Temozolomide plus radiotherapy increased five-year OS in adult glioblastoma

Issue: April 25, 2009

Data from an EORTC-NCIC phase-3 study indicate that radiotherapy in combination with adjuvant temozolomide had a five-year beneficial effect for all prognostic subgroups of people with glioblastoma.

Researchers randomly assigned 573 adults to receive either standard radiotherapy or identical radiotherapy in combination with concomitant temozolomide (Temodar, Schering) followed by up to six cycles of adjuvant temozolomide.

Median follow-up was five years or more. The methylation status of the methyl-guanine methyl transferase gene was retrospectively determined from the tumor tissue of 206 participants. Primary endpoint was OS.

At five year follow-up, OS was 9.8% for people treated with combination therapy vs. 1.9% for people treated with radiotherapy alone (95% CI, 0.5-0.7).

The benefit for combination therapy was found for all subgroups, including people aged 60 to 70 years. However, the strongest predictor for outcome and benefit of combination treatment was the methylation of the MGMT gene. “Methyl-guanine methyl transferase gene methylation status identifies patients most likely to benefit from the addition of temozolomide,” the researchers wrote. – by Jennifer Southall

Stupp R. Lancet Oncol.2009;doi:10.1016/S1470-2045(09)70025-7.

After treatment with surgery and radiotherapy, the outcome for the majority of patients with glioblastoma multiforme remains extraordinarily poor, with few patients alive three years after diagnosis. In the past decade, a great deal has been learned about the mechanisms underlying the development and growth of this tumor. However, these have yet to be translated into clinical improvements for the vast majority of patients.

Temozolomide, an oral alkylating agent, has been used in patients with recurrent high-grade malignant gliomas. The drug is well tolerated and seemed to be of benefit for some patients with this disease. A seminal report by the same group that reports the present study, published in The New England Journal of Medicine in 2005 (NEJM. 352:997-1003), found a significant improvement in short-term survival for those patients who received temozolomide with radiotherapy compared with those who received radiotherapy alone. Although this relationship occurred across all treatment subgroups, those patients with epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA repair gene had a more robust survival advantage.

This gene encodes a DNA repair protein that removes alkyl groups from the O6 position of guanine, an important site of DNA alkylation. Left unrepaired, chemotherapies such as temozolomide are more likely to trigger cytotoxicity and apoptosis. One means of silencing the MGMT gene is by promoter methylation, which is associated with loss of MGMT expression and diminished DNA repair activity. Hegi and colleagues found that methylation of the MGMT gene was associated with longer survival (Clin Can Res. 2004;1871-1874), and their report in 2005 was met with significant excitement, since it showed not only improved survival for a subgroup of patients with high-grade gliomas, but a biologic rationale for future directions in glioblastoma multiforme translational research. In the initial report, the OS curves for temozolomide and radiotherapy and for radiotherapy alone were similar for the first nine months of follow-up, suggesting that MGMT methylation status was not the sole factor determining outcome.

The important follow-up report demonstrated that this survival advantage was not only noted at two years, but continued for at least five years, with nearly 10% of those patients who had received temozolomide being alive compared with 2% of those who received radiotherapy alone. Combined therapy was of benefit in all major subgroups of patients, including patients between 60 and 70 years of age at the time of treatment. As there is some controversy on how aggressive older patients with glioblastoma multiforme are to be treated, this has therapeutic implications. Once again, the epigenetic silencing of MGMT, the enzyme thought to reverse much of temozolomide’s activity, was the strongest predictor of outcome. In a recent study, Glas and colleagues also demonstrated promising outcome in patients with silenced MGMT and treatment with radiotherapy and lomustine and temozolomide combination alkylator therapy (J Clin Oncol. 2009;27:1257-1261). Clearly, these results are encouraging, but unfortunately, for only a minority of patients with glioblastoma multiforme. The authors also caution that even for five-year survivors this was not a cure, as the majority of patients ultimately succumbed of their disease. It continues to show the need for better understanding the biology of the disease and factors resulting in tumor response to therapy. This is of crucial importance as new agents, especially biologic agents, are being evaluated in the management of patients with newly diagnosed and recurrent glioblastoma multiforme. There is risk of discarding effective agents, if biologic subsets of patients are not appropriately recognized.

– Roger Packer, MD

HemOnc Today Editorial Board member