F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study.
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F. Maindrault-Gbel, G. LLedo, B. Chibaudel, L. Mineur, T. Andr, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont OPTIMOX2, a large randomized.
Rationale: OPTIMOX 1 Oxaliplatin Stop and Go Better tolerance Same efficacy results Tournigand, JCO 2006
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F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro,
P.Artru, C. Louvet, A. de Gramont
OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with
metastatic colorectal cancer (MRC). A GERCOR study.
RationaleChemotherapy-free intervals (CFI) have previously been studied in patients receiving 5FU- based therapy:Hejna et al (Br J Cancer (1998) have shown that patients can benefit from 5FU reintroduction after a CFI following 6 months of therapy.
Maughan et al (Lancet 2003) have show in a larger phase III that 3 months 5FU-based chemotherapy followed by CFI achieved the same survival than 5FU until progression.
New combination therapies have improved survival but also increased toxicity, especially the cumulative toxicities like the oxaliplatin sensory neuropathy. The need to preserve the quality of life is the clinical rationale to evaluate CFI.
Plantade et al have shown in a retrospective study presented at ASCO 2006 that patients with MCRC an benefit from CFI, especially in first-line therapy.
Grade3-4 toxicity at each cycle
0
5
10
15
20
25
1 3 5 7 9 11 13 15 17 19 21 23
cycles
% p
atie
nts
FOLFOX4
FOLFOX7
RRAANNDDOOMMIISSAATTIIOONN
FOLFOX4 until progression
FOLFOX7 x 6 cysLV5FU2 x 12 cyFOLFOX7 x6 cy
A
B
Rationale: OPTIMOX 1
Oxaliplatin Stop and Go
Better tolerance
0 25 50 75 100 125 1500.00
0.25
0.50
0.75
1.00
FOLFOX4
FOLFOX7
weeks
prob
abili
ty
20.0 months
21.6 months
p = 0,68
Same efficacy results
Tournigand, JCO 2006
RRAANNDDOOMMIISSAATTIIOONN
maintenance therapy vs chemotherapy-free interval
mFOLFOX7 x 6 cy sLV5FU2 until baseline progressionmFOLFOX7 reintroduction
mFOLFOX7 x 6 cy No maintenance until baseline progressionmFOLFOX7 reintroduction
OPTIMOX 2 Study design
A
B
OPTIMOX2 : chemotherapy-free interval
OPTIMOX1 : maintenance therapy
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 100H0 H2 H24 H48
LV 400 5-FU 3000
sLV5FU2
H0 H2 H24 H48
5FUb 400
Cycles every 14 days, dose mg/m²
CHEMOTHERAPY
OPTIMOX 1
OPTIMOX 2
A
A
Baseline Progression
t
T size
FOLFOX FOLFOX
Progression Baseline progression
Progressionat reintroduction
Chemotherapy-free Interval
Histologically proven colorectal cancer
Unresectable metastases
Mesurable or evaluable metastasis
No prior CT except adjuvant CT if ended 6 months before study entry
CFI according to Initial ResponseChemotherapy-free intervals
0 25 500.00
0.25
0.50
0.75
1.00
CR+PR N=55 median CFI 5.1 months
SD N=29 median CFI 3.9 months
weeks
prob
abili
ty
5.1 months
3.9 months
CFI according to Pc factorsChemotherapy-free Interval
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
prob
abili
ty
8.0 months
4.6 months
PS 2LDH ↑Alk Ph >3ULN> 1 site
PFS of Reintroduction
3.7 months
4.1 months
Progression-free Survival
0 10 20 30 400.00
0.25
0.50
0.75
1.00
optimox1 n=31 median 16 weeks
optimox2 n=51 median 18 weeks
p=.74
weeks
prob
abili
ty
Conclusions (1)Maintenance therapy improves PFS but not DDC
Median duration of chemotherapy-free interval is 20 weeks (4.6 months), 35 weeks (8 months) in patients without adverse prognostic factors
Results in the OPTIMOX 1 arm are comparable to the previous study except DDC, 12.9 vs 10.6 months, which can be explained by a higher reintroduction rate, > 60% vs 40%.
Response rate after reintroduction of FOLFOX could be higher in patients who did not receive maintenance therapy
Conclusions (2)
A break in therapy can be proposed in patients who achieved a response or a stable disease with first-line FOLFOX therapy, especially those without adverse prognostic factors
The next GERCOR study, DREAM, will evaluate maintenance therapy with targeted drugs alone.