COMMENTARY

Which Lung Cancer Patients With CNS Metastases Can Avoid Radiation?

H. Jack West, MD; Hossein Borghaei, DO

Disclosures

May 31, 2018

H. Jack West, MD: Hello. I am Jack West, medical director of the thoracic oncology program at the Swedish Cancer Institute in Seattle. Welcome to Medscape Oncology Insights. Joining me today is Hossein Borghaei, chief of thoracic medical oncology at Fox Chase Cancer Center in Philadelphia.

Today let's talk about brain metastases, an issue for which, historically, we have turned to our radiation oncology colleagues and said, "It is up to you." We had come to the conclusion that most of the systemic therapies did not have good central nervous system (CNS) penetration and we could not be confident that they will work.[1]

in the field of non–small cell lung cancer (NSCLC), at least, we have revised our conclusions based on our growing experience with many of our newer targeted therapies for patients with EGFR mutations or ALK rearrangement, and potentially others.[1] What has really changed things is the increasing FDA approval and availability of therapies—not just as salvage therapies, but now as first-line treatment, such as osimertinib for patients with an EGFR mutation[2]and agents like alectinib or potentially ceritinib, second-generation ALK inhibitors, for those patients. These drugs have good CNS activity. We have seen response rates north of 50%, even approaching 70% and much better, in delaying any CNS progression.[2,3,4]

The question is, can we or should we be sidestepping radiation? Not just whole-brain radiation, but potentially even gamma knife, which we have usually considered as pretty risk-free. These patients are also now living so much longer. We did not used to worry about long-term sequelae of radiation, because there were no long-term sequelae when patients only lived a few months. We now have many patients living for 2, 3, and more years, and potentially we see late side effects of brain radiation. It would be ideal to avoid this side effect, if we can.[5,6]

What is your approach for these patients now? Let's start with asymptomatic subcentimeter brain metastases—are there people in whom you are comfortable forgoing radiation and starting with an agent that we have some confidence will work in the CNS?

Hossein Borghaei, DO: Good question. The answer is yes. I am comfortable with a completely asymptomatic patient with subcentimeter metastases to be observed off of radiation, starting a very effective oral agent, depending on the kind of translocation or mutation that we find.[4,6] That is a discussion that we have in a multidisciplinary conference that includes a radiation oncologist who does neuroradiation oncology. We come up with a good follow-up schedule for the patient, with occasional brain MRIs when we begin for monitoring.

Clearly, if the patient has symptomatic disease or if the MRI shows large metastases with a lot of edema, I tend to forgo the drug, start with radiation, and then go back to the drug. However, in a patient with asymptomatic subcentimeter disease, I feel very comfortable starting with the drug and, as you said, avoiding the potential long-term side effects of any kind of radiation to the brain.

West: This is now becoming a more recognized option, not just by you or me, but now incorporated into NCCN guidelines as an endorsed option to consider and, potentially, really recommend for our patients as we get more experience.[6]While the EGFR and ALK-positive patients are on the leading edge of this, I think this approach also applies to patients who have developed new brain metastases on a first-generation EGFR inhibitor or crizotinib for ALK-positive NSCLC.[7] Those drugs have less CNS activity, but you could switch, potentially, to osimertinib or alectinib.[6] Potentially, patients then avoid radiation.

What about for other patients? Immunotherapy has provided some encouraging anecdotal results in patients with CNS metastases.[6]Chemotherapy, too, has not negligible activity.[6]For other patients, should we begin to extrapolate, walk on perhaps thinner ice, and apply this more broadly instead of just patients with driver mutations?

Borghaei: I would be careful, because with immunotherapy, yes, there are flashes of brilliance; but when it comes to control of disease in the CNS, we don't have solid data.[8,9] It is not like the data we have with osimertinib and alectinib, so I don't feel comfortable starting with an [immunotherapy] agent. I can tell you that my radiation oncology colleagues who, again, take care of our CNS patients, do discuss that with us. They ask us whether we have something that has CNS penetration and whether we can avoid brain radiation. That decision should be made on a case-by-case basis.

With chemotherapy, I feel even less comfortable, honestly. I realize that there's a lot of data suggesting that once you have metastases, the blood-brain barrier is somewhat compromised and chemotherapy can be effective, but over the years, we've done a lot of chemotherapy and we haven't seen the kind of clinical efficacy when it comes to CNS control that we have with the targeted agents you mentioned.[8]

With immunotherapy, our colleagues are looking at specific patient populations with brain metastases being treated with [immunotherapy]. I'm hoping that within the next few weeks or months, we'll have additional data to help us guide these patients through the treatment course.[9,10]

If a patient is asymptomatic and has subcentimeter lesions, I'm willing to try an [immunotherapy] agent with close follow-up and a good discussion with the patient, but we should be cautious.

West: I think that one of the other issues that we're recognizing is that brain metastases is not a binary condition: You have them or you don't. It's a matter of degree.[1,6,8] There's size, number, and symptomatology. You should be much more judicious about someone with a larger lesion with edema, certainly someone with symptoms, than for somebody in whom there is an incidental 2- or 3-mm metastases detected. We're getting so sensitive now with the MRIs. We're seeing more things, and I don't know if we should be rushing down the rabbit hole and forgoing systemic therapy to worry about the radiation right away.

As you say, this is a very fertile area of research.[10] The work that we've seen on defining CNS response and CNS control in patients with an EGFR mutation and ALK rearrangement has blown the barn doors open in terms of the concept of really focusing on CNS control as a relevant endpoint for NSCLC in general. Not just reflexively treating metastases, but actually asking whether there's a best way to do this and not overtreat patients.

Borghaei: I absolutely agree. Again, that's another area where we should [have more data soon]. We're looking forward to that.

West: Great. Hoss, thanks so much for joining me. Excellent discussion.

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