Today we are discussing the role of whole-brain radiotherapy (WBRT) for the treatment of cancer patients with brain metastases with Minesh P. Mehta, MD, a radiation oncologist and the deputy director and chief of radiation oncology at the Miami Cancer Institute at Baptist Health South Florida. Dr. Mehta penned a viewpoint earlier this year discussing new data on the outcomes of cancer patients with brain metastases treated with radiotherapy.
—Interviewed by Anna Azvolinsky
Cancer Network: First, what is the current role of WBRT for patients with brain metastases? Does the use of this type of radiation depend on the primary tumor type or does that not play a role in the decision to treat with WBRT?
Dr. Mehta: This is really a key question, because the role of WBRT in managing patients with brain metastases is undergoing rapid evolution and change. Historically, almost all patients with brain metastases would automatically have received WBRT, but with a lot of emerging data, we are beginning to recognize two specific issues that are changing this particular historical paradigm. One, there are certain side effects of WBRT that some patients are at greater risk of developing compared to others. And in those patients, whenever possible, we want to try to avoid WBRT to minimize or eliminate that risk. And two, there are some patients, some categories and groups of patients, that can very effectively be treated with more focal radiotherapy approaches like stereotactic radiation—for those patients, WBRT can potentially be withheld. But with that, the paradigm is shifting in terms of limiting the use of WBRT in specific subsets of patients with brain metastases.
Cancer Network: In your editorial, you discuss several recently published studies on the efficacy of WBRT in different tumor types. Can you talk about a few of the highlights there?
Dr. Mehta: A couple recent studies have demonstrated that when WBRT is added to focal radiation like stereotactic radiation there is no survival benefit to the addition of WBRT. For example, in a recent study patients with brain metastases were randomized following resection to single fraction stereotactic radiosurgery alone to the tumor bed or with WBRT, and there was no specific survival benefit from the addition of WBRT. In addition to that, a trial performed last year showed that in patients with a limited number of brain metastases, the addition of WBRT compared to stereotactic radiosurgery alone also did not make a difference in terms of overall survival. And so this raises the question that in such patients, if WBRT is added without an incremental benefit in survival—but with the possibility of some toxicity from WBRT—is it actually worth pursuing this therapy?
The answer is not as simple as it may appear, because one thing that WBRT does in all of these patient populations is reduce the further occurrence of brain metastases. And in fact, the risk for further brain metastases in these patients is considerably high, ranging from as low as 30% to as high as 80%, which means that in many of these subpopulations, a significant majority will be at risk for needing further intervention in the brain. The use of upfront radiation actually prevents that, so there is that benefit in many subgroups, which doesn’t necessarily translate to a survival advantage.
In the paper you described, we talked about one specific subset of patients where there appears perhaps to be a survival advantage—these are patients with non–small-cell lung cancer and a limited number of brain metastases who were randomized to stereotactic radiation alone or stereotactic radiation with WBRT. In a post-hoc, subsequent analysis of the data from the trial, the highest graded prognostic assessment score appeared to show benefit in terms of overall survival with the addition of WBRT. I would call this hypothesis-generating, suggesting that patients that are at the least risk of dying from systemic progression in the rest of the body are the ones that are most likely to benefit from the addition of WBRT in terms of survival improvement—the implication is that failure in the brain puts them at risk of dying from intracranial progression. So that is an example of one such group.
Cancer Network: Anything else we have learned from some of these more recent trial results, and are there other important questions that remain?
Dr. Mehta: Another randomized trial looked at the role of WBRT vs best supportive care, and for this particular study the patients that were selected were effectively end-stage patients with significant disease and, therefore, very short life expectancy. This particular trial, the QUARTZ trial, was conducted in the United Kingdom. This trial showed that these patients were not deriving any benefit from the addition of WBRT. The implication here is that for patients that are effectively hospice bound—very poor performance status, extensive disease, etc—WBRT is not going to change survival outcomes.
So that is the other extreme, patients who are doing very poorly—because of a low performance score, extensive intracranial disease, or extracranial disease—those patients will probably not benefit from any interventions such as WBRT. That is another important lesson that we have learned in terms of which patients not to use WBRT in.
Cancer Network: For you as a radiation oncologist, how have these recent data changed the way you view and utilize WBRT in your patients with brain metastases?
Dr. Mehta: I think these data have been quite seminal in changing the utilization of WBRT. I think most people have become far more selective in their use of WBRT. Personally, the way I triage patients is I look at the following categories. First, if a patient has very advanced disease and a very short life expectancy—in other words, they are effectively hospice bound—then perhaps best supportive care and hospice are really the right choices for that patient and one should try to avoid WBRT if it’s not necessary for symptom control.
For a group of patients that likely have longevity on their side and the potential for long-term survival, one would like to assess whether they have significant risk of failing in the rest of the brain if only a focal therapy, such as radiosurgery, is used. These could be patients with non–small-cell lung cancer with EGFR mutations or ALK translocations, or patients with three, four, or more brain metastases for whom radiosurgery is being used and therefore are at a higher likelihood (greater than 50% likelihood) of failing in the rest of the brain. And from the Japanese data we talked about earlier, there is a suggestion of a possible survival improvement—let me emphasize that this is a suggestion—this is not proven because that was not the primary question of the study, but there are patients that appear to derive survival benefit. For those patients, it may be reasonable to utilize WBRT.
And then you have a group of patients that are sort of in the middle. These groups of patients that are in the middle are divided into two categories. Those with limited brain disease and those with extensive brain disease. The limited brain disease patients have historically been divided by the number of brain metastases—for example, three or four as the dividing point—and for a while, conventional wisdom suggested that we could use the number of brain metastases as a dividing line and use that to select which patients should get radiosurgery and which should get WBRT.
But increasingly, more and more of the literature suggest that the number of brain metastases, while relevant, may not be the only factor that is significant. It may also be the volume of disease that is significant, and also the fact that one can effectively treat more than three brain metastases with radiosurgery.
So where is the line? Is it three or four? Is it five? Is it ten? That remains an unanswered question. There are a number of clinical trials attempting to answer that question. Most institutions typically have an arbitrary line that they pick—some will use three or four, some five or six, some will use ten. On the side with fewer numbers of brain metastases, patients tend to get radiosurgery, and on the side with larger numbers, patients tend to get WBRT.
Cancer Network: Thank you so much for joining us today, Dr. Mehta.
Dr. Mehta: A pleasure.