Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 1, pp 115–123

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen)

  • Michele Reni
  • Stefano Cereda
  • Alessia Rognone
  • Carmen Belli
  • Michele Ghidini
  • Simonetta Longoni
  • Clara Fugazza
  • Sara Rezzonico
  • Paolo Passoni
  • Najla Slim
  • Giampaolo Balzano
  • Roberto Nicoletti
  • Stefano Cappio
  • Claudio Doglioni
  • Eugenio Villa
Original Article

Abstract

Purpose

PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6 months PFS (PFS6).

Methods

Chemo-naive patients with stage III or metastatic PA received P (30 mg/m2 day 1 and 15), G (800 mg/m2 day 1 and 15), and capecitabine (1,250 mg/m2/day days 1–28, without a break) and were randomized to receive either D at 25–30 mg/m2 day 1 and 15 (arm A: PDXG regimen) or E at 30 mg/m2 day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28 days for a maximum of 6 months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0 = 40% and P1 = 60%, α = 0.05 and β = 0.10; the study was to enroll 52 patients per arm.

Results

Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients’ characteristics were (A/B) the following: median age 61/59, PS >70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11 months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%.

Conclusions

The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.

Keywords

Capecitabine Chemotherapy Cisplatin Docetaxel Gemcitabine Pancreatic cancer 

References

  1. 1.
    Cascinu S, Falconi M, Valentini V et al (2010) Pancreatic cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21:55–58CrossRefGoogle Scholar
  2. 2.
    Reni M, Sartori N, Mambrini A et al (2010) An Italian study on treatment trends and outcomes of patients with stage III pancreatic adenocarcinoma in the gemcitabine era: is it time to change? Anticancer Drug 21:459–464CrossRefGoogle Scholar
  3. 3.
    Reni M, Pasetto LM, Passardi A et al (2011) Treatment trends in metastatic pancreatic cancer patients: is it time to change? Dig Liv Dis 43:225–230CrossRefGoogle Scholar
  4. 4.
    Berlin JD, Catalano P, Thomas JP et al (2002) Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: eastern cooperative oncology group trial E2297. J Clin Oncol 20:3270–3275PubMedCrossRefGoogle Scholar
  5. 5.
    Herrmann R, Bodoky G, Ruhstaller T et al (2007) Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss group for clinical cancer research and the Central European cooperative oncology group. J Clin Oncol 25:2212–2217PubMedCrossRefGoogle Scholar
  6. 6.
    Cunningham D, Chau I, Stocken C et al (2009) Phase III randomised comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27:5513–5518PubMedCrossRefGoogle Scholar
  7. 7.
    Poplin E, Feng Y, Berlin J et al (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30 min infusion) in patients with pancreatic carcinoma E6201: a trial of the eastern cooperative oncology group. J Clin Oncol 27:3778–3785PubMedCrossRefGoogle Scholar
  8. 8.
    Colucci G, Labianca R, Di Costanzo F et al (2010) Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28:1645–1651PubMedCrossRefGoogle Scholar
  9. 9.
    Sultana A, Tudur Smith C, Cunningham D et al (2008) Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol 25:2607–2615CrossRefGoogle Scholar
  10. 10.
    Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  11. 11.
    Sobrero A, Bruzzi P (2009) Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval. J Clin Oncol 27:5868–5873PubMedCrossRefGoogle Scholar
  12. 12.
    Reni M, Passoni P, Panucci MG et al (2001) Definitive results of phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol 19:2679–2686PubMedGoogle Scholar
  13. 13.
    Reni M, Cordio S, Milandri C et al (2005) Gemcitabine versus cisplatin, epirubicin, 5-fluorouracil, gemcitabine in advanced pancreatic cancer: a phase III trial. Lancet Oncol 6:369–376PubMedCrossRefGoogle Scholar
  14. 14.
    Reni M, Bonetto E, Cordio S et al (2006) Quality of life assessment in advanced pancreatic adenocarcinoma: results from a phase III randomized trial. Pancreatology 6:454–463PubMedCrossRefGoogle Scholar
  15. 15.
    Reni M, Cereda S, Bonetto E et al (2007) Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma: a dose-finding study. Cancer Invest 25:594–598PubMedCrossRefGoogle Scholar
  16. 16.
    Reni M, Cereda S, Bonetto E et al (2007) Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma. Cancer Chemother Pharmacol 59:361–367PubMedCrossRefGoogle Scholar
  17. 17.
    Cunningham D, Starling N, Rao S et al (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46PubMedCrossRefGoogle Scholar
  18. 18.
    Lenzi R, Yalcin S, Evans DB et al (2002) Phase II study of docetaxel in patients with pancreatic cancer previously untreated with cytotoxic chemotherapy. Cancer Invest 20:464–472PubMedCrossRefGoogle Scholar
  19. 19.
    Androulakis N, Kourosis C, Dimopoulos MA et al (1999) Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: a multicenter phase II study. J Clin Oncol 17:1779–1785PubMedGoogle Scholar
  20. 20.
    Venturini M, Durando A, Garrone O et al (2003) Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated, advanced breast carcinoma. Cancer 97:1174–1180PubMedCrossRefGoogle Scholar
  21. 21.
    Alexopoulos A, Karamouzis MV, Rigatos G et al (2004) In vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer: general concepts and future perspectives. Semin Oncol 2:25–30CrossRefGoogle Scholar
  22. 22.
    Rigas JR (2004) Taxane-platinum combinations in advanced non-small cell lung cancer: a review. Oncologist 9:16–23PubMedCrossRefGoogle Scholar
  23. 23.
    Sawada N, Ishikawa T, Fukase Y et al (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019PubMedGoogle Scholar
  24. 24.
    Ricotti L, Tesei A, De Paola F et al (2003) In vitro schedule-dependent interaction between docetaxel and gemcitabine in human gastric cancer cell lines. Clin Cancer Res 9:900–905PubMedGoogle Scholar
  25. 25.
    Maeda S, Sugiura T, Saikawa Y et al (2004) Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism. Cancer Sci 95:679–684PubMedCrossRefGoogle Scholar
  26. 26.
    Greene FL, Page D, Fleming ID et al (eds) (2002) Exocrine pancreas. In: AJCC cancer staging manual, 6th edn. Springer, New York, pp 157–164Google Scholar
  27. 27.
    Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247PubMedCrossRefGoogle Scholar
  28. 28.
    Ajani JA, Welch SR, Raber MN et al (1990) Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 8:147–159PubMedCrossRefGoogle Scholar
  29. 29.
    Reni M, Cereda S, Balzano G et al (2009) Carbohydrate antigen (CA)19–9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 115:2630–2639PubMedCrossRefGoogle Scholar
  30. 30.
    Kulke MH, Tempero MA, Niedzwiecki D et al (2009) Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with Cisplatin, Docetaxel, or Irinotecan in patients with metastatic pancreatic cancer: CALGB 89904. J Clin Oncol 27:5506–5512PubMedCrossRefGoogle Scholar
  31. 31.
    Lutz MP, Van Cutsem E, Wagener T et al (2005) Docetaxel Plus Gemcitabine or Docetaxel Plus Cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European organisation for research and treatment of cancer gastrointestinal group. J Clin Oncol 23:9250–9256PubMedCrossRefGoogle Scholar
  32. 32.
    Cascinu S, Gasparini G, Catalano V et al (1999) A phase I–II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian group for the study of digestive tract cancer (GISCAD). Ann Oncol 10:1377–1379PubMedCrossRefGoogle Scholar
  33. 33.
    Fine RL, Fogelman DR, Schreibman SM et al (2008) The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 61:167–175PubMedCrossRefGoogle Scholar
  34. 34.
    Hess V, Pratsch S, Potthast S et al (2010) Combining gemcitabine, oxaliplatin and capecitabine (GEMOXEL) for patients with advanced pancreatic carcinoma (APC): a phase I/II trial. Ann Oncol 21:2390–2395PubMedCrossRefGoogle Scholar
  35. 35.
    Boeck S, Hoehler T, Seipelt G et al (2008) Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Ann Oncol 19:340–347PubMedCrossRefGoogle Scholar
  36. 36.
    Conroy T, Desseigne F, Ychou M et al (2010) Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. Proc Am Soc Clin Oncol 28:abstr 4010Google Scholar
  37. 37.
    Cantore M, Fiorentini G, Luppi G et al (2004) Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective randomized phase III trial of the Italian society for integrated locoregional therapy in oncology. J Chemother 16:34–39Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Michele Reni
    • 1
  • Stefano Cereda
    • 1
  • Alessia Rognone
    • 1
  • Carmen Belli
    • 1
  • Michele Ghidini
    • 1
  • Simonetta Longoni
    • 1
  • Clara Fugazza
    • 1
  • Sara Rezzonico
    • 1
  • Paolo Passoni
    • 2
  • Najla Slim
    • 2
  • Giampaolo Balzano
    • 3
  • Roberto Nicoletti
    • 4
  • Stefano Cappio
    • 4
  • Claudio Doglioni
    • 5
  • Eugenio Villa
    • 1
  1. 1.Department of OncologySan Raffaele Scientific InstituteMilanItaly
  2. 2.Department of RadiotherapySan Raffaele Scientific InstituteMilanItaly
  3. 3.Department of SurgerySan Raffaele Scientific InstituteMilanItaly
  4. 4.Department of RadiologySan Raffaele Scientific InstituteMilanItaly
  5. 5.Department of PathologySan Raffaele Scientific InstituteMilanItaly

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