFOX7 x 6 cy
A A A A A
FOLFOX7 x 6sLV5FU2
Baseline progression
FOLFOX7 x 6 cy
A A A A
FOLFOX7 x 6Chemotherapy-free interval
Baseline progression
LV 400 5-FU 3000
mFOLFOX7
Oxali 100
H0 H2 H24 H48
LV 400 5-FU 3000
sLV5FU2
H0 H2 H24 H48
5FUb 400
Cycles every 14 days, dose mg/m²
OPTIMOX 1
OPTIMOX 2
A
A
Maindrault-Goebel ASCO Presentation 2006
OPTIMOX 2: Go and Full Stop
t
T size
FOLFOX FOLFOX
Progression Baseline progression
Progressionat reintroduction
Chemotherapy-free Interval
Maindrault-Goebel ASCO Presentation 2006
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 CFI = 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
CaMg = 1 g calcium gluconate and 1 g magnesium sulfate over 30 min pre- and post-oxaliplatin
CONcePT Trial Primary endpoint: TTF for CO vs IO schedule
First-line mCRC, 532 patientsPrimary endpoint: time to failure (TTF)Randomization (2x2):
mFOLFOX7 + bevacizumabCO until Treatment Failure
mFOLFOX7 + bevacizumabIntermittent oxaliplatin
+/- IV CaMgR
270 pts
Grothey et al ASCO 2008
2400
x 8
Cumulative oxaliplatin
680 mg/m2
Months
42400
x 8
8680 mg/m2
2400
200855
2005
200855
x 8 1360 mg/m2 12
etc.
LVOXBEV
5-FU
CONcePT Trial: IO Arm
Grothey et al ASCO 2008
Early reintroduction of oxaliplatin if progression
a log rank test
Unstratified (IO relative to CO), p=0.002a
Stratified by CaMg (IO relative to CO), p=0.003a
Proportionof patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 17
TTF months
COIO
Censored data
N at riskCO:IO:
1 3 5 7 9 11 13 15
6871
5861
3652
2032
621
412
210
14
01
6365
4656
2843
1128
418
412
27
11
TTF (mos)
95% CI
CO 4.2 3.7 - 5.5
IO 5.6 4.7 - 7.0
CONcePT Trial
Grothey et al ASCO 2008
CONcePT Trial
a log rank test
Unstratified (IO relative to CO), p=0.044a
Stratified by Ca/Mg (IO relative to CO), p=0.030a
Proportionof patients
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16 17
PFS months
COIO
Censored data
N at riskCO:IO:
1 3 5 7 9 11 13 15
6871
4655
2943
1327
318
310
08
02
01
6464
3951
2438
724
315
19
03
01
PFS (mos)
95% CI
CO 7.3 6.9 - NE
IO 12.0 8.2 - NE
Grothey et al ASCO 2008
N pts (%) with >1 NTE leading to
CO (n=68)
IO(n=71)
Placebo(n=33)
CaMg(n=35)
Placebo(n=36)
CaMg(n=35)
Discontinuation8 (24) 7 (20) 3 (8) 4 (11)
15 (22) 7 (10)
Delay 1 (3) 0 1 (3) 0
Dose reduction 7 (21) 6 (17) 2 (6) 2 (6)
Delay and dose reduction 0 1 (3) 1 (3) 1 (3)
Delay or dose reduction
8 (24) 7 (20) 3 (8) 3 (9)
15 (22) 6 (8)
CONcePT Trial
Grothey et al ASCO 2008
N016966
Saltz et al. JCO. 2008; 26: 2013-2019
Treatment d/c due to PD in 29% in the bevacizumab-containing arms and 47% in the placebo-containing arms
Prespecified secondary analysis, median on-rx PFS = 10.4 vs 7.9 months (HR, 0.63 [ 0.52 to 0.75 ] )
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 Sample Size: 470 patients; 235 per arm
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
Taberno et al ASCO 2010
Patients at risk
MACRO Trial
Taberno et al ASCO 2010
Some Ongoing Trials• AIO-Studien-gGmbH (n = 760)
– FOLFOX / Bevacizumab x 24 week then maintenance with fluoropyrimdine / bevacizumab OR bevacizumab alone OR full treatment holiday
• Dutch Colorectal Cancer Group (n = 635)– XELOX / Bevacizumab x 6 months then capecitabine / bevacizumab OR
full treatment holiday
• Spanish Cooperative Group (n = 192)– FOLFOX / Cetuximab x 18 weeks then continuation OR cetuximab only
• Swiss Group (n = 238)– Chemotherapy / Bevacizumab x 16-24 weeks then bevacizumab OR full
treatment holiday
Some Ongoing Trials
• FFCD (n = 188)– FOLFIRI / Bevacizumab x 24 week then maintenance
bevacizumab alone OR full treatment holiday
• Lund University Hospital (n = 240)– Chemotherapy / Bevacizumab x 4 months then
bevacizumab / erlotinib OR bevacizumab only
• DREAM / OPTIMOX 3 (n = 640)– FOLFOX or XELOX / Bevacizumab then
bevacizumab / erlotinib OR bevacizumab only
What To Do?• Data can be seen as favoring any approach
– Continuing combination therapy til progression– Maintenance with some of the agents– Full treatment holidays
• Don’t forget about surgery if inoperable operable
• One size (or at least strategy) doesn’t fit all– Patient preferences, goals, quality of life– Low burden disease / asymptomatic versus symptomatic or high burden of disease– Consider initial response to therapy
• Consider a clinical trial for your patient
top related