Therapy for Recurrent High-Grade Gliomas: Does Continuous Dose-Intense Temozolomide Have a Role?

Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center; and Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA

High-grade gliomas (HGG) are the most common malignant primary brain tumors, with an annual incidence in the United States of approximately 15,000 patients. Currently, standard therapy for glioblastomas (WHO grade 4 gliomas) involves maximal safe surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide. Despite optimal therapy, these tumors inevitably recur with a median time-to-tumor progression of approximately 6.9 months, and median survival of only 15 months. For anaplastic gliomas (WHO grade 3 gliomas) treatment with radiotherapy and chemotherapy results in a median time-to-tumor progression of approximately 1.2 to 2.6 years and a median survival of 2 to 7 years.

Treatment options for recurrent HGG are limited. Bevacizumab produces response rates of approximately 20% to 40% in glioblastomas and increases 6-month progression-free survival (PFS6) to approximately 30% to 50%. Based on these results, bevacizumab recently received accelerated approval from the US Food and Drug Administration for treatment of recurrent glioblastomas. Similar results have been obtained with anaplastic gliomas.The results of other therapies for recurrent HGG have been generally disappointing, with PFS6 of only 9% to 16%. Nitrosoureas, such as lomustine and carmustine, increase PFS6 to approximately 21% to 24%,but most other chemotherapeutic agents have minimal activity.

There is increasing evidence that the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) is associated with resistance to therapy with alkylating agents such as temozolomide. Glioblastomas in which the MGMT gene is silenced by promoter methylation have a significantly improved outcome after therapy with temozolomide. In the European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada Clinical Trials Group study comparing radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone, patients whose tumor had a methylated MGMT promoter treated with temozolomide had a median survival of 23.4 months (95% CI, 18.6 to 32.8 months) compared with a median survival of 12.6 months (95% CI, 11.6 to 14.4 months) for patients whose tumors had unmethylated MGMT promoters. In anaplastic gliomas, MGMT methylation status appears to be primarily a prognostic factor rather than a factor predicting treatment response.

Given that prolonged exposure of tumor cells to temozolomide potentially depletes MGMT, there is increasing interest in examining dose-dense regimens in patients who have progressed on standard temozolomide adjuvant therapy consisting of 150 to 200 mg/m² given daily for 5 days every 28 days. Regimens such as 75 to 100 mg/m² of temozolomide administered for 21 of every 28 days have produced PFS6 of 30.3%, while 150 mg/m² for 7 days on, 7 days off produced a PFS6 of 43.8%, although many patients in this study did not have prior chemotherapy. In contrast to these studies suggesting that dose-dense temozolomide regimens may be beneficial in patients with recurrent HGG, a recent trial sponsored by Cancer Research UK (MRC BR12 trial) failed to demonstrate any benefit of the 21 of 28 days regimen over the standard 5 of 28 days regimen in patients with recurrent HGG who were chemotherapy naïve.As a result of these studies, the value of dose-dense regimens remain unproven. The results of the Radiation Therapy Oncology Group 0525 study, which randomly assigned patients with newly diagnosed glioblastoma to either adjuvant temozolomide chemotherapy with the 5 of 28 days regimen or the 21 of 28 days regimen, will become available in 2010 and may provide additional information on the value of dose-dense regimens, although these results will apply only to newly diagnosed glioblastomas rather than recurrent tumors.

In this issue of Journal of Clinical Oncology, Perry report the results of the RESCUE study in which patients with HGG who experience disease progression after receiving temozolomide adjuvant therapy using the standard 5 of 28 days schedule were treated with continuous dose-intense temozolomide at 50 mg/m² daily. There were three main rationales for this regimen. First, continuous exposure of tumor cells to temozolomide potentially depletes MGMT, overcoming resistance.Second, this regimen resulted in delivery of 1,400 mg/m² every 28 days, representing a dose intensification from 750 to 1,000 mg/m² every 28 days using the conventional 5 of 28 days regimen. Third, continuous temozolomide may represent a form of metronomic chemotherapy with potential antiangiogenic effects. The regimen was very well-tolerated and produced an overall PFS6 of 23.9% for patients with glioblastoma and 35.7% for patients with anaplastic glioma. Among patients with glioblastoma, those who recurred early (during the first 3 to 6 months of adjuvant temozolomide) had a PFS6 of 27.3%, while those who experienced disease progression after completion of adjuvant therapy, and never truly experienced treatment failure with temozolomide, had a PFS6 of 35.7%, suggesting that the regimen may be beneficial in these two subgroups. In contrast, those patients who recurred on treatment after receiving more than 6 cycles of temozolomide had a PFS6 of only 7.4% and did not appear to benefit. It is somewhat surprising that patients who progressed early, after only 3 to 6 months on temozolomide, benefited from re-treatment from continuous temozolomide, as these patients may be expected to be most resistant to the drug. Although the investigators were careful to exclude patients who experienced recurrence within the first 3 months after completion of radiotherapy to reduce the likelihood of including patients with pseudoprogression from radiation effects, this phenomenon can occur up to 6 months after radiotherapy, and it is possible that pseudoprogression contributed to the promising results in this early subgroup.

A limitation of this study was that MGMT promoter methylation status was available in only 50 of 120 patients. Overall, 42% of patients had methylated MGMT promoter. The PFS6 in these patients of 42.9% was not significantly different compared with the PFS6 of 37.9% in patients with unmethylated MGMT promoter. In the glioblastoma subgroup, the PFS6 in methylated patients (40%) was also not significantly different from unmethylated patients (36.4%). Other studies of dose-dense temozolomide regimens in recurrent HGG have also failed to find a difference in outcome between patients with methylated and unmethylated MGMT promoters.There are several possible explanations for this failure to detect a difference. One reason may simply be a lack of power to detect a significant difference because of the small number of patients who had tissue available for MGMT testing. A second possibility is that these dose-dense regimens actually do deplete MGMT and help partially overcome resistance. A third possibility is that MGMT is not the primary mechanism of resistance in tumors that progress after treatment with temozolomide. There is increasing evidence suggesting that a subset of recurrent glioblastomas previously treated with temozolomide have mutations in mismatch repair genes, such as MSH6.Because intact mismatch repair is required for cell killing by temozolomide, mismatch repair–deficient tumor cells are resistant to temozolomide, even in the absence of MGMT. Unfortunately, given the lack of tumor tissue before and after exposure to temozolomide from this study, the underlying mechanisms cannot be determined.

Regardless of the precise mechanism of action, the dose-intense temozolomide regimen reported in the RESCUE study shows promise. However, whether it is superior to other dose-intense temozolomide regimens remains to be determined. The DIRECTOR (Comparison of Two Dosing Regimens of Temozolomide in Patients With Progressive or Recurrent Glioblastoma) trial, currently in progress in Germany, compares the 21 of 28 days regimen with the 7 days on/7 days off regimen, but unfortunately does not include a third arm with continuous temozolomide. Formal comparison of the continuous temozolomide regimen from the RESCUE study with other dose-dense regimens, as well as nitrosoureas, will be necessary to determine the most effective chemotherapy for patients with recurrent HGG. It will be crucial that these studies include collection of tumor tissue before and after treatment for analysis of MGMT methylation, as well as the status of other DNA repair pathways, so that that we will have a better understanding of the underlying mechanisms involved in resistance. Until results from these types of studies and Radiation Therapy Oncology Group 0525 become available, the value of dose-dense regimens, such as the one proposed by the RESCUE study, will remain unproven and caution should be used in adopting these regimens as the chemotherapy backbone of future combination therapies for recurrent HGG.