A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas.
OBJECTIVE
Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting.


METHODS
This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions).


RESULTS
Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population.


CONCLUSIONS
Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.
Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. robert.den@jeffersonhospital.org
Robert B
RB
Den
Mitchell
M
Kamrava
Zhi
Z
Sheng
Maria
M
Werner-Wasik
Erin
E
Dougherty
Michelle
M
Marinucchi
Yaacov R
YR
Lawrence
Sarah
S
Hegarty
Terry
T
Hyslop
David W
DW
Andrews
Jon
J
Glass
David P
DP
Friedman
Michael R
MR
Green
Kevin
K
Camphausen
Adam P
AP
Dicker
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D009364:Neoplasm Recurrence, Local / Q000098:blood supply / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D000077157:Sorafenib; D000077204:Temozolomide; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D000077204:Temozolomide