title: First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response.
abstract: 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.
authors.affiliation: Department of Neuro-oncology/Neurology, Erasmus MC, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands. w.taal@erasmusmc.nl
authors.forename: Walter
authors.initials: W
authors.lastname: Taal
authors.forename: Hendrikus J
authors.initials: HJ
authors.lastname: Dubbink
authors.forename: Chris B L
authors.initials: CB
authors.lastname: Zonnenberg
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
authors.forename: Tjeerd J
authors.initials: TJ
authors.lastname: Postma
authors.forename: Johanna M M
authors.initials: JM
authors.lastname: Gijtenbeek
authors.forename: Willem
authors.initials: W
authors.lastname: Boogerd
authors.forename: Floris H
authors.initials: FH
authors.lastname: Groenendijk
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Mathilde C M
authors.initials: MC
authors.lastname: Kouwenhoven
authors.forename: Ronald
authors.initials: R
authors.lastname: van Marion
authors.forename: Irene
authors.initials: I
authors.lastname: van Heuvel
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Jacoline E C
authors.initials: JE
authors.lastname: Bromberg
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy* / Q000235:genetics* / Q000532:radiotherapy; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000532:radiotherapy; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011879:Radiotherapy Dosage; D015996:Survival Rate; D000077204:Temozolomide; D016896:Treatment Outcome; D014314:Trisomy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide