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Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas

Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas Hindawi Publishing Corporation Journal of Oncology Volume 2012, Article ID 193436, 12 pages doi:10.1155/2012/193436 Review Article Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas Katsuyuki Shirai, Michael R. Siedow, and Arnab Chakravarti Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA Correspondence should be addressed to Arnab Chakravarti, arnab.chakravarti@osumc.edu Received 1 May 2011; Accepted 24 May 2011 Academic Editor: Arkadiusz Dudek Copyright © 2012 Katsuyuki Shirai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression- free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas. 1. Introduction shown to regulate tumor angiogenesis [10]. Bevacizumab was developed as a humanized monoclonal antibody against Malignant gliomas such as glioblastoma and anaplastic VEGF. Clinical trials of recurrent glioblastoma showed gliomas are the most common primary brain tumors in benefits of bevacizumab in response rate and PFS [11–13]. adults [1]. Temozolomide and radiotherapy have been Based on these favorable results, bevacizumab was approved demonstrated to improve overall survival in glioblastoma by the US Food and Drug Administration (FDA) for patients [2–4]. Despite advances in diagnosis and therapy, recurrent glioblastoma. For newly diagnosed glioblastoma, prognosis remains poor with a median overall survival of phase II trials showed that the addition of bevacizumab to temozolomide and radiotherapy improves PFS [14, 15]. 12 to 15 months in glioblastoma due to the resistance to radiotherapy and chemotherapy. Although anaplastic Other antiangiogenic drugs have also been investigated and gliomas tend to respond well to these treatments, the median used in several clinical studies [16]. In this paper, we focus on survival time is 2 to 3 years [5, 6]. The prognosis of biological and clinical findings of antiangiogenesis therapy recurrent malignant gliomas is dismal with the median for malignant gliomas. overall survival and progression-free survival (PFS) of 7.5 months and 2.5 months, respectively [7]. More effective 2. Biological Aspects of Antiangiogenic therapeutic strategies are needed for these patients. Therapy for Glioblastoma Malignant gliomas are characterized by vascular prolifer- ation or angiogenesis [8, 9]. Vascular endothelial growth fac- Advances in molecular biology have provided pathogenesis tor (VEGF) is highly expressed in glioblastoma and has been of malignant gliomas. Several clinical and preclinical studies 2 Journal of Oncology proposed that tumor-related blood vessel, called “angiogene- reduce steroid dose. Given the efficacy of bevacizumab for sis”, is required for solid tumor growth, including malignant recurrent glioblastoma in the clinical setting, bevacizumab gliomas [10, 16]. Endothelial proliferation is a marker of monotherapy has since been approved by the FDA. histological grading systems for malignant gliomas because of an association between a degree of microvascularity and 3.2. Toxicity Profile of Bevacizumab. Since VEGF plays an biologic aggressiveness [17]. Glioblastoma is particularly important role in vascular function and physiological angio- characterized by vascular proliferation and the extent of genesis, its inhibition via bevacizumab has been reported necrosis. These findings indicate that tumor antiangiogenesis to cause serious adverse events [34]. The first phase II is a promising candidate to inhibit the growth of malignant study of recurrent glioblastoma treated by bevacizumab and gliomas. VEGF, a critical mediator of angiogenesis, has irinotecan reported that five patients (14%) discontinued emerged as a novel target of antiangiogenic therapy. Glioblas- treatment due to central nervous system (CNS) hemorrhage, toma cells have been shown to secrete VEGF, resulting in deep venous thrombosis, and pulmonary emboli [11]. No the endothelial proliferation and tumor survival in vivo [18]. fatal adverse events were reported in this study. BRAIN VEGF is expressed in malignant gliomas and is associated study reported the detailed information on adverse events of with tumor grade and vascularity [19, 20]. Therefore, it is bevacizumab [12]. Grade ≥3 adverse events were observed postulated that antiangiogenesis suppresses blood flow and in 65.8% and 46.4% of bevacizumab plus irinotecan and inhibits the tumor growth. Monoclonal antibodies against bevacizumab alone groups, respectively. The most com- VEGF were shown to inhibit the growth of glioma cells in mon causes of grade ≥3 adverse events were convulsion, vivo [21]. A VEGF inhibitor directly affects glioma stem hypertension, neutropenia, and fatigue. CNS hemorrhages cells that are more resistant to chemotherapy and radio- of any grades were observed in five patients (3.0%). There therapy [22]. Furthermore, antiangiogenesis can normalize were one fatal adverse event (1.3%) in bevacizumab plus tumor vasculature and decrease interstitial fluid pressure, irinotecan group and two (2.3%) in bevacizumab alone providing an improved delivery of chemotherapeutics and group, respectively. Selecting appropriate patients, early oxygen. Consequently, antiangiogenesis is expected to work assessment of toxicity, and adequate management should be synergistically with radiotherapy and chemotherapy [23, 24]. required to reduce the serious adverse events of bevacizumab. Given these findings, VEGF inhibitors are expected to be a Arterial and venous thromboses are generally reported novel antiangiogenic therapy for malignant gliomas. in treatment of antiangiogenesis therapy, although the inherent risk of these thromboses is higher among malignant glioma patients. A retrospective study of 9849 patients with 3. The Efficacy and Safety of Bevacizumab for malignant gliomas showed that 2-year cumulative incidence Recurrent Malignant Gliomas of symptomatic venous thromboembolism was 7.5% [35]. 3.1. Bevacizumab for Recurrent Glioblastoma. Bevacizumab Further studies are necessary to evaluate the additional was developed as a humanized monoclonal antibody to bind risk of thrombosis in malignant glioma patients treated by VEGF-A, preventing the interaction and activation of VEGF bevacizumab. receptor tyrosine kinases [25, 26]. This drug is approved by Recently, a meta-analysis of randomized control trials in several tumor types showed that bevacizumab in com- the FDA and is in clinical use for the treatment of colorectal cancer, nonsmall cell lung cancer, breast cancer, renal cell bination with chemotherapy increases fatal adverse events carcinoma, and glioblastoma [27]. Table 1 shows several when compared with chemotherapy alone [36]. The overall clinical studies of bevacizumab for recurrent malignant incidence of fatal adverse events was 2.5% in bevacizumab glioma patients. therapy with the common causes being hemorrhage, neu- The first phase II trial for 35 recurrent glioblastoma tropenia, and gastrointestinal tract perforation. Interestingly, was performed to investigate the efficacy of intravenous the type of chemotherapeutic agents was significantly associ- administration of bevacizumab and irinotecan, a topoiso- ated with relative risk of fatal adverse events. The addition merase 1 inhibitor [11]. The 6-month PFS was 46%, and of bevacizumab was associated with increased fatal adverse median overall survival was 10.5 months, respectively. At events in patients receiving taxanes or platinum agents (3.3% least a partial response was observed in 57% of patients. A versus 1.0%) but not in those receiving other agents (0.8% versus 0.9%). In clinical trials of malignant gliomas, the larger, randomized, noncomparative phase II study, called the BRAIN study, was performed using bevacizumab with addition of irinotecan or temozolomide to bevacizumab has or without irinotecan for 167 recurrent glioblastoma. In often been performed and may be associated with lower fatal this study, the response rates were 28.2% and 37.8%, adverse events. However, this meta-analysis did not include and 6-month PFS were 42.6% and 50.3% in bevacizumab the trials of brain tumors, and further investigations are alone and bevacizumab plus irinotecan groups, respectively required to evaluate the fatal adverse events of bevacizumab [12]. Another phase II study of bevacizumab alone for 48 and chemotherapy in malignant gliomas. recurrent glioblastomas showed that response rate was 35% and 6-month PFS was 29%, respectively [13]. These results 3.3. Bevacizumab for Recurrent Anaplastic Gliomas. Anaplas- were more favorable than a previous database of 8 negative tic gliomas have a slightly better prognosis than glioblas- trials having 6-month PFS of 15% for recurrent glioblas- toma [37], and the median survival time is 2 to 3 years. toma patients [7]. Furthermore, an additional advantage of However, there are no standard treatments for progression bevacizumab is its ability to decrease tumor edema and to or recurrence of anaplastic gliomas, and a novel treatment Journal of Oncology 3 Table 1: Bevacizumab for recurrent or newly malignant gliomas. Study Agents Patients RR MPFS 6-PFS MST Ref. Phase II Bevacizumab + irinotecan 35 recurrent GBM 57% 6 months 46% 10.5 months [11] Bevacizumab 85 recurrent GBM 28% 4.2 months 43% 9.2 months Phase II [12] Bevacizumab + irinotecan 82 recurrent GBM 38% 5.6 months 50% 8.7 months Phase II Bevacizumab 48 recurrent GBM 35% 4 months 29% 7.7 months [13] 23 recurrent GBM 61% 5.0 months 30% 10 months Phase II Bevacizumab + irinotecan [28] 9 recurrent AG 67% 7.5 months 56% Not reached Phase II Bevacizumab + irinotecan 33 recurrent AG 61% 7.5 months 55% 16.3 months [29] 20 recurrent GBM 50% 7.3 months 65% 12.5 months [30] Retrospective Bevacizumab + SRT 5 recurrent AG 60% 7.5 months 60% 16.5 months SRS + bevacizumab — 5.2 months — 11.2 months Retrospective [31] 49 recurrent GBM SRS + other drugs — 2.1 months — 3.9 months Bevacizumab + erlotinib 25 recurrent GBM 48% 4.5 months 28% 10.5 months Phase II [32] 32 recurrent AG 31% 5.9 months 44% 17.8 months 70 newly diagnosed Phase II Bevacizumab + RT/TMZ — 13.6 months 88% 19.6 months [14] GBM 125 newly diagnosed [15] Phase II Bevacizumab + RT/TMZ — 13.8 months 87% — GBM Adjuvant bevacizumab 125 newly diagnosed Phase II — 13.8 months — 21.3 months [33] + irinotecan + TMZ GBM RR: response rate; MPFS: median progression-free survival; 6-PFS: 6-month progression-free survival; MST: median overall survival time; GBM: glioblastoma multiforme; AG: anaplastic gliomas; SRT: stereotactic radiotherapy; SRS: stereotactic radiosurgery; RT: radiotherapy; TMZ: temozolomide. strategy is needed. Recent studies have shed light on the evaluated the efficacy and safety of stereotactic radiosurgery antiangiogenic therapy in recurrent anaplastic gliomas. A and adjuvant bevacizumab for recurrent malignant gliomas phase II study of bevacizumab and irinotecan was performed [31]. Median PFS was 5.2 months, and 1-year overall survival in 23 glioblastoma and 9 anaplastic gliomas [28]. The was 50% in glioblastoma patients treated by radiosurgery response rates were 61% and 67%, and 6-month PFS were and adjuvant bevacizumab. These results were significantly 30% and 56% in glioblastoma and anaplastic gliomas, better than radiosurgery and other drugs. The authors con- respectively. Another phase II trial was conducted for 33 cluded that salvage radiosurgery and bevacizumab improve anaplastic gliomas treated by bevacizumab and irinotecan outcomes in recurrent malignant gliomas. [29]. This study included 25 anaplastic astrocytomas and A phase II study of bevacizumab plus erlotinib, an epider- 8 anaplastic oligodendrogliomas. The 6-month PFS and mal growth factor receptor (EGFR) tyrosine kinase inhibitor, overall survivals were 55% and 79%, respectively. At least was performed for patients with recurrent malignant gliomas a partial response was observed in 61% of patients, and [32]. This study included 25 glioblastomas and 32 anaplastic dose of dexamethasone was decreased in 67%. These findings gliomas. The response rate and 6-month PFS were 48% indicate that bevacizumab and irinotecan can be an active and 28% for glioblastoma and 31% and 44% for anaplastic regimen for recurrent anaplastic gliomas. gliomas, respectively. Grade 1 or 2 rash, mucositis, diarrhea, and fatigue were the most common adverse events. The authors concluded that treatment was tolerated, but the 3.4. Additional Treatment to Bevacizumab for Recurrent additional benefits of erlotinib were unclear when compared Malignant Gliomas. The addition of targeting therapy or with historical bevacizumab-containing regimens. These radiotherapy to bevacizumab has been performed for recur- studies indicate that additional therapy to bevacizumab can rent malignant gliomas. Gutin et al. retrospectively analyzed be promising strategy, although it is still unclear which bevacizumab and stereotactic radiotherapy (30 Gy in 5 frac- agent has the efficacy in combination with bevacizumab for tions) for 25 recurrent malignant gliomas [30]. There were 20 glioblastomas and 5 anaplastic gliomas in this study with malignant gliomas. Further studies are required to establish the additional agents to bevacizumab. all patients receiving prior radiotherapy. Response rate was 50%, and 6-month PFS was 65% in glioblastoma patients. Three patients (12%) discontinued treatment due to tumor 4. Resistance to Bevacizumab hemorrhage, wound dehiscence, and bowel perforation, although no radiation necrosis was detected. The authors In the maintenance of bevacizumab, patients with malig- concluded that treatment was well tolerated and beneficial nant gliomas inevitably experience tumor recurrence. Fur- for recurrent malignant gliomas. Cuneo et al. retrospectively thermore, recurrent tumors after bevacizumab failure are 4 Journal of Oncology reported to be more aggressive with rebound edema [38]. 6. Biological Markers Predicting Response Although additional agents to bevacizumab have been A variety of biomarkers predicting the efficacy of beva- attempted for patients after bevacizumab failure, disease cizumab have been reported in several tumor types including prognosis was extremely poor with median PFS of 37.5 days malignant gliomas [51]. These predictive biomarkers are and 6-month PFS of 2%, respectively [39]. The authors expected to lead to a personalized therapy that selects concluded that alternative strategies should be considered patients who can benefit from bevacizumab. Sathornsumetee for these patients. De Groot et al. showed that bevacizumab et al. examined several biological markers in recurrent induced a particularly invasive tumor phenotype expressing malignant gliomas treated by bevacizumab and irinotecan insulin-like growth factor binding protein-2 and matrix [52]. High VEGF expression was significantly associated metalloprotease-2 in glioblastoma [40]. with higher radiographic response (P = 0.024), and high Preclinical studies indicated that alternative pro-angi- carbonic anhydrase 9 expression predicted poor overall ogenic signaling pathways are upregulated in resistance to survival (P = 0.016). Higher hypoxia-inducible factor-2 antiangiogenic therapies [41]. These other angiogenic factors alpha and VEGF receptor-2 expressions were also reported such as fibroblast growth factors and platelet-derived growth to be associated with poor survival in recurrent malignant factors (PDGF) can compensate for the loss of VEGF activ- gliomas treated by bevacizumab and erlotinib [32]. ity under bevacizumab treatment [42]. Additional agents Recently, circulating VEGF concentrations are reported inhibiting other antiangiogenic pathways may suppress these to predict the prognosis in solid tumors treated by beva- resistances, and further clinical and animal studies are clearly cizumab [51, 53]. The measurement of circulating proteins required to overcome the resistance of bevacizumab. is an attractive strategy since blood is easily accessible and the assay is inexpensive. Circulating VEGF concentrations are expected to reflect VEGF-dependent angiogenesis and 5. Imaging of Response to to predict the benefit from bevacizumab [51]. Gururangan Antiangiogenic Therapy et al. examined the VEGFR-2 phosphorylation in peripheral blood mononuclear cells in recurrent malignant gliomas Most studies defined partial and complete responses as radi- and diffuse brainstem glioma treated by bevacizumab ological objective response according to McDonald criteria [54]. They showed that circulating VEGFR-2 was inhibited that are based on contrast-enhanced CT or MRI [43]. How- by bevacizumab, but they did not show information on ever, an accurate assessment of tumor response by conven- whether it is a prognostic biomarker. These clinical trials tional modality is limited, since bevacizumab directly alters have provided some potential predictive markers (e.g. tumor tumor blood vessels [44]. As a result of this, response rate and VEGF expression or circulating markers), which require a 6-month PFS are debatable as a measure of antitumor activ- phase III study for proper evaluation [55]. ity [44]. Norden et al. reported that bevacizumab suppressed enhancing tumor recurrence, but not nonenhancing and 7. Addition of Bevacizumab to infiltrative tumor growth, indicating that bevacizumab may Temozolomide and Radiotherapy for change the recurrence patterns of malignant gliomas [45]. Iwamoto et al. reported that contrast-enhanced MRI did not Newly Diagnosed Glioblastoma adequately evaluate disease status, whereas nonenhancing Several clinical studies have been performed to evaluate tumor recurrence was significantly associated with overall the safety and efficacy of the addition of bevacizumab for survival in recurrent glioblastoma treated by bevacizumab newly diagnosed glioblastoma (Table 1). Lai et al. reported [46]. Given these findings, The Response Assessment in a phase II study of the addition of bevacizumab to the Neuro-Oncology Working Group was established to develop standard treatment of temozolomide and radiotherapy for the new response criteria for clinical trials of brain tumors 70 newly diagnosed glioblastomas [14]. Bevacizumab was [47]. They proposed to incorporate T2 and fluid-attenuated intravenously administered every 2 weeks from the first day inversion recovery (FLAIR) changes on MRI to assess the of treatment. The median overall survival and PFS were infiltrative pattern progression of malignant gliomas. 19.6 and 13.6 months, respectively. The authors concluded Other studies have looked into establishing a reliable that the addition of bevacizumab improved PFS but not radiological modality in antiangiogenesis therapy. Positron overall survival when compared with a control group emission tomography (PET) using [ F] fluorothymidine treated with first-line temozolomide and radiotherapy who (FLT) offers noninvasive assessment of cell proliferation [48]. had mostly received bevacizumab at recurrence. Another The response measured by FLT-PET significantly predicted phase II study also reported preliminary results on the the overallsurvivalinrecurrent glioblastoma treatedby addition of bevacizumab to the standard temozolomide and bevacizumab (P = 0.061) [49]. Recently, Ellingson et al. radiotherapy regimen in 125 newly diagnosed glioblastomas reported that relative nonenhancing tumor ratio, the ratio [15]. In this study, toxicity was minimal, and most patients of FLAIR to contrast-enhancing volume, was predictive for (90%) continued treatment, with median PFS of 13.8 overall survival and PFS in the treatment of bevacizumab for months. Recently, Desjardins et al. reported a phase II study of bevacizumab in combination with temozolomide plus recurrent glioblastoma [50]. Further studies are warranted to establish the imaging modality to evaluate the response to radiotherapy followed by bevacizumab, temozolomide, and irinotecan for 125 newly diagnosed glioblastomas at the antiangiogenic therapy and to predict the prognosis. Journal of Oncology 5 Society for Neuro-Oncology (SNO) annual meeting in 2010 is still challenging [61]. Bevacizumab has been expected to [33]. This study had median overall survival of 21.3 months be a therapeutic modality for radiation retinopathy. Finger and PFS of 13.8 months, respectively. These studies showed reported that intravitreal injection of bevacizumab was effec- encouraging results; however, it is still unclear whether the tive for retinal hemorrhage, exudation, and edema, which addition of bevacizumab to standard temozolomide and improved visual acuity of patients [69]. There were no ocular radiotherapy can improve the overall survival. and systemic side effects by bevacizumab. Furthermore, the Currently, two randomized phase III trials, ROTG 0825 authors recently showed that intravitreal bevacizumab was and AVAGLIO, are ongoing for newly diagnosed glioblas- effective for radiation optic neuropathy [70]. toma treated by temozolomide and radiotherapy with or Although these results indicate that some radiation without bevacizumab [56, 57]. These studies will show the vasculopathies are potentially treatable by bevacizumab, role of bevacizumab in frontline treatment in glioblastoma exacerbation of radiation necrosis by this drug was also patients. reported [71]. It is still unclear how bevacizumab affects the radiation adverse events. Meticulous followup is required 8. The Effect of Bevacizumab on when bevacizumab is administered after radiotherapy. Ani- Radiation Adverse Events mal models of radiation necrosis are needed to investigate the mechanism of bevacizumab. Bevacizumab has been reported to affect the specific adverse events of radiotherapy [58, 59]. Sherman et al. reported 9. Other Antiangiogenic Drugs for that six glioblastoma patients developed severe radiation optic neuropathy following bevacizumab [58]. All of them Malignant Gliomas received 60 Gy in 30 fractions in the initial treatment. VEGF has been shown to be the main player in tumor angio- Patients received a median of 7.5 doses of bevacizumab genesis, and its inhibitor, bevacizumab, has been thoroughly followed by onset of visual symptoms. Although the detailed investigated in clinical and animal studies. Other drugs such mechanism remains unclear, the authors indicated that as pan VEGF receptor tyrosine kinase inhibitors have also bevacizumab decreases optic nerve tolerance to radiation. been reported to inhibit VEGF pathways. Several biological Another case series study reported that bevacizumab induced pathways including integrin, fibroblast growth factor, and optic neuropathy and Brown-Sequard syndrome after irra- PDGF also are associated with the angiogenesis. Currently, diation [59]. The authors hypothesized that bevacizumab following radiotherapy inhibits VEGF-dependent repair of several types of antiangiogenic drugs have been investigated normal neural tissue. and used in clinical trials for recurrent as well as newly In contrast, bevacizumab has been reported to be diagnosed glioblastoma [72]. In this section, we review these effective for the management of radiation necrosis and drugs and the results of clinical trials (Table 2). retinopathy [60, 61]. Radiation necrosis is a serious com- plication of radiotherapy and includes extended edema. 9.1. Cilengitide. Cilengitide competitively binds αvβ3and Pathological findings show that endothelial cell dysfunction αvβ5 integrin receptors that are expressed on tumor cells causes tissue hypoxia and necrosis with the local cytokine and activated endothelial cells during angiogenesis. Cilen- release, including VEGF [62, 63]. Corticosteroids, surgery, gitide can directly inhibit the growth of integrin-expressing anticoagulation, and hyperbaric oxygen have been per- tumor cells and indirectly act as an antiangiogenesis agent formed, although there is no evidence to support routine use [87, 88]. Glioblastoma cells express integrin receptors, and in clinical practice [64]. Retrospective studies have shown cilengitide has shown an antitumor effect in glioblastoma that bevacizumab decreased the edema and improved the xenografts in vivo [89, 90]. A randomized phase II study clinical outcome in patients with radiation necrosis [60, 65– of 81 recurrent glioblastoma was performed to determine 67]. Interestingly, a small randomized trial was recently the efficacy and safety of cilengitide [73]. The patients performed to demonstrate this effect [68]. Patients having were randomly assigned to receive either 500 or 2000 mg radiation necrosis with progressive neurologic symptoms of cilengitide twice weekly. Patients treated with 2000 mg were assigned to bevacizumab (n = 14) and placebo groups showed a trend toward better results with 6-month PFS (n = 7). Bevacizumab was intravenously administered of 15%. The treatment was well tolerated, and significant every 3 weeks for 12 weeks. Radiological response and hematologic toxicity was uncommon. A phase I/IIa study of improvement of neurological symptoms were observed in cilengitide combined with temozolomide and radiotherapy the bevacizumab treated group but not in placebo group. The for 52 newly diagnosed glioblastoma patients was conducted authors concluded that the class I evidence of bevacizumab [74]. This combination therapy was well tolerated without efficacy for radiation necrosis was shown in this study. additional toxicity, and median overall survival was 16.1 Radiation retinopathy is a chronic and progressive con- months. The authors concluded that this regimen showed dition that results from radiation exposure. Retinal vascular promising activity against newly diagnosed glioblastoma endothelial cell damage causes microaneurysms, telang- when compared with historical controls. Based on these iectasias, neovascularization, vitreous hemorrhage, macu- lar edema, and tractional retinal detachment. Radiation results, two randomized trials, CENTRIC and CORE, are currently ongoing to determine the efficacy of cilengitide for retinopathy has been treated by laser photocoagulation, cor- ticosteroids, and anticoagulation, although the management newly diagnosed glioblastoma with or without a methylated 6 Journal of Oncology Table 2: Other antiangiogenesis drugs for recurrent or newly diagnosed malignant gliomas. Target Study Agent Patients RR MPFS 6-PFS MST Ref. Cilengitide (500 mg/day) 41 recurrent GBM 5% 7.9 months 10% 6.5 months Integrin II [73] (2000 mg/day) 40 recurrent GBM 13% 8.1 months 15% 9.9 months 52 Newly diagnosed Integrin I/IIa Cilengitide + RT/TMZ — 8.0 months 69% 16.1 months [74] GBM bFGF II Thalidomide 39 recurrent MG 6% 2.5 months — 7.0 months [75] bFGF II Thalidomide + carmustine 40 recurrent MG 24% 3.3 months 28% — [76] bFGF II Thalidomide + irinotecan 32 recurrent GBM 6% 3.3 months 25% 9.0 months [77] bFGF I Lenalidomide 24 recurrent GBM 0% 1.8 months 13% 6.0 months [78] VEGFR II Cediranib (45 mg/day) 31 recurrent GBM 27% 3.9 months 26% 7.6 months [79] Cediranib (30 mg/day) 325 recurrent GBM — — 16% — VEGFR III Cediranib (20 mg/day) + lomustine — — 35% — [33] Lomustine + placebo — — 26% — 47 newly diagnosed VEGFR II Adjuvant sorafenib + TMZ 13% 6.0 months 50% 12 months [80] GBM VEGFR II Sunitinib 21 recurrent MG 0% 1.6 months — 3.8 months [81] 19 newly diagnosed VEGFR I Vatalanib + RT/TMZ 13% 7.2 months — 16.2 months [82] GBM VEGFR II Pazopanib 35 recurrent GBM 6% 3.0 months 3% 8.8 months [83] PDGFR II Imatinib 31 recurrent GBM 6% 1.7 months 16% 5.2 months [84] Imatinib 120 recurrent GBM — 1.5 months 7% 5.3 months [85] III PDGFR Imatinib + hydroxyurea 120 recurrent GBM — 1.5 months 5% 4.8 months PDGFR R Dasatinib 14 recurrent GBM 0% 0.9 months 0% 2.6 months [86] RR: response rate; MPFS: median progression-free survival; 6-PFS: 6-month progression-free survival; MST: median overall survival time; GBM: glioblastoma multiforme; RT: radiotherapy; TMZ: temozolomide; bFGF: basic fibroblast growth factor; MG: malignant gliomas; VEGFR: vascular endothelial growth factor receptor;PDGFR:platelet-derivedgrowthfactorreceptor; R: retrospective. O -methylguanine-DNA methyltransferase (MGMT) pro- was detected in two patients (6%), and 6-month PFS was 25%, respectively. These results indicate that thalidomide moter [91, 92]. plus cytotoxic agents seem to have a mild antitumor activity 9.2. Thalidomide and Lenalidomide. Thalidomide was devel- for recurrent malignant gliomas patients when compared oped as a sedative drug in 1950s and was withdrawn due with thalidomide alone. to teratogenic effects. However, thalidomide was recently Lenalidomide, a potent structural and functional thali- reported to have an antiangiogenic activity by inhibiting domide analog, has antiangiogenic, anti-inflammatory, and basic fibroblast growth factor (bFGF) [93], which can immunomodulatory activities in preclinical studies [95, 96]. be exploited as an antitumor drug. Several clinical trials This drug is approved by the FDA for myelodysplastic syn- have been performed to assess the efficacy and safety drome with chromosome 5q deletion and multiple myeloma. of thalidomide for vascular tumors including malignant Recently, lenalidomide has been performed for recurrent gliomas. This drug has since been approved by the FDA brain tumors in clinical trials [78, 97]. Fine et al. reported for the treatment of malignant myeloma [94]. Fine et that lenalidomide was well tolerated; however, no objective al. showed a phase II study of thalidomide alone for 39 responses were seen in a phase I study [78]. Median 6-month patients with recurrent malignant gliomas [75]. Thalidomide PFS was 12.5% in recurrent glioblastoma patients. Warren et was well tolerated with modest sedation and constipation, al. conducted a phase I study of lenalidomide for pediatric although median PFS and overall survival were 2.5 months patients with recurrent or progressive brain tumors [97]. and 7.0 months, respectively. Another phase II study of This treatment was well tolerated with the primary toxicity thalidomide combined with carmustine was performed for being myelosuppression. Partial responses were seen in two 40 recurrent malignant gliomas [76]. Although the addition patients (4%) with low-grade gliomas. Because these studies of carmustine seemed to improve the prognosis, the response were phase I trials, further investigations are required to rate and median PFS of combination group were 24% and 3.3 evaluate the antitumor activity for malignant gliomas. months, respectively. Puduvalli et al. reported a phase II trial of thalidomide and irinotecan for 32 recurrent glioblastomas 9.3. VEGF Receptor Tyrosine Kinase Inhibitors (Cediranib, [77]. The combination therapy was well tolerated with mild Sorafenib, Sunitinib, Vatalanib, and Pazopanib). Currently, myelosuppression and sedation. At least a partial response VEGF receptor tyrosine kinase inhibitors are viewed as Journal of Oncology 7 promising antiangiogenic agents in the setting of malignant Despite several trials of VEGF receptor tyrosine kinase gliomas. Cediranib was developed as an oral pan-VEGF inhibitors, the efficacy has not been established. In a receptor tyrosine kinase inhibitor. Preclinical studies showed retrospective study of glioblastoma patients who failed VEGF that cediranib normalized tumor vasculature and decreased receptor tyrosine kinase inhibitors, bevacizumab salvage the edema in glioblastoma, improving the prognosis without therapy still provided benefits with response rate of 21% inhibition of tumor growth [98, 99]. Batchelor et al. and 6-month PFS of 12.5%, respectively [101]. Although conducted a phase II study of cediranib for 31 recurrent there are no comparative studies, VEGF receptor inhibition glioblastoma patients [79]. Patients were administered a therapy may be less effective for malignant gliomas when 45 mg/day dose of cediranib. Partial response according to compared with bevacizumab [102]. the MacDonald criteria was observed in 26.6% of patients, and 6-month PFS was 25.8%. Corticosteroids were reduced 9.4. PDGF Receptor Tyrosine Kinase Inhibitor (Imatinib, Da- or discontinued in 27% of patients. Toxicities were man- satinib, and Tandutinib). The PDGF pathway also plays ageable, and common Grade 3 to 4 toxicities were fatigue, a role in angiogenesis [103]. PDGF receptor inhibitors hypertension, and diarrhea. Furthermore, they showed the (e.g., imatinib, dasatinib, and tandutinib) have been per- changes of growth factors in plasma after cediranib (e.g., formed in clinical trials of malignant gliomas. Imatinib is bFGF, VEGF receptor 1, and matrix metalloproteinase-2), a multitargeted tyrosine kinase inhibitor and blocks PDGF which were associated with treatment response or survival in receptor α,PDGFreceptor β, and c-KIT receptor. Preclinical this therapy. Based on these promising results, the authors study has demonstrated the antitumor effect of imatinib on conducted a phase III study of cediranib for 325 patients glioblastoma cell lines [104]. A phase II study of imatinib with recurrent glioblastoma, and the preliminary results were was performed for 112 recurrent gliomas [84]. The 6-month reported at the 2010 SNO annual meeting [33]. Patients PFS was 16% in glioblastoma, 4.0% in pure/mixed anaplastic were assigned on a 2 : 2 : 1 ratio to cediranib monother- oligodendrogliomas, and 9% in low-grade or anaplastic apy 30 mg/day, combination of cediranib 20 mg/day plus astrocytoma. In 31 glioblastoma patients, response rate was lomustine, and lomustine monotherapy plus placebo groups. 6%, and median survival was 5.2 months, respectively. This The 6-month PFS was 16% in cediranib monotherapy, study indicated that single agent imatinib was well tolerated 34.5% in the combination, and 25.8% in lomustine plus but had limited antitumor activity. A randomized phase III placebo groups, respectively, although the results were not study was conducted for 240 recurrent glioblastoma patients significantly different between these groups. The efficacy of treated by hydroxyurea with or without imatinib [85]. The cediranib monotherapy seems to be less than the initial phase results from the two arms were very similar, and 6-month II study, and the possible reason for this discrepancy is that PFS was 5% in the combination arm and 7% in the imatinib different doses of cediranib were used between two studies. alone arm, respectively. The authors concluded that there Sorafenib and sunitinib are inhibitors of multiple recep- were no clinical benefits from the addition of imatinib. Taken tor tyrosine kinases including VEGF receptor. Sorafenib was together, these results suggest that imatinib is discouraged in approved by the FDA for the treatment of advanced renal cell recurrent glioblastoma patients. carcinoma and hepatocellular carcinoma [100]. Hainsworth Dasatinib and tandutinib are oral molecule inhibitors et al. conducted a phase II trial of concurrent radiotherapy of several targets, including PDGF and c-kit. Dasatinib was and temozolomide followed by adjuvant sorafenib and approved by FDA for the treatment of chronic myelogenous temozolomide for 47 newly diagnosed glioblastomas [80]. leukemia [105]. A retrospective study reported the efficacy This regimen was well tolerated without significant grade of dasatinib for 14 recurrent glioblastomas who failed 3 or 4 toxicities, although median overall survival and PFS bevacizumab therapy [86]. However, objective response rate were 12 months and 6 months, respectively. The authors was 0%, and 6-month PFS was 0%, respectively. Currently, concluded that the addition of sorafenib did not appear a phase II trial of dasatinib (RTOG 0627) is ongoing to to improve the prognosis of these patients. Sunitinib was evaluate the efficacy and safety for recurrent glioblastoma reported in a phase II study of 21 recurrent malignant or gliosarcoma [106]. Combined treatments with tandutinib gliomas [81]. No objective responses were detected, and and bevacizumab are being performed in a phase II study median overall survival and PFS were 3.8 and 1.6 months, for recurrent malignant gliomas [107]. Preliminary results respectively. This study showed that single-agent sunitinib cautioned that neuromuscular junction dysfunction was had insufficient activity for recurrent malignant gliomas. observed in this regimen. Vatalanib is a small molecule inhibitor of VEGF receptor, Although PDGF receptor inhibitors are effective in PDGF receptor, and c-kit. In a phase I trial, vatalanib preclinical studies, it is still unclear whether these drugs was added to the standard regimen of temozolomide and have an antitumor effect in malignant glioma patients. One radiotherapy for 19 newly diagnosed glioblastomas [82]. possible reason for the limited antitumor effect is that PDGF Response rate was 13%, and median overall survival was 16.2 receptor inhibitor such as imatinib cannot cross the blood- months, respectively. Pazopanib is a multitargeted tyrosine brain barrier via the P-glycoprotein efflux pump [108]. kinase inhibitor, including VEGF receptor-1, -2, and -3. A phase II trial of pazopanib was performed for recurrent 10. Summary and Perspectives glioblastoma [83]. However, this drug did not have enough antitumor activity with response rate of 5.7% and median Despite advances in treatment therapeutics, patients with PFS of 3.0 months. malignant gliomas still have poor prognosis. A better 8 Journal of Oncology understanding of tumor angiogenesis has allowed us to aggressive with rebound edema [38]. Preclinical study target VEGF in antiangiogenic therapy. Bevacizumab is showed that other angiogenic factors, such as fibroblast considered as a well-established antiangiogenic therapy in growth factors and PDGF, can compensate for the loss of severalsolid tumors.AphaseIItrialsofrecurrent glioblas- VEGF activity under bevacizumab treatment [42]. A novel toma showed favorable response rates (28% to 57%) and therapeutic strategy is required to overcome the resistance to 6-month PFS (29% to 50.3%) [11–13]. Based on these bevacizumab of malignant gliomas. promising results, bevacizumab was approved by the FDA for An accurate assessment of tumor response by conven- the recurrent glioblastoma. Regarding recurrent anaplastic tional modality is limited in antiangiogenic therapy due gliomas, bevacizumab has been reported to be effective to alterations in tumor blood vessels [44]. The Response as well [28, 29]. Additional therapies (e.g., chemotherapy, Assessment in Neuro-Oncology Working Group proposed targeting therapy, and radiotherapy) to bevacizumab have that T2 and FLAIR changes on MRI should include the been reported for recurrent malignant gliomas, and these response criteria [47]. FDG-FLT is also expected to accurately results were encouraging. However, the timing, dosing, and evaluate the treatment response in bevacizumab due to its the ideal treatment partners of bevacizumab have remained ability to detect cell proliferation [48]. controversial. Further investigations are warranted to estab- Tumor VEGF expressions or circulating markers poten- lish an antiangiogenic treatment for recurrent malignant tially predict the prognosis in malignant glioma treated gliomas. by bevacizumab, although the rational biomarker has not Bevacizumab is expected to be on the frontline treatment been established. Novel biological markers are required to of patients with glioblastoma. Phase II trials have reported investigate, providing a personalized treatment that selects the addition of bevacizumab to standard temozolomide the patients who can benefit from bevacizumab. and radiotherapy regimen for newly diagnosed glioblastoma Although several limitations on antiangiogenic therapy [14, 15]. However, the authors concluded that this regimen have been reported, this treatment is expected to improve improved PFS but not overall survival when compared the prognosis of malignant gliomas. Further investigation is with control group [14]. 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Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas

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Copyright © 2012 Katsuyuki Shirai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Journal of Oncology Volume 2012, Article ID 193436, 12 pages doi:10.1155/2012/193436 Review Article Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas Katsuyuki Shirai, Michael R. Siedow, and Arnab Chakravarti Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA Correspondence should be addressed to Arnab Chakravarti, arnab.chakravarti@osumc.edu Received 1 May 2011; Accepted 24 May 2011 Academic Editor: Arkadiusz Dudek Copyright © 2012 Katsuyuki Shirai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression- free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas. 1. Introduction shown to regulate tumor angiogenesis [10]. Bevacizumab was developed as a humanized monoclonal antibody against Malignant gliomas such as glioblastoma and anaplastic VEGF. Clinical trials of recurrent glioblastoma showed gliomas are the most common primary brain tumors in benefits of bevacizumab in response rate and PFS [11–13]. adults [1]. Temozolomide and radiotherapy have been Based on these favorable results, bevacizumab was approved demonstrated to improve overall survival in glioblastoma by the US Food and Drug Administration (FDA) for patients [2–4]. Despite advances in diagnosis and therapy, recurrent glioblastoma. For newly diagnosed glioblastoma, prognosis remains poor with a median overall survival of phase II trials showed that the addition of bevacizumab to temozolomide and radiotherapy improves PFS [14, 15]. 12 to 15 months in glioblastoma due to the resistance to radiotherapy and chemotherapy. Although anaplastic Other antiangiogenic drugs have also been investigated and gliomas tend to respond well to these treatments, the median used in several clinical studies [16]. In this paper, we focus on survival time is 2 to 3 years [5, 6]. The prognosis of biological and clinical findings of antiangiogenesis therapy recurrent malignant gliomas is dismal with the median for malignant gliomas. overall survival and progression-free survival (PFS) of 7.5 months and 2.5 months, respectively [7]. More effective 2. Biological Aspects of Antiangiogenic therapeutic strategies are needed for these patients. Therapy for Glioblastoma Malignant gliomas are characterized by vascular prolifer- ation or angiogenesis [8, 9]. Vascular endothelial growth fac- Advances in molecular biology have provided pathogenesis tor (VEGF) is highly expressed in glioblastoma and has been of malignant gliomas. Several clinical and preclinical studies 2 Journal of Oncology proposed that tumor-related blood vessel, called “angiogene- reduce steroid dose. Given the efficacy of bevacizumab for sis”, is required for solid tumor growth, including malignant recurrent glioblastoma in the clinical setting, bevacizumab gliomas [10, 16]. Endothelial proliferation is a marker of monotherapy has since been approved by the FDA. histological grading systems for malignant gliomas because of an association between a degree of microvascularity and 3.2. Toxicity Profile of Bevacizumab. Since VEGF plays an biologic aggressiveness [17]. Glioblastoma is particularly important role in vascular function and physiological angio- characterized by vascular proliferation and the extent of genesis, its inhibition via bevacizumab has been reported necrosis. These findings indicate that tumor antiangiogenesis to cause serious adverse events [34]. The first phase II is a promising candidate to inhibit the growth of malignant study of recurrent glioblastoma treated by bevacizumab and gliomas. VEGF, a critical mediator of angiogenesis, has irinotecan reported that five patients (14%) discontinued emerged as a novel target of antiangiogenic therapy. Glioblas- treatment due to central nervous system (CNS) hemorrhage, toma cells have been shown to secrete VEGF, resulting in deep venous thrombosis, and pulmonary emboli [11]. No the endothelial proliferation and tumor survival in vivo [18]. fatal adverse events were reported in this study. BRAIN VEGF is expressed in malignant gliomas and is associated study reported the detailed information on adverse events of with tumor grade and vascularity [19, 20]. Therefore, it is bevacizumab [12]. Grade ≥3 adverse events were observed postulated that antiangiogenesis suppresses blood flow and in 65.8% and 46.4% of bevacizumab plus irinotecan and inhibits the tumor growth. Monoclonal antibodies against bevacizumab alone groups, respectively. The most com- VEGF were shown to inhibit the growth of glioma cells in mon causes of grade ≥3 adverse events were convulsion, vivo [21]. A VEGF inhibitor directly affects glioma stem hypertension, neutropenia, and fatigue. CNS hemorrhages cells that are more resistant to chemotherapy and radio- of any grades were observed in five patients (3.0%). There therapy [22]. Furthermore, antiangiogenesis can normalize were one fatal adverse event (1.3%) in bevacizumab plus tumor vasculature and decrease interstitial fluid pressure, irinotecan group and two (2.3%) in bevacizumab alone providing an improved delivery of chemotherapeutics and group, respectively. Selecting appropriate patients, early oxygen. Consequently, antiangiogenesis is expected to work assessment of toxicity, and adequate management should be synergistically with radiotherapy and chemotherapy [23, 24]. required to reduce the serious adverse events of bevacizumab. Given these findings, VEGF inhibitors are expected to be a Arterial and venous thromboses are generally reported novel antiangiogenic therapy for malignant gliomas. in treatment of antiangiogenesis therapy, although the inherent risk of these thromboses is higher among malignant glioma patients. A retrospective study of 9849 patients with 3. The Efficacy and Safety of Bevacizumab for malignant gliomas showed that 2-year cumulative incidence Recurrent Malignant Gliomas of symptomatic venous thromboembolism was 7.5% [35]. 3.1. Bevacizumab for Recurrent Glioblastoma. Bevacizumab Further studies are necessary to evaluate the additional was developed as a humanized monoclonal antibody to bind risk of thrombosis in malignant glioma patients treated by VEGF-A, preventing the interaction and activation of VEGF bevacizumab. receptor tyrosine kinases [25, 26]. This drug is approved by Recently, a meta-analysis of randomized control trials in several tumor types showed that bevacizumab in com- the FDA and is in clinical use for the treatment of colorectal cancer, nonsmall cell lung cancer, breast cancer, renal cell bination with chemotherapy increases fatal adverse events carcinoma, and glioblastoma [27]. Table 1 shows several when compared with chemotherapy alone [36]. The overall clinical studies of bevacizumab for recurrent malignant incidence of fatal adverse events was 2.5% in bevacizumab glioma patients. therapy with the common causes being hemorrhage, neu- The first phase II trial for 35 recurrent glioblastoma tropenia, and gastrointestinal tract perforation. Interestingly, was performed to investigate the efficacy of intravenous the type of chemotherapeutic agents was significantly associ- administration of bevacizumab and irinotecan, a topoiso- ated with relative risk of fatal adverse events. The addition merase 1 inhibitor [11]. The 6-month PFS was 46%, and of bevacizumab was associated with increased fatal adverse median overall survival was 10.5 months, respectively. At events in patients receiving taxanes or platinum agents (3.3% least a partial response was observed in 57% of patients. A versus 1.0%) but not in those receiving other agents (0.8% versus 0.9%). In clinical trials of malignant gliomas, the larger, randomized, noncomparative phase II study, called the BRAIN study, was performed using bevacizumab with addition of irinotecan or temozolomide to bevacizumab has or without irinotecan for 167 recurrent glioblastoma. In often been performed and may be associated with lower fatal this study, the response rates were 28.2% and 37.8%, adverse events. However, this meta-analysis did not include and 6-month PFS were 42.6% and 50.3% in bevacizumab the trials of brain tumors, and further investigations are alone and bevacizumab plus irinotecan groups, respectively required to evaluate the fatal adverse events of bevacizumab [12]. Another phase II study of bevacizumab alone for 48 and chemotherapy in malignant gliomas. recurrent glioblastomas showed that response rate was 35% and 6-month PFS was 29%, respectively [13]. These results 3.3. Bevacizumab for Recurrent Anaplastic Gliomas. Anaplas- were more favorable than a previous database of 8 negative tic gliomas have a slightly better prognosis than glioblas- trials having 6-month PFS of 15% for recurrent glioblas- toma [37], and the median survival time is 2 to 3 years. toma patients [7]. Furthermore, an additional advantage of However, there are no standard treatments for progression bevacizumab is its ability to decrease tumor edema and to or recurrence of anaplastic gliomas, and a novel treatment Journal of Oncology 3 Table 1: Bevacizumab for recurrent or newly malignant gliomas. Study Agents Patients RR MPFS 6-PFS MST Ref. Phase II Bevacizumab + irinotecan 35 recurrent GBM 57% 6 months 46% 10.5 months [11] Bevacizumab 85 recurrent GBM 28% 4.2 months 43% 9.2 months Phase II [12] Bevacizumab + irinotecan 82 recurrent GBM 38% 5.6 months 50% 8.7 months Phase II Bevacizumab 48 recurrent GBM 35% 4 months 29% 7.7 months [13] 23 recurrent GBM 61% 5.0 months 30% 10 months Phase II Bevacizumab + irinotecan [28] 9 recurrent AG 67% 7.5 months 56% Not reached Phase II Bevacizumab + irinotecan 33 recurrent AG 61% 7.5 months 55% 16.3 months [29] 20 recurrent GBM 50% 7.3 months 65% 12.5 months [30] Retrospective Bevacizumab + SRT 5 recurrent AG 60% 7.5 months 60% 16.5 months SRS + bevacizumab — 5.2 months — 11.2 months Retrospective [31] 49 recurrent GBM SRS + other drugs — 2.1 months — 3.9 months Bevacizumab + erlotinib 25 recurrent GBM 48% 4.5 months 28% 10.5 months Phase II [32] 32 recurrent AG 31% 5.9 months 44% 17.8 months 70 newly diagnosed Phase II Bevacizumab + RT/TMZ — 13.6 months 88% 19.6 months [14] GBM 125 newly diagnosed [15] Phase II Bevacizumab + RT/TMZ — 13.8 months 87% — GBM Adjuvant bevacizumab 125 newly diagnosed Phase II — 13.8 months — 21.3 months [33] + irinotecan + TMZ GBM RR: response rate; MPFS: median progression-free survival; 6-PFS: 6-month progression-free survival; MST: median overall survival time; GBM: glioblastoma multiforme; AG: anaplastic gliomas; SRT: stereotactic radiotherapy; SRS: stereotactic radiosurgery; RT: radiotherapy; TMZ: temozolomide. strategy is needed. Recent studies have shed light on the evaluated the efficacy and safety of stereotactic radiosurgery antiangiogenic therapy in recurrent anaplastic gliomas. A and adjuvant bevacizumab for recurrent malignant gliomas phase II study of bevacizumab and irinotecan was performed [31]. Median PFS was 5.2 months, and 1-year overall survival in 23 glioblastoma and 9 anaplastic gliomas [28]. The was 50% in glioblastoma patients treated by radiosurgery response rates were 61% and 67%, and 6-month PFS were and adjuvant bevacizumab. These results were significantly 30% and 56% in glioblastoma and anaplastic gliomas, better than radiosurgery and other drugs. The authors con- respectively. Another phase II trial was conducted for 33 cluded that salvage radiosurgery and bevacizumab improve anaplastic gliomas treated by bevacizumab and irinotecan outcomes in recurrent malignant gliomas. [29]. This study included 25 anaplastic astrocytomas and A phase II study of bevacizumab plus erlotinib, an epider- 8 anaplastic oligodendrogliomas. The 6-month PFS and mal growth factor receptor (EGFR) tyrosine kinase inhibitor, overall survivals were 55% and 79%, respectively. At least was performed for patients with recurrent malignant gliomas a partial response was observed in 61% of patients, and [32]. This study included 25 glioblastomas and 32 anaplastic dose of dexamethasone was decreased in 67%. These findings gliomas. The response rate and 6-month PFS were 48% indicate that bevacizumab and irinotecan can be an active and 28% for glioblastoma and 31% and 44% for anaplastic regimen for recurrent anaplastic gliomas. gliomas, respectively. Grade 1 or 2 rash, mucositis, diarrhea, and fatigue were the most common adverse events. The authors concluded that treatment was tolerated, but the 3.4. Additional Treatment to Bevacizumab for Recurrent additional benefits of erlotinib were unclear when compared Malignant Gliomas. The addition of targeting therapy or with historical bevacizumab-containing regimens. These radiotherapy to bevacizumab has been performed for recur- studies indicate that additional therapy to bevacizumab can rent malignant gliomas. Gutin et al. retrospectively analyzed be promising strategy, although it is still unclear which bevacizumab and stereotactic radiotherapy (30 Gy in 5 frac- agent has the efficacy in combination with bevacizumab for tions) for 25 recurrent malignant gliomas [30]. There were 20 glioblastomas and 5 anaplastic gliomas in this study with malignant gliomas. Further studies are required to establish the additional agents to bevacizumab. all patients receiving prior radiotherapy. Response rate was 50%, and 6-month PFS was 65% in glioblastoma patients. Three patients (12%) discontinued treatment due to tumor 4. Resistance to Bevacizumab hemorrhage, wound dehiscence, and bowel perforation, although no radiation necrosis was detected. The authors In the maintenance of bevacizumab, patients with malig- concluded that treatment was well tolerated and beneficial nant gliomas inevitably experience tumor recurrence. Fur- for recurrent malignant gliomas. Cuneo et al. retrospectively thermore, recurrent tumors after bevacizumab failure are 4 Journal of Oncology reported to be more aggressive with rebound edema [38]. 6. Biological Markers Predicting Response Although additional agents to bevacizumab have been A variety of biomarkers predicting the efficacy of beva- attempted for patients after bevacizumab failure, disease cizumab have been reported in several tumor types including prognosis was extremely poor with median PFS of 37.5 days malignant gliomas [51]. These predictive biomarkers are and 6-month PFS of 2%, respectively [39]. The authors expected to lead to a personalized therapy that selects concluded that alternative strategies should be considered patients who can benefit from bevacizumab. Sathornsumetee for these patients. De Groot et al. showed that bevacizumab et al. examined several biological markers in recurrent induced a particularly invasive tumor phenotype expressing malignant gliomas treated by bevacizumab and irinotecan insulin-like growth factor binding protein-2 and matrix [52]. High VEGF expression was significantly associated metalloprotease-2 in glioblastoma [40]. with higher radiographic response (P = 0.024), and high Preclinical studies indicated that alternative pro-angi- carbonic anhydrase 9 expression predicted poor overall ogenic signaling pathways are upregulated in resistance to survival (P = 0.016). Higher hypoxia-inducible factor-2 antiangiogenic therapies [41]. These other angiogenic factors alpha and VEGF receptor-2 expressions were also reported such as fibroblast growth factors and platelet-derived growth to be associated with poor survival in recurrent malignant factors (PDGF) can compensate for the loss of VEGF activ- gliomas treated by bevacizumab and erlotinib [32]. ity under bevacizumab treatment [42]. Additional agents Recently, circulating VEGF concentrations are reported inhibiting other antiangiogenic pathways may suppress these to predict the prognosis in solid tumors treated by beva- resistances, and further clinical and animal studies are clearly cizumab [51, 53]. The measurement of circulating proteins required to overcome the resistance of bevacizumab. is an attractive strategy since blood is easily accessible and the assay is inexpensive. Circulating VEGF concentrations are expected to reflect VEGF-dependent angiogenesis and 5. Imaging of Response to to predict the benefit from bevacizumab [51]. Gururangan Antiangiogenic Therapy et al. examined the VEGFR-2 phosphorylation in peripheral blood mononuclear cells in recurrent malignant gliomas Most studies defined partial and complete responses as radi- and diffuse brainstem glioma treated by bevacizumab ological objective response according to McDonald criteria [54]. They showed that circulating VEGFR-2 was inhibited that are based on contrast-enhanced CT or MRI [43]. How- by bevacizumab, but they did not show information on ever, an accurate assessment of tumor response by conven- whether it is a prognostic biomarker. These clinical trials tional modality is limited, since bevacizumab directly alters have provided some potential predictive markers (e.g. tumor tumor blood vessels [44]. As a result of this, response rate and VEGF expression or circulating markers), which require a 6-month PFS are debatable as a measure of antitumor activ- phase III study for proper evaluation [55]. ity [44]. Norden et al. reported that bevacizumab suppressed enhancing tumor recurrence, but not nonenhancing and 7. Addition of Bevacizumab to infiltrative tumor growth, indicating that bevacizumab may Temozolomide and Radiotherapy for change the recurrence patterns of malignant gliomas [45]. Iwamoto et al. reported that contrast-enhanced MRI did not Newly Diagnosed Glioblastoma adequately evaluate disease status, whereas nonenhancing Several clinical studies have been performed to evaluate tumor recurrence was significantly associated with overall the safety and efficacy of the addition of bevacizumab for survival in recurrent glioblastoma treated by bevacizumab newly diagnosed glioblastoma (Table 1). Lai et al. reported [46]. Given these findings, The Response Assessment in a phase II study of the addition of bevacizumab to the Neuro-Oncology Working Group was established to develop standard treatment of temozolomide and radiotherapy for the new response criteria for clinical trials of brain tumors 70 newly diagnosed glioblastomas [14]. Bevacizumab was [47]. They proposed to incorporate T2 and fluid-attenuated intravenously administered every 2 weeks from the first day inversion recovery (FLAIR) changes on MRI to assess the of treatment. The median overall survival and PFS were infiltrative pattern progression of malignant gliomas. 19.6 and 13.6 months, respectively. The authors concluded Other studies have looked into establishing a reliable that the addition of bevacizumab improved PFS but not radiological modality in antiangiogenesis therapy. Positron overall survival when compared with a control group emission tomography (PET) using [ F] fluorothymidine treated with first-line temozolomide and radiotherapy who (FLT) offers noninvasive assessment of cell proliferation [48]. had mostly received bevacizumab at recurrence. Another The response measured by FLT-PET significantly predicted phase II study also reported preliminary results on the the overallsurvivalinrecurrent glioblastoma treatedby addition of bevacizumab to the standard temozolomide and bevacizumab (P = 0.061) [49]. Recently, Ellingson et al. radiotherapy regimen in 125 newly diagnosed glioblastomas reported that relative nonenhancing tumor ratio, the ratio [15]. In this study, toxicity was minimal, and most patients of FLAIR to contrast-enhancing volume, was predictive for (90%) continued treatment, with median PFS of 13.8 overall survival and PFS in the treatment of bevacizumab for months. Recently, Desjardins et al. reported a phase II study of bevacizumab in combination with temozolomide plus recurrent glioblastoma [50]. Further studies are warranted to establish the imaging modality to evaluate the response to radiotherapy followed by bevacizumab, temozolomide, and irinotecan for 125 newly diagnosed glioblastomas at the antiangiogenic therapy and to predict the prognosis. Journal of Oncology 5 Society for Neuro-Oncology (SNO) annual meeting in 2010 is still challenging [61]. Bevacizumab has been expected to [33]. This study had median overall survival of 21.3 months be a therapeutic modality for radiation retinopathy. Finger and PFS of 13.8 months, respectively. These studies showed reported that intravitreal injection of bevacizumab was effec- encouraging results; however, it is still unclear whether the tive for retinal hemorrhage, exudation, and edema, which addition of bevacizumab to standard temozolomide and improved visual acuity of patients [69]. There were no ocular radiotherapy can improve the overall survival. and systemic side effects by bevacizumab. Furthermore, the Currently, two randomized phase III trials, ROTG 0825 authors recently showed that intravitreal bevacizumab was and AVAGLIO, are ongoing for newly diagnosed glioblas- effective for radiation optic neuropathy [70]. toma treated by temozolomide and radiotherapy with or Although these results indicate that some radiation without bevacizumab [56, 57]. These studies will show the vasculopathies are potentially treatable by bevacizumab, role of bevacizumab in frontline treatment in glioblastoma exacerbation of radiation necrosis by this drug was also patients. reported [71]. It is still unclear how bevacizumab affects the radiation adverse events. Meticulous followup is required 8. The Effect of Bevacizumab on when bevacizumab is administered after radiotherapy. Ani- Radiation Adverse Events mal models of radiation necrosis are needed to investigate the mechanism of bevacizumab. Bevacizumab has been reported to affect the specific adverse events of radiotherapy [58, 59]. Sherman et al. reported 9. Other Antiangiogenic Drugs for that six glioblastoma patients developed severe radiation optic neuropathy following bevacizumab [58]. All of them Malignant Gliomas received 60 Gy in 30 fractions in the initial treatment. VEGF has been shown to be the main player in tumor angio- Patients received a median of 7.5 doses of bevacizumab genesis, and its inhibitor, bevacizumab, has been thoroughly followed by onset of visual symptoms. Although the detailed investigated in clinical and animal studies. Other drugs such mechanism remains unclear, the authors indicated that as pan VEGF receptor tyrosine kinase inhibitors have also bevacizumab decreases optic nerve tolerance to radiation. been reported to inhibit VEGF pathways. Several biological Another case series study reported that bevacizumab induced pathways including integrin, fibroblast growth factor, and optic neuropathy and Brown-Sequard syndrome after irra- PDGF also are associated with the angiogenesis. Currently, diation [59]. The authors hypothesized that bevacizumab following radiotherapy inhibits VEGF-dependent repair of several types of antiangiogenic drugs have been investigated normal neural tissue. and used in clinical trials for recurrent as well as newly In contrast, bevacizumab has been reported to be diagnosed glioblastoma [72]. In this section, we review these effective for the management of radiation necrosis and drugs and the results of clinical trials (Table 2). retinopathy [60, 61]. Radiation necrosis is a serious com- plication of radiotherapy and includes extended edema. 9.1. Cilengitide. Cilengitide competitively binds αvβ3and Pathological findings show that endothelial cell dysfunction αvβ5 integrin receptors that are expressed on tumor cells causes tissue hypoxia and necrosis with the local cytokine and activated endothelial cells during angiogenesis. Cilen- release, including VEGF [62, 63]. Corticosteroids, surgery, gitide can directly inhibit the growth of integrin-expressing anticoagulation, and hyperbaric oxygen have been per- tumor cells and indirectly act as an antiangiogenesis agent formed, although there is no evidence to support routine use [87, 88]. Glioblastoma cells express integrin receptors, and in clinical practice [64]. Retrospective studies have shown cilengitide has shown an antitumor effect in glioblastoma that bevacizumab decreased the edema and improved the xenografts in vivo [89, 90]. A randomized phase II study clinical outcome in patients with radiation necrosis [60, 65– of 81 recurrent glioblastoma was performed to determine 67]. Interestingly, a small randomized trial was recently the efficacy and safety of cilengitide [73]. The patients performed to demonstrate this effect [68]. Patients having were randomly assigned to receive either 500 or 2000 mg radiation necrosis with progressive neurologic symptoms of cilengitide twice weekly. Patients treated with 2000 mg were assigned to bevacizumab (n = 14) and placebo groups showed a trend toward better results with 6-month PFS (n = 7). Bevacizumab was intravenously administered of 15%. The treatment was well tolerated, and significant every 3 weeks for 12 weeks. Radiological response and hematologic toxicity was uncommon. A phase I/IIa study of improvement of neurological symptoms were observed in cilengitide combined with temozolomide and radiotherapy the bevacizumab treated group but not in placebo group. The for 52 newly diagnosed glioblastoma patients was conducted authors concluded that the class I evidence of bevacizumab [74]. This combination therapy was well tolerated without efficacy for radiation necrosis was shown in this study. additional toxicity, and median overall survival was 16.1 Radiation retinopathy is a chronic and progressive con- months. The authors concluded that this regimen showed dition that results from radiation exposure. Retinal vascular promising activity against newly diagnosed glioblastoma endothelial cell damage causes microaneurysms, telang- when compared with historical controls. Based on these iectasias, neovascularization, vitreous hemorrhage, macu- lar edema, and tractional retinal detachment. Radiation results, two randomized trials, CENTRIC and CORE, are currently ongoing to determine the efficacy of cilengitide for retinopathy has been treated by laser photocoagulation, cor- ticosteroids, and anticoagulation, although the management newly diagnosed glioblastoma with or without a methylated 6 Journal of Oncology Table 2: Other antiangiogenesis drugs for recurrent or newly diagnosed malignant gliomas. Target Study Agent Patients RR MPFS 6-PFS MST Ref. Cilengitide (500 mg/day) 41 recurrent GBM 5% 7.9 months 10% 6.5 months Integrin II [73] (2000 mg/day) 40 recurrent GBM 13% 8.1 months 15% 9.9 months 52 Newly diagnosed Integrin I/IIa Cilengitide + RT/TMZ — 8.0 months 69% 16.1 months [74] GBM bFGF II Thalidomide 39 recurrent MG 6% 2.5 months — 7.0 months [75] bFGF II Thalidomide + carmustine 40 recurrent MG 24% 3.3 months 28% — [76] bFGF II Thalidomide + irinotecan 32 recurrent GBM 6% 3.3 months 25% 9.0 months [77] bFGF I Lenalidomide 24 recurrent GBM 0% 1.8 months 13% 6.0 months [78] VEGFR II Cediranib (45 mg/day) 31 recurrent GBM 27% 3.9 months 26% 7.6 months [79] Cediranib (30 mg/day) 325 recurrent GBM — — 16% — VEGFR III Cediranib (20 mg/day) + lomustine — — 35% — [33] Lomustine + placebo — — 26% — 47 newly diagnosed VEGFR II Adjuvant sorafenib + TMZ 13% 6.0 months 50% 12 months [80] GBM VEGFR II Sunitinib 21 recurrent MG 0% 1.6 months — 3.8 months [81] 19 newly diagnosed VEGFR I Vatalanib + RT/TMZ 13% 7.2 months — 16.2 months [82] GBM VEGFR II Pazopanib 35 recurrent GBM 6% 3.0 months 3% 8.8 months [83] PDGFR II Imatinib 31 recurrent GBM 6% 1.7 months 16% 5.2 months [84] Imatinib 120 recurrent GBM — 1.5 months 7% 5.3 months [85] III PDGFR Imatinib + hydroxyurea 120 recurrent GBM — 1.5 months 5% 4.8 months PDGFR R Dasatinib 14 recurrent GBM 0% 0.9 months 0% 2.6 months [86] RR: response rate; MPFS: median progression-free survival; 6-PFS: 6-month progression-free survival; MST: median overall survival time; GBM: glioblastoma multiforme; RT: radiotherapy; TMZ: temozolomide; bFGF: basic fibroblast growth factor; MG: malignant gliomas; VEGFR: vascular endothelial growth factor receptor;PDGFR:platelet-derivedgrowthfactorreceptor; R: retrospective. O -methylguanine-DNA methyltransferase (MGMT) pro- was detected in two patients (6%), and 6-month PFS was 25%, respectively. These results indicate that thalidomide moter [91, 92]. plus cytotoxic agents seem to have a mild antitumor activity 9.2. Thalidomide and Lenalidomide. Thalidomide was devel- for recurrent malignant gliomas patients when compared oped as a sedative drug in 1950s and was withdrawn due with thalidomide alone. to teratogenic effects. However, thalidomide was recently Lenalidomide, a potent structural and functional thali- reported to have an antiangiogenic activity by inhibiting domide analog, has antiangiogenic, anti-inflammatory, and basic fibroblast growth factor (bFGF) [93], which can immunomodulatory activities in preclinical studies [95, 96]. be exploited as an antitumor drug. Several clinical trials This drug is approved by the FDA for myelodysplastic syn- have been performed to assess the efficacy and safety drome with chromosome 5q deletion and multiple myeloma. of thalidomide for vascular tumors including malignant Recently, lenalidomide has been performed for recurrent gliomas. This drug has since been approved by the FDA brain tumors in clinical trials [78, 97]. Fine et al. reported for the treatment of malignant myeloma [94]. Fine et that lenalidomide was well tolerated; however, no objective al. showed a phase II study of thalidomide alone for 39 responses were seen in a phase I study [78]. Median 6-month patients with recurrent malignant gliomas [75]. Thalidomide PFS was 12.5% in recurrent glioblastoma patients. Warren et was well tolerated with modest sedation and constipation, al. conducted a phase I study of lenalidomide for pediatric although median PFS and overall survival were 2.5 months patients with recurrent or progressive brain tumors [97]. and 7.0 months, respectively. Another phase II study of This treatment was well tolerated with the primary toxicity thalidomide combined with carmustine was performed for being myelosuppression. Partial responses were seen in two 40 recurrent malignant gliomas [76]. Although the addition patients (4%) with low-grade gliomas. Because these studies of carmustine seemed to improve the prognosis, the response were phase I trials, further investigations are required to rate and median PFS of combination group were 24% and 3.3 evaluate the antitumor activity for malignant gliomas. months, respectively. Puduvalli et al. reported a phase II trial of thalidomide and irinotecan for 32 recurrent glioblastomas 9.3. VEGF Receptor Tyrosine Kinase Inhibitors (Cediranib, [77]. The combination therapy was well tolerated with mild Sorafenib, Sunitinib, Vatalanib, and Pazopanib). Currently, myelosuppression and sedation. At least a partial response VEGF receptor tyrosine kinase inhibitors are viewed as Journal of Oncology 7 promising antiangiogenic agents in the setting of malignant Despite several trials of VEGF receptor tyrosine kinase gliomas. Cediranib was developed as an oral pan-VEGF inhibitors, the efficacy has not been established. In a receptor tyrosine kinase inhibitor. Preclinical studies showed retrospective study of glioblastoma patients who failed VEGF that cediranib normalized tumor vasculature and decreased receptor tyrosine kinase inhibitors, bevacizumab salvage the edema in glioblastoma, improving the prognosis without therapy still provided benefits with response rate of 21% inhibition of tumor growth [98, 99]. Batchelor et al. and 6-month PFS of 12.5%, respectively [101]. Although conducted a phase II study of cediranib for 31 recurrent there are no comparative studies, VEGF receptor inhibition glioblastoma patients [79]. Patients were administered a therapy may be less effective for malignant gliomas when 45 mg/day dose of cediranib. Partial response according to compared with bevacizumab [102]. the MacDonald criteria was observed in 26.6% of patients, and 6-month PFS was 25.8%. Corticosteroids were reduced 9.4. PDGF Receptor Tyrosine Kinase Inhibitor (Imatinib, Da- or discontinued in 27% of patients. Toxicities were man- satinib, and Tandutinib). The PDGF pathway also plays ageable, and common Grade 3 to 4 toxicities were fatigue, a role in angiogenesis [103]. PDGF receptor inhibitors hypertension, and diarrhea. Furthermore, they showed the (e.g., imatinib, dasatinib, and tandutinib) have been per- changes of growth factors in plasma after cediranib (e.g., formed in clinical trials of malignant gliomas. Imatinib is bFGF, VEGF receptor 1, and matrix metalloproteinase-2), a multitargeted tyrosine kinase inhibitor and blocks PDGF which were associated with treatment response or survival in receptor α,PDGFreceptor β, and c-KIT receptor. Preclinical this therapy. Based on these promising results, the authors study has demonstrated the antitumor effect of imatinib on conducted a phase III study of cediranib for 325 patients glioblastoma cell lines [104]. A phase II study of imatinib with recurrent glioblastoma, and the preliminary results were was performed for 112 recurrent gliomas [84]. The 6-month reported at the 2010 SNO annual meeting [33]. Patients PFS was 16% in glioblastoma, 4.0% in pure/mixed anaplastic were assigned on a 2 : 2 : 1 ratio to cediranib monother- oligodendrogliomas, and 9% in low-grade or anaplastic apy 30 mg/day, combination of cediranib 20 mg/day plus astrocytoma. In 31 glioblastoma patients, response rate was lomustine, and lomustine monotherapy plus placebo groups. 6%, and median survival was 5.2 months, respectively. This The 6-month PFS was 16% in cediranib monotherapy, study indicated that single agent imatinib was well tolerated 34.5% in the combination, and 25.8% in lomustine plus but had limited antitumor activity. A randomized phase III placebo groups, respectively, although the results were not study was conducted for 240 recurrent glioblastoma patients significantly different between these groups. The efficacy of treated by hydroxyurea with or without imatinib [85]. The cediranib monotherapy seems to be less than the initial phase results from the two arms were very similar, and 6-month II study, and the possible reason for this discrepancy is that PFS was 5% in the combination arm and 7% in the imatinib different doses of cediranib were used between two studies. alone arm, respectively. The authors concluded that there Sorafenib and sunitinib are inhibitors of multiple recep- were no clinical benefits from the addition of imatinib. Taken tor tyrosine kinases including VEGF receptor. Sorafenib was together, these results suggest that imatinib is discouraged in approved by the FDA for the treatment of advanced renal cell recurrent glioblastoma patients. carcinoma and hepatocellular carcinoma [100]. Hainsworth Dasatinib and tandutinib are oral molecule inhibitors et al. conducted a phase II trial of concurrent radiotherapy of several targets, including PDGF and c-kit. Dasatinib was and temozolomide followed by adjuvant sorafenib and approved by FDA for the treatment of chronic myelogenous temozolomide for 47 newly diagnosed glioblastomas [80]. leukemia [105]. A retrospective study reported the efficacy This regimen was well tolerated without significant grade of dasatinib for 14 recurrent glioblastomas who failed 3 or 4 toxicities, although median overall survival and PFS bevacizumab therapy [86]. However, objective response rate were 12 months and 6 months, respectively. The authors was 0%, and 6-month PFS was 0%, respectively. Currently, concluded that the addition of sorafenib did not appear a phase II trial of dasatinib (RTOG 0627) is ongoing to to improve the prognosis of these patients. Sunitinib was evaluate the efficacy and safety for recurrent glioblastoma reported in a phase II study of 21 recurrent malignant or gliosarcoma [106]. Combined treatments with tandutinib gliomas [81]. No objective responses were detected, and and bevacizumab are being performed in a phase II study median overall survival and PFS were 3.8 and 1.6 months, for recurrent malignant gliomas [107]. Preliminary results respectively. This study showed that single-agent sunitinib cautioned that neuromuscular junction dysfunction was had insufficient activity for recurrent malignant gliomas. observed in this regimen. Vatalanib is a small molecule inhibitor of VEGF receptor, Although PDGF receptor inhibitors are effective in PDGF receptor, and c-kit. In a phase I trial, vatalanib preclinical studies, it is still unclear whether these drugs was added to the standard regimen of temozolomide and have an antitumor effect in malignant glioma patients. One radiotherapy for 19 newly diagnosed glioblastomas [82]. possible reason for the limited antitumor effect is that PDGF Response rate was 13%, and median overall survival was 16.2 receptor inhibitor such as imatinib cannot cross the blood- months, respectively. Pazopanib is a multitargeted tyrosine brain barrier via the P-glycoprotein efflux pump [108]. kinase inhibitor, including VEGF receptor-1, -2, and -3. A phase II trial of pazopanib was performed for recurrent 10. Summary and Perspectives glioblastoma [83]. However, this drug did not have enough antitumor activity with response rate of 5.7% and median Despite advances in treatment therapeutics, patients with PFS of 3.0 months. malignant gliomas still have poor prognosis. A better 8 Journal of Oncology understanding of tumor angiogenesis has allowed us to aggressive with rebound edema [38]. Preclinical study target VEGF in antiangiogenic therapy. Bevacizumab is showed that other angiogenic factors, such as fibroblast considered as a well-established antiangiogenic therapy in growth factors and PDGF, can compensate for the loss of severalsolid tumors.AphaseIItrialsofrecurrent glioblas- VEGF activity under bevacizumab treatment [42]. A novel toma showed favorable response rates (28% to 57%) and therapeutic strategy is required to overcome the resistance to 6-month PFS (29% to 50.3%) [11–13]. Based on these bevacizumab of malignant gliomas. promising results, bevacizumab was approved by the FDA for An accurate assessment of tumor response by conven- the recurrent glioblastoma. Regarding recurrent anaplastic tional modality is limited in antiangiogenic therapy due gliomas, bevacizumab has been reported to be effective to alterations in tumor blood vessels [44]. The Response as well [28, 29]. Additional therapies (e.g., chemotherapy, Assessment in Neuro-Oncology Working Group proposed targeting therapy, and radiotherapy) to bevacizumab have that T2 and FLAIR changes on MRI should include the been reported for recurrent malignant gliomas, and these response criteria [47]. FDG-FLT is also expected to accurately results were encouraging. However, the timing, dosing, and evaluate the treatment response in bevacizumab due to its the ideal treatment partners of bevacizumab have remained ability to detect cell proliferation [48]. controversial. Further investigations are warranted to estab- Tumor VEGF expressions or circulating markers poten- lish an antiangiogenic treatment for recurrent malignant tially predict the prognosis in malignant glioma treated gliomas. by bevacizumab, although the rational biomarker has not Bevacizumab is expected to be on the frontline treatment been established. Novel biological markers are required to of patients with glioblastoma. Phase II trials have reported investigate, providing a personalized treatment that selects the addition of bevacizumab to standard temozolomide the patients who can benefit from bevacizumab. and radiotherapy regimen for newly diagnosed glioblastoma Although several limitations on antiangiogenic therapy [14, 15]. However, the authors concluded that this regimen have been reported, this treatment is expected to improve improved PFS but not overall survival when compared the prognosis of malignant gliomas. Further investigation is with control group [14]. 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