Single-Fraction Stereotactic Body Radiation Therapy (SBRT) Effective for Early Stage Lung Cancer

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, overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Greg Videtic, a radiation oncologist at Cleveland Clinic Cancer Center. He’s here today to talk to us about SBRT for lung cancer. So welcome, Greg. Maybe you can start by telling us a little bit about your role here at Cleveland Clinic.

Gregory Videtic, MD: Thanks, Dale, again, for asking me to take part in this conversation and talk a little bit about what we're doing here in the department with respect to thoracic cancer, and specifically they use a stereotactic body radiotherapy in the treatment and cure of early stage lung cancer. I joined the Clinic in 2003. And after I had joined, the department made a decision to develop a stereotactic body radiotherapy as part of the program goals in managing lung cancer. At that point in time, stereotactic treatment specifically was new and was not widespread within the community. And there were only selected centers that had availed themselves of the machinery to carry out this particular treatment. And so with that in mind, we learned from scratch how to use this device, so to speak, in treating lung cancer. And specifically, the population that we were interested in serving with this particular treatment, was the medically inoperable early stage lung cancer population.

In other words, these were patients who by whatever means had been found to have a potentially curable early stage lung cancer, but because of their medical histories and usually because of pulmonary history in particular, were never felt to be surgical candidates. So historically, they would have been not treated for cure. They usually would have been treated essentially for palliation. So with the development of this program, we learned that this particular tool, which essentially is a very highly focused means of delivering high dose radiotherapy that we could provide two results, which essentially were eradicating lung cancer, effectively curing it in its early stage, but also because of the nature of the treatment and ability to minimize injury to any other part of the chest, that these patients were having no side effects related to the particular treatment.

So it was and it's been still, quite a remarkable phenomenon to treat people who are vulnerable if you like, and offer them cure, but at the same time, be able to tell them that the side effects of the treatment are essentially minimal and especially given their medical histories, will not make them worse off after the therapy. So in a nutshell, that's what's been under development and application for the last 15 years.

Dale Shepard, MD, PhD: And then you had recently presented some data about your experience over as I recall, about 10 years, is that correct? And what did that show?

Gregory Videtic, MD: I like actually emphasizing that it's a ten-year experience, mainly because one of the goals in learning how to use this tool, so to speak, was actually also being very diligent in keeping a prospective data registry of every single patient that we've ever treated. And if you accumulate all the potential data as much as possible regarding any component of their care and who they were as patients, mainly because since we really didn't know this treatment and we were learning how to use it, just like everybody else who was doing it, we thought if we did this in a forward fashion, we'd be able to potentially answer questions in the future and maybe answer questions we weren't aware of at the time. So the context for this first of all, is again, that we've had this very lucky experience, so to speak, of having a very comprehensive developing program for 15 years.

And out of that, we were able to answer some of these questions like this ten-year question, which no other institution has ever published on. So that's part of the background here. The second part background, is that in the same way that we were learning how to use the machine, we are also very conservative in applying the therapy. And essentially from the beginning, when I was working with a physicist who was also very instrumental in making this work, we both agreed that our responsibilities were slightly different. He would help the machinery work really well and I would figure out a way to do the clinical care. And out of that, we had to decide on a treatment regimen because there was no standards at that time. So it was many publications or different small experiences. But the short version is that after looking at the literature, I used a model that had been developed in Japan of treating patients over five consecutive days.

And that model is what we used basically for the first six or seven years of our practice. So we basically looked after everybody the same way. We used the same treatment paradigms, both the clinical point of view as well from the machine point of view. While we were doing that and recognizing that we were learning as much as everyone else, we also were very committed to being engaged in any of the trials that might be opening with respect to that. And because the RTOG, which is the Radiation Therapy Oncology Group leads the radiation trials in the United States, we were really eager to take part in the trials that would be opening with them. So effectively, as the years roll by and starting around 2006, we started also participating in clinical trials besides running our own daily routine practice of a five-fraction regimen. So there were a number of trials that we took part in over the years, such that we looked at using three treatments.

We looked at using four treatments. We looked at using one treatment. And the interesting thing was there were two ongoing trials, one from the RTOG and a parallel trial from the Roswell Park Cancer Institute, that were doing prospective randomized phase two trials investigating single fraction radiotherapy compared to more than one fraction. So the Roswell Park was comparing one to three fractions and the RTOG was comparing one to four fractions. Each of them had the same end point. The first end point was toxicity. And then the second end points were local control and overall survival. While we were taking part in those trials, again, because of the very large referral basis we get from the surgical service with respect to patients, we recognize that some patients either weren't eligible for these trials or might be better served by single fraction. So after a number of experiences using the single fraction and recognizing that it appeared to be safe and effective, we started offering this to patients off protocol.

And so what's happened, and this is really the source of this particular abstract that you asked me about, was that over about a 10 year period, not only were we completing these protocols, which are now published, but we also developed an increasing experience with the use of this particular approach in lung SBRT, which is single-fraction. With the publication of these trials and recognizing that we have one of the largest documented experiences in the country, I thought it would be very helpful to share with the community, the real life experience again, because we can go to our database effectively pull up all of the single fraction treatments we've had. And as I mentioned, we've been doing this for such a long time, that it made sense to give a 10 year experience because again, in the radiation literature, there's very little on long-term experiences in general, but specifically with this treatment, there are none. There are one-year experiences, three-year experiences, five-year experiences.

So we'll be the first to report on 10 years. And again, the idea that that is not simply to report on the cancer rate success, if you like, but also on the patient experience as the treatment matures over time. So again, the goal of this abstract was to look at our patient population over 10 years, both the patients treated on and off protocol. And as you saw from the abstract, we treated over that period of time, over 200 patients, close to 230. And the very gratifying and very reassuring finding was that, as time evolved and as the data matured, the same conclusions that were found in the randomized published trials still were valid. In other words, single-fraction radio therapy for a population of early stage inoperable patients is very effective. It cures at the rate that we would expect. And it's incredibly safe with respect to long-term toxicity, as well as short-term.

And in my experience with this particular fractionation, I get a lot of calls or a lot of emails from other institutions, not so much about the cancer cure rate, because I think most radiation oncologists are very impressed by the efficacy of this, but a lot of the physicians are more often concerned about toxicity and long-term toxicity. So this fills in, I feel like, the void for information on that particular component of care. So I was happy it was accepted for poster at ASTRO. I'm drafting the manuscript. And again, besides relating our own experience, I think, it just provides, again, a nice resource for other radiation oncologists to feel confident about using this treatment and the right clinical scenario.

Saying that it's just also to recognize that not every patient is appropriate for this fractionation. There are specific criteria that make this fractionation appropriate, among which is the relative location of the tumor in the chest. And so far, this is really defined for tumors that are about two centimeters from the mediastinum because of the concerns about potential toxicity to non lung structures. But a lot of the practice is involving these peripheral lung tumors. So along with my colleague, Kevin Stephens, who's the other primary lung cancer radiation oncologists in the group, we decided about a year ago that for the right patient who fits the right criteria, the single-fraction now, is our go-to standard of care on our routine treatments for inoperable lung cancer.

Dale Shepard, MD, PhD: So, two centimeters from the mediastinum. What about the size of the tumor itself? How large a tumor will you treat with a single-fraction for SBRT?

Gregory Videtic, MD: If you look at the protocols, there was an upper size limit of five centimeters. If you actually look at the data on the patients that was collected the median size for most patients with two centimeters. So there's a gap, if you like, in understanding the efficacy for larger tumor sizes. Again, we've tended to be pretty conservative in the sense that we don't usually go beyond protocol defined criteria. And as far as I know and as you can see from the data, our range of tumor sizes is fairly conservative in that sense. It didn't really... The majority of patients were around two centimeters. Again, we didn't treat above five centimeters. That doesn't mean that it's not a reasonable question to ask. We've actually done work at looking at large tumor size with other fractionations, but currently most patients who show up, tend not to show up with big tumors to begin with, since most of these tumors are discovered by chance. They're not really symptomatic. But again, it's an excellent question and maybe one that we would want to explore more carefully in a prospective trial.

Dale Shepard, MD, PhD: So it's good to hear about the toxicity, which as you pointed out, is a really important parameter in terms of this follow-up. But just quickly thinking about patients that may have had a recurrence of their tumor, does it tend to be local or distant?

Gregory Videtic, MD: So the patterns of failure with lung SBRT, I always say they mimic the surgeon. In other words, we get it all. In other words, the local control rates tend to be excellent. They're usually 90% plus, and that's also been demonstrated in the current study. So we really get rid of it very well. The conundrum, whether I'm a surgeon or a radiation oncologist, and we're looking to cure patients, is that patterns of failure outside of the chest. And in treating patients with SBRT, we see the same kind of patterns of failure. The primary pattern of failure, like with early stage operable patients is distant, which means that even though these are staged as early stage by the criteria and the tools that we currently have, lung cancer is still a little bit insidious and that we still see distant failure of about 20 to 30% with time.

And that's presented a challenge because whether you're your surgeon or radiation oncologist, your local therapy is only as good as it isn't. If it is excellent, then we need something that would match and manage the distant failure. And currently, even with surgical patients, there is no standard systemic chemotherapy that's given after a surgical resection of early stage because there's no evidence from phase three trials that improves overall survival. The conundrum for medically inoperable patients with that challenge, is also their medical status. And so typically, even without evidence of a benefit, we also know that clinically these patients likely could never handle conventional chemotherapy, such as platinum-based chemotherapy. So identifying the failure rate as being primarily distant, was just observational without really being able to intervene. The big change that's happened though in the last couple of years, which the medical colleges are grateful for it as well as we are, is the use of immunotherapy in lung cancer.

And it's very clear that immunotherapy has a profound impact on potential survival. It's being investigated in surgical patients now, who are early stage. And we're also looking at it in the inoperable patient population after SBRT. Although we had a study that unfortunately didn't accrue, and this is really not related so much to fractionation per se, there is going to be opening a phase three randomized study of SBRT with, or without immunotherapy augmently. Again, to see if we can answer that question since not only the advantage of immunotherapies from a cancer point of view, but generally speaking, it's much more tolerable than conventional platinum chemotherapy. So, that's, again, a bit of a tangent off of the specifics of single, but again, you're asking the most pertinent question right now, which is if we do so well and we do it so easily and efficiently for patients with a single-fraction, how can we improve their overall outcomes? And typically the drivers of distant failure are going to be size and histology with adenocarcinomas being more at risk than squamous carcinomas.

Dale Shepard, MD, PhD: So this came about because of a need to treat a population of patients that couldn't have surgery. Has there been a shift over that 10 to 15 years that you've been doing this, in terms of who's operable, either from a medical support standpoint or from a change in surgical technique. Is the person that's not operable now the same as the person who wasn't operable 15 years ago?

Gregory Videtic, MD: Again, you ask the right questions in the same way that we're getting better with where you therapy and radio therapy technology and techniques, the same thing has happened in the surgical field. I guess, I'd say the criteria that defined inoperability, which are usually cardiopulmonary status for most patients, even with the best management, that really probably hasn't changed that much. The definition hasn't changed. I guess, to some degree, depending on where you practice, the medical management of such patients might've changed or improved. But I would say, in general, if you're inoperable, you've remained inoperable currently. The surgeons agreed that what we define as high risk operable is the question of the hour. Again, because of competing risks with the impact of the therapies we do as opposed to the cancer benefits we do and so there's been a lot of debate about who does the right thing in that setting.

And again, thankfully, besides debating, we agreed a number of years ago to take part in an ongoing clinical trial, which is a randomized phase three trial in high risk operable patients looking at limited surgical resection. Not conventional but limited because usually these patients have pulmonary issues, limited surgical resection compared to SBRT with a primary endpoint with overall survival. So in that study, which we support, is called the JOLT-Ca/STABLEMATES Trial, people are randomly assigned to one of the two arms. And if you think about it, all of the components, both of the patient and the tumor enter into the overall survival equation. So we've accrued to that trial, it's accruing, and we're hoping that in the next year or two it'll be completed. And that should help establish the standard of care for a newer population, which is considered high risk. So currently the inoperable patients are considered to be SBRT territory, so to speak.

The high-risk is a discussion you have with the patient, offering them the clinical trial or else they're on an understanding of the risks and benefits of either of our approaches. And then obviously there's the operable patient population, which in general, we still consider a lung resection or lobectomy as the standard of care. But you can imagine that there are many patients now who are interested in minimally invasive or low invasion or no invasion kinds of approaches. And we're occasionally dealing with patients now, who respectful that they know that surgical resections standard of care are now asking for lung SBRT, since in other settings, it seems to be mimicking the outcomes with surgery. And I should just mention that again, that these trials are not fractionation dependent, they're really technique dependent. So for example, in the JOLT-Ca/STABLEMATES Trial that we're taking part in, it does not allow for multiple regimens. There's only one fractionation scheme that's used, and that's a three-fraction regimen.

Dale Shepard, MD, PhD: So you mentioned about techniques. So it sounds like you currently have an effective therapy that's well tolerated, but as with everything, you can always make improvements. Have there been changes or the anticipated changes in the radiation techniques themselves, the equipment localization, are there things on the horizon or currently there that have affected this therapy?

Gregory Videtic, MD: As far as the technologies are concerned specifically, we plateaued in the sense that there are some very subtle adaptations that can be still looked at. And some of them have to do with, not cancer related issues, as much as how we identify the tumor, how we manage the motion of the tumor during treatment. So there's still some refinements in there, but they're not dramatic. I'd say the more, not so much technology as much as tool oriented question that some institutions are looking at is an alternative to the use of x-rays and that's the use of protons. And the shortest way I can answer that is protons don't change necessarily the cancer cure rate, the interest with protons has always been whether or not they modify the toxicity rate. So you can imagine that with a treatment that we already know has a very low toxicity rate, the potential benefits of something like protons are probably minimal.

I have to recognize that we don't have protons at the Cleveland Clinic. There are some trials that are looking at protons versus photons, or x-rays in the setting of SBRT, and I'm glad those trials are being done. But frankly, when I've had patients ask me about that particular question, I can actually reassure them that, to the best of my knowledge and experience with protons in this particular setting, I cannot make a recommendation that there's going to be likely any difference in outcomes. Since, as I already said, the outcomes with respect to toxicity are so excellent with SBRT. So it's a great question. But I think actually from that point of view, we're really at the peak with where we could go with SBRT. And that's why, I think, I brought up that issue with the use of immunotherapy potentially to modify failure patterns is probably going to be much more the direction that people are going to be oriented at the present time.

Dale Shepard, MD, PhD: Well, you've certainly provided us with some excellent insight on this area. Do you have any additional comments?

Gregory Videtic, MD: Well, the reason I think this program has been successful is really because of the nature of how we practice here at the clinic. And I want to validate the support actually of the thoracic surgeons in advancing this as much as we've advanced it. We work really well together in recognizing the needs of the patients. And early on, when I first started working with this, it was very clear to me that the thoracic surgery was interested in this because to some degree we were potentially crossing over into their territory, but it was actually embraced by them. It was embraced by the leadership at the time. And I think, that's allowed us to have one of the largest programs in the country and our ability to report on it is really, again, a reflection of the institution. So again, I've been very grateful for it. It was an experience and it's been an experience to learn to do something from scratch and really help patients in an incredible way. So, that's my last thought on the matter.

Dale Shepard, MD, PhD: Well, thank you very much for joining us today.

Gregory Videtic, MD: Thank you. I really appreciate it.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real-time updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.