Effect of adding temozolomide to radiation therapy on the incidence of pseudo-progression.

Recently, there has been greater awareness that combination radiation and temozolomide used to treat glioblastomas may cause increased contrast enhancement on the first post radiation MRI scan. However, this increased enhancement may stabilize or decrease over time and represent pseudo-progression (psPD) rather than true progressive disease. It has never been shown that this phenomenon is greater with combination therapy than radiation alone. To address this question, we reviewed MRI scans in glioblastoma patients treated with radiation alone versus patients treated with radiation and concomitant temozolomide and compared the frequency of psPD in the two groups. Eighteen of 47 patients (38%) treated with radiation alone demonstrated enlargement on their first post-radiation MRI scan and 11 of these 18 (61%) proved to have psPD as defined by no further enlargement on stable therapy for 3 months following radiation. Twenty-four of 45 patients (53%) treated with radiation and temozolomide had enlargement on their first post-radiation MRI scan and 13 of these 24 (54%) had psPD. Median overall survival (OS) in patients with psPD treated with radiation alone was 15.6 versus 12.8 months in those without psPD. Median OS in patients treated with radiation and concomitant temozolomide who had psPD was 24.4 versus 15.9 months in those who did not have psPD. We were unable to detect a difference in OS between the four groups. Presence of psPD, independent of treatment, was associated with prolonged progression-free survival (P = 0.05) but not OS. psPD may be more common in combination therapy but most likely by a small margin.

Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors.

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.