Rectal Spacing With Hyaluronic Acid for Hypofractionated Radiation Therapy for Prostate Cancer, Barrigel®, Journal Club - Zachary Klaassen
March 2, 2023
In this UroToday Journal Club discussion, Zach Klaassen discusses the publication "Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial." The study evaluates the effectiveness of a hyaluronic acid rectal spacer in reducing the risk of acute gastrointestinal toxicity in patients undergoing hypofractionated radiation therapy for prostate cancer. The study is a multicenter, randomized, single-blind trial performed at 12 centers across the United States, Australia, and Spain. The primary endpoint is the proportion of patients with at least a 25% reduction in the rectal volume receiving 54 gray from baseline to subsequent assessment, while the secondary endpoint is the proportion of patients with grade 2 or greater GI toxicity within three months. The study also assesses other important endpoints, including the proportion of patients with minimally clinically significant declines in patient-reported outcomes from baseline to 3 months.
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Read the Full Video Transcript
Christopher Wallis: Hello, and thank you for joining us for this UroToday during club discussion. Today we're talking about a recent publication entitled Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. You can see here the citation for this recent publication in JAMA Oncology.
Hypofractionation of radiation has become widely utilized in prostate cancer treatment the past few years. This approach is both more convenient for patients and more cost-effective by the reduction in number of fractions needed. As you can see on the table on the bottom right, various forms of hypofractionation are recommended by the NCCN for essentially all risk groups. We've seen from randomized trials that there's similar biochemical control in patients with low and intermediate risk disease when hypofractionation is used compared to conventional fractionation. However, there is concerns regarding higher GI toxicity, and in a recent meta-analysis, this was suggested to be approximately 9% higher.
Rectal spacers may reduce the risk of acute GI toxicity in patients undergoing hypofractionated radiation therapy. This is a physical effect, as it increases the distance from the prostate to the rectum, and as a result, reduces the rectal volume receiving a radiation dose. In preliminary data involving 36 patients, there are low rates of grade 2 GI events following placement of the rectal spacer. Additionally, there's prior randomized controlled trial data demonstrating decreased rectal dose and improved late GI toxicity and bowel-related quality of life in patients who had a spacer and were receiving conventionally fractionated radiation therapy.
The rationale of this study is to perform a randomized controlled trial evaluating hyaluronic acid rectal spacer among patients who are going hypofractionated radiotherapy involving 60 gray and 20 fractions to assess two key endpoints. First, the volume of rectal tissue receiving radiotherapy, and second, grade 2 or greater GI toxicity. This is a multicenter, randomized, single-blind trial performed at 12 centers across the United States, Australia, and Spain. Now, adult men aged 18 years and older with biopsy-proven prostate cancer in the preceding 9 months were included. In terms of disease risk, the of clinical T1 or T2 disease, Gleason score of 7 or lower, and a PSA of 20 or lower. Patients were excluded if they had an allergy to hyaluronic acid, very high or very low prostate volumes, a recent TURP, inflammatory bowel disease requiring steroids, lupus, scleroderma, or various bleeding disorders, or if they had bilateral hip implants.
Initially, all enrolled investigators enrolled patients onto the training phase, in which 1:3 patients were treated under a proctor's guidance to ensure that this was a technically acceptable procedure. Following this, patients and investigators moved to the randomized phase, in which there was 2:1 randomization to either the hyaluronic spacer and fiducial markers prior to hypofractionated radiation or fiducial markers alone. Randomization was stratified by a region, the planned use of ADT, and baseline erectile function. Patients were blinded to their assignment with masking during the procedure.
All patients underwent an initial history and physical examination, and if they were randomized to a spacer, underwent a baseline CT or MRI. Within 14 days of randomization, patients underwent the study intervention. The spacer was injected under transrectal ultrasound guidance by a perineal approach, and 9 to 12 ccs of spaces were injected between Denonvilliers fascia and the anterior rectal wall. Anesthesia, whether local or using contra sedation, was at the discussion of the treating physician. All patients subsequently underwent CT or MRI for radiation planning 3 to 10 days after the procedure.
The treating investigator delineated the CTV as well as the PTV and rectum, bladder, penile bulb, and femoral heads. The Dosimetrist created the radiation treatment plan using either an IMRT or VMAT approach. The PTV was prescribed 60 gray and 20 fractions with a 100% isodose line to include at least 99% of the CTV and 98% of the PTV. The max dose was not to exceed 10% of the prescription dose. All CT or MRIs, contours, and treatment plans were then independently reviewed by external experts prior to treatment with replanning where these plans did not meet trial specifications. Replans were required in approximately 22% of scans in the control group and 23% in the spacer group.
Radiation treatment began within 30 days after the fiducial/spatial placement. If ADT was planned, treatment had to begin within 30 to 60 days prior to the fiducial placement placement and then continue for 4 months in total. Clinical evaluation occurred weekly during treatment, and toxicity according to CTCAE was assessed both during therapy and at 3 and 6 months after the initial fiducial or spacer replacement. Patient-reported outcomes were assessed using the EPIC-26 questionnaire, and this was done at baseline 3 months and 6 months. A repeated MRI was performed at 3 months.
The primary study endpoint was the proportion of patients who had at least a 25% reduction in the rectal volume receiving 54 gray from baseline to subsequent assessment. The secondary endpoint was the proportion of patients with grade 2 or greater GI toxicity as assessed using CTCAE version 5 within 3 months. Other important endpoints included the proportion of patients with minimally clinically important declines in patient-reported outcomes from baseline to 3 months. These included bowel, urinary, sexual, and hormonal function.
The sample size was determined based on the proportion of patients with a minimally clinically important decline in EPIC-26 bowel domain at 36 months. They assumed 19% for the spacer group and 40% for the control group, and thus, yield a sample size of 159 patients to allow a one-sided alpha of 0.025 and a power of 80%. Based on this power calculation, the sample size provided greater than 90% power for both their primary and secondary endpoints as described above. The primary endpoint was evaluated in the exact binomial test with a one-sided alpha of 0.03 and the secondary endpoint evaluated Fisher's exact test, and the two-sided alpha here was 0.035. I'm going to hand over to Zach to walk us through the results of this trial.
Zachary Klaassen: Thanks so much, Chris, for that great introduction. This is the participant flow diagram. You can see here that 260 patients were assessed for eligibility. Ultimately, 201 underwent randomization. This included 136 randomized to receive the spacer and 65 randomized to receive the control intervention. Looking at the baseline patient demographics, we can see here this is split by the control group on the right and the spacer group on the left. The median age was the same for both groups, 69 years of age. Median BMI was equivalent, at roughly 28 for both groups. Roughly three-quarters of these patients were white and approximately one-quarter were Hispanic or Latino.
With regards to ECOG performance status, very good performance status for all these patients, over 80% ECOG 0. Gleason score breakdown, roughly three-quarters of these patients in each group were Gleason 7. When we look at the AJCCCT stage, roughly 60-70% of these patients were T1a to T1c, with the remaining predominantly T2a. Median PSA for both groups was equivalent. At 5.6 in the spacer group and 5.7 in the control group. Roughly two-thirds of these patients had good erectile function and roughly one-third of these patients received ADT as part of their treatment plan.
This is a MRI on the left, which is T2 weighted, showing the hyaluronic acid spacer. We can see the prostate here. The Barrigel spacer nicely between the rectum and the prostate, with good symmetry and good coverage of the rectum. The table on the right looks at ease of use for placing the hyaluronic acid spacer. Importantly, nearly 93% of participants in this trial deemed that this was either very easy or easy to use.
This is an important slide looking at the primary outcome. This is radiation dose rectal volume histogram data. The primary endpoint was assessable in 133 out of 136 patients. Notably, 98.5% of patients experienced at least a 25% reduction in the rectal volume of 54 gray to the rectum, which is greater than the 70% acceptable rate delineated in the methods, as Chris mentioned. The mean reduction in baseline was 85%, and we can see here the absolute decline was significant for all of these metrics, with numerical reduction in all protocol rectal DVH metrics.
This looks at the dose volume histogram for the bladder and the penile bulb. On the bladder, we can see there is a slight decrease post spacer injection, with relatively equivalent penile bulb dose when comparing baseline to post spacer ejection.
This is an important slide. This is a comparison of the dose volume histogram metrics between the control group and the spacer group. I've highlighted the rectal metrics here, and we can see that for all of these evaluations from V38 to all the way up to 57 gray, we see a decrease with the spacer group compared to the control group. Particularly for 54 gray, 1.5% in the spacer group compared to 9.1% in the control group.
This table looks at the gastrointestinal and GU toxicity effects by CTCAE version 5. I've highlighted the gastrointestinal toxic effects within 3 months, which was the secondary endpoint, looking at no toxic effects. 84% in the spacer group compared to 55% in the control group. With regards to grade 1, 12.6% in the spacer group compared to 30.8% in the control group. With regards to grade 2, 2.2% in the spacial group compared to 13.8% in the control group. So we do see improved toxic effects in the spacer group compared to control within 3 months. At about 6 months, there's there's less difference. We do see less grade 1 for the spacial group, 0.8% to 8.1% in the control group, and relatively comparable GU toxicity at both 3 and 6 months.
This looks at the proportion of patients with minimally clinical important decline on EPIC-26 at 3 and 6 months. With regards to bowel, which is another important secondary endpoint, we see no minimal decline in 26% versus 37.7% in the control group, which was not statistically significant, and of note, this may be, perhaps, secondary to a lack of power in this comparison.
With regards to discussion points from this trial, this is the first randomized clinical trial evaluating the efficacy of a hyaluronic acid rectal spacer for hypofractionated radiotherapy. Importantly, this study did achieve the primary endpoint of more than 70% of patients in the spacer group achieving a 25% or greater reduction in rectal dose of 54 gray. It also achieved the secondary endpoint, in that the spacer group had reduced acute grade equal to 2 or higher GI toxic effects at 2.9% compared to the control group of 13.8%. When we look at this in comparison to the literature, the GI toxic effects were 2.9%, which is in line with the observed phase II study looking at hyaluronic acid spacers provided to hypofractionated radiotherapy, which was 2.8%. So we do see some comparable effects between the phase two and the randomized trial. The goals for future analyses are to assessed bowel quality of life at 3 years, and also to assess the implications of the spacer on sexual function at 3 years with a stratified analysis by ADT and baseline erectile dysfunction.
In conclusion, the results of this randomized clinical trial found that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Finally, further prospective follow up is planned to characterize the effect of rectal spacing on long-term toxic effects and quality of life. Well, thank you very much for your attention. We hope we enjoyed the UroToday Journal Club of the Barrigel trial published in the Journal of JAMMA Oncology.
Christopher Wallis: Hello, and thank you for joining us for this UroToday during club discussion. Today we're talking about a recent publication entitled Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial. I'm Chris Wallis, an assistant professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, an assistant professor in the Division of Urology at the Medical College of Georgia. You can see here the citation for this recent publication in JAMA Oncology.
Hypofractionation of radiation has become widely utilized in prostate cancer treatment the past few years. This approach is both more convenient for patients and more cost-effective by the reduction in number of fractions needed. As you can see on the table on the bottom right, various forms of hypofractionation are recommended by the NCCN for essentially all risk groups. We've seen from randomized trials that there's similar biochemical control in patients with low and intermediate risk disease when hypofractionation is used compared to conventional fractionation. However, there is concerns regarding higher GI toxicity, and in a recent meta-analysis, this was suggested to be approximately 9% higher.
Rectal spacers may reduce the risk of acute GI toxicity in patients undergoing hypofractionated radiation therapy. This is a physical effect, as it increases the distance from the prostate to the rectum, and as a result, reduces the rectal volume receiving a radiation dose. In preliminary data involving 36 patients, there are low rates of grade 2 GI events following placement of the rectal spacer. Additionally, there's prior randomized controlled trial data demonstrating decreased rectal dose and improved late GI toxicity and bowel-related quality of life in patients who had a spacer and were receiving conventionally fractionated radiation therapy.
The rationale of this study is to perform a randomized controlled trial evaluating hyaluronic acid rectal spacer among patients who are going hypofractionated radiotherapy involving 60 gray and 20 fractions to assess two key endpoints. First, the volume of rectal tissue receiving radiotherapy, and second, grade 2 or greater GI toxicity. This is a multicenter, randomized, single-blind trial performed at 12 centers across the United States, Australia, and Spain. Now, adult men aged 18 years and older with biopsy-proven prostate cancer in the preceding 9 months were included. In terms of disease risk, the of clinical T1 or T2 disease, Gleason score of 7 or lower, and a PSA of 20 or lower. Patients were excluded if they had an allergy to hyaluronic acid, very high or very low prostate volumes, a recent TURP, inflammatory bowel disease requiring steroids, lupus, scleroderma, or various bleeding disorders, or if they had bilateral hip implants.
Initially, all enrolled investigators enrolled patients onto the training phase, in which 1:3 patients were treated under a proctor's guidance to ensure that this was a technically acceptable procedure. Following this, patients and investigators moved to the randomized phase, in which there was 2:1 randomization to either the hyaluronic spacer and fiducial markers prior to hypofractionated radiation or fiducial markers alone. Randomization was stratified by a region, the planned use of ADT, and baseline erectile function. Patients were blinded to their assignment with masking during the procedure.
All patients underwent an initial history and physical examination, and if they were randomized to a spacer, underwent a baseline CT or MRI. Within 14 days of randomization, patients underwent the study intervention. The spacer was injected under transrectal ultrasound guidance by a perineal approach, and 9 to 12 ccs of spaces were injected between Denonvilliers fascia and the anterior rectal wall. Anesthesia, whether local or using contra sedation, was at the discussion of the treating physician. All patients subsequently underwent CT or MRI for radiation planning 3 to 10 days after the procedure.
The treating investigator delineated the CTV as well as the PTV and rectum, bladder, penile bulb, and femoral heads. The Dosimetrist created the radiation treatment plan using either an IMRT or VMAT approach. The PTV was prescribed 60 gray and 20 fractions with a 100% isodose line to include at least 99% of the CTV and 98% of the PTV. The max dose was not to exceed 10% of the prescription dose. All CT or MRIs, contours, and treatment plans were then independently reviewed by external experts prior to treatment with replanning where these plans did not meet trial specifications. Replans were required in approximately 22% of scans in the control group and 23% in the spacer group.
Radiation treatment began within 30 days after the fiducial/spatial placement. If ADT was planned, treatment had to begin within 30 to 60 days prior to the fiducial placement placement and then continue for 4 months in total. Clinical evaluation occurred weekly during treatment, and toxicity according to CTCAE was assessed both during therapy and at 3 and 6 months after the initial fiducial or spacer replacement. Patient-reported outcomes were assessed using the EPIC-26 questionnaire, and this was done at baseline 3 months and 6 months. A repeated MRI was performed at 3 months.
The primary study endpoint was the proportion of patients who had at least a 25% reduction in the rectal volume receiving 54 gray from baseline to subsequent assessment. The secondary endpoint was the proportion of patients with grade 2 or greater GI toxicity as assessed using CTCAE version 5 within 3 months. Other important endpoints included the proportion of patients with minimally clinically important declines in patient-reported outcomes from baseline to 3 months. These included bowel, urinary, sexual, and hormonal function.
The sample size was determined based on the proportion of patients with a minimally clinically important decline in EPIC-26 bowel domain at 36 months. They assumed 19% for the spacer group and 40% for the control group, and thus, yield a sample size of 159 patients to allow a one-sided alpha of 0.025 and a power of 80%. Based on this power calculation, the sample size provided greater than 90% power for both their primary and secondary endpoints as described above. The primary endpoint was evaluated in the exact binomial test with a one-sided alpha of 0.03 and the secondary endpoint evaluated Fisher's exact test, and the two-sided alpha here was 0.035. I'm going to hand over to Zach to walk us through the results of this trial.
Zachary Klaassen: Thanks so much, Chris, for that great introduction. This is the participant flow diagram. You can see here that 260 patients were assessed for eligibility. Ultimately, 201 underwent randomization. This included 136 randomized to receive the spacer and 65 randomized to receive the control intervention. Looking at the baseline patient demographics, we can see here this is split by the control group on the right and the spacer group on the left. The median age was the same for both groups, 69 years of age. Median BMI was equivalent, at roughly 28 for both groups. Roughly three-quarters of these patients were white and approximately one-quarter were Hispanic or Latino.
With regards to ECOG performance status, very good performance status for all these patients, over 80% ECOG 0. Gleason score breakdown, roughly three-quarters of these patients in each group were Gleason 7. When we look at the AJCCCT stage, roughly 60-70% of these patients were T1a to T1c, with the remaining predominantly T2a. Median PSA for both groups was equivalent. At 5.6 in the spacer group and 5.7 in the control group. Roughly two-thirds of these patients had good erectile function and roughly one-third of these patients received ADT as part of their treatment plan.
This is a MRI on the left, which is T2 weighted, showing the hyaluronic acid spacer. We can see the prostate here. The Barrigel spacer nicely between the rectum and the prostate, with good symmetry and good coverage of the rectum. The table on the right looks at ease of use for placing the hyaluronic acid spacer. Importantly, nearly 93% of participants in this trial deemed that this was either very easy or easy to use.
This is an important slide looking at the primary outcome. This is radiation dose rectal volume histogram data. The primary endpoint was assessable in 133 out of 136 patients. Notably, 98.5% of patients experienced at least a 25% reduction in the rectal volume of 54 gray to the rectum, which is greater than the 70% acceptable rate delineated in the methods, as Chris mentioned. The mean reduction in baseline was 85%, and we can see here the absolute decline was significant for all of these metrics, with numerical reduction in all protocol rectal DVH metrics.
This looks at the dose volume histogram for the bladder and the penile bulb. On the bladder, we can see there is a slight decrease post spacer injection, with relatively equivalent penile bulb dose when comparing baseline to post spacer ejection.
This is an important slide. This is a comparison of the dose volume histogram metrics between the control group and the spacer group. I've highlighted the rectal metrics here, and we can see that for all of these evaluations from V38 to all the way up to 57 gray, we see a decrease with the spacer group compared to the control group. Particularly for 54 gray, 1.5% in the spacer group compared to 9.1% in the control group.
This table looks at the gastrointestinal and GU toxicity effects by CTCAE version 5. I've highlighted the gastrointestinal toxic effects within 3 months, which was the secondary endpoint, looking at no toxic effects. 84% in the spacer group compared to 55% in the control group. With regards to grade 1, 12.6% in the spacer group compared to 30.8% in the control group. With regards to grade 2, 2.2% in the spacial group compared to 13.8% in the control group. So we do see improved toxic effects in the spacer group compared to control within 3 months. At about 6 months, there's there's less difference. We do see less grade 1 for the spacial group, 0.8% to 8.1% in the control group, and relatively comparable GU toxicity at both 3 and 6 months.
This looks at the proportion of patients with minimally clinical important decline on EPIC-26 at 3 and 6 months. With regards to bowel, which is another important secondary endpoint, we see no minimal decline in 26% versus 37.7% in the control group, which was not statistically significant, and of note, this may be, perhaps, secondary to a lack of power in this comparison.
With regards to discussion points from this trial, this is the first randomized clinical trial evaluating the efficacy of a hyaluronic acid rectal spacer for hypofractionated radiotherapy. Importantly, this study did achieve the primary endpoint of more than 70% of patients in the spacer group achieving a 25% or greater reduction in rectal dose of 54 gray. It also achieved the secondary endpoint, in that the spacer group had reduced acute grade equal to 2 or higher GI toxic effects at 2.9% compared to the control group of 13.8%. When we look at this in comparison to the literature, the GI toxic effects were 2.9%, which is in line with the observed phase II study looking at hyaluronic acid spacers provided to hypofractionated radiotherapy, which was 2.8%. So we do see some comparable effects between the phase two and the randomized trial. The goals for future analyses are to assessed bowel quality of life at 3 years, and also to assess the implications of the spacer on sexual function at 3 years with a stratified analysis by ADT and baseline erectile dysfunction.
In conclusion, the results of this randomized clinical trial found that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Finally, further prospective follow up is planned to characterize the effect of rectal spacing on long-term toxic effects and quality of life. Well, thank you very much for your attention. We hope we enjoyed the UroToday Journal Club of the Barrigel trial published in the Journal of JAMMA Oncology.