First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Dec 24, 2010Neuro-oncology

Temozolomide chemotherapy after radiotherapy for growing low-grade brain tumors: molecular traits linked to treatment response

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Abstract

The six-month progression-free survival (PFS) rate after temozolomide treatment was 67% in a cohort of 58 patients with recurrent low-grade astrocytoma.

Median overall survival for patients was 14 months.
An objective response to treatment was observed in 54% of patients.
TP53 mutations and loss of chromosome 19q may be associated with PFS.
The majority of tumor samples (86%) exhibited both a methylated MGMT promoter gene and IDH1 mutations.
A significant correlation was found between IDH1 mutations and MGMT promoter methylation.
The interval from the first symptom of low-grade astrocytoma to the start of temozolomide was longer in patients with IDH1 mutations and a methylated MGMT promoter.

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Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.

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First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

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