Study Aims to Explore Treatment Modalities in Patients With Multiple Brain Metastases

David Roberge, MD

Both cognitive and quality of life outcomes have been improved with radiosurgery compared with whole-brain radiotherapy (WBRT) as treatment of patients with 1 to 4 brain metastases. Collaboration between both the Canadian Cancer Trial Group (CCTG) and Alliance for Clinical Trials in Oncology (Alliance) has also led to the demonstration of equivalence in overall survival benefit with radiosurgery and WBRT following resection.

Despite these advances for patients with brain metastases, a gap remains in the treatment of patients with 5 or more metastases. The NCI Brain Malignancies Steering Committee hopes to overcome this challenge with a new trial concept. CCTG and the Alliance are collaborating together to evaluate these treatment approaches in patients with more than 5 brain metastases.

The study aims to improve outcomes in patients with multiple brain metastases. The prevalence of brain metastases is high, as it is the most common brain tumor seen in adult patients. It is commonly observed in adenocarcinoma of the lung, but it is also observed frequently in kidney cancer, melanoma, and breast cancer.

In an interview with Targeted Oncology, David Roberge, MD, associate professor at the University of Montreal and adjuvant professor at McGiull University, discussed the role of radiation treatment in patients with brain metastases and the clinical trial evaluating treatment approaches for patients with more than 5 brain metastases.

TARGETED ONCOLOGY: Can you discuss the prevalence of brain metastases? Are there any specific malignancies where you've seen multiple malignancies more commonly than in other cancers?

Roeberge: Brain metastases are the most common brain tumor seen in adults, so it's very common. In my practice, we see approximately 400 brain metastases patients per year, which is 1 of the most common entities that we see. The most common primary diagnosis is adenocarcinoma of the lung, and then the rest tends to be based sometimes more on a specific center's expertise or interest, so if you have a center that sees a lot of kidney cancer, that might be what you see or a center that has an interest in melanoma, but I would say by breast cancer, then melanoma, and then kidney cancer are the other more common cancers that we see with brain metastases.

TARGETED ONCOLOGY: What outcomes can be expected with radiosurgery when it's performed on patients with multiple brain mets?

Roeberge: Radiation has been the most common modality to manage brain metastasis, and radiosurgery provides a very convenient treatment because patients come 1 time. It also provides a high rate of local control, but it's unclear what it contributes to patient's overall survival or quality of life. In the studies that have been done up until now, the cognitive outcomes were better for radiosurgery than they were for WBRT, but the more metastases you treat, maybe the more risk for adverse events related to radiosurgery. Also, WBRT has changed somewhat in the past years, now with avoiding the hippocampal structures, where there is a significant improvement in a cognitive function versus traditional WBRT, and the addition of memantine (Namenda) with radiotherapy has also decreased the toxicity. Maybe for a patient that's eligible for the CE7 trial for large number of metastases, it's not as obvious what the difference will be between WBRT and radiosurgery and that's without counting economic endpoints and other secondary endpoints.

TARGETED ONCOLOGY: Can you give background on the study and the trial design?

Roeberge: This study is led by the Canadian clinical trials group, and it follows on other studies comparing WBRT to radiosurgery. There have been many studies now with patients with small number of brain metastases like 1 to 3 or 1 to 4 metastasis comparing WBRT and radiosurgery. In those scenarios, the overall survival is typically very similar, and the cognitive outcomes and quality of life tend to be better for radiosurgery, so radiosurgery has replaced WBRT for most of those patients. Recently, the NCIC collaborated with the Alliance group to do a trial in patients that had had surgery for brain metastases looking at radiosurgery in that population. It's a trial that accrued well, especially in Canada, and showed again that the survival was similar with better cognitive outcomes. That's also a treatment that's become more prevalent.

One last area where there wasn't prospective randomized evidence was for patients with large number of metastasis. That was the genesis of this trial. As I said, because of recent improvements or changes in WBRT, it's a more interesting trial, and the outcome is maybe not as predictable seeing as we expect current WBRT to be less toxic than it was in the past. It's a randomized trial of approximately 200 patients that are randomized 1:1 to radiosurgery or WBRT with hippocampal avoidance and with memantine in the management of 5 to 15 brain metastases from a primary solid tumor.

TARGETED ONCOLOGY: What is the key takeaway from this?

Roeberge: The key takeaway is that this is the multicenter trial to answer the question. There's been a lot of movement in clinical practice towards doing this without the prospective evidence. This is our opportunity to answer this question to guide treatments in the future.

TARGETED ONCOLOGY: What ongoing challenges remain with eliminating these tumors?

Roeberge: In my practice over the past 10 or 20 years, the survival has improved substantially in patients with brain metastases. I think a large part of that is more aggressive treatment, is more aggressive follow-up, and another part is changes in systemic therapy. I think a big challenge that's going to come is how to best integrate systemic therapies with local treatments, so which patients need radiosurgery now, which patients can defer radiosurgery because they have an effective systemic option. I think there will be a lot of questions to answer in these patients in the future.

The other challenges are leptomeningeal disease is still sort of an orphan area of oncology, where there's not a lot of data to guide treatment of leptomeningeal disease, and recurrences and patients that have had surgery tend to be very difficult to manage, and we still don't have an optimal treatment for those patients.