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Management of Indolent Lung Cancers

GRACE Video

CNS Disease in ALK-Positive NSCLC: Monitoring and Systemic vs. Radiation Therapy

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GRACE Cancer Video Library - Lung

GCVL_LU-FC05_CNS_Disease_ALK-Positive_NSCLC_Monitoring_Systemic_Radiation_Therapy

 

Dr. Ross Camidge, University of Colorado, discusses management of CNS progression for ALK-positive NSCLC including monitoring frequency and preferences between systemic and radiation therapy.

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As we started to treat ALK-positive patients with crizotinib, it became clear that the brain was somewhat of an Achilles heel. It was a common site for people, when their cancer started to grow, for that to be the site where their cancer was growing, and we know that in many of those cases that’s the only site where the cancer is growing. We know from a small number of studies where people have actually sampled blood levels and from the fluid around the brain that actually very little of the crizotinib is getting in, so it’s maybe just that you have a relatively under-treated part of you.

Now that plus the fact that people fortunately live a long time with ALK-positive lung cancer means that the brain can become this area that will crop up with disease. For me that means you should absolutely keep an eye on the brain. If you have no known disease in the brain I would do an MRI scan at least every six months. If you do have known disease in the brain, even if it’s treated, I would be looking more frequently, possibly as frequently as one scanning the body on treatment, or maybe half as often.

Now if you do have disease in the brain, because the activity of crizotinib is not zero, unless you have a lot of symptoms from the disease in your brain, many people will start on the crizotinib, but obviously keeping a close eye because if you do progress in the brain, then you may have to salvage it.

You can salvage it in a number of different ways. One would tend to stay on the crizotinib and either have local radiotherapy or occasionally surgery depending on the site of the deposits in the brain. For me though, there’s a difference between one type of radiotherapy and another. For example, you can either treat the whole brain, what’s called whole brain radiotherapy, or you can treat individual lesions with what’s called stereotactic radiosurgery or SRS. I very much prefer giving SRS, even to a reasonably large number of lesions, than whole brain radiotherapy for the simple reason that people with ALK-positive disease are now living long enough that they’re manifesting the side effects of whole brain radiotherapy and that can mean word finding difficulties, memory difficulties.

So I think for me if you’re just at the point where you can spot weld a few areas with stereotactic radiosurgery, that’s fine — stay on the crizotinib. But if someone is thinking about whole brain radiotherapy, I would probably switch to a next generation ALK inhibitor rather than do the whole brain radiotherapy because we know they have good activity in the brain.


GRACE Video

How Rate of Progression Can Affect Treatment Decisions

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GRACE Cancer Video Library - Lung

GCVL_LU-F03_Progression_Rate_Affect_Treatment_Decisions

 

Dr. Benjamin Levy, Mount Sinai Health Systems, explains how the rate of progression of a patient’s cancer may affect treatment choices.

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I think we know a lot now about how to treat patients with advanced stage lung cancer, and there are several things that we factor in when we treat patients. One is clearly the genetic makeup of their tumor — we tend to look at this when we’re trying to decide on a targeted drug for these patients. The other is perhaps histology, looking at a particular type of lung cancer whether it be adenocarcinoma or squamous cell, and deciding what type of chemotherapy we’re going to give. One that I would also like to mention that’s sometimes factored into treatment decisions is the variability of the aggressiveness of the tumor, meaning that some lung cancers can be very aggressive, and despite popular belief, some can be quite indolent.

Now while most lung cancers are thought to be more aggressive, I have come across many patients with lung cancers that tend to grow less rapidly, and the thought is: how do we factor this in when we’re making treatment decisions? I think the variability of progression plays out in two clinical scenarios.

One is a patient who is on chemotherapy or even on a targeted drug who’s doing well and tolerating the drug, and in which we are ordering scans every six to twelve weeks and we’re seeing that the tumor is growing but at a very limited pace, and the question is: if the patient is tolerating the chemotherapy or the targeted drug, should that limited pace of growth trigger a treatment change? I would say in our practice, not necessarily. Sometimes if growth is small, or growth is limited, or the pace is limited, sometimes we will keep patients on that particular therapy. My thought is they’re probably deriving some sort of benefit from that therapy if they’re tolerating it.

I think the other scenario where this plays out is for a patient who perhaps hasn’t been tolerating therapy and is on a treatment break. Sometimes not all patients tolerate chemotherapy and may need a treatment break, particularly when they get to maintenance, and the question becomes: if the cancer is growing on scans while they’re on a treatment break, should you reinstitute the drug or even reinstitute another drug? Again, I think that depends on how quickly things are moving along — for patients who may have not tolerated treatment well who are on a treatment break and their cancer is growing very, very slowly, I think it’s reasonable to continue to watch them as long as they understand that the cancer may grow rapidly at some point.

So I think these are important considerations when you’re treating a patient, not only to look at the genetic alterations in the tumor, not only to look at histology, but also to consider the natural evolution of this cancer and how it’s moving, and how quickly it’s growing when making treatment decisions.


GRACE Video

Local Therapy for Limited Acquired Resistance

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GRACE Cancer Video Library - Lung

GCVL_LU-FB06_Local_Therapy_Limited_Acquired_Resistance

 

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

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It’s my privilege to speak to you today about a favorite topic of mine, local therapy for limited acquired resistance.

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So just five years ago, we were celebrating the curves that I’m showing you here. This is great — we have a targeted therapy, it works better than chemotherapy, it’s less toxic, it’s more convenient, demedicalizes the patient’s life, and this is a legitimate victory and I don’t want to take that celebration away, but I think only five years later, I guess now six years later, I think the perspective is a little bit different as our drugs get more effective and the bar goes up.

GCVL_LU-FB06_Local_Therapy_Limited_AR_03 

We say these drugs are lasting less than a year on average — now what? We’re trying to find something other than chemotherapy. There are multiple promising approaches, including next generation drugs aimed at the targeted therapy, but I’m going to talk to you today about a slightly different approach. Before doing so, I want to just share that this story is very analogous for crizotinib and ALK and ROS1, it’s the exact same story.

GCVL_LU-FB06_Local_Therapy_Limited_AR_04

The approach I colloquially call “weeding the garden.”  This approach is what it sounds like — using some kind of local ablation or surgery to take out areas of progression, areas that are growing despite the targeted therapy, the areas that perhaps have a resistance mutation of some kind, and then using the original therapy for the rest of the cancer that’s still well controlled.

GCVL_LU-FB06_Local_Therapy_Limited_AR_05

So when might this make sense, and when might it not? Well the situation  where it surely does not make sense is classical progression. Prior to the advent of targeted therapies and immunotherapies, there was really only one pattern of progression that we mostly saw: when the cancer was going to grow, it grew everywhere and it grew in multiple new spots — not a time when weeding the garden makes good common sense.

We have two new patterns of progression where it does make more common sense. One is oligoprogression — that is what it sounds like, you have progression in just one or two spots, those spots maybe have T790m or some other resistance change, where the rest of the cancer is beautifully controlled still on the targeted therapy. The other situation is when the progression is in an area that the drug doesn’t get to so well. So there’s this filter between the rest of the body and the brain called the blood-brain barrier. Its job is to keep poisons out of the brain and it appropriately sees most of our anti-cancer therapies as poisons and keeps them out of the brain. You can have cancer growing in the brain not because there’s some resistance gene, some secondary mutation or amplification of some gene, but just because the drugs aren’t getting there well. I think that’s another area where it conceptually makes sense to consider weeding the garden.

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For EGFR, I think radiation is a particularly promising approach to do this — at left you can see data preclinically in the lab on why EGFR mutated cells seem to be more sensitive to radiation than non-mutated cells, and at right some human data to back up that this actually happens in real people.

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This approach has been tried retrospectively — the Memorial group here did a mostly surgical series where they got a median time until progression of another ten months after this approach, so they’ve mostly cut out the sites of progression and started TKI back up again.

GCVL_LU-FB06_Local_Therapy_Limited_AR_08 

Our colleagues at Colorado, where we happen to be taping today, have done this in a mixed series of EGFR and ALK patients; they show their data separately for whether the progression was primarily in the brain or elsewhere. When the brain was the primary site of progression, they got another 7.1 months out of targeted therapy. When it was outside of the brain, they got an additional four months.

GCVL_LU-FB06_Local_Therapy_Limited_AR_09 

I have the privilege to lead a study prospectively evaluating this approach for patients with oligoprogression on EGFR mutation. The design is very simple, you have to have gotten benefit out of an EGFR TKI, typically erlotinib in the first line in this country, but no prohibition against gefitinib or afatinib, but now one or two sites, up to five sites, are growing. We do stereotactic radiosurgery to those sites of progression, and then restart a TKI for the remainder of the sensitive disease. My collaborators are shown at right, including many GRACE contributors.

GCVL_LU-FB06_Local_Therapy_Limited_AR_10

[In 2015] Pfizer agreed to fund a very similar study for patients who have previously received a benefit on crizotinib but are now  progressing. The design is rather similar here, where we do radiosurgery to the sites of progression, restart the crizotinib, and because which mutations are sensitive to crizotinib is evolving at the current time, we don’t define this on a molecular basis but on a practical basis — patients who have received benefit but now have growth in four or less spots.

You might reasonably ask me the question, “well we have all these exciting next generation tyrosine kinase inhibitors we’ve heard about on GRACE, we have the clovis compound and the AZ compound for EGFR, we have alectinib and ceritinib for ALK — why not just jump to one of those?” I actually think that would be a perfectly reasonable approach, perhaps the preferred approach when there’s poly progression, but I can show you graphically why you might consider the approach that I’m talking about.

GCVL_LU-FB06_Local_Therapy_Limited_AR_11

So here’s the approach of starting with the first-gen TKI and moving straight to the next-gen TKI. Let’s imagine that my approach of eliminating oligoprogressive disease only has minimal efficacy, only gets you a few extra months on the first line therapy, you might look at this graphically this way: that you’ve inserted an additional therapy, you’ve squeezed a little more juice from the orange, in first line, before moving to that next line. But it’s entirely possible that in reality we get something better than that. So the first of these alternative hypotheses is that we get a longer duration of control — perhaps ten months or a year, replicating the original experience with the first line targeted therapy. Here we have a larger advantage to total cancer control before moving on to chemotherapy. Alternatively, if we’re radiating spots, we may be eliminating some of the spots that are eventually going to cause resistance on second line TKI, and so it’s entirely possible, I would call it my professional fantasy, that we’ll actually not only prolong the duration of benefit of the first line drug, but make the second line drug last longer when we get there. The possibility of that approach is shown at the very bottom — that fantasy phenomenon.

So I thank you for your kind attention.


GRACE Video

Cancer Growth Rate and Managing Slow-Growing Lung Cancers

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Note: This is an older video and may contain outdated information.
Please view this updated video.
 
GRACE Cancer Video Library - Lung

GCVL_LU-F03_Indolent_Lung_Cancer_Management

 

Dr. Jack West, medical oncologist/lung cancer specialist, describes special management considerations for indolent lung cancers that may not require treatment or are at risk for “over-treatment.”

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One of the core questions in managing patients with advanced non-small cell lung cancer is addressing the pace of the disease, because it can really vary a lot. In many cases, and in fact, in most cases of advanced non-small cell lung cancer, the cancer will be progressing at a rate at which you can see things getting worse if you don’t do treatment, over an interval of one or two months.

On the other hand, there are also some cancers that follow a more indolent or slow-growing pace, and in patients with a slow-growing cancer, especially if they don’t have symptoms clearly related to it, it might make sense to hold off on treatment for a longer period of time. So, it is worth asking a few central questions about how best to manage a patient with an indolent cancer, even if it is technically metastatic.

The first question is whether you see any progression at all over a period of, say, six or eight weeks, or maybe even longer, three or four months — because, if you’re not seeing progression over that period of time, it’s hard to have the real incentive to pursue a treatment that can have side effects. We don’t want the treatment to be worse than the disease. Again, if you do see progression at all, you need to ask whether it is clinically significant progression. Just being able to measure some degree of progression if you squint carefully — it is not necessarily enough to justify the side effects of treatment in somebody who is otherwise doing well, and may continue to feel well and do well for many months, or potentially many years, with a cancer that just happens to be quite slow-growing.

A second related question is: if you do see areas of clinically significant progression, is it really just one area that’s growing, or two, or is it multiple areas growing at once? Because, if you see just one or two areas growing, it might make sense to pursue a local therapy, something such as surgery or radiation. On the other hand, if you see multiple areas all growing together, it makes more sense to pursue a whole body, systemic therapy that can treat all these areas at once. But if you see just a single area growing, perhaps, even if it’s against a background of several other areas of known disease, if all of the other areas are growing at such a slow pace that you really don’t necessarily need to worry about them as a threat any time soon, it might make sense to just get the lead runner, to borrow a term in baseball, and address and neutralize the only area the really seems to be leading the charge as a threat.

And then, if we do see areas of multifocal progression, multiple areas growing at once, the leading consideration is going to be systemic therapy. If that’s the case, the leading question after that is: what is the best treatment to pursue — and that’s the subject of other videos here.


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