PACE B Study Analysis: Acute and Late Toxicities in Prostate Cancer Radiotherapy - Ragu Ratnakumaran
October 10, 2023
Phillip Koo interviews Ragu Ratnakumaran about the analysis of the PACE-B study. The study is a phase III international randomized control trial involving 874 patients with low to intermediate-risk prostate cancer. Dr. Ratnakumaran's analysis focuses on the association between acute and late genitourinary and gastrointestinal toxicities in two radiotherapy treatment arms: conventional or moderately hypofractionated radiotherapy and stereotactic ablative radiotherapy (SBRT). He finds that baseline symptoms and acute urinary toxicity are predictive of late urinary toxicity in both treatment arms. The same holds true for bowel toxicity. Dr. Ratnakumaran suggests that these findings can help improve patient selection and tailor treatments, especially as the use of SBRT is likely to increase. He also notes that the study opens avenues for further research on how early interventions could mitigate late side effects.
Biographies:
Ragu Ratnakumaran, MD, MBBS, Clinical Research Fellow, The Royal Marsden Hospital, London, UK
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, Arizona
Biographies:
Ragu Ratnakumaran, MD, MBBS, Clinical Research Fellow, The Royal Marsden Hospital, London, UK
Phillip J. Koo, MD, Division Chief of Diagnostic Imaging, Banner Health MD Anderson Cancer Center, Arizona
Related Content:
ASTRO 2023: The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study
ASTRO 2023: SBRT for Prostate Cancer: Before and After PACE-B
ASTRO 2023: 5-Year Outcomes from PACE B: An International Phase III Randomised Controlled Trial Comparing Stereotactic Body Radiotherapy vs Conventionally Fractionated or Moderately HypoFractionated External Beam Radiotherapy for Localized Prostate Cancer
ASTRO 2023: The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study
ASTRO 2023: SBRT for Prostate Cancer: Before and After PACE-B
ASTRO 2023: 5-Year Outcomes from PACE B: An International Phase III Randomised Controlled Trial Comparing Stereotactic Body Radiotherapy vs Conventionally Fractionated or Moderately HypoFractionated External Beam Radiotherapy for Localized Prostate Cancer
Read the Full Video Transcript
Phillip Koo: Hi, this is Phillip Koo. Welcome to ASCO 2023 here in San Diego, California. We're here covering some important papers that are being presented, one of which is titled "The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study." The presenting author for that is Dr. Ragu Ratnakumaran, who's a clinical research fellow at the Royal Marsden Hospital in the UK. Thank you very much for joining us.
Ragu Ratnakumaran: Thank you for having me today.
Phillip Koo: Before we dive into the data that you're presenting, let's talk a little bit about the PACE B study from a higher level, what that was, and some important findings from that study.
Ragu Ratnakumaran: Yeah. PACE B is a phase III international randomized control trial. It includes 874 patients with low to intermediate-risk prostate cancer, who were randomized between two radiotherapy treatment arms. The first arm was conventional or moderately hypofractionated radiotherapy, and the second arm was stereotactic ablative radiotherapy, where they delivered 36.25 gray to the PTV and 40 gray to the clinical target volume.
The main findings in the toxicity data, which was presented and published last year in the Lancet Oncology, showed, measured using RTOG, very similar GU and GI toxicity outcomes, measured using CTCAE, there was slightly higher urinary toxicity with the SBRT arm.
Phillip Koo: So then your study is looking at CRT and SBRT and the association between acute and late. Can you tell us a little bit about some of the results that you found from that analysis?
Ragu Ratnakumaran: Yeah. What I did was I performed logistic regression analyses to see if there's a correlation between acute and late urinary toxicity and bowel toxicity. And what I did was I separated the SBRT arm with the conventional radiotherapy arm. So, in short, what I found was that in patients who had urinary toxicity, having baseline symptoms and having acute urinary toxicity were all predictive of developing late urinary toxicity. That was true for patients who had SBRT, as well as conventional moderately hypofractionated radiotherapy. And then for bowel toxicity, if you had any acute symptoms during the acute period, which is defined as the first 3 months after radiotherapy, there's an increased risk of developing later bowel toxicity, again, in the SBRT arm and in the conventional or moderately hypofractionated radiotherapy arm.
Phillip Koo: Before you started this journey, I'm sure you had some hypotheses or certain things in mind, and then after you looked at the analysis, what were some of the surprises? Can you tell us about the pre and post-analysis thoughts that you had?
Ragu Ratnakumaran: Yeah. Based on previous studies using older techniques, so over 10 years ago, they've published similar analyses, but these were the older techniques such as 3D conformal radiotherapy approaches, and they did see an association between the two. But when we looked at moderately hypofractionated radiotherapy from studies such as CHHiP and PROFIT, they found that patients in the studies had more acute toxicity initially, particularly bowel toxicity, and then later on down the line when they were comparing the late side effects, there was no difference between the two. So it was interesting to find that there was an association in the SBRT arm and in the conventional moderately hypofractionated arm, because this was not shown previously and has not been published before.
Phillip Koo: Is there any association between the severity of some of these toxicities between acute and late? Maybe you have more severe acute and maybe less severe later?
Ragu Ratnakumaran: Yeah. I focus really on grade 2 symptoms, so grade 2 symptoms generally involve either needing to take medication for them or moderately affecting the activities of daily living. And so, if you had a grade 2 symptom or worse in the acute period, that was predictive for developing a grade 2 symptom or worse in the late period. We didn't see that association with grade 0 and grade 1, and the event rates of grade 3 toxicity were very low in the PACE B study.
Phillip Koo: I think all these studies are wonderful. It's really important for us to figure out how this impacts the clinic and how we manage patients. From your perspective, how should this be interpreted and then integrated into our practice?
Ragu Ratnakumaran: Yeah, that's a really good question. In terms of, this provides information for us, as, I believe, SBRT is going to likely increase its use in prostate cancer. So having this sort of information will help us improve patient selection and tailor our treatments to get the best outcomes for our patients. So now we know that baseline symptoms are really predictive of late toxicity, particularly in the SBRT group. It may be that in patients with significant baseline symptoms, we could decide to treat them with a conventional moderately hypofractionated treatment in preference for SBRT.
It also opens the avenue for further work because now we know that these symptoms at baseline are predictive. We can see if intervening with them at an earlier time point, could go on to reduce the risk of them getting late side effects. Similarly, if a patient comes into the clinic and is experiencing a lot of acute side effects, the next question is, if we intervene earlier, does that, again, prevent late side effects? And so this kind of also opens the opportunity for further research.
Phillip Koo: Great. I imagine you guys are continuing those investigations as well.
Ragu Ratnakumaran: Yeah. Some of the other things we're continuing to work on is looking at how dosimetry, so the dose to critical structures such as the urethra, and the bladder, impacts toxicity. And that work will see, if we do find that correlation between dose and toxicity, we can then develop new constraints and dose thresholds to minimize side effects in the future.
Phillip Koo: Another question I have is, were any other technologies deployed in some of these patients, like spacer devices, before radiotherapy?
Ragu Ratnakumaran: PACE B started recruiting patients in 2012, so it's been going on for nearly over 10 years. So in this trial, spacer devices weren't utilized.
Phillip Koo: Great. Well, thank you very much for joining us and sharing all this information. We look forward to hearing some of the results of your future studies.
Ragu Ratnakumaran: Thank you for having me.
Phillip Koo: Hi, this is Phillip Koo. Welcome to ASCO 2023 here in San Diego, California. We're here covering some important papers that are being presented, one of which is titled "The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study." The presenting author for that is Dr. Ragu Ratnakumaran, who's a clinical research fellow at the Royal Marsden Hospital in the UK. Thank you very much for joining us.
Ragu Ratnakumaran: Thank you for having me today.
Phillip Koo: Before we dive into the data that you're presenting, let's talk a little bit about the PACE B study from a higher level, what that was, and some important findings from that study.
Ragu Ratnakumaran: Yeah. PACE B is a phase III international randomized control trial. It includes 874 patients with low to intermediate-risk prostate cancer, who were randomized between two radiotherapy treatment arms. The first arm was conventional or moderately hypofractionated radiotherapy, and the second arm was stereotactic ablative radiotherapy, where they delivered 36.25 gray to the PTV and 40 gray to the clinical target volume.
The main findings in the toxicity data, which was presented and published last year in the Lancet Oncology, showed, measured using RTOG, very similar GU and GI toxicity outcomes, measured using CTCAE, there was slightly higher urinary toxicity with the SBRT arm.
Phillip Koo: So then your study is looking at CRT and SBRT and the association between acute and late. Can you tell us a little bit about some of the results that you found from that analysis?
Ragu Ratnakumaran: Yeah. What I did was I performed logistic regression analyses to see if there's a correlation between acute and late urinary toxicity and bowel toxicity. And what I did was I separated the SBRT arm with the conventional radiotherapy arm. So, in short, what I found was that in patients who had urinary toxicity, having baseline symptoms and having acute urinary toxicity were all predictive of developing late urinary toxicity. That was true for patients who had SBRT, as well as conventional moderately hypofractionated radiotherapy. And then for bowel toxicity, if you had any acute symptoms during the acute period, which is defined as the first 3 months after radiotherapy, there's an increased risk of developing later bowel toxicity, again, in the SBRT arm and in the conventional or moderately hypofractionated radiotherapy arm.
Phillip Koo: Before you started this journey, I'm sure you had some hypotheses or certain things in mind, and then after you looked at the analysis, what were some of the surprises? Can you tell us about the pre and post-analysis thoughts that you had?
Ragu Ratnakumaran: Yeah. Based on previous studies using older techniques, so over 10 years ago, they've published similar analyses, but these were the older techniques such as 3D conformal radiotherapy approaches, and they did see an association between the two. But when we looked at moderately hypofractionated radiotherapy from studies such as CHHiP and PROFIT, they found that patients in the studies had more acute toxicity initially, particularly bowel toxicity, and then later on down the line when they were comparing the late side effects, there was no difference between the two. So it was interesting to find that there was an association in the SBRT arm and in the conventional moderately hypofractionated arm, because this was not shown previously and has not been published before.
Phillip Koo: Is there any association between the severity of some of these toxicities between acute and late? Maybe you have more severe acute and maybe less severe later?
Ragu Ratnakumaran: Yeah. I focus really on grade 2 symptoms, so grade 2 symptoms generally involve either needing to take medication for them or moderately affecting the activities of daily living. And so, if you had a grade 2 symptom or worse in the acute period, that was predictive for developing a grade 2 symptom or worse in the late period. We didn't see that association with grade 0 and grade 1, and the event rates of grade 3 toxicity were very low in the PACE B study.
Phillip Koo: I think all these studies are wonderful. It's really important for us to figure out how this impacts the clinic and how we manage patients. From your perspective, how should this be interpreted and then integrated into our practice?
Ragu Ratnakumaran: Yeah, that's a really good question. In terms of, this provides information for us, as, I believe, SBRT is going to likely increase its use in prostate cancer. So having this sort of information will help us improve patient selection and tailor our treatments to get the best outcomes for our patients. So now we know that baseline symptoms are really predictive of late toxicity, particularly in the SBRT group. It may be that in patients with significant baseline symptoms, we could decide to treat them with a conventional moderately hypofractionated treatment in preference for SBRT.
It also opens the avenue for further work because now we know that these symptoms at baseline are predictive. We can see if intervening with them at an earlier time point, could go on to reduce the risk of them getting late side effects. Similarly, if a patient comes into the clinic and is experiencing a lot of acute side effects, the next question is, if we intervene earlier, does that, again, prevent late side effects? And so this kind of also opens the opportunity for further research.
Phillip Koo: Great. I imagine you guys are continuing those investigations as well.
Ragu Ratnakumaran: Yeah. Some of the other things we're continuing to work on is looking at how dosimetry, so the dose to critical structures such as the urethra, and the bladder, impacts toxicity. And that work will see, if we do find that correlation between dose and toxicity, we can then develop new constraints and dose thresholds to minimize side effects in the future.
Phillip Koo: Another question I have is, were any other technologies deployed in some of these patients, like spacer devices, before radiotherapy?
Ragu Ratnakumaran: PACE B started recruiting patients in 2012, so it's been going on for nearly over 10 years. So in this trial, spacer devices weren't utilized.
Phillip Koo: Great. Well, thank you very much for joining us and sharing all this information. We look forward to hearing some of the results of your future studies.
Ragu Ratnakumaran: Thank you for having me.