Oligometastatic Prostate Cancer: Unraveling Differences Between Imaging Techniques, Journal Club - Rashid Sayyid & Zachary Klaassen
July 24, 2023
In a discussion Rashid Sayyid and Zach Klaassen, they delve into a study comparing advanced molecular imaging and conventional imaging in detecting metachronous oligometastatic castrate-sensitive prostate cancer. The study used data from phase two trials, including the STOMP and ORIOLE trials, which established the oncologic benefits of metastasis-directed therapy for patients with metachronous oligometastatic prostate cancer. While traditional staging uses conventional imaging, the study highlights the growing use of advanced molecular imaging and its implications on prognosis. The research involved an international multicenter retrospective study with next-generation sequencing of patients' tumors. Dr. Klaassen presents the results, showing patients detected via advanced molecular imaging had fewer TP53 mutations and a better overall survival rate. They conclude that this patient subset may represent a more indolent disease state, stressing the need for considering imaging-detected lesions in future clinical trials.
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center, Augusta, GA
Biographies:
Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center, Augusta, GA
Read the Full Video Transcript
Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto and I'm along with Zach Klaassen, associate professor and program director at Augusta University. We'll be discussing the recent publication looking at clinical and genomic differences between advanced molecular imaging detected and conventional imaging detected metachronous oligometastatic castrate sensitive prostate cancer. This article was recently published in European Urology with Dr. Philip Sutera as the first author. So we know that oligometastatic disease is considered a bit of an intermediary state along the pathway between localized and widespread metastatic disease. Although many experts have challenged this concept and some have argued that it's a unique standalone disease state that isn't necessarily along the continuum. But for all intents and purposes, for the most part, this is considered an intermediary state. And the definition of oligometastasis has varied between three to five metastatic lesions across different disease sites, and that applies also to prostate cancer.
There's evidence from phase two trials that metastasis directed therapy for metachronous oligometastatic prostate cancer confers oncologic benefits. And when I say metachronous oligometastatic, that means a patient who's had radiation therapy or radical prostatectomy primary and then later on developed recurrence and had received metastatic directed therapy, usually in the form of stereotactic body radiation therapy or SBRT to those lesions. And we have four major trials in this setting. We have the STOMP trial, which was a phase two trial, included patients three or less metastatic sites. Importantly, these were staged on choline-PET/CT. And we saw that MDT improved five-year ADT-free survival from 8% to 34%, and then five-year CRPC-free survival from 53% to 76%. Along the similar lines, the ORIOLE trial also looked at MDT for patients who had less than or equal to three metastatic sites detecting on conventional imaging and it showed that SBRT or SABR improved six month progression from 19% to 61%, and improved median progression-free survival at a hazard ratio of 0.3.
Next, we had SABR-COMET which included oligometastatic up to five or less metastatic sites and then pointing this did not only include prostate cancer but other disease sites as well, and we saw an overall survival benefit in this trial. The five-year OS 42% versus 18% without SBRT. And then more recently published in JAMA Oncology, we have the EXTEND trial, which included patients up to five metastases and randomized them to either intermittent ADT alone or intermittent ADT plus MDT. And this was one of the first trials where we saw ADT included as part of the treatment arms, whereas with the other three, freedom from ADT was an outcome of interest. And we saw that adding MDT to intermittent ADT improved progression-free survival at a hazard ratio of 0.25. So clearly there's a different paradigm for these patients and very important to be able to detect them with reliability.
Now, historically, prostate cancer is staged using conventional imaging. When we say conventional imaging, this means CT and a bone scan. But over the last decade we've seen the emergence of numerous advanced molecular imaging modalities. Remember that we mean the choline-PET and the PSMA PET CT. And one of the consequences of that is that we've seen a lead time bias. And what does that mean? Essentially, we detect the metastatic state earlier and these patients inherently have better prognosis compared to when we find them in conventional images. So just because we found them earlier and follow them for longer doesn't necessarily mean that these patients are doing better with this. It just means we're finding them earlier and detecting the natural history earlier. And so, one of the issues with this is that all of these phase three trials of systemic therapy in the metastatic setting depend on conventional imaging to define metastases.
And as such, we don't quite know that if we detect somebody with low versus high volume metastasis on PSMA PET, and again, these are defined with conventional imaging, we don't quite know if we can apply the results of these trials to our patients. So clearly there's a lot of research going on in this field. We need to do a better job of understanding differences between metastatic prostate cancer detected on conventional imaging versus the advanced molecular imaging. And so to this end, the study objective was to compare the clinical and genomic differences between advanced molecular imaging detected and conventional imaging detected oligometastatic castration-sensitive prostate cancer.
And so for this study, the authors performed an international multicenter retrospective study and included men with metachronous oligometastatic prostate cancer. So again, these are patients that had treatment of their primary disease and then it recurred with a small volume of metastatic sites, less than five. Patients had next generation sequencing of either their primary tumor or metastatic site, and pre-specified genes and pathways of interest were determined on the basis literature reports for mCSPC. So they didn't search for every single genus just the ones which were most commonly reported in the literature. And they used STOMP and the ORIOLE trials as their data source, and additionally non-trial patients from Ghent University and Johns Hopkins Hospital. All patients had metachronous oligometastatic disease defined as five or less metastatic lesions. And conventional imaging for this study was defined as CT and bone scan. As for advanced molecular imaging, this could have been PSMA, 11-C choline or 18-F-fluciclovine PET which is the antigen PET scan.
All patients received definitive treatment of prostate, hence what we call metachronous when they recur. Importantly, patients in the advanced molecular imaging group had no lesions detectable in conventional imaging. So this is an earlier stage of disease. And if patients had lesions detected in both the advanced and conventional, then naturally they'd be in the conventional group since the, in theory, inferior modality also found them. The primary endpoint was evaluating clinical and genomic differences between conventional imaging and advanced molecular imaging-detected oligometastatic hormone sensitive disease and the parameters were compared using the Mann-Whitney U test and the Pearson's chi-squared test. And the Mann-Whitney test is chosen as opposed to the equivalent student T-test because it's a small sample size and it's considered a non-parametric test for this reason.
And then secondary endpoints included overall survival, defined as the time from initial localized prostate cancer to death from any cause, or time from oligometastasis from any cause. So they looked at this outcome in two different ways. Survival analysis were performed using Kaplan-Meier curves with comparisons performed using a log-rank test, and a multi-variable Cox regression model was performed using a prior selective variables to account for these and evaluate the robustness of the association. And at this point, I'll turn it over to Zach to go over the results and discussion for this study.
Zach Klaassen: Thanks so much, Rashid, for that great introduction. So this is the baseline characteristic stratified by detection method. As you can see on the right, this is conventional imaging versus advanced molecular imaging, and you can see the corresponding P-values on the far right of this table. So I've highlighted with asterisks the variables that are significantly different between the two. So we'll run through a few of these parameters and specifically highlight the statistically significant parameters. So if we look at median initial PSA, exactly the same between both groups, 7.5. There was a significant difference in ISUP Gleason grade group. We see that for advanced molecular imaging the most common was grade group two, whereas for conventional imaging the most common was grade group, excuse me, for advanced molecular imaging was grade group five at 35%. And for conventional imaging was also grade group five at 41%.
But we do see more grade group three and four in the conventional imaging cohort. When look at median PSA at oligometastasis, significantly lower for advanced molecular imaging at 1.7 compared to 8.0 for conventional imaging. Median age at oligometastasis 68 versus 66.8 for conventional imaging, not statistically significant. No significant difference for number of lesions detected. Most commonly was one for a advanced molecular imaging as well as one for conventional imaging. We look at metastases in the pelvic lymph nodes only. This is where we see more detected for advanced molecular imaging at 40% compared to 24% for conventional imaging. When we look at the initial oligometastasis management, we see that ADT was used in 36% of patients for advanced molecular imaging compared to 52% for conventional imaging, which was statistically significant, and MDT was much more frequently used for advanced molecular imaging at 79% versus 37% for conventional imaging.
Looking now at the oncoplot demonstrating mutation frequency for prostate cancer relevant genes and pathways, and this is broken down again by molecular imaging on the left compared to conventional imaging on the right. And two key take home points from this slide. So at the very top, P53 was only found in 17% of molecular imaging-detected oligometastatic disease compared to 28% for conventional imaging. And on the flip side, SPOP mutations were more common in molecularly detected oligometastatic disease at 17% compared to 9% for conventional imaging. As you can see, below this for PiK3, et cetera, there is no significant difference between these other genes detected. This is the Kaplan-Meier curve of overall survival from time of initial diagnosis, and this is stratified by molecular versus conventional imaging. Molecular only is in orange and conventional imaging is in the red color, and we see a significant difference between these two.
The 10-year OS rate for conventional imaging-detected oligometastatic disease was 85% compared to 100% for advanced molecular imaging with a hazard ratio of 0.12 and a 95% confidence interval of 0.03 to 0.55. A similar looking figure, this is comparing molecular imaging to conventional imaging for overall survival from the time of oligometastatic diagnosis. Again, we see a significant difference between molecular only with improved survival compared to conventional with the splitting of the curves at roughly 24 months from the time of oligometastatic disease. So in this discussion, this is the first report providing evidence that patients with metachronous conventional imaging-detected oligometastatic castrate sensitive prostate cancer have more biologically aggressive disease. And this is indicated by more TP53 mutations as well as experiencing worse clinical outcomes in patients with advanced molecular imaging-detected oligometastatic disease.
Incorporation of advanced molecular imaging for guiding treatment decisions is controversial and has implications for ongoing trials. First, several RCTs in the metastatic castrate sensitive prostate cancer space have established a standard of care that is based on conventional imaging defined disease volume, and it remains uncertain whether these data apply to advanced molecular imaging setting. Secondly, prior MDT studies demonstrated that PSMA PET-guided therapy is associated with a delay in ADT initiation with the hypothesis that this delay is because of better detection and targeting of occult metastatic disease.
So in conclusion, this is the first report on clinical and biological differences between advanced molecular imaging, oligometastatic castrate sensitive prostate cancer, and conventional imaging-detected disease. Patients with advanced molecular imaging-detected disease had fewer TP53 mutations and experienced better overall survival than patients with conventional imaging-detected castrate sensitive prostate cancer. Importantly, this difference in overall survival is observed both from initial diagnosis of localized prostate cancer and from the time of oligometastasis. And this suggests that advanced molecular imaging castrate sensitive prostate cancer may represent a more indolent disease rather than the result of a lead time bias. Finally, the presence of conventional imaging-detected lesions should be considered when evaluating upcoming clinical trials using advanced molecular imaging for staging. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of this recently published article in European Urology.
Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto and I'm along with Zach Klaassen, associate professor and program director at Augusta University. We'll be discussing the recent publication looking at clinical and genomic differences between advanced molecular imaging detected and conventional imaging detected metachronous oligometastatic castrate sensitive prostate cancer. This article was recently published in European Urology with Dr. Philip Sutera as the first author. So we know that oligometastatic disease is considered a bit of an intermediary state along the pathway between localized and widespread metastatic disease. Although many experts have challenged this concept and some have argued that it's a unique standalone disease state that isn't necessarily along the continuum. But for all intents and purposes, for the most part, this is considered an intermediary state. And the definition of oligometastasis has varied between three to five metastatic lesions across different disease sites, and that applies also to prostate cancer.
There's evidence from phase two trials that metastasis directed therapy for metachronous oligometastatic prostate cancer confers oncologic benefits. And when I say metachronous oligometastatic, that means a patient who's had radiation therapy or radical prostatectomy primary and then later on developed recurrence and had received metastatic directed therapy, usually in the form of stereotactic body radiation therapy or SBRT to those lesions. And we have four major trials in this setting. We have the STOMP trial, which was a phase two trial, included patients three or less metastatic sites. Importantly, these were staged on choline-PET/CT. And we saw that MDT improved five-year ADT-free survival from 8% to 34%, and then five-year CRPC-free survival from 53% to 76%. Along the similar lines, the ORIOLE trial also looked at MDT for patients who had less than or equal to three metastatic sites detecting on conventional imaging and it showed that SBRT or SABR improved six month progression from 19% to 61%, and improved median progression-free survival at a hazard ratio of 0.3.
Next, we had SABR-COMET which included oligometastatic up to five or less metastatic sites and then pointing this did not only include prostate cancer but other disease sites as well, and we saw an overall survival benefit in this trial. The five-year OS 42% versus 18% without SBRT. And then more recently published in JAMA Oncology, we have the EXTEND trial, which included patients up to five metastases and randomized them to either intermittent ADT alone or intermittent ADT plus MDT. And this was one of the first trials where we saw ADT included as part of the treatment arms, whereas with the other three, freedom from ADT was an outcome of interest. And we saw that adding MDT to intermittent ADT improved progression-free survival at a hazard ratio of 0.25. So clearly there's a different paradigm for these patients and very important to be able to detect them with reliability.
Now, historically, prostate cancer is staged using conventional imaging. When we say conventional imaging, this means CT and a bone scan. But over the last decade we've seen the emergence of numerous advanced molecular imaging modalities. Remember that we mean the choline-PET and the PSMA PET CT. And one of the consequences of that is that we've seen a lead time bias. And what does that mean? Essentially, we detect the metastatic state earlier and these patients inherently have better prognosis compared to when we find them in conventional images. So just because we found them earlier and follow them for longer doesn't necessarily mean that these patients are doing better with this. It just means we're finding them earlier and detecting the natural history earlier. And so, one of the issues with this is that all of these phase three trials of systemic therapy in the metastatic setting depend on conventional imaging to define metastases.
And as such, we don't quite know that if we detect somebody with low versus high volume metastasis on PSMA PET, and again, these are defined with conventional imaging, we don't quite know if we can apply the results of these trials to our patients. So clearly there's a lot of research going on in this field. We need to do a better job of understanding differences between metastatic prostate cancer detected on conventional imaging versus the advanced molecular imaging. And so to this end, the study objective was to compare the clinical and genomic differences between advanced molecular imaging detected and conventional imaging detected oligometastatic castration-sensitive prostate cancer.
And so for this study, the authors performed an international multicenter retrospective study and included men with metachronous oligometastatic prostate cancer. So again, these are patients that had treatment of their primary disease and then it recurred with a small volume of metastatic sites, less than five. Patients had next generation sequencing of either their primary tumor or metastatic site, and pre-specified genes and pathways of interest were determined on the basis literature reports for mCSPC. So they didn't search for every single genus just the ones which were most commonly reported in the literature. And they used STOMP and the ORIOLE trials as their data source, and additionally non-trial patients from Ghent University and Johns Hopkins Hospital. All patients had metachronous oligometastatic disease defined as five or less metastatic lesions. And conventional imaging for this study was defined as CT and bone scan. As for advanced molecular imaging, this could have been PSMA, 11-C choline or 18-F-fluciclovine PET which is the antigen PET scan.
All patients received definitive treatment of prostate, hence what we call metachronous when they recur. Importantly, patients in the advanced molecular imaging group had no lesions detectable in conventional imaging. So this is an earlier stage of disease. And if patients had lesions detected in both the advanced and conventional, then naturally they'd be in the conventional group since the, in theory, inferior modality also found them. The primary endpoint was evaluating clinical and genomic differences between conventional imaging and advanced molecular imaging-detected oligometastatic hormone sensitive disease and the parameters were compared using the Mann-Whitney U test and the Pearson's chi-squared test. And the Mann-Whitney test is chosen as opposed to the equivalent student T-test because it's a small sample size and it's considered a non-parametric test for this reason.
And then secondary endpoints included overall survival, defined as the time from initial localized prostate cancer to death from any cause, or time from oligometastasis from any cause. So they looked at this outcome in two different ways. Survival analysis were performed using Kaplan-Meier curves with comparisons performed using a log-rank test, and a multi-variable Cox regression model was performed using a prior selective variables to account for these and evaluate the robustness of the association. And at this point, I'll turn it over to Zach to go over the results and discussion for this study.
Zach Klaassen: Thanks so much, Rashid, for that great introduction. So this is the baseline characteristic stratified by detection method. As you can see on the right, this is conventional imaging versus advanced molecular imaging, and you can see the corresponding P-values on the far right of this table. So I've highlighted with asterisks the variables that are significantly different between the two. So we'll run through a few of these parameters and specifically highlight the statistically significant parameters. So if we look at median initial PSA, exactly the same between both groups, 7.5. There was a significant difference in ISUP Gleason grade group. We see that for advanced molecular imaging the most common was grade group two, whereas for conventional imaging the most common was grade group, excuse me, for advanced molecular imaging was grade group five at 35%. And for conventional imaging was also grade group five at 41%.
But we do see more grade group three and four in the conventional imaging cohort. When look at median PSA at oligometastasis, significantly lower for advanced molecular imaging at 1.7 compared to 8.0 for conventional imaging. Median age at oligometastasis 68 versus 66.8 for conventional imaging, not statistically significant. No significant difference for number of lesions detected. Most commonly was one for a advanced molecular imaging as well as one for conventional imaging. We look at metastases in the pelvic lymph nodes only. This is where we see more detected for advanced molecular imaging at 40% compared to 24% for conventional imaging. When we look at the initial oligometastasis management, we see that ADT was used in 36% of patients for advanced molecular imaging compared to 52% for conventional imaging, which was statistically significant, and MDT was much more frequently used for advanced molecular imaging at 79% versus 37% for conventional imaging.
Looking now at the oncoplot demonstrating mutation frequency for prostate cancer relevant genes and pathways, and this is broken down again by molecular imaging on the left compared to conventional imaging on the right. And two key take home points from this slide. So at the very top, P53 was only found in 17% of molecular imaging-detected oligometastatic disease compared to 28% for conventional imaging. And on the flip side, SPOP mutations were more common in molecularly detected oligometastatic disease at 17% compared to 9% for conventional imaging. As you can see, below this for PiK3, et cetera, there is no significant difference between these other genes detected. This is the Kaplan-Meier curve of overall survival from time of initial diagnosis, and this is stratified by molecular versus conventional imaging. Molecular only is in orange and conventional imaging is in the red color, and we see a significant difference between these two.
The 10-year OS rate for conventional imaging-detected oligometastatic disease was 85% compared to 100% for advanced molecular imaging with a hazard ratio of 0.12 and a 95% confidence interval of 0.03 to 0.55. A similar looking figure, this is comparing molecular imaging to conventional imaging for overall survival from the time of oligometastatic diagnosis. Again, we see a significant difference between molecular only with improved survival compared to conventional with the splitting of the curves at roughly 24 months from the time of oligometastatic disease. So in this discussion, this is the first report providing evidence that patients with metachronous conventional imaging-detected oligometastatic castrate sensitive prostate cancer have more biologically aggressive disease. And this is indicated by more TP53 mutations as well as experiencing worse clinical outcomes in patients with advanced molecular imaging-detected oligometastatic disease.
Incorporation of advanced molecular imaging for guiding treatment decisions is controversial and has implications for ongoing trials. First, several RCTs in the metastatic castrate sensitive prostate cancer space have established a standard of care that is based on conventional imaging defined disease volume, and it remains uncertain whether these data apply to advanced molecular imaging setting. Secondly, prior MDT studies demonstrated that PSMA PET-guided therapy is associated with a delay in ADT initiation with the hypothesis that this delay is because of better detection and targeting of occult metastatic disease.
So in conclusion, this is the first report on clinical and biological differences between advanced molecular imaging, oligometastatic castrate sensitive prostate cancer, and conventional imaging-detected disease. Patients with advanced molecular imaging-detected disease had fewer TP53 mutations and experienced better overall survival than patients with conventional imaging-detected castrate sensitive prostate cancer. Importantly, this difference in overall survival is observed both from initial diagnosis of localized prostate cancer and from the time of oligometastasis. And this suggests that advanced molecular imaging castrate sensitive prostate cancer may represent a more indolent disease rather than the result of a lead time bias. Finally, the presence of conventional imaging-detected lesions should be considered when evaluating upcoming clinical trials using advanced molecular imaging for staging. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of this recently published article in European Urology.