Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.

Changing Paradigms—An Update on the Multidisciplinary Management of Malignant Glioma

Camptothecin: current perspectives.

Plant-based anticancer molecules: a chemical and biological profile of some important leads.

Purpose To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. Patients and Methods This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. Results A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor–A or –B were found.

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Phase II Study of Imatinib in Patients With Recurrent Gliomas of Various Histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study

It is widely accepted that tumour growth beyond a few cubic millimetres cannot occur without the induction of a new vascular supply. Inhibiting the development of new blood vessels (antiangiogenesis) is a potential approach to cancer therapy that has attracted interest in recent years. In theory, this approach should be relatively selective for tumour cells. The endothelial cells which form new vascular networks in tumours are responding to angiogenic stimuli produced by the tumour, but are themselves genetically normal. Endothelium in normal tissue, by contrast, is usually quiescent. Vascular endothelial growth factor (VEGF) is the best-characterised pro-angiogenic factor. It is virtually ubiquitous in human tumours, and higher levels have been correlated with more aggressive disease. Effective blockade of the VEGF pathway has been demonstrated with multiple agents: neutralising antibody, receptor tyrosine kinase inhibitors, and ribozyme or antisense molecules targeting expression. Promising preclinical data document the potential of these agents for tumour growth inhibition and even tumour regression, yet translation of novel therapeutics targeting the VEGF pathway to the clinic has proved a substantial challenge in itself. While showing clear evidence of antitumour activity over a broad spectrum of experimental tumours, the proper selection, dose, timing and sequence of anti-VEGF treatment in human cancer is not at all obvious. Classic Phase I dose escalation trial design may need to be modified, as higher doses may not be optimal in all patients or for all tumours. In addition, alternate or secondary biological end points (e.g., non-progression) may be needed for early phase studies to document true activity, so as not to abandon effective agents. Recent studies of the neutralising antibody bevacizumab, and small molecule tyrosine kinase inhibitor SU5416, demonstrate that, while unlikely to be effective as monotherapy, incorporation of VEGF blockade into cytotoxic regimens may increase overall response rates. However, incorporation may also produce new toxicities, including thromboembolic complications and bleeding. Newer oral agents, such as SU6668, SU11248, PTK787/ZK222584 and ZD6474, are particularly interesting for their potential for chronic therapy. Future clinical trials are likely to build on past experience with stricter entry criteria, supportive care guidelines and the use of surrogate markers.

VEGF blocking therapy in the treatment of cancer.

Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme.

T Lesimple

Papers

Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme.