Abstract
Recent clinical trials have demonstrated improvements in survival in patients with malignant gliomas. Laboratory investigations have uncovered genetic alterations that promote gliomagenesis and defined several critical signaling pathways that affect tumor viability, invasiveness, angiogenesis, and resistance to apoptosis. These advances have stimulated interest in new targeted therapies and clinical trial designs to streamline the determination of efficacy. One such advance is the use of a “progression-free” endpoint, which eliminates the need to demonstrate tumor reduction when there is concurrent treatment-associated tissue necrosis and reflects the cytostatic, not cytotoxic, potential of many new agents. An additional advance is the concept of optimal biologic dose rather than maximum tolerated dose. This concept is being evaluated in laboratory correlative studies through analysis of post-treatment tumor samples. Also, clinical trials are expected to become more efficient through design strategies that permit testing (often simultaneously) of several regimens and facilitate definitive comparisons of the most promising treatment arms. Such designs also require smaller accrual numbers for each study. Finally, investigators have increased interest in determining the impact of treatment on other measures, such as symptom burden, functional status, and quality of life as survival has improved.
Similar content being viewed by others
References and Recommended Reading
Stupp R, Mason WP, van den Bent M, et al.:Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM). Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group.Proc ASCO 2004,23:2.
Gilbert M Supko R, Batchelor JG, Batchelor T., et al.:Phase I clinical and pharmacokinetic study of irinotecan in adults with recurrent malignant glioma.Clin Cancer Res 2003,9:2940–2949.
Prados M, Scott D, Rotman CB, et al.:Influence of bromodeoxyuridine radiosensitization on malignant glioma patient survival: a retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group trials (RTOG) for glioblastoma multiforme and anaplastic astrocytoma.Int J Radiat Oncol Biol Phys 1998,40:653–659.
Prados M, Yung D, Jaeckle WK, et al.:Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study.Neuro-oncol 2004,6:44–54.
Vertosick F Jr, Selker RG, Arena VC:Survival of patients with well-differentiated astrocytomas diagnosed in the era of computed tomography.Neurosurgery 1991,28:496–501.
Soffietti R, Chio A, Giordana MT, et al.:Prognostic factors in well-differentiated cerebral astrocytom as in the adult.Neurosurgery 1989,24:686–692.
Druker BJ:Perspectives on the development of a molecularly targeted agent.Cancer Cell 2002,1:31–36.
Tremont-Lukats IW, Gilbert MR:Advances in molecular therapies in patients with brain tumors.Cancer Control 2003,10:125–137.
Maher EA, Furnari FB, Bachoo RM, et al.:Malignant glioma: genetics and biology of a grave matter.Genes Dev 2001,15:1311–1333.
Chakravarti A, Dicker A, Mehta M:The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data.Int J Radiat Oncol Biol Phys 2004,58:927–931.
Mischel PS, Nelson SF, Cloughesy TF:Molecular analysis of glioblastoma: pathway profiling and its implications for patient therapy.Cancer Biol Ther,2:242–247, 2003.
Jaeckle KA, Eyre HJ, Townsend JJ, et al.:Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study.J Clin Oncol 1998,16:3310–3315.
Hegi ME, Diserens AC, Godard S, et al.:Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.Clin Cancer Res 2004,10:1871–1874.
Esteller M, Garcia-Foncillas J, Andion E, et al.:Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents.N Engl J Med 2000,343:1350–1354.
Hegi ME, Diserens AC, Gorlia T, et al.:MGMT gene silencing and benefit from temozolomide in glioblastoma.N Engl J Med 2005,352:997–1003.
Bauman GS, Ino Y, Ueki K, et al.:Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas.Int J Radiat Oncol Biol Phys 2000,48:825–830.
Ino Y, Betensky RA, Zlatescu MC, et al.:Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis.Clin Cancer Res 2001,7:839–845.
Walker MD, Alexander E Jr, Hunt WE, et al.:Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial.J Neurosurg 1978,49:333–343.
Yung WK, Albright RE, Olson J, et al.:A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.Br J Cancer 2000,83:588–593.
Wong ET, Hess KR, Gleason MJ, et al.:Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials.J Clin Oncol 1999,17:2572–2578.
Byar DP, Piantadosi S:Factorial designs for randomized clinical trials.Cancer Treat Rep 1985,69:1055–1063.
Green S, Liu PY, O’Sullivan J:Factorial design considerations.J Clin Oncol 2002,20:3424–3430.
Vray M, Girault D, Hoog-Labouret N, et al.:Methodology for small clinical trials.Therapie 2004,59:273–279, 281–276.
Inoue LY, Thall PF, Berry DA:Seamlessly expanding a randomized phase II trial to phase III.Biometrics 2002,58:823–831.
Thall PF, Wathen JK, Bekele BN, et al.:Hierarchical Bayesian approaches to phase II trials in diseases with multiple subtypes.Stat Med 2003,22:763–780.
Bauer P, Brannath W:The advantages and disadvantages of adaptive designs for clinical trials.Drug Discov Today 2004,9:351–357.
Reardon D, Cloughesy T, Conrad C, et al.:A phase I study of AEE788, a novel multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases, in recurrent GBM patients.J Clin Oncol Proc ASCO 2005,23(16S, Part I of II, June 1 Suppl):3063.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gilbert, M.R. Designing clinical trials for brain tumors: The next generation. Curr Oncol Rep 9, 49–54 (2007). https://doi.org/10.1007/BF02951425
Issue Date:
DOI: https://doi.org/10.1007/BF02951425