Protracted Adjuvant Temozolomide in Glioblastoma Multiforme

Ahmed A. Refae¹, Ahmed Ezzat¹, Dina Ahmed Salem¹, Mervat Mahrous²

¹Clinical Oncology Department, Ain Shams University, Cairo, Egypt.
²Clinical Oncology Department, Al Minia University, Al Minia, Egypt.

DOI: 10.4236/jct.2015.68082                

Abstract

Purpose: Radiotherapy with concurrent temozolomide (TMZ), followed by 6 cycles of adjuvant TMZ, is the standard of care for newly diagnosed Glioblastoma Mulltiforme (GBM). However tumor progression is the role with median survival of almost 14 months. With lack of effective second line chemotherapy, many physicians and some guidelines advocate prolonged use of adjuvant TMZ more than 6 months. We conduct this study to test the efficacy of protracted adjuvant conventional dose TMZ over the standard 6 doses of adjuvant TMZ. Material and Methods: This phase II trial enrolled patients newly diagnosed as GBM, older than age 18 years, with a Karnofsky performance score (KPS) of ≥60, Neurological Performance Scale (NPS) of ≤3. Patients were randomly assigned to the standard concurrent chemoradiotherapy (CCRT) followed by 6 cycles of adjuvant TMZ or the same treatment with more than 6 cycles of adjuvant chemotherapy extended as long as the patient in good performance, with no unacceptable toxicity, no signs of disease progression. The primary end point was OS. Results: A total of 59 patients were recruited in the study and were randomized in two arms. 29 patients joined arm 1 aiming at receiving CCRT followed by adjuvant 6 cycles TMZ (6 cycles arm) and 30 joined arm 2 aiming at receiving the same treatment with more than 6 cycles of TMZ (>6 cycles). 16 patients managed to complete the adjuvant 6 cycles in arm 1. 19 patients in arm 2, completed the 6 cycles with additive more doses with a median of 11 cycles (range: 8 - 23 cycles). Median PFS was 12.1 months for (6 cycles) arm, and 18.8 months for (>6 cycles) arm, HR 0.88 (95% CI: 1.185 - 4.901) (P 0.015); the overall survival for (6 cycles) arm was 18.1 months, versus 24.1 months, HR 0.70 (95% CI: 1.007 - 4.037) (P 0.048). No significant added toxicity was notice and the 4 weekly TMZ was well tolerated. Conclusion: This study concluded that protracted adjuvant TMZ after concurrent chemoradiotherapy could be a feasible strategy for GBM. This strategy warrants a large phase III randomized trial.

Keywords

Glioblastoma Multiforme, Timozolomide, Protracted Course, Efficacy

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Wen, P.Y. and Kesari, S. (2008) Malignant Gliomas in Adults. New England Journal of Medicine, 359, 492-507. http://dx.doi.org/10.1056/NEJMra0708126
[2]	Ricard, D., et al. (2012) Primary Brain Tumours in Adults. Lancet, 379, 1984-1996. http://dx.doi.org/10.1016/S0140-6736(11)61346-9
[3]	Stupp, R., et al. (2005) Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine, 352, 987-996. http://dx.doi.org/10.1056/NEJMoa043330
[4]	Stupp, R., et al. (2009) Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. Lancet Oncology, 10, 459-466. http://dx.doi.org/10.1016/S1470-2045(09)70025-7
[5]	Newlands, E.S., et al. (1997) Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials. Cancer Treatment Reviews, 23, 35-61. http://dx.doi.org/10.1016/S0305-7372(97)90019-0
[6]	Hau, P., et al. (2007) Safety and Feasibility of Long-Term Temozolomide Treatment in Patients with High-Grade Glioma. Neurology, 68, 688-690. http://dx.doi.org/10.1212/01.wnl.0000255937.27012.ee
[7]	Seiz, M., et al. (2010) Long-Term Adjuvant Administration of Temozolomide in Patients with Glioblastoma Multiforme: Experience of a Single Institution. Journal of Cancer Research and Clinical Oncology, 136, 1691-1695. http://dx.doi.org/10.1007/s00432-010-0827-6
[8]	Malkoun, N., et al. (2012) Prolonged Temozolomide for Treatment of Glioblastoma: Preliminary Clinical Results and Prognostic Value of p53 Overexpression. Journal of Neuro-Oncology, 106, 127-133. http://dx.doi.org/10.1007/s11060-011-0643-0
[9]	Khasraw, M., Bell, D. and Wheeler, H. (2009) Long-Term Use of Temozolomide: Could You Use Temozolomide Safely for Life in Gliomas? Journal of Clinical Neuroscience, 16, 854-855. http://dx.doi.org/10.1016/j.jocn.2008.09.005
[10]	Mason, W.P., et al. (2007) Canadian Recommendations for the Treatment of Glioblastoma Multiforme. Current Oncology, 14, 110-117. http://dx.doi.org/10.3747/co.2007.119
[11]	Bokstein, F., et al. (2008) A Common Sense Approach to Radiotherapy Planning of Glioblastoma Multiforme Situated in the Temporal Lobe. International Journal of Radiation Oncology Biology Physics, 72, 900-904. http://dx.doi.org/10.1016/j.ijrobp.2008.01.053
[12]	Kovacs, J.A. and Masur, H. (2000) Prophylaxis against Opportunistic Infections in Patients with Human Immunodeficiency Virus Infection. The New England Journal of Medicine, 342, 1416-1429. http://dx.doi.org/10.1056/NEJM200005113421907
[13]	Macdonald, D.R., et al. (1990) Response Criteria for Phase II Studies of Supratentorial Malignant Glioma. Journal of Clinical Oncology, 8, 1277-1280.
[14]	Ohgaki, H. and Kleihues, P. (2005) Population-Based Studies on Incidence, Survival Rates, and Genetic Alterations in Astrocytic and Oligodendroglial Gliomas. Journal of Neuropathology & Experimental Neurology, 64, 479-489.
[15]	Stewart, L.A. (2002) Chemotherapy in Adult High-Grade Glioma: A Systematic Review and Meta-Analysis of Individual Patient Data from 12 Randomised Trials. The Lancet, 359, 1011-1018. http://dx.doi.org/10.1016/S0140-6736(02)08091-1
[16]	Holdhoff, M. and Grossman, S.A. (2011) Controversies in the Adjuvant Therapy of High-Grade Gliomas. Oncologist, 16, 351-358. http://dx.doi.org/10.1634/theoncologist.2010-0335
[17]	Delion, M., et al. (2010) Glioblastoma Incident Studies from May 2006 to May 2007 in Angers and Nice, France. Neurochirurgie, 56, 499-502. http://dx.doi.org/10.1016/j.neuchi.2010.07.006
[18]	Darlix, A., et al. (2013) Prolonged Administration of Adjuvant Temozolomide Improves Survival in Adult Patients with Glioblastoma. Anticancer Research, 33, 3467-3474.
[19]	Kumar, A.J., et al. (2000) Malignant Gliomas: MR Imaging Spectrum of Radiation Therapy- and Chemotherapy-Induced Necrosis of the Brain after Treatment. Radiology, 217, 377-384. http://dx.doi.org/10.1148/radiology.217.2.r00nv36377
[20]	Brandes, A.A., et al. (1998) Carboplatin and Teniposide Concurrent with Radiotherapy in Patients with Glioblastoma Multiforme: A Phase II Study. Cancer, 82, 355-361. http://dx.doi.org/10.1002/(SICI)1097-0142(19980115)82:2<362::AID-CNCR17>3.0.CO;2-X
[21]	DeAngelis, L.M., Delattre, J.Y. and Posner, J.B. (1989) Radiation-Induced Dementia in Patients Cured of Brain Metastases. Neurology, 39, 789-796. http://dx.doi.org/10.1212/WNL.39.6.789
[22]	Brandes, A.A., et al. (2008) MGMT Promoter Methylation Status Can Predict the Incidence and Outcome of Pseudoprogression after Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma Patients. Journal of Clinical Oncology, 26, 2192-2197. http://dx.doi.org/10.1200/JCO.2007.14.8163
[23]	Seiz, M., et al. (2010) Long-Term Adjuvant Administration of Temozolomide in Patients with Glioblastoma Multiforme: Experience of a Single Institution. Journal of Cancer Research and Clinical Oncology, 136, 1691-1695. http://dx.doi.org/10.1007/s00432-010-0827-6
[24]	Roldan Urgoiti, G.B., Singh, A.D. and Easaw, J.C. (2012) Extended Adjuvant Temozolomide for Treatment of Newly Diagnosed Glioblastoma Multiforme. Journal of Neuro-Oncology, 108, 173-177. http://dx.doi.org/10.1007/s11060-012-0826-3
[25]	Gerber, D.E., et al. (2007) The Impact of Thrombocytopenia from Temozolomide and Radiation in Newly Diagnosed Adults with High-Grade Gliomas. Neuro-Oncology, 9, 47-52. http://dx.doi.org/10.1215/15228517-2006-024
[26]	Grossman, S.A., et al. (2011) Immunosuppression in Patients with High-Grade Gliomas Treated with Radiation and Temozolomide. Clinical Cancer Research, 17, 5473-5480. http://dx.doi.org/10.1158/1078-0432.CCR-11-0774