Risks of adjuvant WBRT may outweigh benefits for limited brain metastases

Andrew B. Lassman, MD

Brain metastases are an incredibly important medical problem as an unmet medical need and the available therapies are inadequate. To understand the scope of the problem, the number of patients diagnosed with brain metastases in the United States each year is approximately 400,000, or about 25% of all patients with cancer. The number of patients diagnosed with breast, lung, or prostate cancer is about 225,000 each. Therefore, the incidence of brain metastases in the population are at least, if not more than, the frequency of those primary diagnoses. So, it’s a huge problem.

Whole brain radiation therapy was developed 60 years ago. It does improve symptoms and it does help control metastases to the brain, but it’s not good for the brain. People develop neurocognitive dysfunction as a consequence of whole brain radiotherapy. But the problem is deferring whole brain radiotherapy clearly leads to an increased likelihood of recurrence of brain metastases. Patients treated with radiosurgery followed by observation have a much higher rate of recurrence of their brain metastases than they do if they get radiosurgery followed by whole brain radiation. Recurrent brain metastases are also not good for the brain. So, people are stuck between two bad choices.

We need better and different options and there are many in development. We know that various targeted agents, such as EGFR inhibitors that attack a druggable EGFR mutation in lung cancer, for example, are associated with dramatically high response rates systemically and those inhibitors also can result in dramatic responses of brain metastases allowing good control with deferral of whole brain radiotherapy. The same can be said of other types of druggable mutations, such as BRAF mutations in melanoma. Immunotherapy in melanoma has also been shown to improve the control of brain metastases.  So these are other drug-based ways we can perhaps exert control over the brain metastases, yet defer whole brain radiotherapy.

In addition, there are some ways to modulate the effects of whole brain radiotherapy itself. In the old days, the technology wasn’t very good. With modern techniques the radiation beam can be bent so that certain critical structures of the brain can be avoided. There is a technique called hippocampal avoidance whole brain radiotherapy. The hippocampus is thought to be integral to memory and memory is the most damaged neurocognitive function by whole brain radiation and is the most closely linked with quality of life. So, if that particular aspect of neurocognitive function can be spared, that would be terrific. There was a study conducted by the radiation therapy oncology group that showed that hippocampal avoidance whole brain radiotherapy had less neurocognitive injury than traditional whole brain radiation therapy when compared to historic controls and now there is a randomized study through the NCI-funded National Clinical Trials Network, Specifically the NRG, to assess that as well.

The final approach is to use some drugs to help directly improve the memory, like memantine, which is used for Alzheimer’s disease. There was another ROTG trial which looked at memantine combined with whole brain radiotherapy and that also looked like it modulated the negative effects of whole brain radiotherapy on neuro-cognition. There will be another study randomizing patients to receive memantine with hippocampal avoidance whole brain radiotherapy as a combination, also by the NRG.

Whole brain radiotherapy has some negative aspects to it, but it clearly helps to control intracranial disease and prolongs survival in those patients in whom the brain metastases are life-limiting. I don’t think it should be discarded, I just think it needs to be used in the appropriate context. We need better therapies and I’m glad to see that those are being studied and are under development.

Brian Michael Alexander, MD, MPH

This scenario is complex, and I take a lot of time to talk to my patients in this setting. If the thought is whole brain radiation does what we want it to do therapeutically — where it reduces the risk for brain metastases — why then doesn’t it translate to improved OS? The answer could be that we do well with salvage therapy, so preventing a metastasis from coming back does not matter if you salvage everything perfectly. The other possible answer is that the progressive disease outside the brain is really what is driving the mortality. That is more of an answer than selecting a population of people who are unlikely to have deaths from progression of disease outside the brain. That may be the only place you find the benefit for whole brain radiation therapy.

This was a very large, well-done study to quantify both the toxicity for the risks and the benefits of this treatment. I think the burden of proof has now switched to ask, “Can we prove that whole brain radiation therapy is beneficial in a subset of patients?” I have this discussion with my patients all the time and it takes a while to go through all the data and frame things so they can make the decision that they want to make.