Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first‐line treatment of patients with glioblastoma multiforme

• Published in: Cancer Vol. 116; no. 15; pp. 3663 - 3669
• Main Authors: Hainsworth, John D., Ervin, Thomas, Friedman, Elke, Priego, Victor, Murphy, Patrick B., Clark, Bobby L., Lamar, Ruth E.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2010; Wiley-Blackwell
• Subjects: Adult; Aged; antiangiogenesis agents; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzenesulfonates - administration & dosage; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - radiotherapy; combined modality; Combined Modality Therapy; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Female; first‐line; Glioblastoma - drug therapy; Glioblastoma - radiotherapy; glioblastoma multiforme; Humans; Male; Medical sciences; Middle Aged; Neurology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Pyridines - administration & dosage; sorafenib; temozolomide; Tumors; Tumors of the nervous system. Phacomatoses; Antineoplastic agent; Human; Nervous system diseases; Tyrosine kinase inhibitor; Concurrent; Enzyme inhibitor; Malignant tumor; Radiotherapy; combined modality; Glioblastoma multiforme; First line treatment; Malignant glioma; Alkylating agent; Cancerology; Sorafenib; Central nervous system disease; first-line; Multikinase inhibitor; Temozolomide; Antiangiogenic agent; Cancer; antiangiogenesis agents
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.25275

BACKGROUND: The current study was conducted to evaluate the efficacy of sorafenib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, when added to standard radiotherapy and temozolomide in the first‐line treatment of patients with glioblastoma multiforme. METHODS: After initial surgical resection or biopsy, patients with newly diagnosed glioblastoma multiforme received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and temozolomide (at a dose of 75 mg/m2 orally daily), followed by 6 months of maintenance therapy with temozolomide (at a dose of 150 mg/m2 orally on Days 1‐5 every 28 days) and sorafenib (at a dose of 400 mg orally twice daily). Patients were re‐evaluated every 2 months; the primary endpoint of the trial was progression‐free survival (PFS). RESULTS: A total of 47 patients were treated; 34 had undergone previous debulking surgery. Nineteen patients withdrew from treatment before the initiation of maintenance therapy with temozolomide and sorafenib (12 because of early tumor progression). Twenty‐eight patients (60% of enrolled patients) received 4 months of maintenance therapy with temozolomide and sorafenib, and 9 patients (19%) completed the planned 6 months of maintenance therapy. The median PFS for the entire group was 6 months (95% confidence interval [95% CI], 3.7‐7 months), with a 1‐year PFS rate of 16%. The median overall survival was 12 months (95%CI, 7.2‐16 months). Maintenance therapy with temozolomide and sorafenib was found to be well tolerated by most patients, with no grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) reported to occur in >10% of patients. CONCLUSIONS: The addition of sorafenib did not appear to improve the efficacy of treatment when compared with the results expected with standard therapy. A substantial percentage of patients (40%) did not receive any maintenance sorafenib, most often because of early disease progression. The administration of angiogenesis inhibitors concurrently with radiotherapy and temozolomide may optimize the opportunity to improve therapy. Cancer 2010. © 2010 American Cancer Society. In this phase 2 trial, sorafenib was added to oral temozolomide, after concurrent radiotherapy and temozolomide, in the first‐line treatment of patients with glioblastoma multiforme. Although generally well tolerated by those patients who went on to receive maintenance therapy, the addition of sorafenib did not appear to improve the efficacy of standard therapy, primarily due to the significant number of patients who developed disease progression before maintenance therapy.