Transcript:Daniel Heng, MD, MPH, FRCPC: Let’s talk about subgroups of patients. Paul, do you want to talk about patients with bone and brain metastases?

Paul Nathan, MBBS, PhD, FRCP: Certainly. They are two difficult-to-treat patient groups, I think. And, the first thing to say is that we often see bone as a primary site of progressive disease in a patient who otherwise is having visceral control on a tyrosine kinase inhibitor (TKI). What, exactly, it is about the bone microenvironment, or drug pharmacokinetics, that we’re unsure about.

Certainly, the bone microenvironment is different and may be doing something to the tumor that makes it less susceptible to TKIs. So, in a situation where somebody is getting visceral benefit from their TKI, but perhaps you’re seeing bony progression, what we tend not to do is to stop the TKI, but we will actively try and get local control of the bony disease, particularly if it’s symptomatic. And, so that would generally use radiotherapy and bisphosphonates or other anti-bone agents. And, then we would try to tease out as much value from their TKI before having to switch.

There is a small group of patients who get significant bony progression, and they become very symptomatic, and local therapies don’t palliate their symptoms adequately and one needs to change to alternative systemic treatments if one can. I should also say that we know that bone is a poor prognostic site of disease, so these patients are often quite symptomatic and don’t do well long-term. I wouldn’t stop. The message is I wouldn’t stop a TKI, simply, because you’ve got limited bony progression.

I think our management of brain disease is changing. The first thing to say is, as a melanoma doctor, we’ve learned over the years to be much more aggressive in management of brain metastases. So, we survey our melanoma patients for brain metastases because we want to allow use of immunotherapeutic agents later, and I wouldn’t be surprised if the renal community ends up moving to a similar place over the next few years.

But with earlier detection of oligometastatic brain disease, and using radical therapies, whether it’s surgery or stereotactic radiosurgery, we know that we can get long-term control in a subset of patients with brain disease if you go after the brain disease, aggressively, and so that’s what we do. In our patients with metastatic disease, when we are scanning them, we don’t exclude brain. In my practice, we used to only image somebody’s head if they were symptomatic. We don’t do that anymore. For patients with metastatic kidney cancer, we always include brain because we want to detect metastatic disease in brain before it becomes clinically evident because, again, we can feel, for some patients we can get intracranial disease control using radical therapies.

There’s no doubt there is a group of patients who have multiple brain metastases, who do benefit from systemic agents with metastatic kidney cancer. And so you can certainly use TKIs to palliate those patients. Most of the patients who have been treated in that way from historical series, had whole brain radiotherapy first, but there isn’t a lot of data showing any difference between whole brain radiotherapy pre-treated patients and their benefit from TKIs, compared to patients who are treated with TKIs only. And I think that’s actually still an open question. But certainly systemic treatment has a place in the management of those patients.

Nizar M. Tannir, MD, FACP: I’m surprised, Paul, that, in UK, your health agency allows you to order routinely MRI of the brain on patients who do not have a neurological symptom. Because, in the US, with the free market, we are getting pushback from insurance companies when we order MRI of the brain. For patients, I do not routinely order MRI of the brain on every patient unless they are enrolled on a clinical trial, and it’s required by the clinical trial. But, off protocol, I do not do it because we’re getting denials for MRI of brain if a patient has no neurological symptom and is neurologically intact.

Susanne Osanto, MD, PhD: And, for melanoma, I think it’s even very different. I’ve done studies with melanoma. If you do it at baseline and it’s completely negative, normal MRI or CT scan, three months later patients can have florid metastases, so the melanoma with a minimum 60% having symptomatic brain metastases during their life is quite different. There’s a preponderancy to grow there.

Paul Nathan, MBBS, PhD, FRCP: So, I was careful what I was advocating. So, for our melanoma patients—and I know we’re not really talking about melanoma— but for our melanoma patients, we include brain imaging for those patients on surveillance. Now, I’m not advocating that for kidney cancer because of the differences in prevalence that you’re saying. But I do think for patients who have metastatic kidney cancer and you’re treating them, I think including brain MRI, even if they’re asymptomatic, is of value. You can argue about the frequency that you might want to do. One other point. We were talking about keeping patients on surveillance who have got indolent disease. Of course, the disaster—and we’ve all had patients like this—there is the handful of patients who when they relapse, they relapse in CNS. So, those are patients that you’ve been watching because they’ve got small volume disease, and then, lo and behold, they end up having...

Susanne Osanto, MD, PhD: That’s the only category that I’m worried about; ones that you’re not starting on systemic treatment. You’re afraid that they will develop micro-mets to the brain, it will grow out, and maybe there will be a disaster. But, in general, the patients in treatment, they usually become symptomatic. They often have just one, or two, or three small lesions which you can easily detect with stereotactic radiotherapy, or even, surgery plus radiotherapy. So my experience with brain mets in kidney cancer is much, much more favorable as compared to melanoma patients.

Paul Nathan, MBBS, PhD, FRCP: I agree with you about the majority. It’s just the patients I’m concerned about are those who only become symptomatic when they’ve got disease that’s of a large enough volume that you no longer have a radical treatment option.

Carlos H. Barrios, MD: I think that that’s a moving target, as we prolong the life of these patients. As in many other diseases in oncology, there is the apparent perception that we’re seeing more CNS compromise, metastatic compromise, and this may be the case. I think that the hardest data that we have, in terms of brain metastases, comes from the 5,000 expanded access study that was done with sunitinib, about, I think, maybe 10 years ago or something of the sort, the end of last decade, where 7% of the patients actually had the brain metastases. That number, just that number, does not necessarily justify, in our practice at least, screening patients that are symptomatic in that regard. But I understand, that as we are having patients who are surviving much longer, that may become an important issue, and certainly clinical trials, in that regard, should be performed because certainly it’s a very serious situation with very dire consequences in handling those patients.

Daniel Heng, MD, MPH, FRCPC: I completely agree with that. I personally don’t screen the CT brain right away, but I think as our patients are living longer, maybe it will become an issue. The treatment of brain metastases and bone metastases I’ve always found unsatisfactory with targeted therapy. And, so things like using SRS, or SABR and surgery, can be very helpful.

Transcript Edited for Clarity