Journal of Radiation Oncology

, Volume 5, Issue 4, pp 363–369 | Cite as

Long-term results of a phase I/II trial of the addition of celecoxib to chemoradiotherapy for locally advanced or recurrent squamous cell carcinoma of the head-and-neck

  • Andrew M. McDonald
  • Roger OveEmail author
  • James A. Bonner
  • Lisle M. Nabell
  • William R. Carroll
  • Nasser Said Al-Naief
  • Margaret Brandwein-Gensler
  • Sharon A. Spencer
Original Research



We performed this open-label phase I/II trial to investigate concurrent celecoxib as a radiosensitizer during chemoradiotherapy.

Methods and materials

Eligible patients included those with newly diagnosed, or recurrent, stage III or IVA locoregionally advanced squamous cell carcinoma of the head-and-neck (SCCHN), excluding nasopharyngeal tumors. The primary tumor was prescribed 70.2 Gy with concurrent weekly carboplatin and paclitaxel. Celecoxib was dosed at 400 mg twice daily, beginning 1 week prior to radiotherapy.


Thirty patients were enrolled between 2002 and 2007. The median age at enrollment was 57.6 years, and the median follow-up for surviving patients was 10.4 years (range 5.9–11.8 years). The complete clinical response rate was 87 %, nearly achieving the primary end point goal of 90 %. The 5-year actuarial disease-free survival (DFS) and overall survival (OS) were 40 and 53.3 %. Fourteen (47 %) patients experienced grade 3 or worse acute hematologic toxicity. Five (17 %) patients experienced grade 4 acute non-hematologic toxicity.


Celecoxib appears to be a safe addition to cisplatin-based chemoradiotherapy for the primary treatment of locoregionally advanced SCCHN. Initial response rates were encouraging, and survival compared favorably with contemporary trials. Unfortunately, concern for cardiac toxicity of the drug led to early closure and limited statistical significance.


Celecoxib Radiosensitization Head-and-neck cancer Radiotherapy Chemotherapy Chemoradiation Squamous cell carcinoma 


Compliance with ethical standards


This trial was supported by Pharmacia/Pfizer and Bristol-Myers-Squibb.

Conflict of interest

James A. Bonner has acted as occasional consultant/honoraria for Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Serono, and Oncolytics. Andrew M. McDonald, Roger Ove, Lisle M. Nabell, William R. Carroll, Nasser Said Al-Naief, Margaret Brandwein-Gensler, and Sharon A. Spencer declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the University of Alabama at Birmingham Institutional Review Board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Ang KK et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Adelstein DJ et al (2003) An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21(1):92–98CrossRefPubMedGoogle Scholar
  3. 3.
    Harrington KJ et al (2009) Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. J Clin Oncol 27(7):1100CrossRefPubMedGoogle Scholar
  4. 4.
    Lewis CM et al (2012) A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 18(5):1435–1446CrossRefPubMedGoogle Scholar
  5. 5.
    Cohen EE et al (2010) Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 28(20):3336–3343CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Egloff AM et al (2014) Phase II study of cetuximab in combination with cisplatin and radiation in unresectable, locally advanced head and neck squamous cell carcinoma: eastern cooperative oncology group trial E3303. Clin Cancer Res 20(19):5041–5051CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Fury, M.G., et al. (2015) A phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity modulated radiation therapy (IMRT) for patients with stage III/IVB head and neck squamous cell carcinoma (HNSCC). Head NeckGoogle Scholar
  8. 8.
    Ang KK et al (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32(27):2940–2950CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mesia R et al (2015) Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol 16(2):208–220CrossRefPubMedGoogle Scholar
  10. 10.
    Chan AT et al (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294(8):914–923CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sorensen HT et al (2003) Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study. Br J Cancer 88(11):1687–1692CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Smalley W et al (1999) Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Intern Med 159(2):161–166CrossRefPubMedGoogle Scholar
  13. 13.
    Sheng H et al (1998) Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58(2):362–366PubMedGoogle Scholar
  14. 14.
    Hsu AL et al (2000) The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem 275(15):11397–11403CrossRefPubMedGoogle Scholar
  15. 15.
    Sawaoka H et al (1999) Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Investig 79(12):1469–1477PubMedGoogle Scholar
  16. 16.
    Masferrer JL et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60(5):1306–1311PubMedGoogle Scholar
  17. 17.
    Kishi K et al (2000) Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res 60(5):1326–1331PubMedGoogle Scholar
  18. 18.
    Petersen C et al (2000) Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor. Clin Cancer Res 6(6):2513–2520PubMedGoogle Scholar
  19. 19.
    Hida T et al (2000) Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 6(5):2006–2011PubMedGoogle Scholar
  20. 20.
    Suntharalingam M et al (2000) The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 47(1):49–56CrossRefPubMedGoogle Scholar
  21. 21.
    Isayeva T et al (2014) African Americans with oropharyngeal carcinoma have significantly poorer outcomes despite similar rates of human papillomavirus-mediated carcinogenesis. Hum Pathol 45(2):310–319CrossRefPubMedGoogle Scholar
  22. 22.
    James K et al (1999) Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst 91(6):523–528CrossRefPubMedGoogle Scholar
  23. 23.
    Pfister DG et al (2014) Head and neck cancers, version 2.2014. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 12(10):1454–1487Google Scholar
  24. 24.
    Beitler JJ et al (2014) Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89(1):13–20CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bourhis J et al (2012) Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol 13(2):145–153CrossRefPubMedGoogle Scholar
  26. 26.
    Kalyankrishna S, Grandis JR (2006) Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 24(17):2666–2672CrossRefPubMedGoogle Scholar
  27. 27.
    Balaban N et al (1996) The effect of ionizing radiation on signal transduction: antibodies to EGF receptor sensitize A431 cells to radiation. Biochim Biophys Acta 1314(1–2):147–156CrossRefPubMedGoogle Scholar
  28. 28.
    Schmidt-Ullrich RK et al (1997) Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15(10):1191–1197CrossRefPubMedGoogle Scholar
  29. 29.
    Bonner JA et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578CrossRefPubMedGoogle Scholar
  30. 30.
    Jimeno A et al (2015) A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncol 51(4):383–388CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Leiker, A., et al., Radiation enhancement of head and neck squamous cell carcinoma by the dual PI3K/mTOR inhibitor PF-05212384. Clin Cancer Res, 2015.Google Scholar
  32. 32.
    Guster JD et al (2014) The inhibition of PARP but not EGFR results in the radiosensitization of HPV/p16-positive HNSCC cell lines. Radiother Oncol 113(3):345–351CrossRefPubMedGoogle Scholar
  33. 33.
    Thun MJ, Namboodiri MM, Heath CW Jr (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325(23):1593–1596CrossRefPubMedGoogle Scholar
  34. 34.
    Oshima M et al (1996) Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87(5):803–809CrossRefPubMedGoogle Scholar
  35. 35.
    Dittmann KH et al (2008) Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int J Radiat Oncol Biol Phys 70(1):203–212CrossRefPubMedGoogle Scholar
  36. 36.
    Gobel C et al (2014) Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity. Cell Death Dis 5:e1568CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schellhorn, M., et al., Celecoxib increases lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1. Oncotarget, 2015.Google Scholar
  38. 38.
    Chan G et al (1999) Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 59(5):991–994PubMedGoogle Scholar
  39. 39.
    Abrahao AC et al (2013) Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma. J Oral Pathol Med 42(10):793–798CrossRefPubMedGoogle Scholar
  40. 40.
    Park SW et al (2010) Celecoxib inhibits cell proliferation through the activation of ERK and p38 MAPK in head and neck squamous cell carcinoma cell lines. Anti-Cancer Drugs 21(9):823–830CrossRefPubMedGoogle Scholar
  41. 41.
    Kim YY et al (2010) Anti-cancer effects of celecoxib in head and neck carcinoma. Mol Cells 29(2):185–194CrossRefPubMedGoogle Scholar
  42. 42.
    Wirth LJ et al (2005) Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 23(28):6976–6981CrossRefPubMedGoogle Scholar
  43. 43.
    Patil VM et al (2015) A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol 51(3):279–286CrossRefPubMedGoogle Scholar
  44. 44.
    Kao J et al (2011) Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer. Cancer 117(14):3173–3181CrossRefPubMedGoogle Scholar
  45. 45.
    Garden AS et al (2004) Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 22(14):2856–2864CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Andrew M. McDonald
    • 1
  • Roger Ove
    • 2
    Email author
  • James A. Bonner
    • 1
  • Lisle M. Nabell
    • 3
  • William R. Carroll
    • 4
  • Nasser Said Al-Naief
    • 5
  • Margaret Brandwein-Gensler
    • 6
  • Sharon A. Spencer
    • 1
  1. 1.Department of Radiation OncologyUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Seidman Cancer Center, Department of Radiation OncologyCase Western Reserve UniversityClevelandUSA
  3. 3.Division of Hematology and OncologyUniversity of Alabama at BirminghamBirminghamUSA
  4. 4.Department of OtolaryngologyUniversity of Alabama at BirminghamBirminghamUSA
  5. 5.Departments of Radiology and PathologyOregon Health and Sciences UniversityORUSA
  6. 6.Department of Pathological and Anatomical SciencesSUNY at the University of BuffaloNYUSA

Personalised recommendations