A Head-to-Head Comparison: 68 Gallium-NODAGA-JR11 and 68 Gallium-DOTATATE PET/CT in Neuroendocrine Tumors, Journal Club - Rashid Sayyid & Zachary Klaassen
August 22, 2023
Rashid Sayyid and Zach Klaassen discuss a head-to-head comparison of 68 Gallium-NODAGA-JR11 and 68 Gallium-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. The study they refer to is a two-center, prospective analysis, which included 48 out of 100 planned patients. The conversation highlights the limited performance characteristics of current somatostatin receptor agonist-based imaging modalities, emphasizing the need for novel methods. The analysis focuses on the improved sensitivity, lesion detection, and image contrast with 68 Gallium-NODAGA-JR11 compared to the classic 68 Gallium-DOTATATE PET, particularly for liver metastases. They conclude that Gallium-NODAGA-JR11 shows better sensitivity and may have a potential impact on the clinical management of a subgroup of patients, illustrating its importance in the field.
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 along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recent publication looking at a head-to-head comparison of 68 Gallium-NODAGA-JR11 and 68 Gallium-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. This analysis of two centers was recently published in the Journal of Nuclear Medicine by Dr. Lin, et al.
So we know that neuroendocrine tumors are a heterogeneous group of neoplasms that arise from endocrine cells and overexpress the somatostatin receptor, which is a G-coupled membrane receptor that serves as a target for molecular imaging and radionuclide therapy. The performance characteristics of current somatostatin receptor agonist-based imaging modalities such as 68 Gallium-DOTATATE remain limited so novel imaging modalities are required in this disease space.
And over the last few decades, somatostatin receptor antagonists have emerged, including JR11, which is a somatostatin receptor two antagonist, and it's been coupled to 68 NODAGA, which we see on the right here. Results from small series suggests that by combining 68 Gallium-NODAGA with JR11, and using that for PET purposes, this may have improved performance characteristics compared to the classic 68 Gallium-DOTATATE PET. Nicholas, et al., demonstrated that this novel NODAGA-JR11 was superior to DOTATATE with regards to sensitivity, lesion detection, and image contrast in patients with low- or intermediate-grade gastroenteropancreatic neuroendocrine tumors.
And as such, the objective of this study was to provide an interim analysis of a prospective two-center study that compares NODAGA-JR11 and DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors.
So this was a prospective, multicenter study across two centers in China, which included patients with histologically proven, metastatic or unresectable, well-differentiated neuroendocrine tumors. It could be grade one or two. Patients could not be on long-acting somatostatin within 28 days of study participation, and both the NODAGA-JR11 and DOTATATE PET were performed within 24 hours of each other with no intervening neuroendocrine tumor-specific treatment. The interim report included 48 of 100 planned patients enrolled between August 2020 and November of 2021.
Just with regards to the logistics of this analysis, the patients received an IV injection of 68 Gallium-DOTATATE on the first day and then they received the NODAGA-JR11 on the second day. All images were performed on a Siemens time-of-flight PET/CT machine. What does time-of-flight PET/CT scan mean? Essentially, it's a higher quality machine that can be used for multiple purposes such as radiation planning, PET, etc. And all are analyzed on a Syngo MultiModality Workplace, again produced by Siemens as well. All the images generated from these scans were reviewed by a board-certified nuclear medicine physician, who were masked to the patients' medical history, and radiopharmaceutical administered. And so when they looked at the images, they recorded the number of lesions, their location, and the uptake, mainly the SUVmax. Unblinding and simultaneous imaging comparison were only permitted after both tests were performed and read, but no changes in the reads were allowed after the unblinding.
The physiologic uptake in normal tissues was recorded and quantified using SUVmax. As many of you may be familiar, this includes the pituitary gland, the lungs, the spleen, the renal cortex, the adrenals, liver, stomach, small intestine, and then the uncinate process of the pancreas. And they also accounted for the fact that these tracers are excreted by the kidneys. And so when they measured in the kidney cortex, they tried to be as far away from the renal pelvis that was draining the tracer. Focal accumulations of the tracer that are not explained by physiologic uptake or benign lesions, for example, bone trauma, hemangioma, and degenerative disease, were considered focal lesions and were correlated with CT findings to ascertain whether these were in fact positive findings.
With regards to the study endpoints and statistical analysis, the sensitivity of 68 NODAGA-JR11 and DOTATATE were compared to the reference standard, which was contrast-enhanced CT or MRI, and this was performed within one year of the PET study. Next, they performed lesion-based sensitivity for each of the NODAGA-JR11 and DOTATATE by calculating it as the percentage of lesions on conventional imaging that are positive for PET uptake. So they looked at the CT or MRIs as reference standard and calculated the number of lesions that were there, and then that serves as the denominator. And looking at the numerator to calculate the lesion-based sensitivity, they looked at the number of lesions that were positive in each of the NODAGA-JR11 PET and then DOTATATE PET as well.
They also performed an alternate calculation of sensitivity by pooling any positive lesion that was detected on any of the three imaging findings. So whether it was on the NODAGA, the DOTATATE, or the CT, any lesion that was positive on any of these modalities served as the denominator as opposed to earlier on, when it was just CT or MRI, and they calculated the sensitivity alternatively using this approach. And then findings of the 68 NODAGA-JR11 would change patients' clinical management if they fulfilled the following criteria that we see on the table. And so the purpose of looking at this is to assess whether using this imaging modality would alter the treatment plan for these patients. So we're looking again at the clinical utility of this new imaging modality.
At this point, I'll turn it over to Zach to go over the results and discussion.
Zach Klaassen: Thanks so much, Rashid. So this first figure looks at a comparison of whole-body maximum-intensity projection of six representative patients. And so the top panel, as you can see on the left, is Gallium-DOTATATE. The bottom panel is Gallium-NODAGA-JR11. And if we focus on DOTATATE for a minute, we see physiological uptake in the pituitary gland, salivary glands, thyroid, adrenal glands, the spleen, and the bowel. Now, we also see this in the bottom panel with Gallium-NODAGA-JR11, but this is much less uptake and minimal compared to the Gallium-DOTATATE scans on the top panel.
This table looks at the comparison of normal-organ SUVmax between Gallium-NODAGA-JR11 and Gallium-DOTATATE PET/CTs. And we can see here, this is the comparison between these two. And for the most part, we see less uptake in the JR11 images, particularly with the spleen, the renal cortex, adrenal glands, pituitary glands, the stomach wall, lung, normal liver, small intestine, pancreas, and bone marrow. So in terms of uptake in normal organs, much less with JR11 compared to DOTATATE.
This figure looks at patient-based comparison of lesion detection. And so the color scheme here is, for blue, it shows that DOTATATE is superior, orange shows that these two imaging modalities are equal, and in gray, it shows that NODAGA-JR11 superior. So if we focus on the two asterisks, these are the ones where JR11 superior, specifically with the number of total lesions as well as liver metastases. With regards to primary tumor bone metastases and lymph node metastases between these two scans, these metrics are essentially equal, as we can see by the broad orange bars in this figure.
This figure looks at a lesion-based comparison of lesion detection. This is a patient with liver metastases. On the left, we have Gallium-DOTATATE. On the right, we have Gallium-NODAGA-JR11. So looking at the DOTATATE images first, particularly on the film here with the circle, we see several liver lesions which are highlighted on the PET/CT. However, with the same patient, with NODAGA-JR11, we see more liver lesions detected as well as higher intensity SUVmax amongst these lesions in the liver compared to the Gallium-DOTATATE PET/CT scan.
This table looks at the uptake of matched lesions on Gallium-NODAGA-JR11 and Gallium-DOTATATE PET/CT scan. The two asterisks actually show the statistically significant difference between these two. So interestingly, for NODAGA-JR11, there's lower bone metastases SUVmax at 8.5 compared to 10.1 for DOTATATE. And with the tumor-to-background ratio for liver metastases, we see higher SUVmax for JR11 at 6.4 compared to 3.1 for DOTATATE. With regards to primary tumor liver metastases, lymph node metastases, and pleural or peritoneal metastases, there was no difference between NODAGA-JR11 and DOTATATE.
With regards to the sensitivity estimation, there were15 patients that had available contrast-enhanced MRI or CT within one year of the study. There were ultimately 180 lesions detected amongst these 15 patients on conventional imaging. 165 were positive on Gallium-NODAGA-JR11 imaging and 139 were positive on Gallium-DOTATATE imaging, so this results in a sensitivity of 91.7% for Gallium-NODAGA-JR11 and 77.2% for Gallium-DOTATATE PET/CT.
This final table looks at the potential impact on clinical management of Gallium-NODAGA-JR11 PET/CT imaging. These are specific patients that had changes in imaging when compared to Gallium-DOTATATE. And ultimately, in 14.5% of patients, Gallium-NODAGA-JR11 PET may have a potential impact on changing clinical management.
So by way of discussion, this study prospectively compared lesion detection ability between Gallium-NODAGA-JR11 and Gallium-DOTATATE in a single group of patients. The results of this study favor Gallium-NODAGA-JR11 because of higher detection ability and better image contrast, specifically for liver metastases.
The potential impact of antagonist PET on clinical management is essential for clinicians to know, but had not been previously reported. And as shown in this study, a subgroup of patients, roughly 14.5%, had more lesions detected on Gallium-NODAGA-JR11, which could have a potential impact on management of these patients. Importantly, as a diagnostic companion for Lutetium-DOTA-JR11, Gallium-NODAGA-JR11 is essential to decide whether patients are eligible for peptide receptor radionuclide therapy with Lutetium-DOTA-JR11. Importantly, the potential impact of Gallium-NODAGA-JR11 on neuroendocrine differentiated prostate cancer remains to be determined.
So in conclusion, Gallium-NODAGA-JR11 shows better sensitivity and a higher target-to-background ratio than Gallium-DOTATATE for metastatic neuroendocrine tumors. Finally, the detection of more lesions by antagonists has a potential impact on clinical management in a subgroup of patients.
We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion.
Rashid Sayyid: Hello, everyone, this is Rashid Sayyid, I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Augusta University, we'll be discussing the recent publication looking at a head-to-head comparison of 68 Gallium-NODAGA-JR11 and 68 Gallium-DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors. This analysis of two centers was recently published in the Journal of Nuclear Medicine by Dr. Lin, et al.
So we know that neuroendocrine tumors are a heterogeneous group of neoplasms that arise from endocrine cells and overexpress the somatostatin receptor, which is a G-coupled membrane receptor that serves as a target for molecular imaging and radionuclide therapy. The performance characteristics of current somatostatin receptor agonist-based imaging modalities such as 68 Gallium-DOTATATE remain limited so novel imaging modalities are required in this disease space.
And over the last few decades, somatostatin receptor antagonists have emerged, including JR11, which is a somatostatin receptor two antagonist, and it's been coupled to 68 NODAGA, which we see on the right here. Results from small series suggests that by combining 68 Gallium-NODAGA with JR11, and using that for PET purposes, this may have improved performance characteristics compared to the classic 68 Gallium-DOTATATE PET. Nicholas, et al., demonstrated that this novel NODAGA-JR11 was superior to DOTATATE with regards to sensitivity, lesion detection, and image contrast in patients with low- or intermediate-grade gastroenteropancreatic neuroendocrine tumors.
And as such, the objective of this study was to provide an interim analysis of a prospective two-center study that compares NODAGA-JR11 and DOTATATE PET/CT in patients with metastatic, well-differentiated neuroendocrine tumors.
So this was a prospective, multicenter study across two centers in China, which included patients with histologically proven, metastatic or unresectable, well-differentiated neuroendocrine tumors. It could be grade one or two. Patients could not be on long-acting somatostatin within 28 days of study participation, and both the NODAGA-JR11 and DOTATATE PET were performed within 24 hours of each other with no intervening neuroendocrine tumor-specific treatment. The interim report included 48 of 100 planned patients enrolled between August 2020 and November of 2021.
Just with regards to the logistics of this analysis, the patients received an IV injection of 68 Gallium-DOTATATE on the first day and then they received the NODAGA-JR11 on the second day. All images were performed on a Siemens time-of-flight PET/CT machine. What does time-of-flight PET/CT scan mean? Essentially, it's a higher quality machine that can be used for multiple purposes such as radiation planning, PET, etc. And all are analyzed on a Syngo MultiModality Workplace, again produced by Siemens as well. All the images generated from these scans were reviewed by a board-certified nuclear medicine physician, who were masked to the patients' medical history, and radiopharmaceutical administered. And so when they looked at the images, they recorded the number of lesions, their location, and the uptake, mainly the SUVmax. Unblinding and simultaneous imaging comparison were only permitted after both tests were performed and read, but no changes in the reads were allowed after the unblinding.
The physiologic uptake in normal tissues was recorded and quantified using SUVmax. As many of you may be familiar, this includes the pituitary gland, the lungs, the spleen, the renal cortex, the adrenals, liver, stomach, small intestine, and then the uncinate process of the pancreas. And they also accounted for the fact that these tracers are excreted by the kidneys. And so when they measured in the kidney cortex, they tried to be as far away from the renal pelvis that was draining the tracer. Focal accumulations of the tracer that are not explained by physiologic uptake or benign lesions, for example, bone trauma, hemangioma, and degenerative disease, were considered focal lesions and were correlated with CT findings to ascertain whether these were in fact positive findings.
With regards to the study endpoints and statistical analysis, the sensitivity of 68 NODAGA-JR11 and DOTATATE were compared to the reference standard, which was contrast-enhanced CT or MRI, and this was performed within one year of the PET study. Next, they performed lesion-based sensitivity for each of the NODAGA-JR11 and DOTATATE by calculating it as the percentage of lesions on conventional imaging that are positive for PET uptake. So they looked at the CT or MRIs as reference standard and calculated the number of lesions that were there, and then that serves as the denominator. And looking at the numerator to calculate the lesion-based sensitivity, they looked at the number of lesions that were positive in each of the NODAGA-JR11 PET and then DOTATATE PET as well.
They also performed an alternate calculation of sensitivity by pooling any positive lesion that was detected on any of the three imaging findings. So whether it was on the NODAGA, the DOTATATE, or the CT, any lesion that was positive on any of these modalities served as the denominator as opposed to earlier on, when it was just CT or MRI, and they calculated the sensitivity alternatively using this approach. And then findings of the 68 NODAGA-JR11 would change patients' clinical management if they fulfilled the following criteria that we see on the table. And so the purpose of looking at this is to assess whether using this imaging modality would alter the treatment plan for these patients. So we're looking again at the clinical utility of this new imaging modality.
At this point, I'll turn it over to Zach to go over the results and discussion.
Zach Klaassen: Thanks so much, Rashid. So this first figure looks at a comparison of whole-body maximum-intensity projection of six representative patients. And so the top panel, as you can see on the left, is Gallium-DOTATATE. The bottom panel is Gallium-NODAGA-JR11. And if we focus on DOTATATE for a minute, we see physiological uptake in the pituitary gland, salivary glands, thyroid, adrenal glands, the spleen, and the bowel. Now, we also see this in the bottom panel with Gallium-NODAGA-JR11, but this is much less uptake and minimal compared to the Gallium-DOTATATE scans on the top panel.
This table looks at the comparison of normal-organ SUVmax between Gallium-NODAGA-JR11 and Gallium-DOTATATE PET/CTs. And we can see here, this is the comparison between these two. And for the most part, we see less uptake in the JR11 images, particularly with the spleen, the renal cortex, adrenal glands, pituitary glands, the stomach wall, lung, normal liver, small intestine, pancreas, and bone marrow. So in terms of uptake in normal organs, much less with JR11 compared to DOTATATE.
This figure looks at patient-based comparison of lesion detection. And so the color scheme here is, for blue, it shows that DOTATATE is superior, orange shows that these two imaging modalities are equal, and in gray, it shows that NODAGA-JR11 superior. So if we focus on the two asterisks, these are the ones where JR11 superior, specifically with the number of total lesions as well as liver metastases. With regards to primary tumor bone metastases and lymph node metastases between these two scans, these metrics are essentially equal, as we can see by the broad orange bars in this figure.
This figure looks at a lesion-based comparison of lesion detection. This is a patient with liver metastases. On the left, we have Gallium-DOTATATE. On the right, we have Gallium-NODAGA-JR11. So looking at the DOTATATE images first, particularly on the film here with the circle, we see several liver lesions which are highlighted on the PET/CT. However, with the same patient, with NODAGA-JR11, we see more liver lesions detected as well as higher intensity SUVmax amongst these lesions in the liver compared to the Gallium-DOTATATE PET/CT scan.
This table looks at the uptake of matched lesions on Gallium-NODAGA-JR11 and Gallium-DOTATATE PET/CT scan. The two asterisks actually show the statistically significant difference between these two. So interestingly, for NODAGA-JR11, there's lower bone metastases SUVmax at 8.5 compared to 10.1 for DOTATATE. And with the tumor-to-background ratio for liver metastases, we see higher SUVmax for JR11 at 6.4 compared to 3.1 for DOTATATE. With regards to primary tumor liver metastases, lymph node metastases, and pleural or peritoneal metastases, there was no difference between NODAGA-JR11 and DOTATATE.
With regards to the sensitivity estimation, there were15 patients that had available contrast-enhanced MRI or CT within one year of the study. There were ultimately 180 lesions detected amongst these 15 patients on conventional imaging. 165 were positive on Gallium-NODAGA-JR11 imaging and 139 were positive on Gallium-DOTATATE imaging, so this results in a sensitivity of 91.7% for Gallium-NODAGA-JR11 and 77.2% for Gallium-DOTATATE PET/CT.
This final table looks at the potential impact on clinical management of Gallium-NODAGA-JR11 PET/CT imaging. These are specific patients that had changes in imaging when compared to Gallium-DOTATATE. And ultimately, in 14.5% of patients, Gallium-NODAGA-JR11 PET may have a potential impact on changing clinical management.
So by way of discussion, this study prospectively compared lesion detection ability between Gallium-NODAGA-JR11 and Gallium-DOTATATE in a single group of patients. The results of this study favor Gallium-NODAGA-JR11 because of higher detection ability and better image contrast, specifically for liver metastases.
The potential impact of antagonist PET on clinical management is essential for clinicians to know, but had not been previously reported. And as shown in this study, a subgroup of patients, roughly 14.5%, had more lesions detected on Gallium-NODAGA-JR11, which could have a potential impact on management of these patients. Importantly, as a diagnostic companion for Lutetium-DOTA-JR11, Gallium-NODAGA-JR11 is essential to decide whether patients are eligible for peptide receptor radionuclide therapy with Lutetium-DOTA-JR11. Importantly, the potential impact of Gallium-NODAGA-JR11 on neuroendocrine differentiated prostate cancer remains to be determined.
So in conclusion, Gallium-NODAGA-JR11 shows better sensitivity and a higher target-to-background ratio than Gallium-DOTATATE for metastatic neuroendocrine tumors. Finally, the detection of more lesions by antagonists has a potential impact on clinical management in a subgroup of patients.
We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion.