Ga-PSMA PET for Evaluation of Response to Chemotherapy for Metastatic Prostate Cancer, Journal Club - Rashid Sayyid & Zachary Klaassen
June 7, 2023
Rashid Sayyid and Zach Klaassen analyze a study on the prognostic role of 68Ga-PSMA-11 PET-based response in prostate cancer patients undergoing taxane-based chemotherapy. The researchers note that traditional assessment tools, such as the Prostate Cancer Working Group 3 criteria, often rely on conventional imaging, limiting the ability to differentiate between responders and those with stable disease within the non-progressive cohort. The study aimed to compare traditional criteria with newer frameworks incorporating PSMA-PET/CT based criteria, such as PERCIST and PSMA PET Progression. The results indicated a high prognostic utility of PSMA PET response criteria for men with metastatic prostate cancer, with the PSMA PET Progression criteria showing the best prognostic value. Despite limitations, such as small cohort size and retrospective analysis, the study's results suggest a need to further explore imaging criteria for better identifying treatment responders.
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
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
Read the Full Video Transcript
Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a urological oncology fellow at the University of Toronto, and along with Zach Klaassen, Assistant Professor and Program Director at Augusta University, we'll be discussing the latest publication looking at The Prognostic Role of 68Ga-PSMA-11 PET-Based Response in Prostate Cancer Patients Undergoing Taxane-Based Chemotherapy. This article was recently published in The Journal of Nuclear Medicine.
We know that taxane-based chemotherapy remains a standard of care option for both mHSPC and mCRPC patients. However, we currently use the Prostate Cancer Working Group 3 criteria for radiographic assessment of treatment response in the metastatic setting, and this relies on conventional imaging in the form of CT and bone scan. This imaging framework stratifies patients into one of two groups: either those with progressive disease or non-progressive disease. Unfortunately within the non-progressive cohort, we're unable to identify patients as responders versus those with stable disease. We know that PSMA-PET/CT has improved the performance characteristics compared to conventional imaging, and as such, has been recommended as an imaging tool in the biochemically recurrent setting.
We have numerous imaging framework across disease sites, including the RECIST 1.1, which is the framework that relies on cross-sectional imaging. We also have PERCIST, which was introduced for FDG PET-based imaging as opposed to PSMA PET-based imaging. Recently, the PSMA PET Progression criteria was proposed by Dr. Fanti et al. for use in patients with metastatic prostate cancer. So clearly, we have many options and these are evolving based on the emerging imaging techniques.
The use of PSMA-PET/CT for the assessment of treatment response in those with metastatic prostate cancer still remains poorly defined. Furthermore, the data regarding the prognostic utility of PSMA-PET/CT compared to traditional frameworks and imaging techniques remain sparse.
As such, the study objective was to compare the prognostic utility of traditional treatment response criteria, such as RECIST, as we said, conventional imaging and PSA-based response, to more novel frameworks that incorporate PSMA-PET/CT based criteria, such as the PERCIST, which is adapted from the 68Ga-PSMA11 PET; also, the similarly adapted Prostate Cancer Working Group 3 framework; and also the PSMA PET Progression criteria which were proposed by Fanti et al.
So for the purpose of this study, the authors included patients with either mHSPC or mCRPC, all undergoing taxane-based chemotherapy, and all patients had a gallium PSMA PET scan both pre- and post-treatment, meaning within three months prior to the initiation of treatment and within three months of completion of the treatment. All these patients were included between January 2014, December 2018, from the Technical University of Munich.
The response assessment was evaluated using two broad methods. We have the conventional methods, which utilize biochemical response, meaning a PSA decline of at least 50% following chemotherapy, and the RECIST 1.1 framework. Next, we had the subheading of PSMA-PET-based methods, the first being PSMA PET Progression, the Fanti et al. criteria, which was defined as appearance of 2+ new PSMA-positive distant lesions, appearance of at least one new positive lesion plus clinical lab data suggestive of progression, and also increase in the size or the PSMA uptake of at least one lesion of at least 30% plus consistent worsening clinical lab data. Any of these three criteria and the patient had evidence of progression.
Next, the authors utilized the PERCIST 1.0 criteria, which was adapted as follows. For the purposes of this framework, five different organ systems are identified, and within each one up to two lesions with the highest PSMA PET uptake on the pre-chemo PET were singled out. Next, a post-chemo PET was compared to the pre-chemo PET, so we have two scans, and those with complete response were those who have absence of PSMA uptake on the second PET, the post-chemo PET, in all target lesions. A partial response was a decrease in the SUVpeak sum, meaning all them added up at least 30% stable either plus 30% or negative 30% in the SUVpeak. Then the progressive disease includes those patients who had an increase of at least 30%. Then also they use the third framework, which is the adapted Prostate Cancer Working Group 3 criteria. The only difference compared to the conventional one is that a PSMA PET is used instead of bone scan for bone lesions.
The authors use summary measures for summarizing continuous and categorical variables. In keeping with most studies, they use survival analysis using Kaplan-Meier curves, and the log-rank tests were used for between group comparisons. Survival was defined as the time from initiation of chemo until any cause death. The associations between the response assessment frameworks individually and overall survival were analyzed using univariate Cox regression analysis. At this point I'll turn it over to Zach to present the results and the discussion of this study.
Zachary Klaassen: Thanks so much for that great introduction, Rashid. This is the clinical characteristics of the 103 patients that were included in this study. The median age was 71 years. You can see here the pre-chemotherapy PSA level for the mHSPC patients was 15 compared to 45 for the mCRPC patients. You can see also that roughly two-thirds of patients had Gleason score greater than or equal to eight. Roughly three-quarters of the patients had excellent ECOG performance status of zero or one. With regard to breakdown of castration status, 55% were metastatic hormone sensitive and 45% were CRPC. In terms of pre-chemo molecular imaging TNM stage, the most common was M1b at 78% compared to 70% M1a. Looking at pattern of metastatic spread, most commonly was lymph nodes and bones at 52%, and second most common was lymph node only at 21%.
With regards to local treatment for prostate cancer, prostate prostatectomy plus or minus lymphadenectomy in 56% of patients and primary external beam radiotherapy in 13% of patients. For type of prior chemotherapy, docetaxel was the overwhelming most common chemotherapy regimen at 92%. At the very bottom reduction in serum PSA greater than or equal to 50% was achieved in 59% of patients.
This looks at the overall response rates by imaging response criteria. You can see the criteria on the left for RECIST 1.1, adapted PERCIST, adapted PCWG3 and the PPP criteria, and we'll highlight several important findings here. For RECIST 1.1, most commonly with stable disease at 37%; for adapted PERCIST most commonly was partial response at 44%; and for the adapted PCWG3, most commonly was no progressive disease at 67%, which was also the most common for the PPP criteria at 60%.
The next several slides will look at Kaplan-Meier estimates, and this is for overall survival by biochemical response. We can see that in the blue is the median overall survival with PSA50 reached. This was the median that was not reached, and when the PSA50 was not reached in green, the median overall survival was 17 months with a statistically significant P value of less than 0.001.
This looks at overall survival by the adapted PERCIST criteria. In red is meeting OS for partial response and complete response, in green is stable disease, and in blue is progressive disease. We can see here again, an early and a substantial splitting of the Kaplan-Meier curve. The median OS for partial and complete response was not reached, for stable disease was 55 months and for progressive disease was 14 months, which was statistically significant.
This Kaplan-Meier looks at adapted PCWG3 stratified by no progressive disease in blue and progressive disease in green. We can see the median OS for no progressive disease was 57 months compared to 14 months for progressive disease, which was also statistically significant.
Finally, this is the Kaplan-Meier estimate of overall survival for PSMA PET Progression. When we look at no progressive disease on PSMA PET Progression criteria, median OS was 57 months compared to 14 months for progressive disease, which was statistically significant with a P value of less than 0.001.
The next two slides will look at Kaplan-Meier estimates of overall survival stratified by castration status. So at the top of this panel, this is PSA50 response, and we can see that for both metastatic hormone sensitive prostate cancer in the top left as well as metastatic castrate resistant prostate cancer in the top right, this was statistically significant when looking at PSA50 responders versus non-responders.
When we look at the adapted PERCIST for metastatic hormone sensitive prostate cancer in the bottom left as well as for mCRPC in the bottom right, when we stratify this by partial and complete response versus stable disease versus progressive disease for both castrate sensitive and castrate resistant disease, the adapted PERCIST criteria also was statistically significant.
Finally, when we look at the adapted PCWG3 for metastatic hormone-sensitive prostate cancer in the top left and for mCRPC in the top right, when we stratify by no progressive versus progressive disease for both disease states, we see statistical significance for adapted PCWG3.
Finally, for the PSMA PET Progression criteria, again stratified by no progressive disease versus progressive disease, for both metastatic hormone sensitive and metastatic castrate resistant prostate cancer there was statistically significant difference in overall survival with this stratification too.
This is the univariable Cox regression analysis for the association of response criteria with overall survival. You can see the criteria that we've been discussing listed here on the left. What we'll highlight here is the C indices. The lowest C indice was PSA50 with a C-index of 0.695; for adapted PERCIST with 0.746; for the adapted PCWG3 was 0.79 and the highest C-indice for assessing overall survival was the PSMA PET Progression criteria with a C-index of 0.765.
By way of discussion for this study, progressive disease as defined by traditional as well as PSMA PET frameworks was associated with at least a two-point fold increased risk of death. Overall, Kaplan-Meier analysis showed that progressive disease by any investigative criteria was associated with significantly worse overall survival. Both the PSMA PET Progression criteria and adapted PERCIST had the highest comparative prognostic value. However, based on the C-index, the PSMA PET Progression criteria was the framework with the highest prognostic value as compared to the other criteria. While the response assessment using PSMA PET Progression criteria is much more feasible in routine clinical practice, given its simple application, the adapted PERCIST criteria provides the potential not only to discriminate between progressive and non-progressive disease, but also to identify responders within this group with substantially better outcomes compared to those with stable disease.
Of course, with this type of study, there's several key limitations including the small cohort, single center, and retrospective analysis. In conclusion, PSMA PET response criteria have high prognostic utility in men with metastatic prostate cancer undergoing taxane-based chemotherapy. PSMA PET Progression criteria is simple to use, identified most patients with progressive disease and showed the best prognostic utility regarding overall survival. Partial and complete response by adapted PERCIST criteria identifies a subgroup of responders showing better outcomes in patients with partial progressive disease or stable disease. Finally, future studies are warranted to amend the current paradigm relying on mere differentiation of progressive versus non-progressive disease and metastatic prostate cancer and to identify true treatment responders by imaging criteria.
We thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussion of this recently published paper in JNM.
Rashid Sayyid: Hello everyone, this is Rashid Sayyid. I'm a urological oncology fellow at the University of Toronto, and along with Zach Klaassen, Assistant Professor and Program Director at Augusta University, we'll be discussing the latest publication looking at The Prognostic Role of 68Ga-PSMA-11 PET-Based Response in Prostate Cancer Patients Undergoing Taxane-Based Chemotherapy. This article was recently published in The Journal of Nuclear Medicine.
We know that taxane-based chemotherapy remains a standard of care option for both mHSPC and mCRPC patients. However, we currently use the Prostate Cancer Working Group 3 criteria for radiographic assessment of treatment response in the metastatic setting, and this relies on conventional imaging in the form of CT and bone scan. This imaging framework stratifies patients into one of two groups: either those with progressive disease or non-progressive disease. Unfortunately within the non-progressive cohort, we're unable to identify patients as responders versus those with stable disease. We know that PSMA-PET/CT has improved the performance characteristics compared to conventional imaging, and as such, has been recommended as an imaging tool in the biochemically recurrent setting.
We have numerous imaging framework across disease sites, including the RECIST 1.1, which is the framework that relies on cross-sectional imaging. We also have PERCIST, which was introduced for FDG PET-based imaging as opposed to PSMA PET-based imaging. Recently, the PSMA PET Progression criteria was proposed by Dr. Fanti et al. for use in patients with metastatic prostate cancer. So clearly, we have many options and these are evolving based on the emerging imaging techniques.
The use of PSMA-PET/CT for the assessment of treatment response in those with metastatic prostate cancer still remains poorly defined. Furthermore, the data regarding the prognostic utility of PSMA-PET/CT compared to traditional frameworks and imaging techniques remain sparse.
As such, the study objective was to compare the prognostic utility of traditional treatment response criteria, such as RECIST, as we said, conventional imaging and PSA-based response, to more novel frameworks that incorporate PSMA-PET/CT based criteria, such as the PERCIST, which is adapted from the 68Ga-PSMA11 PET; also, the similarly adapted Prostate Cancer Working Group 3 framework; and also the PSMA PET Progression criteria which were proposed by Fanti et al.
So for the purpose of this study, the authors included patients with either mHSPC or mCRPC, all undergoing taxane-based chemotherapy, and all patients had a gallium PSMA PET scan both pre- and post-treatment, meaning within three months prior to the initiation of treatment and within three months of completion of the treatment. All these patients were included between January 2014, December 2018, from the Technical University of Munich.
The response assessment was evaluated using two broad methods. We have the conventional methods, which utilize biochemical response, meaning a PSA decline of at least 50% following chemotherapy, and the RECIST 1.1 framework. Next, we had the subheading of PSMA-PET-based methods, the first being PSMA PET Progression, the Fanti et al. criteria, which was defined as appearance of 2+ new PSMA-positive distant lesions, appearance of at least one new positive lesion plus clinical lab data suggestive of progression, and also increase in the size or the PSMA uptake of at least one lesion of at least 30% plus consistent worsening clinical lab data. Any of these three criteria and the patient had evidence of progression.
Next, the authors utilized the PERCIST 1.0 criteria, which was adapted as follows. For the purposes of this framework, five different organ systems are identified, and within each one up to two lesions with the highest PSMA PET uptake on the pre-chemo PET were singled out. Next, a post-chemo PET was compared to the pre-chemo PET, so we have two scans, and those with complete response were those who have absence of PSMA uptake on the second PET, the post-chemo PET, in all target lesions. A partial response was a decrease in the SUVpeak sum, meaning all them added up at least 30% stable either plus 30% or negative 30% in the SUVpeak. Then the progressive disease includes those patients who had an increase of at least 30%. Then also they use the third framework, which is the adapted Prostate Cancer Working Group 3 criteria. The only difference compared to the conventional one is that a PSMA PET is used instead of bone scan for bone lesions.
The authors use summary measures for summarizing continuous and categorical variables. In keeping with most studies, they use survival analysis using Kaplan-Meier curves, and the log-rank tests were used for between group comparisons. Survival was defined as the time from initiation of chemo until any cause death. The associations between the response assessment frameworks individually and overall survival were analyzed using univariate Cox regression analysis. At this point I'll turn it over to Zach to present the results and the discussion of this study.
Zachary Klaassen: Thanks so much for that great introduction, Rashid. This is the clinical characteristics of the 103 patients that were included in this study. The median age was 71 years. You can see here the pre-chemotherapy PSA level for the mHSPC patients was 15 compared to 45 for the mCRPC patients. You can see also that roughly two-thirds of patients had Gleason score greater than or equal to eight. Roughly three-quarters of the patients had excellent ECOG performance status of zero or one. With regard to breakdown of castration status, 55% were metastatic hormone sensitive and 45% were CRPC. In terms of pre-chemo molecular imaging TNM stage, the most common was M1b at 78% compared to 70% M1a. Looking at pattern of metastatic spread, most commonly was lymph nodes and bones at 52%, and second most common was lymph node only at 21%.
With regards to local treatment for prostate cancer, prostate prostatectomy plus or minus lymphadenectomy in 56% of patients and primary external beam radiotherapy in 13% of patients. For type of prior chemotherapy, docetaxel was the overwhelming most common chemotherapy regimen at 92%. At the very bottom reduction in serum PSA greater than or equal to 50% was achieved in 59% of patients.
This looks at the overall response rates by imaging response criteria. You can see the criteria on the left for RECIST 1.1, adapted PERCIST, adapted PCWG3 and the PPP criteria, and we'll highlight several important findings here. For RECIST 1.1, most commonly with stable disease at 37%; for adapted PERCIST most commonly was partial response at 44%; and for the adapted PCWG3, most commonly was no progressive disease at 67%, which was also the most common for the PPP criteria at 60%.
The next several slides will look at Kaplan-Meier estimates, and this is for overall survival by biochemical response. We can see that in the blue is the median overall survival with PSA50 reached. This was the median that was not reached, and when the PSA50 was not reached in green, the median overall survival was 17 months with a statistically significant P value of less than 0.001.
This looks at overall survival by the adapted PERCIST criteria. In red is meeting OS for partial response and complete response, in green is stable disease, and in blue is progressive disease. We can see here again, an early and a substantial splitting of the Kaplan-Meier curve. The median OS for partial and complete response was not reached, for stable disease was 55 months and for progressive disease was 14 months, which was statistically significant.
This Kaplan-Meier looks at adapted PCWG3 stratified by no progressive disease in blue and progressive disease in green. We can see the median OS for no progressive disease was 57 months compared to 14 months for progressive disease, which was also statistically significant.
Finally, this is the Kaplan-Meier estimate of overall survival for PSMA PET Progression. When we look at no progressive disease on PSMA PET Progression criteria, median OS was 57 months compared to 14 months for progressive disease, which was statistically significant with a P value of less than 0.001.
The next two slides will look at Kaplan-Meier estimates of overall survival stratified by castration status. So at the top of this panel, this is PSA50 response, and we can see that for both metastatic hormone sensitive prostate cancer in the top left as well as metastatic castrate resistant prostate cancer in the top right, this was statistically significant when looking at PSA50 responders versus non-responders.
When we look at the adapted PERCIST for metastatic hormone sensitive prostate cancer in the bottom left as well as for mCRPC in the bottom right, when we stratify this by partial and complete response versus stable disease versus progressive disease for both castrate sensitive and castrate resistant disease, the adapted PERCIST criteria also was statistically significant.
Finally, when we look at the adapted PCWG3 for metastatic hormone-sensitive prostate cancer in the top left and for mCRPC in the top right, when we stratify by no progressive versus progressive disease for both disease states, we see statistical significance for adapted PCWG3.
Finally, for the PSMA PET Progression criteria, again stratified by no progressive disease versus progressive disease, for both metastatic hormone sensitive and metastatic castrate resistant prostate cancer there was statistically significant difference in overall survival with this stratification too.
This is the univariable Cox regression analysis for the association of response criteria with overall survival. You can see the criteria that we've been discussing listed here on the left. What we'll highlight here is the C indices. The lowest C indice was PSA50 with a C-index of 0.695; for adapted PERCIST with 0.746; for the adapted PCWG3 was 0.79 and the highest C-indice for assessing overall survival was the PSMA PET Progression criteria with a C-index of 0.765.
By way of discussion for this study, progressive disease as defined by traditional as well as PSMA PET frameworks was associated with at least a two-point fold increased risk of death. Overall, Kaplan-Meier analysis showed that progressive disease by any investigative criteria was associated with significantly worse overall survival. Both the PSMA PET Progression criteria and adapted PERCIST had the highest comparative prognostic value. However, based on the C-index, the PSMA PET Progression criteria was the framework with the highest prognostic value as compared to the other criteria. While the response assessment using PSMA PET Progression criteria is much more feasible in routine clinical practice, given its simple application, the adapted PERCIST criteria provides the potential not only to discriminate between progressive and non-progressive disease, but also to identify responders within this group with substantially better outcomes compared to those with stable disease.
Of course, with this type of study, there's several key limitations including the small cohort, single center, and retrospective analysis. In conclusion, PSMA PET response criteria have high prognostic utility in men with metastatic prostate cancer undergoing taxane-based chemotherapy. PSMA PET Progression criteria is simple to use, identified most patients with progressive disease and showed the best prognostic utility regarding overall survival. Partial and complete response by adapted PERCIST criteria identifies a subgroup of responders showing better outcomes in patients with partial progressive disease or stable disease. Finally, future studies are warranted to amend the current paradigm relying on mere differentiation of progressive versus non-progressive disease and metastatic prostate cancer and to identify true treatment responders by imaging criteria.
We thank you very much for your attention and we hope you enjoyed this UroToday Journal Club discussion of this recently published paper in JNM.