Joint ESMO-ESTRO symposium tackles brain metastases

Joint ESMO-ESTRO symposium explored innovative approaches to the treatment of brain metastases, including prevention in patients with primary cancers, treating patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastases with the combination of lapatinib and capecitabine, and the potential for radiation dose escalation.

The symposium heard that as chemotherapies improve and result in better systemic disease control, the number of patients with brain metastases is likely to increase.

Preventing the development of brain metastasis in patients with primary cancers represents a feasible goal, argued Dr Brunilde Gril, from the National Institutes of Health, Bethesda, M D, USA.

Brain metastases outnumber primary brain tumours by 10 to 1, with the most common primary sites being lung (50 60%), breast (15 20%), melanoma (5 10%) and GI tract (4 6%). Traditional drug therapies are ineffective for brain metastasis, with the blood-brain barrier remaining an obstacle for brain metastasis therapy. “Brain permeable drugs are needed,” said Dr Gril.

Reporting on a study that had recently been undertaken to test the efficacy of 18 compounds, including traditional chemotherapeutics and small molecule inhibitors, in an experimental model of brain metastasis, Dr Gril said that vorinostat, lapatinib, pazopanib, TPI-287, gemcitabine and irinotecan have all been shown to prevent the development of brain metastases. But no drug, he added, has been found to effectively shrink already-established brain metastases.

The next step, said Dr Gil, should be to launch Phase 2 prevention trials in which patients with aggressive primary tumours and limited brain metastases (who have not undergone whole brain radiotherapy) would be randomized to receive a preventive agent or placebo. The endpoint of the trial, Dr Gil added, should be time to development of new metastases.

Brain metastases occur in 3 40% of patients with MBCs that overexpress HER2, explained Dr Thomas Bachelot, from the Centre Leon Berard, Lyon, France. Treating HER-positive breast cancer patients with brain metastasis with a combination of lapatinib and capecitabine prior to local treatment, he said, represented a potential new approach.

Presenting the results of the LANDSCAPE study, Dr Bachelot said that between April 2009 and August 2010, 45 patients with HER2-positive MBC and brain metastases (who had not previously undergone whole brain radiotherapy) received lapatinib 1.250 mg once daily and oral capecitabine 2.000 mg/m2 from day 1 to day 14 every 21 days. Results showed that 86% of patients experienced reductions in tumour volume; the median time to progression was 5.5 months, median time to radiotherapy was 8.3 months, and the median overall survival was 17 months. The most common adverse events were diarrhoea, hand foot syndrome, and nausea.

“Our data suggests this strategy could help delay whole brain radiotherapy associated neurological toxicity,” said Dr Bachelot. The strategy, he added, now deserves further evaluation to confirm the clinical benefits in terms of survival, cognitive function and quality of life.

Professor Claus Belka, from the Ludwig Maximilian University, Munich, Germany, explored the potential role for intensity modulated radiotherapy (IMRT), Intensity-modulated arc therapy (IMAT) and tomotherapy to reduce the neurotoxicity of whole brain radiotherapy. Radiation, he said, has the potential to depopulate neural stem cells and impair neurogenesis through inflammatory processes. Irradiation increases hippocampal apoptosis and decreases hippocampal proliferation, leading to deficits in learning, memory, attention and spatial processing due to radiation-induced hippocampal injury. The late toxicity effect of dementia occurs in more than 11% of patients following radiotherapy, with early toxicity effects including problems with verbal and short term memory recall.

“But only 3% of brain metastases are actually situated within the hippocampus leading to the possibility of introducing strategies to reduce neurotoxicity in whole brain radiotherapy,” said Dr Belka.

IMRT, IMAT and tomotherapy, he said, all seem to have a role in sparing hippocampus structures. “But no data is available on improved neurological outcomes or tumour control,” he said.

Dr Frank Lagerwaard, from the University Medical Centre, Amsterdam, The Netherlands, explored the potential role for radiation dose escalation in patients with brain metastases. While the majority of patients with brain metastases from solid tumours have a prognosis of only a few months based on extracranial tumour activity and performance status, said Dr Lagerwaard, a subset exist who may be able to achieve long term survival if brain metastases are treated aggressively.

Radiosurgery, involving high precision delivery of a single fraction of approximately 20 Gy directed to the lesion results in local control rates of 60 to 90 %, depending on the size and position of the lesion.

The question of whether whole brain radiotherapy (WBRT) should be added to radiotherapy has been a long standing unresolved issue. Proponents of the combination approach highlight the opportunity for better intracranial control; while opponents point out increased neuro-cognitive toxicity.

Techniques such as volumetric intensity modulated arc therapy (VMAT, Rapid Arc), or tomography, which allow fast and accurate delivery of fractionated stereotactic integrated boosts to multiple brain metastases might be used in combination with whole brain radiotherapy. Such integrated approaches, said Dr Lagerwaard, have the advantage of allowing steep dose gradients outside the brain metastases thereby minimizing toxicity.

“But with the exception of a few randomized radio surgery trials, the clinical benefit of dose escalation remains to be defined,” said Dr Langerwaard.