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An Overview of Clinical Trials of Targeted Therapies in Pancreatic Cancer

  • Bassel El-Rayes
Part of the M. D. Anderson Solid Tumor Oncology Series book series (MDA)

Pancreatic cancer is the fourth leading cause of cancer mortality in the United States (1). Over 75% of patients with pancreatic cancer have locally advanced or metastatic disease at diagnosis (2). The median survival of patients with metastatic and locally advanced pancreatic cancer is 3–6 months and 8–10 months, respectively. The only potentially curative treatment is surgical resection. Patients who undergo a potentially curative resection have a median survival of 14–20 months and <20% are long-term survivors because of the development of metastatic disease. Therefore, improvement in the outcome of patients with pancreatic cancer is dependent on the development of more effective systemic therapies.

Gemcitabine is considered the standard chemotherapy in advanced pancreatic cancer. The response rate, median survival and 1-year survival in patients with advanced pancreatic cancer treated with gemcitabine in the pivotal trial were 5.4%, 5.6 months, and 18%, respectively ( 3 ). Combination chemotherapy did not demonstrate any significant survival advantage in randomized trials as compared with single-agent gemcitabine ( 4, 5). In the adjuvant setting, gemcitabine has been shown to be superior to observation ( 6) or 5-fluorouracil ( 7 ). Therefore, the impact of cytotoxic chemotherapy in pancreatic cancer has been at best modest. Nevertheless, most of the new drug development using targeted agents has been based on a gemcitabine platform.

Fundamental processes associated with carcinogenesis include molecular aberrations involving cell cycle control, signal transduction, apoptosis, angiogenesis, and invasion. The identification of agents that target these abnormalities offers an opportunity for the development of effective and selective systemic treatments for pancreatic cancer. Unfortunately, recently conducted clinical trials evaluating the role of novel targeted therapies in pancreatic cancer have demonstrated somewhat disappointing results (Table 33.1 ). This chapter reviews the clinical studies that have been undertaken in patients with pancreatic cancer using targeted agents.

Keywords

Epidermal Growth Factor Receptor Clin Oncol Pancreatic Cancer Cell Pancreatic Cancer Cell Line Advanced Pancreatic Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 0.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. Cancer 2007, 57:43–66.Google Scholar
  2. 2.
    E l-Rayes BF, Philip PA. A review of systemic therapy for advanced pancreatic cancer. Clin Adv Hematol Oncol 2003, 1:430–434.Google Scholar
  3. 3.
    Burris HA 3rd Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer: a randomized trial. J Clin Oncol 1997, 15:2403–2413.PubMedGoogle Scholar
  4. 4.
    Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or meta-static pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004, 22: 3776–3783.CrossRefPubMedGoogle Scholar
  5. 5.
    Louvet C, Labianca R, Hammel P, et al. 2005, Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516.CrossRefPubMedGoogle Scholar
  6. 6.
    Oettle H, Post S, Neuhaus P, et al. 2007, Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297:267–277.CrossRefPubMedGoogle Scholar
  7. 7. Regine W, Winter W, Abrams R. RTOG 9704 a phase III study of adjuvant pre and post chemoradiation 5-FU vs. gemcitabine for resected pancreatic cancer. ASCO 2006.Google Scholar
  8. 8.
    Koshiba T, Hosotani R, Wada M, et al. 1998, Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer 82:642–650.CrossRefPubMedGoogle Scholar
  9. 9.
    Bramhall SR. 1997, The matrix metalloproteinases and their inhibitors in pancreatic cancer. From molecular science to a clinical application. Int J Pancreatol 21:1–12.PubMedGoogle Scholar
  10. 10.
    Watson SA, Morris TM, Robinson G, et al. 1995, Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. Cancer Res 55:3629–3633.PubMedGoogle Scholar
  11. 11.
    Chirivi RG, Garofalo A, Crimmin MJ, et al. 1994, I nhibition of the metastatic spread and growth of B16-BL6 murine melanoma by a synthetic matrix metalloproteinase inhibitor. Int J Cancer 58:460–464.CrossRefPubMedGoogle Scholar
  12. 12.
    Bramhall SR, Rosemurgy A, Brown PD, et al. 2001, Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19: 3447–3455.PubMedGoogle Scholar
  13. 13.
    Bramhall SR, Schulz J, Nemunaitis J, et al. 2002, A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161–167.CrossRefPubMedGoogle Scholar
  14. 14.
    Moore MJ, Hamm J, Dancey J, et al. 2003, Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296–3302.CrossRefPubMedGoogle Scholar
  15. 15.
    Williams CS, Mann M, DuBois RN. 1999, The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916.CrossRefPubMedGoogle Scholar
  16. 16.
    Molina MA, Sitja-Arnau M, Lemoine MG, et al. 1999, Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 59:4356–4362.PubMedGoogle Scholar
  17. 17.
    Merati K, Said Siadaty M, Andea A, et al. 2001, Expression of inflammatory modulator COX-2 in pancreatic ductal adenocarcinoma and its relationship to pathologic and clinical parameters. Amer J Clin Oncol 24:447–452.CrossRefGoogle Scholar
  18. 18.
    Yip-Schneider MT, Barnard DS, Billings SD, et al. 2000, Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 21:139–146.CrossRefPubMedGoogle Scholar
  19. 19.
    Li M, Wu X, Xu XC. 2001, Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway. Clin Cancer Res 7:1010–1016.PubMedGoogle Scholar
  20. 20.
    El-Rayes BF, Ali S, Sarkar FH, et al. 2004, Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines. Mol Cancer Ther 3:1421–1426.PubMedGoogle Scholar
  21. 21.
    El-Rayes BF, Zalupski MM, Shields AF, et al. 2005, A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer. Invest New Drugs 23: 583–590.CrossRefPubMedGoogle Scholar
  22. 22. Smith E, Burris H, Loehrer P, et al. Preliminary report of a phase II trial of gemcitabine combined with celecoxib for advanced pancreatic cancer. ASCO 2003.Google Scholar
  23. 23.
    Adams J, Kauffman M. 2004, Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22:304–311.CrossRefPubMedGoogle Scholar
  24. 24.
    Teicher BA, Ara G, Herbst R, et al. 1999, The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645.PubMedGoogle Scholar
  25. 25.
    Adams J, Palombella VJ, Sausville EA, et al. 1999, Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622.PubMedGoogle Scholar
  26. 26.
    Wang W, Abbruzzese JL, Evans DB, et al. 1999, The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5:119–127.PubMedGoogle Scholar
  27. 27.
    Chandler NM, Canete JJ, Callery MP, 2004, Increased expression of NF-kappa B subunits in human pancreatic cancer cells. J Surg Res 118:9–14.CrossRefPubMedGoogle Scholar
  28. 28.
    Bold RJ, Virudachalam S, McConkey DJ, 2001, Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res 100:11–17.CrossRefPubMedGoogle Scholar
  29. 29.
    Nawrocki ST, Bruns CJ, Harbison MT, et al. 2002, Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 1:1243–1253.PubMedGoogle Scholar
  30. 30.
    Alberts SR, Foster NR, Morton RF, et al. 2005, PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol 16:1654–1661.CrossRefPubMedGoogle Scholar
  31. 31.
    Korc M. 2003, Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2: 8.CrossRefPubMedGoogle Scholar
  32. 32.
    Bergers G, Benjamin LE. 2003, Tumorigenesis and the angiogenic switch. Nat Rev 3: 401–410.Google Scholar
  33. 33.
    Cherrington JM, Strawn LM, Shawver LK. 2000, New paradigms for the treatment of cancer: the role of anti-angiogenesis agents. Adv Cancer Res 79:1–38.CrossRefPubMedGoogle Scholar
  34. 34.
    Ikeda N, Adachi M, Taki T, et al. 1999, Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 9:1553–1563.CrossRefGoogle Scholar
  35. 35.
    Luo J, Guo P, Matsuda K, et al. 2001, Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo. Int J Cancer 92: 361–369.CrossRefPubMedGoogle Scholar
  36. 36.
    Knoll MR, Rudnitzki D, Sturm J, et al. 2001, Correlation of postoperative survival and angiogenic growth factors in pancreatic carcinoma. Hepato-gastroenterology 48:1162–1165.PubMedGoogle Scholar
  37. 37.
    Bruns CJ, Shrader M, Harbison MT, et al. 2002, Effect of the vascular endothelial growth fac-tor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer 102:101–108.CrossRefPubMedGoogle Scholar
  38. 38.
    Kindler HL, Friberg G, Singh DA, et al. 2005, Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23: 8033–8040.CrossRefPubMedGoogle Scholar
  39. 39. Kindler H, Niedzwiecki D, Hollis D, et al. A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB). ASCO 2007.Google Scholar
  40. 40.
    Rebollo A, Martinez AC, 1999, Ras proteins: recent advances and new functions. Blood 94:2971–2980.PubMedGoogle Scholar
  41. 41.
    Bollag G, McCormick F, 1991, Regulators and effectors of ras proteins. Annu Rev Cell Biol 7:601–632.CrossRefPubMedGoogle Scholar
  42. 42.
    Bos JL. 1989, ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689.PubMedGoogle Scholar
  43. 43.
    Leonard DM. 1997, Ras farnesyltransferase: a new therapeutic target. J Med Chem 40: 2971–2990.CrossRefPubMedGoogle Scholar
  44. 44.
    Seufferlein T, Van Lint J, Liptay S, et al. 1999, Transforming growth factor alpha activates Ha-Ras in human pancreatic cancer cells with Ki-ras mutations. Gastroenterology 116: 1441–1452.CrossRefPubMedGoogle Scholar
  45. 45.
    End DW, Smets G, Todd AV, et al. 2001, Characterization of the antitumor effects of the selec-tive farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131–137.PubMedGoogle Scholar
  46. 46.
    Van Cutsem E, van de Velde H, Karasek P, et al. 2004, Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430–1438.CrossRefPubMedGoogle Scholar
  47. 47.
    Alberts SR, Schroeder M, Erlichman C, et al. 2004, Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J Clin Oncol 22:4944–4950.CrossRefPubMedGoogle Scholar
  48. 48.
    El-Rayes BF, LoRusso PM, 2004, Targeting the epidermal growth factor receptor. Br J Cancer 91:418–424.CrossRefPubMedGoogle Scholar
  49. 49.
    Perugini RA, McDade TP, Vittimberga FJ Jr, et al. 2000, Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J Surg Res 90:39–44.CrossRefPubMedGoogle Scholar
  50. 50.
    Wagner M, Cao T, Lopez ME, et al. 1996, Expression of a truncated EGF receptor is associated with inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum. Int J Cancer 68:782–787.CrossRefPubMedGoogle Scholar
  51. 51.
    Yamanaka Y, Friess H, Kobrin MS, et al. 1993, Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 13:565–569.PubMedGoogle Scholar
  52. 52.
    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 25:1960–1966.CrossRefPubMedGoogle Scholar
  53. 53.
    Bruns CJ, Harbison MT, Davis DW, et al. 2000, Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 6:1936–1948.PubMedGoogle Scholar
  54. 54.
    Xiong HQ, Rosenberg A, LoBuglio A, et al. 2004, Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol 22: 2610–2616.CrossRefPubMedGoogle Scholar
  55. 55. Philip PAJ, Fenoglio-Preiser C, Zalupski M, et al. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. ASCO 2007.Google Scholar

Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Bassel El-Rayes
    • 1
  1. 1.Karmanos Cancer CenterWayne State UniversityDetroitUSA

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