VEGF Factor-Directed Therapy in Intracranial Meningioma
A robust association does not inevitably impose a causal relationship. The definitive proof of efficacy will require studies involving VEGF inhibition and evaluation of the effect on PTBE. To this point, 3 case reports and 3 retrospective case series have used systemic VEGF-directed therapy, in particular bevacizumab, in meningiomas (Table 2). Bevacizumab is a humanized monoclonal antibody that inhibits VEGF activity by binding directly to all VEGF isoforms, to form a complex that becomes incapable of binding to receptor sites. It is currently approved by the US FDA for a variety of disorders, including glioblastoma.
In 2010, Puchner and colleagues presented the first case of bevacizumab use in meningioma. Salvage therapy with bevacizumab (10 mg/kg body weight every 2 weeks) was initiated after the recurrence of an anaplastic meningioma following gross-total resection and postoperative adjuvant radiotherapy, and was well tolerated. Six weeks later, contrast-enhancing tumor regressed substantially, and FLAIR and T2-weighted MRI showed reduced edema. These changes were sustained for 6 months after the cessation of therapy. Wilson and Heth reported regression of a partially resected Grade I meningioma after paclitaxel and bevacizumab was used to treat breast cancer for 6 months and 1 year, respectively. Regression of the meningioma was maintained on follow-up MRI 1 year later. Goutagny and colleagues administered bevacizumab at a dose of 5 mg/kg body weight every 2 weeks for 15 months with the primary goal of treating a vestibular schwannoma in a patient with neurofibromatosis Type 2. Concomitantly, an unknown grade meningioma that measured 7.3 cm and grew 38% in volume over the preceding year decreased 22% in size throughout the course of the treatment.
In the first published case series, Nayak and colleagues administered bevacizumab with the primary aim of promoting regression of recurrent atypical and anaplastic menigniomas. The cohort consisted of 15 patients with multiple prior surgeries (median = 3) and sessions of radiotherapy. The median number of recurrences was 4 per patient, and 7 patients received prior chemotherapy. A median of 9 doses of bevacizumab was given over 18 weeks. The median progression-free survival (PFS) was 6.5 months, and 6-month PFS was 44%. Two patients showed minor shrinkage of the enhancing part of the tumor while the remaining cohort had stable disease. Six patients exhibited reduction in peritumoral T2 hyperintense areas on MRI consistent with decreased PTBE. Five patients improved clinically, 9 remained unchanged, and 1 patient's condition deteriorated.
In a similar study, Lou and colleagues treated 14 patients with bevacizumab as salvage therapy where all had recurrent/progressive meningioma. The primary end point was to assess 6-month PFS. Thirteen patients had previously undergone 1 or more resections, fractionated radiotherapy or stereotactic radiosurgery, chemotherapy, or biological targeted therapy, such as octreotide. Chemotherapy was used as an adjunct in 71% of patients. One patient with multifocal disease demonstrated partial response according to the criteria for malignant gliomas, as established by the Response Assessment in Neuro-Oncology. While disease in 2 patients progressed, 11 patients exhibited stable disease. Median PFS and 6-month PFS were 12.2 months and 80%, respectively, for patients with Grade I meningiomas, and 15.8 months and 87.5% for patients with Grade II/III meningiomas, respectively. The therapeutic effect on PTBE was not reported.
In a more recent report by Nune and colleagues, 15 patients neurofibromatosis Type 2 harboring a total of 48 meningiomas of unknown grade were given bevacizumab (5 mg/kg body weight) every 2 weeks. Although the effect on PTBE was not described, 29% of meningiomas showed radiographic response with a 15-month median time to regression. The median PFS and 6-month PFS was 20 months and 93% on a per-patient basis, respectively.
To date, limited data have been published describing the antiedemagenic and antitumoral activity of VEGF-directed therapy for meningioma. However, several retrospective studies suggest that bevacizumab may be an efficacious treatment. Even though the patient population was heterogeneous and most patients in the aforementioned series were heavily pretreated, the outcome compared favorably to that achieved using other salvage systemic therapies. In the Phase II trials of hydroxyurea, temozolomide, irinotecan, imatinib, erlotinib/gefitinib, interferon-α, tamoxifen, mifepristone, and octreotide for recurrent meningiomas, the median PFS ranged from 2 to 15 months. A decrease in PTBE on T2-weighted MRI was noted in 40% of patients, but all patients that had a decrease in PTBE demonstrated clinical improvement or remained stable. The lack of response in the remaining cohort emphasizes that VEGF-directed therapy is only beneficial under specific conditions, such as in the presence of a cerebral-pial blood supply and high VEGF-A to semaphorin-3A ratio. Further evaluation of this issue is warranted to determine which patients will respond best to therapy.
Clinical Studies of VEGF Therapy
A robust association does not inevitably impose a causal relationship. The definitive proof of efficacy will require studies involving VEGF inhibition and evaluation of the effect on PTBE. To this point, 3 case reports and 3 retrospective case series have used systemic VEGF-directed therapy, in particular bevacizumab, in meningiomas (Table 2). Bevacizumab is a humanized monoclonal antibody that inhibits VEGF activity by binding directly to all VEGF isoforms, to form a complex that becomes incapable of binding to receptor sites. It is currently approved by the US FDA for a variety of disorders, including glioblastoma.
In 2010, Puchner and colleagues presented the first case of bevacizumab use in meningioma. Salvage therapy with bevacizumab (10 mg/kg body weight every 2 weeks) was initiated after the recurrence of an anaplastic meningioma following gross-total resection and postoperative adjuvant radiotherapy, and was well tolerated. Six weeks later, contrast-enhancing tumor regressed substantially, and FLAIR and T2-weighted MRI showed reduced edema. These changes were sustained for 6 months after the cessation of therapy. Wilson and Heth reported regression of a partially resected Grade I meningioma after paclitaxel and bevacizumab was used to treat breast cancer for 6 months and 1 year, respectively. Regression of the meningioma was maintained on follow-up MRI 1 year later. Goutagny and colleagues administered bevacizumab at a dose of 5 mg/kg body weight every 2 weeks for 15 months with the primary goal of treating a vestibular schwannoma in a patient with neurofibromatosis Type 2. Concomitantly, an unknown grade meningioma that measured 7.3 cm and grew 38% in volume over the preceding year decreased 22% in size throughout the course of the treatment.
In the first published case series, Nayak and colleagues administered bevacizumab with the primary aim of promoting regression of recurrent atypical and anaplastic menigniomas. The cohort consisted of 15 patients with multiple prior surgeries (median = 3) and sessions of radiotherapy. The median number of recurrences was 4 per patient, and 7 patients received prior chemotherapy. A median of 9 doses of bevacizumab was given over 18 weeks. The median progression-free survival (PFS) was 6.5 months, and 6-month PFS was 44%. Two patients showed minor shrinkage of the enhancing part of the tumor while the remaining cohort had stable disease. Six patients exhibited reduction in peritumoral T2 hyperintense areas on MRI consistent with decreased PTBE. Five patients improved clinically, 9 remained unchanged, and 1 patient's condition deteriorated.
In a similar study, Lou and colleagues treated 14 patients with bevacizumab as salvage therapy where all had recurrent/progressive meningioma. The primary end point was to assess 6-month PFS. Thirteen patients had previously undergone 1 or more resections, fractionated radiotherapy or stereotactic radiosurgery, chemotherapy, or biological targeted therapy, such as octreotide. Chemotherapy was used as an adjunct in 71% of patients. One patient with multifocal disease demonstrated partial response according to the criteria for malignant gliomas, as established by the Response Assessment in Neuro-Oncology. While disease in 2 patients progressed, 11 patients exhibited stable disease. Median PFS and 6-month PFS were 12.2 months and 80%, respectively, for patients with Grade I meningiomas, and 15.8 months and 87.5% for patients with Grade II/III meningiomas, respectively. The therapeutic effect on PTBE was not reported.
In a more recent report by Nune and colleagues, 15 patients neurofibromatosis Type 2 harboring a total of 48 meningiomas of unknown grade were given bevacizumab (5 mg/kg body weight) every 2 weeks. Although the effect on PTBE was not described, 29% of meningiomas showed radiographic response with a 15-month median time to regression. The median PFS and 6-month PFS was 20 months and 93% on a per-patient basis, respectively.
To date, limited data have been published describing the antiedemagenic and antitumoral activity of VEGF-directed therapy for meningioma. However, several retrospective studies suggest that bevacizumab may be an efficacious treatment. Even though the patient population was heterogeneous and most patients in the aforementioned series were heavily pretreated, the outcome compared favorably to that achieved using other salvage systemic therapies. In the Phase II trials of hydroxyurea, temozolomide, irinotecan, imatinib, erlotinib/gefitinib, interferon-α, tamoxifen, mifepristone, and octreotide for recurrent meningiomas, the median PFS ranged from 2 to 15 months. A decrease in PTBE on T2-weighted MRI was noted in 40% of patients, but all patients that had a decrease in PTBE demonstrated clinical improvement or remained stable. The lack of response in the remaining cohort emphasizes that VEGF-directed therapy is only beneficial under specific conditions, such as in the presence of a cerebral-pial blood supply and high VEGF-A to semaphorin-3A ratio. Further evaluation of this issue is warranted to determine which patients will respond best to therapy.