The investigator propose a single-center randomized phase II controlled study designed to compare the management of first recurrence of GBM using etoposide versus tamoxifen.

Inclusion Criteria:

1. Histologically proven GBM with progression after previous first line chemoradiotherapy with temozolomide.

2. Progression documented by MRI with at least one bi-dimensionally measurable target lesion with one diameter of at least 10 mm, visible on two or more axial slices 5 mm apart.

3. Not received radiotherapy within the three months before the diagnosis of progression.

4. Stable or decreasing dose of corticosteroids prior to randomization: corticosteroids (dexamethasone) should be given at the lowest dose needed to control symptoms arising from increased intracerebral edema.

5. ECOG performance 0-2 (Appendix 2).

6. Age from 18-65 years.

7. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.

8. Patients of childbearing / reproductive potential should use adequate birth control methods, as defined by the investigator, during the study treatment period and for a period of 60 days after the last dose of study drug. A highly effective method of birth control is defined as those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.

   Note: abstinence is acceptable if this is established and preferred contraception for the patient and is accepted as a local standard.

9. Laboratory evaluation obtained within 7 days prior to randomization, with adequate function as defined below:

   • ANC ≥ 1.5 x 109/L
   • Platelets ≥ 100 x 109/L
   • Serum creatinine ≤ 1.5 times ULN
   • Total serum bilirubin ≤ 1.5 times ULN
   • ALT < 3 times ULN
   • AST < 3 times ULN
   • Alkaline phosphatase < 3 times ULN

10. Patient must understand and sign an informed consent prior to study registration.

Exclusion Criteria:

1. History of another malignancy or a concurrent malignancy (exceptions include patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ.
2. Uncontrolled hypertension (systolic blood pressure >150 mm Hg or diastolic blood pressure >100 mm Hg).
3. Any arterial or venous thrombosis up to 6 months before registration.
4. Evidence of recent hemorrhage on brain MRI.
5. Substantial cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (> New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.