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MGMT Promoter Methylation Status Can Predict the Incidence and Outcome of Pseudoprogression After Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma Patients

Alba A. Brandes, Enrico Franceschi, Alicia Tosoni, Valeria Blatt, Annalisa Pession, Giovanni Tallini, Roberta Bertorelle, Stefania Bartolini, Fabio Calbucci, Alvaro Andreoli, Giampiero Frezza, Marco Leonardi, Federica Spagnolli, Mario Ermani

From the Medical Oncology Department, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale of Bologna, Bologna; Pathology Department, Bellaria Hospital, University of Bologna, Bologna; Neurosurgery Department, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale of Bologna, Bologna, Italy; Radiotherapy Department, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale of Bologna, Bologna; Neuroradiology Department, Bellaria-Maggiore Hospital, Azienda Unità Sanitaria Locale of Bologna, Bologna; Research and Development Unit, Azienda Ospedale-Università, Padova, Italy; Servizio Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto, Padova, Italy; Neurosciences Department, Statistic and Informatic Unit, Azienda Ospedale-Università, Padova, Italy

Corresponding author: Alba A. Brandes, MD, Department of Medical Oncology, Via Altura 3, 40139, Bologna, Italy; e-mail: alba.brandes{at}yahoo.it

Purpose: Standard therapy for glioblastoma (GBM) is temozolomide (TMZ) administration, initially concurrent with radiotherapy (RT), and subsequently as maintenance therapy. The radiologic images obtained in this setting can be difficult to interpret since they may show radiation-induced pseudoprogression (psPD) rather than disease progression.

Methods: Patients with histologically confirmed GBM underwent radiotherapy plus continuous daily temozolomide (75 mg/m²/d), followed by 12 maintenance temozolomide cycles (150 to 200 mg/m² for 5 days every 28 days) if magnetic resonance imaging (MRI) showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. The first MRI scan was performed 1 month after completing combined chemoradiotherapy.

Results: In 103 patients (mean age, 52 years [range 20 to 73 years]), total resection, subtotal resection, and biopsy were obtained in 51, 51, and 1 cases, respectively. MGMT promoter was methylated in 36 patients (35%) and unmethylated in 67 patients (65%). Lesion enlargement, evidenced at the first MRI scan in 50 of 103 patients, was subsequently classified as psPD in 32 patients and early disease progression in 18 patients. PsPD was recorded in 21 (91%) of 23 methylated MGMT promoter and 11 (41%) of 27 unmethylated MGMT promoter (P = .0002) patients. MGMT status (P = .001) and psPD detection (P = .045) significantly influenced survival.

Conclusion: PsPD has a clinical impact on chemotherapy-treated GBM, as it may express the glioma killing effects of treatment and is significantly correlated with MGMT status. Improvement in the early recognition of psPD patterns and knowledge of mechanisms underlying this phenomenon are crucial to eliminating biases in evaluating the results of clinical trials and guaranteeing effective treatment.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.