A randomized trial of gemcitabine
vs. gemcitabine plus cisplatin
in chemotherapy-naïve
advanced pancreatic carcinoma.
The GIP-1 (Gruppo Italiano Pancreas –
GOIM/GISCAD/GOIRC) study.
G.Colucci1, R.Labianca2, F.Di Costanzo3, V.Gebbia4, G.Cartenì5,
B.Massidda6, L.Frontini7, M.Falconi8, C.Gallo9, M.Di Maio10
on behalf of the GIP-1 Investigators
1National
Cancer Institute, Bari; 2Ospedali Riuniti, Bergamo; 3Azienda Ospedaliero-Universitaria Careggi,
Firenze; 4Università di Palermo, Casa di Cura La Maddalena, Palermo; 5Cardarelli Hospital, Napoli; 6Policlinico
Universitario, Cagliari; 7San Gerardo Hospital, Monza; 8University of Verona, Policlinico G.B.Rossi, Verona;
9Seconda Università, Napoli; 10National Cancer Institute, Napoli, Italy.
ASCO conflict of interest statement
The presenting author, Massimo Di Maio,
has no relationships to disclose
Introduction
• In 1997, single-agent gemcitabine (Gem) became
standard treatment for patients with advanced
pancreatic cancer 1
• Several preclinical data support the combination of
gemcitabine and cisplatin (GemCis) 2,3
• In a randomized trial conducted by GOIM, GemCis
significantly improved response rate and time to
progression 4
1Burris
et al, J Clin Oncol 1997, 15: 2403-13
2Bergman et al, Clin Cancer Res 1996, 2: 521-30
3van Moorsel et al, Br J Cancer 1999, 80: 981-990
4Colucci et al, Cancer 2002, 94: 902-10
Study objective
To evaluate the efficacy of a weekly
schedule of gemcitabine plus cisplatin
compared to standard single-agent
gemcitabine, as first-line treatment of
patients with advanced pancreatic cancer
Study design
R
an
do
m
Control arm
Gemcitabine 1000 mg/m2
1
8 15 22 29 36
1:1
43 50
57
64
71
78
43 50
57
64
71
78
Day
Experimental arm
Strata:
•Center
•KPS (70 vs 80)
•Stage (II-III vs IV)
Gemcitabine 1000 mg/m2
1
8 15 22 29 36
Day
Cisplatin 25 mg/m2
Study population
Inclusion criteria
•
•
•
•
•
Cyto/histological diagnosis of pancreatic cancer
Age 18 – 75
Karnofsky PS  50
Stage II (unresectable) / III / IV (TNM 1997)
No previous chemotherapy
Exclusion criteria
• ANC  2000/L, platelets  100000/L, Hgb  10 g/dL
• Creatinine  UNL, SGOT and SGPT  2.5 x UNL and
bilirubin  1.5 x UNL, unless due to liver metastases
• Brain metastases
Study endpoints
Primary endpoint
• Overall survival
Secondary endpoints
•
•
•
•
•
Progression-free survival
Objective response rate (RECIST)
Clinical benefit (Burris, J Clin Oncol 1997)
Quality of Life (EORTC C30 & PAN26)
Toxicity (NCI – CTC)
Sample size
• 2-tailed : 0.05
• Power: 80%
• Hazard Ratio: 0.74
• 1-yr survival:
• Median survival:
18%  28%
4.8
 6.5 months
• 2 analyses (1 interim, 1 final)
 355 deaths, 400 patients needed
Study conduction
• Enrollment:
– First patient: April 16, 2002
– Last patient: April 19, 2007
• Total number of randomized patients: 400
• Final analysis: December 2008
• Median follow-up: 38 months
Baseline characteristics
Age
median (range)
Gemcitabine
Gemcitabine + Cisplatin
(n = 199)
(n=201)
63 (37-75)
63 (35-75)
Gender
Males
113 (57%)
125 (62%)
86 (43%)
76 (38%)
70
33 (17%)
36 (18%)
80
166 (83%)
165 (82%)
33 (17%)
31 (15%)
165 (83%)
170 (85%)
47 (24%)
56 (28%)
Females
KPS
Stage
II-III
IV
Previous surgery
Treatment compliance
Gem
GemCis
(n = 199)
(n=201)
Missing information
2 (1%)
7 (3%)
Did never start treatment
5 (3%)
6 (3%)
Median
7
8
Range
1-31
1-31
Progression / death
72%
66%
Toxicity / refusal
12%
20%
Other / not specified
16%
14%
Number of administrations
Cause of treatment interruption
Received 2nd line treatment
346 pts with information available
53%
41%
1-yr
OS
Events
Gemcitabine
199
177
8.3
34.0%
Gemcitabine
+ Cisplatin
201
180
7.2
30.7%
0.6
Patients
Median OS
(months)
0.4
Hazard Ratio: 1.10 (0.89 – 1.35)
p = 0.38
0.0
0.2
Probability of survival
0.8
1.0
Overall survival
0
Patients at risk
Gem
199
GemCis 201
26
6
52
12
121
112
64
57
78
18
Months
Weeks
32
32
104
24
130
30
156
36
19
16
8
14
7
9
Overall survival: Cox model
Hazard Ratio
(95% CI)
p
Treatment (GemCis vs Gem)
1.10
0.89 – 1.35
0.39
Gender (Females vs males)
1.02
0.82 – 1.28
0.86
Age (65 vs <65)
0.89
0.72 – 1.12
0.32
Karnofsky PS (80 vs 70)
0.71
0.54 – 0.93
0.01
Stage (IV vs II-III)
1.82
1.34 – 2.47
0.0001
Previous surgery (yes vs no)
0.86
0.67 – 1.10
0.22
1 patient excluded because of missing information for stage
Treatment effect in subgroups
Overall (n=400)
Gender
Male (n=238)
Female (n=162)
Age
< 65 (n=233)
> 65 (n=167)
Stage
II – III (n=64)
IV (n=335)
Karnofsky PS
<= 70 (n=69)
>= 80 (n=331)
Previous surgery
No (n=297)
Yes (n=103)
0,4
0,6
Favours GemCis
0,8
1,0
1,2
1,4
Hazard ratio of death
1,6
1,8
2,0
Favours Gem
0.6
0.8
Patients Events
Median PFS
(months)
6-mo
PFS
Gemcitabine
199
191
3.9
32.9%
Gemcitabine
+ Cisplatin
201
191
3.8
31.8%
0.2
0.4
Hazard Ratio: 0.97 (0.80 – 1.19)
p = 0.80
0.0
Probability of progression-free survival
1.0
Progression-free survival
0
6
12
Patients at risk
Gem
199
GemCis 201
65
63
26
28
18
Months
12
15
24
30
36
6
9
7
4
Objective response*
Gemcitabine
Objective response
Complete response
Partial response
No response
(n=199)
Gemcitabine
+ Cisplatin
(n=201)
20 (10.1%)
26 (12.9%)
2 (1%)
3 (1.5%)
18 (9.0%)
23 (11.4%)
179 (89.9%)
175 (87.1%)
p = 0.37 (2)
*after cycle 1 (7 weeks)
Hematologic toxicity
Gem 189 patients; GemCis 186 patients
Any grade
Severe (G3)
Gem
Gem
Cis
p*
Gem
Gem
Cis
p*
Anemia
39%
51%
0.02
1%
5%
0.03
Neutropenia
36%
45%
0.07
14%
25%
0.007
Febrile neutropenia
1%
-
1
1%
-
1
Thrombocytopenia
30%
58%
<0.001
5%
16%
0.001
*Chi square or Fisher exact test as appropriate
Non-hematologic toxicity
Gem 189 patients; GemCis 186 patients
Any grade
Heart, rhythm
Heart, general
Fatigue
Constipation
Diarrhoea
Nausea
Vomiting
Hair loss
Liver toxicity
Renal toxicity
Neurotoxicity
Toxic deaths
Severe (G3)
Gem
GemCis
p*
Gem
GemCis
p*
1%
41%
17%
9%
37%
19%
1%
23%
1%
2%
2%
40%
16%
12%
38%
23%
7%
15%
2%
3%
0.47
0.12
0.93
0.73
0.22
0.74
0.33
0.002
0.03
0.06
0.12
1%
3%
2%
2%
1%
1%
1%
1%
5%
2%
1%
3%
3%
1
0.50
0.29
0.72
0.62
0.28
0.12
7%
2 (1%)
5%
1%
3 (2%)
0.53
*Chi square or Fisher exact test as appropriate
0.25
0.68
Clinical benefit response
Gemcitabine
(n=183)
Gemcitabine
+ Cisplatin
(n=179)
p*
Pain measures
Pain intensity
35 (19.1%)
26 (14.5%)
Analgesics consumption
21 (11.5%)
17 (9.5%)
38 (20.8%)
26 (14.5%)
2 (1.1%)
3 (1.7%)
39 (21.3%)
26 (14.5%)
3 (1.6%)
3 (1.7%)
42 (23.0%)
27 (15.1%)
Primary measures
Pain
Karnofsky PS
Clinical benefit
Primary measures
Weight
Overall clinical benefit
*Chi square test
0.057
Quality of life
• QoL questionnaires were administered baseline and
every 4 weeks in both arms (up to 6 questionnaires)
• Changes from baseline after 4 weeks are described here
• Global QoL: trend favouring single-agent gemcitabine
(p=0.07)
• Statistically significant differences:
– Social functioning (worse with GemCis, p=0.01)
– Hepatic symptoms (better with GemCis, p=0.01)
– Limitation in planning (worse with GemCis, p=0.006)
GIP-1 trial: conclusions
• The weekly schedule of gemcitabine + cisplatin
as 1st line treatment of advanced pancreatic
cancer did not prolong overall survival
compared to gemcitabine alone
• The addition of cisplatin did not produce any
improvement in terms of PFS, response rate,
clinical benefit or quality of life
Acknowledgements
All the patients and their families
The Investigators and staff at each participating center:
GOIM centers
GISCAD centers
GOIRC centers
G. Colucci, Bari
V. Gebbia, Palermo
G. Cartenì, Napoli
L. Manzione, Potenza
R.V. Iaffaioli, Napoli
N. Gebbia, Palermo
C. Gridelli, Avellino
B. Daniele, Benevento
M. Lopez, Roma
M. Caruso, Catania
G. Lucarelli, Acquaviva d.F.
R. Labianca, Bergamo
L.Frontini – G. Gardani, Monza
E. Piazza, Milano
V. Zagonel, Roma
S. Luzzi Fedeli, Pesaro
C. Graiff, Bolzano
S. Barni, Treviglio
P. Marchetti, Roma
G. Colosini, Manerbio
E. Galligioni, Trento
G. Cruciani, Lugo
F. Di Costanzo, Firenze
B. Massidda, Cagliari
L. Cavanna, Piacenza
R. Mattioli, Fano
P. Carlini, Roma
G. Lelli, Ferrara
S. Ortu, Olbia
F. Artioli, Carpi
F. Pasini, Rovigo
Other centers
M. Sannicolò, Rovereto
F. Carrozza, Campobasso
V. Lorusso, Lecce - Bari
A. Febbraro, Benevento
P. Astorre, Roma
A. Beretta, Como
R. Cellerino, Ancona
V. Fosser, Vicenza
P. Foa, Milano
P. Sandri, S.Vito al T.
S. Iacobelli, Chieti
M. Clerico, Biella
S. Frustaci, Aviano
S.F. Robbiati, Arco
Coordinating center:
F.Perrone, M.Di Maio, E. De Maio, A. Morabito, F.Romano – Napoli
Statistician center:
C.Gallo, G.Signoriello, P.Chiodini, N.Lama - Napoli