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Temozolomide: The evidence for its therapeutic efficacy in malignant astrocytomas.

ABSTRACT: Malignant gliomas are a heterogeneous group of primary central nervous system neoplasms that represent less than 2% of all cancers yet carry a significant burden to society. They are frequently associated with considerable and progressive neurological disability and are ultimately intractable to all forms of treatment. Temozolomide (TMZ) is a new second generation DNA alkylating agent that has become part of malignant astrocytoma management paradigms because of its proven efficacy, ease of administration, and favorable toxicity profile.To review the role of TMZ in the management of malignant astrocytomas (World Health Organization grades III and IV) including newly diagnosed (n) and recurrent (r) anaplastic astrocytomas (AA) and glioblastomas.A series of pivotal clinical trials have established a role for TMZ in the treatment of malignant astrocytomas. A large phase II trial examining the role of TMZ in rAA showed a response rate of 35%, and a 6-month progression-free survival of 46%. This led to the accelerated approval of TMZ by the FDA and the EU for the treatment of rAA. Evidence for a role of TMZ in nAA is currently limited but research is ongoing in this area. The role of TMZ in the management of glioblastoma at the time of recurrence (rGBM) is less impressive but evidence for its activity was demonstrated in two large phase II trials that led to the approval of TMZ for this indication in Europe and Canada but not in the US. A recent large prospective randomized phase III trial showed that the addition of TMZ during and after radiation therapy (RT) in newly diagnosed (nGBM) patients prolonged median overall survival by 2.5 months; perhaps more importantly, the 2-year survival rate for patients receiving TMZ and RT was 26% compared with 10% for those receiving RT alone. Concurrent TMZ with RT followed by adjuvant TMZ has become the standard of care for nGBM patients. Based on the evidence presented in this trial, TMZ received approval from the FDA and the EU for patients with nGBM in 2005.THERE IS EVIDENCE TO SUPPORT THE USE OF TMZ FOR THE FOLLOWING DISEASES IN THE ORDER OF MOST TO LEAST CONVINCING: nGBM, rAA, rGBM, and nAA. This order may quickly change as more trials are being designed and implemented, particularly with novel TMZ dosing schedules.

SUBMITTER: Omar AI

PROVIDER: S-EPMC2899776 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Temozolomide: The evidence for its therapeutic efficacy in malignant astrocytomas.

Omar Ayman I AI Mason Warren P WP

Core evidence 20100615

<h4>Introduction</h4>Malignant gliomas are a heterogeneous group of primary central nervous system neoplasms that represent less than 2% of all cancers yet carry a significant burden to society. They are frequently associated with considerable and progressive neurological disability and are ultimately intractable to all forms of treatment. Temozolomide (TMZ) is a new second generation DNA alkylating agent that has become part of malignant astrocytoma management paradigms because of its proven ef ...[more]

PMID: 20694068

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Project description:Abstract Background While the NOA-08 trial and the NORDIC Elderly trial suggested an O6-methylguanine DNA-methyl transferase (MGMT) status-tailored use of radiotherapy (RT) and temozolomide (TMZ), recent data from the NCIC CE.6/EORTC 26062 showed that hypofractionated RT plus TMZ was superior to RT for unselected elderly patients with an impact of MGMT for the effect of TMZ. Material and Methods This is the long-term update of the NOA-08 trial (German Cancer Trials Registry ID 386 and NCT01502241) that compared efficacy and safety of RT alone to TMZ alone in elderly patients with anaplastic astrocytoma (AA) or glioblastoma (GB), both isocitrate dehydrogenase wildtype, using overall survival (OS) as primary endpoint and event-free survival (EFS) as well as efficacy according to MGMT status as major secondary endpoints. NOA-08 had randomized patients (N=412; 39 AA, 373 GB) > 65 years with a Karnofsky performance score ? 60 in electronically generated blocks of variable length without stratification to receive standard RT to 60 Gy in 30 x 2 Gy fractions or TMZ dosed according to tolerance in a one week on/one week off schedule with tolerability dependent dosing. The trial finished enrolment Nov 2 2009 and demonstrated non-inferiority of TMZ compared with RT (p=0·033). Results In the long-term analysis with a data cut-off Apr 1 2018 median OS was 8·2 [7·0–10·0] months for TMZ treatment versus 9·4 [8·1–10·4] months for RT; hazard ratio (HR)=0·93 (95% CI: 0·76-1·15)] of TMZ versus RT did not differ between both arms. Also, median EFS [3·4 [3·2–4·1] months versus 4·6 [4·2–5·0] months did not differ with a HR=1·02 (0·83-1·25)]. MGMT promoter methylation tested in tumor tissue (82/221 patients, 37·1%) was associated with prolonged OS [13·6 [10·1–16·5] versus 8·0 [6·9-9·9] months; HR=0·53 (0·40-0·70), p<0·0001]. Patients with MGMT promoter methylation had longer OS and EFS when treated with TMZ (18·4 [13·9–24·4] months and 8·5 [6·9–13·3] months) versus RT (9·6 [6·4–13·7] months and 4·8 [4·3–6·2] months, HR 0·44 [0.27–0.70], p<0·001 for OS and 0·46 [0.29–0.73], p=0·001 for EFS). Patients without MGMT promoter methylation had shorter EFS and a shorter OS with the usual testing not significant when treated with TMZ (6·7 [5·6–8·2] months and 3·0 [2·6-3·3] months) versus with RT (10·2 [8·0–12·0] months and 4·6 [3·7-6·4] months), HR 1·33 [0·95-1·87], p=0·099 for OS and 1·86 [1·32-2·62], p<0·001 for EFS). Conclusion Also in the long-term analyses, NOA-08 confirms the non-inferiority of TMZ compared with RT in the treatment of elderly patients with WHO grade III or IV astrocytic gliomas. To improve OS and EFS, MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ and offers unexpectedly favorable long-term outcome with initial TMZ monotherapy.

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Temozolomide: The evidence for its therapeutic efficacy in malignant astrocytomas.

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Temozolomide: The evidence for its therapeutic efficacy in malignant astrocytomas.

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