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Metastatic Pancreatic Cancer: Systemic Therapy

  • Jennifer Brown
  • T. R. Jeffry Evans
Chapter
Part of the Medical Radiology book series (MEDRAD)

Abstract

Infiltrating ductal adenocarcinoma of the pancreas has an aggressive nature. Approximately 90% of patients have surgically unresectable disease at the time of diagnosis. In addition, the majority of the selected patients who undergo potentially curative resection for small, localised lesions inevitably develop recurrent or metastatic disease. Most systemic therapies have limited efficacy in patients with metastatic disease. Gemcitabine, with or without erlotinib, has modest clinical benefit and a marginal survival advantage in patients with metastatic pancreatic cancer and has become a standard of care for these patients. However, the median survival of patients with metastatic pancreatic cancer remains poor and is less than 6 months. This chapter gives an overview of the various monotherapy and combination chemotherapy regimens that have been evaluated in this disease, discusses the studies which have incorporated molecularly targeted agents into the treatment regimens, and highlights the challenges in developing therapeutic strategies to improve survival in metastatic pancreatic cancer.

Keywords

Pancreatic Cancer Objective Response Rate Pancreatic Ductal Adenocarcinoma Advanced Pancreatic Cancer Metastatic 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.

References

  1. Alberts SR, Townley PM, Goldberg RM et al (2002) Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group Phase I study. Ann Oncol 13:553–557PubMedCrossRefGoogle Scholar
  2. Alberts SR, Townley PM, Goldberg RM et al (2003) Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study. Ann Oncol 14:580–585PubMedCrossRefGoogle Scholar
  3. Almoguerra C, Shibata D, Forrester K et al (1998) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554CrossRefGoogle Scholar
  4. Baker CH, Solorzano CC, Fidler IJ (2002) Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res 62:1996–2003PubMedGoogle Scholar
  5. Barone C, Cassano A, Corsi DC et al (2003) Weekly gemcitabine and 24-hour infusional 5-fluorouracil in advanced pancreatic cancer: a phase I–II study. Oncology 64:139–145PubMedCrossRefGoogle Scholar
  6. 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
  7. Bernard S, Noble S, Wilcosky T et al (1986) A phase II study of ifosfamide (IFOS) plus N-acetyl cysteine (NAC) in metastatic measurable pancreatic adenocarcinoma (abstract). Proc Am Soc Clin Oncol 5:328Google Scholar
  8. Bockhorn M, Hsuzuki Y, Xu L et al (2003) Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. Clin Cancer Res 9:4221–4226PubMedGoogle Scholar
  9. Bruns CJ, Solorzano CC, Harbison MT et al (2000) Blockade of the epidermal growth factor receptor signalling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:2926–2935PubMedGoogle Scholar
  10. Bruns CJ, Shrader M, Harbison MT et al (2002) Effect of the vascular endothelial growth factor receptor-2 antibody DC-101 plus gemcitabine on growth, metastasis, and angiogenesis of human pancreatic cancer growing orthotopically in nude mice. Int J Cancer 102:101–108PubMedCrossRefGoogle Scholar
  11. Buroker T, Kim PN, Groppe C et al (1979) 5-FU infusion with mitomycin C versus 5-FU infusion with methyl CCNU in the treatment of advanced upper gastrointestinal cancer. Cancer 44:1215–1221PubMedCrossRefGoogle Scholar
  12. Burris HA, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomised trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  13. Carter SK (1975) The integration of chemotherapy into a combined modality approach for cancer treatment: VI. Pancreatic adenocarcinoma. Cancer Treat Rev 3:193–214CrossRefGoogle Scholar
  14. Cartwright TH, Cohn A, Varkey JA et al (2002) Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 20:160–164PubMedCrossRefGoogle Scholar
  15. Cascinu S, Labianca R, Catalano V et al (2003) Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GESCAD). Ann Oncol 14:205–208PubMedCrossRefGoogle Scholar
  16. Casper ES, Green MR, Kelsen DP et al (1994) Phase II trial of gemcitabine (2′2-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 12:29–34PubMedCrossRefGoogle Scholar
  17. Colucci G, Guiliani F, Gebbia V et al (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomised phase III study of the Gruppo Oncoliga del’Italia Meridionale. Cancer 94:902–910PubMedCrossRefGoogle Scholar
  18. Correale P, Messinese S, Marsili S et al (2003) A novel bi weekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid. Br J Cancer 89:239–242PubMedCentralPubMedCrossRefGoogle Scholar
  19. Corrie P, Mayer A, Shaw J et al (2002) Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients. Br J Cancer 87:716–719PubMedCentralPubMedCrossRefGoogle Scholar
  20. Cubilla AL, Fitzgerald PJ (1975) Morphological patterns of primary nonendocrine human pancreas carcinoma. Cancer Res 35:2234–2248PubMedGoogle Scholar
  21. Cubilla AL, Fitzgerald PJ (1976) Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36:2690–2698PubMedGoogle Scholar
  22. Cunningham D, Chau I, Stocken D et al (2005). Phase III randomised comaprison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. Eur J Cancer Suppl 3:4(abstract 4)Google Scholar
  23. El-Rayes BF, Zalupski MM, Shields AF et al (2003) Phase II study of gemcitabine, cisplatin and infusional fluorouracil in advanced pancreatic cancer. J Clin Oncol 21:2920–2925PubMedCrossRefGoogle Scholar
  24. Evans TRJ, Lofts FJ, Mansi JL et al (1996) A phase II study of continuous-infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer. Br J Cancer 73:1260–1264PubMedCentralPubMedCrossRefGoogle Scholar
  25. Feliu J, Mel R, Borrega P et al (2003) Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas. Ann Oncol 13:1756–1762CrossRefGoogle Scholar
  26. Fjallskog MLH, Lejonklou MH, Oberg KE et al (2003) Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res 9:1469–1473PubMedGoogle Scholar
  27. Ghandi V, Plunkett W (1990) Modulatory activity of 2′2′-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res 50:3675–3680Google Scholar
  28. Grindey GB, Hertel LW, Plunkett W (1990) Cytotoxicity and anti-tumour activity of 2′2′-difluorodeoxycytidine (Gemcitabine). Cancer Invest 8:313–318PubMedCrossRefGoogle Scholar
  29. Hausen R, Quebbman E, Ritch P et al (1988) Continous 5-fluorouracil infusion in carcinoma of the pancreas. Am J Med Sci 295:91–93CrossRefGoogle Scholar
  30. Heinemann V, Hertel L, Grindey GB (1988) Comparison of the cellular pharmacokinetics and toxicity of 2′2′-difluorodeoxycytidine and 1-b-D-arabinofuranasyl cytosine. Cancer Res 48:4024–4031PubMedGoogle Scholar
  31. 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
  32. Hertel W, Boder GB, Kroin JS et al (1990) Evaluation of the anti-tumour activity of gemcitabine (2′2′-difluorodeoxycytidine). Cancer Res 50:4417–4422PubMedGoogle Scholar
  33. Hess V, Salzberg M, Borner M et al (2003) Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase I/II trial. J Clin Oncol 21:66–68PubMedCrossRefGoogle Scholar
  34. Hingorani SR, Petricoin EF, Maitra A et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–449PubMedCrossRefGoogle Scholar
  35. Hingorani SR, Wang L, Multani AS et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483PubMedCrossRefGoogle Scholar
  36. Hruban RH, Goggins M, Parsons J et al (2000a) Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972PubMedGoogle Scholar
  37. Hruban RH, Wilentz RE, Kern SE (2000b) Genetic progression in the pancreatic ducts. Am J Pathol 156:1821–1825PubMedCentralPubMedCrossRefGoogle Scholar
  38. Huang P, Chubb S, Hertel W et al (1991) Action of 2′2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51:6110–6117PubMedGoogle Scholar
  39. Ianniello GP, Orditura M, Rossi A et al (2001) Gemcitabine plus epirubicin in advanced pancreatic cancer: a phase II multicenter trial. Oncol Rep 8:1111–1115PubMedGoogle Scholar
  40. Itakura J, Ishiwata T, Shen B et al (2000) Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer 85:27–34PubMedCrossRefGoogle Scholar
  41. Kanat O, Eurensel T, Kurt E et al (2004) Treatment of metastatic pancreatic cancer with a combination of gemcitabine and 5-fluorouracil: a single center phase II study. Tumori 90:192–195PubMedGoogle Scholar
  42. Kern S, Hruban R, Hollingsworth MA et al (2001) A white paper: the product of a pancreas cancer think tank. Cancer Res 61:4923–4932PubMedGoogle Scholar
  43. Kim TW, Kang HJ, Ahn JH et al (2002) Phase II study of gemcitabine, UFT and leucovorin in patients with advanced pancreatic cancer. Acta Oncol 41:689–694PubMedCrossRefGoogle Scholar
  44. 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 23:8033–8040PubMedCrossRefGoogle Scholar
  45. Kindler HL, Niedzwiecki D, Hollis D et al (2007) 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). J Clin Oncol 25:18s(abstact 4508)Google Scholar
  46. Klimstra DS, Longnecker DS (1994) K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 145:1547–1550PubMedCentralPubMedGoogle Scholar
  47. Kovach JS, Moertel CG, Schuft AJ et al (1974) A controlled study of combined 1, 3-bio(2-chlorethyl)-1-nitrosurea and 5-fluorouracil therapy for advanced gastric and pancreatic cancer. Cancer 33:563–567PubMedCrossRefGoogle Scholar
  48. Kozuch P, Grossbard ML, Barzdins A et al (2001) Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and non cross-resistant treatment for chemotherapy refractory metastatic pancreatic cancer. Oncologist 6:488–495PubMedCrossRefGoogle Scholar
  49. Kralidis E, Aebi S, Friess H et al (2003) Activity of raltitrexed and gemcitabine in advanced pancreatic cancer. Ann Oncol 14:574–579PubMedCrossRefGoogle Scholar
  50. Lee J, Park JO, Kim WS et al (2004) Phase II study of gemcitabine combination with uracil – tegafur in metastatic pancreatic cancer. Oncology 66:32–37PubMedCrossRefGoogle Scholar
  51. Li D, Xie K, Wolff R et al (2004) Pancreatic cancer. Lancet 363:1049–1057PubMedCrossRefGoogle Scholar
  52. Louvet C, Andre T, Hammel P et al (2001) Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM). Ann Oncol 12:675–679PubMedCrossRefGoogle Scholar
  53. Louvet C, Andre T, Lledo G et al (2002) Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study. J Clin Oncol 20:1512–1518PubMedCrossRefGoogle Scholar
  54. 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 GISCARD phase III trial. J Clin Oncol 23:3509–3516PubMedCrossRefGoogle Scholar
  55. 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 92:361–369PubMedCrossRefGoogle Scholar
  56. Mallinson GN, Rake MO, Cocking JB et al (1980) Chemotherapy in pancreatic cancer: results of a controlled, prospective, randomised, multicentre trial. Br Med J 281:1589–1591PubMedCentralPubMedCrossRefGoogle Scholar
  57. Marantz A, Jovtis S, Almira E et al (2001) Phase II study of gemcitabine, 5-fluorouracil, and leucovorin in patients with pancreatic cancer. Semin Oncol 28:44–49PubMedCrossRefGoogle Scholar
  58. Moertel CG (1976) Chemotherapy for gastrointestinal cancer. Clin Gastroenterol 5:777–793PubMedGoogle Scholar
  59. 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
  60. Murad AM, Guimaeres RC, Aragao BC et al (2003) Phase II trial of the use of gemcitabine and 5-fluorouracil in the treatment of advanced pancreatic and biliary tract cancer. Am J Clin Oncol 26:151–154PubMedCrossRefGoogle Scholar
  61. Neoptolemos JP, Stocken DD, Freiss H et al (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200–1210PubMedCrossRefGoogle Scholar
  62. Neri B, Cini G, Doni L et al (2002) Weekly gemcitabine plus epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study. Br J Cancer 87:497–501PubMedCentralPubMedCrossRefGoogle Scholar
  63. Ng SSW, Tsao MS, Nicklee T et al (2002) Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signalling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Ther 1:777–783PubMedGoogle Scholar
  64. Novarino A, Chiappino I, Bertelli GF et al (2004) Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer. Ann Oncol 15:474–477PubMedCrossRefGoogle Scholar
  65. Oettle H, Richards D, Ramanathan R et al (2005) A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 16:1639–1645PubMedCrossRefGoogle Scholar
  66. Oster MW, Gray R, Panasci L et al (1986) Chemotherapy for advanced pancreatic cancer: A comparison of 5-fluorouracil, adriamycin and mitomycin C (FAM) with 5-fluorouracil, streptozotcin and mitomycin C (FSM). Cancer 57:29–33PubMedCrossRefGoogle Scholar
  67. Palmer KR, Kerr M, Knowles G et al (1994) Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Surg 81:882–885PubMedCrossRefGoogle Scholar
  68. Petty RD, Nicolson MC, Skaria S et al (2003) A phase II study of mitomycin-C, cisplatin and protracted infusional 5-fluorouracil in advanced pancreatic carcinoma: efficacy and low toxicity. Ann Oncol 14:1100–1105PubMedCrossRefGoogle Scholar
  69. Philip PA, Zalupski MM, Vaitkevicius VK et al (2001) Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma. Cancer 92:569–577PubMedCrossRefGoogle Scholar
  70. Philip PA, Benedetti C, Fenoglio-Preiser M et al (2007) 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. J Clin Oncol 25:18s(absract 4509)Google Scholar
  71. Rachamalla R, Malamud S, Grossbard ML et al (2004) Phase I dose-finding study of biweekly irinotecan in combination with fixed doses of 5-fluorouracil/leucovorin, gemcitabine and cisplatin (G-FLIP) in patients with advanced pancreatic cancer or other solid tumors. Anticancer Drugs 15:211–217PubMedCrossRefGoogle Scholar
  72. Reni M, Cordio S, Milandri C et al (2005) Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 6:369–376PubMedCrossRefGoogle Scholar
  73. Rocha Lima CM, Savarese D, Bruckner H et al (2002) Irinotecan plus gemcitabine induces both radiographic and CA19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20:1182–1191PubMedCrossRefGoogle Scholar
  74. Rocha Lima C, Green M, Rotche R et al (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 18:3776–3783CrossRefGoogle Scholar
  75. Rothenberg ML, Moore MJ, Cripps MC et al (1996) A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7:347–535PubMedCrossRefGoogle Scholar
  76. Ryan DP, Kulke MH, Fuchs CS et al (2002) A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 94:97–103PubMedCrossRefGoogle Scholar
  77. Sacks H, Berrier J, Reitman D et al (1987) Meta-analysis of randomised controlled trials. N Engl J Med 316:450–455PubMedCrossRefGoogle Scholar
  78. Schneider BP, Ganjoo KN, Seitz OE et al (2003) Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study. Oncology 65:218–223PubMedCrossRefGoogle Scholar
  79. Shepard LC, Levy DE, Berlin JD et al (2004) Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the Eastern Cooperative Oncology Group. Oncology 66:303–309PubMedCrossRefGoogle Scholar
  80. Shi Q, Le X, Peng Z et al (2001) Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 61:4143–4154PubMedGoogle Scholar
  81. Solorzano CC, Baker CH, Bruns CJ et al (2001) Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK787/K222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase. Cancer Biother Radiopharm 16:359–370PubMedCrossRefGoogle Scholar
  82. Stathopoulos GP, Rigatos SK, Dimopoulos MA et al (2003) Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and gemcitabine: a multicenter phase II study by the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 14:388–394PubMedCrossRefGoogle Scholar
  83. Stathopoulos GP, Syrigos K, Polyzos A et al (2004) Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: an intergroup, multicenter, phase II study. Ann Oncol 15:224–229PubMedCrossRefGoogle Scholar
  84. Stocken DD, Buchler MW, Dervenis C et al (2005) Meta-analysis of randomized adjuvant therapy trials for pancreatic cancer. Br J Cancer 92:1372–1381PubMedCentralPubMedCrossRefGoogle Scholar
  85. Sultana A, Tudor Smith C, Cunningham D et al (2007) Meta-Analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol 25:2607–2615PubMedCrossRefGoogle Scholar
  86. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  87. Tobita K, Kijima H, Dowaki S et al (2003) Epidermal growth factor receptor expression in human pancreatic cancer: significance for liver metastasis. Int J Mol Med 11:305–309PubMedGoogle Scholar
  88. Tomao S, Romiti A, Massidda B et al (2002) A phase II study of gemcitabine and tamoxifen in advanced pancreatic cancer. Anticancer Res 22:2361–2364PubMedGoogle Scholar
  89. Tsuzuki Y, Mouta Carreira C, Bockborn M et al (2001) Pancreas microenvironment promotes VEGF expression and tumor growth: novel window models for pancreatic tumor angiogenesis and microcirculation. Lab Invest 81:1439–1451PubMedCrossRefGoogle Scholar
  90. Ueda S, Ogata S, Tsuda H et al (2004) The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29:E1–E8PubMedCrossRefGoogle Scholar
  91. van Cutsem E, Vervenne WL, Bennouna J et al (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27:2231–2237PubMedCrossRefGoogle Scholar
  92. Vasey PA, Evans J (2002) Principles of chemotherapy and drug development. In: Price P, Sikora K (eds) Treatment of cancer. Arnold, London, pp 103–129Google Scholar
  93. von Marschall Z, Cramer T, Hocker M et al (2000) De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. Gastroenterology 119:1358–1372CrossRefGoogle Scholar
  94. Wils J, Bleiberg H, Blijham G et al (1985) Phase II study of epirubicin in advanced adenocarcinoma of the pancreas. Eur J Cancer Clin Oncol 21:191–194PubMedCrossRefGoogle Scholar
  95. Wils J, Kok T, Wagener OJ et al (1993) Activity of cisplatin in adenocarcinoma of the pancreas. Eur J Cancer 29:203–204CrossRefGoogle Scholar
  96. Yeo CJ, Cameron JL, Lillemoe KD et al (2002) Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for peri-ampullary adenocarcinoma, part 2: Randomised controlled trial evaluating survival, morbidity, and mortality. Ann Surg 236:355–366PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Beatson West of Scotland Cancer CentreGlasgowUK
  2. 2.Beatson LaboratoriesUniversity of GlasgowGlasgowUK

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