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Chemotherapy for Glioblastoma: Current Treatment and Future Perspectives for Cytotoxic and Targeted Agents

Chemotherapy for Glioblastoma: Current Treatment and Future Perspectives for Cytotoxic and Targeted Agents

ANTICANCER RESEARCH 29: 5171-5184 (2009)

Review for Glioblastoma: Current Treatment and Future Perspectives for Cytotoxic and Targeted Agents

G. MINNITI1,2, R. MUNI1, G. LANZETTA2, P. MARCHETTI3 and R. MAURIZI ENRICI1

Departments of 1Radiotherapy Oncology and 3Medical Oncology, Sant’ Andrea Hospital University La Sapienza, Rome; 2Department of Neuroscience, NEUROMED Institute, Pozzilli (IS), Italy

Abstract. Glioblastoma is the most frequent and review summarizes the current results with cytotoxic and devastating primary malignant brain tumor in adults. targeted molecular agents in glioblastoma and the Surgery followed by standard radiotherapy with development of new chemoradiation strategies under concomitant and adjuvant chemotherapy with temozolomide evaluation to increase their effectiveness. is the standard of care in patients with glioblastoma, however the prognosis remains poor with a median survival Approximately 176,000 cases of central nervous system in the range of 12-15 months. Common genetic (CNS) cancer are diagnosed per year worldwide, with an abnormalities in glioblastoma are associated with aberrant estimated annual mortality of 128,000 (1). Gliomas are the activation or suppression of cellular signal transduction most frequent intracranial tumor and account for more than pathways and resistance to radiation and chemotherapy. 50% of all primary brain tumors, with glioblastoma Special attention has been focused on targets such as (GBM) being by far the most common and aggressive (2, epidermal receptor, vascular endothelial 3). Treatment of GBM includes surgery, radiotherapy (RT) , platelet-derived growth factor and chemotherapy. Currently, surgery followed by standard receptor, and on pathways such as the phosphatidylinositol- RT with concomitant and adjuvant chemotherapy with 3kinase/Akt/mammalian target of rapamycin and temozolomide is the standard of care in patients with GBM Ras/Raf/mitogen-activated protein-kinase pathways. Several aged <70 years, however the prognosis remains poor, with signal transduction inhibitors have been examined in a median survival of 12-15 months (4). Clearly, there is a preclinical and clinical malignant glioma trials, including desperate need for more effective therapies for patients antiangiogenic agents (, enzastaurin), and with GBM. inhibitors of receptor tyrosine Overexpression, activation, and dysregulation of various kinase ( and ), mammalian target of membrane receptors, signaling pathways, and other factors rapamycin (, ) and occur frequently in GBM (5-7). Therapeutic approaches (cilengitide). Although preliminary clinical results of the targeting these molecules, including inhibitors of epidermal use of targeted agents have not translated into significantly growth factor receptor (EGFR), vascular endothelial growth better survival, more recent phase II trials are exploring the factor receptor (VEGFR), platelet-derivated growth factor combination of multitargeted drugs with cytotoxic receptor (PDGFR), and mammalian target of rapamycin chemotherapy and radiotherapy in order to overcome the (mTOR) have been examined in preclinical and clinical trials resistance of tumors to single-agent targeted therapies. This for malignant glioma. The efficacy of these agents as monotherapies has been modest, at best; however, new multitargeted kinase inhibitors and combinations of single- targeted kinase inhibitors in combination with radiation and Correspondence to: Dr. Giuseppe Minniti, Sant’ Andrea Hospital, cytotoxic chemotherapy will likely play an increasing role in Department of Radiotherapy Oncology, Via di Grottarossa 1035, the management of GBM and several randomized/prospective 00189 Roma, Italy. Tel: +39 0633776034, Fax: +39 0633776608, e-mail: [email protected] studies are ongoing. We have performed a review of the current results with chemotherapy in malignant glioma and Key Words: Glioblastoma, radiotherapy, chemotherapy, temozolomide, of the new treatment strategies that may improve the , review. prognosis for these patients.

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Current Standard Therapy for GBM in the range of 7-9 months and 10-14 months, respectively, which compare favourably with series using RT alone (12-14). Temozolomide is a second-generation imidazotetrazine In 32 elderly patients of 70 years or older treated with derivative, which exerts its cytoxic effects by methylation of standard RT and temozolomide given concomitantly and specific DNA sites. The methylation of the O6 position of adjuvantly, the median survival was 10.8 months and the guanine in DNA is usually regarded as the most critical. median progression-free survival was 6.7 months (12). The 12- Temozolomide is taken orally and is absorbed rapidly, with a month survival and progression-free survival rates were 36% nearly complete bioavailability after oral administration, and 16%, respectively. Longer survival has been reported for acrosses the brain-blood barrier, and achieves high elderly patients who had MGMT promoter methylated (14). concentration in the cerebrospinal fluid. Prolonged schedules with higher cumulative dose of The recently published randomized European and Canadian temozolomide have been explored in order to maximize trial (EORTC 26981/22981-NCIC) (4) has clearly demonstrated MGMT depletion in cancer cells and possibly to increase that the addition of temozolomide to RT, followed by 6 monthly antitumor efficacy (15-17). Regimens using temozolomide cycles of temozolomide provides significant survival benefit with administered 1 week on/1 week off or 21 days on/7 days off minimal additional toxicity in patients with GBM. The reported in patients with recurrent malignant glioma result in a more median survival was 14.6 months with RT plus temozolomide protracted MGMT depletion in blood cells and possibly in and 12.1 months with RT alone, with respective 2-year survival brain tumor tissue. rates of 27% and 10%. The 2-year survival rate improved from Wick et al. (16) reported on 90 patients with recurrent 10.4% for RT alone to 26.5% in the RT plus temozolomide malignant gliomas treated with temozolomide (150 mg/m2) group. A recent up-date of the trial reported the final results, with administered 1 week on and 1 week off, showing a promising a median follow-up of more than 5 years (8). Overall survival median progression-free survival of 24 weeks, being 43.8% at 6 was 27.2% at 2 years, 16.0% at 3 years, 12.1% at 4 years, and months. The RTOG 052/EORTC 26052/220535 trial, led by the 9.8% (6.4-14.0) at 5 years in RT plus temozolomide group, Radiation Therapy Oncology Group (RTOG) along with the versus 10.9%, 4.4%, 3.0%, and 1.9% in the radiotherapy alone European Organisation for Research and Treatment of Cancer group (p<0.0001). A benefit of combined therapy was recorded (EORTC) and the North Central Cancer Treatment Group, in all clinical prognostic subgroups, including younger age, which has enrolled 1,150 patients (closed in June 2008), is extent of resection, and good performance status. Methylation of evaluating if a dose-intensity schedule of temozolomide (75 to the O6-methylguanine-DNA-methyltransferase (MGMT) 100 mg/m2 days 1 to 21 every 28 days for 12 cycles maximum) promoter was the strongest predictor of outcome and benefit improves survival compared with standard chemotherapy from temozolomide chemotherapy. regimen. Currently, in the absence of robust data, the use of The cytotoxic effect of temozolomide is correlated to the dose-intense temozolomide schedules as alternatives to standard intracellular levels of MGMT. MGMT is a critical DNA repair regimens are not recommended in patients with GBM. protein that protects tumor cells against alkylating In summary, temozolomide given concomitantly and chemotherapeutic agents, tranferring the methyl group to an adjuvantly with RT after surgical resection represents the internal cysteine acceptor residue. High levels of MGMT standard of care in patients with GBM. The epigenetic activity in tumor tissue are associated with resistance to silencing of MGMT by promoter methylation is correlated temozolomide (9). Thus, epigenetic silencing of the MGMT with improved survival in patients treated with DNA-repair gene by promoter methylation results in decreased temozolomide. Although the prolonged exposure of cancer levels of MGMT and may enhance temozolomide sensitivity, cells to temozolomide may represent a promising strategy to whereas unmethylated MGMT promoter is associated with overcome resistance mediated by MGMT, at present, the potential temozolomide resistance (8, 10, 11). Hegi et al. (10) clinical relevance of the use of a dose-dense temozolomide reported a survival advantage in GBM patients with schedule remains to be proven. methylated MGMT promoter treated by temozolomide and standard radiotherapy, whereas GBM patients with Targeted Therapies unmethylated MGMT promoter did not seem to have a survival benefit by chemoradiation combination. The 2-year survival GBM is characterized by several aberrantly activated signaling rates for patients with unmethylated and those with methylated pathways. Several growth factor receptors, such as epidermal MGMT promoter treated with standard RT and temozolomide growth factor receptor (EGFR), vascular endothelial growth were 14% and 46%, respectively. factor receptor (VEGFR) and platelet-derivated growth factor The use of standard or hypofractionated RT plus receptor (PDGFR), are overexpressed, amplified and/or concomitant and/or adjuvant temozolomide has been recently mutated, leading to uncontrolled cell proliferation, extended to elderly people with GBM. The reported median angiogenesis, migration, survival and differentiation (18, 19) progression-free survival and median survival durations were (Figure 1). Thus, several targeted agents are being developed

5172 Minniti et al: Chemotherapy for Glioblastoma (Review)

Figure 1. Schematic representation of main oncogenetic signaling pathways and site of action of molecular targeted therapies. EGFR: epidermal growth factor receptor; PDGFR: platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; PLC, phospholipase C; PKC, protein kinase C; P13K, phosphatidylinositol 3’-kinase; PTEN, phosphatase and tensin homolog; Akt, v-akt murine thymoma viral oncogene homolog; mTOR, mammalian-target of rapamycin.

as potential inhibitors of growth factor receptor transduction EGFR Inhibitors pathways and angiogenesis (Table I). The major challenge in the use of targeted therapies is the identification of the optimal EGFR is a 170-kDa receptor member of the therapeutic targets, and to select new agents which can translate ErbB family which consists of four distinct receptors: to survival benefit for patients with GBM. Currently, the use HER1/EGFR (epidermal growth factor receptor), HER2, HER3 of small molecule tyrosine kinases inhibitors (TKIs) and and HER4. It is formed of three major domains: the monoclonal antibodies against EGFR and VEGFR have been extracellular domain, the transmembrane domain and the evaluated in phase II clinical trials as main anti-growth factor cytoplasmatic domain, which harbors the tyrosine kinase receptor strategies. Other potentially useful agents for the activity. Phosphorylation of the tyrosine kinase domain activates treatment of GBM are represented by the PDGFR-, several signaling pathways, such as the phosphatidyl-inositol 3’- mammalian target of rapamycin (mTOR) and integrin kinase (PI3K)/Akt/mTOR, and Ras/mitogen-activated protein inhibitors. A summary of main recent phase II clinical trials of kinase (MAPK) (20, 21). Activation of EGFR pathways results targeted therapies alone or in combination with other treatment in several biological processes, including cell proliferation, modalities in GBM are shown in Table II. angiogenesis, migration, survival and differentiation.

5173 ANTICANCER RESEARCH 29: 5171-5184 (2009)

Table I. Main molecular targeted agents used in the treatment of developed in order to block the EGFR signaling pathways, glioblastoma. including monoclonal antibodies and small molecule TKIs. Preclinical studies with the murine humanized monoclonal Agent Mechanism of action antibody (Erbitux, Merck & Co) have shown that Inhibitors of EGFR inhibition leads to while reducing EGFR proliferation as well as VEGF expression in GBM cells (29). Cetuximab EGFR blocker (monoclonal antibody) An additive cytotoxic effect can be observed in different Gefitinib EGFR TKI GBM cell lines by the addition of cetuximab to Erlotinib EGFR TKI EGFR, Erb-2 TKI radiochemotherapy with temozolomide (30). Currently a Erb-1, Erb-2, Erb-3, Erb-4 TKI one-armed single-center phase I/II trial is evaluating the Pelitinib Irreversible EGFR inhibitor safety and efficacy of combined radiotherapy with BIBW-2992 EGFR and HER2 inhibitor temozolomide and cetuximab as first-line treatment for PDGFR patients with primary GBM (31). mesylate PDGFR TKI, c-Kit, Bcr-Abl Tandutinib PDGFR, FLT3 (FMS-like tyrosine kinase-3), Gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva, Osi c-Kit inhibitor Pharmaceuticals) are two oral, small TKI molecules that VEGFR have been evaluated in several phase I and II studies in Bevacizumab VEGFR blocker (monoclonal antibody) patients with GBM. Phase I and II studies of gefitinib and VEGF trap Pan VEGF blocker erlotinib used as single agents adjuvant to RT have shown no Vatalinib VEGFR-1, VEGFR-2, PDGFR, c-Kit TKI EGFR, HER2 inhibitor major improvements in survival (32-38). In a phase II trial Cediranib Pan-VEGFR, PDGFR, C- TKI that included 53 patients with recurrent GBM, gefitinib was VEGFR, PDGFR, c-Kit TKI well tolerated, however, it resulted in a modest progression- VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, free and median survival of 8.1 and 39.4 weeks respectively c-Kit TKI (33); similar results have been shown by others (29, 31, 32). mTOR Sirolimus mTOR inhibitor Phase II trials of erlotinib single-agent therapy in recurrent Temsirolimus mTOR inhibitor GBM have demonstrated a similar median progression-free Everolimus mTOR inhibitor survival of only 2-3 months, with response rates of 6-25% AP23573 mTOR inhibitor (37-39). In a recent randomized phase II trial (EORTC Brain PKC Tumor Group Study 26034) of erlotinib versus temozolomide Enzastaurin PKC inhibitor RAF-MEK-ERK or carmustine in 110 patients with recurrent GBM, the 6- Tipifarnib Farnesyltransferase inhibitor month progression free survival rate was 11.4% in the Lonafarnib Farnesyltransferase inhibitor erlotinib arm and 24% in the control arm (40). The reported Inhibitor of farnesyltransferase I and clinical evidence clearly suggests that the use of EGFR VEGFR and PDGFR TK inhibitors erlotinib and gefitinib as single agents in patients with progressive GBM is not beneficial. Cilengitide ανβ3 and ανβ5 integrin inhibitor There is little evidence that erlotinib and gefitinib may be EGFR, Epidermal growth factor receptor; VEGF, vascular endothelial associated with survival advantages in a subgroup of patients growth factor; VEGFR, vascular endothelial growth factor receptor; with GBM who have overexpressed, amplified, or mutated PDGFR, platelet-derived growth factor receptor; PKC, protein kinase EGFR in association with intact PTEN or unphosphorylated C; TKI, tyrosine kinase inhibitor. Akt (41, 42). Mellinghoff et al. (42) reviewed the molecular characteristics of 26 patients with malignant gliomas treated with EGFR TKIs. Coexpression of EGFRvIII and PTEN, a EGFR amplification and/or overexpression occur in tumor-suppressor protein that inhibits the PI3K signaling approximately half of GBM cases (22, 23). EGFRvIII is a pathway, was significantly associated with better clinical mutant EGFR variant characterized by deletion of the response to EGFR TKIs. Loss of PTEN may promote extracellular ligand-binding domain, which results in a resistance to EGFR kinase inhibitors. In contrast, Lassman constitutionally active receptor and is reported in 20-40% of et al. (43) found no correlation between sensitivity to GBMs (24, 25). All these alterations are responsible for the erlotinib or gefitinib and changes in expression, activation of EGFR downstream signaling pathways, amplification, phosphorylation, downstream signaling of promote the oncogenic process, and are associated with a EGFR, and genomic changes. negative prognosis (26, 27). Moreover, in the clinical setting, More recently, phase I/II studies testing the combination EGFR overexpression in GBM has been associated with of erlotinib in association with RT and/or temozolomide resistance to radiation therapy (28). Therefore, a large showed conflicting results (44-46). Using this regimen, number of potentially therapeutic targets have been Prados et al. (46) showed a median progression-free survival

5174 Minniti et al: Chemotherapy for Glioblastoma (Review)

Table II. Main recent phase II clinical trials of targeted therapies alone or in combination with cytotoxic chemotherapy and/or radiotherapy in newly diagnosed and recurrent glioblastoma.

Study Treatment Patients Dose of Tumor Response Median Median (n) target agent (CR+PR) PFS OS (mg/day) % (months) (months)

EGFR inhibitors Lieberman et al. (32) Gefitinib 38 500-1000** R 13 2 NA Rich et al. (33) Gefitinib 53 500-1000** R 0 2 10 Uhm et al. (34) Gefitinib 98 500-1000** N NA 7 11 Franceschi et al. (35) Gefitinib 28* 250 R 0 14.3% at 6 months Raizer et al. (37) Erlotinib 30 150 R 0 3 NA Vogelbaum et al. (37) Erlotinib 31 150 R 26 3 6 Cloughesy et al. (38) Erlotinib 48 150-500** R 8 2 NA Brown et al. (44) Erlotinib +TMZ + RT 97 150 N NA NA 15.3 Prados et al. (45) Erlotinib +TMZ + RT 65 100-300** N NA 8.2 19.3 van den Bent et al. (39) Erlotinib vs. TMZ or BCNU 110 100-300** R NA 11.4 vs. 24% NA at 6 months

PDGF inhibitors Reardon et al. (53) Imatinib + hydroxyurea 33 400-1000** R 9 4.5 27% at 6 months Wen et al. (51) Imatinib 34 600-800** R 6 NA NA Raymond et al. (52) Imatinib 51 600-800** R 6 16% at 6 months NA

VEGF inhibitors Vredenburgh et al. (63) Bevacizumab + irinotecan 35 10-15 mg/kg q14-21 R 100 46% at 6 months 77% at 6 months Bokstein et al. (66) Bevacizumab + irinotecan 20 5 mg/kg q14 R 47 25% at 6 months 45% at 6 months Narayana et al. (70) Bevacizumab + TMZ + RT 15 10 mg/kg q14 N 93 59% at 1 year 87% at 12 months Norden et al. (68) Bevacizumab 55 10 mg/kg q14 R 34 42% at 6 months NA Kreisl et al. (64) Bevacizumab + irinotecan*** 48 10 mg/kg q14 R 35^ 4 7.7 Conrad et al. (79) Vatalanib 47 150-2.000 R 4 NA NA Batchelor et al. (82) Cediranib 30 45 qd R 56 3.7 7.7 mTor inhibitors Chang et al. (105) Temsirolimus 43 170-250 R 5 2.3 NA Galanis et al. (106) Temsirolimus 65 250 R 0 2.3 4

Protein kinase C, RAF-MEK- ERK, and integrin inhibitors Fine et al. (110) Enzastaurin versus 167/84 500 R NA 1.5 vs. 2.8 6.6 vs. 7.1 Cloughesy et al. (112) Tipifarnib 67 300-600 bid** R 7 12% at 6 months NA Reardon et al. (119) Cilengitide 81 500-2000 R NA 15% at 6 months 9.9 Stupp et al. (120) Cilengitide + TMZ + RT 52 500 mg i.v. 2 x/w N NA 65% at 6 months NA

TMZ, Temozolomide; RT, radiotherapy; NA, not available; CR, complete response; PR, partial response; PFS, progression-free survival; OS, overall survival. *Series includes some grade III gliomas; **based on enzyme-inducing antiepileptic drug (EIAED) therapy. ***bevacizumab was initially used as single agent and in combination with irinotecan at progression; ^no responses in pts treated with bev+irinotecan at progression.

of 8.2 months and median survival of 19.3 months. EGFRvIII plus wild-type PTEN compared with patients Compared with the EORTC 26981/22981-NCIC conducted without these genotypic features. Moreover, the regimen was by Stupp et al. (4), where patients were treated with RT and associated with significant toxicity, including two grade 5 temozolomide alone, the study showed survival benefit, toxicities (non-neutropenic pneumonias). To date, the especially in patients with MGMT promoter methylation and potential role of erlotinib in association with temozolomide PTEN positivity. By contrast, a recent study of the North and RT remains unclear. Central Cancer Treatment Group (45) using a similar New growth factor receptor inhibitors are emerging as regimen showed no significant additional benefit for erlotinib potential therapeutic agents in GBM. Lapatinib (Tykerb, when combined with RT and temozolomide, and no Glaxo Smith-Kline) is a dual EGFR and ErbB-2 inhibitor differences in survival for patients characterized by that has shown some activity in the treatment of solid

5175 ANTICANCER RESEARCH 29: 5171-5184 (2009) tumors, especially of advanced or metastatic breast cancer patients with recurrent GBM, Raymond et al. (52) reported a (47). Canertinib (Pfizer, New York) is a pan-ErbB inhibitor 6-month progression-free survival of 16% with 3 patients which has shown potent and sustained inhibition of tyrosine who had an objective partial response. Imatinib mesylate kinase activity selective for erbB1, erbB2, erbB3, and erbB4 plus hydroxyurea is associated with better antitumor activity in human cancer cell lines (48). Treatment of athymic nude than imatinib given alone. At a median follow-up of 58 mice bearing xenografts of human SF-767 glioblastoma with weeks, Reardon et al. (53) reported a median progression- canertinib resulted in highly significant suppression of tumor free survival of 14.4 weeks and 6-month progression-free growth (49). However, no clinical data are available in survival of 26% in 33 patients with recurrent GBM. Nine patients with high-grade gliomas. percent of patients achieved radiographic response, and 42% In summary, the patterns of response observed in patients of patients achieved stable disease. The most common treated with EGFR TKIs are disappointing. Despite EGFR toxicities included grade 3 neutropenia in 16% of patients, activating several signaling pathways, such as PI3K/Akt/ thrombocytopenia in 6% of patients, and edema in 6% of mTOR, and Ras/MAPK, it is possible that other growth factor patients. In a phase I study of 55 patients with GBM, the and signaling pathways play a greater role in maintaining the combination of imatinib plus temozolomide was well transformed phenotype of GBM. Erlotinib in association with tolerated (54). Grade 3 or 4 hematological toxicities occurred RT and temozolomide has led to modest or no survival benefit in fewer than 10% of patients. The most common compared to RT plus temozolomide alone, and currently its use nonhematological toxicities included grade 2 nausea/emesis is not advisable in clinical practice. New strategies include the and fatigue in 5% of patients. Overall survival and combination of EGFR TKIs with targeted agents able to inhibit progression-free survival were 45.1 and 26.6 weeks, with a other signaling pathways, and phase II trials testing the 6-month survival of 53%. In summary, in the dose range of association with temsilorus and sorafenib are ongoing 600 to 1,000 mg/d, single-agent imatinib is well tolerated but (http://clinicaltrials.gov/ct2/show/NCT00474786). has limited antitumor activity in patients with recurrent GBM, and available data do not support its use in clinical Platelet-derived Growth Factor Inhibitors practice. Combination regimens incorporating imatinib are encouraging and phase II trials have been planned. Imatinib mesylate (Gleevec, Novartis) is an inhibitor of the kinase activity of multiple growth factor receptors, including VEGF/VEGFR Inhibitors PDGFR, c-Kit, and Bcr-Abl. The PDGF family consists of four members, PDGF-A, -B, -C and -D, which signal Vascular proliferation, or neoangiogenesis, is a distinct through the alpha and beta PDGF receptor (PDGFRα and histopathological characteristic of GBM and is correlated PDGFRβ) tyrosine kinases. Binding of ligands induces with prognosis (55-57). VEGF is a key factor involved in the dimerization and cross-tyrosine phosphorylation of the angiogenetic process that can elicit several responses such as intracellular domain. This results in the activation of PI3K, endothelial cell proliferation, extracellular matrix degradation, MAPK, Jak family kinase, Src family kinase, and cell migration, and expression of other proangiogenic factors phospholipase C-gamma (PLC-γ) signal transduction (matrix metalloproteinase-1, urokinase-type plasminogen pathways. Overexpression of alpha subtype receptor activator and its receptor, plasminogen activator inhibitor-1). (PDGFRα) has been reported in approximately one third of VEGF expression is stimulated by hypoxia, acidosis, and primary glioblastoma (50). c-Kit is a many growth factors as EGF, PDGF, that acts similarly to EGFR and PDGFR and is (HGF), c-Kit and their downstream signaling pathways overexpressed in GBM. c-Kit consists of an extracellular (PI3K-Akt, Ras-MAPK). The main receptors involved in domain, a transmembrane segment, a juxtamembrane relaying VEGF-A signaling are VEGFR-1 and VEFGR-2. segment, and a protein kinase domain. Binding of stem cell The rationale for anti-VEGF/VEGFR therapies has been factor to Kit results in receptor dimerization and activation supported by several in vitro and in vivo studies (58, 59). of several signal transduction pathways including Akt, Src Bevacizumab (Avastin, Genentech) is a humanized murine family kinases, PI3K, PLC-gamma, and Ras/MAPK. monoclonal antibody that selectively blocks VEGF, preventing Imatinib mesylate used as single agent in the dose range the activation of VEGF receptor tyrosine kinases VEGFR1 and of 600 to 1,000 mg/d is generally well tolerated but shows VEGFR2 (60). In patients with metastatic and limited activity in patients with recurrent GBM (51, 52). In a recurrent non-small cell (NSCLC), bevacizumab small phase I/II study of the North American Brain Tumor in combination with conventional chemotherapy resulted in Consortium (51) including 34 patients with recurrent GBM, longer survival (61, 62). Phase II studies in patients with the 6-month progression-free survival was 3%, with only 2 recurrent GBM using bevacizumab alone or in association with and 6 patients who had partial response and stable disease, irinotecan have been reported (63-69) (Table II). Vredenburgh respectively. In a recent phase II EORTC study including 51 et al. (63) reported on 35 patients with recurrent GBM treated

5176 Minniti et al: Chemotherapy for Glioblastoma (Review) with bevacizumab plus irinotecan. Twenty-three patients models, alone or in combination with RT (71-78), and are received bevacizumab at 10 mg/kg plus irinotecan every 2 currently undergoing clinical evaluation in GBM. weeks and 12 patients received bevacizumab 15 mg/kg every Vatalanib is an oral VEGFR-1 and VEGFR-2 TKI that is 21 days and irinotecan on days 1, 8, 22, and 29 for a total of 6 able to inhibit VEGFR, PDGFR, c-Kit and colony- cycles. The 6-month progression-free survival and overall stimulating factor 1 receptor (CSF1R). It has been recently survival rates were 46% and 77%, respectively. Fifty-seven tested in two phase I/II studies given alone or in combination percent of patients had at least a partial radiological response. with cytotoxic chemotherapy (79-80). In a study of 47 One patient developed a CNS hemorrhage, and 4 patients patients with recurrent GBM treated with vatalanib as single developed thromboembolic complications. Kreisl et al. (64) agent, a partial response was shown in 4% and stability of reported on 48 patients with recurrent GBM treated with disease in 56% of patients (79). Reardon et al. (80) reported bevacizumab followed by bevacizumab plus irinotecan at the results of vatalanib in association with either progression of tumor. The median survival and progression-free temozolomide or lomustine in 51 patients. The progression- survival were 31 weeks and 16 weeks, with a respective 6- free survival was 16 weeks in vatalanib plus temozolomide month survival and progression-free survival of 57% and 29%. group and 10 weeks in vatalanib plus lomustine group. A Thirty-five percent of patients achieved a radiographic recent phase I trial from the same authors has shown that response. In contrast, amongst 19 patients treated with vatalanib at doses up to 1000 mg twice-a-day combined with bevacizumab plus irinotecan at progression, the median imatinib and hydroxyurea were well tolerated (81). progression-free survival was only 30 days, with no objective Cediranib is an oral pan-VEGFR TKI that also inhibits radiographic responses. Thromboembolic events (12.5%), PDGFR and C-Kit. Batchelor et al. (82) reported the results hypertension (12.5%), hypophosphatemia (6%), and of cediranib used as single agent in 16 patients with recurrent thrombocytopenia (6%) were the most common drug- GBM, showing a promising median overall survival of 7 associated adverse events. Similar 6-month progression-free months and median progression-free survival of 3.5 months. and overall survival, and discontinuation of steroids for Magnetic resonance imaging (MRI) imaging showed a recurrent GBM to a bevacizumab-based treatment have been significant decrease in tumor enhancement in more than 50% reported by others (65-68), suggesting that bevacizumab of patients. Contrast enhancement decreased after a single improves local control and survival in this patient population. dose of cediranib in all patients, and this was associated with Based on this clinical evidence, more recently the US Food and a significant reduced vasogenic edema. Toxicity was modest Drug Administration (FDA) Oncologic Drugs Advisory and included diarrhea, dysphonia, and hypertension. A phase Committee (ODAC) has approved the use bevacizumab as a III randomized trial comparing the efficacy of cediranib single agent for patients with GBM, with progressive disease monotherapy or the combination of cediranib with lomustine following prior therapy. to the efficacy of lomustine alone is planned (http:// The feasibility of using bevacizumab with chemoradiation in clinicaltrials.gov/ct2/show/NCT00777153). the primary management of GBM has been tested in few studies Sunitinib and sorafenib are two multitarget TKIs that have (69, 70). Narayana et al. (70) treated 15 patients with standard demonstrated potent antitumor and antiangiogenic activity in RT and bevacizumab at the dose of 10 mg/kg on days 14 and 28 preclinical models (72, 75, 77, 78). Sunitinib is a small, and daily temozolomide (75 mg/m2). Subsequently, orally bioavailable molecule which is able to inhibit PDGFR- bevacizumab at the same dose was continued every 2 weeks α and PDGFR-β, as well as VEGFR-1 and -2, and c-KIT. with temozolomide (150 mg/m2) for 12 months. Radiographic Sunitinib has demonstrated efficacy and tolerability in responses were noted in 13 of 14 assessable patients (93%). several phase II/III clinical trials involving patients with One-year progression-free survival and overall survival rates gastrointestinal stromal tumor, metastatic renal cell were 59% and 87%, respectively. Four patients had grade III/IV carcinoma, and is currently tested in breast cancer and nonhematologic toxicities. These positive outcomes have led to NSCLC (83-85). There are no clinical data in patients with the initiation of a new phase III trial (RTOG-0825) testing GBM; however, phase I/II studies of Sunitinib as single- concurrent chemoradiation and adjuvant temozolomide plus agent (http://clinicaltrials.gov/ct2/show/NCT00713388) or in bevacizumab versus conventional chemoradiation and adjuvant combination with irinotecan (http://clinicaltrials.gov/ temozolomide in patients with newly diagnosed GBM. archive/NCT00611728) are ongoing. Sorafenib is one of the Several new antiangiogenic inhibitors have been recently most promising agents targeting PDGFR, VEGFR, and Raf developed, including vatalanib (Novartis Pharmaceuthical), and has been recently approved by the Food and Drug cediranib (Recentin, Astra Zeneca), sunitinib (Sutent, Pfizer), Administration for the treatment of renal cell carcinoma (86- sorafenib (Nexavar, Bayer Pharmaceuticals), vandetanib 88). Strategies to antagonize PKC and ERK pathways in (Zactima, Astra Zeneca), and VEGF trap (, combination seem to be an attractive approach to enhance Regeneron Pharmaceuticals). These targeted agents have therapeutic efficacy in human glioma cells also, and a phase demonstrated antitumor activity in preclinical glioma II evaluation of sorafenib in glioma as a single agent and in

5177 ANTICANCER RESEARCH 29: 5171-5184 (2009) combination with temozolomide or erlotinib is ongoing These evidence has provided the rationale for clinical (http://clinicaltrials.gov/ct2/show/NCT00445588). studies of mTOR inhibitors in GBM. Vandetanib is an inhibitor of VEGFR-2 tyrosine kinase with Temsirolimus (Torisel, Wyeth Pharmaceutical), everolimus additional effects on VEGFR-3 and EGFR (89, 90) that has (Certican, Novartis Pharmaceutical) and AP23573 (ARIAD shown significant antitumor effects in combination with Pharmaceutical) are three synthetic analogs of rapamycin radiotherapy in rat glioma models (91). Phase I/II studies are (sirolimus) currently being tested as potential targeted drugs exploring the use of vandetanib alone or in combination with in GBM. Results of phase II studies using temsirolimus as chemoradiation in patients with malignant glioma (http:// single agent found only a limited activity in recurrent GBM clinicaltrials.gov/ct2/show/NCT00821080 and /NCT00613223), (105, 106). More recently, based on evidence of the however, currently no clinical data are available. synergism between mTOR inhibitors and EGFR TKI (107), VEGF Trap is a 110 kDa soluble protein that is able to ongoing trials have been exploring such a combination (108, bind circulating VEGF, inhibiting its activity (71), and to 109). A phase I study found no significant pharmacokinetics potentiate RT in preclinical GBM xenografts (92). De Groot interaction between sirolimus and gefitinib, with partial et al. (93) reported the results of a phase II trial of VEGF radiological response and stable disease that were seen only Trap monotherapy for 48 patients with recurrent GBM and in 2 and 13 of 34 patients, respectively (108). Similarly, a anaplastic glioma at first relapse. Response rates were 50% study combining gefitinib and everolimus failed to find for the anaplastic glioma group and 30% for the glioblastoma survival benefit of this regimen in comparison with historical group. Grade 3 toxicity occurred in 40% of patients and controls, although a radiological response occurred in about included fatigue, hypertension, hand-foot syndrome, one third of patients (109). lymphopenia, thrombosis and proteinuria, causing the Despite these preliminary disappointing results, several discontinuation of therapy in 25% of patients. studies are exploring the safety and efficacy of mTOR In summary, VEGF inhibitors target one important inhibitors in combination with other targeted agents and/or pathway in brain tumors. Bevacizumab represents the first chemoirradiation. Ongoing phase I/II studies are assessing antiangiogenic agent approved for use in malignant glioma. the maximum tolerable dose and the efficacy of temsirolimus In addition to bevacizumab, there is an array of inhibitors of plus sorafenib (http://www.cancer.gov/clinicaltrials/NCCTG- VEGF, VEGFR, and other relevant targets that could be N0572), temsirolimus plus sorafenib and erlotinib (http:// effective in selected patients with GBM. Combining these clinicaltrials.gov/ct2/show/NCT00335764), and temsirolimus antiangiogenic agents with conventional chemotherapy or or everolimus plus irradiation (http://groups.eortc.be/ radiation is a promising antitumor strategy that is currently brain/html/trials/26082-22081) or chemoradiation with being investigated in several phase II clinical trials with the temozolomide (http://clinicaltrials.gov/ct2/show/NCT005 intent to produce a synergistic antitumor effect and a survival 53150). benefit for patients with GBM, targeting both the tumor cell In summary, although data strongly support the view of and tumor vascular compartment. Certainly, an improved the PTEN/PI3K/AKT pathway as an important target for understanding of resistance to antiangiogenic therapy is drugs, current clinical results on the use of mTOR inhibitors necessary to identify effective strategies for the patients that remains disappointing. A new generation of trials is seeking progress despite treatment. to define whether the combination of two or more targeted drugs together with RT and cytotoxic chemotherapy can Mammalian Target of Rapamycin Inhibitors overcome tumor resistance.

Overactivation of the PI3K/Akt/mTOR pathway seems to Protein Kinase C, RAF-MEK-ERK, play an important role in gliomagenesis (94). Combined and Integrin Inhibitors activation of Ras and Akt leads to the formation of GBM in mice (95). In human GBM, Akt is activated in Enzastaurin is an oral serine/threonine kinase inhibitor that approximately 70% of these tumors, in association with selectively inhibits PKC-β, a mediator of VEGF intracellular loss of PTEN and/or activation of EGFR and PDGFR signaling. Unfortunately, a phase III study comparing tyrosine kinases. Alterations of PTEN expression are lomustine with enzastaurin in recurrent GBM was present in 20-40% of GBM (96, 97), and have been discontinued at the first interim analysis of 266 patients due associated with a worse prognosis, although conflicting to lack of survival benefit of enzastaurin over the control results have been reported (97-99). There is emerging group (109). As for other targeted agents that failed to show evidence suggesting that mTOR is a critical downstream tumor activity when used as single agents, combinations of component in PTEN/Akt signaling (100-103), and enzastaurin with RT (110-111) or temozolomide pharmacological inactivation of mTOR reduces neoplastic (http://www.eortc.be/protoc/26054) are currently being proliferation and tumor size in PTEN-deficient mice (104). investigated in phase I/II studies.

5178 Minniti et al: Chemotherapy for Glioblastoma (Review)

The RAF-MEK-ERK signal transduction pathway is an Conclusion important mediator of dysregulated glioma cell proliferation and angiogenesis. Tipifarnib (Zarnestra, Johnson and The current standard treatment for GBM is chemoradiotherapy Johnson), lonarfanib (Sarasar, Shering-Plough), and with temozolomide following surgical resection. Identification sorafenib (Nexavar, Bayer) may inactivate RAS by inhibiting of many molecular genetic and signal transduction pathways farnesyltransferase. A phase II study conducted in 22 patients involved in oncogenesis have yielded many targeted drugs that with recurrent malignant glioma treated with tipifarnib (300 are currently undergoing clinical evaluation in GBM. Currently, mg twice a day for 21 days every 4 weeks) showed modest several drugs have been tested, including EGFR TKIs (gefitinib evidence of activity, with a 6-month progression-free survival and erlotinib), antiangiogenic agents (bevacizumab, enzastaurin), of 12% (112). Combination of these agents in association and inhibitors of mTOR (temsirolimus, everolimus) and integrin with radiotherapy and chemotherapy has been reported in (cilengitide). Although bevacizumab has been recently approved few studies (113, 114). In a phase I study of 13 patients with for use as a single agent for patients with GBM, with progressive GBM, tipifarnib (200 mg/day) concurrent with standard RT disease, most of the molecular targeted therapy phase II clinical was well tolerated and resulted in a median survival of 12 trials in GBM have not translated into significant survival months (113). Lonafarnib in combination with temozolomide advantages. Better molecular characterization of GBM could resulted in a 6-month progression-free survival of 38% in 23 avoid negative results in large clinical trials enrolling patients with recurrent GBM (114). Phase I/II studies on the heterogeneous cohorts of patients, and potentially allow the combination of tipifarnib, lonarfanib, and sorafenib in design of “individualized” therapies based on the genetic and association with RT, temozolomide and other targeted agents molecular characteristics of each tumor. New chemotherapeutic (http://clinicaltrials.gov/ct2/show) are ongoing, however no strategies are represented by the combination of multitargeted clinical results are currently available. drugs with cytotoxic chemotherapy and radiotherapy in order to Integrins are heterodimeric cell surface adhesion receptors overcome tumor resistance. Randomized clinical trials remain that consist of two noncovalently associated alpha and beta the gold standard for the evaluation of new targeted agents. Most subunits, and function as receptors for extracellullar matrix multicenters randomized European (EORTC) and American proteins such as fibronectin, laminins, collagens, and (RTOG, NABTG) clinical trials are testing these new agents in vitronectin (115). Ligand binding to the extracelluar domain combination with standard chemoradiotherapy (RT plus of integrin receptors results in receptor activation and in the concomitant and adjuvant temozolomide) versus standard transduction of signals essential for cell adhesion, migration, chemoradiotherapy alone. This is important because all the proliferation, differentiation, and survival (116). The integrins patients will be treated appropriately. Hopefully, results from ανβ3 and ανβ5 appear to be particularly important in the these randomized trials and the development of new process of angiogenesis and are expressed in a variety of chemoradiation strategies will translate into real benefit for malignancies, including gliomas. The critical role of integrins patients with GBM. in angiogenesis and association with tumor progression make them an attractive target for anticancer therapy. Cilengitide References (EMD 121974), a cyclic Arg-Gly-Glu (RGD) peptide is a potent and selective inhibitor of the integrins ανβ3 and ανβ5 1 Parkin DM: Global cancer statistics in the year 2000. Lancet (115-118). A phase II study has been conducted in 81 patients Oncol 2: 533-543, 2001. with recurrent GBM randomly assigned to receive either 500 2 Davis FG, Freels S, Grutsch J, Barlas S and Brem S: Survival or 2,000 mg of cilengitide twice weekly on a continuous basis rates in patients with primary malignant brain tumors stratified (119). Cilengitide was well tolerated, with no significant by patient age and tumor histological type: an analysis based toxicities observed in either arm. A modest antitumor activity on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J Neurosurg 88: 1-10, 1998. was observed in both treatment groups, with a 6-month 3 Minniti G, Brada M, Kleihues P and Ohgaki H: Gliomas. In: progression-free survival of 15% and a median overall Prognostic Factors in Cancer, 3rd edition (Gospodarowicz MK, survival of 9.9 months, which were more favorable among O’Sullivan B, Sobin LH (eds.). Hoboken, New Jersey, Wiley J patients treated with 2,000 mg. In a phase I/II trial of RT with & Sons, pp. 307-312, 2006. concomitant and adjuvant cilengitide and temozolomide, 4 Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Stupp et al. (120) reported a 6-month progression-free Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, survival of 69% and a 12-month survival of 67%, with no Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E and Mirimanoff RO; added toxicity. A phase III EORTC 26071-22072 study is European Organisation for Research and Treatment of Cancer testing cilengitide in combination with standard treatment Brain Tumor and Radiotherapy Groups; National Cancer (standard RT with concomitant and adjuvant temozolomide) Institute of Canada Clinical Trials Group: Radiotherapy plus versus standard treatment in patients with newly diagnosed concomitant and adjuvant temozolomide for glioblastoma. GBM with methylated MGMT promoter gene. N Engl J Med 352: 987-996, 2005.

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J Clin Oncol ASCO Annual Meeting Proc 26(Suppl): 2005, 2008. 111 Tabatabai G, Frank B, Wick A, Lemke D, von Kürthy G, Obermüller U, Heckl S, Christ G, Weller M and Wick W: Synergistic antiglioma activity of radiotherapy and enzastaurin. Ann Neurol 61: 153-161, 2007. 112 Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR and Prados MD: Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic Received July 27, 2009 drugs: a North American Brain Tumor Consortium Study. J Clin Revised November 9, 2009 Oncol 24: 3651-3656, 2006. Accepted November 11, 2009

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