Systemic Treatment May Reduce Need for Brain Radiotherapy

BARCELONA — The oncologist’s goal is to provide cancer patients with the most effective and least toxic treatment available. For patients with brain metastases, whole-brain radiotherapy after stereotactic radiosurgery significantly improves tumor control, but it also has greater adverse effects on cognitive function compared with stereotactic radiosurgery alone.
At the European Society for Medical Oncology (ESMO) Congress, Anna Sophie Berghoff, MD, PhD, head of the Central Nervous System Tumor Unit at the Medical University of Vienna in Austria, said that neurotoxic side effects can be avoided in some patients by using systemic treatment as a first-line therapy.
According to joint recommendations from the European Association of Neuro-Oncology and ESMO for the diagnosis and treatment of brain metastases from solid tumors, systemic pharmacotherapy should be considered for most patients with brain metastases. When combined with radiotherapy, the risk for adverse events should be considered for each new drug.
Treatment Without Radiotherapy
Is it possible to treat brain metastases without radiotherapy? “The answer is yes, but we need to define which patients should be treated with systemic pharmacotherapy alone,” said Berghoff.
Results from a trial published in 2013 showed that whole-brain radiotherapy can be delayed in some patients for up to 8 months with the administration of systemic treatment. 
It is becoming increasingly clear that brain metastases can cause a breakdown of the blood-brain barrier, allowing antibodies and other large molecules to pass through it and enter the brain.
Furthermore, small doses of antibody-drug conjugates (ADCs), which combine monoclonal antibodies chemically linked to a cytotoxic payload, can be effective owing to the bystander effect. In this effect, the released cytotoxic agent diffuses to adjacent tumor cells that do not express the target epitope. These agents may exert antitumor effects even if delivery to the brain is limited by the blood-brain barrier. As an example, the experts highlighted the growing evidence supporting the clinical efficacy and manageable toxicity of the ADC trastuzumab deruxtecan (T-DXd) in patients with breast cancer brain metastases.
“These patients all had active, growing brain metastases, but they responded to treatment, and some had a complete response,” said Berghoff. “Brain metastases don’t shrink by themselves, so [this tells us] that the blood-brain barrier is not an obstacle, particularly if we have a very efficient drug.”
In another session at ESMO, researchers presented primary results from the phase 3b/4, open-label DESTINY-Breast12 trial, showing efficacy in 504 patients with HER2-positive metastatic breast cancer. In the 263 participants with brain metastases, the 12-month progression-free survival rate was 61.6%.
“The incidence of brain metastases in HER2-positive metastatic breast cancer is common and, until recently, most patients required radiation therapy, which could be associated with significant toxicity,” said Philippe Aftimos, MD, from the Institut Jules Bordet Université Libre de Bruxelles, Belgium. 
“There were fears that a molecule the size of T-DXd would be too large to cross the blood-brain barrier and would not treat brain metastases,” he added. “But the results have shown positive outcomes for patients with brain metastases.”
First-Line Systemic Therapy
Systemic treatment with ADCs combined with radiotherapy increases the risk for radionecrosis. Systemic treatments are also significantly more effective in newly diagnosed patients with brain metastases compared with those who have recurrent brain metastases. It should, therefore, be considered as a first-line therapy for patients with asymptomatic, untreated brain metastases, according to the experts.
In asymptomatic patients, local therapy can be postponed if an effective systemic treatment is available. However, symptomatic patients, who make up about 70% of those with brain metastases, should receive local therapy, which can later be combined with systemic therapy.
The decision regarding which patients will benefit from systemic therapy and which do not need immediate local treatment should be based on a multidisciplinary discussion involving neuro-oncologists, medical oncologists, neurosurgeons, and radiation oncologists. The discussion should weigh the potential harms and benefits of these treatments for each patient.
Symptoms of brain metastases can be assessed using the Neurologic Assessment in Neuro-Oncology (NANO) Scale, which evaluates patient behavior, gait, strength, ataxia, sensation, visual fields, language, and level of consciousness.
In adults, symptoms can be alleviated with steroids: 4-6 mg of dexamethasone per day for mild symptoms and 16 mg/d for severe symptoms. Dosage should be tapered as soon as symptoms start to decline, and nighttime dosing should be avoided.
“In the end, the patient should make these decisions, but it’s important for the physician to provide the right information,” said Berghoff.
Berghoff declared receiving research funding from Daiichi Sankyo and Roche; honoraria for lectures, consultation or advisory board participation from Roche, Bristol Myers Squibb, Merck, Daiichi Sankyo, AstraZeneca, CeCeVa, Seagen, Alexion, and Servier; and travel support from Roche, Amgen, and AbbVie. Aftimos reported no conflicts of interests related to the topic of the session. 
Moheb Costandi is a freelance writer based in London.
 
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