Pancreatic cancer: Pathobiology, treatment options, and drug delivery

AAPS Journal

Volumn 12, Issue 2, 2010, Pages 223-232

  Li, Jing ^a   Wientjes, M Guillaume ^a   Au, Jessie L S ^a  

^a OHIO STATE UNIVERSITY   (United States)

Author keywords

Cancer stem cells; Drug delivery; Genetic profile; Microenvironment; Pancreatic cancer

Indexed keywords

BRCA2 PROTEIN; CD24 ANTIGEN; CISPLATIN; DOCETAXEL; ERLOTINIB; EXATECAN; FLUOROURACIL; GEMCITABINE; HERMES ANTIGEN; IRINOTECAN; OXALIPLATIN; PACLITAXEL; PEMETREXED; PROTEIN P16; PROTEIN P53; RAD51 PROTEIN; SCLEROPROTEIN; SMAD4 PROTEIN;

ANGIOGENESIS; CANCER COMBINATION CHEMOTHERAPY; CANCER GENE THERAPY; CANCER RESEARCH; CANCER RESISTANCE; CANCER STAGING; CANCER STEM CELL; CANCER SURVIVAL; CELL SURFACE; CLINICAL TRIAL; GENE MUTATION; HUMAN; METASTASIS; NONHUMAN; ONCOGENE; PANCREAS CANCER; PANCREAS ISLET CELL TUMOR; PATHOLOGY; PROTEIN PROTEIN INTERACTION; RNA INTERFERENCE; SHORT SURVEY; STELLATE CELL; STROMA CELL; TUMOR MICROENVIRONMENT; TUMOR SUPPRESSOR GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; COMBINED MODALITY THERAPY; DISEASE PROGRESSION; DRUG DELIVERY SYSTEMS; HUMANS; NEOPLASTIC STEM CELLS; PANCREATIC NEOPLASMS; STEM CELL TRANSPLANTATION;

EID: 77950635816     PISSN: 15507416     EISSN: None     Source Type: Journal    
DOI: 10.1208/s12248-010-9181-5     Document Type: Short Survey

References (117)

1. American Cancer Society. Estimated new cancer cases and deaths by sex, US. http://www.cancer.org. Accessed 20 Dec 2009.
2. Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir. 2004;59:99-111.
3. Borja-Cacho D, Jensen EH, Saluja AK, Buchsbaum DJ, Vickers SM. Molecular targeted therapies for pancreatic cancer. Am J Surg. 2008;196:430-441
4. Gutt R, Liauw SL,Weichselbaum RR. Adjuvant radiotherapy for resected pancreatic cancer: a lack of benefit or a lack of adequate trials? Nat Clin Pract Gastroenterol Hepatol. 2009;6:38-46.
5. Mahalingam D, Kelly KR, Swords RT, Carew J, Nawrocki ST, Giles FJ. Emerging drugs in the treatment of pancreatic cancer. Expert Opin Emerg Drugs. 2009;14:311-328
6. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157-188 (Pubitemid 351488279)
7. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. 2009;38:255-258
8. Niederhuber JE, Brennan MF, Menck HR. The national cancer data base report on pancreatic cancer. Cancer. 1995;76:1671-1677
9. Evans DB, Abbruzzese JL, Willett CG. Cancer of the pancreas. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles & practice of oncology. Philadelphia: Lippincott; 2001. p. 1126-1161
10. AO WHIPPLE, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg. 1935;102:763-779
11. Ueno H, Kosuge T. Adjuvant treatments for resectable pancreatic cancer. J Hepatobiliary Pancreat Surg. 2008;15:468-472
12. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120:899-903. (Pubitemid 15040883)
13. Huguet F, Girard N, Guerche CS, Hennequin C, Mornex F, Azria D. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol. 2009;27:2269-2277
14. Burris III HA, 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;15:2403-2413 (Pubitemid 27251144)
15. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, et al. 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. 2005;23:3509-3516 (Pubitemid 46243495)
16. 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: 1960-1966 (Pubitemid 46972777)
17. van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, et al. Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol. 2002;161: 1541-1547
18. Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE, Lee EY. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res. 1999;59:3547-3551 (Pubitemid 29381849)
19. Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, et al. BRCA2 germ line mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95:214-221 (Pubitemid 36240634)
20. Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57:1731-1734 (Pubitemid 27199667)
21. Radulovich N, Qian JY, Tsao MS. Human pancreatic duct epithelial cell model for KRAS transformation. Methods Enzymol. 2008;439:1-13.
22. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, et al. Abrogation of the Rb/p16 tumorsuppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997;57:3126-3130 (Pubitemid 27351723)
23. Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:9624-9629 (Pubitemid 30650826)
24. Koliopanos A, Avgerinos C, Paraskeva C, Touloumis Z, Kelgiorgi D, Dervenis C. Molecular aspects of carcinogenesis in pancreatic cancer. Hepatobiliary Pancreat Dis Int. 2008;7: 345-356
25. The Kern Laboratory. The genetic profiles of pancreatic cancer. http://pathology2.jhu.edu/pancreas/geneticsweb/profiles.htm. Accessed 15 Dec 2009.
26. Sipos B, Moser S, Kalthoff H, Torok V, Lohr M, Kloppel G. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch. 2003;442:444-452 (Pubitemid 36718311)
27. Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch. 2001;439:798-802.
28. Lewandowski K, Warzocha K, Hellmann A, Skotnicki A, Prejzner W, Foryciarz K, et al. Frequency of BCR-ABL gene mutations in Polish patients with chronic myeloid leukemia treated with imatinib: a final report of the MAPTEST study. Pol Arch Med Wewn. 2009;119:789-794
29. Plath T, Peters M, Detjen K, Welzel M, von Marschall Z, Radke C, et al. Overexpression of pRB in human pancreatic carcinoma cells: function in chemotherapy-induced apoptosis. J Natl Cancer Inst. 2002;94:129-142 (Pubitemid 34121292)
30. Wang W, Abbruzzese J, Evans D, Larry L, Cleary K, Chiao P. The nuclear factor-kappa B Rel A transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119-127 (Pubitemid 29045184)
31. Miyamoto Y, Hosotani R, Wada M, Lee JU, Koshiba T, Fujimoto K, et al. Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology. 1999;56:73-82. (Pubitemid 29043900)
32. Miller D, Fontain M, Kolar C, Lawson T. The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell lines. Cancer Lett. 1996;107:301-306 (Pubitemid 26382004)
33. Song S, Wientjes MG, Gan Y, Au JL. Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Natl Acad Sci U S A. 2000;97:8658-8663 (Pubitemid 30639729)
34. Gan Y, Wientjes MG, Au JL. Expression of basic fibroblast growth factor correlates with resistance to paclitaxel in human patient tumors. Pharm Res. 2006;23:1324-1331 (Pubitemid 43946154)
35. Wei Y, Au JLS. Role of tumour microenvironment in chemoresistance. In: Meadows GG, editor. Cancer growth and progression. The Netherlands: Springer; 2005. p. 285-321.
36. Bhattacharyya M, Lemoine NR. Gene therapy developments for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006;20:285-298
37. Chalasani P, Kurtin S, Dragovich T. Response to a third-line mitomycin C (MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germ line BRCA2 mutation. JOP. 2008;9:305-308 (Pubitemid 351864891)
38. Mackillop WJ, Ciampi A, Till JE, Buick RN. A stem cell model of human tumor growth: implications for tumor cell clonogenic assays. J Natl Cancer Inst. 1983;70:9-16. (Pubitemid 13138325)
39. Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988 (Pubitemid 36418143)
40. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895-902. (Pubitemid 37500174)
41. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730-737 (Pubitemid 27298715)
42. Dome B, Timar J, Dobos J, Meszaros L, Raso E, Paku S, et al. Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer. Cancer Res. 2006;66:7341-7347 (Pubitemid 44197717)
43. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396-401. (Pubitemid 39551674)
44. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 2006;44:240-251 (Pubitemid 44049156)
45. Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu J, Darrow TL, et al. Melanoma, a tumor based on a mutant stem cell? J Invest Dermatol. 2006;126:142-153 (Pubitemid 43336106)
46. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human coloncancer-initiating cells. Nature. 2007;445:111-115 (Pubitemid 46067311)
47. Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25:1696-1708
48. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Müllerian Inhibiting Substance responsiveness. Proc Natl Acad Sci U S A. 2006;103:11154-11159 (Pubitemid 44156488)
49. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313-323 (Pubitemid 47355323)
50. Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol. 2008;14: 3903-3907
51. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030-1037 (Pubitemid 46270758)
52. Olempska M, Eisenach PA, Ammerpohl O, Ungefroren H, Fandrich F, Kalthoff H. Detection of tumor stem cell markers in pancreatic carcinoma cell lines. Hepatobiliary Pancreat Dis Int. 2007;6:92-97 (Pubitemid 46243168)
53. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7:1028-1034 (Pubitemid 32937383)
54. Bao S,WuQ,McLendon RE,HaoY, Shi Q,HjelmelandAB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756-760 (Pubitemid 44949604)
55. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275-284 (Pubitemid 40488633)
56. Li, J. Translational research of suramin as a chemosensitizer in pancreatic cancer. The Ohio State University Ph.D. Dissertation. 2009.
57. Miyamoto H, Murakami T, Tsuchida K, Sugino H, Miyake H, Tashiro S. Tumor-stroma interaction of human pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas. 2004;28:38-44. (Pubitemid 38032243)
58. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68: 918-926 (Pubitemid 351206771)
59. Ozawa F, Friess H, Tempia-Caliera A, Kleeff J, Buchler M. Growth factors and their receptors in pancreatic cancer. Teratog Carcinog Mutagen. 2001;21:27-44. (Pubitemid 33758411)
60. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43: 128-133
61. Luttenberger T, Schmid-Kotsas A, Menke A, Siech M, Beger H, Adler G, et al. Platelet-derived growth factors stimulate proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest. 2000;80:47-55. (Pubitemid 30067379)
62. Phillips PA, Wu MJ, Kumar RK, Doherty E, McCarroll JA, Park S, et al. Cell migration: a novel aspect of pancreatic stellate cell biology. Gut. 2003;52:677-682 (Pubitemid 36528869)
63. Bachem MG, Zhou S, Buck K, Schneiderhan W, Siech M. Pancreatic stellate cells-role in pancreas cancer. Langenbecks Arch Surg. 2008;393:891-900.
64. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004;29:179-187 (Pubitemid 39304974)
65. Jang SH, Wientjes MG, Lu D, Au JL. Drug delivery and transport to solid tumors. Pharm Res. 2003;20:1337-1350 (Pubitemid 37164040)
66. Torchilin VP, Lukyanov AN. Peptide and protein drug delivery to and into tumors: challenges and solutions. Drug Discov Today. 2003;8:259-266 (Pubitemid 36293499)
67. Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007;99:1441-1454
68. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324:1457-1461
69. Olson P, Hanahan D. Cancer. Breaching the cancer fortress. Science. 2009;324:1400-1401
70. Ohigashi H, Ishikawa O, Yokayama S, Sasaki Y, Yamada T, Imaoka S, et al. Intra-arterial infusion chemotherapy with angiotensin-II for locally advanced and nonresectable pancreatic adenocarcinoma: further evaluation and prognostic implications. Ann Surg Oncol. 2003;10:927-934 (Pubitemid 40486859)
71. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453:410-414 (Pubitemid 351693122)
72. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2009;27:4966-4972
73. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525-1531
74. Sobrero A, Ackland S, Clarke S, Perez-Carrion R, Chiara S, Gapski J, et al. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology. 2009;77:113-119
75. Philip PA, Benedetti J, Fenoglio-Preiser C, Zalupski M, et al. Phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma. J Clin Oncol. 2007;25(18S):LBA4509.
76. FountzilasG, BobosM,Kalogera-FountzilaA,XirosN, Murray S, Linardou H, et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Invest. 2008;26:784-793
77. Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, et al. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res. 2006;12:144-151 (Pubitemid 43166188)
78. Cuneo KC, Geng L, Fu A, Orton D, Hallahan DE, Chakravarthy AB. SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation. Int J Radiat Oncol Biol Phys. 2008;71:873-879 (Pubitemid 351749533)
79. Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene. 2000;19:6642-6650 (Pubitemid 32197703)
80. Overall CM, Kleifeld O. Tumour microenvironment-opinion: validating matrix metalloproteinases as drug targets and antitargets for cancer therapy. Nat Rev Cancer. 2006;6:227-239
81. Grzesiak JJ, Ho JC, Moossa AR, Bouvet M. The integrinextracellular matrix axis in pancreatic cancer. Pancreas. 2007;35: 293-301. (Pubitemid 350307370)
82. Liu Z, Guo B, Lopez RD. Expression of intercellular adhesion molecule (ICAM)-1 or ICAM-2 is critical in determining sensitivity of pancreatic cancer cells to cytolysis by human gamma delta-T cells: implications in the design of gamma delta-T-cell-based immunotherapies for pancreatic cancer. J Gastroenterol Hepatol. 2009;24:900-911
83. Zimm S, Cleary SM, Lucas WE, Weiss RJ, Markman M, Andrews PA, et al. Phase I/pharmacokinetic study of intraperitoneal cisplatin and etoposide. Cancer Res. 1987;47:1712-1716 (Pubitemid 17044509)
84. Markman M, Rowinsky E, Hakes T, Reichman B, Jones W, Lewis Jr JL, et al. Phase I trial of intraperitoneal taxol: a Gynecologic Oncology Group study. J Clin Oncol. 1992;10: 1485-1491 (Pubitemid 23059933)
85. Lu Z, Tsai M, Lu D, Wang J, Wientjes MG, Au JL. Tumorpenetrating microparticles for intraperitoneal therapy of ovarian cancer. J Pharmacol Exp Ther. 2008;327:673-682
86. Bakkevold KE, Arnesjo B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater-results of a controlled, prospective, randomised multicentre study. Eur J Cancer. 1993;29A:698-703. (Pubitemid 23077048)
87. Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson III AB. 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. 2002;20:3270-3275 (Pubitemid 34831525)
88. Bernhard J, Dietrich D, Scheithauer W, Gerber D, Bodoky G, Ruhstaller T, et al. Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial-SAKK 44/00-CECOG/PAN.1.3.001. J Clin Oncol. 2008;26:3695-3701
89. Brunner TB, Geiger M, Grabenbauer GG, Lang-Welzenbach M, Mantoni TS, Cavallaro A, et al. Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer. J Clin Oncol. 2008;26:2699-2706
90. Chauffert B, Mornex F, Bonnetain F, Rougier P, Mariette C, Bouche O, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-2001 FFCD/SFRO study. Ann Oncol. 2008;19:1592-1599
91. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24:3946-3952 (Pubitemid 46630743)
92. Herrmann R, Bodoky G, Ruhstaller T, Glimelius B, Bajetta E, Schuller J, et al. 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. 2007;25:2212-2217 (Pubitemid 46954645)
93. Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14:2088-2096 (Pubitemid 46988260)
94. Small Jr W, Berlin J, Freedman GM, Lawrence T, Talamonti MS, Mulcahy MF, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008;26:942-947 (Pubitemid 351398088)
95. Stathopoulos GP, Syrigos K, Aravantinos G, Polyzos A, Papakotoulas P, Fountzilas G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer. 2006;95: 587-592 (Pubitemid 44325898)
96. Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27:2231-2237
97. Yoshitomi H, Togawa A, Kimura F, Ito H, Shimizu H, Yoshidome H, et al. A randomized phase II trial of adjuvant chemotherapy with uracil/tegafur and gemcitabine versus gemcitabine alone in patients with resected pancreatic cancer. Cancer. 2008;113:2448-2456
98. Xiong HQ, Rosenberg A, LoBuglio A, Schmidt W, Wolff RA, Deutsch J, et al. 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. 2004;22:2610-2616 (Pubitemid 41103748)
99. Mihaljevic A, Buchler P, Harder J, Hofheinz R, Gregor M, Kanzler S, et al. A prospective, non-randomized phase II trial of trastuzumab and capecitabine in patients with HER2 expressing metastasized pancreatic cancer. BMC Surg. 2009;9:1.
100. Xiong HQ, Varadhachary GR, Blais JC, Hess KR, Abbruzzese JL, Wolff RA. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer. 2008;113:2046-2052
101. Kim HM, Bang S, Park JY, Seong J, Song SY, Chung JB, et al. Phase II trial of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2009;63:535-541
102. Ina S, Tani M, Kawai M, Hirono S, Miyazawa M, Nishioka R, et al. Phase 2 trial of oral S-1 combined with low-dose cisplatin for unresectable advanced pancreatic cancer. Anticancer Res. 2008;28:2373-2377
103. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200-1210 (Pubitemid 38339364)
104. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230:776-782 (Pubitemid 30191812)
105. Doi R, Imamura M, Hosotani R, Imaizumi T, Hatori T, Takasaki K, et al. Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multiinstitutional trial. Surg Today. 2008;38:1021-1028
106. Morak MJ, van Der GA, Incrocci L, van Dekken H, Hermans JJ, Jeekel J, et al. Adjuvant intra-arterial chemotherapy and radiotherapy versus surgery alone in resectable pancreatic and periampullary cancer: a prospective randomized controlled trial. Ann Surg. 2008;248:1031-1041
107. Oettle H, Richards D, Ramanathan RK, van Laethem JL, Peeters M, Fuchs M, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol. 2005;16:1639-1645 (Pubitemid 41510138)
108. Heinrich S, Schafer M, Weber A, Hany TF, Bhure U, Pestalozzi BC, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248:1014-1022
109. Whitehead RP, Jacobson J, Brown TD, Taylor SA, Weiss GR, Macdonald JS. Phase II trial of paclitaxel and granulocyte colony-stimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study. J Clin Oncol. 1997;15: 2414-2419 (Pubitemid 27251145)
110. Safran H, Dipetrillo T, Iannitti D, Quirk D, Akerman P, Cruff D, et al. Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a Phase I trial. Int J Radiat Oncol Biol Phys. 2002;54:137-141 (Pubitemid 34722787)
111. Shepard RC, Levy DE, Berlin JD, Stuart K, Harris JE, Aviles V, et al. 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. 2004;66:303-309
112. Rougier P, Adenis A, Ducreux M, de Forni M, Bonneterre J, Dembak M, et al. A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma. Eur J Cancer. 2000;36:1016-1025 (Pubitemid 30316427)
113. Rocha Lima CM, GreenMR, Rotche R, Miller JrWH, JeffreyGM, Cisar LA, et al. 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. 2004;22:3776-3783 (Pubitemid 41095218)
114. Cheverton P, Friess H, Andras C, Salek T, Geddes C, Bodoky G, et al. Phase III results of exatecan (Exatecan) versus gemcitabine (Gem) in chemotherapy-naïve patients with advanced pancreatic cancer (APC). J Clin Oncol. 2004;22:14S.
115. Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol. 2006;24: 4441-4447 (Pubitemid 46630982)
116. Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, et al. Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008;9:39-44.
117. 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: 8033-8040 (Pubitemid 46657405)