Treatment with antiangiogenesis drugs may improve the effectiveness of radiation treatment of nervous system tumours that interfere with the hearing of patients with the genetic disorder neurofibromatosis 2 (NF2).

A team of Massachusetts General Hospital (MGH) investigators reports in PNAS Early Edition that use of an antiangiogenesis drug reduced the radiation dose required to shrink tumours in animal models of the NF2-associated tumours called vestibular schwannomas.

They also discovered several mechanisms behind this effect and determined the time window during which radiation therapy produces the best results in the tested model.

"We found that treatment with an antibody blocking the angiogenic factor VEGF improves neurologic function in our mouse model by alleviating tissue edema, which may further improve neurologic function by decreasing muscle atrophy and increasing nerve regeneration, both of which we observed," says Lei Xu, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Radiation Oncology Department, corresponding author of the PNAS report.

"Combining anti-VEGF with radiation therapy allows use of a lower radiation dose, which can achieve better tumour control and minimise radiation-related neurological damage."

NF2 is characterised by benign tumours that develop throughout the nervous system.

The most common site of these tumours is the eighth cranial nerve, which carries hearing and balance information from the ears to the brain.

Although vestibular schwannomas grow slowly, they usually lead to a significant or total hearing loss by young adulthood or middle age.

The tumours can also press on the brain stem, leading to headaches, difficulty swallowing and other serious neurologic symptoms.

While the tumours can be surgically removed or destroyed with radiation treatment, both approaches can also damage hearing.

Several previous investigations had suggested that - unlike other benign tumours - vestibular schwannomas induce the formation of new blood vessels, as malignant tumours do.

A 2009 New England Journal of Medicine study led by Scott Plotkin, MD, PhD, of the Pappas Center for Neuro-Oncology in the MGH Cancer Center reported that treatment with the antiangiogenesis drug bevacizumab caused shrinkage of NF2 schwannomas in most of the treated patients and improved hearing in more than half.

But the limitations of that approach - the fact that not all patients responded, that the hearing improvement was often transient and that some patients could not tolerate long-term bevacizumab treatment - indicated the need to better understand the mechanisms behind the effects of antiangiogenesis on the function of tumour-bearing nerves.

To investigate that question, Xu and Steele laboratory director Rakesh Jain, PhD, collaborated with Plotkin and with Anat Stemmer-Rachamimov, MD, of MGH Molecular Pathology to conduct the current study.

In a series of experiments using several mouse models of nerve tumours they found that treatment with an experimental anti-VEGF drug produced more improved neurologic function than did radiation alone and that treatment reduced tissue edema, alleviating swelling that may compress nearby nerves.

They also found evidence that anti-VEGF treatment enhanced the regeneration of damaged nerves and decreased atrophy in muscles connected to tumour-bearing nerves.

Careful observation of tumour vasculature in a mouse model of NF2 revealed that anti-VEGF treatment reduced the number of abnormal blood vessels within the tumour, a key mechanism behind the successful use of antiangiogenesis drugs to treat several types of cancer.

As also seen in those applications, this normalisation of the tumours' blood supply proved to be temporary, beginning around day 2 of treatment and starting to diminish on day 5.

Administering radiation therapy during that normalisation window had significantly greater effects than did either anti-VEGF or radiation therapy alone, while radiation given outside that time had no additive effect.

Giving radiation during the normalisation window also increased its effectiveness, producing the same beneficial results with half the radiation dosage.

"NF2 is a disease that needs new solutions, and we demonstrated that combining anti-VEGF with radiation therapy can achieve better tumour control, allowing a reduction in radiation dose that can minimise neurological toxicity," says Xu, who is an assistant professor of Radiation Oncology at Harvard Medical School.

"Our study provides compelling rationale and paves the way for further testing of combined therapy in human patients, and we are currently planning a clinical trial."

Source: Massachusetts General Hospital