MRI-Guided vs CT-Guided Stereotactic Body Radiotherapy for Prostate Cancer, The MIRAGE Randomized Clinical Trial Journal Club - Zachary Klaassen
March 2, 2023
In this UroToday Journal Club discussion, Zach Klaassen discusses the publication "Magnetic Resonance Imaging-Guided Versus CT-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial." This study compared CT-guided and MRI-guided SBRT for localized prostate cancer. Results showed that the aggressive margin reduction afforded by MRI guidance allowed a substantial reduction in acute physician-scored toxic effects and improved patient-reported outcome metrics for the MRI arm. Longer term follow-up is needed to determine whether these differences in late urinary or bowel toxic effects will occur and to evaluate differences in sexual outcomes.
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
Chris Wallis: Hello and thank you for joining us for our UroToday Journal Club discussion. Today we're talking about a recent publication entitled Magnetic Resonance Imaging-Guided Versus CT-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE 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 led by Dr. Kishan. SBRT is a form of external beam radiotherapy in which relatively large daily doses of radiotherapy are delivered over five or fewer sessions. There's emerging data from clinical trials that has suggested that SBRT may be a reasonable option for patients across the spectrum of prostate cancer. And you can see here on the right side the most recent NCCN guidelines highlighting in the bottom that SBRT in various approaches may be reasonable across nearly all NCCN risk groups.
Typically, SBRT is administered with linear accelerators using CT-based planning with either planar or x-ray or cone-beam CT to guide radiation delivery. We all know that radiation related toxicity includes both acute and late toxic effects. To potentially mitigate some of these toxic effects, people have explored the use of MR-based LINACs which have recently become available. There are a number of potential advantages to this approach, including the ability to monitor prostate motion directly rather than using fiducial markers, improved accuracy of alignment based on improved soft tissue contracting, and direct use of MRI for contouring, which would eliminate residual error from the fusion of diagnostic MRI to planning CT images. Overall, the effect of utilizing an MR-based approach would allow reductions in the planning target volume margins including areas of the bladder, rectum and others that may contribute to important toxicity.
Despite these theoretical advantages, a clinical benefit to MR-based LINAC has not been established in randomized data. MR-based radiotherapy requires increased resources, therefore, before widespread adoption we should demonstrate clinical benefit. To do this, the authors performed a non-blinded single center phase three randomized controlled trial between May of 2020 and October 2021. They included men 18 years or older with histologically confirmed clinically localized prostate adenocarcinoma. They excluded men who had the presence of non-MRI compatible electronic devices are foreign objects, and those with severe claustrophobia. Patients were randomized in a one-to-one fashion to CT-guided SBRT or MRI-guided SBRT with stratification according to both baseline urinary function, according to the IPSS, as well as prostate volume.
MRI-guided SBRT was delivered using the MRIdian LINAC. No fiducial markers were used in a free-breathing 0.35 Tesla MRI simulation scan using true fast imaging with steady state precision sequencing, was used to allow targeting and intrafraction adjustment. A 0.35 Tesla simulation was used for urethral delineation as well. In the CT-guided SBRT this was delivered using a number of fairly conventional approaches with fiducial markers placed on the day of the planning scan. All patients received a CT-based simulation and a full bladder and empty rectum were required both for simulation and at each treatment. The authors fused 1.5 Tesla to 3 Tesla diagnostic MRIs for contouring. The clinical treatment volume was defined as the prostate and the proximal one centimeter of seminal vesicles for all patients. The planning treatment volume included the CTV expanded isotropically by four millimeters for those patients receiving CT-guided therapy and by two millimeters filled receiving MRI-guided therapy.
Treatment was given as 40 gray and five fractions to 95% of the planning treatment volume every other day. At the investigator's discretion and on the basis of clinical disease characteristics, other additional treatments could be offered including elective nodal radiotherapy in 25 gray in five fractions, a simultaneous integrated boost to intraprostatic lesion as 42 gray in five fractions, a simultaneous integrated boost to a pelvic node as 35 gray in five fractions, as well as the use of androgen deprivation therapy with or without a non-steroidal anti-androgen. Ct-guided SBRT was performed using volumetric- modulated ARC therapy with a cone-beam CT obtained prior to each fraction.
SBRT was then administered without further intrafractional monitoring. In contrast, the MRI-guided SBRT was delivered using a step-and-shoot IMRT approach with the prostate aligned prior to each fraction using true fast imaging with steady state precision MRI. A cine MRI was obtained four per every second. If more than 10% of the prostate moved outside a three millimeter previously delineated boundary, a beam hold was initiated automatically and adjustment was performed. In terms of outcome adjudication, patients were assessed at baseline and at each scheduled follow-up, including one and three months. The primary outcome was the incidence of acute genital urinary grade two or greater toxicity according to CTCAE version 4.03. This was evaluated from the start of SBRT to 90 days following the completion of therapy. Secondary outcomes included acute GI toxicity as well as changes in IPSS and EPIC-26 domains.
In terms of these patient reported outcomes, clinically relevant cutoffs were considered. 18 points for urinary incontinence, 14 points for urinary obstructive or irritated symptoms, 12 points for bowel function and 24 points for sexual function. In terms of statistical analysis, the authors initially designed the study to identify a 14% decrease in acute GU toxicity from 29% to 15% and in doing so with 300 accrued patients they would have an 83.7% power to detect a one-sided alpha of zero point a 0.025. A pre-specified interim futility analysis was predicated on 100 patients reaching their 90 day follow up. Alpha spending was utilized with 0.03 allocated to the interim analysis and 0.019 allocated to the final analysis. The chi-squared test was used to compare GU toxicity and the Fisher's exact test to compare GI toxicity between treatment groups. They further performed subgroup analysis based on baseline IPSS and prostate volume.
In post-hoc exploratory analysis, the authors use logistic regression models to identify predictors of acute GU toxicity in multivariable models. Candidate variables were added to the models on the basis of univariable statistical significance and clinical relevance. The penalized regression method least absolute shrinkage and selection operator, LASSO, approach was used to identify a subset of variables that were predictive of the primary endpoint. Differences in longitudinal patient reported outcomes were compared using the Mann-Whitney test. And at this point in time I'm now going to hand it over to Zach to walk us through the results of the MIRAGE study.
Zach Klaassen: Thanks so much, Chris, for that great introduction and review of the methods. So in the MIRAGE study, 178 patients were assessed for eligibility. Ultimately, all these patients were randomized including 88 to the CT-guided SBRT arm and 90 to the MRI-guided SBRT arm. Ultimately, there were 76 men included in the primary endpoint analysis for the CT arm and 78 in the primary analysis endpoint for the MRI-guided arm. This is a look at the baseline characteristics for this study. You can see the median age was 71 for each of these groups. In terms of risk group, there was slightly more unfavorable intermediate risk patients at 51% in the MRI arm compared to 32% in the CT arm. However, we see that there was some more high risk and very high risk patients in the CT arm versus the MRI arm. With regards to extracapsular extension on MRI, roughly a quarter of these patients, roughly 14% had seminal vesicle invasion MRI, 74% in the CT arm and 62% in the MRI arm received ADT.
A nodal boost was used in roughly one quarter of the patients in both arms. A rectal spacer was used roughly half the time in each of these arms. A prior TURP was quite rare at 4% in the CT arm and 6% in the MRI arm. With regards to prostate size, the median was well-balanced between these groups, roughly 40CC. IPSSS was also well-balanced, six in the CT arm and a median of seven in the MRI arm, and baseline GI comorbidity was 23% in the CT arm and 15% in the MRI arm. This is the main table for analysis of the toxic effects. We can see here lots of numbers so I'm going to walk through this sequentially. Essentially, these P values correlate to a comparison between the grade greater than or equal to two toxic effects in the MRI versus the CT arm. The asterisks are the points that are statistically different between these two groups. So with regards to GU toxic events, any event greater than or equal to two was significantly higher in the CT arm at 43.4% versus 24.4% in the MRI arm.
Similarly with urinary frequency, higher in the CT arm, 31.6% grade greater than or equal to two toxic events versus 15.4% in the MRI arm. Similar with urinary retention, 27.6% in the CT arm and 11.5% in the MRI arm. When we look at gastrointestinal toxic events at the bottom of this table, any gastrointestinal toxic event greater than or equal to two, 10.5% in the CT arm and none in the MRI arm. Similarly diarrhea, 6.4% in the CT arm, none in the MRI arm. And proctitis, 6.4% in the CT arm and none in the MRI arm. At least in the acute phase there was no difference in sexual function between these two groups. This figure looks at the acute GU and GI toxic effects in terms of more of a figure form. On the left is acute GU toxic effects. On the right is acute GI toxic effects. In terms of the color scheme, zero is the very light blue, one is slightly darker, two is slightly darker than one, and three is the darkest.
And to quickly summarize, there was no grade three events in the MRI arm for either GU or GI toxic effects. We see several in the acute GU CT arm and we see none in the MRI arm. What's really important is the grade two. So if we look at the CT arm, acute GU toxic effects was more than the MRI arm and similarly in the acute GI toxic effects, there was no grade two GI toxic effects in the MRI arm and several in the CT arm. This is switching over to the patient reported outcomes now and we can see that this is for a urinary incontinence score. What's interesting here is at one month, the MRI arm was significantly improved compared to the CT arm, but at three months there's no statistical difference between this metric for each of these arms. This is the change in clinically relevant IPSS. Again, at one month we see significantly worse for CT patients, which is statistically significant, but again at three months this becomes statistically non-significant.
Moving over to GI toxic effects for the bowel domain score, similar to the GU toxic effects at one month, significantly worse for the CT arm compared to the MRI arm, but again at three months the statistical significance is gone and there's equivalence between the MRI and the CT arm. This also holds true for the change in clinically relevant bowel domain score. Significantly worse for the CT arm at one month and no difference at three months when we compare the CT and the MRI arms for a change in clinically relevant bowel domain score. So several points for discussion in this trial, this RCT showed that MRI guidance led to a significant reduction to both physician-scored toxic effects and patient-reported symptom burden in the acute timeframe following prostate SBRT. Acute grade greater than or equal to two, GU and GI toxic effects were reduced with absolute differences of 19% for GU and 10.5% for GI.
As mentioned, there was no grade three GU or grade greater than or equal to two GI toxic events in the MRI arm. Concerns regarding MRI guidance in general pertain largely to the logistical issues involving upfront equipment costs and treatment times. The post imaging delivery time was greater in patients receiving MRI guidance than those receiving CT guidance at 1133 seconds for MRI and 232 seconds for CT scan. Logistical concerns must be weighed against the benefit to patients since acute toxic effects from treatment were substantially reduced with MRI guidance.
So in conclusion, this is the first phase three RCT comparing CT-guided SBRT with MRI-guided SBRT for localized prostate cancer. This study demonstrated that the aggressive margin reduction afforded by MRI guidance allowed a substantial reduction in acute physician scored toxic effects and also showed improved patient reported outcome metrics for the MRI arm. Longer term follow up is necessary to determine whether these differences in late urinary or bowel toxic effects will occur and to evaluate differences in sexual outcomes. We thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the recently published MIRAGE trial in JAMA Oncology.
Chris Wallis: Hello and thank you for joining us for our UroToday Journal Club discussion. Today we're talking about a recent publication entitled Magnetic Resonance Imaging-Guided Versus CT-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE 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 led by Dr. Kishan. SBRT is a form of external beam radiotherapy in which relatively large daily doses of radiotherapy are delivered over five or fewer sessions. There's emerging data from clinical trials that has suggested that SBRT may be a reasonable option for patients across the spectrum of prostate cancer. And you can see here on the right side the most recent NCCN guidelines highlighting in the bottom that SBRT in various approaches may be reasonable across nearly all NCCN risk groups.
Typically, SBRT is administered with linear accelerators using CT-based planning with either planar or x-ray or cone-beam CT to guide radiation delivery. We all know that radiation related toxicity includes both acute and late toxic effects. To potentially mitigate some of these toxic effects, people have explored the use of MR-based LINACs which have recently become available. There are a number of potential advantages to this approach, including the ability to monitor prostate motion directly rather than using fiducial markers, improved accuracy of alignment based on improved soft tissue contracting, and direct use of MRI for contouring, which would eliminate residual error from the fusion of diagnostic MRI to planning CT images. Overall, the effect of utilizing an MR-based approach would allow reductions in the planning target volume margins including areas of the bladder, rectum and others that may contribute to important toxicity.
Despite these theoretical advantages, a clinical benefit to MR-based LINAC has not been established in randomized data. MR-based radiotherapy requires increased resources, therefore, before widespread adoption we should demonstrate clinical benefit. To do this, the authors performed a non-blinded single center phase three randomized controlled trial between May of 2020 and October 2021. They included men 18 years or older with histologically confirmed clinically localized prostate adenocarcinoma. They excluded men who had the presence of non-MRI compatible electronic devices are foreign objects, and those with severe claustrophobia. Patients were randomized in a one-to-one fashion to CT-guided SBRT or MRI-guided SBRT with stratification according to both baseline urinary function, according to the IPSS, as well as prostate volume.
MRI-guided SBRT was delivered using the MRIdian LINAC. No fiducial markers were used in a free-breathing 0.35 Tesla MRI simulation scan using true fast imaging with steady state precision sequencing, was used to allow targeting and intrafraction adjustment. A 0.35 Tesla simulation was used for urethral delineation as well. In the CT-guided SBRT this was delivered using a number of fairly conventional approaches with fiducial markers placed on the day of the planning scan. All patients received a CT-based simulation and a full bladder and empty rectum were required both for simulation and at each treatment. The authors fused 1.5 Tesla to 3 Tesla diagnostic MRIs for contouring. The clinical treatment volume was defined as the prostate and the proximal one centimeter of seminal vesicles for all patients. The planning treatment volume included the CTV expanded isotropically by four millimeters for those patients receiving CT-guided therapy and by two millimeters filled receiving MRI-guided therapy.
Treatment was given as 40 gray and five fractions to 95% of the planning treatment volume every other day. At the investigator's discretion and on the basis of clinical disease characteristics, other additional treatments could be offered including elective nodal radiotherapy in 25 gray in five fractions, a simultaneous integrated boost to intraprostatic lesion as 42 gray in five fractions, a simultaneous integrated boost to a pelvic node as 35 gray in five fractions, as well as the use of androgen deprivation therapy with or without a non-steroidal anti-androgen. Ct-guided SBRT was performed using volumetric- modulated ARC therapy with a cone-beam CT obtained prior to each fraction.
SBRT was then administered without further intrafractional monitoring. In contrast, the MRI-guided SBRT was delivered using a step-and-shoot IMRT approach with the prostate aligned prior to each fraction using true fast imaging with steady state precision MRI. A cine MRI was obtained four per every second. If more than 10% of the prostate moved outside a three millimeter previously delineated boundary, a beam hold was initiated automatically and adjustment was performed. In terms of outcome adjudication, patients were assessed at baseline and at each scheduled follow-up, including one and three months. The primary outcome was the incidence of acute genital urinary grade two or greater toxicity according to CTCAE version 4.03. This was evaluated from the start of SBRT to 90 days following the completion of therapy. Secondary outcomes included acute GI toxicity as well as changes in IPSS and EPIC-26 domains.
In terms of these patient reported outcomes, clinically relevant cutoffs were considered. 18 points for urinary incontinence, 14 points for urinary obstructive or irritated symptoms, 12 points for bowel function and 24 points for sexual function. In terms of statistical analysis, the authors initially designed the study to identify a 14% decrease in acute GU toxicity from 29% to 15% and in doing so with 300 accrued patients they would have an 83.7% power to detect a one-sided alpha of zero point a 0.025. A pre-specified interim futility analysis was predicated on 100 patients reaching their 90 day follow up. Alpha spending was utilized with 0.03 allocated to the interim analysis and 0.019 allocated to the final analysis. The chi-squared test was used to compare GU toxicity and the Fisher's exact test to compare GI toxicity between treatment groups. They further performed subgroup analysis based on baseline IPSS and prostate volume.
In post-hoc exploratory analysis, the authors use logistic regression models to identify predictors of acute GU toxicity in multivariable models. Candidate variables were added to the models on the basis of univariable statistical significance and clinical relevance. The penalized regression method least absolute shrinkage and selection operator, LASSO, approach was used to identify a subset of variables that were predictive of the primary endpoint. Differences in longitudinal patient reported outcomes were compared using the Mann-Whitney test. And at this point in time I'm now going to hand it over to Zach to walk us through the results of the MIRAGE study.
Zach Klaassen: Thanks so much, Chris, for that great introduction and review of the methods. So in the MIRAGE study, 178 patients were assessed for eligibility. Ultimately, all these patients were randomized including 88 to the CT-guided SBRT arm and 90 to the MRI-guided SBRT arm. Ultimately, there were 76 men included in the primary endpoint analysis for the CT arm and 78 in the primary analysis endpoint for the MRI-guided arm. This is a look at the baseline characteristics for this study. You can see the median age was 71 for each of these groups. In terms of risk group, there was slightly more unfavorable intermediate risk patients at 51% in the MRI arm compared to 32% in the CT arm. However, we see that there was some more high risk and very high risk patients in the CT arm versus the MRI arm. With regards to extracapsular extension on MRI, roughly a quarter of these patients, roughly 14% had seminal vesicle invasion MRI, 74% in the CT arm and 62% in the MRI arm received ADT.
A nodal boost was used in roughly one quarter of the patients in both arms. A rectal spacer was used roughly half the time in each of these arms. A prior TURP was quite rare at 4% in the CT arm and 6% in the MRI arm. With regards to prostate size, the median was well-balanced between these groups, roughly 40CC. IPSSS was also well-balanced, six in the CT arm and a median of seven in the MRI arm, and baseline GI comorbidity was 23% in the CT arm and 15% in the MRI arm. This is the main table for analysis of the toxic effects. We can see here lots of numbers so I'm going to walk through this sequentially. Essentially, these P values correlate to a comparison between the grade greater than or equal to two toxic effects in the MRI versus the CT arm. The asterisks are the points that are statistically different between these two groups. So with regards to GU toxic events, any event greater than or equal to two was significantly higher in the CT arm at 43.4% versus 24.4% in the MRI arm.
Similarly with urinary frequency, higher in the CT arm, 31.6% grade greater than or equal to two toxic events versus 15.4% in the MRI arm. Similar with urinary retention, 27.6% in the CT arm and 11.5% in the MRI arm. When we look at gastrointestinal toxic events at the bottom of this table, any gastrointestinal toxic event greater than or equal to two, 10.5% in the CT arm and none in the MRI arm. Similarly diarrhea, 6.4% in the CT arm, none in the MRI arm. And proctitis, 6.4% in the CT arm and none in the MRI arm. At least in the acute phase there was no difference in sexual function between these two groups. This figure looks at the acute GU and GI toxic effects in terms of more of a figure form. On the left is acute GU toxic effects. On the right is acute GI toxic effects. In terms of the color scheme, zero is the very light blue, one is slightly darker, two is slightly darker than one, and three is the darkest.
And to quickly summarize, there was no grade three events in the MRI arm for either GU or GI toxic effects. We see several in the acute GU CT arm and we see none in the MRI arm. What's really important is the grade two. So if we look at the CT arm, acute GU toxic effects was more than the MRI arm and similarly in the acute GI toxic effects, there was no grade two GI toxic effects in the MRI arm and several in the CT arm. This is switching over to the patient reported outcomes now and we can see that this is for a urinary incontinence score. What's interesting here is at one month, the MRI arm was significantly improved compared to the CT arm, but at three months there's no statistical difference between this metric for each of these arms. This is the change in clinically relevant IPSS. Again, at one month we see significantly worse for CT patients, which is statistically significant, but again at three months this becomes statistically non-significant.
Moving over to GI toxic effects for the bowel domain score, similar to the GU toxic effects at one month, significantly worse for the CT arm compared to the MRI arm, but again at three months the statistical significance is gone and there's equivalence between the MRI and the CT arm. This also holds true for the change in clinically relevant bowel domain score. Significantly worse for the CT arm at one month and no difference at three months when we compare the CT and the MRI arms for a change in clinically relevant bowel domain score. So several points for discussion in this trial, this RCT showed that MRI guidance led to a significant reduction to both physician-scored toxic effects and patient-reported symptom burden in the acute timeframe following prostate SBRT. Acute grade greater than or equal to two, GU and GI toxic effects were reduced with absolute differences of 19% for GU and 10.5% for GI.
As mentioned, there was no grade three GU or grade greater than or equal to two GI toxic events in the MRI arm. Concerns regarding MRI guidance in general pertain largely to the logistical issues involving upfront equipment costs and treatment times. The post imaging delivery time was greater in patients receiving MRI guidance than those receiving CT guidance at 1133 seconds for MRI and 232 seconds for CT scan. Logistical concerns must be weighed against the benefit to patients since acute toxic effects from treatment were substantially reduced with MRI guidance.
So in conclusion, this is the first phase three RCT comparing CT-guided SBRT with MRI-guided SBRT for localized prostate cancer. This study demonstrated that the aggressive margin reduction afforded by MRI guidance allowed a substantial reduction in acute physician scored toxic effects and also showed improved patient reported outcome metrics for the MRI arm. Longer term follow up is necessary to determine whether these differences in late urinary or bowel toxic effects will occur and to evaluate differences in sexual outcomes. We thank you very much for your attention. We hope we enjoyed this UroToday Journal Club discussion of the recently published MIRAGE trial in JAMA Oncology.