Alternating vs continuous FOLFIRI in advanced colorectal cancer (ACC): a
randomized GISCAD trial Roberto Labianca
Ospedali Riuniti – Bergamo, Italy
Floriani I, Cortesi E, Isa L, Zaniboni A, Marangolo M, Frontini L, Barni S, Beretta GD, Sobrero A
Abs 3505
Pre-clinical data (Sobrero, 2000)Intermittent (2 month pauses) vs continuous exposure of HCT-8 cell cultures to 5FU appears to double the time to the development of drug resistance
Clinical data (Douillard, 2000) FOLFIRI vs De Gramont
RR 35%PFS 6.7 mOS 17.4 m
RATIONALE
AIM
To evaluate whether intermittent FOLFIRI is at least as effective as
continuous FOLFIRI (chemotherapy given until progression in both arms)
in advanced, previously untreated, colorectal cancer patients
ACCRUAL
First random: July, 2001
Last random: June, 2005
Total number of patients: 337
Eligible patients: 331
(Arm A 163 / Arm B 168)
Participating centres: 27
FOLFIRI x 2 m
EVALUATION
PD
STOPx 2 m
A
B
II line(OHP)
CR, PR, SDRANDOM
FOLFIRI x 2 m
FOLFIRI x 2 m
FOLFIRI x 4 m
Every 4 m until PD
EVALUATION
Primary Overall Survival (OS)
Secondary Progression Free Survival (PFS) Toxicity
ENDPOINTS
INCLUSION CRITERIAHistologically/cytologically proven ACC
No previous CT for advanced disease
Measurable disease
PS 0-2 (ECOG) / Age 18-75 yrs
No RT on target lesions
Normal renal, hepatic and bone marrow functions
Written informed consent
EXCLUSION CRITERIA
Serious concomitant diseasesCNS metastasesOther malignanciesMore than 4 weeks between screening and start of therapy
STATISTICAL ASSUMPTIONS
Delta for accepting non inferiority of intermittent treatment: 4 mos (from a median survival of 15 mos to 11), which can be translated in an upper limit of 95% CI of the HR equal to 1.36
Alpha: 2.5%, one-sided
Power : 80%,
Required events: 301
Intention to treat on eligible patients
PATIENT CHARACTERISTICS
ARM A ARM B
Median age – yrs 64.3 64.5
Male - % 68.1 57.2
ECOG-PS
0
1
2
67.5
29.5
3.0
64.0
34.8
1.2
PATIENT CHARACTERISTICS ARM A ARM B
Tumor site - %
Colon
Rectum
75.3
24.7
68.4
31.6
Previous therapies - %
None
Only adj CT
Only RT
Both
68.5
21.0
1.9
8.6
71.6
17.4
1.3
9.7
TREATMENT COMPLIANCE
ARM A ARM B
Completed
- without changes
64.7
39.2
56.5
30.6
Interrupted 35.3 42.9
Never begun 0 0.7
Still on treatment 11 pts 11 pts
OBJECTIVE RESPONSE
ARM A ARM B
COMPLETE 4.2 3.0
PARTIAL 29.4 33.5
STABLE 31.4 35.1
PROGRESSION 35.0 28.4
TOXICITY Grade 1-2 Grade 3 Grade 4
DIARRHOEA arm A
B
43.343.6
3.02.6
0.60.6
NAUSEA A B
25.019.9
2.42.6
0.60.6
VOMITING A B
18.321.2
1.22.6
00.6
MUCOSITIS A B
17.717.4
00.6
00
ALOPECIA A B
23.821.8
0.62.6
0.60
TOXICITY Grade 1-2 Grade 3 Grade 4
FEVER arm A B
19.626.0
9.8
11.53.03.2
NEUTROPENIA A B
12.819.3
1.8 2.6
00
ANAEMIA A
B
4.9 4.5
00
01.3
PLATELETSA
B42.737.8
3.0 3.2
00.6
PFSMedian f-up: 30 m
Median time to PD:Arm A 6.2 mArm B 6.5 m
Cox analysis (after adjustment for gender, age and site): HR: 1.01 (0.78-1.27)
148 168149 163
Events Totals
Patients at RiskArm AArm B
163 85 32 14 9168 82 34 14 8
'
Arm AArm B
Pro
gre
ssio
n F
ree
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Months from randomisation0 6 12 18 24
OS Median f-up: 30 m
Median survival time:Arm A 16.9 mArm B 17.6 m
Cox analysis (after adjustment for gender, age and site): HR: 1.03 (0.78-1.35)
118 16898 163
Events Totals
Patients at RiskArm AArm B
163 136 91 50 34 13168 135 100 59 36 23
'
Arm AArm B
Ove
rall
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Months from randomisation0 6 12 18 24 30
II LINE THERAPY (%)
ARM A ARM B
FOLFOX
OHP - based
55.0
4.1
59.1
51.5
3.0
54.5
Other 1.3 8.3
None 39.6 37.2
CONCLUSIONS
At the present time, our results suggest:
a non inferiority of intermittent versus continuous treatment for both PFS and OSa similar toxicity profile
We are planning further studies on this strategy, including also biologicals
THANKS TO:
All our patients, who gave their precious contribution for advancing independent clinical research
The following centres, for their professional involvement: Bergamo (Beretta), Gorgonzola (Isa), Roma-Policlinico (Cortesi), Brescia (Zaniboni) , Genova (Sobrero), Ravenna (Marangolo), Monza (Frontini), Treviglio (Barni), Avellino (Nicolella), Candiolo (Aglietta), Padova (Pasetto), Roma-FBF (Corsi), Lecco (Ucci), MI-Sacco (Piazza), Noale (D’Andrea), Faenza (Gambi), Roma-S.Andrea (Bossoni), Mantova (Aitini), Pesaro (Giordano), Biella (Clerico), Roma-Celio (Astorre), Sesto SG (Scanzi), MI-OSCB (Martignoni), Pavia (Bernardo), Bolzano (Graiff), Rho (Pavia), S.Donato Mil. (Luporini)