Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: A review

Molecules

Volumn 13, Issue 8, 2008, Pages 1897-1922

  Koukourakis, Georgios V ^a   Kouloulias, Vassilios ^a   Koukourakis, Michael J ^b   Zacharias, Georgios A ^c   Zabatis, Haralabos ^d   Kouvaris, John ^e  

^a NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS   (Greece)

^b University Hospital of Thrace   (Greece)

^c Technological Institution of Athens   (Greece)

^d UNIVERSITY OF WEST ATTICA   (Greece)

^e UNIVERSITY OF ATHENS   (Greece)

Author keywords

Cancer treatment; Capecitabine; Xeloda

Indexed keywords

ANTINEOPLASTIC AGENT; CAPECITABINE; DEOXYCYTIDINE; DRUG DERIVATIVE; FLUOROURACIL; PRODRUG;

HUMAN; MORTALITY; NEOPLASM; REVIEW; TREATMENT OUTCOME;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DEOXYCYTIDINE; FLUOROURACIL; HUMANS; NEOPLASMS; PRODRUGS; TREATMENT OUTCOME;

EID: 50949105874     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules13081897     Document Type: Review

References (73)

1. Rich, T.A.; Shepard, R.C.; Mosley, S.T. Four decades of continuing innovation with fluorouracil: Current and future approaches to fluorouracil chemoradiation therapy. J. Clin. Oncol. 2004, 22, 2214-2232.
2. Milano, G.; Etienne, M.C.; Renée, N.; Thyss, A.; Schneider, M.; Ramaioli, A.; Demard, F. Relationship between fluorouracil systemic exposure and tumour response and patient survival. J. Clin. Oncol. 1994, 12, 1291-1295.
3. Meta Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J. Clin. Oncol. 1998, 16, 301-308.
4. Anderson, N.; Lokich, J. Controversial issues in 5-fluorouracil infusion use. Dose intensity, treatment duration, and cost comparisons. Cancer 1992, 70, 998-1002.
5. Bollag, W.; Hartmann, H.R. Tumor inhibitory effects of a new fluorouracil derivative: 5′ Deoxy 5 fluorouridine. Eur. J. Cancer 1980, 16, 427-432.
6. Bajetta, E.; Colleoni, M.; Rosso, R.; Sobrero, A.; Amadori, D.; Comella, G.; Marangolo, M.; Scanni, A.; Lorusso, V.; Calabresi, F. Prospective randomised trial comparing fluorouracil versus doxifluridine for the treatment of advanced colorectal cancer. Eur. J. Cancer 1993, 29A, 1658-1663.
7. Miwa, M.; Ura, M.; Nishida, M.; Sawada, N.; Ishikawa, T.; Mori, K.; Shimma, N.; Umeda, I.; Ishitsuka, H. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur. J. Cancer 1998, 34, 1274-1281.
8. PrelBudman, D.R.; Meropol, N.J.; Reigner, B.; Creaven, P.J.; Lichtman, S.M.; Berghorn, E.; Behr, J.; Gordon, R.J.; Osterwalder, B.; Griffin, T. Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine. J. Clin. Oncol. 1998, 16, 1795-1802.
9. Nutley, N.J. Xeloda (capecitabine) [product information]; Roche Pharmaceuticals, 2003.
10. Hoff, P.M.; Ansari, R.; Batist, G.; Cox, J.; Kocha, W.; Kuperminc, M.; Maroun, J.; Walde, D.; Weaver, C,; Harrison, E.; Burger, H.U.; Osterwalder, B.; Wong, A.O.; Wong, R. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J. Clin. Oncol. 2001, 19, 2282-2292.
11. Braun, A.H.; Achterrath, W.; Wilke, H.; Vanhoefer, U.; Harstrick, A.; Preusser P. New systemic frontline treatment for metastatic colorectal carcinoma. Cancer 2004, 100, 1558-1577.
12. Van Cutsem, E.; Twelves, C.; Cassidy, J.; Allman, D.; Bajetta, E.; Boyer, M.; Bugat, R.; Findlay, M.; Frings, S.; Jahn, M.; McKendrick, J.; Osterwalder, B.; Perez-Manga, G.; Rosso, R.; Rougier, P.; Schmiegel, W.H.; Seitz, J.F.; Thompson, P.; Vieitez, J.M.; Weitzel, C.; Harper, P. Xeloda Colorectal Cancer Study Group. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J. Clin. Oncol. 2001, 19, 4097-4106.
13. Ishikaw, T.; Fukase, Y.; Yamamoto, T.; Sekiguchi, F.; Ishitsuka, H. Antitumor activities of a novel fluoropyrimidine, N4-pentyloxycarbonyl 5′ deoxy S fluorocytidine (capecitabine). Bid. Pharm. Bull. 1998, 21, 713-717.
14. Van Cutsem, E.; Findlay, M.; Osterwalder, B.; Kocha, W.; Dalley, D.; Pazdur, R.; Cassidy, J.; Dirix, L.; Twelves, C.; Allman, D.; Seitz, J.F.; Schölmerich, J.; Burger, H.U.; Verweij, J. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: Results of a randomized phase II study. J. Clin. Oncol. 2000, 18, 1337-1345.
15. Cassidy, J.; Tabernero, J.; Twelves, C.; Brunet, R.; Butts, C.; Conroy, T.; Debraud, F.; Figer, A.; Grossmann, J.; Sawada, N.; Schöffski, P.; Sobrero, A.; Van Cutsem, E.; Díaz-Rubio, E. XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J. Clin Oncol. 2004, 22, 2084-2091.
16. Zeuli, M.; Nardoni, C.; Pino, M.S.; Gamucci, T.; Gabriele, A.; Ferraresi, V.; Giannarelli, D.; Cognetti, F. Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer. Ann. Oncol. 2003, 14, 1378-1382.
17. Borner, M.M.; Dietrich, D.; Stupp, R.; Morant, R.; Honegger, H.; Wernli, M.; Herrmann, R.; Pestalozzi, B.C.; Saletti, P.; Hanselmann, S.; Müller, S.; Brauchli, P.; Castiglione-Gertsch, M.; Goldhirsch, A.; Roth, A.D. Phase II study of capecitabine andoxaliplatin in first and second line treatment of advanced or metastatic colorectal cancer. J. Clin. Oncl. 2002, 20, 1759-1766.
18. Shields, A.F.; Zalupski, M.M.; Marshall, J.L.; Meropol, N.J. Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: A phase II trial. Cancer 2004, 100, 531-537.
19. Bajetta, E.; Di Bartolomeo, M.; Mariani, L.; Cassata, A.; Artale, S.; Frustaci, S.; Pinotti, G.; Bonetti, A.; Carreca, I.; Biasco, G.; Bonaglia, L.; Marini, G.; Iannelli, A.; Cortinovis, D.; Ferrario, E.; Beretta, E.; Lambiase, A.; Buzzoni, R. Italian Trials in Medical Oncology (I.T.M.O.) Group. Randomized multicenter phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 2004, 100, 279-287.
20. Patt, Y.Z.; Lin, E.; Liebman, J. Capecitabine plus irinotecan: A highly active first line treatment for metastatic colorectal cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 228.
21. Cartwright, T.H.; Encarnacion, C.; Vukelja, S.J. A phase II open label study of capecitabine in combination with irinotecan as first-line treatment for metastatic colorectal cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 271.
22. Kim, T.W.; Kang, W.K.; Park, J.O. Phase II study of irinotecan plus capecitabine as first-line chemotherapy in advanced colorectal cancer. Proc. Am. Soc. Clin. Oncol. 2003, 22, 1278.
23. Bosset, J.F.; Collette, L.; Calais, G.; Mineur, L.; Maingon, P.; Radosevic-Jelic, L.; Daban, A.; Bardet, E.; Beny, A.; Ollier, J.C. EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. New Engl. Med. 2006, 355, 1114-1123.
24. Bosset, J.F.; Calais, G.; Mineur, L.; Maingon, P.; Radosevic-Jelic, L.; Daban, A.; Bardet, E.; Beny, A.; Briffaux, A.; Collette, L. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results - EORTC 22921. J. Clin. Oncol. 2005, 23, 5620-5627.
25. Gérard, J.P.; Conroy, T.; Bonnetain, F.; Bouché, O.; Chapet, O.; Closon-Dejardin, M.T.; Untereiner, M.; Leduc, B.; Francois, E.; Maurel, J.; Seitz, J.F.; Buecher, B.; Mackiewicz, R.; Ducreux, M.; Bedenne, L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J. Clin. Oncol. 2006, 24, 4620-4625.
26. Dupuis, O.; Vie, B.; Lledo, G.; Hennequin, C.; Noirclerc, M.; Bennamoun, M.; Jacob, J.H. Preoperative treatment combining capecitabine withradiation therapy in rectal cancer: a GERCOR Phase II Study. Oncology 2007, 73, 169-176.
27. Desai, S.P.; El-Rayes, B.F.; Ben-Josef, E.; Greenson, J.K.; Knol, J.A.; Huang, E.H.; Griffith, K.A.; Philip, P.A.; McGinn, C.J.; Zalupski, M.M. phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. Am. J. Clin. Oncol. 2007, 30, 340-345.
28. Korkolis, D.P.; Boskos, C.S.; Plataniotis, G.D.; Gontikakis, E.; Karaitianos, I.J.; Avgerinos, K.; Katopodi, A.; Xinopoulos, D.; Dimitroulopoulos, D.; Beroukas, K.; Vassilopoulos, P.P. Preoperative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer. Anticancer Res. 2007, 27, 541-545.
29. Willeke, F.; Horisberger, K.; Kraus-Tiefenbacher, U.; Wenz, F.; Leitner, A.; Hochhaus, A.; Grobholz, R.; Willer, A.; Kähler, G.; Post, S.; Hofheinz, R.D. A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer. Br. J. Cancer 2007, 96(6), 912-917.
30. Velenik, V.; Anderluh, F.; Oblak, I.; Strojan, P.; Zakotnik, B. Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat. Med. J. 2006, 47, 693-700.
31. Krishnan, S.; Janjan, N.A.; Skibber, J.M.; Rodriguez-Bigas, M.A.; Wolff, R.A.; Das, P.; Delclos, M.E.; Chang, G.J.; Hoff, P.M.; Eng, C.; Brown, T.D.; Crane, C.H.; Feig, B.W.; Morris, J.; Vadhan-Raj, S.; Hamilton, S.R.; Lin, E.H. Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 2006, 66, 762-771.
32. De Paoli, A.; Chiara S.; Luppi, G.; Friso, M.L.; Beretta, G.D.; Del Prete, S.; Pasetto, L.; Santantonio, M.; Sarti, E.; Mantello, G.; Innocente, R.; Frustaci, S.; Corvò, R.; Rosso, R. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann. Oncol. 2006, 17, 246-251.
33. Machiels, J.P.; Duck, L.; Honhon, B.; Coster, B.; Coche, J.C.; Scalliet, P.; Humblet, Y.; Aydin, S.; Kerger, J.; Remouchamps, V.; Canon, J.L.; Van Maele, P.; Gilbeau, L.; Laurent, S.; Kirkove, C.; Octave-Prignot, M.; Baurain, J.F.; Kartheuser, A.; Sempoux, C. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann. Oncol.. 2005, 16, 1898-1905.
34. Kim, J.C.; Kim, T.W.; Kim, J.H.; Yu, C.S.; Kim, H.C.; Chang, H.M.; Ryu, M.H.; Park, J.H.; Ahn, S.D.; Lee, S.W.; Shin, S.S.; Kim, J.S.; Choi, E.K. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 2005, 63, 346-353.
35. Kim, J.S.; Kim, J.C.; Cho, M.J.; Degroote, M.A.; Fulton, K.; Huitt, G.; Lynch, D.A. Comparison of the efficacy of oral capecitabine versus bolus 5-FU in preoperative radiotherapy of locally advanced rectal cancer. J. Korean Med. Sci. 2006, 21, 52-57.
36. O'Shaughnessy, J.; Miles, D.; Vukelja, S.; Moiseyenko, V.; Ayoub, J.P.; Cervantes, G.; Fumoleau, P.; Jones, S.; Lui, W.Y.; Mauriac, L.; Twelves, C.; Van Hazel, G.; Verma, S.; Leonard, R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J. Clin. Oncol. 2002, 20, 2812-2823.
37. Gradishar, W.J.; Meza, L.A.; Amin, B.; Samid, D.; Hill, T.; Chen, Y.M.; Lower, E.E.; Marcom, P.K .Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: A multicenter phase II study. J. Clin. Oncol. 2004, 22, 2321-2327.
38. Ghosn, M.; Farhat, F.; Kattan, J. Final results of a phase II study of vinorelbine in combination with capecitabine as first line chemotherapy for metastatic breast cancer. Proc. Am. Soc. Clin. Oncol. 2003, 22, 270.
39. O'Shaughnessy, J.A.; Blum, J.; Moiseyenko, V. Randomized, open label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclosphosphamide, methotrexate and 5 fluorouracil) as first line therapy for advanced/metastatic breast cancer. Ann. Oncol. 2001, 12, 1247-1254.
40. Talbot, D.C.; Moiseyenko, V.; Van Belle, S.; O'Reilly, S.M.; Alba Conejo, E.; Ackland, S.; Eisenberg, P.; Melnychuk, D.; Pienkowski, T.; Burger, H.U.; Laws, S.; Osterwalder, B. Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br. J. Cancer 2002, 86, 1367-1372.
41. Blum, J.L.; Jones, S.E.; Buzdar, A.U.; LoRusso, P.M.; Kuter, I.; Vogel, C.; Osterwalder, B.; Burger, H.U.; Brown, C.S.; Griffin, T. Multicenter phase II study of capecitabine in paclitaxel refractory metastatic breast cancer. J. Clin. Oncol. 1999, 17, 485-493.
42. Reichardt, P.; Von Minckwitz, G.; Thuss-Patience, P.C.; Jonat, W.; Kölbl, H.; Jänicke, F.; Kieback, D.G.; Kuhn, W.; Schindler, A.E.; Mohrmann, S.; Kaufmann, M.; Lück, H.J. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane containing therapy. Ann. Oncol. 2003, 14, 1227-1233.
43. Fumoleau, P.; Largillier, R.; Clippe, C.; Dièras, V.; Orfeuvre, H.; Lesimple, T.; Culine, S.; Audhuy, B.; Serin, D.; Curé, H.; Vuillemin, E.; Morère, J.F.; Montestruc, F.; Mouri, Z.; Namer, M. Multicenter, phase II study evaluating capecitabine monotherapy in patients with anthracycline and taxane pretreated metastatic breast cancer. Eur. J. Cancer 2004, 40, 536-542
44. Blum, J.L.; Dieras, V.; Lo Russo, P.M.; Horton, J.; Rutman, O.; Buzdar, A.; Osterwalder, B. Multicenter, Phase II study of capecitabine in taxane pretreated metastatic breast carcinoma patients. Cancer 2001, 92, 1759-1768.
45. Wist, E.A.; Sommer, H.H.; Ostenstad, B.; Risberg, T.; Bremnes,Y.; Mjaaland, I. Oral capecitabine in anthracycline-and Taxane-pretreated advanced/ metastatic breast cancer. Acta Oncol. 2004, 43, 186-189.
46. Batista, N.; Perez-Manga, G.; Constenla, M.; Ruiz, A.; Carabantes, F.; Castellanos, J.; Gonzalez, M.; Villman, K.; Söderberg, M.; Ahlgren, J.; Casinello, J.; Regueiro, P.; Murias, A. Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline pre-treated advanced/metastatic breast cancer. Br.J. Cancer 2004, 90, 1740-1746.
47. Minea, L.N.; Stanculeanu, D.L.; Cringeanu, A. Capecitabine monotherapy for elderly patients with metastatic breast cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 797.
48. Sawada, N.; Ishikawa, T.; Fukase, Y.; Nishida, M.; Yoshikubo, T.; Ishitsuka, H. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin. Cancer Res. 1998, 4, 1013-1019.
49. Gaui, M.F.; Amorim, G.; Arcuri, R.A.; Pereira, G.; Moreira, D.; Djahjah, C.; Biasoli, I.; Spector, N. A phase II study of second-line neoadjuvant chemotherapy with capecitabine and radiation therapy for anthracycline-resistant locally advanced breast cancer. Am. J. Clin. Oncol. 2007, 30(1), 78-81.
50. Ishitsuka, H. Capecitabine: Preclinical pharmacology studies. Inst. New Drugs. 2000, 18, 343-354.
51. Sivridis, E.; Giatromanolaki, A.; Papadopoulos, I.; Gatter, K.C.; Harris, A.L.; Koukourakis, M.I. Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: Correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis. Br. J. Cancer 2002, 86, 1465-1471.
52. Morant, R.; Bernhard, J.; Dietrich, D.; Gillessen, S.; Bonomo, M.; Borner, M.; Bauer, J.; Cerny, T.; Rochlitz, C.; Wernli, M.; Gschwend, A.; Hanselmann, S.; Hering, F.; Schmid, H.P. Capecitabine in hormone-resistant metastatic prostatic carcinoma a phase II trial. Br. J. Cancer 2004, 90, 1312-1317.
53. Ferrero, J.; Berdah, J.F.; Chamorey, E. A combination of docetaxel-capecitabine in patients with hormone refractory advanced prostate cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4624.
54. Wenzel, C.; Locker, G.J.; Schmidinger, M.; Mader, R.; Kramer, G.; Marberger, M.; Rauchenwald,M.; Zielinski, C.C.; Steger, G.G. Capecitabine in the treatment of metastatic renal cell carcinoma failing immunotherapy. Am. J. Kidney Dis. 2002, 39, 48-54.
55. Pagliaro, L.C.; Perez, C.A.; Tu, S.M. Phase II study of capecitabine single-agent therapy in patients with metastatic renal cell carcinoma. Proc. Am. Soc. Clin. Oncol. 2003, 22, 1780.
56. Padrik, P.; Leppik, K.; Arak, A. A phase II study of combination therapy with capecitabine and interferon alfa2A in patients with metastatic renal cell carcinoma Proc. Am. Soc. Clin. Oncol. 2003, 22, 1626.
57. Oevermann, K.; Buer, J.; Hoffmann, R.; Franzke, A.; Schrader, A.; Patzelt, T.; Kirchner, H.; Atzpodien, J. Capecitabine in the treatment of metastatic renal cell carcinoma. Br. J. Cancer 2000, 83, 583-587.
58. Stadler, W.M.; Halabi, S.; Ernstoff, M.S. A phase II study of gemcitabine and capecitabine in patients with metastatic renal cell cancer: A report of cancer and leukaemia group B #90008. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4515.
59. Vaishampayan, U.N.; Heilbrun, L.K.; Eliason, J. Phase II trial of weekly docetaxel and capecitabine in advanced renal cell carcinoma. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4672.
60. Tsukagoshi, S.; Saga, Y.; Suzuki, N.; Fujioka, A.; Nakagawa, F.; Fukushima, M.; Suzuki, M. Thymidine phosphorylase mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo. Int. J. Oncol. 2003, 22, 961-967.
61. Vasey, P.A.; McMahon, L.; Paul, J.; Reed, N.; Kaye, S.B. A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer. Br. J. Cancer 2003, 89, 1843-1848.
62. Rischin, D.; Phillips, K.A.; Friedlander, M.; Harnett, P.; Quinn, M.; Richardson, G.; Martin, A phase II trial of capecitabine in heavily pre-treated platinum resistant ovarian cancer. Gynecol. Oncol. 2004, 93, 417-421.
63. Therasse, P.; Arbuck, S.G.; Eisenhauer, E.A.; Wanders, J.; Kaplan, R.S.; Rubinstein, L.; Verweij, J.; Van Glabbeke, M.; van Oosterom, A.T.; Christian, M.C.; Gwyther, S.G. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. New guidelines to evaluate the response to treatment in solid tumors. J. Natl. Cancer Inst. 2000, 92, 205-216.
64. Hubner, R.; Ahmad, T.; Rigs, A. Epirubicin-carboplatin-capecitabine (ECarboX) in relapsed ovarian cancer: A phase I/II trial. Proc. Am. Soc. Clin. 2004, 23, 5109.
65. Okusaka, T.; Kosuge, T. Systemic chemotherapy for pancreatic cancer. Pancreas 2004, 28, 301-304.
66. Cartwright, T.H.; Cohn, A.; Varkey, J.A.; Chen, Y.M.; Szatrowski, T.P.; Cox, J.V.; Schulz, J.J. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J. Clin. Oncol. 2002, 20, 160-164.
67. Hess,V.; Salzberg, M.; Borner, M.; Morant, R.; Roth, A.D.; Ludwig, C.; Herrmann, R. Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: A phase I/II trial. J. Clin. Oncol. 2003, 21, 66-68.
68. Scheithauer, W.; Schüll, B.; Ulrich-Pur, H.; Schmid, K.; Raderer, M.; Haider, K.; Kwasny, W.; Depisch, D.; Schneeweiss, B.; Lang, F.; Kornek, G.V. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: A randomized phase II trial. Ann. Oncol. 2003, 14, 97-104.
69. Stathopoulos, G.P.; Syrigos, K.; Polyzos, A.; Fountzilas, G.; Rigatos, S.K.; Ziras, N.; Potamiannou, A.; Tsiakopoulos, I.; Androulakis, N.; Aravantinos, G.; Athanasiadis, A.; Papakotoulas, P.; Georgoulias, V. Front-line treatment of inoperable or metastatic pancreatic cancer with gemcitabine and capecitabine: An intergroup, multicenter, phase II study. Ann. Oncol. 2004, 15, 224-229.
70. Chang, H.M.; Kim, T.W.; Ahn, J.H. Phase II study of gemcitabine, capecitabine and cisplatin in patients with advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4219.
71. Fine, R.L.; Fogelman, D.R.; Schreibman, S. GTX chemotherapy for metastatic pancreatic cancer: Response survival and toxicity data. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4271.
72. Heinemann, V.; Golf, A.; Seipelt, G. Randomised trial of capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (GemOx) in advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. 2004, 23, 4108.
73. Saif, M.W.; Black, G.; Roy, S.; Bell, D.; Russo, S.; Eloubeidi, M.A.; Steg, A.; Johnson, M.R.; Zelterman, D.; Diasio, R.B. Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase. Cancer J. 2007, 13, 247-56.