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 Investigators1National 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: 981-9904Colucci 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

Random

Strata:•Center•KPS (70 vs 80)•Stage (II-III vs IV)

Control armGemcitabine 1000 mg/m2

Cisplatin 25 mg/m2

1 8 15 22 29 36 43 57 64 7150 78

Experimental armGemcitabine 1000 mg/m2

1 8 15 22 29 36 43 57 64 7150 78

1:1

Study design

Day

Day

Study populationInclusion 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: 18% 28%• Median survival: 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 characteristicsGemcitabine Gemcitabine +

Cisplatin

(n = 199) (n=201)

Age median (range)

63 (37-75) 63 (35-75)

Gender

Males 113 (57%) 125 (62%)

Females 86 (43%) 76 (38%)

KPS

70 33 (17%) 36 (18%)

80 166 (83%) 165 (82%)

Stage

II-III 33 (17%) 31 (15%)

IV 165 (83%) 170 (85%)

Previous surgery 47 (24%) 56 (28%)

Treatment complianceGem GemCis

(n = 199) (n=201)

Missing information 2 (1%) 7 (3%)

Did never start treatment 5 (3%) 6 (3%)

Number of administrations

Median 7 8

Range 1-31 1-31

Cause of treatment interruption

Progression / death 72% 66%

Toxicity / refusal 12% 20%

Other / not specified 16% 14%

Received 2nd line treatment346 pts with information available 53% 41%

Patients Events

Median OS

(months)

1-yr

OS

Gemcitabine 199 177 8.3 34.0%

Gemcitabine + Cisplatin

201 180 7.2 30.7%

Patients at risk Gem 199 121 64 32 19 8 7 GemCis 201 112 57 32 16 14 9

Hazard Ratio: 1.10 (0.89 – 1.35)p = 0.38

Overall survival

6 12 18 24 30 36Months

0

1 patient excluded because of missing information for stage

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

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)

Favours GemCis Favours Gem

Treatment effect in subgroups

Hazard ratio of death

0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

of

pro

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ssio

n-f

ree

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Patients Events

Median PFS

(months)

6-mo

PFS

Gemcitabine 199 191 3.9 32.9%

Gemcitabine + Cisplatin

201 191 3.8 31.8%

Patients at risk Gem 199 65 26 12 6 - - GemCis 201 63 28 15 9 7 4

Hazard Ratio: 0.97 (0.80 – 1.19)p = 0.80

Progression-free survival

6 12 18 24 30 36Months

0

Objective response*

Gemcitabine

(n=199)

Gemcitabine + Cisplatin

(n=201)

Objective response 20 (10.1%) 26 (12.9%)Complete response 2 (1%) 3 (1.5%)

Partial response 18 (9.0%) 23 (11.4%)

No response 179 (89.9%) 175 (87.1%)

p = 0.37 (2)

*after cycle 1 (7 weeks)

Hematologic toxicity

Any grade Severe (G3)

GemGemCis

p* GemGemCis

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

Gem 189 patients; GemCis 186 patients

*Chi square or Fisher exact test as appropriate

Non-hematologic toxicity

Any grade Severe (G3)

Gem GemCis p* Gem GemCis p*Heart, rhythm 1% 2% 0.47 1% 1% 1

Heart, general - 2% 0.12 - 1% 0.50Fatigue 41% 40% 0.93 3% 5% 0.29Constipation 17% 16% 0.73 2% 2% 0.72

Diarrhoea 9% 12% 0.22 2% 1% 0.62Nausea 37% 38% 0.74 1% 3% 0.28Vomiting 19% 23% 0.33 1% 3% 0.12Hair loss 1% 7% 0.002Liver toxicity 23% 15% 0.03 7% 5% 0.53Renal toxicity - 2% 0.06 - -Neurotoxicity 1% 3% 0.12 - 1% 0.25Toxic deaths 2 (1%) 3 (2%) 0.68

Gem 189 patients; GemCis 186 patients

*Chi square or Fisher exact test as appropriate

Clinical benefit responseGemcitabine

(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%)

Primary measures

Pain 38 (20.8%) 26 (14.5%)

Karnofsky PS 2 (1.1%) 3 (1.7%)

Clinical benefit

Primary measures 39 (21.3%) 26 (14.5%)

Weight 3 (1.6%) 3 (1.7%)

Overall clinical benefit

42 (23.0%) 27 (15.1%)

0.057

*Chi square test

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

AcknowledgementsAll the patients and their familiesThe Investigators and staff at each participating center:

GOIM centers GISCAD centers GOIRC centersG. Colucci, Bari R. Labianca, Bergamo F. Di Costanzo, Firenze

V. Gebbia, Palermo L.Frontini – G. Gardani, Monza B. Massidda, CagliariG. Cartenì, Napoli E. Piazza, Milano L. Cavanna, Piacenza

L. Manzione, Potenza V. Zagonel, Roma R. Mattioli, Fano R.V. Iaffaioli, Napoli S. Luzzi Fedeli, Pesaro P. Carlini, RomaN. Gebbia, Palermo C. Graiff, Bolzano G. Lelli, FerraraC. Gridelli, Avellino S. Barni, Treviglio S. Ortu, Olbia

B. Daniele, Benevento P. Marchetti, Roma F. Artioli, CarpiM. Lopez, Roma G. Colosini, Manerbio F. Pasini, Rovigo

M. Caruso, Catania E. Galligioni, Trento Other centersG. Lucarelli, Acquaviva d.F. G. Cruciani, Lugo M. Sannicolò, Rovereto

F. Carrozza, Campobasso P. Astorre, Roma V. Fosser, VicenzaV. Lorusso, Lecce - Bari A. Beretta, Como P. Foa, MilanoA. Febbraro, Benevento R. Cellerino, Ancona P. Sandri, S.Vito al T.

S. Iacobelli, Chieti M. Clerico, Biella S. Frustaci, AvianoS.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