VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma

Wachsberger, Phyllis; Burd, Randy; Cardi, Christopher; Thakur, Mathew L.; Daskalakis, Constantine; Holash, Jocelyn; Yancopouloš, George D.; Dicker, Adam P.

doi:10.1016/j.ijrobp.2006.11.011

Cited by 119 publications

(65 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The rationale for combining bevacizumab and radiotherapy is based on the potential radiosensitizing benefit of bevacizumab. The potential for such synergistic effects has been proposed both for the ability of anti-angiogenic agents to normalize blood vessels (thereby reducing tumor hypoxia), and for its ability to counteract the effects of radiation-induced VEGF secretion from tumor cells [25,[29][30][31][32][33]. More recently, Cuneo et al [34] analyzed the outcomes of 49 patients with recurrent GBM.…”

Section: Discussionmentioning

confidence: 99%

Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case–control study

et al. 2011

View full text Add to dashboard Cite

We evaluated the efficacy and safety of gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumab combined with chemotherapy in 11 patients with recurrent glioblastoma multiforme who experienced tumor progression despite aggressive initial multi-modality treatment. Our experience included eight male and three female patients. The median patient age at GKSR was 62 years (range 46-72 years). At the time of GKSR, seven patients had a first recurrence and four had two or more recurrences. The median interval from the initial diagnosis until GKSR was 17 months (range 5-34.5 months). The median tumor volume was 13.6 cm(3) (range 1.2-45.1 cm(3)) and the median margin dose of GKSR was 16 Gy (range 13-18 Gy). Following GKSR, bevacizumab was administrated with irinotecan in nine patients and with temozolomide in one patient. One patient was treated with bevacizumab monotherapy. The treatment outcomes were compared to 44 case-matched controls who underwent GKSR without additional bevacizumab. At a median of 13.7 months (range 4.6-28.3 months) after radiosurgery, tumor progression was evident in seven patients. The median progression-free survival (PFS) was 15 months (95% confidential interval (CI), 6.5-23.3 months). Six-month and 1-year PFS rates were 73 and 55%, respectively. The median overall survival (OS) from GKSR was 18 months (95% CI, 10.1-25.7 months) and 1-year OS rate was 73%. One patient (9%) experienced grade III toxicity and one patient (9%) had major adverse radiation effects. Compared with patients who did not receive bevacizumab, the patients who received bevacizumab had significantly prolonged PFS (15 months vs. 7 months, P = 0.035) and OS (18 months vs. 12 months, P = 0.005), and were less likely to develop an adverse radiation effect (9 vs. 46%, P = 0.037). The combination of salvage GKSR followed by bevacizumab added potential benefit and little additional risk in a small group of patients with progressive glioblastoma. Further experience is needed to define the efficacy and long-term toxicity with this strategy.

show abstract

Section: Discussionmentioning

confidence: 99%

Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case–control study

et al. 2011

View full text Add to dashboard Cite

show abstract

“…For all three tumor types, this was achieved at a dose of 2.5 mg/kg VEGF Trap given twice weekly: at this dose, free VEGF Trap (blue curve) is severalfold the level of complex (green curve), and past this point further dose escalation yields only modest incremental increases in complex levels (green curve) and in anti-tumor efficacy (red curve). In other tumor types, such as U87 glioblastoma, higher levels of VEGF Trap are required to achieve maximal efficacy (22).…”

Section: Vegf Trap Complex Levels Provide Guidance On When Efficacioumentioning

confidence: 99%

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Rudge

Holash

Hylton

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

191

150

View full text Add to dashboard Cite

VEGF is the best characterized mediator of tumor angiogenesis. Anti-VEGF agents have recently demonstrated impressive efficacy in human cancer trials, but the optimal dosing of such agents must still be determined empirically, because biomarkers to guide dosing have yet to be established. The widely accepted (but unverified) assumption that VEGF production is quite low in normal adults led to the notion that increased systemic VEGF levels might quantitatively reflect tumor mass and angiogenic activity. We describe an approach to determine host and tumor production of VEGF, using a high-affinity and long-lived VEGF antagonist now in clinical trials, the VEGF Trap. Unlike antibody complexes that are usually rapidly cleared, the VEGF Trap forms inert complexes with tissue- and tumor-derived VEGF that remain stably in the systemic circulation, where they are readily assayable, providing unprecedented capability to accurately measure VEGF production. We report that VEGF production is surprisingly high in non-tumor-bearing rodents and humans, challenging the notion that systemic VEGF levels can serve as a sensitive surrogate for tumor load; tumor VEGF contribution becomes significant only with very large tumor loads. These findings have the important corollary that anti-VEGF therapies must be sufficiently dosed to avoid diversion by host-derived VEGF. We further show that our assay can indicate when VEGF is optimally blocked; such biomarkers to guide dosing do not exist for other anti-VEGF agents. Based on this assay, VEGF Trap doses currently being assessed in clinical trials are in the efficacious range.

show abstract

“…In a preclinical study, VEGF Trap plus radiation was better than radiation alone in controlling tumor growth in a U87 subcutaneous xenograft model [21]. In this study, VEGF Trap was not studied with TMZ.…”

Section: Discussionmentioning

confidence: 85%

“…VEGF secretion assays reflect the mean and SE of at least three independent experiments, each data point performed in triplicate. In tumor growth delay studies, mixed-effects regression (previously described [19][20][21]) was used to model tumor volume as a function of time and treatment). Mixed effects regression was used for analysis of animal data because it does not depend on an arbitrary end point, tumor size, but uses the repeated tumor size measurements obtained over the entire study period, while appropriately handling unbalanced data (i.e., different number of measurements for different animals) and the correlation of each animal's measurements over time.…”

Section: Discussionmentioning

confidence: 99%

Cediranib enhances control of wild type EGFR and EGFRvIII-expressing gliomas through potentiating temozolomide, but not through radiosensitization: implications for the clinic

et al. 2011

Self Cite

View full text Add to dashboard Cite

Glioblastomas (GBM) frequently overexpress the epidermal growth factor receptor (wtEGFR) or its mutant, EGFRvIII, contributing to chemo- and radioresistance. The current standard of care is surgery followed by radiation therapy with concurrent temozolomide (TMZ) followed by adjuvant TMZ. New treatment strategies for GBM include blockade of EGFR signaling and angiogenesis. Cediranib is a highly potent receptor tyrosine kinase inhibitor that inhibits all three VEGF receptors. This study investigated the radiosensitizing potential of cediranib in combination with TMZ in U87 GBM xenografts expressing wtEGFR or EGFRvIII. U87 GBM cells stably transfected with either wtEGFR or EGFRvIII were injected into the hind limbs of nude mice. Cediranib was dosed at 3 mg/kg daily five times a week orally for 2 weeks. TMZ was dosed at 10 mg/kg once only on day 0. Radiotherapy (RT) consisted of 3 fractions of 5 Gy (days 0-2). Cediranib did not radiosensitize either tumor type; however, cediranib did enhance the effectiveness of TMZ in both transfectants. Our results suggest that combining cediranib with temozolomide in the clinic will lead to improved tumor control.

show abstract

VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma

Cited by 119 publications

References 27 publications

Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case–control study

Salvage gamma knife stereotactic radiosurgery followed by bevacizumab for recurrent glioblastoma multiforme: a case–control study

VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade

Cediranib enhances control of wild type EGFR and EGFRvIII-expressing gliomas through potentiating temozolomide, but not through radiosensitization: implications for the clinic

Contact Info

Product

Resources

About