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49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology

Los Angeles, California / October 28-November 1, 2007

Interest in adjuvant use of the oral alkylating agent temozolomide (TMZ) for treatment of glioblastoma multiforme (GBM) followed reports of single-agent activity in recurrent glioma. Additionally, evidence suggested that this agent depletes the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Low levels of MGMT in tumour tissue are associated with longer survival in patients with GBM receiving chemotherapy.

In a phase II clinical trial, chemoradiotherapy with TMZ followed by as many as six cycles of adjuvant TMZ resulted in a two-year survival of 31% in patients with GBM (Stupp et al. J Clin Oncol 2002;20:1375-82). Those encouraging results led to a phase III multinational trial co-sponsored by the National Cancer Institute of Canada (NCIC) and the European Organization for Research and Treatment of Cancer (EORTC).

Landmark Trial

The NCIC-EORTC trial compared the same regimens as in the phase II trial. Patients 18 to 70 years of age (median age was 56 years old) with newly diagnosed and histologically confirmed GBM and only those whose performance status was <2 were eligible for the study. Within six weeks of the glioblastoma diagnosis, 573 patients were randomized to standard focal radiotherapy (RT) alone or to RT plus concomitant TMZ, followed by adjuvant TMZ. The adjuvant regimen consisted of a maximum of six cycles of TMZ 150-200 mg/m2 daily, for five days, every 28 days. RT consisted of 2 Gy fractions for a total dose of 60 Gy. The primary end point was overall survival. After a median follow-up of 28 months, results of the trial demonstrated a median survival of 14.6 months in the TMZ group vs. 12.1 months with RT alone. Two-year survival was more than twofold greater in patients who received TMZ: 26.5% vs. 10.4%, P<0.001 (Stupp et al. N Engl J Med 2005;352:987-96) (Figure 1).

According to Dr. Dennis Shrieve, Chair of Radiation Oncology, University of Utah School of Medicine and Huntsman Cancer Institute, Salt Lake City, “In the world of treating brain tumours, a survival difference of this magnitude is considered a home run. At the tail end, the survival curves continued to separate, such that patients in the TMZ group had almost a threefold increase in long-term survival, suggesting that a subgroup of patients might be getting greater benefit from the treatment. With these results, TMZ plus RT became the standard of care worldwide for patients with glioblastoma,” he told delegates.

Figure 1. NCIC-EORTC Trial: Improved Survival

A companion article to the report on the primary results provided additional evidence that long-term survival in glioblastoma might be a realistic goal of treatment with an agent such as TMZ, Dr. Shrieve continued. Investigators in the NCIC-EORTC trial reported findings from an examination of the methylation status of the MGMT DNA repair gene and its association with survival (Hegi et al. N Engl J Med 2005;352:997-1003). Methylation silences the repair gene and has been associated with improved survival.

Methylation status was available for a subgroup of 206 patients. About 45% of the patients had methylated MGMT. MGMT promoter methylation conferred a highly favourable prognosis, irrespective of treatment (hazard ratio 0.45, P<0.001). However, a significantly greater benefit was observed in patients randomized to TMZ, as MGMT methylation was associated with a median survival of 21.7 months compared with 15.3 months among patients who received RT alone (P=0.007).

“TMZ conferred a huge survival advantage in patients with methylated MGMT,” confirmed Dr. Shrieve. “In that subgroup, two-year survival was almost 50% with TMZ compared with about 20% in patients who received RT alone.”

Despite the favourable results with adjuvant TMZ, the possibility of long-term survival in patients with GBM remains an unanswered question, noted Dr. René-Olivier Mirimanoff, University Hospital Centre, Lausanne, Switzerland. However, as these long-term data from the NCIC-EORTC trial have demonstrated, patients are living longer and their survival might become a possibility.

Potential for Long-term Survival

Patients have now been followed for a median of five years. Those randomized to TMZ have a four-year survival of 12%, fourfold greater than the 3% observed in patients treated with RT alone, Dr. Mirimanoff reported. The magnitude of the survival difference between treatment groups increased with follow-up At a mean follow-up of 45.9 months, median survival was 12.1 months in the group RT vs. 14.6 months with combination therapy
. Long-term Survival

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Analysis of data by MGMT methylation status demonstrated almost a twofold increase in four-year survival in patients with methylated MGMT treated with TMZ compared with the entire TMZ cohort (22% vs. 12%). Additionally, patients with favourable prognostic indicators (younger age and good performance status) fared much better with TMZ. They demonstrated a four-year survival of 28.4% compared with 6.8% with RT alone (P=0.012).

Even in patients with unmethylated MGMT, treatment with TMZ conferred a substantial survival advantage. Only 1% of patients randomized to RT alone were still alive at two years, compared with 15% of TMZ-treated patients. The RT group had no survivors at three years, whereas 11% patients with unmethylated MGMT remained alive at years 3 and
MZ (Table 2).

Table 2. MGMT Gene Status: Survival at Four Years

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“We can say that in this previously universally fatal disease, there is now some hope for a substantial minority of patients with glioblastoma,” confirmed Dr. Mirimanoff. “This is a breakthrough in the treatment of glioblastoma. Twenty years ago, we had no options for patients and long-term survival was inconceivable. Now patients with glioblastoma may live longer with a good quality of life. They can look forward to much more activity than in the past. They can continue to be followed and receive additional treatment. They might be operated on again. They can receive new chemotherapy. The results of this study have led to a huge change in the management of patients with glioblastoma,” Dr. Mirimanoff told delegates.

A quality-of-life assessment showed that adding TMZ to RT did not adversely affect quality of life, even in patients whose quality of life had already been affected by the disease itself. Data are pending from an updated analysis of quality of life, “but we have no reason to think there will be a change between the two arms,” remarked Dr. Mirimanoff.

ASTRO board member Dr. Anthony Zietman, Harvard Medical School, Boston, Massachusetts, mentioned that Dr. Mirimanoff’s presentation “is the good news story of this meeting. It shows that in this previously invariably and rapidly fatal disease, we may actually be turning the corner and that it is now possible for some patients to see some light at the end of the tunnel.”

Platform for Future Development

Dr. Mirimanoff suggested that the combination therapy would provide the platform for continued development of therapy for glioblastoma. In fact, Dr. Shrieve elaborated, “Evaluation of new strategies involving TMZ has already begun.” Much of the investigation focuses on how to take advantage of the prognostic importance of MGMT methylation status. In particular, cancer researchers have begun to examine ways to combat treatment resistance conferred by unmethylated MGMT.

One approach would be to use dose-dense schedules of TMZ to deplete the MGMT enzyme. Preliminary studies have shown that high-dose TMZ can quickly reduce MGMT enzyme levels by more than 70% (Tolcher et al. Br J Cancer 2003;88:1004-11). Whether the effect on MGMT translates into a clinical benefit for patients remains to be seen, indicated Dr. Shrieve.

Another strategy under investigation involves combining TMZ with inhibitors of poly (ADP-ribose) polymerase (PARP), an enzyme that stimulates DNA repair by activating the base excision repair pathway. Blocking PARP makes cancer cells more sensitive to RT and to alkylating agents such as TMZ, as explained by Dr. Lawrence Kleinberg, Co-Director, Stereotactic Radiosurgery and Associate Professor of Radiation Oncology and Neurosurgery, Johns Hopkins University, Baltimore, Maryland.

In a preliminary clinical study involving patients with metastatic malignant melanoma, the combination of TMZ and the investigational PARP inhibitor AG-014699 led to partial responses in four of 20 patients and disease stabilization in four others (Plummer et al. J Clin Oncol 2006;24(suppl):Abstract 8013).

“There is reason to believe that a PARP inhibitor might work especially well with TMZ. TMZ’s alkylating activity causes three types of DNA injury and PARP is required to repair all three types of injury,” he told the audience.

Additional Strategies

Newer targeted therapies have also attracted interest as interventions to build on the survival improvements achieved with TMZ and RT. In particular, inhibitors of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) provide a promising rationale for use in the treatment of malignant glioma and other types of cancer.

EGFR is amplified or overexpressed in half of all patients with GBM, explained Dr. Kleinberg. The EGFR vIII mutation is commonly found in association with GBM, and the frequency of the mutation increases as histology progresses from low-grade disease to anaplastic astrocytoma to GBM.

A new generation of EGFR inhibitors is needed, Dr. Kleinberg continued, as the currently available agents have activity in only a small proportion of patients. The investigational oral EGFR inhibitor ABT-888 has demonstrated activity in in vitro studies and in preclinical models, including glioma models.

The rationale for using a VEGF inhibitor in GBM comes from the recognition that angiogenesis has a major role in the disease process, declared Dr. Shrieve. Hypoxia is a hallmark feature of GBM. It is associated with radiation resistance, tumour growth, and upregulation of VEGF, which spurs the tumour angiogenesis needed for long-term survival in a hypoxic environment.

The oral pan-VEGF inhibitor cediranib (AZD2171) has demonstrated activity in preliminary clinical evaluation. In a study involving 30 patients with recurrent glioma treatment with the VEGF inhibitor resulted in radiographic responses in 16 patients, nine of whom had objective partial responses (Batchelor et al. J Clin Oncol 2007;25(suppl):Abstract 2001). The potential for combining a VEGF inhibitor with RT hinges on therapeutic timing or scheduling. For example, an inhibitor of VEGF type 2 receptor was evaluated in combination with RT. The receptor inhibitor had the expected additive effect when administered on days 1 to 3 and day 5 of RT but had significantly greater activity when administered on day 4 (Winkler et al. Cancer Cell 2004;6:553-63).

“Antiangiogenic therapy may have an added benefit in GBM by normalization of tumour vasculature and by direct cytotoxic activity resulting from inhibition of neovascularization,” stated Dr. Shrieve.

Summary

GBM continues to have a poor prognosis for many patients, often leading to death in a matter of months. However, after 20 to 30 years of minimal progress, clear-cut evidence has emerged to show that long-term survival is possible for a substantial proportion of patients. Combining the oral alkylating agent TMZ with RT, followed by adjuvant TMZ, has emerged as a new direction in GBM treatment strategies. In a landmark multinational clinical trial, this combination quadrupled the number of patients alive at four years as compared with RT alone. For a subset of patients approaching 50%—those with the methylated or inactivated form of the MGMT gene—survival at four years exceeded 20%. Patients with favourable prognostic factors derive a similar survival benefit by adding TMZ to radiation therapy. Building on the advances achieved with the TMZ/RT combination, investigation has turned to strategies to silence activated MGMT. Use of novel therapies, such as inhibitors of EGFR and VEGF, figures prominently in future therapeutic plans, including strategies that combine novel therapies with chemotherapeutic agents and RT. Although still a major cause of morbidity and mortality, GBM should no longer be considered an invariably fatal disease.