Clinical outcomes of ¹⁷⁷lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer—a prospective pilot study in an Asian population

This is the first published article in Southeast Asia regarding the use of 177 lutetium-prostate-specific membrane antigen therapy for prostate cancer treatment. Objective: Metastatic castration-resistant prostate cancers are aggressive tumours with poor prognosis. Prostate-specific membrane antigen-targeted radionuclide therapy is a potential treatment for these patients. Here, we report our initial experience in Singapore. Methods : Twenty men (median age 70) with progressive disease were prospectively recruited. Prostate-specific membrane antigen and fluorodeoxyglucose-PET/computed tomography were performed to confirm high prostate-specific membrane antigen-expression. Up to four cycles of lutetium-prostate-specific membrane antigen-I&T at 6-8 weekly intervals were administered. Patients were restaged 3 months following treatment. Primary endpoints were prostate-specific antigen decline ≥50% and treatment-related toxicity. Additional endpoints included radiological and clinical response as well as progression-free survival and overall survival from first cycle. Results : Sixty-seven cycles were administered (median 4 cycles per patient, mean 6.5 GBq per cycle). Sixty five percent had ≥1 line of prior chemotherapy, 90% abiraterone, enzalutamide or both, and 30% radium-223 radionuclide therapy. All had bone metastases and 35% had visceral metastases. Prostate-specific antigen decline ≥50% was achieved in 50%. Grade 3-4 hematotoxicity was seen in up to 15%. Grade 3-4 non-hematotoxicity was not observed. Eleven patients had restaging scans 3 months post-treatment (5 = partial response, 6 = progressive disease). Fifty-seven percent (4/7) with bone pain had pain improvement. Median progression-free survival was 5.9 months and median overall survival 13.1 months. Patients with prostate-specific antigen decline ≥50% had longer progression-free survival and overall survival. Conclusion : Lutetium-prostate-specific membrane antigen-I&T therapy is effective with tolerable side effects in our local setting. Prostate-specific antigen decline ≥50% is associated with longer progression-free survival and overall survival. Thang SP, Lam WWC, Tong AKT, Allen JC Jr, Ler ASL, Tay YS, Somanesan S, Kanesvaran R, Wong ASC, Ng DCE. Clinical outcomes of 177lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer-a prospective pilot study in an Asian population. Nucl Med Commun . 2020 Jul;41(7):618-628. doi : 10.1097/MNM.0000000000001179. PMID: 32282629. PI : Dr Thang Sue Ping, Email: thang.sue.ping@singhealth.com.sg

11C-Metomidate PET-CT versus adrenal vein sampling to subtype primary aldosteronism: a prospective clinical trial

This clinical trial is the first ever published trial in Asia Pacific regarding the clinical use of a novel tracer to evaluate primary aldosteronism versus standard of care adrenal vein sampling and measure clinical outcomes for surgical cure. This multi-centre trial was led by endocrinologists in collaboration with nuclear medicine physicians from SingHealth and National University Health System. This study was funded by National Medical Research Council (NMRC), Singapore. R.S. Foo was supported by NMRC, Singapore and A∗Star Biomedical Research Council. T.H. Puar was supported by the NMRC Research Training Fellowship award, Singapore. Objective: Adrenal vein sampling (AVS) is recommended to subtype primary aldosteronism, but it is technically challenging. We compared 11C-Metomidate-PET-computed tomography (PET-CT) and AVS for subtyping of primary aldosteronism. Methods: Patients with confirmed primary aldosteronism underwent both AVS and 11C-Metomidate PET-CT (post-dexamethasone). All results were reviewed at a multidisciplinary meeting to decide on final subtype diagnosis. Primary outcome was accuracy of PET versus AVS to diagnosis of unilateral primary aldosteronism based on post-surgical biochemical cure. Secondary outcome was accuracy of both tests to final subtype diagnosis. Results: All 25 patients recruited underwent PET and successful AVS (100%). Final diagnosis was unilateral in 22 patients, bilateral in two and indeterminate in one due to discordant lateralization. Twenty patients with unilateral primary aldosteronism underwent surgery, with 100% complete biochemical success, and 75% complete/partial clinical success. For the primary outcome, sensitivity of PET was 80% [95% confidence interval (95% CI): 56.3-94.3] and AVS was 75% (95% CI: 50.9-91.3). For the secondary outcome, sensitivity and specificity of PET was 81.9% (95% CI: 59.7-94.8) and 100% (95% CI: 15.8-100), and AVS was 68.2% (95% CI: 45.1-86.1) and 100% (95% CI: 15.8-100), respectively. Twelve out of 20 (60%) patients had both PET and AVS lateralization, four (20%) PET-only, three (15%) AVS-only, while one patient did not lateralize on PET or AVS. Post-surgery outcomes did not differ between patients identified by either test. Conclusion: In our pilot study, 11C-Metomidate PET-CT performed comparably to AVS, and this should be validated in larger studies. PET identified patients with unilateral primary aldosteronism missed on AVS, and these tests could be used together to identify more patients with unilateral primary aldosteronism. Puar TH, Khoo CM, Tan CJ, Tong AKT, Tan MCS, Teo AE, Ng KS, Wong KM, Reilhac A, O'Doherty J, Gomez-Sanchez CE, Kek PC, Yee S, Tan AWK, Chuah MB, Lee DHM, Wang KW, Zheng CQ, Shi L, Robins EG, Foo RSY; PA CURE investigators. 11C-Metomidate PET-CT versus adrenal vein sampling to subtype primary aldosteronism : a prospective clinical trial. J Hypertens . 2022 Jun 1;40(6):1179-1188. doi : 10.1097/HJH.0000000000003132. PMID: 35703880.

Iodine Radiolabelled Mesenchymal stem cell (MSC)-Exosomes and their CD73 enzymatic activities

Background: Mesenchymal Stem Cell (MSC)-derived exosomes have shown therapeutic potential in the areas of cardiovascular, orthopaedic, ophthalmologic, immune, dermatologic diseases and radiation sickness. Efficient radioisotope-labelling of exosomes remains as a challenging process. We aim to radiolabel exosomes with iodine-131 using both chloramine-T and Pierce Iodination methods, and characterized I-labelled exosomes via their CD73 enzymatic activities. Co-PI: Dr David Ng Chee Eng, Email: david.ng.c.e@singhealth.com.sg Dr Yang Changtong, Email: yang.changtong@sgh.com.sg

Radiochemical Feasibility of Mixing of 99mTcMAA and Y90-Microspheres with Omnipaque Contrast

Background: Yttrium-90 ( 90 Y) microspheres are widely used for the treatment of liver-dominant malignant tumours. They are infused via catheter into the hepatic artery branches supplying the tumour under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin ( 99m Tc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumour, the 90Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumour. The radiochemical purity of mixing 90Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing 99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing 90Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy. PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg Co-PI: Dr Huang Hian Liang, Email: huang.hian.liang@singhealth.com.sg Link: Yang CT, Ngam PI, Phua VJX, Yu SWK, Apoorva G, Ng DCE, Huang HL. Radiochemical Feasibility of Mixing of 99m Tc-MAA and 90 Y-Microspheres with Omnipaque Contrast. Molecules. 2022 Nov 7;27(21):7646. doi : 10.3390/molecules27217646. PMID: 36364476; PMCID: PMC9656951.

68Ga-Radiolabelled Triphenylphosphonium PET tracer for mitochondrial targeting neuroblastoma imaging

Background: Lipophilic organic cation triphenylphosphonium (TPP) represents a novel mitochondrial targeting molecular probe. A series of its derivatives have been labelled with Cu-64 radioisotope for imaging mitochondrial rich glioma tumours. We aim to develop 68Ga-radiolabeled TPP tracers for rhabdomyosarcoma tumour targeting; and to study the effects of targeting moiety, bifunctional chelator on biodistribution of the tracers. TPP ligands were radiolabelled with 68Ga at high efficiency and isolated in high purity. In vivo biodistribution studies showed uptake of 68Ga tracers to the rhabdomyosarcoma tumours using cell line RHB14-0120 was found with high tumour-to normal tissue ratio. PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg Co-PI: Dr Khor Yiu Ming, Email: khor.yiu.ming@singhealth.com.sg

Radiolabelled anti-disialoganglioside GD2 antibody imaging in human neuroblastoma orthotopic PDX: A theranostic proof of concept

Background: The development of an imaging radiotracer based on Ch.14.18 CHO anti-GD2 antibody and perform preclinical studies, using the SPECT isotope 125 I and PET isotope 124 I. In vitro evaluation performed in immortalized NB cell lines (ATCC) and in patient-derived cell lines followed by ex vivo biodistribution (BioD)/PharmacoKinetics (PK) studies in patient-derived xenograft tumour mice models, coupled with in vivo SPECT/CT, PET/CT Imaging and immunohistochemical (IHC) correlation. PI: Dr Khor Yiu Ming, Email: khor.yiu.ming@singhealth.com.sg Co-PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg Dr Kelvin Loke Siu Hoong, Email: kelvin.loke.s.h@singhealth.com.sg

Biodistribution, Dosimetry and Pharmacokinetic analysis of dynamic 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl] Benzonitrile[18F]FPEB PET In An Asian Population

Background: A PET radioligand targeting the central mGluR5 receptor [18F]FPEB has been used to determine its biodistribution, kinetics and radiation dosimetry in an Asian population as an index of baseline mGluR5 receptor availability. It was found that no discernible ethnic differences in [18F] FPEB whole-body radiation dosimetry, regional cerebral dosimetry and pharmacokinetics between Asian and Western population, suggesting that [18F] FPEB may be suitable for the use across different ethnicities. PI: Dr David Ng Chee Eng, Email: david.ng.c.e@singhealth.com.sg Co-PI : Dr Yang Changtong, Email: yang.changtong@sgh.com.sg X Dr Xie Wanying, Email: xie.wanying@singhealth.com.sg

Highlights-of-Research-Projects | Singapore General Hospital

This is the first published article in Southeast Asia regarding the use of ¹⁷⁷lutetium-prostate-specific membrane antigen therapy for prostate cancer treatment.
Objective: Metastatic castration-resistant prostate cancers are aggressive tumours with poor prognosis. Prostate-specific membrane antigen-targeted radionuclide therapy is a potential treatment for these patients. Here, we report our initial experience in Singapore.
Methods: Twenty men (median age 70) with progressive disease were prospectively recruited. Prostate-specific membrane antigen and fluorodeoxyglucose-PET/computed tomography were performed to confirm high prostate-specific membrane antigen-expression. Up to four cycles of lutetium-prostate-specific membrane antigen-I&T at 6-8 weekly intervals were administered. Patients were restaged 3 months following treatment. Primary endpoints were prostate-specific antigen decline ≥50% and treatment-related toxicity. Additional endpoints included radiological and clinical response as well as progression-free survival and overall survival from first cycle.
Results: Sixty-seven cycles were administered (median 4 cycles per patient, mean 6.5 GBq per cycle). Sixty five percent had ≥1 line of prior chemotherapy, 90% abiraterone, enzalutamide or both, and 30% radium-223 radionuclide therapy. All had bone metastases and 35% had visceral metastases. Prostate-specific antigen decline ≥50% was achieved in 50%. Grade 3-4 hematotoxicity was seen in up to 15%. Grade 3-4 non-hematotoxicity was not observed. Eleven patients had restaging scans 3 months post-treatment (5 = partial response, 6 = progressive disease). Fifty-seven percent (4/7) with bone pain had pain improvement. Median progression-free survival was 5.9 months and median overall survival 13.1 months. Patients with prostate-specific antigen decline ≥50% had longer progression-free survival and overall survival.
Conclusion: Lutetium-prostate-specific membrane antigen-I&T therapy is effective with tolerable side effects in our local setting. Prostate-specific antigen decline ≥50% is associated with longer progression-free survival and overall survival.
Thang SP, Lam WWC, Tong AKT, Allen JC Jr, Ler ASL, Tay YS, Somanesan S, Kanesvaran R, Wong ASC, Ng DCE. Clinical outcomes of 177lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer-a prospective pilot study in an Asian population. Nucl Med Commun . 2020 Jul;41(7):618-628. doi : 10.1097/MNM.0000000000001179. PMID: 32282629.
PI: Dr Thang Sue Ping, Email: thang.sue.ping@singhealth.com.sg

This clinical trial is the first ever published trial in Asia Pacific regarding the clinical use of a novel tracer to evaluate primary aldosteronism versus standard of care adrenal vein sampling and measure clinical outcomes for surgical cure. This multi-centre trial was led by endocrinologists in collaboration with nuclear medicine physicians from SingHealth and National University Health System.
This study was funded by National Medical Research Council (NMRC), Singapore. R.S. Foo was supported by NMRC, Singapore and A∗Star Biomedical Research Council. T.H. Puar was supported by the NMRC Research Training Fellowship award, Singapore.
Objective: Adrenal vein sampling (AVS) is recommended to subtype primary aldosteronism, but it is technically challenging. We compared 11C-Metomidate-PET-computed tomography (PET-CT) and AVS for subtyping of primary aldosteronism.
Methods: Patients with confirmed primary aldosteronism underwent both AVS and 11C-Metomidate PET-CT (post-dexamethasone). All results were reviewed at a multidisciplinary meeting to decide on final subtype diagnosis. Primary outcome was accuracy of PET versus AVS to diagnosis of unilateral primary aldosteronism based on post-surgical biochemical cure. Secondary outcome was accuracy of both tests to final subtype diagnosis.
Results: All 25 patients recruited underwent PET and successful AVS (100%). Final diagnosis was unilateral in 22 patients, bilateral in two and indeterminate in one due to discordant lateralization. Twenty patients with unilateral primary aldosteronism underwent surgery, with 100% complete biochemical success, and 75% complete/partial clinical success. For the primary outcome, sensitivity of PET was 80% [95% confidence interval (95% CI): 56.3-94.3] and AVS was 75% (95% CI: 50.9-91.3). For the secondary outcome, sensitivity and specificity of PET was 81.9% (95% CI: 59.7-94.8) and 100% (95% CI: 15.8-100), and AVS was 68.2% (95% CI: 45.1-86.1) and 100% (95% CI: 15.8-100), respectively. Twelve out of 20 (60%) patients had both PET and AVS lateralization, four (20%) PET-only, three (15%) AVS-only, while one patient did not lateralize on PET or AVS. Post-surgery outcomes did not differ between patients identified by either test.
Conclusion: In our pilot study, 11C-Metomidate PET-CT performed comparably to AVS, and this should be validated in larger studies. PET identified patients with unilateral primary aldosteronism missed on AVS, and these tests could be used together to identify more patients with unilateral primary aldosteronism.
Puar TH, Khoo CM, Tan CJ, Tong AKT, Tan MCS, Teo AE, Ng KS, Wong KM, Reilhac A, O'Doherty J, Gomez-Sanchez CE, Kek PC, Yee S, Tan AWK, Chuah MB, Lee DHM, Wang KW, Zheng CQ, Shi L, Robins EG, Foo RSY; PA CURE investigators. 11C-Metomidate PET-CT versus adrenal vein sampling to subtype primary aldosteronism : a prospective clinical trial. J Hypertens . 2022 Jun 1;40(6):1179-1188. doi : 10.1097/HJH.0000000000003132. PMID: 35703880.

Background: Mesenchymal Stem Cell (MSC)-derived exosomes have shown therapeutic potential in the areas of cardiovascular, orthopaedic, ophthalmologic, immune, dermatologic diseases and radiation sickness. Efficient radioisotope-labelling of exosomes remains as a challenging process. We aim to radiolabel exosomes with iodine-131 using both chloramine-T and Pierce Iodination methods, and characterized I-labelled exosomes via their CD73 enzymatic activities.
Co-PI: Dr David Ng Chee Eng, Email: david.ng.c.e@singhealth.com.sg
Dr Yang Changtong, Email: yang.changtong@sgh.com.sg

Background: Yttrium-90 (⁹⁰Y) microspheres are widely used for the treatment of liver-dominant malignant tumours. They are infused via catheter into the hepatic artery branches supplying the tumour under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (^99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumour, the 90Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumour. The radiochemical purity of mixing 90Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing 99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing 90Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.
PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg
Co-PI: Dr Huang Hian Liang, Email: huang.hian.liang@singhealth.com.sg
Link: Yang CT, Ngam PI, Phua VJX, Yu SWK, Apoorva G, Ng DCE, Huang HL. Radiochemical Feasibility of Mixing of 99m Tc-MAA and 90 Y-Microspheres with Omnipaque Contrast. Molecules. 2022 Nov 7;27(21):7646. doi : 10.3390/molecules27217646. PMID: 36364476; PMCID: PMC9656951.

Background: Lipophilic organic cation triphenylphosphonium (TPP) represents a novel mitochondrial targeting molecular probe. A series of its derivatives have been labelled with Cu-64 radioisotope for imaging mitochondrial rich glioma tumours. We aim to develop 68Ga-radiolabeled TPP tracers for rhabdomyosarcoma tumour targeting; and to study the effects of targeting moiety, bifunctional chelator on biodistribution of the tracers. TPP ligands were radiolabelled with 68Ga at high efficiency and isolated in high purity. In vivo biodistribution studies showed uptake of 68Ga tracers to the rhabdomyosarcoma tumours using cell line RHB14-0120 was found with high tumour-to normal tissue ratio.
PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg
Co-PI: Dr Khor Yiu Ming, Email: khor.yiu.ming@singhealth.com.sg

Background: The development of an imaging radiotracer based on Ch.14.18 CHO anti-GD2 antibody and perform preclinical studies, using the SPECT isotope ¹²⁵I and PET isotope ¹²⁴I. In vitro evaluation performed in immortalized NB cell lines (ATCC) and in patient-derived cell lines followed by ex vivo biodistribution (BioD)/PharmacoKinetics (PK) studies in patient-derived xenograft tumour mice models, coupled with in vivo SPECT/CT, PET/CT Imaging and immunohistochemical (IHC) correlation.
PI: Dr Khor Yiu Ming, Email: khor.yiu.ming@singhealth.com.sg
Co-PI: Dr Yang Changtong, Email: yang.changtong@sgh.com.sg
Dr Kelvin Loke Siu Hoong, Email: kelvin.loke.s.h@singhealth.com.sg

Background: A PET radioligand targeting the central mGluR5 receptor [18F]FPEB has been used to determine its biodistribution, kinetics and radiation dosimetry in an Asian population as an index of baseline mGluR5 receptor availability. It was found that no discernible ethnic differences in [18F] FPEB whole-body radiation dosimetry, regional cerebral dosimetry and pharmacokinetics between Asian and Western population, suggesting that [18F] FPEB may be suitable for the use across different ethnicities.
PI: Dr David Ng Chee Eng, Email: david.ng.c.e@singhealth.com.sg
Co-PI: Dr Yang Changtong, Email:
yang.changtong@sgh.com.sg

X Dr Xie Wanying, Email: xie.wanying@singhealth.com.sg

Highlights of Research Projects

List of Research Highlights