Andrew Brenner, MD: We did talk about HER2CLIMB and the use of tucatinib, trastuzumab, and capecitabine, but the patient in this setting hasn't received that yet. So, I think that's an appropriate regimen for this patient. And you know, the response rates as much as 50% significant survival advantage over the control arm. So, in this patient that would be my go-to.

Joyce O’Shaughnessy, MD: You know, that makes a lot of sense. And particularly if somebody had just small amounts, let's say of pulmonary mets, and they went into a nice CR, those tend to be things that can be well controlled. We have other options. And then if they're continuing to blossom in the brain, it makes sense. It just makes sense to do less in the way of SRS. Although I realize we don't have a survival study yet, though.

Andrew Brenner, MD: Sure, we have to consider what we gain with SRS as well. We need to put SRS in the appropriate context because we like to think of SRS as we're doing, you know, it's very precise, and we're really going to change outcomes with SRS versus other modalities. And SRS really only impacts the time to neurocognitive failure. It doesn't really change survival. If you look at the studies randomizing SRS against whole brain radiation, it helps our patients do better, but not live longer. Nowadays, we do also have options with whole brain radiation with hippocampal avoidance, and the level of toxicity has gone down with that. So, I think it's really important as we think about these patients and when to treat them and how aggressive to be to keep in mind what we're trying to improve in terms of symptoms and whether we're making a difference in terms of their survival. So, we can find a four-millimeter lesion and do SRS, but, and that might prevent them from having the neurocognitive decline if they were to get whole brain radiation. But let's say for sake of argument that that same patient went on to a different systemic regimen without senescent penetration and it grew to two centimeters or even three centimeters. The data in terms of SRS versus whole brain radiation shows better neurocognitive improvement but doesn't show a survival. So, would you get really much difference in terms of quality of life if you did whole brain radiation plus hippocampal avoidance in that patient? That's a question and it is yet to be answered, right? Because we're just now starting to use whole brain radiation with hippocampal avoidance. But just because you're doing SRS early does not mean necessarily that you are going to dramatically improve survival, first of all. And second of all, that we can't prevent neurocognitive failure with other modalities.

Joyce O’Shaughnessy, MD: It makes an argument in my mind for trying an effective systemic therapy, you know, to try, you know, 50% response rate of active brain mets is quite good. That's response rate. That's going to remind some stable disease and minor reduction, etc. So, it seems like it's a little bit scary. We're used to the SRS. You know, we're used to bringing that in. Our radiation colleagues are following the patient along. We have to have good multidisciplinary communication, right? Right? So, we have to know, hey, we've got something good here we could try besides more SRS, you know? And I am doing that a bit more. I have had a fair amount of radiation necrosis over time, you know?

Virginia Kaklamani, MD: And I think that's why it's important if you have that 4mm asymptomatic lesion, why not wait? Watch the patient, repeat the MRI every six to eight weeks, and then just make sure that you're examining the patient well and then just wait until you really have progression of disease that you need to treat.

Joyce O’Shaughnessy, MD: And try bringing the tucatinib. And bring in the tucatinib. And try to stop it, you know? Stop it and just forestall that need.

Virginia Kaklamani, MD: What was important with HER2CLIMB was that the tucatinib delayed progression of new brain metastases. This is extremely powerful. And so, we all get nervous when we see patients with brain metastases. But with this data, I think it's important to realize that yes, you can give this regimen and then just wait and watch.

Joyce O’Shaughnessy, MD: Andrew, how do you treat symptomatic edema from radiation necrosis? Let's say if it's not resectable, do you tend to want to resect it or do you try to use some Bevacizumab or other type of approaches?

Andrew Brenner, MD: That's a great question. So, the first thing is making sure what you're dealing with is actually radiation necrosis. And so that's sometimes going to be challenging. We use some imaging modalities like perfusion and delayed contrast enhancement, which are delayed contrast enhancements. It's a little bit of a more recent imaging technique. But we try to first do as good of a job as we can of reassuring ourselves that what we're dealing with is a treatment effect. Once we do that, I think steroids are the mainstay. Then the question becomes if the patient is intolerant of steroids. In our patient population, unfortunately, we have a lot of patients with diabetes. And we tend to see a lot of that get uncontrolled with steroids, patients unable to tolerate either long term or high doses of steroids. And then with ongoing steroid usage, you tend to see a lot of steroid myopathies, where they're just not able to get out of the chair because their muscles are weak. And so that can be really life changing. So once a patient is not able to tolerate the steroids, then you need to ask yourself either about Bevacizumab, which does work, and I use low doses and infrequent dosing and see excellent results with that. Or to go in and clean out the necrotic debris by surgery, because that's a one-time thing. Sometimes these patients have a very accessible lesion, especially if these lesions are very cortical, very superficial, very easy to get to sometimes without damaging white matter or any of the patient with more problems. Then you can just have a craniotomy to clean it out and not have to be on continuous therapy with something like Bevacizumab for several weeks, which also can increase the risk of deep venous thrombosis, pulmonary embolism, hypertension, proteinuria. So, I think the first thing is always to use the steroids. But if the steroids either are not doing a good job or if the patient is not tolerant of them, then you need to consider both a craniotomy to remove the necrotic debris or bevacizumab. The bevacizumab dose, there's different regimens out there in terms of for radiation necrosis. I like to use 7.5mg/kg at a very decreased frequency every four weeks because it means they don't have to come as often. And I will usually do anywhere between three and six doses and then discontinue.