Ultra-Hypofractionated Radiotherapy for Soft Tissue Sarcoma

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-Directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Shauna Campbell, a Radiation Oncologist and Co-Director of the Cleveland Clinic Sarcoma Program. She's here today to discuss ultra hypofractionated radiotherapy for soft tissue sarcoma. So welcome Shauna.

Shauna Campbell, DO: Dr. Shepherd, thank you for having me.

Dale Shepard, MD, PhD: Absolutely. So give us a little bit of an idea, what do you do here at Cleveland Clinic?

Shauna Campbell, DO: So I am a radiation oncologist here at Cleveland Clinic. I specialize in the treatment of sarcomas as well as head and neck cancer. And I get to serve alongside you as co-director of our sarcoma program.

Dale Shepard, MD, PhD: Excellent. So we are going to talk about ultra hypofractionated radiation therapy. So let's take a couple steps back. So a lot of different kind of people might be listening in different backgrounds, fractionation. Tell us what is fractionation? What's hypo fractionation, ultra hypo fractionation? Give us an idea what exactly we're talking about here?

Shauna Campbell, DO: So fractionation is how we describe the delivery of our radiation. Historically, radiation was always delivered anywhere from five, six, seven weeks of treatment. Patients came once a day Monday to Friday. So radiation therapy was overall a somewhat longer process. What's happened over the last 15 to 20 years has been a progression of our technology and ability to deliver radiation in a more precise way with improved sparing of normal tissue, and that's what we refer to as intensity modulated radiation therapy. So as IMRT and then we've been able to refine the delivery of IMRT even more with volumetric arc therapy. We have been able to shorten our courses of radiation across multiple cancers and disease sites from six, seven, eight, weeks down to much shorter courses and that's what we call hypo fractionation.

So you're giving fewer number of fractions and hypo fractionation is typically described as a dose of radiation over approximately two and a half gram per fraction. And that results in the courses being much shorter. So typically anywhere between five fractions to 15 to 20 fractions is what we would call hypofractionated radiation. We refer to this study as ultra hypofractionated, because it is that five fractions. Typically, in radiation oncology, when you see something being delivered in five fractions, it's often called stereotactic body radiation or SBRT. However, because this is preoperative and the dose that we use, we don't refer to it as SBRT. So that's why we've chosen to call it ultra hypofractionated radiation.

Dale Shepard, MD, PhD: And so when we think about the amount of energy delivered to the tumor, is it adjusted so that, is it the same total energy that you're using and then just in smaller fractions or does that compressed or how does that work?

Shauna Campbell, DO: Yeah, so the dose that we give on a day-to-day basis with hypofractionated radiation is going to be higher. So typically historically standard radiation would be about two gray per fraction. When you give hypofractionated radiation, you're giving more like three, four, six grade per fraction. When you give a higher dose per fraction, you do not need to deliver as high of a total dose because of the biological effect. I don't want to bore everybody and get too much into the radio biology or physics of it, but what happens is when you get into the hypofractionated radiation, you can give a lower dose of radiation overall just because the biology of it is a little bit different.

So in the context of sarcoma and sort of looking at this type of radiation, historically we would give 50 gray in 25 fractions. So that would be 25 days of radiation with a dose of radiation of two gray per day. And what we're doing in this study in most of these studies is 30 gray in five fractions. So that's six gray per treatment and that's given either daily or every other day. So when you just hear those numbers, that's three times as much in a day, but you can give a lower total dose of radiation, because the effectiveness is higher.

Dale Shepard, MD, PhD: All right. So you mentioned the study. So this year at the ASTRO meeting, the American Society for Radiation Oncology, you and your group presented some data about a meta-analysis looking at ultra hypofractionated radiation. So tell us a little bit about what you did.

Shauna Campbell, DO: Yeah, so in this study what we did, so we have our own institutional experience with ultra hypofractionated preoperative radiation for soft tissue sarcomas. But because sarcoma is overall a rare disease, every institution who publishes about this tends to have a limited number of patients, usually between 25 to 50 patients per institution on average. So what we did is anytime you have smaller studies like this, if you want to understand bigger picture, what you do is you search the literature and you look for all of the studies related to this and you compile the data together. So what we did was we did a database search and looked through all of the hypofractionated studies and we sought out the ones that met our criteria that we could aggregate the results and we could comment on two year local control. And we could also comment on major wound healing complications because those are two of the most important endpoints when you're looking at soft tissue sarcoma.

From there we were able to find that there was seven studies that met our criteria. Overall, these studies were more limited in size. However, this resulted in a total of 209 patients within these studies. There were a couple polish series that dated back to, there was one from 2014, an update in 2021 that did not actually include enough information for us to be able to establish the two-year local control and wound healing complication rates. So they weren't included in this analysis. But looking at those seven studies with the 209 patients, we were able to use Bayesian methods for statistical estimation looking at two year local control and major wound healing complications in this group of patients. Now when we think about cancer in clinical trials and studies, typically we're looking at, when you look at a meta-analysis, you're usually looking at high hundreds if not thousands of patients.

But because soft tissue sarcoma is more of a rare disease and implementation of ultra hypofractionated radiation for soft tissue sarcomas is only done by a handful of centers around the US as well as around the world. That's why we're dealing with a much smaller number of total patients here. But still this is important because it is a rare disease, this kind of evidence is still very valuable. Now, some may criticize that 209 patients is not enough evidence for practice changing implementation. However, what we have to acknowledge is our gold standard of a phase three randomized study comparing standard preoperative radiation of 50 gram 25 fractions versus 30 gram in five fractions. A phase three study like this is not currently designed or in process of being implemented. So it would be years before we could do that.

And then you're going to need at least three years of follow-up to be able to report on rock solid local controlled numbers. So this would be something, it would likely be almost a decade if we were to do this study before we would actually have the results of that large randomized trial. And also the funding for that trial would be very challenging as well in today's climate.

Dale Shepard, MD, PhD: So when we think about looking at the results that you got from a local control rate wound healing, any surprises?

Shauna Campbell, DO: No. So what we were able to determine is looking at the studies overall. The first thing whenever you do a new study or new investigation is you want to make sure your cancer control rates are not inferior. What we found within this population of 209 patients that the two-year local control was 96.9%, which is very promising. Over 90% is very acceptable and this is very comparable and even exceed when we look at historical studies like RTOG 0630 was a study that was completed and that local control was far less than this. So it's very reassuring that to your local control just about 97% is very reassuring. Now ultimately it will be good to see further maturation of this data to see things like three year local control and eventually five year local control. But certainly two years is a very good starting point and I think can help all of us be reassured that this is likely oncologically an effective treatment approach.

And then the next outcome we looked at was major wound healing complications, because that is one of the biggest downsides of preoperative radiation is it does increase about doubles your risk of wound healing complication rates if somebody was to not have radiation before surgery for soft tissue sarcoma. So overall, when we looked at the major wound healing complication rates for all of these patients, it was 30.6%, which was again very falls within the realm of acceptability comparable with preoperative standard fractionation radiation. So what we're seeing is very good local control at the two-year point and we're seeing an acceptable rate of major wound healing complications, which is also reassuring.

We also looked at the acute side effects. One of the main things we noticed with radiation for soft tissue sarcomas, they tend to be closer to the skin surface. So dermatitis is something that is associated with preoperative radiation. For this group of patients in those that it was available, a grade two dermatitis was 12.7%. So overall very low grade three, 2.2%. So again, very low rates of acute side effects well tolerated and there was very limited late toxicity noted. But of course we have to acknowledge the more limited, so we can't say too much about the late toxicity yet. But overall reassuring.

Dale Shepard, MD, PhD: When we think about wound healing after the radiation, these studies, our experience, how long are they waiting between the end of radiation and surgery?

Shauna Campbell, DO: So typically in standard preoperative radiation with 50 grand, 25 fractions, so standard fractionation, you're typically going to surgery between four to six weeks after completion of radiation. And in this meta-analysis, most of the studies followed that there were two studies, most notably one of the polish studies as well as our study that did have more of an immediate surgical resection. So our institutional experience here was we were historically doing 30 gram five fractions followed by immediate surgical resection. And in our latest update we've actually noticed the wound healing complication rates is actually a little bit over that 30% that we see in the pooled analysis here it's going to be closer to 38 to 40%. So as an institution and as a group, we've looked at that and said, looking at these other studies that have shown slightly lower rates of major wound healing complication, we have now adopted going to that delayed surgical resection of four to six weeks.

Now immediate surgery is certainly very convenient for the patient, but keeping in mind when we do five fractions for these patients, a lot of these tend to be younger, still working, have families, you can do five treatments of radiation like a Monday to Friday, they can go back to work, they can work during those five treatments and they can continue to work all the way up until surgery. So even though we're not doing that immediate surgical resection right now, you can still continue your daily activities, go back to normal life as best as they can, and go to surgery four to six weeks later.

Dale Shepard, MD, PhD: Taking a really long course of radiation, shrinking it down, doing surgery about the same period of time. Is this being widely adopted by other centers at this point or no?

Shauna Campbell, DO: No. So this hasn't been widely adopted yet. As far as doing the five fraction preoperative, there was a hypofractionated course that was presented from MD Anderson. There was a clinical trial that they did, which was very reassuring as well. Good local control, acceptable rates of wound healing complication rates. So that is something that was recently added to the literature. But I would say there's really only a handful of centers that are doing this right now. Looking at just the five fraction preoperative radiation.

Dale Shepard, MD, PhD: What do you think is driving the hesitancy for more centers to do this?

Shauna Campbell, DO: I think it's mostly unfamiliarity. In a lot of community centers, a lot of those radiation oncologists may not even be seen. The patients preoperatively. There's a lot of surgeons that are going to immediately resect a tumor and then send the patient for postoperative radiation. We know from historical studies that preoperative radiation versus postoperative ratio, they have equivalent oncologic control rates, but the toxicity profiles are different. In standard preoperative radiation, we can use a lower total dose of radiation, which is 50 gram, and that does result in an increase in your wound healing complication rates. However, that has less long-term toxicity compared with postoperative radiation and the postoperative setting. Instead of 50 gray, you're doing 60 gray in 30 fractions and that doesn't have an increase in wound healing complication rates. But what we do see is an increase in late stiffness in edema of the extremity wound healing complications are something we can typically get patients through and are reversible.

The late toxicity associated with postoperative radiation of joint stiffness and edema, those tend to be more irreversible. So overall in the literature, if you can do pre-op its favor, however, there's still a very large population out there that's going to immediate surgery with postoperative radiation. So I think that's one of the big barriers. And in radiation oncology, we tend to have a very high bar for accepting new data, especially something that's as drastic from going from 25 treatments down to five treatments. There's more of a trend in radiation oncology, I would say, to adopt things like 15 fraction hypofractionated, so a little bit more gentler fractionation. So just hasn't been a big uptake in this, which I think at this point is appropriate because we're still dealing with several small institutional series. So I think this meta-analysis is a good first step, but I think continuing to do five fraction preoperative, continuing to learn from it, we're likely still several years before this is widely adopted in the community. And in all honesty, it may be a decade before it's widely adopted.

Dale Shepard, MD, PhD: And I guess when we think about something being slow to come into practice, you mentioned pre-op versus post-op, there's the referral pattern at that step, but then the radiation oncologists themselves may have a preference. And what about patient preference? I mean, one would think that patients would prefer shorter courses. Is there a hesitant sort of nature with patients, because of the untested nature? How much pushback do you get from patients? They kind of want to do it, but maybe don't want to do it?

Shauna Campbell, DO: Yeah. Usually with patients, I'm very honest with them when counseling them on, because anybody I present five fraction preoperative to, we discuss that there's limited data on this, it's small series, but we talk about what our institutional experience is. We talk about the wound healing, complication rates. Overall patients tend to be, as soon as they hear that one week is an option versus five weeks, that convenience factor usually drives a lot of decision making, which is why as radiation oncologists and along with the orthopedic surgeons, we're very careful about who we offer this to. So if I think somebody is at a really high risk for wound healing complication rates or if they're at risk for a positive margin, if we're looking for the tumor to shrink down with preoperative radiation, those are all patients, I would still favor doing the five weeks of preoperative radiation. And we still do that for people. So it's not like everybody's receiving five fraction ultra hypofractionated preoperative radiation. It's a special population of patients.

Dale Shepard, MD, PhD: And I guess when we think about that patient selection, what are some of the things that do come into play? Are there particular histologies that are more favorable? Are there certain locations that you're a little bit more worried about the wound healing aspect? What are size of tumors? Maybe a little bit more specifically what those factors might be?

Shauna Campbell, DO: Yeah, so when it comes to histology, we know that myxoid liposarcomas are your most sensitive sarcoma to radiation. That's really the main histology that we can really see downsizing with radiation. So those patients, we tend to still use our standard fractionated radiation for those patients and sort of wait for the down staging. Otherwise, most histologies are considered for this without question. These are sort of non-Ewing sarcoma, non-rhabdomyosarcoma patients. So whether it be UPS, myxofibrosarcoma, those are all things that we consider for this regarding tumor size. So if somebody has a large T3 tumor or a T4 tumor, those were still favoring doing standard fractionation for like when you're talking somebody's got a 12 centimeter tumor.

By the time you sort of draw your radiation expansions on that, you're going to be pushing 1820 centimeters. So for those patients, we'll still favor doing standard fractionation. If somebody has a tumor that is growing around or pushing on blood vessels or bone that were concerned, you could end up with a positive margin. Again, we may favor the standard fractionation for those cases as well. With respect to wound healing complication rates, we know that lower extremity has a higher risk of wound healing complication after surgery and with the addition of radiation, however, we will still do lower extremity sarcomas with hypofractionated radiation with this five fractions. So we will still do that.

Dale Shepard, MD, PhD: So what's the next step? Where are we going from here?

Shauna Campbell, DO: So at our institution, we still practice 30 grand and five fractions preoperatively for select soft tissue sarcomas before going to surgery. Again, in an ideal world, a randomized phase three study would give us the high quality of evidence to really adopt this. Without question sort of understanding the landscape of cooperative groups clinical trial funding and understanding that there isn't a trial currently under design, I really don't think we're going to have that high quality of evidence for a very long time, if ever. So I think the institutions that are within this meta-analysis, I think will continue sort of treating patients within our expertise and our experience. And what we do is every couple of years you continue to publish your updated series and looking at these in aggregate. So multi-institutional analysis, looking at direct patient level evidence is probably going to be the next best step, because there are limitations within a meta-analysis.

You're looking at a group of patients in a number. Whereas with patient level, multi-institution, you'll be able to associate every patient with their local control, the wound healing complication rates. So we'll have even more information from that. So that's likely going to be the next thing we'll see come out in within a couple of years.

Dale Shepard, MD, PhD: Well, excellent. So good to see your driving innovation for our patients and appreciate your insights today.

Shauna Campbell, DO: Thank you for having me.

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