Investigational New Drugs

, Volume 31, Issue 6, pp 1573–1579

Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A gemcad study

  • M. Martin-Richard
  • R. Gallego
  • C. Pericay
  • J. Garcia Foncillas
  • B. Queralt
  • E. Casado
  • J. Barriuso
  • V. Iranzo
  • I. Juez
  • L. Visa
  • E. Saigi
  • A. Barnadas
  • X. Garcia-Albeniz
  • J. Maurel
PHASE II STUDIES

Summary

Background Cisplatin and fluoropyrimidine (CF) are standard first- line treatment in advanced gastric cancer, but no second-line treatment has yet been established. We present a phase II study in which we evaluated the efficacy and toxicity of the combination of Sorafenib (S), and Oxaliplatin as second-line therapy. Methods Patients with progressive gastric adenocarcinoma after CF- first-line, ECOG 0–2, and measurable disease were included. The primary objective was PFS. Treatment doses were Oxaliplatin 130 mg/m2/3 weeks and Sorafenib 800 mg/bid/d. Results We included 40 patients. CR was 2.5 % and SD was 47.2 %. Grade 3–4 toxic effects were neutropenia (9.8 %), thrombocytopenia (7.3 %), neurotoxicity (4.9 %) and diarrhea (4.9 %). Median PFS was 3 months (95 %CI: 2.3–4.1) and median OS was 6.5 months (95 % CI: 5.2–9.6). Time to progression (TTP) to first line therapy was a prognosis factor. Median OS was 9.7 months when time-to-progression during first-line chemotherapy was >6 months and 5.6 m when it was <6 months (p = 0.04). Conclusions Time-to-progression under a CF-based first-line therapy determines subgroups of GC patients with different prognosis. The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF appears safe, but our results do not support the implementation of a phase III trial.

Keywords

Advanced gastric adenocarcinoma Second-line treatment Antitarget therapies Oxaliplatin Sorafenib 

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62:10–29CrossRefPubMedGoogle Scholar
  2. 2.
    Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO et al (1997) Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8:163–168CrossRefPubMedGoogle Scholar
  3. 3.
    Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587–591PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Jo JC, Lee JL, Ryu MH, Sym SJ, Lee SS et al (2007) Docetaxel monotherapy as a second-line treatment after failure of fluoropyrimidine and platinum in advanced gastric cancer: experience of 154 patients with prognostic factor analysis. Jpn J Clin Oncol 37:936–941CrossRefPubMedGoogle Scholar
  5. 5.
    Baize N, Abakar-Mahamat A, Mounier N, Berthier F, Caroli-Bosc FX (2009) Phase II study of paclitaxel combined with capecitabine as second-line treatment for advanced gastric carcinoma after failure of cisplatin-based regimens. Cancer Chemother Pharmacol 64:549–555CrossRefPubMedGoogle Scholar
  6. 6.
    Kunisaki C, Imada T, Yamada R, Hatori S, Ono H et al (2005) Phase II study of docetaxel plus cisplatin as a second-line combined therapy in patients with advanced gastric carcinoma. Anticancer Res 25:2973–2977PubMedGoogle Scholar
  7. 7.
    Sun Q, Hang M, Xu W, Mao W, Hang X et al (2009) Irinotecan plus capecitabine as a second-line treatment after failure of 5-fluorouracil and platinum in patients with advanced gastric cancer. Jpn J Clin Oncol 39:791–796CrossRefPubMedGoogle Scholar
  8. 8.
    Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103PubMedGoogle Scholar
  9. 9.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
  10. 10.
    Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597CrossRefPubMedGoogle Scholar
  11. 11.
    Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L et al (2009) Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 27:4454–4461CrossRefPubMedGoogle Scholar
  12. 12.
    Liang B, Wang S, Zhu XG, Yu YX, Cui ZR et al (2005) Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. World J Gastroenterol 11:623–628PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G et al (2002) Circulating VEGF levels in the serum of gastric cancer patients: correlation with pathological variables, patient survival, and tumor surgery. Ann Surg 236:37–42PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Juttner S, Wissmann C, Jons T, Vieth M, Hertel J et al (2006) Vascular endothelial growth factor-D and its receptor VEGFR-3: two novel independent prognostic markers in gastric adenocarcinoma. J Clin Oncol 24:228–240CrossRefPubMedGoogle Scholar
  15. 15.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefPubMedGoogle Scholar
  16. 16.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134CrossRefPubMedGoogle Scholar
  17. 17.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M et al (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46CrossRefPubMedGoogle Scholar
  18. 18.
    Soulie P, Bensmaine A, Garrino C, Chollet P, Brain E et al (1997) Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer. Eur J Cancer 33:1400–1406CrossRefPubMedGoogle Scholar
  19. 19.
    Maurel J, Cervantes A, Conill C, Salazar R, Martin-Richard M et al (2005) Phase I trial of oxaliplatin in combination with cisplatin, protacted-infusion fluorouracil, and radiotherapy in advanced esophageal and gastroesophageal carcinoma. Int J Radiat Oncol Biol Phys 62:91–96CrossRefPubMedGoogle Scholar
  20. 20.
    Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K et al (2005) Results of a phase I trial of sorafenib (BAY 43–9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer. Clin Colorectal Cancer 5:188–196CrossRefPubMedGoogle Scholar
  21. 21.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
  22. 22.
    Kim DY, Kim JH, Lee SH, Kim TY, Heo DS et al (2003) Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer. Ann Oncol 14:383–387CrossRefPubMedGoogle Scholar
  23. 23.
    Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ et al (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360:563–572CrossRefPubMedGoogle Scholar
  24. 24.
    Schmoll HJ, Cartwright T, Tabernero J, Nowacki MP, Figer A et al (2007) Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 25:102–109CrossRefPubMedGoogle Scholar
  25. 25.
    Jeong J, Jeung HC, Rha SY, Im CK, Shin SJ et al (2008) Phase II study of combination chemotherapy of 5-fluorouracil, low-dose leucovorin, and oxaliplatin (FLOX regimen) in pretreated advanced gastric cancer. Ann Oncol 19:1135–1140CrossRefPubMedGoogle Scholar
  26. 26.
    Kim C, Lee JL, Choi YH, Kang BW, Ryu MH et al (2012) Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. Investig New Drugs 30:306–315CrossRefGoogle Scholar
  27. 27.
    Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, et al. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol 28:2947–2951Google Scholar
  28. 28.
    Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29:3968–3976Google Scholar
  29. 29.
    Tabernero J (2013) REGARD Phase 3, randomized trial of Ramucirumab in patinets with metastatic Gastric or GEj adenocarcinoma following progression on first.ine chemotherapy. Ann Oncol 24:iv11–iv24Google Scholar
  30. 30.
    Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 47:2306–2314Google Scholar
  31. 31.
    Kang JH, Lee SI, Lim do H, Park KW, Oh SY, et al. Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone. J Clin Oncol 30:1513–1518Google Scholar
  32. 32.
    Bohanes P, Courvoisier DS, Perneger TV, Morel P, Huber O, et al. Survival predictors for second-line chemotherapy in Caucasian patients with metastatic gastric cancer. Swiss Med Wkly 141:w13249Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • M. Martin-Richard
    • 1
  • R. Gallego
    • 2
  • C. Pericay
    • 3
  • J. Garcia Foncillas
    • 4
  • B. Queralt
    • 5
  • E. Casado
    • 6
  • J. Barriuso
    • 7
  • V. Iranzo
    • 8
  • I. Juez
    • 9
  • L. Visa
    • 2
  • E. Saigi
    • 3
  • A. Barnadas
    • 1
  • X. Garcia-Albeniz
    • 10
  • J. Maurel
    • 2
  1. 1.Department of Medical OncologyHospital de la Santa Creu I Sant PauBarcelonaSpain
  2. 2.Department of Medical OncologyHospital ClinicBarcelonaSpain
  3. 3.Department of Medical OncologyCOrporación Parc TauliBarcelonaSpain
  4. 4.Department of Medical OncologyClínica Universitaria de NavarraPamplonaSpain
  5. 5.Department of Medical OncologyHospital Josep TruetaGironaSpain
  6. 6.Department of Medical OncologyFundación AlthaiaBarcelonaSpain
  7. 7.Department of Medical OncologyHospital La PazMadridSpain
  8. 8.Department of Medical OncologyHospital GeneralValenciaSpain
  9. 9.MD AndersonMadridSpain
  10. 10.Department of EpidemiologyHarvard School of Public HealthBostonUSA

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