Neuroprotection in Small Cell Lung Cancer: Insights from the NRG CC003 Trial

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program, and co-director of the Cleveland Clinic Sarcoma program.

Today I'm happy to be joined by Dr. Greg Videtic, Director of the Thoracic Radiation Oncology program here at Cleveland Clinic. He was previously a guest on this podcast to discuss the role of SBRT for early stage lung cancer. That episode is still available for you to listen to. Today he's here to discuss neuroprotection in patients with small cell lung cancer, insights from the NRG CC003 trial. Welcome back, Greg.

Gregory Videtic, MD: Dale, it's really nice to be here. Happy to be with you, and happy to talk about some of the work that we do here to help our patients.

Dale Shepard, MD, PhD: Excellent. Remind me a little bit. We talked about the fact you're the Director of the Thoracic Radiation Oncology group, but what does that mean? What do you do here at the Clinic?

Gregory Videtic, MD: My responsibilities are primarily focused on chest tumors, so that means anything involving the lungs, anything involving the esophagus. Also I was responsible and still am in terms of the development on something you mentioned I talked about before, which is stereotactic body radiotherapy or SBRT. I'm the chest guy, if you like, and that helps me think about how I can support development of research, for example, or clinical trials, plus it lets me be the representative in our overall lung cancer program, which involves medical oncologists, surgeons, pulmonologists, and somebody like me.

Dale Shepard, MD, PhD: Excellent. We're going to talk about neuroprotection and patients that are getting radiation therapy for small cell lung cancer. Give us a really high-level overview of what normally happens. What's the typical things that we do for protection of the brain? We have a whole bunch of different people that might be listening and may be not familiar.

Gregory Videtic, MD: In fact, what I'll do is I'll take just a little step back to give the framework of why this is even an interesting question in something like lung cancer, because I think most people would have a hard time leaping from the chest to the brain and trying to understand why that would be relevant. One of the realities is that, even though smoking is decreasing as far as it being a social behavior ... and what that means, it's also led to a decrease in the prevalence and incidence of lung cancer ... it unfortunately still is the number one killer. Within lung cancer there are different kinds of cancers and there are two main groups, and they're based on what the appearance of the cancer is under the microscope.

The most common cancer is something called non-small cell lung cancer, and the least common is called small cell lung cancer. What's interesting, again from an experience point of view, is that small cell lung cancer, maybe 20 years ago when I started, was maybe about a quarter of the people that I would see. Now it's only about 15%, and that's really a result of the drop in smoking. I'm putting that plug in for the best cure for lung cancer is not smoking, actually.

Within the small cell population, what makes small cell a little bit different than non-small cell besides its appearance is its behavior. Unfortunately when people are diagnosed with small cell lung cancer, the majority of them, about two-thirds of them, will have advanced disease or extensive disease. That makes our job primarily helping the person cope with their symptoms, relieving symptoms, and also stopping the cancer from impairing their quality of life and how long they live.

It's a different entity than the smaller subset of patients, which is about a third of them, which have limited disease, so disease only in the chest, and that's a population that we hope to cure and offer them cure through a variety of means. Traditionally it's been through the use of chemotherapy and radiation.

For a very long time, what's been recognized is that, as much as we want to get rid of the cancer in the chest, the sneaky thing that small cell cancer likes to do is actually to hide somewhere, and it tends to hide in the brain. It has a propensity for finding a back door and settling down in the brain. In the past, even when people had very good results in their chests, so the chemotherapy helps get rid of the cancer, the radiation gets rid of the cancer in the chest.

The chemotherapy part, which is the part that goes throughout the body and tries to prevent any cancer from developing anywhere else in the body other than the chest, unfortunately, chemotherapy doesn't tend to go into the brain, so this was what was called a sanctuary site, and it was long ago recognized that if you don't address what's going on in the brain, then unfortunately, no matter how well you're doing chest treatments, the person unfortunately will develop cancer in the brain.

In about the last 30 or 40 years, as a means of protecting the brain, we use very low amounts of radiation to prevent development of something that might be there. I always call it an insurance policy. It's not that there is cancer, it's just that we know that there's a tendency, and untreated patients will eventually develop brain tumors. It actually helps prevent brain tumors from developing, and hopefully helps people not suffer from that.

The other interesting thing that was long ago recognized was that not only does giving some preventative or insurance radiation to the brain prevent the cancer from declaring itself, it also helps people live longer. The reason I give you that framework is, so even in 2024 when I meet somebody and we talk about the challenges and the burdens of them having a lung cancer, one of the ways that we talk about how we're going to help them is talking about how the cancer behaves and how we want to help them. That includes, as I just said, looking after what's going on in the chest and also preventing something developing in the brain.

As you can imagine, when patients are given a lung cancer diagnosis, that's enough of an overwhelming idea just to grapple with. Then when you're meeting somebody and talking not about just their chest but maybe treating their brain, obviously for all of us, the brain is the seat of who we are, so people sometimes have a very overwhelmed anxiety about looking after things in a part of the body that's so precious to them and potentially so sensitive.

One of the discussions that I often have at that beginning is, "Whatever we're going to do, we're going to do the best, but we actually want to make sure that we don't harm you in the process." As you can imagine, any treatment, whether it's radiation, chemotherapy, naturally will have some side effects, and that's normal and it's expected. We gauge the benefit of our treatments by trying to make sure the side effects don't overwhelm the person. In the chest there's a range of side effects that we know are caused by radiation, and generally we talk about that.

Then when we talk about the brain, we talk about the potential side effects that might come out of, again, giving them an insurance treatment that will prevent a cancer from developing. Naturally, most people, when you talk about something like that, their biggest fear is, "Am I going to change as a person? Are you going to give me something like dementia? Is that what is going to be the outcome?" Because for a lot of people, the fear is not so much even the cancer as much as the burden of the treatment.

One of the assurances that historically we've given individuals is that, even if we're treating the brain, two parts of it are important. First of all, the amount of radiation is very low, so it's not going to damage them permanently, so they will not get something like a dementia. Because we're doing some treatment, there's certain parts of the brain that tend to be a little more sensitive, and that's what we call the short-term memory part.

Even when I historically would talk to someone and would encourage them to get this treatment, I would acknowledge that, "Your brain is an alive organism, so to speak, and there's things that might change, and you might notice in the first year that you have the 'I forget where my keys are' experience. That's a short-term memory issue. It's not about deep memory or personality."

We've also recognized that, just like other parts of the body heal, that kind of short-term memory loss can be recovered. Like all things, the question has been, even if we do have some recovery, can we prevent more than we see naturally? Anything else? Can we do something to try and mitigate that even more?

That's a long explanation as to where this idea has come about doing something preventing cancer, but also trying to mitigate a side effect that for a lot of people is still a little bit scary to hear about, that they might have some short-term memory issues.

Dale Shepard, MD, PhD: I guess just to solidify that whole notion of the toxicity, is this something that most patients will have some element of impairment that improves, and it's just kind of how bad is it, or does it only happen in a few of the patients?

Gregory Videtic, MD: That's a really good question. I talk to it in the sense that most people will experience something, and most people will recover. Again, I've had the privilege of looking after a lot of people now for the last period of time that I've been in the Clinic, and I think to quantify it as to say there's probably a minority of patients, but it's enough that maybe one person in five will still say, "Gosh, I'm okay. I know I'm normal, but man, I still have that. If I don't think about it, write it down, I'm going to forget something in the very short term."

I think that's been the big issue. It's not that it's a profound loss. I mean, historically people were treated and were recognized to do okay, but like everything, if you can make even an improvement for a good number of people, even in a smaller area of their experience, it's still worth it. That's where that comes from.

Dale Shepard, MD, PhD: Gotcha. We're going to talk a little bit about a trial that you participated in that looked at trying to spare part of the brain to minimize some of these side effects. Tell us a little bit about the trial.

Gregory Videtic, MD: Yeah, that's a nice summary of the intention of what we were involved with. There's a national research cooperative group called the RTOG, which is part of another basically larger group called NRG. The RTOG focuses on radiation questions, and the Cleveland Clinic in the radiation department has been a very strong supporter of these trials. Again, the notion of a trial is helping patients and advancing our understanding of what our treatments do for them.

There's a colleague who works out of Chicago named Dr. Vinay Gandhi, and he's been very involved in studying impact of radiation on brain function. He's led studies in patients who unfortunately might have brain disease like brain metastases, and he's done a lot of work in that. His natural progression was when he realized that, when you're treating patients who do have brain disease and you can mitigate some of the side effects of the treatment with radiation, maybe we should look at patients who we're actually curing and who we're trying to prevent cancer actually causing them injury. Maybe we can actually see if we can limit the radiation injury.

The genesis of this trial, which was run by the RTOG, had that premise, which is it's not about the amount of radiation, because we understand its efficacy. It was more about, "Hey, if we can do this for patients who do have brain tumors, let's see if we can do it for patients where we're offering insurance therapy." That was the idea behind this trial, which was numbered as CC003.

The goal of this trial was to establish two things. First of all, it arose out of obviously a lot of previous experience, but the primary goal started as making sure that we maintained the basic premise, which is if we're going to protect the brain from memory changes that may come from radiation, we also make sure that we don't at the same time lose control of the cancer, so they had a cancer control first part. Then when that was established, then it moved to the second part of the trial where the primary question was, does focusing on preventing memory loss actually happen when we use a specific radiation delivery.

Just to insert at this point, this was very dependent on technology. In a way, the way of delivering radiation has been very standard for many, many, many years, but the ability to spare parts of the brain where the memory components are really depends on understanding and visualizing those parts of the brain. You need high-level imaging, things like MRIs. You can't just do it with a regular X-ray. The second part was you needed a way of delivering radiation which could shape and protect that area. In a way, although the radiation itself does the same thing and that never was a question, a lot of the genesis of this was really driven by technological advancements in terms of delivery and also in terms of imaging.

Dale Shepard, MD, PhD: The study essentially was using traditional radiation in one arm, and then in the other arm it was doing this thing where you spared the hippocampus?

Gregory Videtic, MD: Correct. Absolutely right.

Dale Shepard, MD, PhD: When you looked at those two groups, what was the impact on cancer outcomes?

Gregory Videtic, MD: Importantly, in the first part they showed no difference in terms of control, which was very reassuring. In other words, even sparing that part of the brain, which is a small part but an important part ... the hippocampus is in the lower part of the brain ... thankfully there was no sign that those patients might have had an increased rate of brain failure. That was the first, most reassuring thing, because we wouldn't want people to have more cancer in the context of trying to preserve their memory. That was the first step, and once that was established, then we could move on to the second step.

The second step involved exactly like you said. You're giving standard radiation, comparing it to this technologically-driven radiation that spares the hippocampus. The measure of memory preservation is putting patients through a series of very established cognitive testing. It's called psychometric testing. There were a number of tests that were administered to both groups.

The primary goal in this study was to see whether or not that special radiation would prevent a decrease in memory at a specified point in time. Basically it was at six months, and they had a very specific test called the Hopkins Verbal Learning Test, its recall component. They were measuring that in both groups with the idea of seeing was there any change one way or another, favoring or not favoring this new experimental radiotherapy.

Dale Shepard, MD, PhD: When they did that and they did this particular test, was there a benefit to sparing the hippocampus?

Gregory Videtic, MD: What's very interesting was that in fact, they did not show a difference with that test. That's a little bit surprising, but that's the point of doing a randomized study, which is you take patients, you assign them randomly to each group, so they presumably and did have the same characteristics, and you measure then equivalently whatever the outcomes are. In each of the two arms, the measurements at six months, the declines that we're seeing were equivalent, both in the standard traditional radiation and in the experimental radiation.

You might ask then, "Well, if that's the case, then why is this an important study?" What they also measured, in a forward fashion or a prospective fashion, was there were a whole gamut of other tests that they used that measure recall and memory, and those were specified. What the study showed actually was that the experimental radiation, whatever the test you would use, prevented early changes in memory. Unlike the first endpoint, which was a very specific test where they showed no differences, when you looked at the gamut of all of the tests combined, there was a significant difference.

The formal word was it decreased the rate of first failure in any cognitive test. That's why that's become a big deal, because traditionally in a Phase III trial, you'd like the primary endpoint to be the one that drives change, which is understandable. They made a very strong case when this was presented that any change in any cognitive measure is actually significant for the quality of life experience of patients. That's why this particular study was selected last year for presentation at our annual meeting, because of that particular endpoint, although it was a secondary endpoint.

Dale Shepard, MD, PhD: Big-picture from a patient perspective, I guess a very practical question is we have these established psychometric tests, which are used certainly in a research setting, but are those used as much in a clinical setting? Is it more of a research construct, or when patients are coming back, do you actually test them?

Gregory Videtic, MD: That's a really, really good question. In reality, we don't use those in everyday care, which brings the point of does the patient actually have benefit. It may not be linked to a specific test at a particular time. I think that's exactly the point.

Obviously when you design a study, you have to have very tangible and very discrete markers. I think in the end of the day, that's how we've interpreted as well. Since we're not specifically measuring every patient's function on every visit and we're looking at the global experience, it made a lot of sense then to say, "Well, this is actually a significant finding, not significant because it's actually statistically significant," which it was, "but actually significant in the quality of life experience for patients."

Out of that, that has driven for a lot of people, and certainly here at the Clinic, a shift away from the traditional, which again, I must emphasize it's not about one is harmful and the other is not harmful. It's that the experimental mitigates things that we would want, which is we still deliver great cancer care, but we're enhancing the quality of life experience for patients by trying to minimize some of the things that could impact on their daily life.

Dale Shepard, MD, PhD: You mentioned before the technological aspect of having radiation that does this sparing.

Gregory Videtic, MD: Yes.

Dale Shepard, MD, PhD: Is this something that is maybe able to be done in most settings? Radiation oncology seems to be all about what equipment you have and the capabilities. Is this widely applicable, or is this more in specialized centers?

Gregory Videtic, MD: That's a very good question. Probably in 2024, the majority of centers, even community centers, now are very well equipped with the technology that would deliver this. For example, within the Clinic system we have our main campus system, we have the regional system, all of which can do this. I think that's very important. You can't just do something in the absence of its applicability. This is something that's fairly generalizable, I'd say at least in the United States, because we have the capacity because people are generally very well equipped now.

I think one reassurance, that I just again want to come back to this point, is that if somebody were in a setting for whatever reason where it wasn't available, you still have reassurance that you're still doing the right thing by doing the treatment itself, even in a conventional way. Because again, this is about cure and prevention of brain metastases ever developing. Like all things, you have to respect the environment in which people are, but generally speaking, in the United States this would be very, very generalizable.

Dale Shepard, MD, PhD: It's great that this ends up being globally positive and helpful for patients. I guess to close, I think it's important always to think about how these things are even done. You mentioned this was being done through a cooperative group. Just give us a really quick overview of what that's all about and why these cooperative groups are important. It's something really important here at the Clinic. It enables us to get these things done. Maybe just a little insight in terms of how we can actually accomplish these.

Gregory Videtic, MD: The idea behind a cooperative group is in the word cooperative. It's supposed to be something that is generalizable to most institutions. It's not supposed to be esoteric and limited to academic institutions. That's the first point, and that's one of the ideas of the RTOG, that whatever radiation question comes up, it's got to be something that most people can do.

The second thing is the quality control is very important in these studies. That's one of the hallmarks, again, of cooperative groups. Where we all invest in supporting the institutional support that we get to make sure we give good care, the cooperative group confirms that by making sure that exactly what we say we're doing, we are doing. That gives reassurance to patients also that, if we're doing these things, it's in the setting of something that's actually been verified by a higher authority as well.

Ultimately, I think whenever I talk about doing any trials with patients, it's for their benefit. It's for understanding that they may get something for their own sake out of the experience. We don't offer trials to people unless it makes sense for their betterment. Sometimes, unfortunately, trials don't always give us the answer we want. Perhaps in talking about this one, things proved to be interesting in terms of the outcomes, but the goal is to make it worthwhile for the patient. I think that's one of the reasons we support it, because that's our orientation at the Clinic.

Dale Shepard, MD, PhD: That's fantastic. It's a really important area of research and some great findings. Appreciate you sharing insights.

Gregory Videtic, MD: You're welcome. Again, I am very grateful that I work in a place that supports us doing that, and patients are eager for these things. They want to know how they can help themselves. I'm glad we can do these works together.

Dale Shepard, MD, PhD: Very good. Thank you.

Gregory Videtic, MD: Thanks.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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