New Care Option for Elderly Patients With Gliomas?

Roxanne Nelson

July 06, 2012

July 6, 2012 — For newly diagnosed elderly patients, temozolomide (Temodar) alone is a noninferior treatment to radiotherapy for malignant gliomas. This means that the spectrum of care can be broadened in this population, according to a phase 3 study published in the July issue of the Lancet Oncology.

The current standard of care for older adults with glioblastoma or anaplastic astrocytoma is surgical resection or biopsy, followed by involved-field radiotherapy, note the authors, led by Wolfgang Wick, MD, chair of the Department of Neuro-Oncology at the University of Heidelberg in Germany.

The study suggests that single-agent temozolomide offers an alternative to radiotherapy in this patient population.

Median survival was 8.6 months for patients treated with temozolomide alone, compared with 9.6 months for those treated with radiotherapy alone (hazard ratio [HR], 1.09; P noninferiority = .033).

Median event-free survival did not significantly differ between the temozolomide and radiotherapy groups (3.3 vs 4.7 months; HR, 1.15; P noninferiority = .043).

Greater Benefit in Subgroup of Patients

For nonelderly patients, the standard of care for glioblastoma or anaplastic astrocytoma is concomitant and adjuvant radiochemotherapy with temozolomide. This approach appears to be particularly beneficial to patients who have tumors that exhibit promoter methylation of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene, which encodes a DNA repair protein associated with alkylator resistance.

Dr. Wick and colleagues found tumor MGMT promoter methylation in 73 (35%) of the 209 elderly patients tested. In that group, MGMT promoter methylation was associated with an overall survival of 11.9 months; unmethylated status was associated with an overall survival of 8.2 months (HR, 0.62; P = .014).

In patients with MGMT promoter methylation, event-free survival was longer in patients treated with temozolomide than in those treated with radiotherapy (8.4 vs 4.6 months). However, for patients with no methylation of the MGMT promoter, event-free survival was shorter (3.3 vs 4.6 months).

Validation Needed

These findings suggest that in elderly patients with newly diagnosed glioblastoma, temozolomide provides a therapeutic advantage for those with MGMT methylated tumors, writes David A. Reardon, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, in an accompanying comment.

These results require validation, he cautions, although they suggest that "testing of tumor MGMT methylation status in elderly patients with newly diagnosed glioblastoma should be a priority."

Single-agent temozolomide and radiotherapy alone seem equally effective.

"If the status cannot be ascertained, however, the study findings suggest that single-agent temozolomide and radiotherapy alone seem equally effective," he writes.

Dr. Reardon notes that geriatric neuro-oncology is becoming a major focus in cancer therapy, and the results of this study, along with others that focus on this population, "address a major knowledge deficiency in neuro-oncology."

"Nonetheless, the optimization of outcomes remains a major challenge in elderly patients with glioblastoma, especially those excluded from clinical trials because of poor performance status scores," he adds. "Clearly, prospective testing of MGMT methylation status and other potentially relevant markers, such as gene expression profiles and isocitrate dehydrogenase mutation, will be crucial in therapeutic studies to build on the precedent set by Wick and colleagues."

Study Details

Dr. Wick and colleagues previously reported "encouraging progression-free survival" at 6 months in elderly patients with recurrent disease treated with a 1-week on/1-week off regimen of temozolomide.

On the basis of those results, the German Neuro-oncology Working Group conducted this phase 3 trial of 412 older patients newly diagnosed with anaplastic astrocytoma or glioblastoma.

Of this group, 195 patients were randomly assigned to temozolomide and 178 to radiotherapy; all patients received at least 1 dose of treatment and were included in efficacy analyses.

Temozolomide 100 mg/m² was administered on days 1 to 7 (1-week on/1-week off schedule). Increases or decreases in dosing were done in 25 mg/m² steps, on the basis of blood cell counts and general tolerability of the treatment regimen. Radiation therapy was given over 6 to 7 weeks, in fractions of 1.8 to 2.0 Gy, to a total 60.0 Gy.

Most of the patients tolerated treatment well, and no grade 5 adverse events were reported. Grade 2 to 4 adverse events were more frequent in the temozolomide group in all categories except for cutaneous adverse effects. The most commonly observed grade 3 or 4 adverse events were neutropenia (16 in the temozolomide group vs 2 in the radiotherapy group), lymphocytopenia (46 vs 1), thrombocytopenia (14 vs 4), elevated liver enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs 8).

The study was funded by Merck Sharp & Dohme. Several of the authors report receiving consulting and lecture fees or research support from Merck Sharp & Dohme, as noted in the paper. Dr. Reardon reports receiving honoraria from Merck/Schering Corporation.

Lancet Oncol. 2012;13:656-657, 707-715. Comment, Abstract

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