_:b499217962 "2"^^ . _:b499217970 . . _:b499217973 "2"^^ . . _:b499217981 . _:b499217972 "2"^^ . . _:b499217980 . _:b499217893 . _:b499217975 "2"^^ . _:b17255607 "Currently there is no standard therapy for recurrent GBM and the estimated 6-month progression-free survival (PFS) rate for patients with recurrent disease is 9\u201328% (6\u201311) with a 1-year survival rate of 14\u201332% (>>6<<\u20138,10,11). Therefore, new treatment strategies for recurrent GBM are needed." . _:b17255614 . _:b499217983 . _:b499217974 "2"^^ . _:b499217982 . _:b17255639 . _:b499217969 "2"^^ . _:b499217836 "6"^^ . _:b499217970 . _:b499217977 . _:b17255623 . _:b499217839 "5"^^ . _:b499217968 "2"^^ . _:b499217837 "6"^^ . . . _:b17255637 . _:b17255614 "Bevacizumab (Avastin\u00AE) is a monoclonal antibody that inhibits VEGF and is currently approved for a range of metastatic cancers (colorectal, non-small-cell lung, breast, ovarian cancer and renal cancers) (>>16<<\u201319) as well as for use in adults with recurrent GBM in many countries including the USA (20,21)." . _:b499217976 . . _:b499217838 "5"^^ . _:b499217971 "2"^^ . _:b499217834 "6"^^ . _:b499217979 . _:b499217970 "2"^^ . _:b499217835 "6"^^ . _:b499217978 . _:b499217981 "2"^^ . . _:b17255601 _:b17255616 . _:b17255601 _:b17255617 . _:b17255602 "Glioblastoma (GBM) is the most aggressive form of primary malignant brain tumor and the prognosis for patients with GBM is poor (>>1<<,2); the majority will relapse following initial treatment and <10% are alive at 5 years (3)." . _:b499217989 . _:b17255601 _:b17255618 . _:b499217980 "2"^^ . . _:b499217832 "10"^^ . _:b499217833 "8"^^ . _:b499217988 . _:b499217983 "2"^^ . . _:b499217991 . _:b499217845 "5"^^ . _:b499217982 "2"^^ . _:b17255604 "Glioblastoma (GBM) is the most aggressive form of primary malignant brain tumor and the prognosis for patients with GBM is poor (1,2); the majority will relapse following initial treatment and <10% are alive at 5 years (>>3<<). The standard treatment for patients with newly diagnosed GBM is surgical resection followed by temozolomide (TMZ) and radiotherapy (RT), and then adjuvant TMZ alone (Stupp regimen) (4)." . _:b499217990 . _:b499217844 "5"^^ . _:b499217977 "2"^^ . _:b499217847 "4"^^ . _:b17255631 . _:b499217985 . . _:b499217976 "2"^^ . _:b499217984 . _:b499217846 "5"^^ . _:b499217979 "2"^^ . . . _:b499217987 . _:b17255636 "This is consistent with other findings that suggest that bevacizumab may have corticosteroid-sparing effects in patients with recurrent GBM (>>39<<). Corticosteroid reduction may reduce infection rates and other related toxicities and therefore is expected to improve the health-related quality of life for patients." . _:b499217841 "5"^^ . _:b499217978 "2"^^ . _:b499217986 . _:b499217840 "5"^^ . _:b499217989 "2"^^ . _:b499217917 . _:b17255606 . _:b17255635 . _:b499217843 "5"^^ . _:b499217988 "2"^^ . _:b499217870 . _:b499217901 . _:b499217842 "5"^^ . _:b499217991 "2"^^ . _:b17255615 "Early Phase II studies in patients with recurrent GBM showed the efficacy of bevacizumab in combination with irinotecan (22,>>23<<). Subsequently, two Phase II studies (24\u201326) showed the efficacy of single-agent bevacizumab with regard to response rates and 6-month PFS in patients with recurrent GBM who had previously received RT and TMZ. These two studies formed the" . _:b499217853 "4"^^ . _:b499217959 . _:b499217990 "2"^^ . _:b499217852 "4"^^ . _:b499217985 "2"^^ . _:b499217855 "3"^^ . _:b499217926 . _:b499217993 . _:b499217984 "2"^^ . _:b499217854 "4"^^ . _:b499217992 . . _:b499217987 "2"^^ . . _:b499217849 "4"^^ . _:b499217986 "2"^^ . _:b17255608 "Currently there is no standard therapy for recurrent GBM and the estimated 6-month progression-free survival (PFS) rate for patients with recurrent disease is 9\u201328% (6\u201311) with a 1-year survival rate of 14\u201332% (6\u20138,>>10<<,11). Therefore, new treatment strategies for recurrent GBM are needed." . _:b499217952 . _:b499217848 "4"^^ . _:b499217994 . . _:b499217871 . _:b17255619 _:b17255624 . _:b17255619 _:b17255625 . _:b499217851 "4"^^ . _:b17255619 _:b17255626 . _:b17255619 _:b17255627 . _:b17255619 _:b17255628 . _:b499217957 . _:b17255619 _:b17255629 . _:b499217850 "4"^^ . _:b17255619 _:b17255630 . . . _:b17255619 _:b17255631 . . . _:b499217861 "3"^^ . . . . _:b17255619 _:b17255620 . _:b499217860 "3"^^ . _:b17255619 _:b17255621 . _:b17255634 "In addition, the 1-year survival rate for GBM patients (34.5%) was as good as the published data (14\u201332%) (6\u20138,>>10<<,11)." . _:b17255619 _:b17255622 . _:b499217993 "2"^^ . _:b17255619 _:b17255623 . _:b17255619 _:b17255640 . _:b499217863 "3"^^ . _:b17255619 _:b17255641 . _:b499217992 "2"^^ . _:b17255611 "High levels of VEGF are expressed in GBM cells (12,>>13<<), and hypoxia and acidosis, conditions commonly seen in solid tumors, upregulate VEGF expression in glioma cells in vivo (14)." . _:b499217862 "3"^^ . _:b17255619 _:b17255632 . _:b499217857 "3"^^ . _:b17255619 _:b17255633 . _:b17255619 _:b17255634 . _:b17255613 . _:b499217994 "2"^^ . _:b17255619 _:b17255635 . . _:b17255619 _:b17255636 . _:b17255646 "AEs were assessed throughout the study and were graded according to the Common Terminology Criteria for AEs version 3.0 (>>35<<). Body weight, vital signs and laboratory tests were assessed prior to the start of each cycle." . _:b499217856 "3"^^ . _:b499217890 . _:b17255619 _:b17255637 . _:b17255619 _:b17255638 . _:b17255619 _:b17255639 . _:b499217859 "3"^^ . _:b499217982 . _:b499217858 "3"^^ . _:b499217869 "3"^^ . _:b499217868 "3"^^ . _:b17255605 "The standard treatment for patients with newly diagnosed GBM is surgical resection followed by temozolomide (TMZ) and radiotherapy (RT), and then adjuvant TMZ alone (Stupp regimen) (>>4<<). Treatment options for patients with recurrent GBM, however, are limited and include repeat resection, RT and systemic chemotherapy, such as TMZ, nitrosoureas, platinum-based regimens (carboplatin, cisplatin), cyclophosphamide," . _:b499217837 . _:b499217989 . . _:b17255642 _:b17255644 . _:b499217871 "3"^^ . _:b17255642 _:b17255645 . _:b17255642 _:b17255646 . _:b499217993 . _:b499217870 "3"^^ . _:b499217830 . _:b17255642 _:b17255643 . _:b499217853 . _:b499217865 "3"^^ . . _:b499217864 "3"^^ . _:b499217921 . _:b499217867 "3"^^ . . . _:b499217866 "3"^^ . . _:b499217977 . . _:b17255604 . _:b499217877 "3"^^ . . _:b499217876 "3"^^ . _:b499217843 . _:b499217868 . _:b499217879 "3"^^ . . _:b17255612 . _:b499217878 "3"^^ . _:b499217987 . _:b499217873 "3"^^ . _:b499217903 . . _:b499217872 "3"^^ . _:b499217978 . _:b499217875 "3"^^ . . . _:b499217874 "3"^^ . . _:b17255618 "Moreover, other studies have shown the efficacy of bevacizumab in recurrent GBM whether given as a single agent (27) or combined with irinotecan (28,29) and other chemotherapies, such as etoposide, carboplatin and fotemustine (>>30<<\u201333). Given the current evidence for bevacizumab in recurrent GBM in Western patient populations, we investigated the efficacy and safety of single-agent bevacizumab in a Phase II, single-arm, open-label study (JO22506) in Japanese" . _:b499217885 "3"^^ . _:b17255605 . _:b17255609 "Currently there is no standard therapy for recurrent GBM and the estimated 6-month progression-free survival (PFS) rate for patients with recurrent disease is 9\u201328% (6\u201311) with a 1-year survival rate of 14\u201332% (6\u20138,10,>>11<<). Therefore, new treatment strategies for recurrent GBM are needed." . _:b499217884 "3"^^ . . _:b499217887 "2"^^ . _:b17255645 "They were assessed by an independent radiology facility (IRF) by reference to Macdonald's Criteria (>>34<<). Response was classified according to the following categories: complete response (CR), partial response (PR), no change (NC) and PD. Confirmation of the response was determined on two consecutive assessments \u22654 weeks apart: patients who" . _:b499217886 "2"^^ . _:b499217864 . . _:b499217881 "3"^^ . _:b499217880 "3"^^ . _:b17255618 . _:b499217883 "3"^^ . . _:b499217882 "3"^^ . . _:b499217893 "2"^^ . _:b499217910 . _:b499217867 . _:b499217892 "2"^^ . . _:b499217895 "2"^^ . . . _:b499217894 "2"^^ . . _:b499217889 "2"^^ . . _:b499217929 . _:b499217888 "2"^^ . . . _:b499217891 "2"^^ . _:b499217890 "2"^^ . _:b499217829 . _:b499217901 "2"^^ . _:b499217828 . _:b499217930 . _:b499217900 "2"^^ . _:b499217831 . "10.1093%2Fjjco%2Fhys121" . _:b499217903 "2"^^ . . _:b499217830 . _:b499217902 "2"^^ . _:b499217897 "2"^^ . _:b499217937 . _:b499217915 . _:b499217852 . _:b499217896 "2"^^ . _:b499217891 . _:b499217899 "2"^^ . _:b17255628 "In addition, in our study bevacizumab improved the 6-month PFS and the ORR in the subgroups of patients who were aged <50 or <60 years compared with older patients. Although neither our study nor the previously published study (>>24<<) was powered to detect a statistical difference in these subgroups, the results could suggest that earlier administration of bevacizumab, or treatment with bevacizumab in younger patients, may lead to better tumor response and is" . _:b17255602 . _:b499217898 "2"^^ . _:b17255617 . . _:b499217837 . . _:b499217909 "2"^^ . _:b499217836 . _:b499217908 "2"^^ . _:b499217839 . _:b499217911 "2"^^ . _:b499217838 . _:b499217927 . . _:b499217910 "2"^^ . . _:b499217833 . _:b499217953 . _:b499217905 "2"^^ . . _:b499217975 . _:b499217832 . _:b499217904 "2"^^ . _:b17255625 "for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (6,7,10,11,37), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (>>24<<)." . _:b499217835 . . _:b499217907 "2"^^ . _:b499217834 . . _:b499217906 "2"^^ . _:b499217845 . _:b17255633 "In addition, the 1-year survival rate for GBM patients (34.5%) was as good as the published data (14\u201332%) (>>6<<\u20138,10,11)." . _:b499217919 . . _:b499217917 "2"^^ . _:b499217844 . . . _:b499217916 "2"^^ . _:b17255610 "High levels of VEGF are expressed in GBM cells (>>12<<,13), and hypoxia and acidosis, conditions commonly seen in solid tumors, upregulate VEGF expression in glioma cells in vivo (14)." . _:b499217847 . _:b499217919 "2"^^ . _:b499217846 . _:b499217918 "2"^^ . _:b499217841 . . _:b499217892 . . _:b499217913 "2"^^ . _:b499217840 . _:b499217847 . _:b499217912 "2"^^ . _:b499217843 . _:b499217904 . . _:b499217915 "2"^^ . . _:b499217842 . _:b499217914 "2"^^ . _:b499217853 . . _:b499217897 . _:b499217852 . _:b499217836 . . _:b499217855 . _:b499217883 . _:b17255614 . _:b17255629 "The median OS of 10.5 months in GBM patients and 9.4 months in all patients was longer than that reported in other GBM trials (5.0\u20137.3 months) (>>6<<\u20138,10,11) and comparable with data with single-agent bevacizumab (9.3 months) (24,25)." . . _:b17255627 "The 6-month PFS and ORR results were better for patients who had experienced one relapse than for those who had experienced two relapses, which is the same as a previously published observation (>>24<<). In addition, in our study bevacizumab improved the 6-month PFS and the ORR in the subgroups of patients who were aged <50 or <60 years compared with older patients." . _:b499217854 . _:b499217849 . _:b499217848 . . _:b499217851 . _:b17255610 . _:b499217850 . _:b17255643 "Six-month PFS was defined as the percentage of patients who remained alive and progression free at 24 weeks and was chosen based on published evidence demonstrating its extrapolation to the overall survival (OS) (>>6<<,7). Secondary efficacy endpoints included the 1-year survival, PFS, objective response rate (ORR), duration of response (DOR), OS and disease control rate (DCR)." . _:b17255630 . . _:b17255607 . _:b499217895 . _:b499217857 . _:b499217861 . _:b17255606 . _:b499217860 . . . _:b499217863 . _:b17255614 . . _:b499217909 . _:b499217862 . _:b499217857 . _:b499217856 . _:b499217945 . _:b499217859 . . _:b499217888 . _:b499217858 . _:b17255622 . _:b499217869 . . _:b499217848 . _:b499217849 . _:b499217868 . _:b499217850 . . _:b499217851 . . _:b499217852 . _:b499217853 . _:b17255629 . _:b499217871 . _:b499217854 . _:b499217855 . _:b499217840 . _:b499217841 . _:b499217870 . _:b499217842 . _:b499217843 . _:b499217844 . _:b499217845 . _:b499217865 . _:b499217846 . _:b499217847 . _:b499217832 . _:b499217833 . _:b499217864 . _:b499217834 . _:b499217835 . _:b499217836 . _:b499217837 . . . _:b499217867 . _:b499217838 . _:b499217839 . _:b499217866 . . . _:b499217828 . _:b499217829 . _:b499217839 . _:b499217877 . _:b499217830 . _:b499217831 . _:b499217876 . _:b499217869 . _:b17255621 . _:b499217879 . _:b499217902 . _:b17255637 . _:b17255632 "The median OS of 10.5 months in GBM patients and 9.4 months in all patients was longer than that reported in other GBM trials (5.0\u20137.3 months) (6\u20138,10,11) and comparable with data with single-agent bevacizumab (9.3 months) (>>24<<,25). In addition, the 1-year survival rate for GBM patients (34.5%) was as good as the published data (14\u201332%) (6\u20138,10,11)." . _:b499217878 . _:b499217861 . _:b17255621 "These data are numerically higher than those reported for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (6,>>7<<,10,11,37), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (24)." . . _:b499217949 . _:b499217873 . _:b17255639 . _:b499217872 . . _:b17255632 . _:b499217967 . _:b17255613 "In a mouse model, monoclonal antibodies to VEGF have been shown to inhibit the growth of the C6 glioma (>>15<<). Bevacizumab (Avastin\u00AE) is a monoclonal antibody that inhibits VEGF and is currently approved for a range of metastatic cancers (colorectal, non-small-cell lung, breast, ovarian cancer and renal cancers) (16\u201319) as well as for use in" . _:b499217875 . _:b499217876 . _:b499217829 . _:b499217874 . _:b499217846 . . _:b499217885 . _:b499217912 . _:b499217913 . _:b499217884 . . _:b499217914 . _:b499217915 . _:b17255628 . _:b499217916 . _:b499217936 . _:b499217917 . _:b499217887 . _:b499217918 . _:b499217919 . _:b499217904 . _:b499217905 . _:b17255644 . _:b499217886 . _:b499217906 . _:b499217882 . . _:b499217907 . _:b17255634 . _:b499217908 . _:b499217856 . _:b499217909 . _:b499217881 . _:b499217910 . _:b499217911 . _:b499217896 . . _:b499217897 . _:b499217880 . _:b499217898 . _:b499217899 . _:b499217900 . _:b499217901 . _:b499217883 . _:b499217902 . _:b499217903 . _:b17255625 . _:b499217888 . _:b499217889 . _:b499217882 . _:b499217890 . _:b499217891 . _:b17255603 . _:b499217958 . _:b499217892 . _:b17255626 "however, subsequently the Response Assessment in Neuro-Oncology (RANO) Working Group has recommended assessing MRI T2-weighted or fluid-attenuated inversion recovery (FLAIR) of non-enhancing lesions in addition to enhancing lesions (>>38<<). As the Macdonald's Criteria only assess contrast-enhancing lesions, there are risks that pseudoprogression and pseudoresponses may be considered real treatment effects." . . _:b499217893 . _:b499217893 . _:b499217894 . _:b499217895 . _:b17255627 . _:b499217860 . _:b499217947 . _:b499217834 . _:b499217880 . _:b499217881 . _:b499217892 . _:b17255646 . . _:b499217882 . . . _:b17255614 . _:b499217883 . _:b499217884 . . _:b499217885 . . _:b499217886 . _:b499217895 . _:b499217887 . _:b499217872 . _:b499217873 . _:b499217894 . _:b499217874 . _:b499217875 . _:b499217876 . _:b499217877 . _:b499217889 . _:b499217878 . . _:b499217879 . _:b499217864 . _:b499217865 . _:b499217888 . _:b499217866 . _:b499217867 . _:b17255645 . _:b17255616 . _:b499217868 . _:b17255635 "In addition, the 1-year survival rate for GBM patients (34.5%) was as good as the published data (14\u201332%) (6\u20138,10,>>11<<)." . _:b499217869 . _:b17255633 . _:b499217891 . _:b499217964 . _:b499217870 . _:b499217871 . _:b499217856 . _:b499217857 . _:b499217890 . _:b499217858 . _:b499217859 . _:b499217860 . _:b499217861 . _:b499217901 . _:b499217862 . _:b499217863 . _:b499217900 . _:b499217903 . _:b499217872 . . . _:b499217902 . . _:b499217928 . _:b499217897 . _:b499217896 . . _:b499217899 . . . . _:b17255617 "Moreover, other studies have shown the efficacy of bevacizumab in recurrent GBM whether given as a single agent (>>27<<) or combined with irinotecan (28,29) and other chemotherapies, such as etoposide, carboplatin and fotemustine (30\u201333)." . _:b499217898 . . _:b499217971 . _:b499217909 . _:b499217877 . _:b499217849 . _:b499217908 . . _:b17255608 . _:b499217911 . _:b499217900 . . _:b499217910 . _:b499217905 . _:b499217904 . _:b499217955 . _:b499217855 . . _:b499217866 . _:b499217907 . _:b499217906 . _:b17255606 . _:b499217917 . _:b499217916 . _:b499217838 . . . _:b499217919 . _:b499217935 . _:b499217918 . _:b499217874 . _:b499217913 . _:b499217912 . _:b499217894 . _:b499217915 . _:b499217918 . _:b499217983 . _:b499217914 . _:b17255626 . _:b17255623 "These data are numerically higher than those reported for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (6,7,10,>>11<<,37), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (24)." . _:b499217965 . _:b499217990 . _:b499217880 . _:b499217991 . _:b499217889 . _:b499217956 . . . . _:b17255616 "Subsequently, two Phase II studies (>>24<<\u201326) showed the efficacy of single-agent bevacizumab with regard to response rates and 6-month PFS in patients with recurrent GBM who had previously received RT and TMZ." . _:b499217896 . . . _:b499217932 . _:b17255618 . _:b499217923 . . _:b499217933 . . _:b499217994 . . _:b499217963 . . _:b499217974 . . . _:b17255639 "In our study, and in the other single-agent bevacizumab studies (>>24<<\u201326,40), bevacizumab was administered after prior treatment with TMZ and RT." . . . . _:b17255611 . _:b499217916 . . _:b17255636 . . _:b499217973 . . . . . _:b499217905 . . . . _:b17255642 "patients and methods" . _:b499217938 . . . _:b17255620 "These data are numerically higher than those reported for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (>>6<<,7,10,11,37), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (24)." . . . _:b499217961 . _:b499217920 . _:b17255629 . _:b17255641 "There are many novel targeted agents under investigation for the treatment of gliomas (>>43<<); however, results with these new agents have been disappointing to date. Single-target agents alone may not be able to prevent tumor growth given the multiple pathways involved in many intracellular processes of tumor development." . . _:b499217946 . . _:b499217886 . _:b17255631 "The median OS of 10.5 months in GBM patients and 9.4 months in all patients was longer than that reported in other GBM trials (5.0\u20137.3 months) (6\u20138,10,>>11<<) and comparable with data with single-agent bevacizumab (9.3 months) (24,25)." . _:b499217944 . . . _:b17255640 "In our study, and in the other single-agent bevacizumab studies (24\u201326,>>40<<), bevacizumab was administered after prior treatment with TMZ and RT." . _:b17255638 . _:b499217986 . . _:b499217842 . _:b17255618 . _:b499217979 . _:b499217881 . _:b17255640 . . . _:b499217879 . . . _:b17255604 . _:b499217941 . _:b17255605 . _:b17255624 "These data are numerically higher than those reported for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (6,7,10,11,>>37<<), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (24)." . . . . _:b17255606 . . _:b499217939 . . _:b17255633 . _:b17255607 . . _:b17255624 . _:b499217863 . . _:b499217976 . _:b499217831 . _:b17255601 . _:b499217980 . . _:b17255602 . _:b499217898 . . . . _:b17255603 . _:b17255633 . . _:b17255612 . _:b17255613 . _:b499217832 . . _:b17255614 . . _:b499217954 . _:b499217854 . . . _:b17255615 . _:b499217942 . _:b17255608 . . _:b17255609 . _:b17255643 . _:b499217835 . _:b499217985 . _:b17255610 . _:b17255611 . . _:b17255620 . . _:b17255621 . _:b499217828 . _:b17255622 . . . _:b17255623 . _:b499217911 . _:b17255606 "Currently there is no standard therapy for recurrent GBM and the estimated 6-month progression-free survival (PFS) rate for patients with recurrent disease is 9\u201328% (>>6<<\u201311) with a 1-year survival rate of 14\u201332% (6\u20138,10,11)." . _:b17255616 . _:b499217844 . _:b17255617 . _:b499217934 . _:b17255618 . _:b17255620 . _:b499217845 . . . _:b17255619 . _:b17255628 . _:b499217931 . _:b17255629 . . _:b17255630 . . _:b499217907 . _:b17255631 . _:b499217925 . . _:b17255624 . . _:b17255625 . _:b17255626 . _:b499217885 . _:b499217925 . _:b17255627 . _:b17255629 . . _:b499217922 . _:b499217924 . _:b499217976 . _:b17255636 . _:b499217977 . _:b499217978 . _:b499217979 . _:b499217972 . _:b499217927 . _:b499217980 . _:b17255637 . _:b499217981 . _:b499217841 . _:b499217982 . _:b499217983 . _:b499217926 . . _:b499217912 . _:b17255638 . _:b499217950 . _:b499217968 . . _:b499217969 . _:b499217970 . _:b499217960 . _:b499217921 . _:b499217971 . _:b499217908 . _:b17255639 . _:b17255603 "Glioblastoma (GBM) is the most aggressive form of primary malignant brain tumor and the prognosis for patients with GBM is poor (1,>>2<<); the majority will relapse following initial treatment and <10% are alive at 5 years (3)." . _:b499217972 . _:b499217973 . _:b499217974 . _:b499217920 . _:b499217975 . _:b499217960 . _:b17255632 . _:b499217961 . _:b499217962 . _:b499217984 . _:b499217963 . _:b499217992 . _:b499217923 . _:b499217964 . _:b17255633 . . _:b17255619 . . _:b499217965 . . _:b499217966 . _:b499217922 . _:b499217967 . _:b499217952 . _:b17255634 . _:b499217925 "2"^^ . _:b499217840 . _:b499217953 . . _:b499217954 . _:b499217955 . _:b499217933 . _:b17255642 . _:b17255635 . _:b499217924 "2"^^ . _:b499217956 . _:b499217957 . _:b499217958 . _:b499217959 . _:b499217932 . _:b499217944 . _:b17255644 . _:b17255606 . _:b499217927 "2"^^ . _:b499217945 . _:b499217946 . _:b499217947 . _:b17255606 . _:b499217935 . _:b499217948 . _:b17255645 . _:b17255607 . _:b499217926 "2"^^ . _:b499217949 . . _:b499217950 . _:b499217951 . _:b17255607 . _:b499217934 . _:b499217921 "2"^^ . _:b17255646 . _:b499217936 . . _:b17255601 "introduction" . _:b499217937 . _:b499217938 . _:b499217939 . _:b499217929 . _:b499217920 "2"^^ . . _:b499217940 . _:b499217941 . _:b499217942 . _:b499217865 . _:b17255612 "High levels of VEGF are expressed in GBM cells (12,13), and hypoxia and acidosis, conditions commonly seen in solid tumors, upregulate VEGF expression in glioma cells in vivo (>>14<<). In a mouse model, monoclonal antibodies to VEGF have been shown to inhibit the growth of the C6 glioma (15). Bevacizumab (Avastin\u00AE) is a monoclonal antibody that inhibits VEGF and is currently approved for a range of metastatic cancers" . _:b499217928 . _:b499217943 . . _:b17255640 . _:b499217923 "2"^^ . _:b499217928 . _:b499217929 . _:b499217914 . _:b499217930 . _:b499217931 . _:b499217931 . _:b499217922 "2"^^ . _:b17255641 . _:b17255615 . _:b499217932 . _:b499217833 . . _:b499217933 . _:b499217934 . _:b499217935 . _:b499217930 . _:b499217920 . _:b499217933 "2"^^ . _:b17255642 . _:b499217921 . _:b499217922 . . _:b499217941 . _:b499217923 . _:b499217924 . _:b17255643 . _:b499217932 "2"^^ . _:b499217925 . _:b499217926 . _:b499217927 . _:b499217940 . . _:b499217935 "2"^^ . . _:b499217924 . _:b17255601 . _:b499217943 . _:b499217934 "2"^^ . . _:b499217942 . _:b499217884 . _:b499217929 "2"^^ . _:b499217937 . _:b499217928 "2"^^ . _:b499217951 . _:b499217936 . _:b499217931 "2"^^ . _:b17255630 "The median OS of 10.5 months in GBM patients and 9.4 months in all patients was longer than that reported in other GBM trials (5.0\u20137.3 months) (6\u20138,>>10<<,11) and comparable with data with single-agent bevacizumab (9.3 months) (24,25)." . _:b499217939 . _:b499217930 "2"^^ . _:b499217940 . . _:b499217938 . _:b499217941 "2"^^ . _:b499217949 . _:b499217940 "2"^^ . _:b499217948 . . _:b499217943 "2"^^ . . _:b499217906 . _:b499217951 . . _:b499217942 "2"^^ . _:b499217950 . _:b499217937 "2"^^ . . _:b499217945 . _:b499217969 . _:b499217873 . _:b499217936 "2"^^ . _:b499217878 . _:b17255644 "Six-month PFS was defined as the percentage of patients who remained alive and progression free at 24 weeks and was chosen based on published evidence demonstrating its extrapolation to the overall survival (OS) (6,>>7<<). Secondary efficacy endpoints included the 1-year survival, PFS, objective response rate (ORR), duration of response (DOR), OS and disease control rate (DCR)." . _:b499217966 . _:b499217944 . "PMC0" . _:b499217939 "2"^^ . _:b499217992 . _:b499217993 . _:b499217848 . _:b499217994 . _:b499217947 . . _:b499217938 "2"^^ . . _:b499217946 . . _:b499217949 "2"^^ . _:b499217984 . . _:b499217985 . _:b499217986 . _:b499217987 . _:b499217957 . _:b499217988 . _:b499217948 "2"^^ . _:b499217989 . _:b499217899 . _:b499217990 . _:b499217991 . _:b499217956 . _:b499217951 "2"^^ . _:b499217959 . _:b499217851 . _:b499217950 "2"^^ . . _:b499217958 . _:b499217945 "2"^^ . _:b499217953 . _:b17255641 . _:b499217859 . _:b499217944 "2"^^ . _:b499217913 . _:b499217850 . _:b17255622 "These data are numerically higher than those reported for other studies with other chemotherapy and/or RT regimens (6-month PFS 9\u201321% and ORR 4\u20139%) (6,7,>>10<<,11,37), and comparable with those reported for single-agent bevacizumab (42.6 and 28.2% for 6-month PFS and ORR, respectively) (24)." . _:b499217952 . _:b499217947 "2"^^ . . _:b499217955 . . _:b499217946 "2"^^ . _:b499217988 . _:b499217954 . _:b499217957 "2"^^ . _:b17255619 "discussion" . _:b499217965 . . _:b499217956 "2"^^ . . . _:b499217964 . _:b499217875 . _:b499217959 "2"^^ . . . _:b499217967 . _:b499217958 "2"^^ . _:b499217966 . _:b17255606 . _:b499217953 "2"^^ . . _:b17255638 "Bevacizumab was well tolerated in our study and the incidence of AEs of special interest to bevacizumab was similar to that seen in other published studies with single-agent bevacizumab (24\u201326,>>40<<). No new bevacizumab safety signals were seen in this Japanese population." . . _:b499217961 . _:b17255601 _:b17255602 . _:b499217952 "2"^^ . _:b499217943 . _:b17255601 _:b17255603 . _:b17255601 _:b17255604 . _:b17255601 _:b17255605 . _:b499217960 . _:b17255601 _:b17255606 . _:b499217955 "2"^^ . . _:b17255601 _:b17255607 . _:b17255601 _:b17255608 . . _:b17255609 . _:b499217963 . _:b17255601 _:b17255609 . _:b17255601 _:b17255610 . _:b499217954 "2"^^ . _:b17255601 _:b17255611 . _:b499217862 . _:b17255601 _:b17255612 . _:b17255601 _:b17255613 . _:b499217962 . _:b17255601 _:b17255614 . _:b499217965 "2"^^ . _:b17255601 _:b17255615 . . _:b499217973 . _:b17255616 . _:b499217964 "2"^^ . _:b499217972 . _:b499217967 "2"^^ . _:b499217831 "10"^^ . _:b499217948 . _:b499217981 . _:b499217975 . . _:b499217966 "2"^^ . _:b499217968 . _:b17255637 "Bevacizumab was well tolerated in our study and the incidence of AEs of special interest to bevacizumab was similar to that seen in other published studies with single-agent bevacizumab (>>24<<\u201326,40). No new bevacizumab safety signals were seen in this Japanese population." . _:b499217830 "12"^^ . _:b499217974 . _:b499217961 "2"^^ . . _:b499217887 . _:b499217858 . _:b499217829 "12"^^ . _:b499217969 . _:b499217960 "2"^^ . _:b499217968 . _:b499217963 "2"^^ . _:b499217828 "14"^^ . _:b499217962 . _:b499217971 .