How to cite: Beyer, David C. “Updates in Radiation Oncology: Of Brachytherapy and Beams” November 12, 2017. Accessed Feb 2018. https://grandroundsinurology.com/Brachytherapy-and-Beams/
David C. Beyer, MD, reviews recent data regarding external beam radiation, brachytherapy, androgen deprivation therapy (ADT) as it relates to radiation oncology and prostate cancer treatment.
Updates in Radiation Oncology: Of Brachytherapy and Beams
I’ve always said radiation oncologists and urologists are kind of joined at the hip or you might say joined at the prostate, and I think any good radiation oncology program needs to update us on what’s going on in the world of urology and I think similarly what is going on in the world of radiation oncology should be of interest to this audience. So this is my update of what has happened in the past 12 months if you were sleeping. I have no disclosures, and again anyone who wants to take a little side trip up to Sedona and pay us a visit, we would love to see you there.
ARS Question 1:
Compared to dose escalated external beam radiation therapy, radiation with a brachytherapy boost does one of four things.
A.) It improves the ten-year biochemical control for any intermediate risk but not high-risk patients
B.) It improves the ten-year overall survival in all subgroups except for low-risk
C.) It improves the ten-year biochemical control for all sub-groups
D.) It improves the ten-year biochemical control for all sub-groups but with a prevalence of 20% late GU toxicity more than four years out
So, if you could choose your preferred answer, would it be, A, B, C, or D?
So the plurality seems to think that it improves ten-year survival with a 20% late GU toxicity. That isn’t actually quite right, and I’ll show you the slides before we’re done. Actually, Group C is the correct answer, and I’ll show you the slides on that as well.
So the second question, relating to some recently published data from the RTOG9202 had a publication within the past few weeks that shows that with long follow up: A) IMRT radiation to 73.4 in 8.2 weeks is superior to—sorry that is 9202. This is oh yeah. My mistake. IMRT radiation of 73.4 in 8.2 weeks is superior to 70 Grey in 5.6 weeks; B) four months of ADT is comparable to 28 months ADT for most endpoints, disease-free survival, cause-specific survival and distant metastasis; C) overall survival shows a significant difference for patients only with Gleeson 8 or above; or D) most GU toxicity is seen in the first five years after radiotherapy. Tell us what you think.
All right. We’re going to talk about that because in fact 9202 actually had nothing to do with the dose schedule in question A. 9202 did show that there is a difference between 4 months and 28 months in most of those sub-groups, and actually the overall survival was not different in the statistical sense, so the correct answer is going to be D) and I will show you why.
I’ll start with a quote. I picked this up from the New York Review of Books, which I regularly read. It’s called, “It’s difficult to see what is genuinely new, harder still to admit ignorance in the face of it.” So we’ve got a few things today that I’m going to throw at you that I think really are new and hopefully we’ll get people to change some of their thoughts. I’m going to talk about some broad themes, some external beam data, some brachytherapy data and some ADT data as it relates to radiation oncology.
So I’m going to start by talking about normal tissue toxicity. Some of you may be aware of the hydrogel spacer that has been marketed. This is a slide form the European trial that they did when this was first under development, and you can see on the left a prostate and a rectum. As a radiation oncologist, I look at this and the separation between that prostate and that rectum means a lot because that space is where I have to thread the needle with my radiation beam. It’s where you have to cut, but when you are cutting there is a nice tissue plane there. For me that tissue plane is meaningless, so I need some way to protect the rectum when I’m treating the prostate, and in the middle slide you can see injection of some gel that is only visible on MRI. You can’t see it on CT, which is the left-sided image, but it is pretty clear to anybody that that rectum and that prostate are now separated in this case by 11 millimeters, and that is exactly what we need in theory to reduce our rectal dose. The slide on the far right shows that six months later it is gone, and I will tell you in the U.S. pivotal trial, the middle slide, 100% of the time it was there three months after the injection and in six months after the injection 100% of the time it was gone, so again trying to show you things that are really hot off the press. This is again within the past couple of weeks.
The European study is now mature. They followed their patients and had five–year data, and I just wanted to share that with you because for a patient population that looks kind of like what we normally see in treatment volumes that is what the PTB is, that are kind of like what we normally see there is a substantial drop in rectal dose when you put that little space between prostate and rectum. The volume that receives 70% of the dose you can see drops from 32% in an untreated patient to 20% in the patient with the gel, and that makes a difference because if you look at moderate bowel urgency, moderate loss of control or moderate bowel habits, and here we are talking all rectal toxicities and not talking GU stuff, it is a significant difference that it is clinically significant and statistically significant and I always like to point out, you know, radiologists like to tell me that their patients don’t have any incontinence, and radiation oncologists like to tell me their patients don’t have any late toxicities but in fact 7%, 14% depending on what question you ask the patient, moderate or greater GI toxicities, and that can be ameliorated with a little gel injection. That is one that I think should be on your radar. Even if you are not doing it right now you probably will be seeing it in the near future.
RTOG0415 has been recently published. It is now out in the JCO and again I think everyone should be aware of this trial because this is part of a major trend that is happening in the world of radiation oncology, which is fractionation. Some of you may be aware breast cancer patients historically were 6.5 weeks of radiation. It is now three weeks or radiation or more in enlightened centers. Prostate cancer the same thing is happening, and people need to be prepared for it, so they took a cohort of patients that had low risk prostate cancer, they stratified them by their different risk factors and what kind of radiation treatment they had. It was a non-inferiority design to the trial, they randomized them between two dose schedules, and basically as urologists what you care about is not the dose, but the number of weeks, and so 8.2 weeks that is your typical course of radiation, that is what most patients get 73.8 plus or minus a few fractions versus 28 fractions, this is a schedule that Pat Kapalian [phonetic] published when he was at the Cleveland Clinic, single institution, looked pretty good, just no comparator group so here it is 1,000 men randomized between these two with follow-up that is almost six years, and as you can guess from my excitement, this is actually a non-inferior treatment, so in all respects, in all of the outcome data points that they looked at there was no advantage to going 8 weeks over going 5.5 weeks. The only advantage is it keeps the clinic schedule busier, but it doesn’t do a lot for the patient. From the patient’s perspective, these are indistinguishable curves, completely non-inferior.
So we know that giving fewer fractions has the potential to change the landscape of what we are doing with radiation and prostate cancer, and I say watch that space, it is going to be happening, it can happen in any clinic anywhere in the country today. Some people are pushing this envelope even further, have been doing so for a number of years, and are going to what we call extreme hypofractionation, a full course prostate cancer treatment delivered in about five days. There is basic laboratory data, theoretical data based on what radio biologists call the alpha beta ratio. Don’t worry about exactly what it means but the alpha beta ratio is how we measure the impact of larger or smaller doses of radiation on a particular tissue, and basic laboratory data says that for prostate cancer we might be better with larger fractions, and there is mouse data that suggests that larger fractions are biologically more effective that they slow the rate of progression and reduce the likelihood of metastasis. If you radiate a tissue, you implant it into the mouse, it won’t metastasize if subjected to large doses of radiation as much as it does to small, so there are some theoretical advantages and there’s some human data that is starting to come out that is really showing not superiority but at the very least some equivalence, and I think that is exciting.
Some of you may know this as the Cyberknife. Cyberknife is the brand name of a machine that delivers high-dose radiation. We sometimes call it stereotactic body radiation therapy, SBRT is the acronym that you will see. sometimes people call it stereotactic ablative radiation or SABR because people just like to have great acronyms.
Cyberknife data you will generally see it referred to as Cyberknife from institutions that use the Cyberknife. They like to promote the brand name and I’ve got to admit it is one of the most sexy names that people have come up with for a treatment device, but this is out of Staten Island. Dr. Katz has published a number of times on his experience, 500 men, fairly long follow up now, he was bolder than I was, has a lot of higher risk patients that I perhaps would have shied away from at the beginning, gave 35 to 36.25 as his dose in five daily fractions and for the radiation oncologists in the audience, this is the expansion that he used. And when he looks at either dose level it really doesn’t seem to make much difference, the biochemical disease-free survival is really comparable to anything that has been published for more conventional treatments. This was not a comparison of SBRT versus conventional radiation, but this is kind of very provocative and some would say hypothesis generating.
Sunnybrook has done the same thing, they call it SABR, they don’t like to—they obviously don’t have a Cyberknife, they have 114 patients they followed 102 months. This was a poster that was presented at ASTRO just a few weeks ago looking at their biochemical failure. You can see this one is going up. The other curve came down, but in fact 5% eight year recurrence rate is pretty good for a population that is mostly low-risk we’ll acknowledge that, but I think it is worth noting that and again you probably can’t read the slide, but there are a fair number of studies out there and I show you this in a table just so that you realize that this is not just one or two outliers that are doing something funky in their neighborhood. There are a lot of studies that have started to do this, a fair number of patients and pretty similar dose schedules, the outlier in terms of dose is Zimmerman at the bottom. He treated in nine fractions, and I’ll tell you any stereotactic treatment that you see that gave nine fractions was done outside of the United States. We have some billing issues that require if you are going to get paid for it it has to be five or fewer fractions, and that kind of constraints what people are testing, but in fact around the world there are schedules that are out to 10 fractions that have been hypothesized as the right dose. But there is really nothing that says the higher dose is—higher total doses are better, but there is some theoretical data that says the higher daily doses that matter.
Quality of life again comparing one dose of SBRT to another, no particular difference in quality of life at a number of endpoints. Dr. Katz as I said looked at some high-risk patients and obviously high-risk patients don’t do as well with any treatment, and these were 14% of his population had hormones, I assume that was overwhelmingly in the high-risk group. I don’t know that for a fact, but he looked at the high risk group and there’s another poster at ASTRO a couple of weeks ago telling us that other people are looking at high risk patients with SBRT so again this is coming and there are a couple of multi-center trials, FASTER and SATURN that are looking at treating not only the prostate but the pelvic lymph nodes, you give 40 Gy in five fractions to the prostate and you give 25 Gy in five fractions to the pelvic lymph nodes. I have not had the nerve to do this yet. I wouldn’t recommend this for most people in most clinics at this point. This is not anywhere near standard of care, but this is absolutely what people are thinking, and I think it is just part of that larger trend of fewer and fewer fractions. Again if there’s any radiation oncologists in the audience, the V20, the volume of rectum that received 20 Gy if it was over 55 cc correlated with a significant risk of rectal toxicities. You can see from the curve in the middle there is a big separation at that 20 so if anyone wants to be doing this, which is again I don’t recommend doing this off trial right now but the V20 matters. UCLA has been doing this for a number of years, but they have relatively short follow-up in this really high-risk group that had pelvic lymph nodes treated with SBRT. But again very encouraging results out of a couple of groups this year at ASTRO. I expect we’re going to be seeing more follow up on these populations. I expect we are going to be seeing more data.
This hypofractionation thing is real. It’s not just a couple of guys out in the wilderness doing something different. ASTRO, AUA and ASCO have together worked on a guideline. This guideline is either right at the end of the comment period or has just closed, I’m not sure, I can’t tell you what the guideline says, it says not for distribution or dissemination, because the guideline is unapproved, but these three organizations are putting their stamp on a guideline that deals with hypofractionation that deals with this low-dose hypofractionation, 28 fractions and the high SBRT kind of fractionation, so take a look at on the AUA website, the ASTRO website the ASCO website, this is going to be out there within probably a couple of months, and where guidelines go hopefully clinical practice follows, and I think we’re going to be seeing some changes in what is happening in your communities.
For those of you who have wondered, it probably keeps you up at night wondering, I’ve heard about a PSA bounce with brachytherapy. I’ve heard about it with external beam. I wonder if it happens with SBRT. Well, in fact it does, and now you can sleep well at night. RTOG0232 was presented at ASTRO last year. It was published this year and so people have had an opportunity to look under the hood and see what this is all about. 0232 was a trial looking at brachytherapy and for many years we had a school that said intermediate risk prostate cancer needs combined modality, they can’t have external beam because—they can’t have seeds alone because brachytherapy alone is not good enough, they need external beam along with brachytherapy, and under the leadership of Dr. Prestig [phonetic] RTOG0232 set out to answer that question. They did a non-inferiority design again. They compared two arms intermediate risk patients who had brachytherapy, some with, some without external beam. It was randomized. It was a really well-done trial with central dosimetry and I was a participant in this. We had to jump through a lot of hoops to keep patients on this trial. Freedom from progression was absolutely non-inferior, there was no difference in terms of outcomes, for brachytherapy patients, whether we added external beam or not for this intermediate risk group.
The biochemical failure again whether you looked at the Phoenix definition or ASTRO definition, there was no difference whatsoever, they are going to be doing sub-group analysis on these, this is the whole cohort, they are going to be breaking out by PSA, by Gleason score and all of the things that are in there, but for now this is what we have, and I think it is actually rather compelling because I think this could put the nail in the coffin of the combined modality for at least low intermediate risk patients. It looks like the patient population in the PROTECT trial who actually had either surgery or radiation, and I think that kind of gives it—it passes the smell test.
They looked at adverse events and there are indeed as you may know more acute and in particular late toxicities amongst the patients who had combined modality, so not only is it not inferior to do brachytherapy alone and you reduce your risk of late toxicities and call them on the just to show you what you guys are most concerned about this is any late, any—this is GI, this is GU, and you can see a substantial difference in the toxicities between the two arms, based on whether they had external beam, 12%, 7%, and 53%, 36%, so there is really no question in my mind we’re at the point where we should no longer be offering combined modality to intermediate risk patients.
That brings me to the ASCEND trial, which was presented at the ASCO GU meeting maybe a year and a half ago, two years. It was presented at ASTRO, it’s been talked about quite a bit and is finally in print. Again you can take a look at it, there are two articles in the International Journal of Radiation Oncology, Biology, and Physics. I’m sure you all subscribe to it.
The ASCEND trial was done to answer the question that has been nagging at a lot of us. When we first started doing IMRT I remember having my urologist come to me and say, these intermediate risk patients, these high intermediate risk patients maybe we should be doing IMRT because you can do that now and we don’t have to deal with the side effects from the brachytherapy and so a lot of the world started doing this and started shifting towards IMRT instead of offering brachytherapy as we had done in the 90s and early 2000s. So they did a simple randomization. They said, well in this era, we’ve got to do dose escalation, patients need high doses, so everyone got 45 gy to the pelvis, and then they got a boost, and the boost was either done with external beam or it was done with brachytherapy and in all patients received a short course of hormone therapy. these were high intermediate and high risk patients, so this is a different population than was eligible for the RTOG0232. These are people for whom there is limited data although my own data suggests they may not need the external beam. There is limited data that looks at these patients without the external beam. So the external beam is kind of standard, so do they need the brachy or should we just do the whole thing with external beam, and in fact when they looked at all of the endpoint showed a difference in biochemical control, and all of the subgroups for all of the patients, for intermediate and for high-risk patients, these were not only statistically significant, these were visually significant. These numbers actually look a lot different to the eyes. It is not like a new drug where there might be 5%. I think this is a fairly compelling study, and it is really hard to ignore. The overall survival was not different among the populations but that may change with time.
Are you surprised by this? Well, you shouldn’t be because in fact there have been other studies that have looked and shown similar results in single institution studies. This is a matched pair done by Dr. Pickles up in Vancouver, very similar outcomes for all low-risk and intermediate risk. The National Cancer Database was queried a number of years ago and they looked at brachytherapy alone or external or external beam plus brachytherapy versus external beam alone, and in fact brachytherapy is superior in every one of these populations. This isn’t quite as dramatic as the ASCEND trial, but for those of you who have done any work in the NCDV there is a lot of noise in that data. The ICR [phonetic] has done similar work and has really given its seal of approval on brachytherapy and despite that, brachytherapy is being done less and less over time. It does boggle my mind, and it’s something that as an advocate for many years I find hard to believe, but this is the data also from the NCDB so you know, it is kind of suffers from the faults, but this is the kind of thing that the NCDB is good for.
They queried and said, at your institution how many seed implants are being done. And the blue line represents those institutions over time going from about 2004 to I think it was up until 2012. The blue line represents those institutions that are doing 12 or fewer cases a year, that is one a month, and this line down here is those institutions that are doing 53 or more a year, that is one a week. You can see that the group that is doing fewer and fewer is growing, and what is really scary is that is also seen in academic medical centers. This is what is happening across the country in our training programs people are not learning how to do these procedures, and a vicious cycle this is probably leading to us doing less of it. And it is worth noting the ascend trial published a separate paper looking a toxicity, and in the toxicity you can see I believe the top one is GU and this is GI there is an increase in toxicity amongst these patients. A lot of these patients have a harder time, and that is part of the conversation that I have with my patients when they are being considered for this. It is-it does have more urinary toxicity and it is inescapable, but what they showed in this trial, this is incidence, and this is prevalence, and the prevalence of late toxicities meaning many of these patients might have had a urinary structure that got dilated and they are better, they might have had proctitis and it got better so these are the people who are continuing to have problems, and when you get out to four years, we’re at about 8% or so that are still experiencing some toxicities from their treatment, above and beyond what they would have gotten just from the external beam. So the prevalence is lower than the incident, and the prevalence is really down in the single digits. ED surprised me, well you know, you can see right off the bat, ED in both the black which is the dose escalated external beam and the red, which is the low-dose brachytherapy and you know everyone suffers ED at year one, well that is not a surprise, they all got 9 months of ADT but if you look at it over time, it is actually not that different between the two modalities, which did surprise me.
In the interest of time I’m going to blow through 0526 quickly, but this was presented at ASTRO again a couple of weeks ago. It’s looking at using brachytherapy as a salvage treatment for patients who have had failed external beam. Some of us have been doing this for years and there are a lot of single institution publications on this. This is the first real attempt to do a multi-center trial with central dosimetry yada yada, a relatively small trial, but based on this relatively small trial we can say that it seems promising, there is an increase in late GI and GU adverse events that is based on the dose that was delivered, and the treatment efficacy we don’t know because that is the statisticians won’t let us even look at that yet until the study has matured a little bit, but I want you to be aware that this is out there as one of the modalities. There are a number of trials that have looked at radiation and hormones over the years going back to the 1980s when looking at DES and Megace as a modality and you can see you know a listing of the big multi-center trials, well RTOG9202 started in 1992 just published their most recent follow-up again within the past couple of weeks. These were locally advanced patients. This was the first RTOG trial that incorporated PSA in the entry. They all received two months of hormones before and during, and then they were randomized to plus or minus two more years of Goserelin, and this was just published again in the International Journal of Radiation Oncology and you can see this is for the whole population. The disease free survival in the upper left shows a statistically significant difference favoring those patients who received long-term, a long course of hormone therapy. The distant metastasis-free survival in the upper right again statistically significant favoring the longer course of therapy and the disease-specific survival a slight difference, it is just barely statistically significant and the overall survival was not statistically significant.
Many of you know one of the earlier studies that looked at 9202 one of the earlier publications reported on the high risk group because it looked like here was a trend towards an overall survival benefit in this group and again the disease free survival distant metastasis here you see even more benefit in distant metastasis free survival and disease-free survival. The overall survival looked like it was getting pretty close to being significant. The curves come together. It has as P. value of 0.08 which my statistics teacher taught me almost statistically significant is the same as not statistically significant, so that is where this stands as of now, there is no statistical significance to this, but it certainly is compelling for all of the other endpoints, late GU, late toxicities, GI and GU almost always, particularly when it comes to GU toxicities were in that first five-year period you can see in the right-hand curve, the toxicity kind of plateaus after five years, it really doesn’t keep going up as much. The GI actually keeps going up quite a bit even after five years, it is not your problem, but it does happen.
I’m going to skip this set in the interest of time. I’m going to tell you there was a recent study presented at ASTRO looking at a new PET agent. I don’t know if that is in one of the other talks later, but the F18 Fluciclovine was used as an agent to look at patients who had recurrent disease. Most of these were post-prostatectomy, they had a SPA of 0.6 and these are patients that you see every day. They did a scan to see where the outcomes, where the disease was and in fact their primary endpoint was change in treatment and in fact based on this 23% modified the radiation fields, 21% shifted to systemic treatment, and 15 shifted to watch and wait from external beam. Based on that, they actually stopped the study because they thought they met their primary end point in this interim analysis.
Another study again if there are any radiation oncologists in the room to be aware this is in Practical Radiation Oncology they did a C11 PET study on patients who were going got get whole pelvic radiation for prostate cancer, and the dark green nodes are lymph nodes that would not have been in the RTOG approved pelvic fields. The lighter blue green nodes are those nodes that would have been treated by the fields recommended by the RTOG, so what this is telling us is even when we are treating the nodes, we are not doing as good a job as we think, and we may need to incorporate some of this sort of imaging in the future to try and plan our radiation fields.