ORIGINAL ARTICLE

JOP. J Pancreas (Online) 2005; 6(4):325-333.

Gastrointestinal Bleeding Associated with Concurrent Capecitabine and Radiotherapy in Patients with Pancreatic Cancer

Muhammad Wasif Saif1, John S Moody2, Suzanne M Russo2

1Division of Hematology-Oncology and 2Division of Radiation Oncology, Department of Medicine, University of Alabama at Birmingham (UAB). Birmingham, AL, USA

ABSTRACT

Context Capecitabine is currently being evaluated for the treatment of a variety of gastrointestinal malignancies.

Objective The aim of this study is to report on the incidence of late gastrointestinal bleeding in patients with pancreatic cancer who received concurrent capecitabine and abdominal irradiation followed by prolonged capecitabine therapy.

Patients We reviewed the medical records of 24 patients (13 female, 11 males; median age of 64.5 years): 22 cases of adenocarcinoma and 2 cases of neuroendocrine carcinoma. Initially, 4 patients underwent surgical resection. Median follow-up was 10.3 months.

Interventions Patients received capecitabine (600-800 mg/m2 orally twice daily) with concurrent radiation (50.4-54.0 Gy). Patients who were resected received an additional 2-4 cycles of capecitabine; otherwise, capecitabine was given indefinitely until disease progression occurred.

Main outcome measure Incidence of late gastrointestinal bleeding.

Results Three patients developed gastrointestinal bleeding after concurrent capecitabine and irradiation and 2 of these patients died as a result of this toxicity.

Conclusions Our study indicates that serious gastrointestinal bleeding is a possible late complication associated with concurrent capecitabine and irradiation therapy for pancreatic cancer followed by additional capecitabine therapy. Caution and close monitoring should therefore be used when continuing capecitabine therapy in this setting.

Full text  HTML format  PDF format


References

  1. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3:330-8. [More details]

  2. Lewis NL, Meropol NJ. Oral fluoropyrimidines in cancer treatment. Cancer Invest 2000; 18:747-60. [More details]

  3. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluoruracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34:1274-81. [More details]

  4. Ishikawa T, Utoh M, Sawada N, Nishida M, Fukase Y, Sekiguchi F, Ishitsuka H. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharmacol 1998; 55:1091-7. [More details]

  5. Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45:291-7. [More details]

  6. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2000; 284:3043-5. [More details]

  7. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991, 21; 109-22. [More details]

  8. Lawrence TS, Davis MA, Tang HY, Maybaum J. Fluorodeoxyuridine-mediated cytotoxicity and radiosensitization require S-phase progression. Int J Radiat Oncol Biol Phys 1996; 70:273-80. [More details]

  9. Grem JL. 5-Fluoropyrimidines In: Chabner BA, Longo DL, eds. Cancer Chemotherapy and Biotherapy:Principles and Practice. 2nd Ed. Philadelphia, PA, USA: Lippencott, 1996:149-211. [More details]

  10. Canman CE, Lawrence TS, Shewach DS, Tang HY, Maybaum J. Resistance to fluorodeoxyuridine –induced DNA damage and cytotoxicity correlates with an elevation of deoxyuridine triphosphatase activity and failure to accumulate deoxyuridine triphosphate. Cancer Res 1993; 53:5219-24. [More details]

  11. Grem JL, Mulcahy RT, Miller EM, Allegra CJ, Fischer PH. Interaction of deoxyuridine with fluorouracil and dipyridamole in human colon cancer cell line. Biochem Pharmacol 1989; 38:51-9. [More details]

  12. Houghton JA, Tillman DM, Harwood FG. Ratio of 2’-deozyadenosine-5’-triphosphate/thymidine-5’-triphosphate influences the commitment of human colon carcinoma cells to thymidineless death. Clin Cancer Res 1995; 1:723-30. [More details]

  13. Jones S, Willmore E, Durkacz BW. The effect of 5-fluoropyrimidines on nascent DNA synthesis in Chinese hamster ovary cells monitored by pH-step alkaline and neutral elution. Carcinogenesis 1994; 15:2435. [More details]

  14. Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 1999; 5:2948-53. [More details]

  15. Cartwright TH, Cohn A, Varkey JA, Chen YM, Szatrowski TP, Cox JV, Schulz JJ. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002; 20:160-4. [More details]

  16. Crane CH , EllisLM, Oreilly M, Ho L, Abbruzzese JL, Evans DB, et al. RhuMab VEGF (bevacizumab) with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer: An active, well tolerated regimen. Int J Radiat Oncol Biol Phys 2004; 60(Suppl 1):S149. [More details]

  17. Hess V, Salzberg M, Borner M, Morant R, Roth AD, Ludwig C, Herrmann R. Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a phase i/ii trial. J Clin Oncol 2003; 21:66-8. [More details]

  18. Vaishampayan UN, Ben-Josef E, Philip PA, Vaitkevicius VK, Du W, Levin KJ, Shields AF. A single-institution experience with concurrent capecitabine and radiation therapy in gastrointestinal malignancies. Int J Radiat Oncol Biol Phys 2002; 53:675-9. [More details]

  19. Reese T, Tanner J, Frings S, Dunst J. Capecitabine combined with simultaneous radiotherapy in rectal cancer: A phase I study (Abstr.). Int J Radiat Oncol Biol Phys 2000; 48:120-1. [More details]

  20. Ngan S, Zalcberg J, Kell A, Michael M, MacKay J, Lim Joon, et al. A phase I study of capecitabine combined with radiotherapy locally advanced potentially operable rectal cancer (Abstract). Proc ASCO 2001; 20:591, 104a. [More details]

  21. Yoon WH, Choi JH, Kim JR, Kim T, Lim K, Hwang B, et al. Enhanced tumoricidal effect of preoperative chemoradiation using capecitabine for locally advanced rectal cancer (Abstract). Proc ASCO 2001; 20:2165, 104b. [More details]

  22. Ortmann E, Hohenberg G. Treatment side effects. Case 1. Radiation recall phenomenon after administration of capecitabine. J Clin Oncol 2002; 20:3029-30. [More details]

  23. Jeffrey G, Truss C, Saif MW. Radiation recall syndrome associated with capecitabine. The Journal of Applied Research. 2004; 4:495-8. [More details]

  24. Ishii H, Okada S, Tokuuye K, Nose H, Okusaka T, Yoshimori M, et al. Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma. Cancer 1997; 79:1516-20. [More details]

  25. Brown MC. Multisite mucous membrane bleeding due to a possible interaction between warfarin and 5-fluorouracil. Pharmacotherapy 1997; 17:631-633. [More details]

  26. Okusaka T, Ito Y, Ueno H, Ikeda M, Takezako Y, Morizane C, et al. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 2004; 91:673-7. [More details]

  27. Pipas JM, Mitchell SE, Barth RJ Jr, Vera-Gimon R, Rathmann J, Meyer LP, et al. Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 2001; 50:1317-22. [More details]

  28. Talamonti MS, Catalano PJ, Vaughn DJ, Whittington R, Beauchamp RD, Berlin J, Benson AB 3rd. Eastern cooperative oncology group phase i trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity. J Clin Oncol 2000; 18:3384-9. [More details]

Keywords Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Toxicity; Fluorouracil; Gastrointestinal Hemorrhage; Pancreatic Neoplasms; Radiotherapy; Thymidine Phosphorylase

Correspondence Muhammad Wasif Saif: wasif.saif@ccc.uab.edu