乌鸦传媒

CHICAGO -- Patients with newly diagnosed glioblastoma lived no longer with the addition of bevacizumab (Avastin) to chemoradiation than they did without it, results of a large multicenter trial showed.

Patients lived about 16 months whether they received chemoradiation alone or with the angiogenesis inhibitor. Progression-free survival (PFS) did increase with bevacizumab, but the difference did not meet the trial's definition of statistical significance.

The addition of bevacizumab to chemoradiation did add to toxicity, Mark R. Gilbert, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported here at the American Society of Clinical Oncology.

"I think there was a hope and an expectation that the use of bevacizumab in newly diagnosed glioblastoma would improve patient outcome and, hopefully, survival, and that was not achieved with the study, so that was a disappointment," Gilbert told 乌鸦传媒.

"The study was set up to look at different subgroups of patients based on molecular characterization," he added. "None of those subgroups, as prespecified by the study, showed any survival advantage. We also looked at various clinical prognostic groups and didn't find a particular group that benefited."

Ongoing analysis has suggested that a molecularly characterized subgroup that would benefit from bevacizumab might still be identified, said Gilbert.

Chemoradiation with temozolomide is standard of care for patients with newly diagnosed glioblastoma. Though the treatment has improved survival, prognosis remains poor for many patients. Studies of bevacizumab had suggested the angiogenesis inhibitor might offer a survival advantage in glioblastoma, leading to the multicenter, randomized trial.

Investigators randomized 626 patients to temozolomide-based chemoradiation with or without bevacizumab. Patients in the bevacizumab arm started the agent 4 weeks into the radiation therapy protocol and continued for 6 to 12 cycles of maintenance therapy.

The trial had co-primary endpoints of overall survival and PFS. Secondary outcomes included the impact of treatment on MGMT methylation (a previously identified marker of response to temozolomide) and an analysis of tumor gene expression.

The results showed a median overall survival of 15.7 months with the addition of bevacizumab and 16.1 months without the targeted agent. PFS improved slightly in the bevacizumab arm (10.7 versus 7.3 months, P=0.004), but the difference did not meet the prespecified level of statistical significance (P=0.002).

MGMT methylation did predict improved overall survival (23.2 versus 14.3 months, P<0.001) and PFS (14.1 versus 8.2 months, P<0.001). However, neither MGMT methylation nor a nine-gene expression signature predicted benefit from treatment with bevacizumab. Patients with the best prognosis (MGMT methylation and favorable gene signature) had a trend toward worse survival with bevacizumab (15.7 versus 25.0 months, P=0.08).

The addition of bevacizumab was associated with more grade 3+ toxicity, primarily neutropenia, hypertension, and venous thromboembolism.

Analysis neurocognitive function and quality of life, which will be reported separately, showed a greater symptom burden and decline in neurocognitive function in patients treated with bevacizumab.

"Bevacizumab received FDA approval for recurrent glioblastoma based on dramatic radiographic activity in several phase II trials," ASCO spokesperson Howard Fine, MD, of New York University in New York City, said in a statement. "Now, two separate multinational randomized, phase III trials demonstrate that bevacizumab modestly increases progression-free survival but not overall survival for newly diagnosed patients.

"Although bevacizumab will clearly continue to have an important role in the treatment of patients with glioblastoma, the timing of its use, the specific subpopulation of patients that benefit the most, and the biological and clinical consequences of chronic vascular endothelial growth factor inhibition on glioma and normal cells within the central nervous system needs to be clarified."

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