PACE-C Trial Results: SBRT vs Moderate Hypofractionation for High-Risk Prostate Cancer - Alison Tree
October 13, 2024
Zachary Klaassen interviews Alison Tree about the PACE-C trial, comparing moderate hypofractionation to stereotactic body radiotherapy (SBRT) in unfavorable and high-risk prostate cancer patients. Dr. Tree discusses the trial design, which randomized 1,208 men to receive either standard 60 Gy in 20 fractions over four weeks or SBRT with 36.25-40 Gy in five fractions. The acute toxicity results show similar genitourinary side effects between arms, with slightly higher gastrointestinal toxicity in the SBRT arm, particularly when measured by CTCAE criteria. Patient-reported outcomes indicate that most symptoms resolve by 12 weeks post-treatment. Dr. Tree notes that these results are comparable to those from the PACE-B trial in lower-risk patients. While awaiting long-term oncological outcomes expected around 2027-2028, Dr. Tree suggests that SBRT may offer a convenient option for patients with similar acute toxicity profiles to conventional fractionation.
Biographies:
Alison Tree, BSc, MBBS, FRCR, MD, Consultant Clinical Oncologist, The Royal Marsden NHS, London, UK
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Alison Tree, BSc, MBBS, FRCR, MD, Consultant Clinical Oncologist, The Royal Marsden NHS, London, UK
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by Dr. Alison Tree, who is a clinical oncologist at the Royal Marsden Hospital in the UK. Alison, thanks so much for joining us today.
Alison Tree: Oh, my pleasure. Thanks for having me on.
Zachary Klaassen: We're doing a nice collection of discussions around ESTRO 2024. There's been some great data coming out of that, and the data we'll discuss today fits perfectly in terms of the PACE-C Trial looking at moderate hypofractionation versus SBRT in unfavorable and even high-risk prostate cancer. Maybe just give us a little genesis of the background of this trial, how it came to be.
Alison Tree: Yeah, so you're probably aware already of the PACE. It's now become an umbrella of trials, actually. We had PACE-A comparing SBRT to surgery, PACE-B comparing conventional moderate hypofractionation to SBRT, but that was limited to very favorable risk prostate cancer. A few low risk, but mostly favorable intermediate risk prostate cancer.
The genesis of this trial was to ask the same questions: can we use SBRT to treat men with higher risk disease to try and move that treatment up into the higher risk men?
Zachary Klaassen: Excellent. Excellent. Maybe just take us through the trial design of PACE-C and tell our listeners what those arms entailed for the trial.
Alison Tree: Yeah, sure. I'll just share some slides if I may. PACE-C was a Phase III, multicenter, international, open-label, randomized trial, and we actually recruited 1,208 men. And in terms of their risk groups, the maximum T stage—and this is an MRI T stage—was T3a. They could have a small amount of Gleason 4+4, but most were lower Gleason grades. And the maximum PSA allowed was 30, and all men were planned to have ADT.
We were really aiming for the group that needed about six months of ADT, but COVID intervened, so a lot of men went on to ADT for a bit longer than planned. And the randomization was between what is now our standard of care, which is 60 Gy in 20 fractions over four weeks, versus the experimental arm of SBRT. And the doses we used in PACE are 36.25 Gy to the PTV and 40 Gy to the CTV—so the prostate with no margin—and the centers could give the treatment over one or two weeks. And of course, the trial is designed and powered to answer the biochemical control question, but today we're just talking about the acute toxicity.
Zachary Klaassen: Okay, excellent. Perfect. So just walk us through some of those key results. It looks like you have baseline characteristics and some of the toxicity as well.
Alison Tree: Yeah, that's right. So just to give you an idea of the spread: a lot of men were Gleason 3+4, some men—about 20%—were 4+3. And then just over a third had high-risk features, at least one high-risk feature, which you can see there. And most of the men, as per standard of care, were treated with LHRH agonists, a small number treated with other methods of hormones, and about 20% were on alpha blockers at baseline. And we could discuss the significance of that in a minute if you like.
Zachary Klaassen: Sure.
Alison Tree: So the key results here: this is the GU toxicity, and so this is just acute toxicity—from the first day of treatment out to 12 weeks after completion of treatment. And what you can see here is that the GU toxicity was very similar on the RTOG scale over time. Absolute numbers here. So no significant difference between the four-week and the five-day schedule. And then with the GI toxicity, slightly worse with SBRT—not significant for a secondary endpoint—but you can see there is a large number of men getting some grade two toxicity. The grade three toxicity rates were really low, well below 1% for all of these endpoints. So that's reassuring, isn't it?
Zachary Klaassen: And it looks like those—if you go back one second—it looks like those on the right side with the GU toxicity about six weeks out, they kind of come back to even between the two arms. Is that correct?
Alison Tree: Yeah, that's right. So the peaks occur at different times, and we maybe discuss that on the next slide as well, because of course the treatments are different lengths, so it's hard to pitch when to ask your patients how they feel, but you are right. So the peak is a little bit earlier for SBRT, but by about six weeks after treatment—six to eight weeks—most people are feeling pretty much back to normal.
Zachary Klaassen: Excellent.
Alison Tree: And this is the same data. So on the left, the RTOG GI toxicity and on the right, the CTCAE GI toxicity. So a little bit different here. So no difference significantly on RTOG toxicity. But what we found from PACE-B was that CTCAE is a more sensitive measure of symptoms—it triggers more events, if you like. So the GI toxicity on the CTCAE scale is worse for SBRT, and this was statistically significant. But as you've just already picked up on the last slide, there's a discordance about the time points and when we measure those things, so that may explain some of the difference.
Then the most important thing is what the patients say to us. This is just a single question from EPIC about how much of a bother is your bladder function or your bowel function. So bladder on the left of this slide, and these are stacked bar graphs where men having a big problem have the red color—the small number at the top—and then with a moderate problem are the orange color. And so you can see on the left there is a toxicity—a short-term toxicity—for many men with the urinary system, particularly at four weeks. But that's pretty much back to normal by 12 weeks. And a similar picture for bowel on the right-hand side of the screen with slightly more symptoms seen in the SBRT arm when you ask the patients at four weeks. Does that make sense?
Zachary Klaassen: Absolutely. No, that looks good. I guess I'll put you on the spot a little bit here. Do you know how many patients may have gotten rectal spacers to try to decrease—
Alison Tree: Yeah, in this trial, zero because it's not something that we standardly do in the UK. So this is all data without spacers.
Zachary Klaassen: Okay, perfect. So you mentioned PACE-B in the introduction. How does the toxicity from PACE-C maybe compare to the PACE-B data?
Alison Tree: Yeah, it looks incredibly similar. So as you might have expected, but actually in PACE-C, because some of the men had higher-risk disease, we included more seminal vesicles. We included ADT, which probably didn't make too much difference. But overall, the toxicity rates were almost identical in percentages, so very consistent across both trials.
Zachary Klaassen: Excellent. And we've certainly seen in this unfavorable, intermediate, and high risk, this is where we need high-quality data. The radiation oncologists are generally much better at doing trials than the surgeons are—as a surgeon. But I think this is incredibly important, and so we'll look forward to the clinical oncology outcomes. Any idea when we may see some of that data?
Alison Tree: So we're hoping maybe 2027, 2028 maybe, but obviously we have to wait for five years, as you know, for the biochemical outcomes. So we are just publishing the PACE-B outcomes this year, and so we have to wait. We have to be patient, don't we, as prostate oncologists?
Zachary Klaassen: That's right. That's right. No, that's excellent. So maybe a couple of take-home messages for our patients and our listeners and our oncologists as they're listening to this discussion. How do we take this data in 2024 as we wait for the oncology outcomes?
Alison Tree: Yeah, absolutely. So I think what we can say for sure from PACE-C is that the acute toxicity is very similar to what we saw in PACE-B. So perhaps a little more upset in the bowel function temporarily, but seems to settle by the end of the period. So many men would choose that over longer fractionations for convenience. Obviously, biochemically, we need to wait for the outcomes to be sure, but I think as the evidence develops, we are getting increasingly confident that the PSA control is going to be similar, but obviously we'll have to wait for the results to be sure.
Zachary Klaassen: Excellent. Alison, thanks so much for joining us and for your expertise and time today.
Alison Tree: Pleasure. Nice to see you.
Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by Dr. Alison Tree, who is a clinical oncologist at the Royal Marsden Hospital in the UK. Alison, thanks so much for joining us today.
Alison Tree: Oh, my pleasure. Thanks for having me on.
Zachary Klaassen: We're doing a nice collection of discussions around ESTRO 2024. There's been some great data coming out of that, and the data we'll discuss today fits perfectly in terms of the PACE-C Trial looking at moderate hypofractionation versus SBRT in unfavorable and even high-risk prostate cancer. Maybe just give us a little genesis of the background of this trial, how it came to be.
Alison Tree: Yeah, so you're probably aware already of the PACE. It's now become an umbrella of trials, actually. We had PACE-A comparing SBRT to surgery, PACE-B comparing conventional moderate hypofractionation to SBRT, but that was limited to very favorable risk prostate cancer. A few low risk, but mostly favorable intermediate risk prostate cancer.
The genesis of this trial was to ask the same questions: can we use SBRT to treat men with higher risk disease to try and move that treatment up into the higher risk men?
Zachary Klaassen: Excellent. Excellent. Maybe just take us through the trial design of PACE-C and tell our listeners what those arms entailed for the trial.
Alison Tree: Yeah, sure. I'll just share some slides if I may. PACE-C was a Phase III, multicenter, international, open-label, randomized trial, and we actually recruited 1,208 men. And in terms of their risk groups, the maximum T stage—and this is an MRI T stage—was T3a. They could have a small amount of Gleason 4+4, but most were lower Gleason grades. And the maximum PSA allowed was 30, and all men were planned to have ADT.
We were really aiming for the group that needed about six months of ADT, but COVID intervened, so a lot of men went on to ADT for a bit longer than planned. And the randomization was between what is now our standard of care, which is 60 Gy in 20 fractions over four weeks, versus the experimental arm of SBRT. And the doses we used in PACE are 36.25 Gy to the PTV and 40 Gy to the CTV—so the prostate with no margin—and the centers could give the treatment over one or two weeks. And of course, the trial is designed and powered to answer the biochemical control question, but today we're just talking about the acute toxicity.
Zachary Klaassen: Okay, excellent. Perfect. So just walk us through some of those key results. It looks like you have baseline characteristics and some of the toxicity as well.
Alison Tree: Yeah, that's right. So just to give you an idea of the spread: a lot of men were Gleason 3+4, some men—about 20%—were 4+3. And then just over a third had high-risk features, at least one high-risk feature, which you can see there. And most of the men, as per standard of care, were treated with LHRH agonists, a small number treated with other methods of hormones, and about 20% were on alpha blockers at baseline. And we could discuss the significance of that in a minute if you like.
Zachary Klaassen: Sure.
Alison Tree: So the key results here: this is the GU toxicity, and so this is just acute toxicity—from the first day of treatment out to 12 weeks after completion of treatment. And what you can see here is that the GU toxicity was very similar on the RTOG scale over time. Absolute numbers here. So no significant difference between the four-week and the five-day schedule. And then with the GI toxicity, slightly worse with SBRT—not significant for a secondary endpoint—but you can see there is a large number of men getting some grade two toxicity. The grade three toxicity rates were really low, well below 1% for all of these endpoints. So that's reassuring, isn't it?
Zachary Klaassen: And it looks like those—if you go back one second—it looks like those on the right side with the GU toxicity about six weeks out, they kind of come back to even between the two arms. Is that correct?
Alison Tree: Yeah, that's right. So the peaks occur at different times, and we maybe discuss that on the next slide as well, because of course the treatments are different lengths, so it's hard to pitch when to ask your patients how they feel, but you are right. So the peak is a little bit earlier for SBRT, but by about six weeks after treatment—six to eight weeks—most people are feeling pretty much back to normal.
Zachary Klaassen: Excellent.
Alison Tree: And this is the same data. So on the left, the RTOG GI toxicity and on the right, the CTCAE GI toxicity. So a little bit different here. So no difference significantly on RTOG toxicity. But what we found from PACE-B was that CTCAE is a more sensitive measure of symptoms—it triggers more events, if you like. So the GI toxicity on the CTCAE scale is worse for SBRT, and this was statistically significant. But as you've just already picked up on the last slide, there's a discordance about the time points and when we measure those things, so that may explain some of the difference.
Then the most important thing is what the patients say to us. This is just a single question from EPIC about how much of a bother is your bladder function or your bowel function. So bladder on the left of this slide, and these are stacked bar graphs where men having a big problem have the red color—the small number at the top—and then with a moderate problem are the orange color. And so you can see on the left there is a toxicity—a short-term toxicity—for many men with the urinary system, particularly at four weeks. But that's pretty much back to normal by 12 weeks. And a similar picture for bowel on the right-hand side of the screen with slightly more symptoms seen in the SBRT arm when you ask the patients at four weeks. Does that make sense?
Zachary Klaassen: Absolutely. No, that looks good. I guess I'll put you on the spot a little bit here. Do you know how many patients may have gotten rectal spacers to try to decrease—
Alison Tree: Yeah, in this trial, zero because it's not something that we standardly do in the UK. So this is all data without spacers.
Zachary Klaassen: Okay, perfect. So you mentioned PACE-B in the introduction. How does the toxicity from PACE-C maybe compare to the PACE-B data?
Alison Tree: Yeah, it looks incredibly similar. So as you might have expected, but actually in PACE-C, because some of the men had higher-risk disease, we included more seminal vesicles. We included ADT, which probably didn't make too much difference. But overall, the toxicity rates were almost identical in percentages, so very consistent across both trials.
Zachary Klaassen: Excellent. And we've certainly seen in this unfavorable, intermediate, and high risk, this is where we need high-quality data. The radiation oncologists are generally much better at doing trials than the surgeons are—as a surgeon. But I think this is incredibly important, and so we'll look forward to the clinical oncology outcomes. Any idea when we may see some of that data?
Alison Tree: So we're hoping maybe 2027, 2028 maybe, but obviously we have to wait for five years, as you know, for the biochemical outcomes. So we are just publishing the PACE-B outcomes this year, and so we have to wait. We have to be patient, don't we, as prostate oncologists?
Zachary Klaassen: That's right. That's right. No, that's excellent. So maybe a couple of take-home messages for our patients and our listeners and our oncologists as they're listening to this discussion. How do we take this data in 2024 as we wait for the oncology outcomes?
Alison Tree: Yeah, absolutely. So I think what we can say for sure from PACE-C is that the acute toxicity is very similar to what we saw in PACE-B. So perhaps a little more upset in the bowel function temporarily, but seems to settle by the end of the period. So many men would choose that over longer fractionations for convenience. Obviously, biochemically, we need to wait for the outcomes to be sure, but I think as the evidence develops, we are getting increasingly confident that the PSA control is going to be similar, but obviously we'll have to wait for the results to be sure.
Zachary Klaassen: Excellent. Alison, thanks so much for joining us and for your expertise and time today.
Alison Tree: Pleasure. Nice to see you.