Controversies in Neuro-Oncology

Malignant gliomas are characterized by an extensive vasculature. The most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF), is therefore a therapeutic target for anti-angiogenic therapy. This chapter focuses on different functional characteristics of VEGF and its receptors in the angiogenesis process. Furthermore, the effects of decreasing or blocking VEGF using the humanized monoclonal antibody to VEGF, bevacizumab (Avastin), are discussed. The possible mechanisms of activity of this agent, as well as potential problems with this drug are also discussed.

Glioblastoma multiforme (GBM) is the most aggressive cancer and has the worst prognosis of all malignant gliomas at diagnosis. At the time of disease recurrence/progression, GBM has an even worse prognosis. Vascular proliferation is an important marker in the histological grading of gliomas. Malignant gliomas overexpress VEGF, the principal mediator of tumor angiogenesis, the levels of which correlate directly with tumor vascularity and grade, and inversely with prognosis. Bevacizumab is a humanized monoclonal antibody against VEGF. Bevacizumab with irinotecan has been approved by the US Food and Drug Administration (FDA) for colorectal cancer. Bevacizumab is also FDA approved as a first line treatment for nonsmall cell lung cancer in combination with carboplatin and paclitaxel, has obtained accelerated approval for metastatic HER2-negative breast cancer patients in combination with paclitaxel, and most recently, accelerated approval for recurrent glioblastoma multiforme as single agent. In the first FDA approved phase II trial for recurrent malignant glioma patients published patients received irinotecan [125 mg/m2 for patients on non enzyme inducing antiepileptic drug (EIAED) or not on an antiepileptic drug, and 340 mg/m2 for patients on EIAED] intravenously (IV) every two weeks in combination with bevacizumab 10 mg/kg IV every two weeks. Thirty-two patients were enrolled and a radiographic response rate of 63% was observed [1 complete response (CR) and 19 partial responses (PRs)]. A 6-month PFS of 38% for all patients and a 6-month overall survival of 72% were observed. Following these findings, multiple studies with irinotecan and other agents more commonly used in malignant gliomas were initiated to evaluate alternative bevacizumab-based regimens for recurrent malignant glioma patients. In the vast majority, all those studies showed an unprecedented increase in PFS and response rate in malignant glioma patients treated with bevacizumab as a single agent or in combination, as well a significant improvement in the quality of life of the patients exposed to bevacizumab. However, the utilization of a bevacizumab based regimen for recurrent malignant gliomas has opened a brand new field in neuro-oncology. Further study is needed to determine optimal managements and enhance the quality of life for these patients.

Bevacizumab is the first new drug approved for malignant glioma in a decade and demonstrates the potential for antiangiogenic therapy in the management of these patients. It has demonstrated improved radiographic response and progression free survival rates compared to historical controls as monotherapy. Bevacizumab has also been shown to improve patient symptoms of disease and decrease steroid requirements contributing to improved quality of life for glioma patients. Optimal combinations with other standard and targeted therapies are under investigation, as well as new imaging techniques to evaluate response to therapy, motivated in part by concerns over suspected increase potential for tumor invasion.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), recently received accelerated approval by the US Federal and Drug Adminstration as single-agent for recurrent glioblastomas (GBM). Preclinical studies suggest that inhibition of VEGF and radiotherapy (RT) have a synergistic effect in gliomas. We recently conducted a pilot study of bevacizumab and hypo-fractionated stereotactic RT for patients with recurrent GBM and anaplastic gliomas (AG). Patients received bevacizumab (10 mg/kg IV) every 2 weeks of 28-day cycle and 30 Gy of hypofractionated stereotactic RT in 5 fractions after the first cycle of bevacizumab. Twenty-five patients (20 GBM and 5 AG) were included. For the GBM cohort, overall response rate was 50%, 6-month progression free survival was 65% and median overall survival was 12.5 months. Bevacizumab with hypofractionated RT is an active regimen in malignant gliomas and is currently being studied in newly-diagnosed glioblastomas in combination with temozolomide.

In patients with recurrent malignant glioma, bevacizumab therapy achieves high response rates, prolonged progression-free survival, and reduced corticosteroid requirements. However, progressive disease during bevacizumab therapy is the rule. Resistance to bevacizumab may be mediated by upregulation of alternative pro-angiogenic factors or an infiltrative tumor growth pattern characterized by vascular co-option. Clinically, bevacizumab failure is often followed by rapid progression and death. In patients with progressive disease despite bevacizumab monotherapy, adding cytotoxic chemotherapy has not proven beneficial. Similarly, when patients develop progressive disease despite bevacizumab and chemotherapy, continuing bevacizumab and changing the concurrent chemotherapy agent is not effective. Combining bevacizumab with anti-invasion therapies is an appealing approach that has yet to be investigated in clinical trials. Additional research into mechanisms of resistance to anti-angiogenic therapy is needed in order to develop other promising strategies.

Given the marked upregulation of angiogenesis in glioblastoma, the integration of anti-angiogenic agents into treatment approaches is a highly attractive consideration. Preclinical data support an anti-tumor benefit with anti-angiogenic agents in GBM models. However, translation of these agents into the clinic was initially tempered by concern that anti-angiogenics may be associated with severe complications in brain tumor patients including hemorrhages and strokes. Extensive clinical experience to date provides reassurance that such complications are rare and that anti-angiogenics can be safely administered to brain tumor patients. Furthermore, clinical trials conducted among recurrent GBM patients using either bevacizumab, a humanized monoclonal antibody against the primary mediator of tumor angiogenesis, vascular endothelial growth factor (VEGF), or VEGF-receptor tyrosine kinase inhibitors such as cediranib, demonstrate encouraging evidence of anti-tumor benefit. In particular, durable radiographic responses observed among recurrent GBM patients were sufficiently frequent to lead to accelerated approval by the U.S. Food and Drug Administration for bevacizumab in May, 2009. Ongoing efforts are evaluating additional strategies to augment the anti-tumor benefit of anti-angiogenic agents for recurrent patients as well as the safety and efficacy of these agents among newly diagnosed GBM patients.

Malignant gliomas are one the most aggressive form of brain tumors and the current standard of care, combination chemoradiotherapy, prolongs survival to slightly more than a year after treatment. Current chemotherapeutic strategies produce limited benefit due to the rapid emergence of resistance. New strategies, among other things, are looking to target the prolific vascularization that supports the rapid growth of these malignant brain tumors. Several anti-angiogenic agents are in clinical testing, primarily as “salvage” therapies, after initial disease progression, and among these, the most mature data are for bevacizumab (Avastin), recently approved for salvage by the FDA, having shown success in a few Phase I/II trials. A small number of phase II trials have also provided very preliminary results with the up-front use of this agent, and at least two large Phase III trials are underway to determine whether bevacizumab will provide added benefit to patients with glioblastoma, when added to the initial chemoradiotherapy regimen. This paper lays out the rationale behind using bevacizumab in combination with radiotherapy, and discusses the up-front trials.

Angiogenesis, largely driven by vascular endothelial growth factor (VEGF) is essential to the growth of glioblastoma (GBM). Furthermore, a mesenchymal gene signature related to vascular proliferation has been identified in a subset of poor prognosis GBM patients suggesting that a proangiogenic phenotype negatively influences survival. Therefore, disruption of the angiogenic cascade is a logical therapeutic target. Recently, antiangiogenic therapy using bevacizumab, a VEGF targeting antibody, has shown promise against recurrent GBMs. A Phase III double blind placebo-controlled trial, RTOG 0825 was recently launched to compare conventional concurrent chemoradiation and adjuvant temozolomide plus bevacizumab versus treatment without bevacizumab in patients with newly diagnosed glioblastoma. MGMT methylation status and molecular profile are incorporated into the stratification design. This will not only balance the two treatment arms for these prognostic factors, but also may lead to prospective determination of optimal, individualized therapy based on tumor specific molecular profiles.

Bevacizumab recently received approval from the United States Food and Drug Administration for use in recurrent glioblastoma. Although, most patients tolerate bevacizumab with tolerable side effects, occasional patients sustain life-threatening complications and many others require medical management in order to continue on the drug. This chapter reviews the spectrum of bevacizumab complications in patients with malignant glioma, including mechanism when known as well as management.

High-grade gliomas are associated with a small risk of spontaneous intratumoral hemorrhage. A significant percentage of patients with high-grade glioma develop a deep venous thrombosis or pulmonary embolus, requiring anticoagulation. Because bevacizumab administration can be complicated by hemorrhage at the site of tumor or at other sites, a clinical concern for increasing the risk of intracranial hemorrhage arises when treating high-grade glioma patients who have a deep venous thrombosis or pulmonary embolus with therapeutic anticoagulation and concurrent bevacizumab. Evidence to date does not indicate that there is an increased risk of intracranial hemorrhage when bevacizumab is combined with anticoagulation in this setting.

Gliomas, particularly those that are malignant, are rapidly fatal often within 2 years despite the use of surgery followed by radiation therapy with concomitant and then maintenance therapy. Angiogenesis is an important aspect of malignant glioma biology that is reviewed. As such it has become a target for therapy, via the ligand (VEGF) or its receptor (VEGFR). There are several trails, prospective and retrospective, that had shown the benefits of bevacizumab therapy alone or in combination with chemotherapy, often CPT-11. We review the scientific basis for targeting this aspect of tumor biology and the prospective data that exists to date. Still many questions remain as to the optimal schedule but also whether there is an added benefit with the addition of chemotherapy.

Avastin is thought to normalize tumor vasculature and restore the blood brain barrier, resulting in less enhancement and peritumoral edema. Conventional measurements of tumor response such as the Macdonald criteria are based on the dimensions of enhancing tumor. Converting enhancing to non-enhancing tumor could therefore be considered treatment response, even in the absence of change in tumor size. But it is unknown if reduction in enhancement, by itself, correlates with patient outcome measures such as progression free and overall survival. In general change in tumor size is thought to be a more accurate biomarker of response, underscoring the importance of assessing faintly-enhancing or non-enhancing tumor burden in patients following Avastin therapy. Unfortunately non-enhancing tumor can be difficult to distinguish from other causes of increased T2 signal intensity, including peritumoral edema and radiation-induced gliosis, which are common among glioblastoma patients. This difficulty has led to efforts to find alternative ways to measure non-enhancing tumor, as well as to characterize additional biomarkers for tumor response that correlate with outcome measures and add value to standard MRI. One area of active research is the use of physiologic imaging, which has the potential to detect drug effects before change in tumor size is evident.

Avastin generates a decrease in vascular permeability in GBM which is marked by a decrease in cerebral edema and a decrease in contrast enhancement as seen on magnetic resonance imaging. These effects on the tumor vasculature may be mistakenly referred to as tumor responses because the historical method of measuring tumor response is based on tumor size assessed by contrast enhancement. This may explain why the few prospective phase II trials and several retrospective studies of Avastin in GBM report high radiographic response rates (30-60%) but modest improvements in progression-free survival and overall survival. Improved radiographic criteria for detecting disease progression in this context are needed and should be used in larger, randomized clinical trials which determine the magnitude of the survival benefit from Avastin.

Although, the recent use of bevacizumab has resulted in significant imaging responses, it appears that the impact on overall survival may be more limited, likely illustrating the fact that imaging responses may not correlate well with overall survival. given that vascular endothelial growth factor (VEGF) the ligand to which bevacizumab binds is responsible for a significant component of the permeability of the blood-brain-barrier (BBB), it will be important to distinguish effects on the BBB from true anti-tumor effects. This paper will illustrate the patterns of responses seen typically on post-Gd and FLAIR MRI. We also illustrate several patterns of tumor progression seen in patients treated with long-term bevacizumab in order to illustrate the range of novel imaging changes being seen in this clinical setting. The addition of bevacizumab to the clinical armamentarium for the treatment of glioblastoma has enhanced clinical outcomes, but it has come with the need to understand the range of imaging effects for this novel targeted therapy.

Abnormal gadolinium enhancement has been the standard characteristic for the measurements of brain tumors in clinical trials, but new therapies that target the vascular components of tumors have highlighted the shortcomings of enhancement as a measurement tool. Inhibitors of vascular endothelial growth factor (VEGF), such as bevacizumab, can produce rapid changes in the degree of contrast enhancement within malignant gliomas and in the extent of surrounding hyperintense T2-weighted signal. These effects, which are consistent with decreasing permeability of tumor capillaries, make it exceedingly difficult to employ conventional measures of tumor size in the setting of clinical trials. This chapter will review these issues and describe approaches to tumor measurement in the era of VEGF inhibitors.

Glioblastomas are histopathologically defined by endothelial proliferation and exhibit a uniquely elevated microvessel density compared to the surrounding normal tissue from which they derive, as compared to other tumor types. Clinical efficacy of the VEGF neutralizing antibody bevacizumab (avastin) in the treatment of other solid tumors led to a pair of phase II clinical trials studying bevacizumab treatment in recurrent human glioblastomas. Encouraging results from these trials led to the accelerated FDA approval of bevacizumab in the treatment of recurrent glioblastomas. However, extended bevacizumab treatment can lead to the development of infiltrative tumor on MRI with limited neurosurgical or chemotherapy options. Future studies will be needed to be able to identify tumors that are on their way to developing this appearance before it happens, in order to effectively use new potent anti-angiogenic agents like bevacizumab in the treatment of glioblastomas or symptomatic radiation necrosis associated with glioblastomas for which bevacizumab treatment may also be effective.

Malignant gliomas are optimally managed with maximal surgical resection followed by radiation and chemotherapy. Drug delivery challenges and chemoresistance limits the efficacy of standard chemotherapeutic agents. Understanding glioma biology has led to the development of a variety newer molecular targeting agents which have begun to show exciting preliminary results. Bevacizumab (Avastin) is one such drug likely to play a key role in malignant glioma therapy. We review the current literature in regard to the use of bevacizumab and its adverse effects in neurosurgical patients.

Background: Angiogenesis is a common theme in cancer and accordingly, antiangiogenic therapies are increasingly utilized for the treatment of cancer including cancers of the central nervous system (CNS). At present, proof of principle of antiangiogenic therapy for CNS tumors has only been realized for recurrent glioblastoma (GBM). Methods: A literature review of the use of bevacizumab and other antiangiogenic therapies in neuro-oncology apart from the treatment of recurrent GBM. Results: Several potential applications for antiangiogenic therapy are suggested by the limited literature presently available including; recurrent anaplastic gliomas, elderly newly diagnosed GBM, unresectable high-grade gliomas with significant mass effect requiring high dose steroid (up-front therapy), radiation necrosis with mass effect, pseudoprogression requiring surgical intervention, highly angiogenic non-glioma primary brain tumors (i.e. vestibular schwannomas, meningioma, hemangiopericytoma, hemangioblastoma), brain metastases in bevacizumab responsive cancers (i.e. renal cell, ovarian, breast and non-small cell lung cancers), up-front treatment of newly diagnosed GBM, radiation optic neuropathy and treatment of selected intracranial sarcomas. Conclusions: Bevacizumab and other angiogenic inhibitory therapies appear to have the potential to treat a variety of brain tumors and brain tumor treatmentrelated conditions such as pseudoprogression and radiation necrosis. To date; however, these novel applications of angiogenesis inhibitors remain conjectural given that majority of data is retrospective or exploratory.

Avastin for Treatment of Central Nervous System Radiation Necrosis

Radiation therapy continues to be a common therapy for most primary central nervous system (CNS) tumors, tumors that metastasize to the CNS, and tumors of the head and neck. Radiation injury is an inevitable side effect in many of these cases. Understanding the pathophysiology and clinical manifestation of different stages of radiation injury is crucial for developing methods to maximally mitigate radiation injury. In this chapter, we discuss the classification of radiation injury and emphasize the potential mechanisms of radiation necrosis. More importantly, our clinical experience and ongoing clinical studies of treatment for radiation necrosis are discussed. Hopefully, these efforts will substantially assist the field of treatment of radiation necrosis to move forward.

Background: The treatment of recurrent anaplastic glioma (AG) like all high-grade gliomas (HGG) is problematic, as only partially effective therapeutic modalities are available and there is a lack of a standard therapy for recurrence. Methods: A literature review of the use of bevacizumab for recurrent HGG including five studies involving recurrent AG. Results: In the 5 studies of bevacizumab for the treatment of recurrent AG (n=140 patients) neuroradiographic response rates were as follows; complete response 0-20%, partial response 34-68% (median 52%), and stable disease 5-59% (median 16%). Median overall survival was 28 weeks (range 18-35 weeks) and progression free survival at 6- and 12-months was 55% (range 32-68%) and 23% (16-39%) respectively. Conclusions: Bevacizumab therapy appears to increase response of recurrent AG by 2-fold and 6- month progression free survival by 1.5 fold without a clear benefit with respect to overall survival. Toxicity of bevacizumab therapy is manageable and most often comprised of hypertension, proteinuria and fatigue. To date, there are no multi-institutional prospective trials evaluating the role of bevacizumab for the treatment of recurrent AG notwithstanding the increasingly common use of bevacizumab for this indication.

Treatment of recurrent glioma remains a therapeutic challenge. Unprecedented high response rates associated with rapid clinical improvement have been observed. Despite the absence of definitive data and while definitive trial has not even been started, regulatory approval was requested. And while the United States Food and Drug Administration granted accelerated approval based on 2 small uncontrolled phase II trials, the European Medicines Agency rejected the application.

VEGF Signaling Pathways in Glioblastoma: Is the Evidence Sufficient for Widespread Use? A European Perspective

First uncontrolled trials suggest significant activity of bevacizumab in recurrent glioblastoma. However, many questions still remain unresolved, in particular in view of the occurrence of pseudo-responses, the development of gliomatosis cerebri, the unclear impact on survival, and the high costs associated with this treatment. Further studies need to focus the early identification of responders, better combination regimen, and on the assessment of survival benefit. The widespread use of bevacizumab prior to registration may actually become an obstacle for the answering of some of these questions.

Bevacizumab (Avastin®) is an antibody to the vascular endothelial derived growth factor (VEGF) that has been approved for the treatment of several human cancers, including in May 2009 in the US, recurrent glioblastoma. Approval for recurrent glioblastoma was based on an increased response rate defined by neuroradiology and on favourable outcome measures regarding surrogate parameters of quality of life and overall survival, compared with historical controls. The approval of bevacizumab despite the lack of an appropriate controlled registration trial has provoked a heated discussion on the minimal requirements for approval of an agent in an orphan-like indication with urgent medical need, such as recurrent glioblastoma. A registration trial for bevacizumab in newly diagnosed glioblastoma is planned.

Although, therapies directed to the vasculature of malignant gliomas are equally attractive in Europe and the United States of America (US), limited access to both trials and lack of approval by the European Medicines Agency (EMEA) prevented a de facto introduction into the current standard of care as seen in the US, where the compound is registered for recurrent glioblastoma since 05/2009. To date, the STEERING trial using the protein kinase C beta (PKC-.) inhibitor enzastaurin, the REGAL trial applying the vascular endothelial receptor inhibitor (VEGFR) cediranib, the PTK787/ZK trial and the upcoming dasatinib trial comprise the only structured European experience with such molecularly targeted drugs. Several national initiatives using bevacizumab (Avastin®) are now in place to fill the obvious gap. Despite the clear medical need for novel therapies for recurrent malignant glioma, neurooncology in Europe advocates randomized rather than uncontrolled trials to obtain additional data clarifying the role for bevacizumab in malignant gliomas.

Sunitinib malate (sunitinib) is an orally absorbed small molecule inhibitor of multiple cellular kinases including the family of “Vascular Endothelial Growth Factor Receptors” (VEGFRs), “Platelet Derived Growth Factor Receptors” (PDGFR-alfa and -beta ), c-Kit, FLT1, FLK1/KDR, the FLT3 and RET kinases. Treatment with sunitinib offers a proven survival benefit and is registered for the treatment of patients with advanced renal cell carcinoma and GIST (two respectively HIF/VEGF and PDGFR or KIT dependent cancers) but sunitinib has also demonstrated meaningful anti-tumor activity against a subset of other common cancers (including breast, colon and non-small cell lung cancer). Increased receptor tyrosine kinase signaling involving the VEGF/VEGFR ligand/receptors but also KIT and PDGFR receptor signaling causes profound neo-angiogenesis and may contribute to cellular proliferation and survival of high-grade gliomas (HGG) of the central nervous system (CNS). Furthermore, the KIT, PDGFRa and VEGFR2 genes are frequently amplified and over-expressed in HGG and therefore represent an attractive molecular target for inhibition by sunitinib. Notwithstanding its attractive drug profile, sunitinib has so far not been widely investigated for the treatment of central nervous system glioma. Only recently, the first results from an exploratory clinical trial of sunitinib for recurrent HGG have become available. These early results (obtained with a continuous 37,5 mg/day regimen) indicate that sunitinib has a measurable but transient inhibitory effect on the pathological increase in cerebral blood volume and -flow within recurrent gliomas but that this effect is transient in time and associated with limited clinical benefit. In addition considerable “off target” toxicity (mainly skin and hematological toxicity) were observed that may interfere with further development of sunitinib in this indication. Ongoing phase II studies on sunitinib should further delineate the potential role of this drug in the treatment of CNS glioma at diagnosis and recurrence. Potentially, individual molecular profiling of gliomas to predict their dependence on specified kinase signaling will aid to determine the utility of sunitinib treatment over alternative more specific VEGF(R) targeted agents.

Cilengitide is a novel cyclic peptide that demonstrates anti-integrin activity. In laboratory studies, cilengitide binds with high affinity to the intergrins αvβ3 and αvβ5. It blocks proliferation of cells expressing this class of integrins and results in antiangiogenic and antitumor activity in animal models. Cilengitide has found a niche for clinical development in the population of patients affected by malignant glioma. The clinical evaluation has thus far found an overall high safety profile with limited toxicity and improved clinical outcomes in both recurrent and newly diagnosed glioma patients. This review intends to provide an overview of the preclinical development, summary of clinical trials to date, and update on ongoing and active therapeutic studies.

Sorafenib is a multi-targeted receptor tyrosine kinase inhibitor (TKI), with activity against vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, Raf-1, B-Raf, C-Raf, and plateletderived growth factor receptor (PDGFR) -α and -β. Currently, sorafenib has regulatory approval for use in metastatic renal cell carcinoma and hepatocellular carcinoma. An attractive activity profile, pre-clinical evidence of antitumor activity in human malignant glioma models and a promising safety profile have led to recent phase I/II clinical trials for patients with malignant gliomas. Here we review the current data, and future directions for the development of sorafenib for malignant glioma.

Vascular endothelial growth factor (VEGF) is the key protein in the regulation of pathological angiogenesis, a hallmark of glioblastomas. Inhibition of VEGF has become a major strategy in glioma therapy. Most clinical trial data generated to date have been with bevacizumab, a humanized monoclonal antibody against VEGF. Aflibercept (VEGF Trap; Regeneron, Inc.), is an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2 which binds to all isoforms of VEGF and to placental growth factor (PlGF). The avidity with which aflibercept binds to VEGF-A and VEGF-B is significantly higher than that for bevacizumab. The toxicities observed include hypertension and proteinuria and are similar to those with other therapies targeting the VEGF pathway. A phase II trial in patients with relapsed high-grade glioma demonstrated encouraging activity. Ongoing trials are evaluating aflibercept in combination with temozolomide and radiation in newly-diagnosed glioblastoma.

Targeting tumor-derived angiogenesis has emerged as a promising new treatment strategy in patients with glioblastoma. Cediranib (Recentin™) is a potent oral inhibitor of vascular endothelial growth factor (VEGF) receptors and has demonstrated improved progression-free survival in an uncontrolled phase II study of patients with recurrent glioblastoma. The drug is taken orally, once daily, and has a manageable side effect profile. In addition, it has potent anti-edema and steroid-sparing effects that might improve the quality of life of glioblastoma patients. Several clinical trials are ongoing testing cediranib in patients with gliomas.

Although, the use of temozolomide, as described by Stupp et al. has been hailed as one of the landmark breakthroughs for malignant gliomas, this diagnosis still portends one of the worst prognosis in oncology. Bevacizumab (Avastin) was reported to have favorable results and an acceptable toxicity profile in the treatment of glioblastoma multiforme (GBM) patients who progressed on temozolomide. Given the addition of this potent new treatment agent into the glioma arsenal, and the introduction of a new class of treatment medications it represents; it will be useful to review its clinical history and compare and contrast the experience and pitfalls other oncology sub-specialties have had with this agent.