Extended Daily Schedule of Temozolomide in Recurrent Glioblastoma: Single-Institution Report on a Series of 43 Patients


Background: Despite advances in surgical and first-line adjuvant treatment, glioblastoma multiforme (GBM) always recurs as disease natural history. Currently, there is no consensus as to the optimal second-line treatment of recurrent GBM. Patients and Methods: This is a retrospective study of a series of adult patients consecutively treated at a single institution for supratentorial cerebral GBM at first relapse. All patients had previously received the standard concomitant radiochemotherapy protocol as first-line therapy. At recurrence/progression, all patients were treated with a metronomic temozolomide (TMZ) schedule at a daily dosage of 50 mg/m2 of body surface. Radiologic, clinical, and laboratory data were collected for all patients, with a minimum follow-up of 18 months. Results: From January 2010 to June 2011, 43 patients were treated at our facility. A mean of 10 metronomic TMZ cycles (range, 3 - 21) was administered. Radiologically, we observed 2 complete responses (4.6%), 16 partial responses (37.2%), 18 stable disease (41.9%) and 7 progressive disease (16.3%). Steroids administration was safely tapered in 23 patients (53.5%). Karnofsky-Performance-Status (KPS) results improved in 20 patients (46.5%), stabilized in 20 (46.5%), and worsened in 3 patients (7.0%), with a mean KPS score increased from 65.1 at baseline to 75.3 at follow-up. Six-month progression-free survival was 53.5. One year after recurrence/progression diagnosis, 22 patients were still alive, with a 1-year overall survival rate of 51.6%. Conclusions: The proposed TMZ schedule seems a safe and effective option for patients with recurrent GBM, with high radiologic response rates and good clinical impact. Strict clinical observation of patients may enable obtaining better results than those already present in the literature and further investigation appears auspicable.

Share and Cite:

A. D’Elia, V. Maiola, M. Manucci, A. Pichierri, A. Frati, F. Giangaspero and M. Salvati, "Extended Daily Schedule of Temozolomide in Recurrent Glioblastoma: Single-Institution Report on a Series of 43 Patients," Journal of Cancer Therapy, Vol. 5 No. 2, 2014, pp. 155-166. doi: 10.4236/jct.2014.52019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] D. N. Louis, H. Ohgaki, O. D. Wiestler and W. K. Cavenee, “World Health Organization Classification of Tumours of the Central Nervous System,” IARC Press, Lyon, 2007.
[2] R. Stupp, M. E. Hegi, M. J. van den Bent, et al., “Changing Paradigms: An Update on the Multidisciplinary Management of Malignant Glioma,” Oncologist, Vol. 11, No. 2, 2006, pp. 165-180. http://dx.doi.org/10.1634/theoncologist.11-2-165
[3] M. Salvati, A. D’Elia, A. I. Formichella and A. Frati, “Insights into Pharmacotherapy of Malignant Glioma in Adults,” Expert Opin Pharmacother Oct, Vol. 10, No. 14, 2009, pp. 2279-2290.
[4] W. Wick, M. Platten and M. Weller, “New (Alternative) Temozolomide Regimens for the Treatment of Glioma,” Neuro-Oncology, Vol. 11, No. 1, 2009, pp. 69 -79. http://dx.doi.org/10.1215/15228517-2008-078
[5] M. F. Stevens, J. A. Hickman, S. P. Langdon, et al., “Antitumor Activity and Pharmacokinelics in Mice of 8-Carbamoyl-3-Methyl-Imidazo[5.I-d]-l.2.3.5-Lelrazin-4(3H)-One (CCRG 81045; M & B 39831). A Novel Drug with Potential as an Alternative to Dacarbazine,” Cancer Reseach, Vol. 47, 1987, pp. 5846-5852.
[6] C. Brock, E. S. Newlands, S. R. Wedge, et al., “Phase I Trial of Temozolomide Using an Extended Continuous Oral Schedule,” Cancer Research, Vol. 58, 1998, pp. 4363-4367.
[7] E. S. Newlands, M. F. G. Stevens, S. R. Wedge, et al., “Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials,” Cancer Treatment Reviews, Vol. 23, No. 1, 1997, pp. 35-61. http://dx.doi.org/10.1016/S0305-7372(97)90019-0
[8] R. Stupp, W. Mason, M. van den Bent, et al., “Rariotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma,” The New England Journal of Medicine, Vol. 352, No. 10, 2005, pp. 987-996. http://dx.doi.org/10.1056/NEJMoa043330
[9] W. Wick, J. P. Steinbach, W. M. Kuker, et al., “One Week on/One Week off: A Novel Active Regimen for Temozolomide for Recurrent Glioblastoma,” Neurology, Vol. 62, No. 11, 2004, pp. 2113-2115. http://dx.doi.org/10.1212/01.WNL.0000127617.89363.84
[10] A. A. Brandes, A. Tosoni, G. Cavallo, et al., “Temozolomide 3 Weeks on and 1 Week off as First-Line Therapy for Recurrent Glioblastoma: Phase II Study from Gruppo Italiano Cooperative Dineuro-Oncologia (GICNO),” British Journal of Cancer, Vol. 95, 2006, pp. 1155-1160.
[11] A. Tosoni, G. Cavallo, M. Ermani, et al., “Is Protracted Low-Dose Temozolomide Feasible in Glioma Patients,” Neurology, Vol. 66, No. 3, 2006, pp. 427-429. http://dx.doi.org/10.1212/01.wnl.0000 196465.83423.ec
[12] E. Franceschi, A. Omuro, A. Lassman, et al., “Salvage Temozolomide for Prior Temozolomide Responders,” Cancer, Vol. 104, No. 11, 2005, pp. 2473-2476. http://dx.doi.org/10.1002/cncr.21564
[13] J. Perry, P. Rizek, R. Cashman, M. Morrison and T. Morrison, “Temozolomide Rechallenge in Recurrent Malignant Glioma by Using a Continuous Temozolomide Schedule: The ‘Rescue’ Approach,” Cancer, Vol. 113, No. 8, 2008, pp. 2152-2157. http://dx.doi.org/10.1002/cncr.23813
[14] M. Weller, “Temozolomide and MGMT Forever?” Neuro-Oncology, Vol. 12, No. 3, 2010, pp. 219-220. http://dx.doi.org/10.1093/neuonc/noq016
[15] M. E. Hegi, L. Liu, J. Herman, et al,. “Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation with Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity,” Journal of Clinical Oncology, Vol. 26, No. 25, 2008, pp. 4189-4199.
[16] M. Esteller, J. Garcia-Foncillas, E. Andion, et al., “Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents,” The New England Journal of Medicine, Vol. 343, No. 19, 2000, pp. 1350-1354. http://dx.doi.org/10.1056/NEJM200011093431901
[17] M. E. Hegi, A.-C. Diserens, S. Godard, et al., “Clinical Trial Substantiates the Predictive Value of O-6-Methylguanine-DNA Methyltransferase Promoter Methylation in glioblastoma Patients Treated with Temozolomide,” Clinical Cancer Research, Vol. 10, 2004, pp. 1871-1874. http://dx.doi.org/10.1158/ 1078-0432.CCR-03-0384
[18] C. Schold, D. Kokkinakis, S. Chang, et al., “O6-Benzylguanine Suppression of O6-Alkylguanine-DNA Alkyltransferase in Anaplastic Gliomas,” Neuro-Oncology, Vol. 6, No. 1, 2004, pp. 28-32.
[19] L. Karayan-Tapon, V. Quillien, J. Guilhot, et al., “Prognostic Value of O6-Methylguanine-DNA Methyltransferase Status in Glioblastoma Patients, Assessed by Five Different Methods,” Journal of Neuro-Oncology, Vol. 97, No. 3, 2010, pp. 311-322. http://dx.doi.org/10.1007/s11060-009-0031-1
[20] A. W. Tolcher, S. L. Gerson, L. Denis, et al., “Marked inactivation of O6-Alkylguanine-DNA Alkyltransferase Activity with Protracted Temozolomide Schedules,” British Journal of Cancer, Vol. 88, No. 7, 2003, pp. 1004-1011. http://dx.doi.org/10.1038/sj.bjc.6600827
[21] K. H. Plate and W. Risau, “Angiogenesis in Malignant Gliomas,” Glia, Vol. 15, No. 3, 1995, pp. 339-347. http://dx.doi.org/10.1002/glia.440150313
[22] S. P. Leon, R. D. Folkerth and P. M. Black, “Microvessel Density Is a Prognostic Indicator for Patients with Astroglial Brain Tumors,” Cancer, Vol. 77, No. 2, 1996, pp. 362-372.
[23] J. Dietrich, A. Norden and P. Wen, “Emerging Antiangiogenic Treatments for Gliomas—Efficacy and Safety Issues. Review,” Current Opinion in Neurology, Vol. 21, No. 6, 2008, pp. 736-744.
[24] S. Kesari, D. Schiff, L. Doherty, et al., “Phase II Study of Metronomic Chemotherapy for Recurrent Malignant Gliomas in Adults,” Neuro-Oncology, Vol. 9, No. 3, 2007, pp. 354-363.
[25] R. S. Kerbel and B. A. Kamen, “The Anti-Angiogenic Basis of Metronomic Chemotherapy,” Nature Reviews Cancer, Vol. 4, 2004, pp. 423-436. http://dx.doi.org/10.1038/nrc1369
[26] M. W. Kieran, C. D. Turner, J. B. Rubin, et al., “A Feasibility Trial of Antiangiogenic (Metronomic) Chemotherapy in Pediatric Patients with Recurrent or Progressive Cancer,” Journal of Pediatric Hematology/Oncology, Vol. 27, No. 11, 2005, pp. 573-581. http://dx.doi.org/10.1097/01.mph. 0000183863.10792.d4
[27] J. Tuettenberg, R. Grobholz, T. Korn, F. Wenz, R. Erber and P. Vajkoczy, “Continuous Low-Dose Chemotherapy plus Inhibition of Cyclooxygenase-2 as an Antiangiogenic Therapy of Glioblastoma Multiforme,” Journal of Cancer Research and Clinical Oncology, Vol. 131, No. 1, 2005, pp. 31-40. http://dx.doi.org/10.1007/s00432-004-0620-5
[28] F. Bertolini, S. Paul, P. Mancuso, et al., “Maximum Tolerable Dose and Low-Dose Metronomic Chemotherapy Have Opposite Effects on the Mobilization and Viability of Circulating Endothelial Progenitor Cells,” Cancer Reseach, Vol. 63, 2003, pp. 4342-4346.
[29] G. Bocci, G. Francia, S. Man, et al., “Thrombospondin-1, a Mediator of the Antiangiogenic Effects of Low-Dose Metronomic Chemotherapy,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 22, 2003, pp. 12917-12922. http://dx.doi.org/10.1073/ pnas.2135406100
[30] J. Perry, K. Belanger, W. Mason, et al., “Phase II Trial of Continuous Dose-Intense Temozolomide in Recurrent Malignant Glioma: RESCUE Study,” Journal of Clinical Oncology, Vol. 28, No. 12, 2010, pp. 2051-2057. http://dx.doi.org/10.1200/JCO.2009.26.5520
[31] D. S. Kong, J. I. Lee, J. H. Kim, S. T. Kim, W. S. Kim, Y. L. Suh, S. M. Dong and D. H. Nam, “Phase II Trial of Low-Dose Continuous (Metronomic) Treatment of Temozolomide for Recurrent Glioblastoma,” Neuro-Oncology, Vol. 12, No. 3, 2010, pp. 289-296. http://dx.doi.org/10.1093/neuonc/nop030
[32] W. B. Pope, A. Lai, P. Nghiemphu, P. Mischel and T. F. Cloughesy, “MRI in Patients with High-Grade Gliomas Treated with Bevacizumab and Chemotherapy,” Neurology, Vol. 66, No. 8, 2006, pp. 1258-1260. http://dx.doi.org/10.1212/01.wnl.0000208958.29600.87
[33] A. D. Norden, G. S. Young, K. Setayesh, A. Muzikansky, R. Klufas, G. L. Ross, A. S. Ciampa, L. G. Ebbeling, B. Levy, J. Drappatz, S. Kesari and P. Y. Wen, “Bevacizumab for Recurrent Malignant Gliomas: Efficacy, Toxicity, and Patterns of Recurrence,” Neurology, Vol. 70, No. 10, 2008, pp. 779-787. http://dx.doi.org/10.1212/01.wnl.0000304121.57857.38
[34] J. Vredenburgh, A. Desjardins, J. E. Herndon II, J. M. Dowell, D. A. Reardon, J. A. Quinn, J. N. Rich, S. Sathornsumetee, S. Gururangan, M. Wagner, D. D. Bigner, A. H. Friedman and H. S. Friedman, “Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma,” Clinical Cancer Research, Vol. 13, No. 30, 2007, pp. 1253-1259. http://dx.doi.org/10.1158/1078-0432.CCR-06-2309
[35] T. Kreisl, L. Kim, K. Moore, P. Duic, C. Royce, I. Stroud, N. Garren, M. Mackey, J. A. Butman, K. Camphausen, J. Park, P. S. Albert and H. A. Fine, “Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma,” Journal of Clinical Oncology, Vol. 27, No. 5, 2009, pp. 740-745. http://dx.doi.org/10.1200/JCO.2008.16.3055
[36] D. R. Macdonald, T. L. Cascino, S. C. Schold Jr. and J. G. Cairncross, “Response Criteria for Phase II Studies of Supratentorial Malignant Glioma,” Journal of Clinical Oncology, Vol. 8, No. 7, 1990, pp. 1277-1280.
[37] J. Tuettenberg, R. Grobholz, M. Seiz, M. A. Brockmann, F. Lohr, F. Wenz and P. Vajkoczy, “Recurrence Pattern in Glioblastoma Multiforme Patients Treated with Anti-Angiogenic Chemotherapy,” Journal of Cancer Research and Clinical Oncology, Vol. 135, No. 9, 2009, pp. 1239-1244.
[38] E. S. Newlands., G. R. Blackledge, J. A. Slack, G. J. Rustin, D. B. Smith, N. S. Stuart, C. P. Quarterman, R. Hoffman, M. F. G. Stevens and M. H. Brampton, “Phase I Trial of Temozolomide (CCRG 81045: M&B 39831: NSC 362856),” British Journal of Cancer, Vol. 65, No. 2, 1992, pp. 287-291.
[39] P. Y. Wen, A. D. Norden, J. Drappatz and E. Quant, “Response Assessment Challenges in Clinical Trials of Gliomas,” Current Oncology Reports, Vol. 12, No. 1, 2010, pp. 68-75.
[40] E. T. Wong, K. R. Hess, M. J. Gleason, K. A. Jaeckle, A. P. Kyritsis, M. D. Prados, V. A. Levin and W. K. Yung, “Outcomes and Prognostic Factors in Recurrent Glioma Patients Enrolled onto Phase II Clinical Trials,” Journal of Clinical Oncology, Vol. 17, No. 8, 1999, pp. 2572-2578.
[41] K. Lamborn, A. Yung, S. Chang, P. Y. Wen, T. F. Cloughesy, L. M. DeAngelis, H. I. Robins, F. S. Lieberman, H. A. Fine, K. L. Fink, L. Junck, L. Abrey, M. R. Gilbert, M. Mehta, J. G. Kuhn, K. D. Aldape, J. Hibberts, P. M. Peterson, M. D. Prados and North American Brain Tumor Consortium, “Progression-Free Survival: An Important End Point in Evaluating Therapy for Recurrent High-Grade Gliomas,” Neuro-Oncology, Vol. 10, No. 2, 2008, pp. 162-170. http://dx.doi.org/10.1215/15228517-2007-062
[42] M. C. Chamberlain, M. J. Glantz, L. Chalmers, A. Van Horn and A. E. Sloan, “Early Necrosis Following Temodar and Radiotherapy in Patients with Glioblastoma,” Journal of Neuro-Oncology, Vol. 82, No. 1, 2007, pp. 81-83. http://dx.doi.org/10.1007/s11060-006-9241-y
[43] D. Brandsma, L. Stalpers, W. Taal, P. Sminia and M. J. van den Bent, “Clinical Features, Mechanisms, and Management of Pseudoprogression in Malignant Gliomas,” Lancet Oncology, Vol. 9, No. 5, 2008, pp. 453-461. http://dx.doi.org/10.1016/S1470-2045(08)70125-6
[44] W. Taal, D. Brandsma, H. G. de Bruin, J. E. Bromberg, A. T. Swaak-Kragten, P. A. E. S. Smitt, C. A. van Es and M. J. van den Bent, “Incidence of Early Pseudo-Progression in a Cohort of Malignant Glioma Patients Treated with Chemoirradiation with Temozolomide,” Cancer, Vol. 113, No. 2, 2008, pp. 405-410. http://dx.doi.org/10.1002/cncr.23562
[45] A. A. Brandes, A. Tosoni, F. Spagnolli, et al., “Disease Progression or Pseudoprogression after Concomitant Radiochemotherapy Treatment: Pitfalls in Neurooncology,” Neuro-Oncology, Vol. 10, No. 3, 2008, pp. 361-367. http://dx.doi.org/10.1215/15228517-2008-008
[46] P. Y. Wen, D. R. Macdonald, D. A. Reardon, et al., “Proposal for an Updated Response Criteria in High-Grade Gliomas,” Journal of Clinical Oncology (in press).
[47] R. F. Barajas Jr., J. S. Chang, M. R. Segal, A. T. Parsa, M. W. McDermott, M. S. Berger and S. Cha, “Differentiation of Recurrent Glioblastoma Multiforme from Radiation Necrosis after External Beam Radiation Therapy with Dynamic Susceptibility Weighted Contrast-Enhanced Perfusion MR Imaging,” Radiology, Vol. 253, No. 2, 2009, pp. 486-496. http://dx.doi.org/10.1148/radiol.2532090007
[48] L. S. Hu, L. C. Baxter, K. A. Smith, B. G. Feuerstein, J. P. Karis, J. M. Eschbacher, S. W. Coons, P. Nakaji, R. F. Yeh, J. Debbins and J. E. Heiserman, “Relative Cerebral Blood Volume Values to Differentiate High-Grade Glioma Recurrence from Posttreatment Radiation Effect: Direct Correlation between Image-Guided Tissue Histopathology and Localized Dynamic Susceptibility-Weighted Contrast-Enhanced Perfusion MR Imaging Measurements,” American Journal of Neuroradiology, Vol. 30, No. 3, 2009, pp. 552-558. http://dx.doi.org/10.3174/ajnr.A1377
[49] E. Matsusue, J. R. Fink, J. K. Rockhill, T. Ogawa and K. R. Maravilla, “Distinction between Glioma Progression and Post-Radiation Change by Combined Physiologic MR Imaging,” Neuroradiology, Vol. 52, No. 4, 2010, pp. 297-306. http://dx.doi.org/10.1007/s00234-009-0613-9
[50] A. A. Brandes, E. Franceschi, A. Tosoni, S. Bartolini, A. Bacci, R. Agati, C. Ghimenton, S. Turazzi, A. Talacchi, M. Skrap, G. Marucci, L. Volpin, L. Morandi, S. Pizzolitto, M. Gardiman, A. Andreoli, F. Calbucci and M. Ermani, “O6-Methylguanine DNA-Methyltransferase Methylation Status Can Change between First Surgery for Newly Diagnosed Glioblastoma and Second Surgery for Recurrence: Clinical Implications,” Neuro-Oncology, Vol. 12, No. 3, 2010, pp. 283-288. http://dx.doi.org/10.1093/ neuonc/nop050
[51] A. Omuro, T. Chan, L. Abrey, M. Khasraw, A. S. Reiner, T. J. Kaley, L. M. DeAngelis, A. B. Lassman, C. P. Nolan, I. T. Gavrilovic, A. Hormigo, C. Salvant, A. Heguy, A. Kaufman, J. T. Huse, K. S. Panageas, A. F. Hottinger and I. Mel, “Phase II Trial of Continuous Low Dose Temozolomide for Patients with Recurrent Malignant Glioma,” Neuro-Oncology, Vol. 15, No. 2, 2013, pp. 242-250.

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.