Journal Mobile Options
Table of Contents
Vol. 72, No. 5-6, 2007
Issue release date: February 2008
Oncology 2007;72:330–337

Dose-Finding Phase I and Pharmacokinetic Study of Capecitabine (Xeloda) in Combination with Epirubicin and Cyclophosphamide (CEX) in Patients with Inoperable or Metastatic Breast Cancer

Saji S. · Toi M. · Morita S. · Iwata H. · Ito Y. · Ohno S. · Kobayashi T. · Hozumi Y. · Sakamoto J.
aDepartment of Surgery and Breast Oncology, Division of Clinical Trials and Research, Tokyo Metropolitan Komagome Hospital, bClinical Chemotherapy, Cancer Institute Hospital and cDepartment of Hematology and Oncology, Jikei University School of Medicine, Tokyo, dDepartment of Surgery, Graduate School of Medicine and eDepartment of Epidemiology and Health Care Research, School of Public Health, Kyoto University, Kyoto, fDepartment of Breast Oncology, Aichi Cancer Center Hospital, Aichi, gDepartment of Breast Oncology, National Kyushu Cancer Center, Fukuoka, hDepartment of Surgery, Jichi Medical School, Tochigi, and iMedical Administration Course of Masters Degree Program, Nagoya University, Nagoya, Japan

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Objective: The present study aimed to identify the recommended dose (RD) of capecitabine, epirubicin and cyclophosphamide (CEX) combination treatment for inoperable or metastatic breast cancer and to assess response rate, tolerability and pharmacokinetics in Japanese patients. Methods: Patients received 3-week cycles of fixed-dose intravenous cyclophosphamide (600 mg/m2, day 1), intravenous epirubicin (75–100 mg/m2, day 1) and oral capecitabine (628–900 mg/m2 twice daily, days 1–14). Dose escalation/deescalation decisions for consecutive cohorts were made using the continual reassessment method (CRM). RD was defined as dose level closest to that causing dose-limiting toxicity (DLT) in 33% of patients. Results: Among the 17 patients enrolled, 3 experienced DLT (hand-foot syndrome, anorexia, mucositis; all grade 3) and 3 (18%) febrile neutropenia. Based on CRM calculation, mean DLT occurrence probabilities (90% confidence intervals in parentheses) for levels 2, 3 and 4 were 21% (8–42%), 35% (17–56%) and 56% (38–71%), respectively. Level 3 was thus chosen as the RD. Combination treatment did not affect pharmacokinetic parameters of capecitabine, epirubicin or their metabolites. Objective responses were achieved by 7 patients (41%), including partial responses in 4 of 6 patients (67%) receiving the RD. Conclusion: CEX represents a well-tolerated regimen, and RD for Japanese patients was determined to be capecitabine 900 mg/m2 twice daily in combination with epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 using the CRM.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Hortobagyi GN: Treatment of breast cancer. N Engl J Med 1998;339:974–984.
  2. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569–1583.
  3. Trent JC, Valero V, Booser DJ, Esparza-Guerra LT, Ibrahim N, Rahman Z, Vernillet L, Patel S, David CL, Murray JL, Cristofanilli M, Hortobagyi GN: A phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a phase II study as first-line therapy in metastatic breast cancer. Clin Cancer Res 2003;9:2426–2434.
  4. Jones SE, Savin MA, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24:5381–5387.
  5. 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.
  6. Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B: Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000;45:291–297.
  7. 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.
  8. Endo M, Shinbori N, Fukase Y, Sawada N, Ishikawa T, Ishitsuka H, Tanaka Y: Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5′-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 1999;83:127–134.
  9. Toi M, Atiqur Rahman M, Bando H, Chow LW: Thymidine phosphorylase (platelet-derived endothelial-cell growth factor) in cancer biology and treatment. Lancet Oncol 2005;6:158–166.
  10. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–493.
  11. Blum JL, Dieras V, Lo Russo PM, 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.
  12. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, 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.
  13. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O’Shaughnessy JA: Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2006;24:4384–4390.
  14. Gradishar WJ, Meza LA, Amin B, Samid D, Hill T, Chen YM, Lower EE, Marcom PK: Capecitabine plus paclitaxel as front-line combination therapy for metastatic breast cancer: a multicenter phase II study. J Clin Oncol 2004;22:2321–2327.
  15. Xu L, Song S, Zhu J: A phase II trial of trastuzumab (H) + capecitabine (X) as first-line treatment in patients (pts) with HER2-positive metastatic breast cancer (MBC). Ann Oncol 2006;17(suppl 9):169P.
  16. Wardley A, Anton-Torres A, Pivot X: Trastuzumab plus docetaxel with or without capecitabine in patients with HER2-positive advanced/metastatic breast cancer: primary efficacy results from a randomised phase II study (CHAT). Ann Oncol 2006;17(suppl 9):LBA6.
  17. Lybaert W, Wildiers H, Neven P: Multicentre phase II study of capecitabine (X), docetaxel (T) ± trastuzumab (H) as neoadjuvant treatment for patients (pts) with locally advanced breast cancer (LABC): preliminary safety and efficacy results. Ann Oncol 2006;17(suppl 9):154P.
  18. Venturini M, Durando A, Garrone O, Colozza MA, Contu A, Stevani I, Genta F, Bighin C, Lambiase A, Del Mastro L: Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated, advanced breast carcinoma. Cancer 2003;97:1174–1180.
  19. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733–2743.
  20. Joensuu H, Hemminki A, Tanner M: Phase III, randomized study of docetaxel (T) + capecitabine (X) (TX) followed by cyclophosphamide (C) + epirubicin (E) + X (CEX) vs. T followed by C + E + fluorouracil (F) (CEF) as adjuvant treatment for patients (pts) with early breast cancer (BC): an interim safety analysis. Proc Am Soc Clin Oncol 2005;23(suppl):719.
  21. Roché H, Deporte R, Berton-Rigaud D: Updated safety findings from a randomized phase II trial of capecitabine + epirubicin + cyclophosphamide (CEX) vs. 5-FU epirubicin + cyclophosphamide (FEC) as neoadjuvant therapy in patients (pts) with operable breast cancer (BC). Ann Oncol 2006;17(suppl 9):261P.
  22. Bonnefoi H, Biganzoli L, Mauriac L, Cufer T, Schaefer P, Atalay G, Piccart M: An EORTC phase I study of capecitabine (Xeloda) in combination with fixed doses of cyclophosphamide and epirubicin (CEX) as primary treatment for large operable or locally advanced/inflammatory breast cancer. Eur J Cancer 2003;39:1277–1283.
  23. Ishitsuka H: Capecitabine: preclinical pharmacology studies. Invest New Drugs 2000;18:343–354.
  24. O’Quigley J, Pepe M, Fisher L: Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics 1990;46:33–48.
  25. Ishizuka N, Morita S: Practical implementation of the continual reassessment method; in Crowley J, Ankerst DP (eds): Handbook of Statistics in Clinical Oncology, ed 2. Boca Raton, CRC Press, 2005.
  26. Morita S, Toi M, Kobayashi T, Ito Y, Hozumi Y, Ohno S, Iwata H, Sakamoto J: Application of a continual reassessment method to a phase I clinical trial of capecitabine in combination with cyclophosphamide and epirubicin (CEX) for inoperable or recurrent breast cancer. Jpn J Clin Oncol 2004;34:104–106.
  27. Ebi H, Sigeoka Y, Saeki T, Kawada K, Igarashi T, Usubuchi N, Ueda R, Sasaki Y, Minami H: Pharmacokinetic and pharmacodynamic comparison of fluoropyrimidine derivatives, capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR). Cancer Chemother Pharmacol 2005;56:205–211.
  28. Reigner B, Blesch K, Weidekamm E: Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001;40:85–104.
  29. Villalona-Calero MA, Weiss GR, Burris HA, Kraynak M, Rodrigues G, Drengler RL, Eckhardt SG, Reigner B, Moczygemba J, Burger HU, Griffin T, Von Hoff DD, Rowinsky EK: Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J Clin Oncol 1999;17:1915–1925.
  30. Pronk LC, Vasey P, Sparreboom A, Reigner B, Planting AS, Gordon RJ, Osterwalder B, Verweij J, Twelves C: A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer 2000;83:22–29.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50