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42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

Despite improvements in standard therapy for malignant glioma, prognosis remains poor, stated Dr. Mark Gilbert, Deputy Chair, Department of Neuro-Oncology, and Associate Professor of Medicine, University of Texas M.D. Anderson Cancer Center, Houston. Surgery has a threefold purpose in the management of glioma: reducing tumour bulk; symptom improvement (palliation); and biopsy to permit a definitive histologic diagnosis.

The extent of surgery in glioma remains controversial. No randomized trial has evaluated the impact of more vs. less extensive surgery, although studies based on prospective and retrospective data collection have provided some support for more extensive surgery, noted Dr. Gilbert. One interesting analysis in the literature involved 416 patients who underwent surgical resection for glioblastoma multiforme. Preoperative and post-operative tumour volume was measured in each case. The analysis showed that >98% resection was associated with significant improvement (P<0.0001) in survival (Lacroix et al. J Neurosurg 2001;95(2):190-8).

A randomized trial of surgery with or without implantation of carmustine wafers suggested another strategy to improve outcome in patients with newly diagnosed malignant glioma. Patients who received intraoperative carmustine had a statistically significant (P=0.03) 29% improvement in survival (Westphal et al. Neuro-Oncology 2003;5(2):79-88). However, some of the patients were found not to have glioblastomas, and when they were removed from the analysis, the impact of carmustine on survival was not as significant.

More than 25 years ago, the addition of radiotherapy to surgery was shown to improve mean survival in patients with malignant glioma (Walker et al. N Engl J Med 1980;303(23):1323-9). However, results have not been consistent. For example, an evaluation of external beam radiation therapy followed by brachytherapy failed to show a survival advantage in patients with newly diagnosed glioblastoma multiforme (Prados et al. Int J Radiat Oncol Biol Phys 1992;24(4):593-7).

More recently, radiosurgery was evaluated in newly diagnosed glioblastoma patients. All patients received external beam radiation plus carmustine and were randomized to a radiosurgery boost. The addition of radiosurgery did not improve median survival (Souhami et al. Int J Radiat Oncol Biol Phys 2004;60(3):853-60).

Several notable obstacles have limited the role of chemotherapy in malignant glioma. Problems have included poor drug penetration into the tumour, systemic toxicity, drug-drug interactions and intrinsic tumour resistance to chemotherapy, Dr. Gilbert told delegates. Consequently, most trials have demonstrated only a modest impact on survival (Medical Research Council Brain Tumour Working Party. J Clin Oncol 2001; 19(2):509-18). A meta-analysis of 12 randomized clinical trials of chemotherapy for malignant glioma demonstrated a 15% reduction in the relative risk of death compared to patients who did not receive chemotherapy (Stewart et al. Lancet 2002;359 (9311):1011-8).

Promising Directions

Clinical evaluation of the alkylating agent temozolomide has yielded more encouraging data relative to chemotherapy’s role in the management of glioblastoma. Notably, a phase III study compared surgery and radiotherapy with or without temozolomide (Stupp et al. N Engl J Med 2005;352(10):987-96). Co-sponsored by the National Cancer Institute of Canada, the trial showed significant improvement in progression-free survival (PFS), median overall survival and two-year survival in patients who received the compound (Table 1). A subset analysis revealed a consistent benefit with use of the agent, regardless of patient age, sex, resection, performance status, cognitive function or history of steroid therapy.

Table 1. Survival Outcomes

“We now have level I evidence from a phase III trial that supports the chemoradiation regimen as the new standard of care for patients with glioblastoma,” Dr. Gilbert stated. “As we go forward, we will need to build on this treatment platform.”

The compound’s clinical development has taken advantage of emerging knowledge about the molecular underpinnings of malignant glioma. Overexpression of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) is associated with tumour resistance to chemotherapy, explained Dr. Roger Stupp, Multidisciplinary Oncology Centre, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. The repair protein transfers the alkyl group from the O6 position of guanine, one of the targets of alkylating agents, to the active site of the enzyme in a “suicide” reaction. In the process, guanine is restored, whereas MGMT becomes irreversibly inactivated. Methylation of the O6 position of guanine is thought to be the primary mediator of temozolomide’s cytotoxicity.

“Tumours with low MGMT expression are most susceptible to chemotherapy with a methylating agent, such as temozolomide,” Dr. Stupp told delegates.

MGMT expression by a tumour can help predict response to the compound. In the phase III trial which demonstrated the benefit of concurrent temozolomide and radiation therapy, patients with a methylated MGMT promoter enjoyed a significant improvement in overall survival (P=0.007) while those with a non-methylated MGMT promoter experienced only a marginal benefit (P=0.06). In this latter group however, PFS was significantly improved with adjuvant temozolomide (P=0.02) (Hegi et al. N Engl J Med 2005;352(10):997-1003) (Figure 1).

Figure 1. MGMT
it from TMZ Treatment

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Emerging Therapeutic Strategies

Recognition of the role of MGMT in malignant glioma has given rise to potential new strategies to maximize tumour sensitivity to alkylating agents. The strategies include treatment with MGMT inhibitors (such as O6-benzylguanine), MGMT depletion by continuous temozolomide administration or the addition of chloroethylating agents, and combining the alkylating agent with the nuclear enzymes Poly(ADP) polymerase (PARP) 1 and 2, which detect DNA breaks and recruit base excision repair enzymes.

A phase I clinical trial has demonstrated the feasibility of combining temozolomide with O6-benzylguanine in patients with malignant glioma (Quinn et al. J Clin Oncol 2005;23(28):7178-87). Though only a dose-finding study, the trial resulted in one complete response that has persisted for almost three years, indicated Dr. Stupp.

Dose-dense schedules have demonstrated its ability to achieve significant reductions in MGMT activity. Studies have indicated that dose-dense temozolomide can reduce MGMT activity by 72 to 73% in a matter of days, depending on the dose (Tolcher et al. Br J Cancer 2003;88(7):1004-11). However, no clinical data exist at this point to show that effective MGMT depletion translates into increased antitumour activity, emphasized Dr. Stupp.

The Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) have launched a phase III study to determine wether MGMT promoter methylation has prognostic value in malignant glioma and to demonstrate the feasibility of MGMT promoter status determination. The primary objective is to overcome tumour resistance by continuous depletion of the cellular MGMT reservoir. Drs. Gilbert and Stupp are chairing the study.

Results from a small clinical trial by Dr. E. Ruth Plummer, Northern Institute for Cancer Research, University of Newcastle Upon Tyne, UK, and colleagues examined the effect of combining temozolomide with PARP-1 (Proc Am Soc Clin Oncol 2006;24:456S[abstract 8013]). The ongoing study eventually will include 40 patients with metastatic melanoma. Among the first 20 evaluable patients, four partial responses (25%) have been documented and four other patients had prolonged disease stabilization. Single-agent temozolomide would have been expected to achieve a response rate of about 15%, Dr. Stupp commented.

Oligodendrogliomas

A growing body of evidence shows that molecular features have major prognostic and predictive implications in glioma, such as MGMT promoter methylation in glioblastoma multiforme. A key clinical objective for the future will likely focus on how to incorporate that knowledge into the clinical management of gliomas, said Dr. Martin van den Bent, Daniel den Hoed Cancer Centre, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Combined loss of chromosomal arms 1p and 19q is associated with up to 70% of oligodendrogliomas. Almost 10 years ago, a clinical trial demonstrated a 100% response to chemotherapy among oligodendrogliomas with 1p/19q loss, compared to a response rate of 25% among non-1p/19q loss tumours (Cairncross et al. J Natl Cancer Inst 1998;90(19):1473-9).

In separate clinical trials, the RTOG and EORTC have shown that adjuvant or neoadjuvant chemotherapy improves PFS in patients with anaplastic oligodendroglioma. The trials also showed that combined loss of 1p/19q is the major prognostic factor for survival. However, the combined chromosomal deletion did not predict benefit from chemotherapy. While the estimated median PFS was 69 months, the median overall survival has not been reached (Abrey et al. J Neurooncol 2003;65(2):127-34).

“Absence of combined 1p/19q loss identifies patients in whom upfront chemotherapy (procarbazine/lomustine/vincristine) does not increase PFS,” Dr. van den Bent confirmed. “If upfront chemotherapy is considered in oligodendroglial tumours, 1p/19q might help in decision making.”

As a result of the clinical implications of 1p/19q loss and MGMT methylation, the next generation of clinical trials in anaplastic glioma will be based primarily on molecular classification rather than clinical morphology.

Targeting Signal Transduction

The next generation of candidate therapies for glioblastoma increasingly will integrate signal transduction inhibitors and other targeted therapies into clinical management, observed Dr. Minesh Mehta, Professor and Chair, Department of Human Oncology, University of Wisconsin, Madison. One promising clinical strategy involves targeting epidermal growth factor receptor (EGFR), which is overexpessed, amplified or mutated in 50 to 70% of cases of glioblastoma multiforme.

However, EGFR’s role in glioblastoma is not straightforward. A retrospective review of 156 patients involved in RTOG studies showed that increased EGFR expression did not have an impact on survival (Chakravarti et al. Int J Radiat Oncol Biol Phys 2005; 62(2):318-27). “EGFR alone is not prognostic,” cautioned Dr. Mehta.

Moreover, clinical trial findings by Dr. Arnab Chakravati, Associate Professor of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues presented here failed to show a survival advantage compared to historical controls when the EGFR inhibitor gefitinib was added to radiation therapy for patients with newly diagnosed glioblastoma multiforme (Proc Am Soc Clin Oncol 2006;24:64S[abstract 1527]).

Another recent study provided additional insight into the role of EGFR expression in glioblastoma. Investigators examined expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumour-suppressor protein PTEN in patients with recurrent malignant glioma treated with EGFR inhibitors (Mellinghoff et al. N Engl J Med 2005;353(19):2012-24). Comparison of seven patients who had significant tumour shrinkage and 19 who did not showed that co-expression of EGFRvIII and PTEN was significantly associated with responsiveness to EGFR inhibitors (P<0.001).

Noting that glioblastomas are highly angiogenic, Dr. Mehta predicted that angiogenesis inhibitors will receive extensive evaluation as potential therapy for the tumours.

Encouraging results also emerged from an RTOG trial that paired radiation therapy with the vascular endothelial growth factor (VEGF) inhibitor enzastaurin for treatment of glioblastoma multiforme. Of 36 evaluable patients, 14 (39%) had major objective responses, including one complete response (Fine et al. Proc Am Soc Clin Oncol 2005;23:Abstract 1504).

Additional encouragement has emerged from a retrospective analysis of patients whose recurrent high-grade gliomas were treated with the anti-VEGF antibody bevacizumab plus chemotherapy. Of 14 patients with follow-up MRI scans, seven patients had partial responses, three had stable disease and one had progressive disease. Four of 10 patients with glioblastoma multiforme had major responses (Pope et al. Neurology 2006;66(8):1258-60).

The multitargeted tyrosine kinase inhibitor sorafenib works through multiple pathways that are important in radioresistance, noted Dr. Mehta. Combining such a multi-pathway inhibitor with radiation therapy offers yet another promising approach to treatment of malignant gliomas.

“A number of important molecular pathways for glioblastoma multiforme growth have been identified,” Dr. Mehta concluded. “Taken singly, their prognostic significance is not well established. Combination profiles such as EGFRvIII and PTEN might be highly predictive of response. Inhibitors of these pathways are being tested, but early results are of mixed significance. Many of these inhibitors synergize with radiation therapy. Multi-target blockade may provide a future investigational opportunity.”

Summary

“Molecular diagnostics are becoming a part of neuro-oncology trials,” Dr. van den Bent told delegates. “Planned trials will allow further analysis of role-specific molecular lesions. Outside of clinical trials, however, molecular diagnostics still has a limited impact on clinical decision-making. The one exception is when upfront chemotherapy is contemplated for patients with oligodendrogliomas.”