Please select the eligibility criteria that correspond to the clinical trial below.
Title: Temozolomid (One Week on/One Week Off) Versus Strahlentherapie in Der Primärtherapie Anaplastischer Astrozytome Und Glioblastome Bei älteren Patienten: Eine Randomisierte Phase III-Studie (Methvsalem)
Brief Summary: The study aims to optimize the treatment of elderly subjects (\> 65) with anaplastic astrocytoma and glioblastoma. Current treatment policies tend to be no more than palliative. There is no consensus as to how radical the surgery should be. Involved-field radiotherapy is the treatment most likely to be accepted apart from supportive and palliative measures. The role of chemotherapy is barely defined. Study data available to date does not suggest that this patient population would benefit from combined radiochemotherapy. The aim of the study is to verify the hypothesis that first-line chemotherapy with one week on/one week off temozolomide is not inferior to extended-field radiotherapy in the first-line treatment of anaplastic astrocytoma and glioblastoma in the elderly (\> 65 age group). The primary endpoint is median survival, as life expectancy is limited to several months. Secondary endpoints are response rates in both arms (CR, PR, MacDonald et al. 1990), median progression-free survival, 1-year and 2-year survival rates, definition of MGMT as molecular genetic prognostic or predictive markers, and quality of life. Theoretically, it should be possible to preserve quality of life in the first-line chemotherapy arm of the study.


Options:
A: DISEASE CHARACTERISTICS:

* Histopathologically confirmed glioblastoma multiforme

  * Grade IV disease by WHO classification
  * Newly diagnosed disease
* Initial diagnostic surgery or biopsy performed within the past 4 weeks
* Not a candidate for standard radiotherapy (60Gy/30 fractions over 6 weeks) in combination with temozolomide

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Absolute granulocyte count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* ALT and AST \< 2.5 times ULN
* No known hypersensitivity to temozolomide or compounds with similar chemical composition to temozolomide
* No history of other malignancies except adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years
* No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that would preclude study treatment
* No other condition (e.g., psychological or geographical) that would preclude study compliance

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy
* No prior radiotherapy
* No prior or concurrent investigational therapy
* No concurrent surgical procedures for tumor debulking
* No concurrent stereotactic boost radiotherapy
* No other concurrent chemotherapy, immunotherapy, or biological therapy
* No concurrent epoetin alfa
* Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for at least 14 days
B: Inclusion Criteria:

* Unifocal, supratentorial recurrent glioblastoma
* Prior course of standard treatment
* Complete resection of all contrast enhancing areas
* age ≥ 18 years of age
* Karnofsky Performance Score 60% or higher
* For women with childbearing potential, (and men) adequate contraception.
* Ability of subject to understand character and individual consequences of the clinical trial
* Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

* Multifocal glioblastoma of gliomatosis cerebri
* Time interval of less than 6 months after primary radiotherapy
* Previous re-irradiation or prior radiosurgery of prior treatment with interstitial radioactive seeds
* refusal of the patients to take part in the study
* Patients who have not yet recovered from acute toxicities of prior therapies
* Known carcinoma \< 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy
* Pregnant or lactating women
* Participation in another clinical study or observation period of competing trials, respectively.
C: Inclusion Criteria:

* Male or female ≥ 18 years of age
* Histologically confirmed de novo glioblastoma multiforme (grade IV)
* First recurrence after adjuvant treatment (surgery followed by radiotherapy and temozolomide chemotherapy with or without bevacizumab) in patients who have not received further therapeutic interventions
* For patients not undergoing a second surgery at the time of relapse, recurrent disease must include at least one bi-dimensionally measurable contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on an MRI scan done within 2 weeks prior to randomization
* Documented progression of disease as defined by RANO criteria at least 12 weeks after completion of radiotherapy, unless the recurrence is outside the radiation field or has been histologically documented
* Have adequate bone marrow function, liver function, and renal function, as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:

  * Hemoglobin \>9.0 g/dl
  * Absolute neutrophil count (ANC) \>1500/mm3 without transfusions or granulocyte colony stimulating factor and other hematopoietic growth factors
  * Platelet count ≥100,000/μl
  * White blood cell count (WBC) \>3.0 x 109/L
  * Total bilirubin \<1.5 times the upper limit of normal
  * ALT and AST \<3 x upper limit of normal (\<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
  * Serum creatinine \<1.5 x upper limit of normal
  * Alkaline phosphatase \<2.5 x ULN (\<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
  * PT-INR/PTT \<1.5 x upper limit of normal (Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists per medical history)
  * Lipase ≤ 1.5 x the ULN
* Glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
* Analyses of MGMT methylation status on tumoral tissue at first surgery (at own institution)
* Understand, be willing to give consent, and sign the written informed consent form (ICF) prior to undergoing any study-specific procedure
* If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment
* If female and of childbearing potential, or if male, agree to use adequate contraception (eg, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug
* World Health Organization (WHO) Performance status ≤ 1 (or Karnofsky performance status (KPS) ≥70)) within 14 days prior to the initiation of study treatment
* Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
* Patients may have undergone surgery for the recurrence; the histological report must document a glioblastoma recurrence. If operated:

  * at least 28 days and maximum 42 days interval from the surgery is required prior to administration of study drugs and patients should have fully recovered
  * Exclusion Criteria:
* Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort)
* Radiotherapy within 12 weeks prior to the diagnosis of progression, if the lesion is in the radiation field,
* Have had systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation of study treatment
* Positioning of carmustin wafers during first or second surgery
* Other active or inactive malignancy (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma). Malignancy will be considered inactive if patients are in complete remission for at least 3 years prior to study entry
* Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor
* Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment
* Are pregnant
* Are breastfeeding
* Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed)
* Have congestive heart failure classified as New York Heart Association Class 2 or higher
* Have had unstable angina (angina symptoms at rest) or new-onset angina ≤ 3 months prior to screening.
* Have had a myocardial infarction \< 6 months prior to initiation of study treatment
* Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
* Have uncontrolled hypertension (systolic blood pressure \[SBP\] \> 140 mmHg or diastolic blood pressure \[DBP\] \> 90 mmHg) despite optimal medical management
* Have had arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months prior to the initiation of study treatment
* Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0)
* Have a known history of human immunodeficiency virus infection
* Have either active or chronic hepatitis B or C requiring treatment with antiviral therapy
* Have a history of organ allograft
* Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity
* Have had a hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment
* Have a non-healing wound, ulcer, or bone fracture
* Have renal failure requiring hemodialysis or peritoneal dialysis
* Have dehydration ≥ Grade 1 (NCI-CTCAE v 4.0)
* Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained
* Have persistent proteinuria \> 3.5 g/24 hours measured by urine protein creatinine ratio from a random urine sample (Grade 3, NCI-CTCAE v 4.0)
* Have any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
* Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
* Have any malabsorption condition
* Recurrent disease located outside of the brain
D: Inclusion Criteria:

* Histologically confirmed supratentorial anaplastic astrocytoma or glioblastoma
* Age \> 65
* Karnofsky performance score \> 60%
* Neutrophilic granulocyte count \> 1500/µl
* Platelet count \> 100 000/µl
* Hemoglobin \> 10 g/dl
* Serum creatinine \< 1.5 times the lab's upper normal limit
* AST or ALT \< 3 times the lab's upper normal limit
* Alkaline phosphatase \< 3 times the lab's upper normal limit
* No previous systemic chemotherapy
* No previous radiotherapy to the brain
* Written consent

Exclusion Criteria:

* Serious medical or neurological condition with a poor prognosis
* HIV infection
* Second cancer requiring radiotherapy or chemotherapy (contact the study coordinat if necessary)
* Hypersensitivity to temozolomide
* Conditions associated with regular vomiting that might affect oral administration of the drugs
* Psychological, familial, social or geographical circumstances with major implications for compliance with the study visit schedule
* Patient was taking part in other intervention studies within a month of starting this study

Answer: D