Medpedia

• Brain and Central Nervous System Tumors

DISEASE CHARACTERISTICS:
-  Newly diagnosed tumors of the brain or spinal cord, meeting one of the following
criteria:
-  Histologically* confirmed diagnosis of 1 of the following high-grade gliomas:
-  Glioblastoma (WHOº IV)
-  Anaplastic astrocytoma (WHOº III)
-  Gliosarcoma (WHOº III or IV)
-  Anaplastic oligo-astrocytoma NOTE: *Histological requirement may be waived
for other types of brainstem glioma
-  Radiologically proven diffuse intrinsic pontine glioma
-  Second malignancy or disseminate metastases or multifocal tumors are allowed if the
field of irradiation is not too large
-  No diffuse metastases making craniospinal irradiation necessary
PATIENT CHARACTERISTICS:
-  No cardiorespiratory insufficiency requiring medical respiration
-  No low blood pressure requiring systemic catecholamines
-  No severe neurological damage (e.g., coma)
-  No tetraplegia without possibility to communicate
-  No other poor clinical condition
-  Not pregnant
-  Fertile patients must use effective contraception
-  No hypersensitivity to methotrexate, cisplatin, vincristine, lomustine, or ifosfamide
-  No other malignancy preceding radiotherapy that does not allow further radiation
PRIOR CONCURRENT THERAPY:
-  No prior chemotherapy for brain tumor
-  The following prior therapies are allowed:
-  Mistletoe
-  H15 (extract of Boswellia serrata)
-  Homeopathy therapy with dilution > 4D
-  Alternative medicine without proven efficacy
-  No prior radiotherapy for brain tumor
-  No concurrent alcohol or tobacco consumption
-  No concurrent participation in another study

OBJECTIVES:

Primary

-  Determine if the addition of high-dose methotrexate prior to standard treatment
improves survival of patients with malignant high-grade glioma or diffuse intrinsic
pontine glioma as compared to standard treatment only.

Secondary

-  Determine if the addition of high-dose methotrexate, as compared to standard treatment
only, improves the tumor response of these patients.

-  Determine if high-dose methotrexate, compared to standard treatment only, improves the
progression-free or event-free survival of these patients.

-  Determine if high-dose methotrexate, as compared to standard treatment only, improves
the health status (quality of life) of these patients.

-  Determine if consolidation therapy improves the overall, progression-free, or
event-free survival rates as compared to the historical control group.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified
according to tumor location includes pons (yes vs no) and complete or nearly complete
resection (yes vs no).

-  Surgery: All patients are encouraged to undergo radical resection of the tumor to
reduce intracranial pressure, remove as much tumor tissue as possible, and obtain tumor
tissue for histological diagnosis. Within 14 days after surgery, patients proceed to
induction chemotherapy.

-  Induction therapy: Patients are randomized to 1 of 2 treatment arms.

-  Arm I:

-  High-dose methotrexate with leucovorin calcium: Patients receive high-dose
methotrexate IV over 24 hours on days 1 and 15 and leucovorin calcium IV
every 6 hours on days 2-3 an 16-17. Patients proceed to chemoradiotherapy 4
weeks later.

-  Chemoradiotherapy (course 1): Patients undergo external beam radiotherapy
once daily, 5 days a week, for approximately 6 weeks. Beginning on the first
day of radiotherapy, patients receive cisplatin IV over 1 hour on days 1-5,
etoposide IV over 2 hours on days 1-3, and vincristine IV on days 5, 12, 19,
26, and 33. Patients proceed to course 2 of chemoradiotherapy 7 days prior to
completion of radiotherapy.

-  Chemoradiotherapy (course 2): Patients receive ifosfamide IV over 1 hour and
cisplatin IV over 1 hour on days 1-5, etoposide IV over 2 hours on days 1-3,
and vincristine IV on day 5. Patients proceed to consolidation chemotherapy 4
weeks later.

-  Arm II: Patients receive chemoradiotherapy courses 1 and 2 as in arm I and proceed
to consolidation chemotherapy 4 weeks later.

-  Consolidation chemotherapy: Patients receive vincristine IV on days 1, 8, and 15, oral
lomustine once on day 2, and oral prednisone once daily on days 1-17. Treatment repeats
every 6 weeks for up to 8 courses.

Quality of life is assessed 1 week after surgery, after completion of chemoradiotherapy, at
1, 4, and 13 months after completion of consolidation chemotherapy, and then annually for 3
years.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

• Drug: cisplatin
  Given IV
• Drug: etoposide
  Given IV
• Drug: ifosfamide
  Given IV
• Drug: lomustine
  Given IV
• Drug: methotrexate
  Given IV
• Drug: prednisone
  Given IV
• Drug: vincristine sulfate
  Given IV

• Overall survival (OS) rate at 5.5 years
  Safety Issue: No
• Comparison of OS, progression-free survival, and event-free survival with historical control annually
  Safety Issue: No
• Long-term sequelae annually
  Safety Issue: No
• Tumor response
  Safety Issue: No
• Progression-free survival
  Safety Issue: No
• Event-free survival
  Safety Issue: No
• Health status
  Safety Issue: No

• Christoph Kramm, MD
  Study Chair, University Children's Hospital

• M. D. Anderson Cancer Center at University of Texas
  Houston, Texas, 77030-4009, United States
  Active, not recruiting

• Gesellschaft fur Padiatrische Onkologie und Hamatologie - Germany
  Lead Sponsor
• United States: Federal Government

• Clinical trial summary from the National Cancer Institute's PDQ® database
  http://cancer.gov/clinicaltrials/GPOH-HIT-GBM-D