Clinical Journal of Gastroenterology

, Volume 3, Issue 6, pp 307–317 | Cite as

Gastrointestinal bleeding during anti-angiogenic peptide vaccination in combination with gemcitabine for advanced pancreatic cancer

  • Hitomi Nagayama
  • Kazufumi Matsumoto
  • Naoyuki Isoo
  • Hideki Ohno
  • Naoyuki Takahashi
  • Takashi Nakaoka
  • Masaru Shinozaki
  • Makoto Watanabe
  • Yusuke Inoue
  • Fumitaka Nagamura
  • Naoki Oyaizu
  • Naohide Yamashita
Case Report

Abstract

Most pancreatic cancer patients are diagnosed at the advanced stages, and no therapy is superior to gemcitabine alone. To confirm the feasibility and efficacy of a novel clinical intervention using tumor vessel-specific anti-angiogenic peptide vaccination, we conducted a clinical phase I/II trial using HLA-A*2402/A*0201-restricted vascular endothelial growth factor receptor type 1 (VEGFR1)-derived peptide vaccination in combination with gemcitabine for advanced pancreatic cancer (http://www.clinical-trials.gov; NCT00683358 and NCT00683085). Four of the enrolled patients (n = 2 for HLA-A*2402 and n = 2 for HLA-A*0201 protocol, respectively), defined as having progressive disease according to the Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v.1.0), failed to respond to the therapy. Another two patients enrolled in HLA-A*2402 protocol dropped out of the study due to rapid disease progression. Grade 2–3 hematologic toxicities were observed in all cases, but the treatment was well tolerated with minimal systemic adverse events. One case in HLA-A*2402 protocol and another case in HLA-A*0201 protocol suffered complicated gastrointestinal (GI) bleeding during vaccination. The causal relationship between GI bleeding and VEGFR1-peptide vaccination is unclear according to the pathologic examination. These studies terminated prematurely because of the advanced stage of the disease in the enrolled patients on entry to the study. Despite GI bleeding, peptide vaccination provides a feasible treatment option for many advanced pancreatic cancer patients.

Keywords

Pancreatic cancer Peptide vaccination VEGFR1 Gemcitabine GI bleeding 

References

  1. 1.
    Niederhuber JE, Brennan MF, Menck HR. The National Cancer Database Report on pancreatic cancer. Cancer. 1995;76:1671–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Shaib YH, Davila JA, El-Serag HB. The epidemiology of pancreatic cancer in the United States: changes below the surface. Aliment Pharmacol Ther. 2006;24:87–94.PubMedCrossRefGoogle Scholar
  3. 3.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.PubMedGoogle Scholar
  4. 4.
    Di Marco M, Di Cicilia R, Macchini M, Nobili E, Vecchiarelli S, Brandi G, et al. Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? (Review). Oncol Rep. 2010;23:1183–92.PubMedCrossRefGoogle Scholar
  5. 5.
    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. 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. 2007;25:1960–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomized phase II study. Lancet. 2008;371:2101–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Borja-Cacho D, Jensen EH, Saluja AK, Buchsbaum DJ, Vickers SM. Molecular targeted therapies for pancreatic cancer. Am J Surg. 2008;196:430–41.PubMedCrossRefGoogle Scholar
  8. 8.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumor activity. Nat Rev Cancer. 2008;8:579–91.PubMedCrossRefGoogle Scholar
  10. 10.
    Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Shibuya M, Yamaguchi S, Yamane A, Ikeda T, Tojo A, Matsushime H, et al. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990;5:519–24.PubMedGoogle Scholar
  13. 13.
    Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000;85:27–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Wey JS, Fan F, Gray MJ, Bauer TW, McCarty MF, Somcio R, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–38.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536–41.PubMedCrossRefGoogle Scholar
  17. 17.
    Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, et al. Phase I trial of bevacizumab plus escalating doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1432–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Giantonio BJ, Levy DE, O’Dwyer PJ, Meropol NJ, Catalano PJ, Benson AB 3rd. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol. 2006;17:1399–403.PubMedCrossRefGoogle Scholar
  20. 20.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI treatment referral center trial TRC-0301. J Clin Oncol. 2006;24:3354–60.PubMedCrossRefGoogle Scholar
  23. 23.
    Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25:1539–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Cao Y, Tan A, Gao F, Liu L, Liao C, Mo Z. A meta analysis of randomized controlled trials comparing chemotherapy plus bevacizumab with chemotherapy alone in metastatic colorectal cancer. Int J Colorectal Dis. 2009;24:677–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Herbst RS, O’Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer. J Clin Oncol. 2007;25:4743–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, et al. Outcome for elderly, advanced-stage non-small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008;26:60–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol. 2009;27:1227–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.PubMedCrossRefGoogle Scholar
  31. 31.
    Sandler AB, Schiller JH, Gray R, Dimery I, Brahmer J, Samant M, et al. Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced, unresectable non-small-cell lung cancer treated with carboplatin and paclitaxel plus bevacizumab. J Clin Oncol. 2009;27:1405–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Ko AH, Dito E, Schillinger B, Venook AP, Xu Z, Bergsland EK, et al. A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable? Invest New Drugs. 2008;26:463–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005;23:8033–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol. 2006;24:1145–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505–12.PubMedCrossRefGoogle Scholar
  37. 37.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Kindler HL, Nieddzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine with placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H. Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 2006;12:5841–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Date Y, Kimura A, Kato H, Sasazuki T. DNA typing of the HLA-A gene: population study and identification of four new alleles in Japanese. Tissue Antigens. 1996;47:93–101.PubMedCrossRefGoogle Scholar
  41. 41.
    Miyazawa M, Ohsawa R, Tsunoda T, Hirono S, Kawai H, Tani M, et al. Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer Sci. 2010;101:433–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Hitomi Nagayama
    • 1
  • Kazufumi Matsumoto
    • 2
  • Naoyuki Isoo
    • 1
  • Hideki Ohno
    • 1
  • Naoyuki Takahashi
    • 1
  • Takashi Nakaoka
    • 1
  • Masaru Shinozaki
    • 3
  • Makoto Watanabe
    • 4
  • Yusuke Inoue
    • 4
  • Fumitaka Nagamura
    • 2
  • Naoki Oyaizu
    • 5
  • Naohide Yamashita
    • 1
  1. 1.Division of Advanced Medical Science, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  2. 2.Department of Clinical Trial Safety Management, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  3. 3.Department of Surgery, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  4. 4.Division of Radiology, The Institute of Medical ScienceThe University of TokyoTokyoJapan
  5. 5.Division of Pathology, Research Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan

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