Radiographic and Histopathologic Observations After Combined EGFR Inhibition and Hypofractionated Stereotactic Radiosurgery in Patients With Recurrent Malignant Gliomas

Schwer, Amanda; Kavanagh, Brian D.; McCammon, R.; Gaspar, Laurie E.; Masters, B.K. Kleinschmidt-De; Stuhr, Kelly; Chen, Changhu

doi:10.1016/j.ijrobp.2008.06.1919

Cited by 15 publications

(6 citation statements)

References 12 publications

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“…Similar favorable results of fractionated stereotactic re-irradiation are documented in the literature [3,4,8,29]. More recent studies reported the integration of modern targeted chemotherapy into stereotactic re-irradiation and preliminary results are encouraging [10,17,25].…”

Section: Discussionsupporting

confidence: 73%

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

et al. 2011

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Section: Discussionsupporting

confidence: 73%

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

et al. 2011

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“…Moreover, the convenience of a condensed treatment schedule is an important consideration, especially in patients with recurrent glioma who often have poor performance status, limited mobility, and a short expected life span. Overall, data from studies employing re-irradiation at disease recurrence, alone 17–30 or in combination with temozolomide 31–37 , nitrosourea 38 , sorafenib 39 , sunitinib, 40 gefitinib, 41 panobinostat 42 or bevacizumab 12,13,38,43 support a therapeutic benefit with minimal toxicity. In particular, most of these studies have consistently reported a median OS in excess of 10 months, which compares favorably to available salvage chemotherapy or biologic therapies that typically achieve median OS of 7–9 months.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, most of these studies have consistently reported a median OS in excess of 10 months, which compares favorably to available salvage chemotherapy or biologic therapies that typically achieve median OS of 7–9 months. However, it must be noted that with few exceptions, 9,40,41 the vast majority of these studies is retrospective, therefore carrying inherent limitations and potential selection bias.…”

Section: Discussionmentioning

confidence: 99%

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma

Clarke

Neil

Terziev

et al. 2017

International Journal of Radiation Oncology*Biology*Physics

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Purpose It has been reported previously that the combination of bevacizumab with hypofractionated stereotactic re-irradiation (HFSR) with 30Gy (6GyX5 fractions) was safe and efficacious in recurrent glioblastomas and high-grade gliomas (HGG). Because most recurrences are local, developing intensified HFSR dosing schedules remains of interest. We hypothesized that in combination with bevacizumab, HFSR doses could be further escalated, and designed a prospective phase I trial to establish the maximum tolerated dose (MTD) of a 3-fraction HFSR delivered concomitantly with standard doses of bevacizumab. Materials and Methods Patients with recurrent HGG with KPS ≥ 60, history of standard fractionated initial radiation, tumor volume at recurrence ≤ 40cc and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 Phase I dose escalation trial design was utilized, with dose-limiting toxicities (DLT) defined as any grade 3–5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10mg/kg every two weeks. HFSR was initiated after two bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy/fraction. Results A total of 3 patients were enrolled at the 9GyX3 dose level cohort, 5 enrolled in the 10GyX3 cohort and 7 in the 11GyX3 cohort. One DLT of grade 3 fatigue and cognitive deterioration possibly related to HFSR was observed in the 11GyX3 cohort, and this dose was declared the MTD in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival (OS) was 13 months. Conclusions Re-irradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11GyX3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison to our previous 6GyX5 schedule. Promising OS warrants further investigation.

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“…22 The PFS6 was comparable with baseline in all 8 evaluable studies with EGFR inhibitors as single-agent therapy, was possibly increased in 2 of 5 evaluable studies with combined EGFR and mTOR inhibition including 1 study with a number of anaplastic gliomas, 23,24 and was increased in 1 of 4 evaluable studies with EGFR inhibition combined with conventional therapy, which included a relevant number of anaplastic gliomas. 25 When EGFR inhibition was combined with VEGFR ligand binding by bevacuzimab, the PFS6 was 24%. 16 The PFS6 was comparable with baseline using both evaluable single-agent mTOR inhibitors.…”

Section: Progression-free Survivalmentioning

confidence: 99%

Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies

2010

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The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small-molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCbeta, and PDGFR.

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Radiographic and Histopathologic Observations After Combined EGFR Inhibition and Hypofractionated Stereotactic Radiosurgery in Patients With Recurrent Malignant Gliomas

Cited by 15 publications

References 12 publications

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme

Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma

Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies

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