Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial

Abstract

A B S T R A C T PurposeRadiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and MethodsThis phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of Ն 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. ResultsA total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P ϭ .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P ϭ .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P Ͻ .001), PFS (8.7 v 5.7 months; HR, 1.63; P Ͻ .001), and response (P ϭ .012). There was increased grade Ն 3 toxicity in arm 2 (34% v 53%; P Ͻ .001), mostly lymphopenia and fatigue. ConclusionThis study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes

“…PS and age are established prognostic factors for first-line as well as for second-line treatments [14,[32][33][34][35][36]. Recent studies set a threshold of KPS 60 % (corresponding to ECOG 2) as a prerequisite for tumour specific treatment interventions [4,5,37,38] as inferior PS is associated with increased side effects from any intervention and lowers the chance of clinical benefit [14,36,39]. The greatest consensus in our analysis was identified in unfit patients corresponding to a low PS.…”

“…No consensus was obvious in all other occasions, despite approval and its steroid-sparing properties. The reason for this low overlap might be related to the absence of a controlled clinical trial for the use of bevacizumab in recurrent glioblastoma or the recently reported failure in the first-line treatment setting [4,38]. Moreover, conflicting results about a negative impact on neuro-cognition may also hamper widespread use of this compound [44,45].…”

“…TMZ) progression-free survival (PFS) and overall survival (OS) remain poor with 6.9 and 14.2 months, respectively [2]. Recently, four large phase III trials failed to improve outcome after first-line therapy in terms of OS [3][4][5][6]. Hence, effective salvage treatment of recurrent glioblastoma remains a demanding problem in neuro-oncology.…”

Long-term exposure to irinotecan reduces cell migration in glioma cells

“…It carries a very poor prognosis with mean overall survival of [12][13][14][15][16][17] months. Despite testing a multitude of chemotherapy agents and strategies, very little progress has been made in extending the life expectancy of those diagnosed with a GBM, since the establishment of the Stupp protocol (a combination of radiotherapy and temozolomide) a decade ago [2,3]. This is believed to be due to a high level of intrinsic drug resistance [4] combined with the fact that these tumours tend to diffusely invade the local brain parenchyma making it difficult to identify the perimeter and effectively remove them surgically [5][6][7].…”

Mathematical model of cancer growth controled by metronomic chemotherapies

“…(4) In the hot spots of a tumor, the part of proliferant cells between tumor cells is of 20 to 30 % [47,54]. (5) Resistance mechanisms make the tumor start growing again after 6 to 8 month in the MTD protocol [27]. (6) Metronomic chemotherapies seem to be more efficient than MTD chemotherapies after 8 to 9 months [18].…”