A Promising New Treatment for Malignant Gliomas
Abstract & Commentary
By Andrew B. Lassman, MD, Assistant Attending Neurologist, Memorial Sloan-Kettering Cancer Center. Dr. Lassman reports no financial relationship relevant to this field of study.
Synopsis: New combination chemotherapy protocol for malignant glioma improves 6-month progression-free survival for a dismal disease.
Source: Vredenburgh JJ, et al., Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma, Clin Cancer Res. 2007 Feb 15;13(4):1253-1259.
Patients with recurrent malignant gliomas (World Health Organization grade III-IV tumors) were treated with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin; Genentech) and the topoisomerase 1 inhibitor irinotecan (CPT11) in a phase II prospective clinical trial. There were 32 patients, 9 with grade III gliomas (7 anaplastic astrocytoma (AA), 2 anaplastic oligodendroglioma (AO)) and 23 with grade IV gliomas (glioblastoma multiforme (GBM)). Responses (at least 50% decrease in cross-sectional area of contrast enhancing tumor on brain MRI) were seen in 63% of patients (61% for GBMs, 67% for AA/AO). The median progression-free survival (length of time patients were alive and without tumor growth) was 23 weeks (20 weeks for GBM, 30 weeks for AA/AO). Complications included thrombo-embolic events in 4 patients, including 3 with deep venous thromboses or pulmonary emboli and one with ischemic stroke. There were no central nervous system hemorrhages. Therefore, the combination is active in recurrent malignant glioma with acceptable toxicity.
Commentary
Gliomas of WHO grade II-IV are diffusely infiltrative tumors that are not surgically curable and carry a dismal prognosis. GBMs are the most aggressive and most common subtype with a median survival of approximately 12 months despite aggressive surgery, radiotherapy, and chemotherapy. The most commonly used treatment strategy for newly diagnosed GBM is maximal surgical resection followed by concurrent radiotherapy and chemotherapy with the DNA alkylating agent temozolomide (Temodar; Schering-Plough) followed by at least 6 monthly cycles of adjuvant temozolomide (Stupp R et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-996.) However, essentially all patients eventually develop disease recurrence, for which prognosis is dismal.
The results of the phase II study of bevacizumab + irinotecan by Vredenburgh et al suggest that the treatment they employed is superior to any other presently available therapy. Most chemotherapy regimens for recurrent GBM are associated with response rates of 20% or less, where the authors here reported 61% response rate. Another commonly used outcome measure in recurrent GBM trials is the 6-month progression-free survival rate (6mPFS rate), defined as the percentage of patients who are alive and free of tumor growth 6 months after starting an experimental therapy. Use of the 6mPFS rate to measure efficacy helps to account for durability of response as well as tumor stabilization (neither tumor growth nor response). For patients with GBM, pooled results of 8 negative phase II trials generated a 6mPFS rate of 15% (Wong ET, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999 Aug;17(8):2572-2578.). The 6mPFS rate observed here was 30% for patients with GBM, again suggesting the superior efficacy of this regimen.
However, it remains unclear whether the responses seen, and 6mPFS rate calculated, which depends on radiographic measurement of enhancing disease, is a true reflection of underlying tumor cell death or simply a masking of blood-brain barrier breakdown measured by gadolinium uptake. For example, contrast enhancement can shrink dramatically following treatment with corticosteroids (Watling CJ, et al. Corticosteroid-induced magnetic resonance imaging changes in patients with recurrent malignant glioma. J Clin Oncol. 1994 Sep;12(9):1886-1889.). although the underlying tumor has not significantly changed. It is possible that bevacizumab is having a similar effect, although the authors make strong arguments to the contrary. It also remains unclear whether the irinotecan contributes significantly to the responses, or whether the same results would be seen by bevacizumab alone. Finally, it should be noted that although the 6mPFS rate for patients with recurrent GBM reported here (30%) exceeded that of the Wong study (15%), the 95% confidence intervals overlapped (16%-57% vs 10%-19%), further emphasizing the need for the ongoing larger confirmatory multicenter study that is in progress to determine the level of significance to attach to these results.
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