Bevacizumab Alone Versus Dose-dense Temozolomide Followed by Bevacizumab for Recurrent Glioblastoma, Phase III

Inclusion Criteria:

1. Histologically proven diagnosis of glioblastoma (including giant cell glioblastoma and gliosarcoma) by WHO2007 criteria.
2. For patients who did not undergo surgery for recurrent disease; pre-registration contrast MRI should confirm; (i)progressive or recurrent glioblastoma; (ii)no evidence of acute or subacute cerebral hemorrhage at enrolment; (iii)presence of a measurable lesion.
3. For patients who underwent surgery for recurrent disease; (i)progressive or recurrent glioblastoma must be confirmed on contrast MRI before reoperation; (ii)glioblastoma or anaplastic astrocytoma must be histologically identified in the tissue resected at reoperation; (iii)presence of measurable lesions is not mandatory on pre-registration contrast MRI (more than 4 days after reoperation); (iv)no MRI evidence of aggravating cerebral hemorrhage.
4. No evidence of tumors in the cerebellum, brain stem, optic nerve, olfactory nerve, and pituitary gland.
5. No evidence of meningeal dissemination or gliomatosis cerebri.
6. Prior treatment for newly-diagnosed glioblastoma (or diffuse astrocytoma (Grade II) or anaplastic astrocytoma (Grade III)) with postoperative TMZ administered concomitantly with radiotherapy (\>=54 Gy for \<=69 years old; \>=30 Gy for \>=70 years old) and at least for two cycles (5/28d) as an adjuvant treatment have been given.
7. No history of prior treatment with stereotactic radiotherapy (ex. Gamma-knife/Cyberknife), proton beam irradiation, neutron capture therapy, and chemotherapies except standard dose TMZ and immunotherapy (vaccines, immune checkpoint inhibitors, antibodies etc.), bevacizumab (12 weeks or more after termination of prior upfront bevacizumab use) that were combined with TMZ, and intraoperative placement of carmustine wafers, for glioblastoma (including diffuse astrocytoma (Grade II) and anaplastic astrocytoma (Grade III) at onset) diagnosed with WHO2007 criteria.

   Time periods required from the last day of the prior treatment indicated at registration.

   ①Peptide vaccination, immune checkpoint inhibitors, antibodies: 4 weeks.

   ②Bevacizumab: 12 weeks.
8. More than 90 days after completion of radiotherapy. For those who underwent reoperation, between 21 and 28 days postoperatively.
9. Age between 20 and 75 years at enrolment.
10. Karnofsky Performance Status \>= 60 within 14 days before enrolment.
11. No prior treatment with chemotherapy, molecular targeted therapy, or radiotherapy to head and neck area for other malignancies.
12. Adequate organ function.
13. Written informed consent.

Exclusion Criteria:

1. Synchronous or metachronous (within 5 years) malignancy, except for carcinoma in situ or mucosal tumors curatively treated with local therapy
2. Active infection requiring systemic therapy
3. Body temperature \>= 38 degrees Celsius at registration
4. Women during pregnancy, possible pregnancy, within 28 days after delivery, or breast-feeding
5. Psychosis or with psychotic symptom
6. Continuous systemic use of immunosuppressant except for steroid
7. Uncontrolled diabetes mellitus
8. Unstable angina within 3 weeks, with a history of myocardial infarction within 6 months, or New York Heart Association (NYHA) class II or greater congestive heart failure
9. Inadequately controlled hypertension (cannot be controlled to a systolic pressure of \>= 150 mmHg and a diastolic pressure of \>= 100 mmHg)
10. History of symptomatic cerebrovascular disorder (including subarachnoid hemorrhage, cerebral infarction and transient ischemic attack) within 6 months or history of vascular disorder requiring intervention (including venous/arterial thrombosis or embolism and aortic aneurysm) within 6 moths
11. History of grade \>= 2 hemoptysis within 28 days
12. History of hemorrhagic tendency (e.g., coagulation disorder) or any grade \>= 3 hemorrhage within 28 days
13. History of gastrointestinal perforation, fistula, abdominal abscess or uncontrolled peptic ulcer within 6 months
14. Interstitial pneumonia, pulmonary fibrosis, or severe lung emphysema
15. Severe non-healing wound or traumatic fracture at enrolment
16. Hypersensitivity to Chinese Hamster Ovary-derived drugs or other recombinant antibodies
17. Gadolinium allergy
18. Positive HIV antibody
19. Positive Hepatitis B (HB)s antigen