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)