Skip to main content

Advertisement

SpringerLink
Log in

A phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer

  • Phase I Studies
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC).

Methods: CRT comprised of 5FU (1000 mg/m2/day, days 1–4, weeks 1 & 5), cisplatin (75 mg/m2, days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose.

Results: Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 – >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 – >24.8) and 19.6 months (95% CI 7.3 – >39) respectively.

Conclusions: A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Refaely Y, Krasna MJ (2002) Multimodality therapy for esophageal cancer. Surg Clin North Am 82:729–746

    Article  PubMed  Google Scholar 

  2. Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:2241–2252

    Article  PubMed  CAS  Google Scholar 

  3. al-Sarraf M, Martz K, Herskovic A et al (1997) Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 15:277–284

    Google Scholar 

  4. Cooper JS, Guo MD, Herskovic A et al (1999) Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. Jama 281:1623–1627

    Article  PubMed  CAS  Google Scholar 

  5. Stahl M, Stuschke M, Lehmann N et al (2005) Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23:2310–2317

    Article  PubMed  Google Scholar 

  6. Walsh TN, Noonan N, Hollywood D et al (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462–467

    Article  PubMed  CAS  Google Scholar 

  7. Berger AC, Farma J, Scott WJ et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330–4337

    Article  PubMed  Google Scholar 

  8. Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916

    Article  PubMed  CAS  Google Scholar 

  9. Shamma A, Yamamoto H, Doki Y et al (2000) Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus. Clin Cancer Res 6:1229–1238

    PubMed  CAS  Google Scholar 

  10. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ (1998) Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinomas. Cancer Res 58:2929–2934

    PubMed  CAS  Google Scholar 

  11. Zimmermann KC, Sarbia M, Weber AA et al (1999) Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 59:198–204

    PubMed  CAS  Google Scholar 

  12. von Rahden BH, Stein HJ, Puhringer F et al (2005) Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma. Cancer Res 65:5038–5044

    Article  PubMed  CAS  Google Scholar 

  13. Souza RF, Shewmake K, Beer DG et al (2000) Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells. Cancer Res 60:5767–5772

    PubMed  CAS  Google Scholar 

  14. Morgan G, Vainio H (1998) Barrett's oesophagus, oesophageal cancer and colon cancer: an explanation of the association and cancer chemopreventive potential of non-steroidal anti-inflammatory drugs. Eur J Cancer Prev 7: 195–199

    Article  PubMed  CAS  Google Scholar 

  15. Masferrer JL, Leahy KM, Koki AT et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60:1306–1311

    PubMed  CAS  Google Scholar 

  16. Sweeney CJ (2003) Why cyclooxygenase-2 inhibition plus chemotherapy? Am J Clin Oncol 26:S122–S125

    PubMed  Google Scholar 

  17. Ratnasinghe D, Daschner PJ, Anver MR et al (2001) Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible? Anticancer Res 21:2141–2147

    PubMed  CAS  Google Scholar 

  18. Uchida K, Schneider S, Yochim JM et al (2005) Intratumoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 11:3363–3368

    Article  PubMed  CAS  Google Scholar 

  19. Kishi K, Petersen S, Petersen C et al (2000) Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res 60:1326–1331

    PubMed  CAS  Google Scholar 

  20. Milas L, Kishi K, Hunter N et al (1999) Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase-2 enzyme. J Natl Cancer Inst 91:1501–1504

    Article  PubMed  CAS  Google Scholar 

  21. Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance? J Natl Cancer Inst 95:1440–1452

    PubMed  CAS  Google Scholar 

  22. Greene FL et al (2002) AJCC cancer staging manual. Springer-Verlay, New York

    Google Scholar 

  23. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  24. Bombardier C, Laine L, Reicin A et al (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343:1520–1528, 1522 p following 1528

    Google Scholar 

  25. FitzGerald GA, Patrono C (2001) The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 345:433–442

    Article  PubMed  CAS  Google Scholar 

  26. Silverstein FE, Faich G, Goldstein JL et al (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. Jama 284:1247–1255

    Article  PubMed  CAS  Google Scholar 

  27. Harris RC Jr (2002) Cyclooxygenase-2 inhibition and renal physiology. Am J Cardiol 89:10D–17D

    Article  PubMed  CAS  Google Scholar 

  28. Bresalier RS, Sandler RS, Quan H et al (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102

    Article  PubMed  CAS  Google Scholar 

  29. Solomon SD, McMurray JJ, Pfeffer MA et al (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071–1080

    Article  PubMed  CAS  Google Scholar 

  30. Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with selective COX-2 inhibitors. Jama 286:954–959

    Article  PubMed  CAS  Google Scholar 

  31. Lorenz M, Slaughter HS, Wescott DM et al (1999) Cyclooxygenase-2 is essential for normal recovery from 5-fluorouracil-induced myelotoxicity in mice. Exp Hematol 27:1494–1502

    Article  PubMed  CAS  Google Scholar 

  32. Leese PT, Hubbard RC, Karim A et al (2000) Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 40:124–132

    Article  PubMed  CAS  Google Scholar 

  33. Govindan R, McLeod H, Mantravadi P et al (2004) Cisplatin, fluorouracil, celecoxib, and RT in resectable esophageal cancer: preliminary results. Oncology (Williston Park) 18:18–21

    Google Scholar 

  34. Enzinger PC et al (2004) Phase II trial of cisplatin, irinotecan, celecoxib and concurrent radiotherapy followed by surgery for locally advanced esophageal cancer. ASCO GI Symposium

Download references

Acknowledgments

Juliana Di Iulio for her assistance with data management.

Author information

Authors and Affiliations

  1. Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    S. J. Dawson, M. Michael, J. Biagi, K. F. Foo, M. Jefford & J. R. Zalcberg

  2. Department of Radiation Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    S. Y. Ngan, T. Leong & A. Hui

  3. Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    A. D. Milner

  4. Division of Surgical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Victoria, 8006, Australia

    R. J. S. Thomas

  5. The University of Melbourne, Parkville, Victoria, 3010, Australia

    M. Jefford & J. R. Zalcberg

Authors
  1. S. J. Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Michael
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Biagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. F. Foo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Jefford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Y. Ngan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Leong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. D. Milner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. J. S. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J. R. Zalcberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. J. Dawson.

Additional information

This trial has been presented in part at the American Society of Clinical Oncology Gastrointestinal Symposium January 2006.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dawson, S.J., Michael, M., Biagi, J. et al. A phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer. Invest New Drugs 25, 123–129 (2007). https://doi.org/10.1007/s10637-006-9016-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-006-9016-5

Keywords

Search

Navigation