1. LV5FU2-cisplatin followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: Preliminary results of a randomized phase III trial (FFCD 0301).
E. Mitry, L. Dahan, M. Ychou, J. Arthaud, M. Gasmi, J. Raoul, C. Mariette, J. M. Phelip, L. Bedenne, J.F. Seitz, Fédération Francophone de Cancérologie Digestive

2. Abstract
Background:
Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997). The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002). This randomized multicenter phase III trial compared LV5FU2-P followed by gemcitabine in arm A versus gemcitabine followed by LV5FU2-P in arm B to evaluate the best sequence.
Methods:
Pts with measurable MPA, PS 0-2, non prior CT, were randomly assigned to receive either LV5FU2-P (2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or 2, followed by gemcitabine (1,000 mg/m2 for 7 weeks out of 8 and then 3 weeks out of 4) at progression or toxicity (arm A) or the opposite sequence (arm B). Randomization was done using minimization with stratification according to center, PS tumoral localization and infusion duration. Primary endpoint was OS. It was required to include 202 pts and observe 170 deaths to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%). Secondary endpoints included progression free-survival (PFS) after first and second line, toxicity, quality of life (QLQ-C30) and percentage of second line in each arm.
Results:
From 08/2003 to 05/2006, 202 pts were included in 33 centers, 102 in arm A and 100 in arm B. Median age (62 [ ] vs 64 [ ] years), male/female ratio (1.7 vs 1.7), PS 0-1 (76.5% vs 83%), previous surgery (22.5% vs 27%). After a median follow-up of 33,6 months [min 17; max 48], 185 pts had died. Median OS for arm A was 6.6 months [95% CI- 5.2 to 8.4] versus 8.2 months [95% CI- 6.1 to 9.7] for arm B (HR B vs A 0.95 [95% CI ], Log Rank p = 0.72). 1- year and 2-year survival rates were 29.5% and 8% for arm A versus 34.5% and 3.5% for arm B, respectively.
Conclusions:
This trial failed to reach its primary endpoint and both sequences achieved a similar efficacy with no significant differences between the two arms in median OS. Updated results (including response, PFS and toxicity analyses) will be presented at the meeting.

3. Introduction
Pts with metastatic pancreatic adenocarcinoma (MPA) have a poor prognosis with no major survival improvement since the introduction of gemcitabine (Burris 1997).
The LV5FU2-P regimen was reported as safe and active with a 9 months median overall survival (OS) in a phase II trial (Taïeb 2002).

4. Gemcitabine followed by LV5FU2-P at progression or toxicity
Study design
Multicentre phase III study
To compare the best sequence of chemotherapy
Stratification:
Centre
WHO PS (0,1 vs 2)
Location (head vs other)
GEM infusion rate
Arm A: LV5FU2-P followed by Gemcitabine at progression or toxicity
Arm B:
Gemcitabine followed by LV5FU2-P at progression or toxicity R
(Minimization)
Gemcitabine: 1000 mg/m² on D1 as a 30 mn infusion or with an infusion rate of 10 mg/m2/min* , weekly 7 weeks /8, then 3 weeks / 4
LV5FU2-P: 2-hour infusion of LV 200 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 mg/m2 every 2 weeks, with cisplatin 50 mg/m2 as a 2-hour infusion on D1 or D2
(* Each participating centre had to always use the same administration method)

5. Primary endpoint : overall survival Secondary endpoints
(Time interval between randomization and death from all causes)
Secondary endpoints
Progression Free survival (Time interval between randomization and first progression or death from all causes)
Progression free survival after 1st and 2nd line
Proportion of patients receiving a second line
Tolerance
Quality of life (EORTC QLQ-C30)

6. Statistical analyses :
Sample Size : inclusion of 202 pts with 170 deaths required to detect an expected improvement in median OS from 6.5 to 10 months in arm A (bilateral α = 5% and β = 20%)
Strict intent to treat analyses
Fischer exact test or Chi2 to compare qualitative variables
Wilcoxon test to compare continuous variables
Survival calculated using Kaplan Meier estimation
Log Rank and stratified Log Rank to compare survival curves
Univariate Cox analyses to calculate Hazard Ratio and its 95% CI
Median Follow-up calculated using Reverse Kaplan Meier method

7. Inclusion criteria Pathologically-proven pancreatic adenocarcinoma
Metastatic disease (locally advanced patients excluded)
Measurable disease
No previous chemotherapy
WHO performance status 0-2
Age ≥18 years
Life expectancy > 2 months
Adequate biologic parameters
Written informed consent

8. Enrollment Period of inclusion: 08-2003 to 05-2006
33 participating centres
202 patients randomized (Arm A: 102, arm B: 100) 5 untreated patients (Arm A: 1, Arm B: 4)
Date of point: October, 1st 2007 Number of death : 188 pts Arm A: 93 (91.2%) Arm B: 95 (95.0%)
Median follow-up time: 44 months
Intent to treat popultation: 202 pts Evaluable for tolerance: 197 pts
5 untreated patients : raison = inconnue pour le moment

9. Baseline characteristics
ARM A n (%)
ARM B n (%) n
102
100
Median age years [range]
62 [40-84]
64.5 [39-81]
WHO PS
28 (27.4)
30 (30.0) 1
51 (50.0)
53 (53.0) 2
22 (21.6)
14 (14.0)
unknown
1 (1.0)
3 (3.0)
Male
65 (63.7)
65 (64.0)
Primary tumor location
Head
57 (55.9)
49 (49.0)
Other
44 (43.1)
50 (50.0)
Unknown
Stage
Metastatic
100 (99.0)
99 (99.0)
Metastatic sites
Liver
87 (85.3)
90 (90.0)
Peritoneum
11 (10.8)
17 (17.0)
Lymph nodes
18 (17.6)
24 (24.0)
Lung
15 (14.7)
12 (12.0)
CA 19.9 (n, median value UI/ml)
95, 565
95, 560
No statistically significant difference between treatment groups

10. Treatment administration
ARM A n=102
ARM B n=100 p
Pts receiving a 2nd line
69 (67.7%)
55 (55%)
0.127
LV5FU2-P
Line of treatment
First line
Second line
N of pts with at least 1 administration
101 (99.0 %)
55 (55 %)
<0.001
Median number of cycles [range] (1 cycle = 1 month)
3 [1-16]
2 [1-9]
0.8
Median dose (mg) [range]
Bolus 5FU
1248 [0-3440]
1285 [0-1764]
Continuous 5FU
7236 [ ]
7628 [ ]
0.055
Cisplatin
155 [0-440]
160 [0-200]
0.2
GEMCITABINE
69 (67.7 %)
96 (96 %)
Median number of cycles [range]
1[1-14]
3 [1-13]
0.0024
Gemcitabine
[ ]
5100 [ ]
0.159

11. Tolerance (grade 3-4 toxicity per patient)
ARM A (%)
ARM B (%) p
LV5FU2-P
Line of treatment
First
Second
Safety population N
With available Toxicity reports
101 99 55
All toxicities
79.8
70.91
0.2
Hematological toxicity
49.5
34.5
0.1
Non-hematological toxicity
54.5
50.9
0.7
GEMCITABINE 69 68 96 94
75.0
64.9
58.8
35.1
0.002
51.5
46.8
0.084
Overall toxicity (1st + 2nd line)
87.0
81.1
0.256
60.0
43.2
0.018
70.0
63.2
0.311

12. Tumor response (Best observed overall response, RECIST criteria)
ARM A n=102 n (%)
ARM B n=100 n (%) p
Complete response
3 (2.9)
4 (4.0)
0.78
Partial response
16 (15.7)
18 (18.0)
Stable disease
39 (38.2)
37 (37.0)
Progression
24 (23.5)
17 (17.0)
Non evaluable
2 (1.9)
1 (1.0)
Unknown
18 (17.6)
23 (23.0)

13. Overall survival ARM A ARM B 6.63 [5.27 – 8.07] 8.03 [5.93 – 9.97]
Primary endpoint of the study
ARM A
ARM B
P (log-rank)
Median survival months [95% CI]
6.63 [5.27 – 8.07]
8.03 [5.93 – 9.97]
0.77

14. Progression free-survival
ARM A
ARM B
P (log-rank)
Median PFS months [95% CI]
3.83 [2.36 – 7.03]
4.73 [ ]
0.90
PFS 1st line, PFS 2nd line : not yet available

15. Conclusion
The primary endpoint of the study is not reached : there is no significant difference in overall survival between arm A and B
More patients received a second-line when treated with LV5FU2-P in first-line (non significant)
Gemcitabine appears to be more toxic when given in second line. While the overall toxicity was not different between arms we observe an increase of overall hematological toxicities for arm A.
=> Gemcitabine remains the first choice in the front-line treatment of advanced pancreatic adenocarcinoma