Капецитабин: клинические проявления и тактика лечения побочных эффектов

1. Budman DR, Meropol NJ, Reigner B et al. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol 1998; 16: 1795–802.
2. Miwa M, Ura M, Nishida M et al. 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: 1274–81.
3. Takebayashi Y, Akiyama S, Akiba S et al. Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 1996; 88: 1110–7.
4. Nio Y, Kimura H, Tsubono M et al. Antitumor activity of 50-deoxy-5-flourouridine in human digestive organ cancer xenografts and pyrimidine nucleoside phosphorylase activity in normal and neoplastic tissues from human digestive organs. Anticancer Res 1992; 12: 1141–6.
5. Schuller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45: 291–7.
6. Hoff PM, Ansari A, Batist G et al. 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: 2282–92.
7. Van Cutsem E, Twelves C, Cassidy J et al. 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: 4097–106.
8. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Pharmacokinetics 1989; 16: 215–37.
9. Sternberg CN, Reichardt P, Holland M. Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. Eur J Oncol Nurs 2004; 8 (Suppl. 1): S4–S15.
10. Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001; 40: 85–104.
11. Reigner B, Verweij J, Dirix L et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res 1998; 4: 941–8.
12. Roche. Xeloda (capecitabine). [product information]. Nutley: Roche Pharmaceuticals; 2003.
13. Mackean M, Planting A, Twelves C et al. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 1998; 16: 2977–85.
14. Judson IR, Beale PJ, Trigo JM et al. A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug. Invest New Drugs 1999; 17: 49–56.
15. Poole C, Gardiner J, Twelves C et al. Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (XELODA) in cancer patients. Cancer Chemother Pharmacol 2002; 49: 225–34.
16. Twelves C, Glynne-Jones R, Cassidy J et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999; 5: 1696–702.
17. Nicolic-Tomasevic Z, Jelic S, Cassidy J et al. Fluoropyrimidine therapy: hyperbilirubinemia as a consequence of hemolysis. Cancer Chemother Pharmacol 2005; 56: 594–602.
18. Evans TR, Pentheroudakis G, Paul J et al. A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophagogastric adenocarcinoma. Ann Oncol 2002; 13: 1469–78.
19. Villalova-Calero MA, Weiss GR, Burris HA et al. Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J Clin Oncol 1999; 6: 1915–25.
20. O'Shaughnessy J. Capecitabine and docetaxel in advanced breast cancer: analyses of a phase III comparative trial. Oncol 2002; 16 (10 Suppl. 12): 17–22.
21. Delord JP, Pierga JY, Dieras V et al. Dose escalation and pharmacokinetic study of capecitabine (Xeloda) and irinotecan (CPT-11) in gastro-intestinal tumors: preliminary results. Proc Am Soc Clin Oncol 2005; 21: 397a.
22. Punt A, Nortier R, Ten Bokkel Huinick W. Combination of irinotecan and capecitabine as first line treatment in advanced colorectal cancer: results of a phase II multicenter trial. Eur J Cancer 2003; 1 (Suppl. 5): S85.
23. Brickel K, Porter D, Thompson P. Phenytoin toxicity due to fluoropyrimidines (5FU/capecitabine): three case reports. Br J Cancer 2003; 89: 615–6.
24. Schaller G. Drug interaction of capecitabine and phenytoin in the therapy of cerebral and visceral metastatic breast cancer. Ann Oncol 2000; 11 (Suppl. 4): 12–39.
25. Gunes A, Coskun U, Boruban C et al. Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients. Basic Clin Pharmacol Toxicol 2006; 98: 197–200.
26. Shah HR, Ledbetter L, Diasio R, Saif MW. A retrospective study of coagulation abnormalities in patients receiving concomitant capecitabine and warfarin. Clin Colorectal Cancer 2006; 5: 354–8.
27. Saif MW. An adverse interaction between warfarin and fluoropyrimidines revisited. Clin Colorectal Cancer 2005; 5: 175–80.
28. Kanamitsu SI, Ito K, Okuda H et al. Prediction of in vivo drug–drug interactions based on mechanism-based inhibition from in vitro data: inhibition of 5-fluorouracil metabolism by (E)-5-(2-bromovinyl) uracil. Drug Metab Dispos 2000; 28: 467–74.
29. Beltz RE, Poland LL. Inhibition of 5-fluorouracil activation by oxipurinol in preparations of normal rat tissues and Jensen sarcoma: tumor-selective stimulation by inosine. Cancer Commun 1991; 3: 271–6.
30. Howell SB, Wung WE, Taetle R et al. Modulation of 5-fluorouracil toxicity by allopurinol in man. Cancer 1981; 48: 1281–9.
31. Garewal HS, Ahmann FR, Alberts DS. Lack of inhibition by oxipurinol of 5-FU toxicity against human tumor cell lines. Cancer Treat Rep 1983; 67: 495–8.
32. Harvey VJ, Slevin ML, Dilloway MR et al. The influence of cimetidine on the pharmacokinetics of 5-fluorouracil. Br J Clin Pharmacol 1984; 18: 421–30.
33. Dilloway MR, Lant AF. Effect of H2-receptor antagonists on the pharmacokinetics of 5-fluorouracil in the rat and monkey. Biopharm Drug Dispos 1991; 12: 17–28.
34. Cassidy J, Dirix L, Bisset D et al. A phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. Clin Cancer Res 1998; 4: 2755–61.
35. Chang DZ, Olencki T, Budd GT et al. Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics. Cancer Chemother Pharmacol 2001; 48: 493–8.
36. Xeloda (Capecitabine) tablets: prescribing information. Available online at: http://www.fdagov/cder/foi/label/2005/020896s016lbl.pdf.
37. Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl Med 2005; 352: 2696–4.
38. Lamberti C, Sauerbruch T, Glasmacher A. Adjuvant capecitabine is at least as effective as fluorouracil plus leucovorin for survival in people with resected stage III colon cancer. Cancer Treat Rev 2005; 31: 648–52.
39. Saif MW, Tejani MA. Safety of capecitabine use in patients with liver dysfunction. Clin Adv Hematol Oncol 2007; 5: 730–2.
40. Cancer Therapy Evaluation Program, 2006. Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS. (http://ctep.cancer.gov).
41. Braun AH, Achterrath W, Wilke H et al. New systemic frontline treatment for metastatic colorectal carcinoma. Cancer 2004; 100: 1558–77.
42. Bajetta E, Bartolomeo MD, Mariani L et al. Randomized multicenter phase II of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer 2004; 100: 279–87.
43. Rea DW, Nortier JWR, Ten Bokkel Huinink WW et al. A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol 2005; 16: 1123–32.
44. Kim TW, Kang WK, Chang HM et al. Multicenter phase II study of oral capecitabine plus irinotecan as first-line chemotherapy in advanced colorectal cancer: a Korean cancer study group trial. Acta Oncol 2005; 44: 230–5.
45. Cartwright T, Lopez T, Vukelja SJ et al. Results of a phase II open-label study of capecitabine in combination with irinotecan as first-line treatment for metastatic colorectal cancer. Clin Colorectal Cancer 2005; 5: 50–6.
46. Shields AF, Zalupski MM, Marshall JL, Meropol NJ. Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine. Cancer 2003; 100: 531–7.
47. Borner MM, Dietrich D, Stupp R et al. Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer. J Clin Oncol 2002; 20: 1759–66.
48. Cassidy J, Tabernero J, Twelves C et al. Xelox (capecitabine plus oxilaplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22: 2084–91.
49. Zeuli M, Nardoni C, Pino MS et al. Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer. Ann Oncol 2003; 14: 1378–82.
50. Scheithauer W, McKendrick J, Begdie S et al. Oral capecitabine as an alternative to iv 5-FU-based adjuvant therapy for colon cancer: safety results of a randomized phase III trial. Ann Oncol 2003; 14: 1735–43.
51. Van Cutsem E, Hoff PM, Harper P et al. Oral capecitabine vs iv 5-FU and LV: integrated efficacy data and novel analyses from two large, randomized phase III trials. Br J Cancer 2004; 90: 1190–7.
52. Cassidy J, Twelves C, Van Cutsem E et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-FU/LV. Ann Oncol 2002; 13: 566–75.
53. Twelves C, Boyer M, Findlay M et al. Capecitabine (Xeloda) improves medical resource use compared with 5-FU plus LV in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer 2001; 37: 597–604.
54. Goldberg RM, Morton RF, Sargent DJ. N9741: oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (lv) or oxal +CPT-11 in advanced colorectal cancer. Updated efficacy and quality of life (qol) data from an intergroup study. Proc Am Soc Clin Oncol 2003; 22: 252a.
55. De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–47.
56. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23–30.
57. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905–14.
58. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicenter randomized trial. Lancet 2000; 355: 1041–7.
59. Schmoll HJ, Tabernero J, Nowacki M. Early safety findings from a phase III trial of capecitabine plus oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer. Proc Am Soc Clin Oncol 2005; Abstr. 3523.
60. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl Med 2004; 350: 2343–51.
61. Dunst J, Reese T, Debus J. Phase-II study of preoperative chemoradiation with capecitabine in rectal cancer. Proc Am Soc Clin Oncol 2004; 23: Abstr. 3559.
62. Lin EH, Skibber J, Delcos M. Phase II study of capecitabine and concomitant boost radiotherapy (XRT) in patients (pts) with locally advanced rectal cancer (LARC). J Clin Oncol 2005; 23 (Suppl. 16s): Abstr. 3593.
63. Dupuis O, Vie B, Liedo G. Capecitabine (X) chemoradiation (CRT) in the preoperative treatment of patients (pts) with rectal adenocarcinomas: a phase II GERCOR trial. Proc Am Soc Clin Oncol 2004; 23: Abstr. 3538.
64. Krishnan S, Janjan NA, Skibber JM et al. 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: 762–71.
65. Kim JC, Kim TW, Kim JH et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2005; 63: 346–53.
66. Glynne-Jones R, Dunst J, Sebag-Montefiore D. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful we been? Ann Oncol 2006; 17: 361–71.
67. Machiels JP, Duck L, Honhon B et al. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study. Ann Oncol 2005; 16: 1898–5.
68. Rodel C, Liersch T, Hermann RM et al. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol 2007; 25: 110–7.
69. Rodel C, Grabenbauer GG, Papadopoulos T et al. Phase I/II trial of capecitabine, oxaliplatin and radiation for rectal cancer. J Clin Oncol 2003; 21: 3098–4.
70. Machiels JPP, Duck L, Honhon B. Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with locally advanced rectal adenocarcinomas: the RadiOxCape Study. Proc Am Soc Clin Oncol G1 2005; Abstr. 245.
71. Willeke F, Tiefenbacher U, Hochhaus A. Phase II trial of capecitabine and irotecan in combination with concurrent radiotherapy for neoadjuvant treatment of locally advanced rectal cancer. J Clin Oncol 2005; 23 (Suppl. 16S): 268s (Abstr. 3589).
72. Gollins SW, Myint S, Levine E. Phase I study of radiotherapy (RT) plus concurrent irinotecan (CPT-11) and capecitabine (CAP) as preoperative downstaging treatment for locally advanced inoperable rectal cancer. J Clin Oncol 2005; 23 (Suppl. 16S): 262s (Abstr. 3565).
73. Talbot DC, Moiseyenko V, Van Belle S et al. Randomized phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 2002; 86: 1367–72.
74. Blum JL, Jones S, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–93.
75. Reichardt P, Von Minckwitz G, Thus-Patience PC et al. 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: 1227–33.
76. Fumoleau P, Largillier R, Clippe C et al. Multicentre phase II study evaluating capecitabine monotherapy in patients with anthracycline and taxane pretreated metastatic breast cancer. Eur J Cancer 2004; 40: 536–42.
77. Blum JL, Dieras V, Lo Russo PM et al. Multicenter phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92: 1759–68.
78. Wist EA, Sommer HH, Ostenstad B et al. Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer. Acta Oncol 2004; 43: 186–9.
79. Kalbakis K, Kouroussis C, Kakolyris S et al. Salvage chemotherapy with high-dose leucovorin (LV) and 48-h continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with metastatic breast cancer (MBC) pretreated with anthracycline and taxanes. Br J Cancer 2001; 85: 798–802.
80. O'Shaughnessy JA, Blum J, Moiseyenko V. Randomized open-label phase II trial of oral capecitabine (Xeloda) vs a reference arm of iv CMF as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001; 12: 1247–54.
81. Bajetta E, Procopio G, Celio L et al. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005; 23: 2155–61.
82. O'Shaughnessy J, Miles D, Vukelja S et al. 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: 2812–23.
83. Lee KS, Lee ES, Kwon YM. Mature results from a randomized phase III trial of docetaxel/capecitabine (TX) vs. doxorubicin/cyclophosphamide (AC) as primary chemotherapy for patients (pts) with stage II/III breast cancer (BC). Breast Cancer Res Treat 2005; 94 (Suppl. 1): S224.
84. Blum JL, Dees C, Negron A. A phase II trial of combination therapy with capecitabine (C) and weekly paclitaxel (P) for metastatic breast cancer (MBC): preliminary results in taxanes-naive patients. Breast Cancer Res Treat 2004; 88 (Suppl. 1): S202.
85. Batista N, Perez-Manga G, Constenla M et al. Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Br J Cancer 2004; 90: 1740–6.
86. Ghosn M, Kattan J, Farhat F et al. Phase II trial of capecitabine and vinorelbine as first-line chemotherapy for metastatic breast cancer patients. Anticancer Res 2006; 26: 2451–6.
87. Welt A, Von Minckwitz G, Oberhoff C et al. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. Ann Oncol 2005; 16: 64–9.
88. Ahn JH, Kim SB, Kim TW et al. Capecitabine and vinorelbine in patients with metastatic breast cancer previously treated with anthracycline and taxane. J Korean Med Sci 2004; 19: 547–53.
89. Nole F, Catania C, Sanna G et al. Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer. Ann Oncol 2006; 17: 322–9.
90. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–9.
91. Xu L, Song S, Zhu J. A phase II trial of trastuzumab (H) plus capecitabine (X) as first-line treatment in patients (pts) with HER 2-positive metastatic breast cancer (MBC). Breast Cancer Res Treat 2005; 94 (Suppl. 1): S281.
92. Yamamoto D, Iwase S, Kitamura K et al. Multicenter phase II study of trastuzumab (H) and capecitabine (X) as first-or second-line treatment in HER2-overexpressing metastatic breast cancer. (Japan Breast Cancer Study Group: JBCSG-003). J Clin Oncol 2005; 23: 78s (Meeting Abstracts).
93. Schaller G, Bangemann N, Gonsch T. Capecitabine and trastuzumab: a phase II study in HER2-overexpressing metastatic breast cancer (MBC) patients pretreated with anthracyclines and/or taxanes. Breast Cancer Res Treat 2005; 94 (Suppl. 1): S95.
94. Chan A, Tubiana N, Ganju V. Optimal tolerance of an all-oral combination chemotherapy (CT) of oral vinorelbine (NVBo), capecitabine (C) with/without trastuzumab (T) in metastatic breast cancer (MBC) patients (pts): safety results of two international multicenter studies. J Clin Oncol 2006; 24: 576s.
95. Minea L, Stanculeanu DL, Cringeanu A. Capecitabine monotherapy for elderly patients with metastatic breast cancer. J Clin Oncol 2004; 21 (14S): 76s.
96. Hess D, Thurlimann B, Pagani O et al. Phase I–II trial of capecitabine and vinorelbine in elderly patients (pts >65y) with metastatic breast cancer (MBC): SAKK 25/99 for the Swiss Group of Clinical Cancer Research, Berne, Switzerland. Proc Am Soc Clin Oncol 2002; 21: 274b.
97. Braud A, Joly F, Rios M. Preservation of activities of daily living (ADL) in a phase-II impact study of oral capecitabine and vinorelbine in the treatment of metastatic carcinomas in patients 70 and older: the GERICO-01 Study by the French FNCLCC Group. J Clin Oncol 2004; 22 (Suppl. 14S): 768s.
98. Longo F, Magnolfi E, Borgomastro A. Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC). J Clin Oncol 2004; 22 (Suppl. 14S): 86s.
99. Procopio G, Bajetta E, Gattinoni L. Safety and activity of capecitabine in elderly patients (pts) with advanced breast cancer. Proc Am Soc Clin Oncol 2003; 22: 759.
100. Jonker DJ, Vincent M, Kerr I. Dose reduced first-line capecitabine monotherapy in older and less fit patients with advanced colorectal cancer. Proc Am Soc Clin Oncol Gi 2004; Abst. 212.
101. Escudero P, Verge V, Feliu J. A study of capecitabine in elderly patients as first line treatment in advanced or metastatic colorectal cancer. Proc Am Soc Clin Oncol 2003; 22: 775.
102. Carreca I, Cornella L, Mairino V. Oral capecitabine plus oxaliplatin (XELOX regimen) in elderly patients with advanced colorectal carcinoma (ACC): Southern Italy Cooperative Oncology Group (SICOG 0108) phase II study. Proc Am Soc Clin Oncol 2004; 22: 731.
103. Lopez-Gomez L, Escudero P, Yubero A. XELOX (capecitabine and oxaliplatin) as first-line treatment for elderly patients with advanced/metastatic colorectal cancer. J Clin Oncol 2004; 22 (Suppl. 14): 291s.
104. Twelves C, Butts C, Cassidy J et al. XELOX (capecitabine plus oxaliplatin), a safe and active first-line regimen for elderly patients with metastatic colorectal cancer (MCRC): post hoc analysis of a large phase II study. J Clin Oncol 2004; 23: 258s.
105. Bollina R, Beretta G, Toniolo D. Capecitabine (C) and irinotecan (I) (CAPIRI): a good combination in elderly patients (pts) with advanced colorectal cancer (ACRC) as first line chemotherapy (CT). Preliminary results of a phase II trial. Proc Am Soc Clin Oncol 2003; 22: 332.
106. Feliu J, Escudero P, Losa F. A phase II study of capecitabine in elderly patients as first-line treatment for patients with advanced or metastatic colorectal cancer. J Clin Oncol 2004; 22 (Suppl. 14S): 261s.
107. Cassidy J, Scheithauer W. Capecitabine (X) vs. bolus 5-FU/leucovorin (LV) as a adjuvant therapy for colon cancer (the X-ACT study): positive efficacy results of a phase III trial. J Clin Oncol 2004; 22 (Suppl. 14S): 246s.
108. Ersler WB. Capecitabine use in geriatric oncology: an analysis of current safety, efficacy, and quality of life data. Crit Rev Oncol Hem 2006; 58: 68–78.
109. Saif MW, Diasio R. Is capecitabine safe in GI cancer patients with dihydropyrimidine dehydrogenase (DPD) deficiency? Clin Colorectal Cancer 2006; 5: 359–62.
110. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330–8.
111. Mattison LK, Ezzeldin H, Carpenter M et al. Rapid identification of dihydropyrimidine dehydrogenase deficiency by using a novel 2-13C-urasil breath test. Clin Cancer Res 2004; 10: 2652–8.
112. Van Kuilenburg AB, Klumpen HJ, Westermann AM et al. Increased dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil and leucovorin. Eur J Cancer 2007; 43: 459–65.
113. Lu Z, Zhang R, Carpenter JT, Diasio RB. Decreased dihydropyrimidine dehydrogonase activity in a population of patients with breast cancer: implications for 5-fluorouracil-based chemotherapy. Clin Cancer Res 1998; 4: 325–9.
114. Morrison GB, Bastian A, Dela Rosa T et al. Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncol Nurs Forum 1997; 24: 83–8.
115. Mattison LK, Fourie J, Hirao Y et al. The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2–13C]dihydrouracil. Clin Cancer Res 2002; 12: 549–55.
116. Asgari MM, Haggerty JG, Mcniff JM et al. Expression and localization of thymidine phosphorylase/platelet-derived endothelial cell growth factor in skin and cutaneous tumors. J Cutan Pathol 1999; 26: 287–94.
117. Mrozek-Orlowski ME, Frye DK, Sanborn HM. Capecitabine: nursing implications of a new oral chemotherapeutic agent. Oncol Nurs Forum 1999; 26: 753–62.
118. Blum JL, Smith SE, Buzbar AU. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–93.
119. Saif MW, Elfiky A, Diasio R. Hand foot syndrome (HFS) variant in DPD-deficient patient treated with capecitabine. Clin Colorectal Cancer 2006; 6: 219–23.
120. Chin SF, Tchen N, Oza AM. Use of 'bag balm' as topical treatement of palmarplantar erythrodysesthesia syndrome in patients receing selected chemotherapeutic agents. Proc Am Soc Clin Oncol 2001; 20: Abstr. 1632.
121. Andres R, Mayordomo JI, Lara R et al. Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes. Clin Breast Cancer 2005; 6: 158–62.
122. Fan L, Liu WC, Zhang YJ et al. Oral Xeloda plus bi-platinu two-way combined chemotherapy in treatment of advanced gastrointestinal malignancies. World J Gastroenterol 2005; 11: 4300–4.
123. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capecitabine-induced HFS and antitumor activity. Oncology 2002; 16 (12 Suppl. 14): 31–7.
124. Vakalis D, Loannides D, Lazaridou E et al. Acral erythema induced by chemotherapy with cisplatin. Br J Dermatol 1998; 139: 750–1.
125. Esteve E, Schillio Y, Vaillant Let al. Efficacite de la corticothe  rapie se quentielle dans un cas d'e  rythe`me acral douloureux secondaire au 5-fluoro-uracile a' fortes doses. Ann Med Interne (Paris) 1995; 146: 192–3.
126. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 2006; 12: 131–41.
127. Becker K, Erckenbrecht JF, Haussinger D, Fieling T. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs 1999; 57: 475–84.
128. Saif MW, Szabo E, Grem J, Hamilton M. The clinical syndrome of 5-FU cardiotoxicity. Proceedings of American Society of Oncology 2001; 20 (Part I): 404a.
129. Teixeira L, Barry S, Debourdeau P et al. Cardiotoxicity of 5-fluorouracil. Bull Cancer 2004; 91 (Suppl. 3): 154–8.
130. Saif MW, Tomita M, Ledbetter L, Diasio RB. Capecitabine-related cardiotoxicity: recognition and management. J Support Oncol 2008; 6: 41–8.
131. Aksoy S, Karaca B, Dincer M, Yalcin S. Common etiology of capecitabine and fluorouracil-induced coronary vasospasm in a colon cancer patient. Ann Pharmacother 2005; 39: 573–4.
132. Jensen SA, Sorensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 2006; 58: 487–93.
133. Quinney SK, Sanghani P, DavisWI. Hydrolysis of capecitabine to 50-deoxy-5-fluorocytidine by human carboxylesterase and inhibition by loperamide. J Pharmacol Exp Ther 2005; 313: 1011–6.
134. Jansman FGA, Sleijfer DT, De Graaf J. Management of chemotherapyinduced adverse effects in the treatment of colorectal cancer. Drug Safety 2001; 24: 353–67.
135. Cheng KK, Chang AM. Palliation of oral mucositis symptoms in pediatric patients treated with cancer chemotherapy. Cancer Nurs 2003; 26: 476–84.
136. Saif MW, Fekrazad MH, Lyerly R, Diasio R. Hypokalemia secondary to capecitabine: a hidden toxicity? Therapeutics and Clinical Risk Management 2007; 3: 177–80.
137. Haller et al. American Society of Clinical Oncology, 2006. Abstract 3514.
138. Hoff et al. J Clin Oncol 2001; 19: 2282–92.
139. Twelves et al. N Engl J Med 2005; 352: 2696–704.
140. Blum et al. J Clin Oncol 1999; 17: 485–93.
141. O'Shaughnessy et al. J Clin Oncol 2002; 20: 2812–23.

________________________________________________

Muhammad Wasif Saif1, Nikos A.Katirtzoglou2, Kostas N.Syrigos1, 2

1 Medical Oncology, Yale University School of Medicine, Section of Medical Oncology, New Haven, Connecticut, USA;
2 Oncology Unit, Third Department of Medicine, Athens Medical School, Sotiria General Hospital, Athens, Greece Anti-Cancer Drugs 2008; 19: 447–64