Lack of Benefit of Extending Temozolomide Treatment in Patients with High Vascular Glioblastoma with Methylated MGMT.

María Del Mar Álvarez-Torres,Juan M García-Gómez,Carmen Balaña,Elies Fuster-García,Josep Puig

doi:10.3390/cancers13215420

Abstract

Simple SummaryDespite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity, as well as the lack of benefit of temozolomide in patients with a highly vascular tumor.In this study, we evaluated the benefit on survival of the combination of methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included in the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of extending temozolomide treatment for patients with high vascular glioblastomas, even presenting MGMT methylation. Preliminary results suggest that patients with moderate vascularity and methylated MGMT glioblastomas would benefit more from prolonged adjuvant chemotherapy.

Highlights

Glioblastoma patients remain a devastating prognosis of 12–15 months from diagnosis [1,2] despite an intrusive treatment including tumor resection, radiotherapy, and concomitant and maintenance chemotherapy with temozolomide [3]
We aimed to evaluate the lack of benefit of temozolomide for methylation of the O6methylguanine-DNA methyltransferase (MGMT) methylated patients with high vascular glioblastomas, since previous results published in [47] concluded that the combined effect of MGMT methylation and moderate vascularity of the tumor causes a benefit in glioblastoma patient overall survival
We investigated the correlation between the number of temozolomide cycles and MGMT status for the high- and moderate-vascular groups and we found that only for the moderate-vascular group, both variables were significantly associated with patient survival

Summary

Introduction

Glioblastoma patients remain a devastating prognosis of 12–15 months from diagnosis [1,2] despite an intrusive treatment including tumor resection, radiotherapy, and concomitant and maintenance chemotherapy with temozolomide [3]. This standard treatment, proposed by Stupp in 2005 [3], was demonstrated to be the most effective in terms of overall survival but, due to strong interpatient heterogeneity, it is not efficient for all patients [4]. The European Association of Neuro-oncology guidelines recommend six cycles of maintenance therapy [34]

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