Müge AKMANSU, Haluk AŞIKOĞLU, Özge petek ERPOLAT, Hüseyin BORA

Concomitant application of cyclooxygenase-2 inhibitor and whole brain radiotherapy in patients with brain metastasis

Amaç: Beyin metastazı, kanser hastalarında morbidite ve mortalitenin en önemli nedenlerinden biridir. Lokal kontrolü artırmak için yaklaşımlardan biri siklooksigenaz-2 inhibitoru (selekoksib) gibi radyoduyarlılığı artıran ajanları kullanmaktır. Bu çalışma rezeke edilemeyen beyin metastazlı hastalarda tüm beyin ışınlaması ile eşzamanlı kullanılan selekoksibin güvenirliliğini ve etkinliğini değerlendirmeyi amaçlamaktadır. Yöntemler: Selekoksib (400 mg/günlük doz) ile birlikte veya tek başına tüm beyin ışınlaması (10 fraksiyonda 30 Gy, 2 haftada) alan beyin metastazlı 30 hasta prospektif olarak değerlendirildi. Selekoksib+radyoterapi grubunda olan 30 hastanın 17si, sadece radyoterapi alan gruptaki 13 hasta ile karşılaştırıldı. Radyoterapi bitiminden sonraki 60ıncı günde radyolojik yanıt, norolojik ve performans durumu ile birlikte norolojik ve hematolojik toksisiteler değerlendirildi. Bulgular: Selekoksib+radyoterapi grubunda ortalama tümör hacmi 7.9 $mm^{3}$ ten 3.3 $mm^{3}$ e azaldı. Sadece radyoterapi alan grupta tedavi öncesi değerler ile karşılaştırıldığında ortalama tümör hacminde bir değişiklik gözlenmedi. Tedavi grupları arasındaki ortalama tümör hacminin farkı istatistiksel olarak anlamlıydı (p=0.001). İlaveten, objektif yanıt oranları selekoksib ve radyoterapi grubunda yüksek bulundu (p=0.002). Ancak, radyoterapiye selekoksib eklenmesinin norolojik ve performans durumunu önemli ölçüde düzeltmediği izlendi. Hastalarda hematolojik ve nörolojik toksisite gözlenmedi. Sonuç: Tüm beyin radyoterapisi ile eşzamanlı selekoksib uygulamasının beyin metastazlarının tedavisinde etkili ve güvenli olduğu bulundu. Ancak, sonuçlarımızı doğrulamak için daha ileri çalışmalara ihtiyaç vardır. (Gazi Med J 2012; 23: 70-6)

Beyin metastazlı hastalarda eşzamanlı siklooksigenaz-2 inhibitoru ve tüm beyin radyoterapi uygulaması

Objective: Brain metastasis is one of the important causes of morbidity and mortality in cancer patients. One approach for improving local control is applying agents such as cyclooxygenase-2 inhibitor (celecoxib) that enhance radiosensitivity. This study was aimed to evaluate the safety and efficacy of the celecoxib which is delivered concomitant to whole brain radiotherapy in patients with unresectable brain metastasis. Methods: Thirty patients with brain metastasis, who received whole brain radiotherapy (30 Gy in 10 fractions over 2 weeks) alone or with celecoxib (a dose of 400 mg/day) were evaluated prospectively. Seventeen of 30 patients were in the celecoxib+radiotherapy group compared to 13 patients who were in the radiotherapy only group. The radiological response, neurological and performance status with neurological and hematological toxicities were assessed at the $60^{th}$ day following radiotherapy. Results: Mean tumor volume was reduced from 7.9 $mm^{3}$ to 3.5 $mm^{3}$ in the celecoxib+radiotherapy group. In the radiotherapy only group, we did not observe any changes in mean tumor volume (8.9 $mm^{3}$) compared to pretreatment values. The difference of mean tumor volumes between treatment groups was statistically significant (p=0.001). Moreover, objective response ratios were higher in the celecoxib and radiotherapy group (p=0.002). However, the addition of celecoxib to radiotherapy did not improve neurological and performance status significantly. No hematological and neurological toxicities were observed in patients. Conclusion: Concomitant application of celecoxib with whole brain radiotherapy was found effective and safe in the treatment of brain metastasis. However, further studies are required to validate our results. (Gazi Med J 2012; 23: 70-6)

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1. Posner JB, editor. Neurologic complications of Cancer. Philadelphia: F.A. Davis Company 1995.p.282-310.
2. Cairncross JG, Kim JH, Posner JB. Radiation therapy for brain metastases. Ann Neurol 1980; 7: 529-41.
3. van der Steen-Banasik E, Hermans J, Tjho-Heslinga R, Caspers R, Leer JW. The objective response of brain metastases on radiotherapy. A prospective study using computer tomography. Acta Oncol 1992; 31: 777-80.
4. Nieder C, Berberich W, Nestle U, Niewald M, Walter K, Schnabel K. Relation between local result and total dose of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 1995; 33: 349-55.
5. Niemiec M, Glogowski M, Tyc-Szczepaniak D, Wierzchowski M, Kepka L. Characteristics of long-term survivors of brain metastases from lung cancer. Rep Pract Oncol Radiother 2011; 16: 49-53.
6. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37: 745-51.
7. Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 2000; 47: 1001-6.
8. Chidel MA, Suh JH, Reddy CA, Chao ST, Lundbeck MF, Barnett GH. Application of recursive partitioning analysis and evaluation of the use of whole brain radiation among patients treated with stereotactic radiosurgery for newly diagnosed brain metastases. Int J Radiat Oncol Biol Phys 2000; 47: 993-9.
9. Nieder C, Nestle U, Motaref B, Walter K, Niewald M, Schnabel K. Prognostic factors in brain metastases: should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes. Int J Radiat Oncol Biol Phys 2000; 46: 297-302.
10. Agboola O, Beroit B, Cross P, DaSilva V, Esche B, Lesiuk H, et al. Prognostic factors derived from recursive partitioning analysis (RPA) of Radiation Oncology Group (RTOG) brain metastasis trials applied to surgically resected and irradiated brain metastatic cases. Int J Radiat Oncol Biol Phys 1998; 42: 155-9.
11. Larson DA, Rubenstein JL, Mcdermott MW: Treatment of Metastatic Cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, Lippincott Williams & Wilkins, 2005. p. 2323-36.
12. Klenke FM, Abdollahi A, Bischof M, Gebhard MM, Ewerbeck V, Huber PE, et al. Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo. Strahlenther Onkol 2011; 187: 45-51.
13. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12: 1063-73.
14. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999; 18: 7908-16.
15. Hull MA, Fenwick SW, Chapple KS, Scott N, Toogood GJ, Lodge JP. Cyclooxygenase- 2 expression in colorectal cancer liver metastases. Clin Exp Metastasis 2000; 18: 21-7.
16. Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN. Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 2000; 60: 6045-51.
17. Nishimura G, Yanoma S, Mizuno H, Kawakami K, Tsukuda M. A selective cyclooxygenase-2 inhibitor suppresses tumor growth in nude mouse xenografted with human head and neck squamous carcinoma cells. Jpn J Cancer Res 1999; 90: 1152-62.
18. Stolina M, Sharma S, Lin Y, Dohadwala M, Gardner B, Luo J, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000; 164: 361-70.
19. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306-11.
20. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-52.
21. Phillips RK, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002; 50: 857-60.
22. Milas L, Mason KA, Crane CH, Liao Z, Masferrer J. Improvement of radiotherapy or chemoradiotherapy by targeting COX- 2 enzyme. Oncology 2003; 17: 15-24.
23. Raju U, Nakata E, Yang P, Newman RA, Ang KK, Milas L. In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase- 2 enzyme: mechanistic considerations. Int J Radiation Oncology Biol Phys 2002; 54: 886-94.
24. Pyo H, Choy H, Amorino GP, Kim JS, Cao Q, Hercules SK, et al. A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase- 2. Clin Cancer Res 2001; 7: 2998-3005.
25. Milas L, Kishi K, Hunter N, Mason K, Masferrer JL, Tofilon PJ. Enhancement of tumor response to gamma-radiation by an inhibitor of cyclooxygenase- 2 enzyme. J Natl Cancer Inst 1999; 91: 1501-4.
26. Kwok Y, Patchell RA, Regine WF. Palliation of Brain and Spinal Cord Metastasis. In: Halperin EC, Perez CA, Brady LW. Principles and Practice of Radiation Oncology. 5th ed. Philadelphia, Lippincott Williams and Wilkins, 2008. p. 1974.
27. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995; 31: 1341-6.
28. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-10.
29. Clarke LP, Velthuizen RP, Clark M, Gaviria J, Hall L, Goldgof D, et al. MRI measurement of brain tumor response: comparison of visual metric and automatic segmentation. Magn Reson Imaging 1998; 16: 271-9.
30. Grossman SA, Burch PA. Quantitation of tumor response to anti-neoplastic therapy. Semin Oncol 1988; 15: 441-54.
31. Kang SG, Kim JH, Nam DH, Park K. Clinical and radiological prognostic factors of anaplastic oligodendroglioma treated by combined therapy. Neurol Med Chir 2005; 45: 232-9.
32. Davey P. Brain Metastases: treatment options to improve outcomes. CNS Drugs 2002; 16: 325-38.
33. Patchell RA. The management of brain metastases. Cancer Treat Rev 2003; 29: 533-40.
34. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665-72.
35. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280: 1485-9.
36. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322: 494-500.
37. Komarnicky LT, Phillips TL, Martz K, Asbell S, Isaacson S, Urtasun R. A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG- 7916). Int J Radiat Oncol Biol Phys 1991; 20: 53-8.
38. Prados MD, Seiferheld W, Sandler HM, Buckner JC, Phillips T, Schultz C, et al. Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404. Int J Radiat Oncol Biol Phys 2004; 58: 1147-52.
39. Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W, et al. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003; 21: 2529-36.
40. Verger E, Gil M, Yaya R, Vinolas N, Villa S, Pujol T, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys 2005; 61: 185-91.
41. Shaw E, Scott C, Suh J, Kadish S, Stea B, Hackman J, et al. RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database. J Clin Oncol 2003; 21: 2364-71.
42. Michalowski AS. On radiation damage to normal tissues and its treatment. II. Anti-inflammatory drugs. Acta Oncol 1994; 33: 139-57.
43. Furuta Y, Hunter N, Barkley T Jr, Hall E, Milas L. Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res 1988; 48: 3008-13.
44. Milas L, Furuta Y, Hunter N, Nishiguchi I, Runkel S. Dependence of indomethacin- induced potentiation of murine tumor radioresponse on tumor host immunocompetence. Cancer Res 1990; 50: 4473-7.
45. Cerchietti LC, Bonomi MR, Navigante AH, Castro MA, Cabalar ME, Roth BM. Phase I/II study of selective cyclooxygenase-2 inhibitor celecoxib as a radiation sensitizer in patients with unresectable brain metastases. J Neurooncol 2005; 71: 73-81.
46. Liao Z, Komaki R, Milas L, Yuan C, Kies M, Chang JY, et al. A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer. Clin Cancer Res 2005; 11: 3342-8.
47. Murray KJ, Scott C, Greenberg HM, Emami B, Seider M, Vora NL, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997; 39: 571-4.
48. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase- 2. N Engl J Med 2001; 345: 433-42.
49. Stormer E, Bauer S, Kirchheiner J, Brockmoller J, Roots I. Simultaneous determination of celecoxib, hydrocelecoxib, and carboxycelecoxib in human plasma using gradient reversed-phase liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 783: 207-12.
50. Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005; 142: 481-9.