Cancer Res Treat.  2006 Feb;38(1):30-34.

Optimal Timing for the Administration of Capecitabine with Preoperative Chemoradiation for Locally Advanced Rectal Cancer

• Noh YJ
• Choi WS
• Kim JH
• Kim JC
• Yu CS
• Kim HC
• Kim TW
• Chang HM
• Ryu MH
• Ahn SD
• Lee SW
• Shin SS
• Lee JE
• Choi EK

Abstract

PURPOSE
Capecitabine is an oral fluoropyrimidine carbamate and it is known as an effective radiosensitizer. Capecitabine and its metabolite reach their peak concentration in the plasma at 1~2 hours after a single oral administration of capecitabine and the levels fall rapidly thereafter. To verify the radiosensitizing effect of capecitabine that is based on such pharmacokinetic characteristics, we performed a retrospective analysis on the optimal timing of capecitabine administration with performing preoperative chemoradiation for locally advanced rectal cancer.
MATERIALS AND METHODS
Among 171 patients who were treated with preoperative radiotherapy and concurrent capecitabine administration for rectal cancer, 56 patients were administered capecitabine at 1~2 hours before radiotherapy (group A), and at other time in the other 115 patients (group B). Total mesorectal excision was done at 4 to 6 weeks after the completion of chemoradiation. The radiosensitizing effect of capecitabine was evaluated on the basis of the pathological response.
RESULTS
Complete pathological regression of the primary tumor was observed in 12 patients (21.4%) for group A and in 11 patients (9.6%) for group B (p=0.031). Residual disease less than 0.5 cm (a good response) was observed in 19 patients (33.9%) for group A and in 23 patients (20.0%) for group B (p=0.038). On multivariate analysis, the capecitabine ingestion time showed marginal significance.
CONCLUSION
When performing preoperative chemoradiation for locally advanced rectal cancer, the radiosensitizing effect of capecitabine was enhanced when it was administered 1 hour before radiotherapy.

Keyword

Rectal neoplasms; Combined modality therapy; Capecitabine

MeSH Terms

Administration, Oral
Combined Modality Therapy
Eating
Humans
Multivariate Analysis
Plasma
Radiation-Sensitizing Agents
Radiotherapy
Rectal Neoplasms*
Retrospective Studies
Capecitabine
Radiation-Sensitizing Agents

Reference

1. Rich T, Gunderson LL, Lew R, Galdibini JJ, Cohen AM, Donaldson G. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer. 1983; 52:1317–1329. PMID: 6192900.

2. Mendenhall WM, Million RR, Pfaff WW. Patterns of recurrence in adenocarcinoma of the rectum and rectosigmoid treated with surgery alone: implications in treatment planning with adjuvant radiation therapy. Int J Radiat Oncol Biol Phys. 1983; 9:977–985. PMID: 6863077.

3. Gunderson LL, Sargent DJ, Tepper JE, O'Connell MJ, Allmer C, Smalley SR, et al. Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer; a pooled analysis. Int J Radiat Oncol Biol Phys. 2002; 54:386–396. PMID: 12243812.

4. Cedermark B, Johansson H, Rutqvist LE, Wilking N. Stockholm Colorectal Cancer Study Group. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Cancer. 1995; 75:2269–2275. PMID: 7712435.

5. Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997; 336:980–987. PMID: 9091798.

6. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001; 345:638–646. PMID: 11547717.

7. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2000; 284:1008–1015. PMID: 10944647.

8. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985; 312:1465–1472. PMID: 2859523.

9. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med. 1991; 324:709–715. PMID: 1997835.

10. Tepper JE, O'Connell M, Niedzwiecki D, Hollis DR, Benson AB 3rd, Cummings B, et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control-final report of intergroup 0114. J Clin Oncol. 2002; 20:1744–1750. PMID: 11919230.

11. Ishikawa T, Utoh M, Sawada N, Nishida M, Fukase Y, Sekiguchi F, et al. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem Pharmacol. 1998; 55:1091–1097. PMID: 9605432.

12. 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-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998; 34:1274–1281. PMID: 9849491.

13. 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; 45:291–297. PMID: 10755317.

14. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, 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; 19:4097–4106. PMID: 11689577.

15. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, 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; 19:2282–2292. PMID: 11304782.

16. Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet. 2001; 40:85–104. PMID: 11286326.

17. Tepper JE. Cancer of the Colon, Rectum and Anus. ASTRO 2004 refresher course, 305. In : presented at 46th Annual meeting of the ASTRO (American Society for Therapeutic Radiology and Oncology);

18. Kim JS, Kim JS, Cho MJ, Song KS, Yoon WH. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2002; 54:403–408. PMID: 12243814.

19. Kim JC, Kim TW, Kim JH, Yu CS, Kim HC, Chang HM, et al. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2005; 63:346–353. PMID: 15913913.

20. Dunst J, Reese T, Sutter T, Zuhlke H, Hinke A, Kolling-Schlebusch K, et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol. 2002; 20:3983–3991. PMID: 12351595.

21. Cassidy J, Twelves C, Cameron D, Steward W, O'Byrne K, Jodrell D, et al. Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface, and creatinine clearance as factors influencing systemic exposure in cancer patients. Cancer Chemother Pharmacol. 1999; 44:453–460. PMID: 10550565.

22. Reigner B, Verweij J, Dirix L, Cassidy J, Twelves C, Allman D, et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res. 1998; 4:941–948. PMID: 9563888.

23. Yu CS, Kim JH, Lee JH, Kim TW, Chang HM, Namgung H, et al. Efficacy of preoperative radio-chemotherapy in patients with advanced low rectal cancer. J Korean Soc Coloproctol. 2004; 20:46–51.

24. De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, et al. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study. Ann Oncol. 2006; 17:246–251. PMID: 16282246.