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G.Colucci 1 , R.Labianca 2 , F.Di Costanzo 3 , V.Gebbia 4 , G.Carten ì 5 ,

A randomized trial of gemcitabine vs. gemcitabine plus cisplatin in chemotherapy-na ï ve advanced pancreatic carcinoma. The GIP-1 (Gruppo Italiano Pancreas – GOIM/GISCAD/GOIRC) study. G.Colucci 1 , R.Labianca 2 , F.Di Costanzo 3 , V.Gebbia 4 , G.Carten ì 5 ,

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G.Colucci 1 , R.Labianca 2 , F.Di Costanzo 3 , V.Gebbia 4 , G.Carten ì 5 ,

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  1. 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.

  2. ASCO conflict of interest statement The presenting author, Massimo Di Maio, has no relationships to disclose

  3. 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

  4. 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

  5. Study design Control arm Random Gemcitabine 1000 mg/m2 1 8 15 22 29 36 43 50 57 64 71 78 1:1 Day Experimental arm • Strata: • Center • KPS (70 vs 80) • Stage (II-III vs IV) Gemcitabine 1000 mg/m2 1 8 15 22 29 36 43 50 57 64 71 78 Day Cisplatin 25 mg/m2

  6. 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

  7. 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)

  8. 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

  9. 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

  10. Baseline characteristics

  11. Treatment compliance

  12. Overall survival Hazard Ratio: 1.10 (0.89 – 1.35) p = 0.38 0 6 12 18 24 30 36 Months

  13. Overall survival: Cox model 1 patient excluded because of missing information for stage

  14. Treatment effect in subgroups Favours GemCis Favours Gem

  15. Progression-free survival Hazard Ratio: 0.97 (0.80 – 1.19) p = 0.80 0 6 12 18 24 30 36 Months

  16. Objective response*

  17. Hematologic toxicity Gem 189 patients; GemCis 186 patients *Chi square or Fisher exact test as appropriate

  18. Non-hematologic toxicity Gem 189 patients; GemCis 186 patients *Chi square or Fisher exact test as appropriate

  19. Clinical benefit response *Chi square test

  20. 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)

  21. 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

  22. Acknowledgements All the patients and their families The Investigators and staff at each participating center:

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