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Journal of Neuro-Oncology

, Volume 71, Issue 1, pp 73–81 | Cite as

Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases

  • Leandro C. A. CerchiettiEmail author
  • Marcelo R. Bonomi
  • Alfredo H. Navigante
  • Monica A. Castro
  • Maria E. Cabalar
  • Berta M. C. Roth
Clinical Study

Summary

PurposeThe primary goal of this phase I/II study was to evaluate the feasibility, safety and efficacy of celecoxib administered concomitant to radiotherapy to treat unresectable BM. Patients and methods: Patients with measurable BM by CT or MRI, unresectability criteria by a neurosurgeon and RPA-RTOG class II were eligible. Celecoxib was administered at 400 mg/day during the entire course of radiotherapy. All patients were irradiated with 60Co beams to whole-brain dose of 32 Gy (20 fractions of 1.6 Gy each two times a day with a 6 h interval between treatments) followed by a 22.4 Gy boost (same fractionation schedule) over evident lesions. Results: Twenty-seven patients were treated. The concurrent regimen was well tolerated with 15 cases of mild dyspepsia. Alopecia (NCI grades 1–2) was the most important side effect. Three patients presented rash/desquamation of moderate intensity. Radiological responses occurred in 18 of 25 valuable patients (72), with five complete responses (CR). Symptomatic responses were reported in 25 of 27 patients (92.6), with 20 CR. The overall response rate (considering complete plus partial responses) was 66.7. Percentile 50 for time-to-progression, time-to-neurological-progression and functional-independence-time were 3, 6.25 and 6.7 months, respectively. Median survival time was 8.7 months. Conclusion: Our initial results suggest that radiotherapy plus celecoxib is safe and a possible active treatment for patients with BM. Further investigation in a randomized trial is warranted to validate its clinical utility.

Keywords

brain metastases celecoxib cyclooxygenase radiation radiosensitizer 

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References

  1. Walker, AE, Robins, M, Weinfeld, FD 1985Epidemiology of brain tumors: the national survey of intracranial neoplasmsNeurology35219224PubMedGoogle Scholar
  2. Gaspar, L, Scott, C, Rotman, M, Asbell, S, Phillips, T, Wasserman, T, McKenna, WG, Byhardt, R 1997Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trialsInt J Radiat Oncol Biol Phys37745751Google Scholar
  3. Gaspar, LE, Scott, C, Murray, KJ, Curran, W 2000Validation of the RTOG recursive partitioning analysis classification for brain metastasesInt J Radiat Oncol Biol Phys4710011006Google Scholar
  4. Agboola, O, Benoit, B, Cross, C, Da Silva, V, Esche, B, Lesiuk, H, Gonsalves, C 1998Prognostic factors derived from recursive partition analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastatic casesInt J Radiation Oncol Biol Phys42155159Google Scholar
  5. Nieder, C, Nestle, U, Motaref, B, Walter, K, Niewald, M, Schnabel, K 2000Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classesInt J Radiation Oncol Biol Phys46297302Google Scholar
  6. FitzGerald, GA, Patrono, C 2001The coxibs, selective inhibitors of cyclooxygenase-2N Engl J Med345433442CrossRefPubMedGoogle Scholar
  7. Raju, H, Nakata, E, Yang, P, Newman, RA, Ang, KK, Milas, L 2002In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistics considerationsInt J Radiation Oncology Biol Phys54886894Google Scholar
  8. Pyo, H, Choy, H, Amorino, GP, Kim, JS, Cao, Q, Hercules, SK, DuBois, RN 2001A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2Clin Cancer Res729983005Google Scholar
  9. Milas, L, Kishi, K, Hunter, N, Mason, K, Masferrer, JL, Tofilon, PJ 1999Enhancement of tumor response to -radiation by an inhibitor of cyclooxygenase-2 enzymeJ Natl Cancer Inst9115011504Google Scholar
  10. Vecht, ChJ, Hovestadt, A, Verbiest, HB, Vliet, JJ, Putten, WL 1994Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per dayNeurology44675680Google Scholar
  11. Cohen, N, Strauss, G, Lew, R, Silver, D, Recht, L 1988Should prophylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases? A retrospective analysis.JClin Onco1616211624Google Scholar
  12. Tang, C, Shou, M, Mei, Q, Rushmore, TH, Rodrigues, AD 2000Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-ll inhibitorJ Pharmacol Exp Ther293453459Google Scholar
  13. Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, Carbone, PP 1982Toxicity and response criteria of the Eastern Cooperative Oncology GroupAm J Clin Oncol5649655PubMedGoogle Scholar
  14. Jones, MK, Wang, H, Peskar, BM, Levin, E, Itani, RM, Sarfeh, IJ, Tarnawski, AS 1999Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healingNat Med514181423CrossRefPubMedGoogle Scholar
  15. Kishi, K, Petersen, S, Petersen, C, Hunter, N, Mason, K, Masferrer, JL, Tofilon, PJ, Milas, L 2000Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitorCancer Res6013261331Google Scholar
  16. Williams, CS, Mann, M, DuBois, RN 1999The role of cyclooxygenases in inflammation, cancer, and developmentOncogene1879087916Google Scholar
  17. Ryu, HS, Chang, KH, Yang, HW, Kim, MS, Kwom, HC, Oh, KS 2000High cyclooxygenase-2 expression in stage IB cervical cancer with lymph node metastasis or parametrial invasionGynecol Oncol76320325Google Scholar
  18. Michalowski, AS 1994On radiation damage to normal tissues and its treatment II. Anti-inflammatory drugs.Acta Oncol33139157Google Scholar
  19. Milas, L, Furuta, Y, Hunter, N, Nishiguchi, I, Runkel, S 1990Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetenceCancer Res5044734477Google Scholar
  20. Furuta, Y, Hunter, N, Barkley, T, Hall, E, Milas, L 1988Increase in radioresponse of murine tumors by treatment with indomethacinCancer Res4830083013Google Scholar
  21. Masferrer, JL, Leahy, KM, Koki, AT, Zweifel, BS, Settle, SL, Woerner, BM, Edwards, DA, Flickinger, AG, Moore, RJ, Seibert, K 2000Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitorsCancer Res6013061311PubMedGoogle Scholar
  22. Dicker, AP, Williams, TL, Grant, DS 2001Targeting angiogenic processes by combination rofecoxib and ionizing radiationAm J Clin Oncol24438442Google Scholar
  23. Soslow, RA, Dannenberg, AJ, Rush, D, Woerner, BM, Khan, KN, Masferrer, J, Koki, AT 2000COX-2 is expressed in human pulmonary, colonic, and mammary tumorsCancer8926372645PubMedGoogle Scholar
  24. Wolff, H, Saukkonen, K, Anttila, S, Karjalainen, A, Vainio, H, Ristimaki, A 1998Expression of cyclooxygenase-2 in human lung carcinomaCancer Res5849975001Google Scholar
  25. Hwang, D, Scollard, D, Byrne, J, Levine, E 1998Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancerJ Natl Cancer Inst90455460Google Scholar
  26. Denkert, C, Kobel, M, Berger, S, Siegert, A, Leclere, A, Trefzer, U, Hauptmann, S 2001Expression of cyclooxygenase 2 in human malignant melanomaCancer Res61303308Google Scholar
  27. Kim, HJ, Wu, HG, Park, IA, Ha, SW 2003High cyclooxygenase-2 expression is related with distant metastasis in cervical cancer treated with radiotherapyInt J Radiat Oncol Biol Phys551620Google Scholar
  28. Milas, L, Komaki, R, Hachiya, T, Bubb, RS, Ro, JY, Langford, L, Sawaya, R, Putnam, JB, Alien, P, Cox, JD, McDonnell, TJ, Brock, W, Hong, WK, Roth, JA, Milas, L 2003Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small cell lung cancer and brain metastasesClinical Cancer Res110701076Google Scholar
  29. Hull, MA, Fenwick, SW, Chappie, KS, Scott, N, Toogood, GJ, Lodge, JP 2001Cyclooxygenase-2 expression in colorectal cancer liver metastasesClin Exp Metastasis182127Google Scholar
  30. Steinauer, KK, Gibbs, I, Ning, S, French, JN, Armstrong, J, Knox, SJ 2000Radiation induces upregulation of cyclooxygenase-2 (COX-2) protein in PC-3 cellsInt J Rad Oncol Biol Phys48325328Google Scholar
  31. Milas, L, Hanson, WR 1995Eicosanoids and radiationEur J Cancer31 A15801585Google Scholar
  32. Petersen, C, Petersen, S, Milas, L, Lang, FF, Tofilon, PJ 2000Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitorClin Cancer Res625132520Google Scholar
  33. Williams, CS, Watson, AJ, Sheng, H, Helou, R, Shao, J, DuBois, RN 2001Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo modelsCancer Res6060456051Google Scholar
  34. Wachsberger, P, Burd, R, Dicker, AP 2003Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interactionClin Cancer Res919571971Google Scholar
  35. Burd, R, Choy, H, Dicker, A 2003Potential for inhibitors of cyclooxygenase-2 to enhance tumor radioresponseHarris, RE eds. COX-2 Blockade in Cancer Prevention and TherapyHumana Press IncTotowa, New Jersey301311Google Scholar
  36. Blumenthal, RD, Waskewich, C, Goldenberg, DM, Lew, W, Flefleh, C, Burton, J 2001Chronotherapy and chronotoxicity of the cyclooxygenase-2 inhibitor, celecoxib, in athymic mice bearing human breast cancer xenograftsClin Cancer Res731783185Google Scholar
  37. Stormer, E, Bauer, S, Kirchheiner, J, Brockmoller, J, Roots, I 2003Simultaneous determination of celecoxib, hydrocelecoxib, and carboxycelecoxib in human plasma using gradient reversed-phase liquid chromatography with ultraviolet absorbance detectionJ Chromatogr B Analyt Technol Biomed Life Sci783207212Google Scholar
  38. Davey, P 2002Brain Metastases: treatment options to improve outcomesCNS Drugs16325338PubMedGoogle Scholar
  39. Murray, KJ, Scott, C, Greenberg, HM, Emami, B, Seider, M, Vora, NL, Olson, C, Whitton, A, Movsas, B, Curran, W 1997A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the radiation therapy oncology group (RTOG) 9104Int J Radial Oncol Biol Phys39571574Google Scholar
  40. Ma, BB, Bristow, RG, Kim, J, Siu, LL 2003Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agentsJ Clin Oncol2127602776Google Scholar
  41. Bonner, JA, Raisch, KP, Trummell, HQ, Robert, F, Meredith, RF, Spencer, SA, Buchsbaum, DJ, Saleh, MN, Stackhouse, MA, LoBuglio, AF, Peters, GE, Carroll, WR, Waksal, HW 2000Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation in head and neckJ Clin Oncol184753Google Scholar
  42. Bianco, C, Bianco, R, Tortora, G, Damiano, V, Guerrieri, P, montemaggi, P, Mendelsohn, J, Placido, S, Bianco, AR, Ciardiello, F 2000Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotideClin Cancer Res643434350Google Scholar
  43. Milas, L, Mason, K, Hunter, N, Petersen, S, Yamakawa, M, Ang, K, Mendelsohn, J, Fan, Z 2000In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibodyClin Cancer Res6701708Google Scholar
  44. Bonner, JA, Maihle, J, Folven, BR, Christianson, TJ, Spain, K 1994The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivitiesInt J Radiat Oncol Biol Phys29243247Google Scholar
  45. Thames, HD, Withers, HR, Peters, LJ, Fletcher, GH 1982Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationshipsInt J Radiat Oncol Biol Phys8219222Google Scholar
  46. Mehrabi, MR, Serbecic, N, Tamaddon, F, Kaun, C, Huber, K, Pacher, R, Wild, T, Mall, G, Wojta, J, Glogar, HD 2002Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart diseaseCardiovasc Res56214224Google Scholar
  47. Fenton, BM, Beauchamp, BK, Paoni, SF, Okunieff, P, Ding, I 2001Characterization of the effects of antiangiogenic agents on tumor pathophysiologyAm J Clin Oncol24453457Google Scholar
  48. Nieder, C, Andratschke, N, Grosu, AL, Molls, M 2003Recursive partitioning analysis (RFA) class does not predict survival in patients with four or more brain metastasesStrahlenther Onkol11620Google Scholar
  49. Kondziolka, D, Patel, A, Lunsford, LD, Kassam, A, Flickinger, JC 1999Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastasesInt J Rad Oncol Biol Phys45427434Google Scholar
  50. Gutin, PH 1977Corticosteroid therapy in patients with brain tumorsNatl Cancer inst Monogr28814Google Scholar
  51. Weissman, DE, Dufer, D, Vogel, V, Abeloff, MD 1987Corticosteroid toxicity in neuro-oncology patientsJ Neuroncol5125128Google Scholar
  52. Marshall, LF, King, JK, Langfitt, TW 1977The complications of high-dose Corticosteroid therapy in neurosurgical patients: a prospective studyAnn Neurol1201203Google Scholar
  53. Kyrkanides, S, Moore, AH, Olschowka, JA, Daeschner, JC, Williams, JP, Hansen, JT, Kerry O’Banion, M 2002Cyclooxygenase-2 modulates barin inflammation-related gene expression in central nervous System radiation injuryMol Brain Res104159169Google Scholar
  54. Portnow, J, Suleman, S, Grossman, SA, Eller, S, Carson, K 2002A cyclooxygenase-2 (COX-2) inhibitor compared with dexamethasone in a survival study of rats with intracerebral 9L gliosarcomasNeuro-oncol42225Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Leandro C. A. Cerchietti
    • 1
    • 4
    Email author
  • Marcelo R. Bonomi
    • 2
  • Alfredo H. Navigante
    • 1
    • 3
  • Monica A. Castro
    • 1
  • Maria E. Cabalar
    • 3
  • Berta M. C. Roth
    • 2
  1. 1.Translational Research UnitUniversidad de Buenos AiresArgentina
  2. 2.Department of Radiotherapy and RadiologyUniversidad de Buenos AiresArgentina
  3. 3.Department of Internal Medicine, Instituto de Oncologia Angel H. RoffoUniversidad de Buenos AiresCiudad de Buenos AiresArgentina
  4. 4.Albert Einstein Cancer CenterBronxUSA

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