Combination Treatment with Low-Dose Protracted Temozoloamide and Bevacizumab for Heavily Pretreated Patients with Recurrent Glioblastoma

Abstract & Commentary

By Bindu Kanapuru, MD, Institute for Advanced Studies in Aging and Geriatric Medicine, Falls Church, VA. Dr. Kanapuru reports no financial relationships relevant to this field of study.

Synopsis: In this Phase 2 trial, 32 heavily pretreated patients including those who received adjuvant temozolamide, were treated with daily low-dose temozolamide at 50 mg/m2 and twice-weekly Bevacizumab. The treatment was well tolerated with a median progression-free survival of 15.8 weeks and a median overall survival of 37 weeks. However, this was lower than those reported in studies with single-agent bevacizumab and bevacizumab/irinotecan combination.

Source: Desjardins A, et al. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 2012;18:1302-1312.

Very few therapeutic options are currently available for patients with recurrent glioblastoma multiforme (GBM), and median survival continues to be dismal for untreated patients. GBM is characterized by endothelial proliferation and increased expression of vascular endothelial growth factor. Consequently, treatment with single-agent bevacizumab resulted in an objective response rate of 28.2%, 6-month progression-free survival (PFS) rate of 42.6%, and median overall survival time longer than 9 months. When combined with irinotecan, 6-month PFS improved to 50.3%, but no difference in median survival was observed (8.7 months).1 Concurrent treatment with temozolamide during radiation followed by a 5-day course every month for 6 months has become the standard of care in the first-line setting.2 However, benefit appears to be confined predominantly to those with a mutated promoter for the (O6-methylguanine DNA methyltransferase) MGMT gene.3 Prolonged low-dose therapy with temozolamide has the potential to overcome the resistance of an unmethylated promoter of MGMT,4 as well as demonstrable antiangiogenic activity, and has been associated with clinical responses even in patients who had prior treatment with temozolamide.5 Consequently combining bevacizumab with low-dose prolonged temozolamide may provide additive angiogenic effect and at the same time sensitize the cells to alkylating chemotherapy.

The authors performed a Phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who previously had received radiation therapy and temozolomide.

The patients were heavily pretreated with more than three-fourths having received two or more treatment regimens, and there was no limit on the number of prior chemotherapy regimens for trial entry. Thirty-two adult patients were enrolled. Patients received temozolomide 50 mg/m2 daily and bevacizumab 10 mg/kg intravenously every 14 days. No pneumocystis carinii prophylaxis was given. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks.

The authors observed a 6-month PFS rate of 18.8% (95% confidence interval [CI], 7.6%-33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6-month OS rate was 62.5% (95% CI, 43.5%-76.7%), and the 12-month OS rate was 31.3% (95% CI, 16.4%-47.3%). PFS and OS did not differ significantly in patients who did or did not receive prior adjuvant therapy with 5-day temozolamide, or in those who had MGMT expression low or increased. However, patients who were on steroids during treatment had PFS of only 7.9 weeks, which was lower than 16.4 weeks seen with patients off steroids. Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site within the brain. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia.

The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was more heavily pretreated than patients in previous studies.

Commentary

Effective treatment for recurrent glioblastoma has been elusive until the recent trials with bevacizumab, which have shown promising activity in this setting. As single agent or in combination with irinotecan after failing standard therapy, bevacizumab is associated with objective response rates of nearly 30% and median OS of nearly 9 months. Although the response rates in this trial were less than 20%, it is still encouraging as the population included those who had progression on prior temozolamide regimens as well as bevacizumab. The regimen was well tolerated even in this heavily pretreated population, and no pneumocystis carinii pneumonia was reported, despite lack of prophylaxis. In addition, PFS and OS did not differ based on the MGMT status or prior use of adjuvant temozolamide.

However, despite being well tolerated, there was one treatment-related death among 32 patients. It is also hard to infer that the regimen is active in those who have increased MGMT as the number of patients was too small to make this conclusion. As other studies using similar dosing regimens have shown better response rates, albeit in treating patients at first recurrence,6 this regimen may be considered as a viable option in that setting, particularly as a way to overcome MGMT resistance.

References

1. Friedman HS, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-4740.

2. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996.

3. Hegi ME, et al. MGMT gene silencing and benefit from temo- zolomide in glioblastoma. N Engl J Med 2005;352:997-1003.

4. Tolcher AW, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003;88:1004-1011.

5. Verhoeff JJ, et al. Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 2010;21:1723-1727. Epub 2010 Jan 11.

6. Kong DS, et al. Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro-Oncol 2010;12:289-296.