Antiangiogenic therapy for patients with glioblastoma: current challenges in imaging and future directions.

Glioblastoma (GBM) is the most common primary malignant brain tumor, and despite recent advances in therapy, the prognosis for patients with GBM remains dismal. The median survival of newly diagnosed GBM patients is 15 months when treated with the current standard of care, which is a multimodality approach that includes maximal surgical resection followed by concurrent chemoradiation and 6 months of adjuvant temozolomide [1]. GBM is one of the most vascular tumors known, and there has been great interest in developing antiangiogenic agents for the treatment of GBM [2]. One of the key regulators of angiogenesis is VEGF, which induces tumor vascularization and facilitates tumor growth [3]. Bevacizumab is a humanized monoclonal antibody that targets VEGF, and was recently awarded accelerated approval by the US FDA as a single agent for use in recurrent GBM based on results of two Phase II trials [4,5]. A number of other antiangiogenic agents that target VEGF, PDGF, integrins and FGF are being evaluated in the treatment of newly diagnosed and recurrent GBM. Glioblastoma is characterized by abnormal vasculature and a blood–brain barrier (BBB) that is significantly more permeable than normal brain tissue [6]. This increased permeability results in contrast material leaking out of tumor capillaries and increasing enhancement on T1-weighted images. Antiangiogenic agents such as bevacizumab and cediranib can rapidly decrease enhancement after initiation of treatment [7], producing an apparently high ‘response rate’. Some of the improvement observed on contrast-enhanced MRI scan results from a rapid normalization of abnormally permeable blood vessels that restores, at least in part, the integrity of the BBB. Hence, use of this class of drugs results in higher response rates compared with historical controls [4,5,7]. The use of antiangiogenic drugs likely alters the image characteristics of enhancing tumor more effectively than that of nonenhancing tumor. Hence, the extent of reduction in contrast enhancement may not reflect the true anti-tumor activity of the antiangiogenic agent. Not infrequently, the radiographic image observed after antiangiogenic therapy suggests a radiographic response that is more impressive than the clinical benefit derived from the therapy; thus the term ‘pseudoresponse’ has been used to define such a situation [8]. ‘Pseudoresponse’ highlights the limitation that contrast enhancement is only a surrogate marker of tumor burden, and may in part be a reflection of disruption of the BBB. Antiangiogenic agents have been shown to improve survival primarily by reducing tumor-associated edema in experimental animal models [9]. One of the mechanisms of tumor progression after the use of antiangiogenic agents is that of vascular co-option, in which Manmeet S Ahluwalia