If patients live longer, they have a greater risk of cognitive dysfunction associated with whole-brain radiotherapy, but they also have a greater risk of failing elsewhere in the brain if whole-brain radiotherapy is not used. It’s a two-edged sword.— Minesh Mehta, MBChB
The advent of more effective systemic therapies, which extend patients’ lives, has also resulted in an increasing incidence of brain metastases, for which clinicians must determine appropriate treatment. Whole-brain radiotherapy has been the traditional treatment modality, but stereotactic radiosurgery, which focuses multiple high-dose radiation beams with great precision across the target, is an increasingly preferred approach. Minesh Mehta, MBChB, an expert in radiation oncology, recently reviewed stereotactic radiosurgery for brain metastases in the Journal of Oncology Practice.1 Dr. Mehta, Deputy Director at the Miami Cancer Institute and Chair of Radiation Oncology at Baptist Health South Florida, spoke with The ASCO Post about this issue.
Refining the Role of Whole-Brain Radiotherapy
Why is stereotactic radiosurgery, as it compares with whole-brain radiotherapy, an important topic for discussion now?
The role of whole-brain radiotherapy is changing, substantially based on a number of recent important clinical trials. Consequently, the role of whole-brain radiotherapy needs to be redefined. We need to ensure that the results of the current trials are interpreted in the appropriate context, thus leading to the appropriate use of these modalities.
What might be the misperceptions from these clinical trials?
There might be overly generous interpretations, extending the studies’ conclusions to patient populations where they may be less relevant or less directly applicable. The risk is that clinicians will look at the data that apply to one category of patients and inappropriately apply them to another category of patients.
How should clinicians determine which modality to use for brain metastases?
I think the decision today is to identify which patients require whole-brain radiotherapy and which do not, and there are a number of ways to approach this question. The first is to identify patients in whom the likelihood of benefit is nonexistent or very small. These would be patients who are extremely ill or have a poor performance status, a substantial amount of extracranial disease, or a short life expectancy. These are typically patients who should receive best supportive care and hospice. Treatment with whole-brain radiotherapy will not improve either their overall survival or their quality of life. It is crucial to identify these patients and spare them any sort of interventional therapy, whether whole-brain radiotherapy or stereotactic radiosurgery.
Now we move from this extremely fragile population to patients in whom an intervention is likely to be beneficial. Here, what becomes crucial is to identify patients who will have potentially different outcomes. For example, if we have patients with a good performance status, we can get a prognostic score using the diagnosis-specific graded prognostic assessment. Patients with a good (high) score would be expected to have better overall survival. For these patients, there are several factors to consider. First, for patients with a high diagnosis-specific graded prognostic assessment score and a limited number of metastatic lesions—let’s say one to four relatively small ones—treatment would typically be with stereotactic radiosurgery.
One of the controversies is whether whole-brain radiotherapy is of value for this group. The controversy stems from two assumptions: first, that whole-brain radiotherapy does not add a survival benefit in this group, and second, that whole-brain radiotherapy is associated with a high risk of cognitive deficits.
When we look at these suppositions with more detailed introspection, we find the answers are not as simple as you would assume. For example, a Japanese randomized trial of patients with non–small cell lung cancer with one to four brain metastases found that patients with high diagnosis-specific graded prognostic assessment scores had improved survival with the addition of whole-brain radiotherapy to stereotactic radiosurgery.2 Therefore, it is quite possible that for patients who are unlikely to die of extracranial disease progression, improving intracranial control has the potential to translate into a survival benefit. It is worth having this discussion regarding this combined-modality approach with patients. Whether we can apply the diagnosis-specific graded prognostic assessment score in other tumor types remains unclear at this time.
Should all patients who undergo resection of brain lesions receive postoperative radiotherapy?
Yes, all of these patients should, based on the available data to date. There is a randomized trial in patients with a single brain metastasis who were resected and then randomized to receive postoperative whole-brain radiotherapy or no radiotherapy.3 In this category of patients, with a single lesion, there was a clear benefit from the use of postoperative whole-brain radiotherapy. The effect was large: Recurrence of tumor anywhere in the brain was observed in only 18% of patients receiving radiotherapy, compared with 70% for patients who did not receive radiotherapy. So there is no question that for this subset, there is a benefit to using radiotherapy.
I think increasingly the question is whether we replace whole-brain radiotherapy with focal or stereotactic radiotherapy. The answer is unknown at this point, and the results of a randomized trial to be presented at the American Society for Radiation Oncology (ASTRO) 2016 will possibly provide more data in this respect. Meanwhile, the existing data show that postoperative whole-brain radiotherapy for single brain metastases is the standard of care.
Integrating Radiotherapy With Other Agents in Lung Cancer
How are you integrating radiation therapy with targeted agents in non–small cell lung cancer?
We know that prognosis is better for patients with brain metastases if they have driver mutations, such as those in the epidermal growth factor receptor (EGFR) or rearrangements in ALK. There are two implications of this: If patients live longer, they have a greater risk of cognitive dysfunction associated with whole-brain radiotherapy, but they also have a greater risk of failing elsewhere in the brain if whole-brain radiotherapy is not used. It’s a two-edged sword. We don’t have randomized trial data yet, but retrospective data emerging at the institutional level are suggesting that when targeted agents are combined with radiotherapy—whether whole-brain radiotherapy or stereotactic radiosurgery—overall survival is significantly improved. Which of these modalities you use is a judgment call based on the specific characteristics of the patient.
How are you incorporating radiation therapy into treatment with immune checkpoint inhibitors?
This is a very exciting and intriguing area. There are many logical reasons to combine checkpoint inhibitors and radiotherapy. Radiation therapy can potentially enhance the antitumor effect of these drugs. Theoretically, here’s how it works: Radiation to a small target, especially in high doses in a limited number of fractions, has the ability to kill tumor cells and unleash antigens, which in turn mount an immune response against the tumor. The checkpoint inhibitor not only sustains that response, but the effect is global: It affects all tumors in the body. The premise here is that the use of stereotactic radiosurgery to one or a handful of metastases might actually produce an enhanced overall antitumor effect and improve outcomes. Trials are in development that will test this concept.
Opportunities and Challenges
What other opportunities and challenges are relevant in this field right now?
The future is in recognizing that for many of these tumors that carry driver mutations, we have effective targeted agents whose efficacy is hampered by their limited blood-brain barrier penetrability. The next generation of targeted agents shows more potential for such penetrability, so we may have the ability to use them to control microscopic disease in the brain while we target macroscopic disease with stereotactic radiosurgery. The combination of radiotherapy with blood-brain barrier–penetrating agents might be an important new frontier as these agents come on line. ■
Disclosure: Dr. Mehta reported no potential conflicts of interest.
2. Sperduto PW, Shanley R, Luo X, et al: Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; post-stratified by the graded prognostic assessment. Int J Radiat Oncol Biol Phys 90:526-531, 2014.