Daniel M. Keller, PhD

April 30, 2012

April 30, 2012 (Miami, Florida) — The use of bevacizumab to treat recurrent glioblastoma multiforme (GBM) may raise the risk for secondary gliosarcoma (GS).

Bevacizumab (Avastin, Genentech), an antivascular endothelial growth factor (VEGF) antibody, has been approved for the treatment of recurrent GBM since 2009.

Isaac Yang, MD, assistant professor in the Department of Neurosurgery at the University of California, Los Angeles (UCLA), and a member of the Brain Tumor Program at the Jonnson Comprehensive Cancer Center, presented the new findings from 351 patients with recurrent GBM or gliosarcoma treated at UCLA.

"We found a significant increase in secondary gliosarcoma in the patients who received bevacizumab, and this difference was an absolute risk increase of approximately 14.6%," Dr. Yang told the conference delegates.

The results were presented here at the 80th Annual Scientific Meeting of the American Association of Neurological Surgeons.

Rare Variant

Even with advances in surgery, radiation therapy, and chemotherapy, the median survival time for patients with GBM is on the order of 12 to 18 months. VEGF is a family of proteins that promote angiogenesis and vascular permeability. Anti-VEGF antibodies can block these effects.

GS is a rare variant of GBM that has gliomatous and sarcomatous features, and most are primary tumors. Secondary GSs are usually diagnosed at surgery for previously resected and irradiated GBM and "have a greater propensity for extracranial metastases," Dr. Yang said. In addition, "there are some reports suggesting that the outcome of gliosarcoma is worse than glioblastoma."

To investigate whether the incidence of secondary GS is increased with the use of bevacizumab in patients with GBM, Dr. Yang and colleagues reviewed the records of all patients with recurrent GBM or GS treated at UCLA Medical Center between 1995 and 2011. They gathered information on chemotherapy, including the use and treatment duration of bevacizumab, along with patient data and clinical follow-up, and they reviewed the surgical histopathologic findings to confirm GBM at the first surgery as well as tumor types at subsequent surgeries.

Patients with GS on initial surgery and patients treated with bevacizumab before the first surgery were excluded from the study. The average age at first resection was 51 years, and 231 of the patients were men.

Among the patients who had received bevacizumab, the incidence of secondary GS was 15.4% (6 of 39 patients), compared with 0.6% among patients who had not received it (2 of 312) (P < .0001).

The male-to-female ratio did not differ between the 2 cohorts, and age, tumor location, and radiation dose did not correlate with the incidence of secondary GS. The average duration of bevacizumab treatment did not differ between the patients who developed secondary GS (4 months) and those who did not (6 months) (P = .256). On average, secondary GS was diagnosed 7 months after bevacizumab therapy.

No Effect on Survival Times

The overall survival times did not differ greatly between groups treated with bevacizumab or not and those who developed secondary GS or not. Of note, the worst survival times were for patients who did not receive bevacizumab and did not develop secondary GS.

Overall Survival Times

Treatment Survival Duration After Initial Diagnosis (mo)
Bevacizumab, secondary GS 16.1
No bevacizumab, secondary GS 19.2
Bevacizumab, no secondary GS 18.5
No bevacizumab, no secondary GS 13.8

 

Looking just at the effect of bevacizumab on survival time after initial diagnosis, Dr. Yang said patients who received the drug "had an overall survival a little over 18 months, and patients who did not receive bevacizumab had average survival of approximately 14 months" (P = .117). He concluded that "bevacizumab did not appear to be correlated significantly with overall survival."

There was an initial survival advantage of receiving bevacizumab, but at about 20 months, the Kaplan-Meier survival curve fell off sharply for the bevacizumab group.

Dr. Yang noted that the study, while producing some statistically significant results, was small and from a single institution, with possible selection bias. Still ahead is the task of molecular profiling of the GBM tumors to identify distinct genotypes. He also noted that the study points out a correlation between the use of bevacizumab and the development of secondary GS but does not provide a mechanism for how bevacizumab may affect the development of secondary GS.

He concluded that the study findings suggest that the development of secondary GS is significantly correlated with the use of bevacizumab, and bevacizumab may have an important role in the pathogenesis of secondary GS.

Clear Insight

Russell Lonser, MD, chief of neurosurgery at the National Institutes of Health in Bethesda, Maryland, was the invited discussant for the study.

"Despite the potential limitations of this study, which include the retrospective nature of the study, possible sampling error histologically, the limited number of cases that developed gliosarcoma, as well as different potential treatment paradigms, this study does give us insights based on the potent results that Isaac displayed and should provide a clear insight into Avastin use affecting glioblastoma, as well as to tell us more about the pathobiology of gliosarcoma," he said. "I think that the future investigations into these mechanisms as well as the effect on survival by Avastin will be a very important study that Isaac and his group is intending to do."

He commented to Medscape Medical News that bevacizumab has other positive effects that Dr. Yang did not mention, including that it keeps cerebral edema down, and patients show symptomatic improvement. "I'd want it if I had a GBM," he said.

Any change in practice to limit the use of bevacizumab would require a randomized clinical trial, and because the drug is already approved, such a trial would be very unlikely, Dr. Lonser said.

Dr. Yang and Dr. Lonser have disclosed no relevant financial relationships.

80th Annual Scientific Meeting of the American Association of Neurological Surgeons: Abstract 608. Presented April 16, 2012.

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