Our objective is to assess treatment efficacy, safety and pattern of response and recurrence in patients with recurrent high-grade glioma treated with bevacizumab and irinotecan. We reviewed retrospectively 51 patients with recurrent high-grade glioma treated with this combination at the Henry Ford Hermelin Brain Tumor Center from 11/15/2005 to 04/01/2008. The 6-month progression-free survival (PFS) for anaplastic gliomas (AGs) was 78.6 and 63.7% for glioblastoma. The median PFS was 13.4 months for AG and 7.6 months for those with glioblastoma. The overall survival rate (OS) at 6 months was 85.7% for AG and 78.0% for glioblastoma. The 12-month OS was 77.9% for AG and 42.6% for glioblastoma. The median OS time for AGs was not reached and was 11.5 months for those with glioblastoma. Thirty-six out of 51 (70.59%) patients demonstrated partial (32/51) or complete (4/51) radiographic response to treatment and 8/51 (15.69%) remained stable. Of the 38 who demonstrated progression on post-gadolinium studies, 23 showed distant progression with or without local recurrence. Seven patients showed progression on FLAIR without concordant findings on post-Gd sequences. Six patients (11.76%) discontinued treatment due to a treatment-emergent adverse event, including one with end-stage renal failure and another with gastric perforation. No symptomatic intracranial hemorrhages were reported. Patients with recurrent high-grade glioma treated with bevacizumab plus irinotecan demonstrate an excellent radiographic response rate and improved clinical outcome when compared to historical data. The high rate of distant tumor progression suggests that tumors may adapt to inhibition of angiogenesis by increased infiltration and vascular co-option.

Bevacizumab appears to produce radiographic response and clinical benefits in the treatment of patients with cerebral radionecrosis.

After withdrawal of bevacizumab in patients with recurrent high-grade glioma, we have observed a rapid tumour re-growth or "rebound" radiographic phenomenon with accelerated clinical decline. We retrospectively reviewed 11 patients treated at the Henry Ford Hermelin Brain Tumor Center with recurrent high-grade glioma who demonstrated a rebound progression pattern after the discontinuation of bevacizumab. The original tumour area-of-enhancement increased by a mean of 158%, when compared to the rebound magnetic resonance imaging. After rebound, no patients (0/8) showed a response to next-line treatments that did not include bevacizumab. The median survival of those re-treated with bevacizumab was 149 and 32 days for those who received other regimens. Abrupt discontinuation of bevacizumab after recurrence often leads to a dramatic rebound phenomenon and rapid clinical decline. Slow tapering of the bevacizumab dose after tumour progression may prevent this from occurring and improve responsiveness to next-line therapies.

The purpose of this study was to assess the usefulness of diffusion weighted imaging as an additional imaging biomarker for treatment response in recurrent/progressive malignant gliomas treated with bevacizumab alone or in combination with other chemotherapeutic agents. Twenty patients treated with bevacizumab alone or concurrent chemotherapy were followed up with serial MR imaging. Volume and ADC values of contrast enhancing lesion (CEL(vol), CEL(ADC)) and also of non-enhancing lesion (NEL(vol), NEL(ADC)) were obtained. CEL(vol) showed a progressive decrease in non-progressors with a median percentage change of -73.2% (P = 0.001) as compared to -33.4% for progressors by 1 year/last imaging (P = 0.382). NEL(vol) also showed a decrease in non-progressors on follow up imaging though only significant for 3 months follow up (P = 0.042). In progressors, CEL(vol) and NEL(vol) showed initial decrease followed by slight increase by 1 year/last imaging though not significant (P value of 0.382 and 0.46, respectively). CEL(ADC) and NEL(ADC) in non-progressors did not show any statistically significant change though there was slight trend for positive percent change especially for CEL(ADC) by 1 year/last imaging follow up study (P value of 0.077 and 0.339, respectively). Progressors showed a progressive negative percent change of CEL(ADC) and NEL(ADC). In progressors, NEL(ADC) decreased at 6 weeks (P = 0.054), 3 months (P = 0.023) and 1 year/last (P = 0.078) as compared to baseline study and was also statistically significant as compared to non-progressors at 6 weeks (P = 0.047) and 3 months (P = 0.025). CEL(ADC) and NEL(ADC) appear to follow different trends over time for non-progressors and progressors with a stable to slightly progressive increase in non-progressors and a progressive decrease in progressors, especially early on. These findings suggest that DWI may be used as an additional imaging biomarker for early treatment response.

Bevacizumab and irinotecan are effective against recurrent malignant gliomas. However, at subsequent progression, patients rarely respond to a second bevacizumab-containing chemotherapeutic regimen. Salvage re-irradiation with bevacizumab for recurrent but bevacizumab naive malignant gliomas showed encouraging results. We performed a retrospective review of the medical records of 23 patients treated with either fractionated stereotactic radiotherapy (FSRT) or stereotactic radiosurgery (SRS) after progression on an initial bevacizumab regimen. Patients were treated after re-irradiation with bevacizumab but combined with a different chemotherapy. We then compared them to another 23 patients who progressed on an initial bevacizumab + chemotherapy regimen. These patients did not receive re-irradiation but bevacizumab was continued combined with a different chemotherapy. Patients treated with FSRT/SRS/bevacizumab had a longer median progression-free period (2.6 vs. 1. 7 months, P = 0.009), longer median post FSRT/SRS treatment survival (7.2 vs. 3.3 months, P = 0.03) and higher radiographic response rate (22 vs. 0%, P = 0.049). FSRT or SRS followed by bevacizumab + chemotherapy may have a role for patients who progress on bevacizumab.