Standard Management of Stage IV Colorectal Cancer: Start and Stop, Maintenance, Chemotherapy Holidays

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Standard Management of Stage IV Colorectal
Cancer Start and Stop, Maintenance,
Chemotherapy Holidays
Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer
Institute Boston, MA
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Disclosures

• Consultant Sanofi-aventis
• Research funding (to DFCI or CALGB) Pfizer,
  BMS, Astra Zeneca
• NCI research funding

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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)

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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

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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 lt0.02
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
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First-Line Irinotecan
Treatment was continued until one of the
following occurred disease progression,
unacceptable adverse effects, or the withdrawal
of consent by the patient.
R A N D O M I Z e
Irinotecan
N226
5-FU/LV (Mayo Clinic)
N226
IFL(bolus 5-FU/LV/ Irinotecan)
N231
5-FU/LV (AIO or de Gramont regimen)
R A N D O M I Z e
N198
Treatment was given until disease progressed,
the patient developed unacceptable toxic effects,
or consent was withdrawn.
Irinotecan/5-FU/LV (AIO or de Gramont regimen)
N187
Saltz LB et al. N Engl J Med. 2000343905
Douillard JY et al. Lancet. 20003551041.
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First-Line Oxaliplatin
R A N D O M I Z E
Treatment was continued until disease
progression or unacceptable toxicity occurred or
until a patient chose to discontinue treatment.
De Gramont 5-FU/LV
N210
N210
FOLFOX
R A N D O M I Z E
Treatment continued until toxicity limited,
patient became surgical candidate, patient
refusal, loss to f/u, death
Chronomodulated 5-FU/LV
N100
N100
Oxaliplatin Chrono 5-FU/LV
De Gramont et al. JCO. 2000 18 2938-47
Giacchetti et al. JCO. 2000 18 136-47
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NCCTG 9741
R A N D O M I Z E
IFL
N245
FOLFOX (5-FU/LV/Oxali)
N246
Irinotecan/Oxaliplatin
N250
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
Goldberg JCO 2004.
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NCCTG 9741
IFL ? 67 ceased treatment due to disease
progression or FOLFOX ? 42 IROX ? 55
Goldberg JCO 2004.
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Log Kill Kinetics
Rate of tumor volume regression is proportional
to the rate of growth.
Schmidt C JNCI J Natl Cancer Inst
2004961492-1493
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Gompertzian Model of Tumor Growth and
NortonSimon hypothesis
Rate of tumor volume regression is proportional
to the rate of growth.
Schmidt C JNCI J Natl Cancer Inst
2004961492-1493
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Lung Cancer Experience

• Continuation of 2 and 3 drug combinations beyond
  4-6 cycles does not improve survival

Socinski M A et al. JCO 2002201335-1343
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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

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Continuous v Intermittent Therapy MRC Trial

Responding or stable disease after 12 weeks
Maughan et al The Lancet. 2003. 361 457-64.
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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

PFS HR 1.20 (0.96-1.49) favor continuous
Maughan et al The Lancet. 2003. 361 457-64.
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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.
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Continuous v Intermittent Therapy2nd Line
Irinotecan
Progressed on fluoropyrimidine therapy
Lal R et al. JCO 2004223023-3031
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Continuous v Intermittent Therapy2nd 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 2004223023-3031
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Continuous v Intermittent TherapyGISCAD Trial
E V A L U A T I O N
E V A L U A T I O N
A
FOLFIRI x 2 m
FOLFIRI x 2 m
STOP x 2 m
RANDOM
CR, PR, SD
B
FOLFIRI x 2 m
FOLFIRI x 4 m
2nd Line (OHP)
Every 4 m until PD
PD
Labiana ASCO 2006
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Continuous v Intermittent TherapyGISCAD Trial
Labianca R et al. Ann Oncol 2011221236-1242
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Continuous v Intermittent TherapyGISCAD Trial
Median OS 17 v 18 months HR 0.88 (0.691.14)
Median chemo-free interval 3.5 months
Median PFS 6 v 6 months HR 1.03 (0.811.29)
Labianca R et al. Ann Oncol 2011221236-1242
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OPTIMOX 1 Trial of Maintenance
FOLFOX4 until Progression
R A N D O M I Z e
N311
FOLFOX7 x 6 cycles sLV5FU2 x up to 12
cycles FOLFOX7 x 6 cycles
N309
Only 40 reintroduced oxaliplatin 18.5 early
progression/death 18.4 toxicity (including
neuropathy) 5.5 surgery 17.5 unknown
Tournigand et al. JCO 200624394-400
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OPTIMOX 1 Trial of Maintenance
Tournigand et al. JCO 200624394-400
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OPTIMOX 1 Trial of Maintenance
Duration of Disease Control
Tournigand et al. JCO 200624394-400
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OPTIMOX 1 Trial of Maintenance
PFS
OS
Tournigand et al. JCO 200624394-400
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OPTIMOX 1 Trial of Maintenance
Grade 3 / 4 Toxicity
Grade 3 Neurotoxicity
Tournigand et al. JCO 200624394-400
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OPTIMOX 2 Go and Full Stop
Chibaudel B et al. JCO 2009275727-5733
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OPTIMOX 2 Go and Full Stop
mFOLFOX7
sLV5FU2
5FUb 400
LV 400
5-FU 3000
LV 400
5-FU 3000
Oxali 100
H0 H2 H24
H48
H0 H2 H24
H48
OPTIMOX 1
Baseline progression
A
A
A
A
A
A
FOLFOX7 x 6 cy
FOLFOX7 x 6
sLV5FU2
OPTIMOX 2
Baseline progression
A
A
A
A
A
A
Chemotherapy-free interval
FOLFOX7 x 6 cy
FOLFOX7 x 6
Cycles every 14 days, dose mg/m²
Maindrault-Goebel ASCO Presentation 2006
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OPTIMOX 2 Go and Full Stop
T size
Chemotherapy-free Interval
t
FOLFOX
FOLFOX
Progression at reintroduction
Progression
Baseline progression
Maindrault-Goebel ASCO Presentation 2006
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OPTIMOX 2 Go and Full Stop
HR 0.71 (95 CI, 0.51 to 0.99 P .046
Median duration of maintenance therapy 4.8
months in the arm 1 Median duration of CFI 3.9
months in arm 2.
Chibaudel B et al. JCO 2009275727-5733
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OPTIMOX 2 Go and Full Stop
PFS HR 0.61 P .0017
OS HR 0.88 P 0.42
Chibaudel B et al. JCO 2009275727-5733
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CONcePT Trial Primary endpoint TTF for CO vs IO
schedule
First-line mCRC, 532 patients Primary endpoint
time to failure (TTF) Randomization (2x2)
mFOLFOX7 bevacizumab CO until Treatment Failure
R
/- IV CaMg
mFOLFOX7 bevacizumabIntermittent oxaliplatin
CaMg 1 g calcium gluconate and 1 g magnesium
sulfate over 30 min pre- and post-oxaliplatin
Grothey et al ASCO 2008
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CONcePT Trial IO Arm
5-FU
Cumulative oxaliplatin
Months
LV
2400
200
OX
85
BEV
5
x 8
680 mg/m2
4
2400
200
5
Early reintroduction of oxaliplatin if
progression
x 8
8
680 mg/m2
2400
200
85
5
x 8
1360 mg/m2
12
etc.
Grothey et al ASCO 2008
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CONcePT Trial
TTF (mos) 95 CI
CO 4.2 3.7 - 5.5
IO 5.6 4.7 - 7.0
Unstratified (IO relative to CO), p0.002a
Stratified by CaMg (IO relative to CO), p0.003a
a log rank test
Grothey et al ASCO 2008
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CONcePT Trial
PFS (mos) 95 CI
CO 7.3 6.9 - NE
IO 12.0 8.2 - NE
Grothey et al ASCO 2008
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CONcePT Trial
N pts () with gt1 NTE leading to CO (n68) CO (n68) IO(n71) IO(n71)
N pts () with gt1 NTE leading to Placebo (n33) CaMg (n35) Placebo (n36) CaMg (n35)
Discontinuation 8 (24) 7 (20) 3 (8) 4 (11)
Discontinuation 15 (22) 15 (22) 7 (10) 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)
Delay or dose reduction 15 (22) 15 (22) 6 (8) 6 (8)
Grothey et al ASCO 2008
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N016966
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 )
Saltz et al. JCO. 2008 26 2013-2019
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MACRO Trial
Non-inferiority design Sample Size 470
patients 235 per arm Assuming 10 months as
median PFS Non-inferiority limit of 7.6 m
(HR1.32) One sided alpha 0.025, one side
Power 80
Taberno et al ASCO 2010
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MACRO Trial
Taberno et al ASCO 2010
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MACRO Trial
Taberno et al ASCO 2010
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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

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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

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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
• Dont forget about surgery if inoperable ?
  operable
• One size (or at least strategy) doesnt 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