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Wu R, Zhu W, Shao F, Wang J, Li D, Tuo Z, Yoo KH, Wusiman D, Shu Z, Ge W, Yang Y, Ke M, Wei W, Heavey S, Cho WC, Feng D. Expanding horizons in theragnostics: from oncology to multidisciplinary applications. LA RADIOLOGIA MEDICA 2025; 130:613-628. [PMID: 40042756 DOI: 10.1007/s11547-025-01971-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 02/05/2025] [Indexed: 03/17/2025]
Abstract
Theragnostics is the integration of treatment and diagnosis, involving a drug or technology that combines diagnostic imaging with targeted therapy. This approach utilizes imaging to identify specific biological targets, which are then used to deliver therapeutic effects for the benefit of patients. The effectiveness and potential of theragnostics in improving patient outcomes are supported by significant clinical trials and technological innovations. Theragnostics has demonstrated its capacity to deliver targeted and real-time interventions, making it adaptable to diverse clinical domains. Its applications range from visualizing and eradicating tumors to addressing complex neurological disorders and cardiovascular diseases. The integration of nanomaterials and advancements in molecular biology further enhance the capabilities of theragnostics, promising a future where treatments are highly personalized, and diseases are understood and managed at a molecular level previously unattainable. Our comprehensive overview focuses on the current advancements in theragnostics applications across different disease domains. We highlight the role of molecular imaging technologies, such as PET/CT scans, in early diagnosis and treatment. Additionally, we explore the potential of chemokines as molecular imaging targets in systemic inflammatory diseases and central nervous system pathologies. In conclusion, the progression of theragnostics represents a transformative phase in medical practice, providing new avenues for precise treatment and improved patient outcomes. Its multidisciplinary nature and continuous innovation have the potential to profoundly impact the future of medical research and clinical practice, as well as revolutionizing the treatment and management of a wide array of diseases.
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Affiliation(s)
- Ruicheng Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Weizhen Zhu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fanglin Shao
- Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People's Republic of China
| | - Jie Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Dengxiong Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhouting Tuo
- Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Koo Han Yoo
- Department of Urology, Kyung Hee University, Seoul, South Korea
| | - Dilinaer Wusiman
- Department of Comparative Pathobiology, College of Veterinary Medicine, West Lafayette, USA
- Purdue Institute for Cancer Research, Purdue University, Westlll Lafayette, IN, USA
| | - Ziyu Shu
- Department of Earth Science and Engineering, Imperial College London, London, SW7 2AZ, UK
| | - Wenjing Ge
- Department of Clinical Neurosciences, University of Cambridge, R3, Box 83, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Yubo Yang
- Department of Urology, Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, 404000, China
| | - Mang Ke
- Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China
| | - Wuran Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Susan Heavey
- Division of Surgery & Interventional Science, University College London, London, W1W 7TS, UK.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.
| | - Dechao Feng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, China.
- Division of Surgery & Interventional Science, University College London, London, W1W 7TS, UK.
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Hallqvist A, Brynjarsdóttir E, Krantz T, Sjögren M, Svensson J, Bernhardt P. 177Lu-DOTATATE in Combination with PARP Inhibitor Olaparib Is Feasible in Patients with Somatostatin-Positive Tumors: Results from the LuPARP Phase I Trial. J Nucl Med 2025; 66:707-712. [PMID: 40015919 DOI: 10.2967/jnumed.124.268902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/06/2025] [Indexed: 03/01/2025] Open
Abstract
This phase I trial aimed to assess the feasibility and toxicity of combining the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib with 177Lu-DOTATATE in patients with somatostatin receptor-positive tumors, with the goal of enhancing treatment efficacy through the inhibition of tumor cell DNA repair mechanisms. Methods: Eighteen patients were enrolled, mostly with pancreatic or small intestinal neuroendocrine tumors or atypical lung carcinoids. Patients received a standard dose of 177Lu-DOTATATE (7,400 MBq) for up to 4 cycles, combined with escalating doses of olaparib (50-300 mg twice a day [BID]). The primary objective was to evaluate toxicity using National Cancer Institute Common Toxicity Criteria version 5.0. Secondary objectives included time to progression, overall survival, response rate, and dosimetry variables. Results: The combination of olaparib and 177Lu-DOTATATE was generally well tolerated. Five patients did not complete the 4 cycles because of progression, noncompliance, and carcinoid crisis after the first 177Lu-DOTATATE infusion. Among the remaining patients, thrombocytopenia was the primary dose-limiting toxicity, observed in 3 patients at the 300-mg dose level. Other toxicities were mild, predominantly low-grade bone marrow suppression, nausea, and fatigue. Conclusion: This study demonstrates that combining olaparib with 177Lu-DOTATATE is feasible, with toxicity primarily related to thrombocytopenia. On the basis of the findings, we recommend a starting dose of 200 mg BID for future studies, with the potential to escalate to 300 mg BID depending on patient tolerance. Further investigation in larger, randomized trials is warranted to assess the clinical efficacy of this combination and optimize dosing strategies.
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Affiliation(s)
- Andreas Hallqvist
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden;
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Elva Brynjarsdóttir
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Tomas Krantz
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marie Sjögren
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Johanna Svensson
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Peter Bernhardt
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden; and
- Department of Medical Physics and Medical Bioengineering, Sahlgrenska University Hospital, Gothenburg, Sweden
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Speicher T, Burgard C, Rosar F, Bastian M, Bartholomä M, Maus S, Ezziddin S. Superior Response of CAP-PRRT of G3 NET When Switching to the Somatostatin Receptor Antagonist LM3: Intraindividual Proof-of-concept. Clin Nucl Med 2025:00003072-990000000-01689. [PMID: 40302124 DOI: 10.1097/rlu.0000000000005938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/27/2025] [Indexed: 05/01/2025]
Abstract
We present a 67-year-old man with inoperable metastatic G3 NET of the pancreas. The lesions were intensely positive in [68Ga]Ga-DOTATOC PET/CT and only weakly positive in the supplementary [18F]-FDG PET/CT. Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate, after longstanding efficacy with repetitive retreatments over 7 years, eventually resulted only in disease stabilization without partial regression of lesions. After switching PRRT to the somatostatin receptor antagonist [177Lu]Lu-DOTA-LM3, a marked therapy response was observed, in remarkable contrast to the stable disease effect of 177Lu-octreotate seen right before. This interesting image illustrates the superior therapeutic efficacy of somatostatin antagonist PRRT over agonist-based PRRT.
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Affiliation(s)
- Tilman Speicher
- Department of Nuclear Medicine, Saarland University, Homburg, Germany
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Tuncel M, Kaya G, Kodaz O, Türkan C, Tuncalı MÇ. The Randomized, Phase 2 Trial LuCAP Study. J Nucl Med 2025:jnumed.125.269549. [PMID: 40274372 DOI: 10.2967/jnumed.125.269549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 04/26/2025] Open
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Puranik AD, Dev ID, Prasad V. Frontiers in radiopharmaceuticals for neuroendocrine tumors. J Neuroendocrinol 2025; 37:e70006. [PMID: 39961670 DOI: 10.1111/jne.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 03/20/2025]
Abstract
Neuroendocrine tumors encompass a wide range of tumors which originate from neural crest cells. These tumors were thought to be rare tumors, however, with the advent of advanced diagnostic techniques along with better understanding of the clinical presentation and histology of these tumors, the incidence of these tumors is exponentially rising. As the incidence and detection rate of NENs increased, the concept of 'heterogeneity' came into picture, which in turn led to dual-tracer imaging with addition of FDG PET/CT. Despite an imaging-based decision-making approach for NENs, there is still a significant subset of patients where the imaging-based biomarkers fall short in disease assessment, prognostication and improving outcomes. Alternate pathways as well as better peptide vectors for targeting the somatostatin receptor need to be studied. In this article, we address the existing as well as emerging trends in radiopharmaceuticals used for NENs, which are likely to impact not just the diagnostic algorithms in future, but also management strategies.
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Affiliation(s)
- Ameya D Puranik
- Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Indraja D Dev
- Department of Nuclear Medicine and Molecular Imaging, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Vikas Prasad
- Mallinckrodt Institute of Radiology, Washington University in Saint Louis, Saint Louis, Missouri, USA
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Satapathy S, Aggarwal P, Sood A, Chandekar KR, Das CK, Gupta R, Khosla D, Das N, Kapoor R, Kumar R, Singh H, Shukla J, Kumar A, Mittal BR. 177Lu-DOTATATE Plus Capecitabine Versus 177Lu-DOTATATE Alone in Patients with Advanced Grade 1/2 Gastroenteropancreatic Neuroendocrine Tumors (LuCAP): A Randomized, Phase 2 Trial. J Nucl Med 2025; 66:238-244. [PMID: 39778968 DOI: 10.2967/jnumed.124.268617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
177Lu-DOTATATE has emerged as a viable treatment strategy for advanced well-differentiated grade 1/2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Few retrospective studies have shown concomitant 177Lu-DOTATATE with radiosensitizing low-dose capecitabine to be effective in advanced NETs. However, this has not been validated in prospective randomized-controlled trials. Methods: In this investigator-initiated, parallel-group, open-label, phase 2 trial, patients with grade 1/2 GEP-NETs, having progressive somatostatin receptor-positive, locally advanced, or metastatic disease on 68Ga-DOTANOC PET/CT, were randomly assigned in a 1:1 ratio to 177Lu-DOTATATE plus capecitabine (experimental arm) or 177Lu-DOTATATE only (control arm). 177Lu-DOTATATE was administered at approximately 7.4 GBq/cycle intravenously, for up to 4 cycles, at 8 wk intervals, whereas capecitabine was given at 1,250 mg/m2/d orally from day 0 to day 14 of each cycle of 177Lu-DOTATATE. The primary endpoint was the objective response rate. Secondary endpoints included the disease control rate, progression-free survival, overall survival, and adverse events. Results: Seventy-two patients (median age, 53 y; range, 18-79 y) were enrolled. The objective response rate was 33.3% (95% CI, 18.6-50.9%) in the experimental arm versus 30.6% (95% CI, 16.4-48.1%) in the control arm (P = 0.800). The disease control rate was 88.9% (95% CI, 73.9-96.9%) and 91.7% (95% CI, 77.5-98.2%) in the experimental and control arms, respectively (P = 1.000). The estimated median progression-free survival in the experimental arm was 29 mo (95% CI, 22-29 mo) versus 31 mo (95% CI, 29-32 mo) in the control arm (P = 0.401). The median overall survival was not reached in either arm (P = 0.876). Overall, adverse events of at least grade 3 were noted in 7 patients in the experimental arm versus 6 patients in the control arm (P = 0.759). Conclusion: Based on the results of this trial, the addition of low-dose capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs did not lead to superior radiographic responses. Further studies are needed to evaluate its potential role in high-grade NETs.
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Affiliation(s)
- Swayamjeet Satapathy
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Piyush Aggarwal
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India;
| | - Kunal R Chandekar
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Chandan K Das
- Department of Clinical Haematology and Medical Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
- Montefiore Medical Center, Bronx, New York
| | - Rajesh Gupta
- Department of GI Surgery, HPB and Liver Transplantation, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Divya Khosla
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India; and
| | - Namrata Das
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India; and
- Proton International London Ltd., University College London Hospitals, London, United Kingdom
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India; and
| | - Rajender Kumar
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Harmandeep Singh
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaya Shukla
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Kumar
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Bhagwant Rai Mittal
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Zhang B, Xue L, Wu ZB. Structure and Function of Somatostatin and Its Receptors in Endocrinology. Endocr Rev 2025; 46:26-42. [PMID: 39116368 DOI: 10.1210/endrev/bnae022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 07/16/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024]
Abstract
Somatostatin analogs, such as octreotide, lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors. Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy combined with the protein structure prediction platform AlphaFold has been used to determine the 3-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the 3-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.
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Affiliation(s)
- Bo Zhang
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Xue
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhe Bao Wu
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325005, China
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Saldarriaga Vargas C, Andersson M, Bouvier-Capely C, Li WB, Madas B, Covens P, Struelens L, Strigari L. Heterogeneity of absorbed dose distribution in kidney tissues and dose-response modelling of nephrotoxicity in radiopharmaceutical therapy with beta-particle emitters: A review. Z Med Phys 2024; 34:491-509. [PMID: 37031068 PMCID: PMC11624361 DOI: 10.1016/j.zemedi.2023.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/20/2023] [Accepted: 02/27/2023] [Indexed: 04/08/2023]
Abstract
Absorbed dose heterogeneity in kidney tissues is an important issue in radiopharmaceutical therapy. The effect of absorbed dose heterogeneity in nephrotoxicity is, however, not fully understood yet, which hampers the implementation of treatment optimization by obscuring the interpretation of clinical response data and the selection of optimal treatment options. Although some dosimetry methods have been developed for kidney dosimetry to the level of microscopic renal substructures, the clinical assessment of the microscopic distribution of radiopharmaceuticals in kidney tissues currently remains a challenge. This restricts the anatomical resolution of clinical dosimetry, which hinders a thorough clinical investigation of the impact of absorbed dose heterogeneity. The potential of absorbed dose-response modelling to support individual treatment optimization in radiopharmaceutical therapy is recognized and gaining attraction. However, biophysical modelling is currently underexplored for the kidney, where particular modelling challenges arise from the convolution of a complex functional organization of renal tissues with the function-mediated dose distribution of radiopharmaceuticals. This article reviews and discusses the heterogeneity of absorbed dose distribution in kidney tissues and the absorbed dose-response modelling of nephrotoxicity in radiopharmaceutical therapy. The review focuses mainly on the peptide receptor radionuclide therapy with beta-particle emitting somatostatin analogues, for which the scientific literature reflects over two decades of clinical experience. Additionally, detailed research perspectives are proposed to address various identified challenges to progress in this field.
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Affiliation(s)
- Clarita Saldarriaga Vargas
- Radiation Protection Dosimetry and Calibrations, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium.
| | - Michelle Andersson
- Radiation Protection Dosimetry and Calibrations, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; Medical Physics Department, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Céline Bouvier-Capely
- Institut de Radioprotection et Sûreté Nucléaire (IRSN), PSE-SANTE/SESANE/LRSI, Fontenay-aux-Roses, France
| | - Wei Bo Li
- Institute of Radiation Medicine, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Balázs Madas
- Environmental Physics Department, Centre for Energy Research, Budapest, Hungary
| | - Peter Covens
- In Vivo Cellular and Molecular Imaging Laboratory, Vrije Universiteit Brussel, Brussels, Belgium
| | - Lara Struelens
- Radiation Protection Dosimetry and Calibrations, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Lidia Strigari
- Department of Medical Physics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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9
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Mallak N, Yilmaz B, Meyer C, Winters C, Mench A, Jha AK, Prasad V, Mittra E. Theranostics in Neuroendocrine Tumors: Updates and Emerging Technologies. Curr Probl Cancer 2024; 52:101129. [PMID: 39232443 DOI: 10.1016/j.currproblcancer.2024.101129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 05/22/2024] [Indexed: 09/06/2024]
Abstract
Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.
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Affiliation(s)
- Nadine Mallak
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Burcak Yilmaz
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Catherine Meyer
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Celeste Winters
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Anna Mench
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Abhinav K Jha
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA; Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, US
| | - Vikas Prasad
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, US
| | - Erik Mittra
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA.
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Jewell K, Kostos L, Emmerson B, Hofman MS. Combination Strategies and Targeted Radionuclide Therapies. Semin Nucl Med 2024; 54:612-621. [PMID: 38897821 DOI: 10.1053/j.semnuclmed.2024.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
Combination models utilising treatments from two or more therapeutic classes are well established in cancer care. In the new era of theranostic (theragnostic) medicine there is an ongoing need to identify and refine novel combination strategies to optimise multidisciplinary care for conditions commonly encountered in nuclear medicine such as neuroendocrine neoplasms (NEN), prostate cancer (PCa), and thyroid cancer, along with seeking advancements in molecular imaging and therapy techniques for other tumour streams. This concise review explores the background of theranostic monotherapy, established approaches to combination strategies in theranostics, and emerging targeted radionuclide therapies in use or under active investigation, with a focus on Australian-led studies.
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Affiliation(s)
- Kerry Jewell
- Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, VIC; Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC
| | - Louise Kostos
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC
| | - Brittany Emmerson
- Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, VIC; Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC
| | - Michael S Hofman
- Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, VIC; Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC.
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11
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Santo G, Di Santo G, Virgolini I. Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: Agonist, Antagonist and Alternatives. Semin Nucl Med 2024; 54:557-569. [PMID: 38490913 DOI: 10.1053/j.semnuclmed.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/14/2024] [Accepted: 02/14/2024] [Indexed: 03/17/2024]
Abstract
Peptide receptor radionuclide therapy (PRRT) today is a well-established treatment strategy for patients with neuroendocrine tumors (NET). First performed already more than 30 years ago, PRRT was incorporated only in recent years into the major oncology guidelines, based on its proven efficacy and safety in clinical trials. Following the phase 3 NETTER-1 trial, which led to the final registration of the radiopharmaceutical Luthatera® for G1/G2 NET patients in 2017, the long-term results of the phase 3 NETTER-2 trial may pave the way for a new treatment option also for advanced G2/G3 patients as first-line therapy. The growing knowledge about the synergistic effect of combined therapies could also allow alternative (re)treatment options for NET patients, in order to create a tailored treatment strategy. The evolving thera(g)nostic concept could be applied for the identification of patients who might benefit from different image-guided treatment strategies. In this scenario, the use of dual tracer PET/CT in NET patients, using both [18F]F-FDG/[68Ga]Ga-DOTA-somatostatin analog (SSA) for diagnosis and follow-up, is under discussion and could also result in a powerful prognostic tool. In addition, alternative strategies based on different metabolic pathways, radioisotopes, or combinations of different medical approaches could be applied. A number of different promising "doors" could thus open in the near future for the treatment of NET patients - and the "key" will be thera(g)nostic!
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Affiliation(s)
- Giulia Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria; Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Gianpaolo Di Santo
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Irene Virgolini
- Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria.
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Bodei L, Jayaprakasam VS, Ying Wong BZ, Aparici CM. Neuroendocrine Tumors: Beta Labeled Radiopeptides. PET Clin 2024; 19:e1-e11. [PMID: 40199623 DOI: 10.1016/j.cpet.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Peptide receptor radionuclide therapy (PRRT) consists of administrating a radiolabeled octreotide derivative that targets somatostatin receptors present on the cell membrane of neuroendocrine tumor cells. Although PRRT was initially performed with 90Y-peptides, currently 177Lu-peptides represent the predominant form of treatment. PRRT results in significant tumor and symptomatic control in patients. Like with other available systemic therapies, responses are relatively short-lived. Several new peptides and strategies to improve the efficacy and tolerability of PRRT have been proposed. A critical step is individualizing treatments based on specific dosimetric estimates for the tumor and normal organs, and determining tissue radiosensitivity.
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Affiliation(s)
- Lisa Bodei
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
| | - Vetri Sudar Jayaprakasam
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Weill Cornell Medical College of Cornell University, New York, NY, USA
| | | | - Carina Mari Aparici
- Division of Nuclear Medicine, Department of Radiology, University of Stanford, Stanford, CA, USA
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13
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Turner JH. Theranostic Innovation by Humane N-of-One Cancer Care in Real-World Patients. Cancer Biother Radiopharm 2024; 39:323-329. [PMID: 38324047 DOI: 10.1089/cbr.2023.0198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024] Open
Abstract
Patients with relapsed or refractory metastatic cancer unresponsive to standard therapies have motivated nuclear physicians to develop innovative radioligands, precisely targeted to tumor molecular receptors, for effective treatment of specific advanced malignancies. Individual practitioners in departments of nuclear medicine across the world have performed first-in-human studies on compassionate patient usage N-of-One protocols. These physician-sponsored studies then evolved into early-phase clinical trials and obtained real-world data to demonstrate real-world evidence of effectiveness in prolonging survival and enhancing quality of life of many so-called "End-Stage" cancer patients. Virtually all the therapeutic radiopharmaceuticals in current clinical oncology have been discovered and developed into effective specific treatments of targetable cancers by individual doctors in the course of their hospital practice. Pharma industry was not involved until many years later when performance of mandated Phase 3 randomized controlled trials became necessary to achieve regulatory agency approval. This article traces the history of several novel theranostic agents developed from compassionate N-of-One studies by hospital physicians over the past 36 years. It acknowledges the collegiality and collaboration of individual nuclear medicine specialists, worldwide, in pioneering effective humane therapy of particular advanced cancers unresponsive to conventional treatments.
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Affiliation(s)
- J Harvey Turner
- Department of Nuclear Medicine, The University of Western Australia, Fiona Stanley Fremantle Hospitals Group, Murdoch, Australia
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14
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Di Franco M, Zanoni L, Fortunati E, Fanti S, Ambrosini V. Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update. Curr Oncol Rep 2024; 26:538-550. [PMID: 38581469 PMCID: PMC11063107 DOI: 10.1007/s11912-024-01526-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 04/08/2024]
Abstract
PURPOSE OF REVIEW This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). RECENT FINDINGS Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.
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Affiliation(s)
- Martina Di Franco
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
| | - Lucia Zanoni
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Emilia Fortunati
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Fanti
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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15
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Tham WY, Huang HL, Tai DWM, Allen JC, Hwang JSG, Loh LM, Goh BKP, Ong SYK, Kek PC, Tan DMY, Ng DCE, Loke KSH. Treatment and Long-Term Safety Outcomes of Peptide Receptor Radionuclide Therapy for Metastatic Neuroendocrine Tumours: An Asian Experience. Neuroendocrinology 2024; 114:840-847. [PMID: 38531329 DOI: 10.1159/000538523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 03/14/2024] [Indexed: 03/28/2024]
Abstract
PURPOSE Peptide receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NETs). It has been shown to be effective and well tolerated in patients with metastatic NETs in several centres in the USA, Europe, and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. METHODS One hundred and seven (107) patients with metastatic NETs who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST 1.1 and qualitative analysis were examined. The overall and progression-free survival curves were also evaluated. RESULTS The median progression-free survival was 49 months. Response assessment after completion of treatment showed that 33 (37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression-free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. CONCLUSION Our results show that PRRT is safe and effective in the treatment of metastatic NET in the Asian population. There was a significant difference in the progression-free survival curves between low-grade and high-grade NET and in the progression-free and overall survival comparing the number of cycles received.
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Affiliation(s)
- Wei Ying Tham
- Singapore General Hospital, Department of Nuclear Medicine and Molecular Imaging, Singapore, Singapore
| | - Hian Liang Huang
- Singapore General Hospital, Department of Nuclear Medicine and Molecular Imaging, Singapore, Singapore
| | - David Wai Meng Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - John C Allen
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | | | - Lih Ming Loh
- Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre Singapore, Singapore, Singapore
- Surgery Academic Clinical Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Simon Y K Ong
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Peng Chin Kek
- Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
| | - Damien M Y Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - David C E Ng
- Singapore General Hospital, Department of Nuclear Medicine and Molecular Imaging, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Kelvin S H Loke
- Singapore General Hospital, Department of Nuclear Medicine and Molecular Imaging, Singapore, Singapore
- Duke-NUS Graduate Medical School, Singapore, Singapore
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16
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AghaAmiri S, Ghosh SC, Hernandez Vargas S, Halperin DM, Azhdarinia A. Somatostatin Receptor Subtype-2 Targeting System for Specific Delivery of Temozolomide. J Med Chem 2024; 67:2425-2437. [PMID: 38346097 PMCID: PMC10896214 DOI: 10.1021/acs.jmedchem.3c00223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 12/04/2023] [Accepted: 12/12/2023] [Indexed: 02/23/2024]
Abstract
Temozolomide (TMZ) is a DNA alkylating agent that produces objective responses in patients with neuroendocrine tumors (NETs) when the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is inactivated. At high doses, TMZ therapy exhausts MGMT activity but also produces dose-limiting toxicities. To reduce off-target effects, we converted the clinically approved radiotracer 68Ga-DOTA-TOC into a peptide-drug conjugate (PDC) for targeted delivery of TMZ to somatostatin receptor subtype-2 (SSTR2)-positive tumor cells. We used an integrated radiolabeling strategy for direct quantitative assessment of receptor binding, pharmacokinetics, and tissue biodistribution. In vitro studies revealed selective binding to SSTR2-positive cells with high affinity (5.98 ± 0.96 nmol/L), internalization, receptor-dependent DNA damage, cytotoxicity, and MGMT depletion. Imaging and biodistribution analysis showed preferential accumulation of the PDC in receptor-positive tumors and high renal clearance. This study identified a trackable SSTR2-targeting system for TMZ delivery and utilizes a modular design that could be broadly applied in PDC development.
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Affiliation(s)
- Solmaz AghaAmiri
- The
Brown Foundation Institute of Molecular Medicine, McGovern Medical
School, The University of Texas Health Science
Center at Houston, 1881 East Road, 3SCR6.4680, Houston, Texas 77054, United States
| | - Sukhen C. Ghosh
- The
Brown Foundation Institute of Molecular Medicine, McGovern Medical
School, The University of Texas Health Science
Center at Houston, 1881 East Road, 3SCR6.4680, Houston, Texas 77054, United States
| | - Servando Hernandez Vargas
- The
Brown Foundation Institute of Molecular Medicine, McGovern Medical
School, The University of Texas Health Science
Center at Houston, 1881 East Road, 3SCR6.4680, Houston, Texas 77054, United States
| | - Daniel M. Halperin
- Department
of Gastrointestinal Medical Oncology, The
University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Ali Azhdarinia
- The
Brown Foundation Institute of Molecular Medicine, McGovern Medical
School, The University of Texas Health Science
Center at Houston, 1881 East Road, 3SCR6.4680, Houston, Texas 77054, United States
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17
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Taherifard E, Bakhtiar M, Mahnoor M, Ahmed R, Cavalcante L, Zhang J, Saeed A. Efficacy and safety of temozolomide-based regimens in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis. BMC Cancer 2024; 24:192. [PMID: 38347461 PMCID: PMC10860315 DOI: 10.1186/s12885-024-11926-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/27/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND Recent advances in the management of pancreatic neuroendocrine tumors (pNETs) highlight the potential benefits of temozolomide, an alkylating agent, for these patients. In this meta-analysis, we aimed to assess the outcome of temozolomide, alone or in combination with other anticancer medications in patients with advanced pNET. METHODS Online databases of PubMed, Web of Science, Embase, the Cochrane Library, and ClinicalTrials.gov were searched systematically for clinical trials that reported the efficacy and safety of temozolomide in patients with advanced pNET. Random-effect model was utilized to estimate pooled rates of outcomes based on Response Evaluation Criteria in Solid Tumors criteria, biochemical response, and adverse events (AEs). RESULTS A total of 14 studies, providing details of 441 individuals with advanced pNET, were included. The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control rate (DCR) of 85.3% (95% CI of 74.9%-91.9%), and a more than 50% decrease from baseline chromogranin A levels of 44.9% (95% CI of 31.6%-49.0%). Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% CI of 12.0%-41.5%), respectively. The main severe AEs encompassed hematological toxicities. CONCLUSIONS In conclusion, our meta-analysis suggests that treatment with temozolomide, either as a monotherapy or in combination with other anticancer treatments might be an effective and relatively safe option for patients with advanced locally unresectable and metastatic pNET. However, additional clinical trials are required to further strengthen these findings. This study has been registered in PROSPERO (CRD42023409280).
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Affiliation(s)
- Erfan Taherifard
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Muhammad Bakhtiar
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Mahnoor Mahnoor
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Rabeea Ahmed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Janie Zhang
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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18
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Tolboom N, Verger A, Albert NL, Fraioli F, Guedj E, Traub-Weidinger T, Morbelli S, Herrmann K, Zucchetta P, Plasschaert SLA, Yakushev I, Weller M, Glas M, Preusser M, Cecchin D, Barthel H, Van Weehaeghe D. Theranostics in Neurooncology: Heading Toward New Horizons. J Nucl Med 2024; 65:167-173. [PMID: 38071569 DOI: 10.2967/jnumed.123.266205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/23/2023] [Indexed: 02/03/2024] Open
Abstract
Therapeutic approaches to brain tumors remain a challenge, with considerable limitations regarding delivery of drugs. There has been renewed and increasing interest in translating the popular theranostic approach well known from prostate and neuroendocrine cancer to neurooncology. Although far from perfect, some of these approaches show encouraging preliminary results, such as for meningioma and leptomeningeal spread of certain pediatric brain tumors. In brain metastases and gliomas, clinical results have failed to impress. Perspectives on these theranostic approaches regarding meningiomas, brain metastases, gliomas, and common pediatric brain tumors will be discussed. For each tumor entity, the general context, an overview of the literature, and future perspectives will be provided. Ongoing studies will be discussed in the supplemental materials. As most theranostic agents are unlikely to cross the blood-brain barrier, the delivery of these agents will be dependent on the successful development and clinical implementation of techniques enhancing permeability and retention. Moreover, the international community should strive toward sufficiently large and randomized studies to generate high-level evidence on theranostic approaches with radioligand therapies for central nervous system tumors.
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Affiliation(s)
- Nelleke Tolboom
- Department of Radiology and Nuclear Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Antoine Verger
- IADI, INSERM, UMR 1254, Department of Nuclear Medicine and Nancyclotep Imaging Platform, CHRU-Nancy, Université de Lorraine, Nancy, France
| | - Nathalie L Albert
- Department of Nuclear Medicine, University Hospital of Munich, Munich, Germany
| | - Francesco Fraioli
- Institute of Nuclear Medicine, University College London, London, United Kingdom
| | - Eric Guedj
- Département de Médecine Nucléaire, Hôpital de la Timone, CERIMED, Institut Fresnel, Aix Marseille University, APHM, CNRS, Centrale Marseille, Marseille, France
| | - Tatjana Traub-Weidinger
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Silvia Morbelli
- IRCCS Ospedale Policlinico San Martino, Genoa Italy
- Nuclear Medicine Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Ken Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium-University Hospital Essen, Essen, Germany
| | - Pietro Zucchetta
- Department of Nuclear Medicine, University Hospital of Padova, Padova, Italy
| | | | - Igor Yakushev
- Department of Nuclear Medicine, School of Medicine, Technical University of Munich and Munich Center for Neurosciences-Brain and Mind, Munich, Germany
| | - Michael Weller
- Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Martin Glas
- Division of Clinical Neurooncology, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, University Duisburg-Essen and German Cancer Consortium, Essen, Germany
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Diego Cecchin
- Nuclear Medicine Unit, Department of Medicine-DIMED, University Hospital of Padua, Padua, Italy
| | - Henryk Barthel
- Department of Nuclear Medicine, Leipzig University Medical Centre, Leipzig, Germany; and
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19
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Turner JH. Cancer Care by Committee to be Superseded by Personal Physician-Patient Partnership Informed by Artificial Intelligence. Cancer Biother Radiopharm 2023; 38:497-505. [PMID: 37366774 DOI: 10.1089/cbr.2023.0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023] Open
Abstract
Multidisciplinary tumor boards (MTBs) have become the reference standard of cancer management, founded upon randomized controlled trial (RCT) evidence-based guidelines. The inordinate delays inherent in awaiting formal regulatory agency approvals of novel therapeutic agents, and the rigidities and nongeneralizability of this regimented approach, often deny cancer patients timely access to effective innovative treatment. Reluctance of MTBs to accept theranostic care of patients with advanced neuroendocrine tumors (NETs) and metastatic castrate-resistant prostate cancer resulted in decades of delay in the incorporation of 177Lu-octreotate and 177Lu-prostate-specific membrane antigen (PSMA) into routine clinical oncology practice. Recent developments in immunotherapy and molecular targeted precision therapy, based on N-of-One individual multifactorial genome analyses, have greatly increased the complexity of decision-making. Burgeoning specialist workload and tight time frames now threaten to overwhelm the logistically, and emotionally, demanding MTB system. It is hypothesized that the advent of advanced artificial intelligence technology and Chatbot natural language algorithms will shift the cancer care paradigm from a MTB management model toward a personal physician-patient shared-care partnership for real-world practice of precision individualized holistic oncology.
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Affiliation(s)
- J Harvey Turner
- Department of Nuclear Medicine, Fiona Stanley Fremantle Hospitals Group, The University of Western Australia, Murdoch, Australia
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20
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Diamantopoulos LN, Kalligeros M, Halfdanarson TR, Diamantis N, Toumpanakis C. Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies. BIOLOGY 2023; 12:1069. [PMID: 37626955 PMCID: PMC10452098 DOI: 10.3390/biology12081069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 08/27/2023]
Abstract
There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.
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Affiliation(s)
- Leonidas N. Diamantopoulos
- Department of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA;
| | - Markos Kalligeros
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | | | - Nikolaos Diamantis
- Department of Medical Oncology, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK;
| | - Christos Toumpanakis
- Neuroendocrine Tumor Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK
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21
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Fortunati E, Bonazzi N, Zanoni L, Fanti S, Ambrosini V. Molecular imaging Theranostics of Neuroendocrine Tumors. Semin Nucl Med 2023; 53:539-554. [PMID: 36623974 DOI: 10.1053/j.semnuclmed.2022.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 12/23/2022] [Indexed: 01/08/2023]
Abstract
Neuroendocrine neoplasms (NEN) are rare and heterogeneous tumors, originating mostly from the gastro-entero-pancreatic (GEP) tract followed by the lungs. Multidisciplinary discussion is mandatory for optimal diagnostic and therapeutic management. Well-differentiated NEN (NET) present a high expression of somatostatin receptors (SSTR) and can be studied with [68Ga]-DOTA-peptides ([68Ga]Ga-DOTANOC, [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE) PET/CT to assess disease extension and the eligibility for peptide receptor radionuclide therapy (PRRT). SSTR-analogues labelled with 90Y or 177Lu have been used since mid-90s for NET therapy. PRRT is now considered an effective and safe treatment option for SSTR-expressing NET: following the approval of 177Lu-DOTATATE by FDA and EMA, PRRT is now part of the therapeutic algorithms of the main scientific societies. New strategies to improve PRRT efficacy and to reduce its toxicity are under evaluation (eg, personalization of treatment schemes, the selection of the most suitable patients, improvement of response assessment criteria, optimization of treatment sequencing, feasibility of PRRT-retreatment, combination of PRRT with other treatments options). Recently, several emerging radiopharmaceuticals showed encouraging results for both imaging and therapy (eg, SSTR-analogues labelled with 18F, SSTR-antagonists for both diagnosis and therapy, alpha-labelling for therapy, radiopharmaceuticals binding to new cellular targets). Aim of this review is to focus on current knowledge and to outline emerging perspectives for NEN's diagnosis and therapy.
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Affiliation(s)
- Emilia Fortunati
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy.
| | - Norma Bonazzi
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Lucia Zanoni
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Stefano Fanti
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy; Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy; Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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22
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Pomykala KL, Hadaschik BA, Sartor O, Gillessen S, Sweeney CJ, Maughan T, Hofman MS, Herrmann K. Next generation radiotheranostics promoting precision medicine. Ann Oncol 2023; 34:507-519. [PMID: 36924989 DOI: 10.1016/j.annonc.2023.03.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more.
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Affiliation(s)
- K L Pomykala
- Institute for Artificial Intelligence in Medicine, University Hospital Essen, Essen, Germany
| | - B A Hadaschik
- Department of Urology, University Hospital Essen, Essen, Germany
| | - O Sartor
- School of Medicine, Tulane University, New Orleans, USA
| | - S Gillessen
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Università della Svizzera Italiana, Lugano, Switzerland; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - C J Sweeney
- Dana-Farber Cancer Institute, Boston, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, USA
| | - T Maughan
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | - M S Hofman
- Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - K Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany.
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23
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Satapathy S, Chandekar KR, Bal C. Gastro-Enteric-Pancreatic Neuroendocrine Tumor Treatment: Actinium-225-DOTATATE and Combined Therapies. PET Clin 2023; 18:215-221. [PMID: 36858746 DOI: 10.1016/j.cpet.2022.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023]
Abstract
The role of lutetium-177-DOTATATE in advanced well-differentiated gastro-entero-pancreatic neuroendocrine tumors is well established. However, there is a scope for improving treatment outcomes. Actinium-225-DOTATATE is a form of targeted alpha therapy (TAT) that results in more efficient tumor cell killing owing to the substantially higher linear energy transfer of alpha particles. Systemic TAT is also safe given that the shorter path length of the alpha particles spares the surrounding healthy tissue and results in relatively fewer adverse events. Combination therapies with radiosensitizing and other chemotherapeutic agents have also gained popularity, especially in the setting of higher grade and fluorodeoxyglucose-avid tumors.
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Affiliation(s)
- Swayamjeet Satapathy
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Kunal Ramesh Chandekar
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
| | - Chandrasekhar Bal
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
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Kong G, Hicks RJ. PRRT for higher-grade neuroendocrine neoplasms: What is still acceptable? Curr Opin Pharmacol 2022; 67:102293. [PMID: 36195008 DOI: 10.1016/j.coph.2022.102293] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/25/2022] [Accepted: 09/01/2022] [Indexed: 01/25/2023]
Abstract
Peptide receptor radionuclide therapy (PRRT) is a widely accepted treatment for progressive grade 1 and 2 (G1-2) gastroenteropancreatic neuroendocrine tumors (NET). There is increasing evidence that PRRT is effective for selected patients with well-differentiated (WD) G3 NET, which are now separated from neuroendocrine carcinoma (NEC). These preliminary data have led to prospective PRRT trials currently in progress. This article provides an update of the current role of PRRT for patients with WD-G3 NET, highlighting the importance of patient selection based on molecular imaging phenotype, as well as outlining some potential future directions in this field. Upcoming prospective trials will help define the role, sequencing, and optimization of PRRT to improve outcomes of patients with WD-G3 NET.
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Affiliation(s)
- Grace Kong
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
| | - Rodney J Hicks
- The University of Melbourne Department of Medicine, St Vincent's Hospital, Melbourne, Australia.
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Navalkissoor S, Gnanasegaran G, Grossman A. Optimisation of radioligand therapy in neuroendocrine tumours: Current and evolving evidence. J Neuroendocrinol 2022; 34:e13208. [PMID: 36346690 DOI: 10.1111/jne.13208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/23/2022] [Accepted: 10/02/2022] [Indexed: 11/27/2022]
Abstract
Treatment of neuroendocrine tumours (NETs) with radioligand therapy (RLT) for example, 177 Lu-DOTATATE is generally well-tolerated and prolongs time to progression in most patients. However, approximately 20% of patients are nonresponders. In addition, complete responses are rare (<5% of patients), and durable responses beyond 3-4 years are uncommon. This article will discuss factors which may improve the outcomes of PRRT by using biomarkers to identify patients at high risk to be nonresponders (imaging and liquid biomarkers) and will examine mechanisms to potentially improve/optimise current RLT treatment strategies. These include mechanisms to potentiate the effects of RLT, increase tumour absorbed dose, overcoming radio-resistance and upregulation of somatostatin receptors, although larger studies will be required to demonstrate which techniques are going to be most efficacious in clinical practice.
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Affiliation(s)
- Shaunak Navalkissoor
- Department of Nuclear Medicine, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK
| | - Gopinath Gnanasegaran
- Department of Nuclear Medicine, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK
| | - Ashley Grossman
- NET Unit, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK
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26
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Choudhury S, Agrawal A, Rangarajan V, Puranik A, Bal M, Chaudhari V, Bhandare M, Purandare N, Shah S, Ramaswamy A, Ostwal V, Shrikhande SV. Impact of FDG PET/CT Scan in Changing Management of Well-Differentiated Neuroendocrine Tumors With Ki67 Index Less Than or Equal to 5. Clin Nucl Med 2022; 47:e676-e681. [PMID: 36215398 DOI: 10.1097/rlu.0000000000004365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES This study aimed to see the impact of FDG PET/CT with somatostatin receptor PET (SSTR PET) in directing the treatment plan in lower-grade well-differentiated neuroendocrine tumors (NETs) with Ki67 index ≤5%. METHODS Sixty-three NET cases with Ki67 index ≤5% with both FDG PET and SSTR PET ( 68 Ga-DOTANOC PET) were included for this retrospective observational study. FDG PET findings were classified into positive, weakly positive, and negative based on a visual scale. Clinical factors considered while referring for FDG PET scan were audited from electronic medical records. The addition of chemotherapy was considered as FDG-directed change in treatment. RESULTS Sixty patients showed intense SSTR expression in the primary and metastatic sites (if present). Three patients showed no evidence of SSTR expression, in whom the scans were done after resection of the primary tumor. The FDG PET was positive in 25 (39.6%), weakly positive in 11 (17.4%), and negative in 27 (42.8%). Specific clinical reason for doing FDG PET was found in 34 patients, and in the remaining 29, there was no justification or specific indication for doing the FDG study; 73.5% of patients from the former group was either FDG positive or weakly positive, and 26.5% were negative; in the other group, 62.1% were FDG-negative, and 37.9% were positive ( P = 0.004). Treatment-naive patients with symptom duration of ≤5 months were associated with more FDG positivity than patients with >5 months' symptom duration ( P = 0.006). FDG PET/CT led to change in management in 17.4% of all the patients, 9.6% of grade 1, and 25% of grade 2 patients. CONCLUSIONS In lower-grade NET, FDG positivity was seen in a sizable number of the cases, and this led to change in management in 17.4% of the cases. Specific clinical features could be utilized to successfully discriminate between FDG-avid and non-FDG-avid disease in lower-grade NETs, and this had impact in management change as well.
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Affiliation(s)
- Sayak Choudhury
- From the Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Centre Advanced Centre for Treatment, Research and Education in Cancer
| | - Archi Agrawal
- Departments of Nuclear Medicine and Molecular Imaging
| | | | | | | | | | | | | | - Sneha Shah
- Departments of Nuclear Medicine and Molecular Imaging
| | - Anant Ramaswamy
- Medical Oncology, Tata Memorial Hospital, Homi Bhaba National Institute, Mumbai, India
| | - Vikas Ostwal
- Medical Oncology, Tata Memorial Hospital, Homi Bhaba National Institute, Mumbai, India
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McClellan K, Chen EY, Kardosh A, Lopez CD, Del Rivero J, Mallak N, Rocha FG, Koethe Y, Pommier R, Mittra E, Pegna GJ. Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors. Cancers (Basel) 2022; 14:4769. [PMID: 36230691 PMCID: PMC9563314 DOI: 10.3390/cancers14194769] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/24/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogenous group of malignancies originating from neuroendocrine cells of the gastrointestinal tract, the incidence of which has been increasing for several decades. While there has been significant progress in the development of therapeutic options for patients with advanced or metastatic disease, these remain limited both in quantity and durability of benefit. This review examines the latest research elucidating the mechanisms of both up-front resistance and the eventual development of resistance to the primary systemic therapeutic options including somatostatin analogues, peptide receptor radionuclide therapy with lutetium Lu 177 dotatate, everolimus, sunitinib, and temozolomide-based chemotherapy. Further, potential strategies for overcoming these mechanisms of resistance are reviewed in addition to a comprehensive review of ongoing and planned clinical trials addressing this important challenge.
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Affiliation(s)
- Kristen McClellan
- School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA
| | - Emerson Y. Chen
- Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Adel Kardosh
- Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Charles D. Lopez
- Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nadine Mallak
- Division of Molecular Imaging and Therapy, Oregon Health & Science University, Portland, OR 97239, USA
| | - Flavio G. Rocha
- Division of Surgical Oncology, Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Yilun Koethe
- Dotter Department of Interventional Radiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rodney Pommier
- Division of Surgical Oncology, Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Erik Mittra
- Division of Molecular Imaging and Therapy, Oregon Health & Science University, Portland, OR 97239, USA
| | - Guillaume J. Pegna
- Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
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Somatostatin Receptor Theranostics for Refractory Meningiomas. Curr Oncol 2022; 29:5550-5565. [PMID: 36005176 PMCID: PMC9406720 DOI: 10.3390/curroncol29080438] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas progressing after surgery and radiotherapy. The aim of this study was to provide outcomes of patients harboring refractory meningiomas treated by 177Lu-DOTATATE and an overall analysis of progression-free survival at 6 months (PFS-6) of the same relevant studies in the literature. Eight patients with recurrent and progressive WHO grade II meningiomas were treated after multimodal pretreatment with 177Lu-DOTATATE between 2019 and 2022. Primary and secondarily endpoints were progression-free survival at 6-months (PFS-6) and toxicity, respectively. PFS-6 analysis of our case series was compared with other similar relevant studies that included 86 patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC. Our retrospective study showed a PFS-6 of 85.7% for WHO grade II progressive refractory meningiomas. Treatment was clinically and biologically well tolerated. The overall analysis of the previous relevant studies showed a PFS-6 of 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21); and 0 % for WHO grade III (n = 12). For all grades (n = 86), including unknown grades, PFS-6 was 58.1%. SSTR-targeted PRRT allowed us to achieve prolonged PFS-6 in patients with WHO grade I and II progressive refractory meningiomas, except the most aggressive WHO grade II tumors. Large scale randomized trials are warranted for the better integration of PRRT in the treatment of refractory meningioma into clinical practice guidelines.
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Bodei L, Herrmann K, Schöder H, Scott AM, Lewis JS. Radiotheranostics in oncology: current challenges and emerging opportunities. Nat Rev Clin Oncol 2022; 19:534-550. [PMID: 35725926 PMCID: PMC10585450 DOI: 10.1038/s41571-022-00652-y] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2022] [Indexed: 12/20/2022]
Abstract
Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics - the combination of diagnostic imaging with targeted therapy - is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.
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Affiliation(s)
- Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA
| | - Ken Herrmann
- German Cancer Consortium, University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA.
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Pharmacology, Weill Cornell Medical School, New York, NY, USA.
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Ali SS, Raj R, Kaur T, Weadick B, Nayak D, No M, Protos J, Odom H, Desai K, Persaud AK, Wang J, Govindarajan R. Solute Carrier Nucleoside Transporters in Hematopoiesis and Hematological Drug Toxicities: A Perspective. Cancers (Basel) 2022; 14:cancers14133113. [PMID: 35804885 PMCID: PMC9264962 DOI: 10.3390/cancers14133113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/18/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Anticancer nucleoside analogs are promising treatments that often result in damaging toxicities and therefore ineffective treatment. Mechanisms of this are not well-researched, but cellular nucleoside transport research in mice might provide additional insight given transport’s role in mammalian hematopoiesis. Cellular nucleoside transport is a notable component of mammalian hematopoiesis due to how mutations within it relate to hematological abnormities. This review encompasses nucleoside transporters, focusing on their inherent properties, hematopoietic role, and their interplay in nucleoside drug treatment side effects. We then propose potential mechanisms to explain nucleoside transport involvement in blood disorders. Finally, we point out and advocate for future research areas that would improve therapeutic outcomes for patients taking nucleoside analog therapies. Abstract Anticancer nucleoside analogs produce adverse, and at times, dose-limiting hematological toxicities that can compromise treatment efficacy, yet the mechanisms of such toxicities are poorly understood. Recently, cellular nucleoside transport has been implicated in normal blood cell formation with studies from nucleoside transporter-deficient mice providing additional insights into the regulation of mammalian hematopoiesis. Furthermore, several idiopathic human genetic disorders have revealed nucleoside transport as an important component of mammalian hematopoiesis because mutations in individual nucleoside transporter genes are linked to various hematological abnormalities, including anemia. Here, we review recent developments in nucleoside transporters, including their transport characteristics, their role in the regulation of hematopoiesis, and their potential involvement in the occurrence of adverse hematological side effects due to nucleoside drug treatment. Furthermore, we discuss the putative mechanisms by which aberrant nucleoside transport may contribute to hematological abnormalities and identify the knowledge gaps where future research may positively impact treatment outcomes for patients undergoing various nucleoside analog therapies.
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Affiliation(s)
- Syed Saqib Ali
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Ruchika Raj
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Tejinder Kaur
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Brenna Weadick
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Debasis Nayak
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Minnsung No
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Jane Protos
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Hannah Odom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Kajal Desai
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Avinash K. Persaud
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
| | - Joanne Wang
- Department of Pharmaceutics, College of Pharmacy, University of Washington, Seattle, WA 98195, USA;
| | - Rajgopal Govindarajan
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (S.S.A.); (R.R.); (T.K.); (B.W.); (D.N.); (M.N.); (J.P.); (H.O.); (K.D.); (A.K.P.)
- Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +1-614-247-8269; Fax: +1-614-292-2588
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Bartolomei M, Berruti A, Falconi M, Fazio N, Ferone D, Lastoria S, Pappagallo G, Seregni E, Versari A. Clinical Management of Neuroendocrine Neoplasms in Clinical Practice: A Formal Consensus Exercise. Cancers (Basel) 2022; 14:2501. [PMID: 35626105 PMCID: PMC9140035 DOI: 10.3390/cancers14102501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/16/2022] [Indexed: 02/01/2023] Open
Abstract
Many treatment approaches are now available for neuroendocrine neoplasms (NENs). While several societies have issued guidelines for diagnosis and treatment of NENs, there are still areas of controversy for which there is limited guidance. Expert opinion can thus be of support where firm recommendations are lacking. A group of experts met to formulate 14 statements relative to diagnosis and treatment of NENs and presented herein. The nominal group and estimate-talk-estimate techniques were used. The statements covered a broad range of topics from tools for diagnosis to follow-up, evaluation of response, treatment efficacy, therapeutic sequence, and watchful waiting. Initial prognostic characterization should be based on clinical information as well as histopathological analysis and morphological and functional imaging. It is also crucial to optimize RLT for patients with a NEN starting from accurate characterization of the patient and disease. Follow-up should be patient/tumor tailored with a shared plan about timing and type of imaging procedures to use to avoid safety issues. It is also stressed that patient-reported outcomes should receive greater attention, and that a multidisciplinary approach should be mandatory. Due to the clinical heterogeneity and relative lack of definitive evidence for NENs, personalization of diagnostic-therapeutic work-up is crucial.
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Affiliation(s)
- Mirco Bartolomei
- Azienda Ospedaliero-Universitaria di Ferrara, Presidio Ospedaliero Arcispedale Sant’Anna di Cona, 44124 Ferrara, Italy;
| | - Alfredo Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Massimo Falconi
- Pancreas Surgical Unit, ENETS Center of Excellence, San Raffaele Hospital IRCCS, Vita Salute University, 20132 Milan, Italy;
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncologya and Neuroendocrine Tumors, European Institute of Oncology, 20132 Milan, Italy;
| | - Diego Ferone
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, IRCCS, Ospedale Policlinico San Martino, Università di Genova, 16132 Genova, Italy;
| | - Secondo Lastoria
- Nuclear Medicine Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, 80131 Naples, Italy;
| | - Giovanni Pappagallo
- School of Clinical Methodology IRCCS “Sacred Heart–Don Calabria” Hospital; 37024 Negrar di Valpolicella, Italy;
| | - Ettore Seregni
- Nuclear Medicine Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20132 Milano, Italy;
| | - Annibale Versari
- Nuclear Medicine Unit, Azienda Unità Sanitaria Locale-IRCCS of Reggio Emilia, 42100 Reggio Emilia, Italy;
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32
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Syguła A, Ledwon A, Hasse-Lazar K, Jurecka-Lubieniecka B, Michalik B, Paliczka-Cieślik E, Zeman M, Chmielik E, Sczasny J, Jarzab B, Handkiewicz-Junak D. In patients with well-differentiated neuroendocrine tumours, there is no apparent benefit of somatostatin analogues after disease control by peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging 2022; 49:3841-3851. [PMID: 35503379 DOI: 10.1007/s00259-022-05792-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/03/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasms (NEN), and SSAs given as maintenance. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN after disease control by PRRT. METHODS This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally advanced, or metastatic, histologically confirmed well-differentiated NEN; no symptoms/biochemical diagnosis of carcinoid syndrome; no SSAs or ≤ 3 months of SSAs before PRRT; and stable disease or partial or complete response after PRRT. Altogether, 115 patients were randomised 2:1 to an SSA group (n = 74) given octreotide acetate LAR every 4 weeks, or a control group (n = 41) receiving only best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon NEN progression. The primary endpoint was progression-free survival (PFS), the secondary endpoint, and overall survival (OS). RESULTS Median (25th-75th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18-10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, and 19/41 (46%) in the control group (p = 0.01). Eighty-eight/115 patients (76%) died, 58/74 (78%) in the SSA group, and 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was 4.7 (2.8-7.7) years in the SSA group, and 6.4 (4.1-not reached) years in controls. Overall, median OS was 6.6 years. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively). CONCLUSIONS In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicentre study with a relatively homogeneous sample.
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Affiliation(s)
- Aleksandra Syguła
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Aleksandra Ledwon
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Kornelia Hasse-Lazar
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Beata Jurecka-Lubieniecka
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Barbara Michalik
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Ewa Paliczka-Cieślik
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Marcin Zeman
- The Oncologic and Reconstructive Surgery Clinic, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Ewa Chmielik
- Tumor Pathology Department, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Joanna Sczasny
- Radiology and Diagnostic Imaging Department, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Barbara Jarzab
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland
| | - Daria Handkiewicz-Junak
- Department of Nuclear Medicine and Endocrine Oncology, Gliwice Branch, Maria Sklodowska-Curie National Research Institute of Oncology, Wybrzeże Armii Krajowej 16, 44-101, Gliwice, Poland.
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Kennedy KR, Turner JH, MacDonald WBG, Claringbold PG, Boardman G, Ransom DT. Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy. Cancer 2022; 128:2182-2192. [PMID: 35363879 DOI: 10.1002/cncr.34191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Peptide receptor radionuclide therapy (PRRT) has shown favorable results in neuroendocrine tumors (NETs). Long-term safety and efficacy data for 177 Lu-octreotate PRRT, particularly in combination with chemotherapy, is lacking. METHODS The authors conducted a retrospective review of the long-term toxicity and survival outcomes of 104 patients with advanced NETs treated on 4 phase 2 clinical trials with Lutetium-177-octreotate (177 Lu-octreotate) PRRT, mostly in combination with chemotherapy. Median follow-up was 68 months, which represents the longest follow-up study of 177 Lu-octreotate PRRT for NETs to date. RESULTS Median progression-free survival (PFS) was 37 months, and median overall survival (OS) was 71 months. Five- and 10-year OS were 62% and 29%, and 5- and 10-year PFS were 36% and 21%, respectively, demonstrating 177 Lu-octreotate can provide durable responses. PRRT was well tolerated with 1.9% of patients developing chronic renal impairment and 1% of patients developing long-term thrombocytopenia. Interestingly, there was a relatively high rate of myelodysplasia (MDS)/leukemia (6.7%), possibly attributable to the longer follow-up (with all except 1 case occurring more than 4 years after PRRT treatment) or to the addition of concurrent chemotherapy. CONCLUSIONS Lutetium-177-Octreotate PRRT remains an efficacious and well tolerated treatment in long-term follow-up. For clinicians deciding on the timing of PRRT for individual patients, the 6.7% long-term risk of MDS/leukemia needs to be balanced against the 21% PFS at 10 years.
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Affiliation(s)
- Kim R Kennedy
- Fiona Stanley Hospital, Cancer Centre, Murdoch, Western Australia, Australia
| | - John Harvey Turner
- Fiona Stanley Hospital, Cancer Centre, Murdoch, Western Australia, Australia
| | | | | | - Glenn Boardman
- Fiona Stanley Hospital, Cancer Centre, Murdoch, Western Australia, Australia
| | - David T Ransom
- Fiona Stanley Hospital, Cancer Centre, Murdoch, Western Australia, Australia
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Gosain R, Gupta M, Roy AM, Strosberg J, Glaser KM, Iyer R. Health-Related Quality of Life (HRQoL) in Neuroendocrine Tumors: A Systematic Review. Cancers (Basel) 2022; 14:1428. [PMID: 35326587 PMCID: PMC8946839 DOI: 10.3390/cancers14061428] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 12/28/2022] Open
Abstract
Therapeutic advancements in neuroendocrine tumors (NETs) have improved survival outcomes. This study aims to review the impact of the current therapeutics on health-related quality of life (HRQoL) in NET patients. A literature review was performed utilizing PubMed, The Cochrane Library, and EMBASE, using the keywords "Carcinoid", "Neuroendocrine tumor", "NET", "Quality of life", "Chemotherapy", "Chemoembolization", "Radiofrequency ablation", "Peptide receptor radionucleotide therapy", "PRRT", "Surgery", "Everolimus", "Octreotide", "Lanreotide", "Sunitinib", and "Somatostatin analog". Letters, editorials, narrative reviews, case reports, and studies not in English were excluded. Out of 2375 publications, 61 studies met our inclusion criteria. The commonly used instruments were EORTC QLQ-C30, FACT G, and EORTC- QLQ GI.NET-21. HRQoL was assessed in all pivotal trials that led to approvals of systemic therapies. All systemic therapies showed no worsening in HRQoL. The NETTER-1 study was the only study to show a statistically significant improvement in HRQoL in several domains. The trial examining sunitinib versus placebo in pancreatic NETs showed no change in QoL, except for worsening of diarrhea. In addition to clinical outcomes, patient-reported outcomes are a key element in making appropriate treatment decisions. HRQoL data should be readily provided to patients to assist in shared decision-making.
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Affiliation(s)
- Rohit Gosain
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, UPMC Chautauqua Hospital, Jamestown, NY 14701, USA;
| | - Medhavi Gupta
- Program in Women’s Oncology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02912, USA;
| | - Arya Mariam Roy
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Jonathan Strosberg
- Department of Gastro Intestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612, USA;
| | - Kathryn M. Glaser
- Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Renuka Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
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Ambrosini V, Zanoni L, Filice A, Lamberti G, Argalia G, Fortunati E, Campana D, Versari A, Fanti S. Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors. Cancers (Basel) 2022; 14:1055. [PMID: 35205805 PMCID: PMC8870358 DOI: 10.3390/cancers14041055] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/10/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs.
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Affiliation(s)
- Valentina Ambrosini
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
- Nuclear Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Lucia Zanoni
- Nuclear Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Angelina Filice
- Nuclear Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.F.); (A.V.)
| | - Giuseppe Lamberti
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Giulia Argalia
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
| | - Emilia Fortunati
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
| | - Davide Campana
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Annibale Versari
- Nuclear Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; (A.F.); (A.V.)
| | - Stefano Fanti
- Department of Experimental Diagnostic and Specialized Medicine, University of Bologna, 40138 Bologna, Italy; (V.A.); (G.L.); (G.A.); (E.F.); (D.C.); (S.F.)
- Nuclear Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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Peptide Receptor Radionuclide Therapy with [ 177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions. Cancers (Basel) 2022; 14:cancers14030584. [PMID: 35158852 PMCID: PMC8833790 DOI: 10.3390/cancers14030584] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Neuroendocrine neoplasms have been usually described as infrequent tumors, but their incidence has been rising over time. [177Lu]Lu-DOTA-TATE (PRRT-Lu) was approved by the European Medicines Agency and by the Food and Drug Administration as the first radiopharmaceutical for peptide receptor radionuclide therapy in progressive gastroenteropancreatic NET. PRRT-Lu is considered a therapeutic option in progressive SSTR-positive NETs with homogenous SSTR expression. The NETTER-1 study demonstrated that PRRT-Lu yielded a statistically and clinically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001), as well as a clinical trend towards improvement in OS. These results made scientific societies incorporate PRRT-Lu into their clinical guidelines; however, some questions still remain unanswered. Abstract This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.
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Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies. Cancers (Basel) 2021; 14:cancers14010129. [PMID: 35008293 PMCID: PMC8749814 DOI: 10.3390/cancers14010129] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/13/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Peptide receptor radionuclide therapy (PRRT) is a systemic treatment consisting of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. This will subsequently cause lethal DNA damage to the tumor cell. The only target that is currently used in widespread clinical practice is the somatostatin receptor, which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review focuses on the basic principles and clinical applications of PRRT, and discusses several PRRT-optimization strategies. Abstract Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose–effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.
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Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale. Biomedicines 2021; 9:biomedicines9111570. [PMID: 34829796 PMCID: PMC8615768 DOI: 10.3390/biomedicines9111570] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).
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Aerts A, Eberlein U, Holm S, Hustinx R, Konijnenberg M, Strigari L, van Leeuwen FWB, Glatting G, Lassmann M. EANM position paper on the role of radiobiology in nuclear medicine. Eur J Nucl Med Mol Imaging 2021; 48:3365-3377. [PMID: 33912987 PMCID: PMC8440244 DOI: 10.1007/s00259-021-05345-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 03/28/2021] [Indexed: 12/16/2022]
Abstract
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
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Affiliation(s)
- An Aerts
- Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
| | - Uta Eberlein
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
| | - Sören Holm
- Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University Hospital Copenhagen, Copenhagen, Denmark
| | - Roland Hustinx
- Division of Nuclear Medicine and Oncological Imaging, University Hospital of Liège, GIGA-CRC in vivo Imaging, University of Liège, Liège, Belgium
| | - Mark Konijnenberg
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Lidia Strigari
- Medical Physics Department, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fijs W B van Leeuwen
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerhard Glatting
- Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, Germany
| | - Michael Lassmann
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
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Combination Therapies with PRRT. Pharmaceuticals (Basel) 2021; 14:ph14101005. [PMID: 34681229 PMCID: PMC8538931 DOI: 10.3390/ph14101005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) is a successful targeted radionuclide therapy in neuroendocrine tumors (NETs). However, complete responses remain elusive. Combined treatments anticipate synergistic effects and thus better responses by combining ionizing radiation with other anti-tumor treatments. Furthermore, multimodal therapies often have a balanced toxicity profile. To date, few studies have evaluated the effect of combination therapies with PRRT, some of them phase I/II trials. This review will focus on several clinically tested, tailored approaches to improving the effects of PRRT. The aim is to help clinicians in the treatment planning of NETs to choose the most effective and safe treatment for each patient in the sense of personalized medicine. Current promising combination partners of PRRT are somatostatin analogues (SSAs), chemotherapy, molecular targeted treatment, liver radioembolization, and dual radionuclide PRRT (Lutetium-177-PRRT combined with Yttrium-90-PRRT).
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Das S, Al-Toubah T, Strosberg J. Chemotherapy in Neuroendocrine Tumors. Cancers (Basel) 2021; 13:4872. [PMID: 34638356 PMCID: PMC8507720 DOI: 10.3390/cancers13194872] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/16/2022] Open
Abstract
The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.
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Affiliation(s)
- Satya Das
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37209, USA;
| | - Taymeyah Al-Toubah
- Moffitt Cancer Center, Department of Gastrointestinal Oncology, Tampa, FL 33612, USA;
| | - Jonathan Strosberg
- Moffitt Cancer Center, Department of Gastrointestinal Oncology, Tampa, FL 33612, USA;
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Satapathy S, Mittal BR, Sood A, Sood A, Kapoor R, Gupta R, Khosla D. 177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A Single-Institution Experience. JCO Glob Oncol 2021; 7:1167-1175. [PMID: 34288699 PMCID: PMC8457785 DOI: 10.1200/go.21.00103] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/10/2021] [Accepted: 06/23/2021] [Indexed: 01/03/2023] Open
Abstract
PURPOSE To compare the efficacy and safety of 177Lu-DOTATATE plus radiosensitizing capecitabine and octreotide long-acting release (LAR) as first-line systemic therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). MATERIALS AND METHODS Data of consecutive patients of advanced inoperable or metastatic grade 1 or 2 GEP-NETs treated with first-line 177Lu-DOTATATE plus radiosensitizing capecitabine or octreotide LAR from September 2012 to December 2019 were collected and analyzed for response, toxicity, and survival outcomes. RESULTS Seventy-six patients (median age: 53 years; range 14-81 years) with treatment-naïve advanced grade 1 or 2 GEP-NETs were included. Thirty-six patients received a median cumulative dose of 27.3 GBq of 177Lu-DOTATATE intravenously at 8-12 weeks' intervals along with 1,250 mg/m2 oral capecitabine on days 0-14 of each cycle of 177Lu-DOTATATE, whereas 40 patients were administered 30 mg octreotide LAR intramuscularly every 4 weeks. Using response evaluation criteria in solid tumor 1.1, the objective response rate was 38% in the 177Lu-DOTATATE arm compared with 15% in the octreotide LAR arm (P = .025), whereas the disease control rates were 88% and 67% in 177Lu-DOTATATE and octreotide LAR arms, respectively (P = .035). The median durations of progression-free survival in the 177Lu-DOTATATE and octreotide LAR arms were 54 months and 16 months, respectively (P = .017), whereas the median overall survival was not reached and not significantly different across both the arms. Of the treatment-related adverse events, no major difference was observed in the occurrence of grade 3 or 4 toxicities between the two treatment arms. CONCLUSION First-line systemic 177Lu-DOTATATE plus radiosensitizing capecitabine achieved better radiologic response and longer progression-free survival compared with octreotide LAR in patients with advanced grade 1 or 2 GEP-NETs. Future randomized controlled trials are, however, required to determine the best treatment sequence for the treatment-naïve patients with advanced GEP-NETs.
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Affiliation(s)
- Swayamjeet Satapathy
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Bhagwant R. Mittal
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Apurva Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Kapoor
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajesh Gupta
- Department of Surgical Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Divya Khosla
- Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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Suman SK, Subramanian S, Mukherjee A. Combination radionuclide therapy: A new paradigm. Nucl Med Biol 2021; 98-99:40-58. [PMID: 34029984 DOI: 10.1016/j.nucmedbio.2021.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/23/2021] [Accepted: 05/06/2021] [Indexed: 12/15/2022]
Abstract
Targeted molecular radionuclide therapy (MRT) has shown its potential for the treatment of cancers of multiple origins. A combination therapy strategy employing two or more distinct therapeutic approaches in cancer management is aimed at circumventing tumor resistance by simultaneously targeting compensatory signaling pathways or bypassing survival selection mutations acquired in response to individual monotherapies. Combination radionuclide therapy (CRT) is a newer application of the concept, utilizing a combination of radiolabeled molecular targeting agents with chemotherapy and beam radiation therapy for enhanced therapeutic index. Encouraging results are reported with chemotherapeutic agents in combination with radiolabeled targeting molecules for cancer therapy. With increasing awareness of the various survival and stress response pathways activated after radionuclide therapy, different holistic combinations of MRT agents with radiosensitizers targeting such pathways have also been explored. MRT has also been studied in combination with beam radiotherapy modalities such as external beam radiation therapy and carbon ion radiation therapy to enhance the anti-tumor response. Nanotechnology aids in CRT by bringing together multiple monotherapies on a single nanostructure platform for treating cancers in a more precise or personalized way. CRT will be a key player in managing cancers if correctly tailored to the individual patient profile. The success of CRT lies in an in-depth understanding of the radiobiological principles and pathways activated in response.
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Affiliation(s)
- Shishu Kant Suman
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai 400094, India
| | - Suresh Subramanian
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai 400094, India
| | - Archana Mukherjee
- Radiopharmaceuticals Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Mumbai 400094, India.
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44
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Peptide receptor radionuclide therapy for GEP-NET: consolidated knowledge and innovative applications. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00443-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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45
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Neuroendocrine Tumor Theranostics: An Update and Emerging Applications in Clinical Practice. AJR Am J Roentgenol 2021; 217:495-506. [PMID: 34076455 DOI: 10.2214/ajr.20.23349] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE. Theranostics have shown great promise for delivering precision medicine, particularly in neuroendocrine tumors (NETs). The clinical applications of radiolabeled somatostatin analogues in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and are currently integrated into the management guidelines of NETs. This article summarizes the available literature on different somatostatin receptor-targeting radiopharmaceuticals with theranostic potential in NETs, pheochromocytomas, and paragangliomas. We discuss the clinical application, administration, and toxicity of recent FDA-approved radionuclide therapies, including 177Lu-DOTATATE in advanced gastroenteropancreatic NETs and 131I-MIBG in advanced paragangliomas and pheochromocytomas. CONCLUSION. Several studies support the safety and clinical efficacy of peptide receptor radionuclide therapies in disease control and quality-of-life improvement in patients with NETs and report potential benefits of combined radionuclide treatment approaches. The utility and pitfalls of functional imaging in therapy response assessment and surveillance of NETs remain to be established.
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Zidan L, Iravani A, Oleinikov K, Ben-Haim S, Gross DJ, Meirovitz A, Maimon O, Akhurst T, Michael M, Hicks RJ, Grozinsky-Glasberg S, Kong G. Efficacy and safety of 177Lu-DOTATATE in lung neuroendocrine tumors: a bi-center study. J Nucl Med 2021; 63:218-225. [PMID: 34049983 DOI: 10.2967/jnumed.120.260760] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 04/21/2021] [Indexed: 11/16/2022] Open
Abstract
To assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR) positive lung neuroendocrine tumor (NET). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at two ENETS Centres of Excellence. Morphological imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 months after completion of 177Lu-DOTATATE. Concordance between two response assessment methods was evaluated by Kappa statistics. Progression-free survival (PFS) and overall survival (OS) was estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on CTCAE version 5. Results: Of 48 patients (median age, 63 years, 13 female), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Majority (40, 83%) received somatostatin analogs and 10 patients (20%) had prior everolimus, chemotherapy or both. All patients had high SSR expression (≥ modified Krenning score 3) on pre-treatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27GBq (range 6-43GBq). At median follow-up of 42 months, the median PFS and OS were 23 months (95% CI 18-28 months) and 59 months (95% CI 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT response categories were: partial response, 20% (95% CI 10-35%) and 44% (95% CI 30-59%); stable disease, 68% (95% CI 52-80%) and 44% (95% CI 30-59%) and progressive disease 12% (95% CI 5-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted Kappa of 0.51 (95% CI 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had longer OS compared to those with no response, NR vs 52 months (95% CI 28-64), HR 0.2 (95% CI 0.1-0.6), p 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia/leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Grace Kong
- Peter MacCallum Cancer Centre, Australia
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47
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Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv 2021; 4:4091-4101. [PMID: 32877524 DOI: 10.1182/bloodadvances.2020002583] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022] Open
Abstract
For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.
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48
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Wahl RL, Chareonthaitawee P, Clarke B, Drzezga A, Lindenberg L, Rahmim A, Thackeray J, Ulaner GA, Weber W, Zukotynski K, Sunderland J. Mars Shot for Nuclear Medicine, Molecular Imaging, and Molecularly Targeted Radiopharmaceutical Therapy. J Nucl Med 2021; 62:6-14. [PMID: 33334911 DOI: 10.2967/jnumed.120.253450] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine.
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Affiliation(s)
- Richard L Wahl
- Mallinckrodt Institute of Radiology, Washington University St. Louis, Missouri
| | | | - Bonnie Clarke
- Research and Discovery, Society of Nuclear Medicine and Molecular Imaging, Reston, Virginia
| | - Alexander Drzezga
- Department of Nuclear Medicine, University of Cologne, Cologne, Germany, German Center for Neurodegenerative Diseases, Bonn-Cologne, Germany, and Institute of Neuroscience and Medicine, Molecular Organization of the Brain, Forschungszentrum Jülich, Jülich, Germany
| | - Liza Lindenberg
- Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Arman Rahmim
- Departments of Radiology and Physics, University of British Columbia, Vancouver, British Columbia, Canada; Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, British Columbia, Canada
| | - James Thackeray
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Gary A Ulaner
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, and Molecular Imaging and Therapy, Hoag Cancer Center, Newport Beach, California
| | - Wolfgang Weber
- Department of Nuclear Medicine, Technical University Munich, Munich, Germany
| | - Katherine Zukotynski
- Departments of Medicine and Radiology, McMaster University, Hamilton, Ontario, Canada; and
| | - John Sunderland
- Departments of Radiology and Physics, University of Iowa, Iowa City, Iowa
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49
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Satapathy S, Mittal BR, Sood A, Verma R, Panda N. Efficacy and safety of concomitant 177Lu-DOTATATE and low-dose capecitabine in advanced medullary thyroid carcinoma: a single-centre experience. Nucl Med Commun 2021; 41:629-635. [PMID: 32371670 DOI: 10.1097/mnm.0000000000001205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIMS Peptide receptor radionuclide therapy (PRRT) has been shown to be useful in inoperable/metastatic medullary thyroid carcinoma (MTC). However, the role of concomitant PRRT and low-dose capecitabine therapy has not yet been studied in these patients. This study was conducted to evaluate the efficacy and safety of this combination approach in advanced MTC. MATERIALS AND METHODS This was a retrospective, single-centre study. Data of consecutive patients of advanced inoperable/metastatic MTC treated with concomitant Lu-DOTATATE+capecitabine, from January 2014 to August 2018, were collected and analysed for radiological, molecular and biochemical responses and treatment-related toxicity. RESULTS Eight patients with advanced MTC received a median cumulative dose of 20.9 GBq (interquartile range 8.9-27.7 GBq) Lu-DOTATATE over 1-4 cycles and 1250 mg/m capecitabine from days 0 to 14 of each PRRT cycle. Radiological response according to Response Evaluation Criteria in Solid Tumours 1.1 criteria could be assessed in seven patients. Six out of seven patients (86%) had stable disease, while disease progression was observed in 1/7 (14%) patients. However, molecular response, as per the European Organization for Research and Treatment of Cancer criteria, was observed in all the seven patients. Biochemical response with reduction in serum calcitonin levels was observed in 3/5 (60%) patients. With the exception of grade 2 anaemia in one patient, no other significant toxicity was observed in this cohort. CONCLUSION Our results indicate the efficacy and safety of concomitant Lu-DOTATATE and capecitabine in advanced MTC. Larger randomized controlled trials are, however, required to establish the role of capecitabine as a radiosensitizer along with PRRT in these patients.
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Affiliation(s)
| | | | | | - Roshan Verma
- Otolaryngology (Head and Neck Surgery), Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Naresh Panda
- Otolaryngology (Head and Neck Surgery), Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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50
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Wu W, Chen J, Bai C, Chi Y, Du Y, Feng S, Huo L, Jiang Y, Li J, Lou W, Luo J, Shao C, Shen L, Wang F, Wang L, Wang O, Wang Y, Wu H, Xing X, Xu J, Xue H, Xue L, Yang Y, Yu X, Yuan C, Zhao H, Zhu X, Zhao Y. The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020). JOURNAL OF PANCREATOLOGY 2021; 4:1-17. [DOI: 10.1097/jp9.0000000000000064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.
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Affiliation(s)
- Wenming Wu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yihebali Chi
- Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yiqi Du
- Department of Gastroenterology, Changhai Hospital Affiliated to Navy Medical University, Shanghai
| | - Shiting Feng
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Li Huo
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yuxin Jiang
- Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital of Fudan University
| | - Jie Luo
- Department of Pathology, China-Japan Friendship Hospital, Beijing
| | - Chenghao Shao
- Department of Pancreatic-biliary Surgery, Changzheng Hospital, Navy Medical University, Shanghai
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing
| | - Feng Wang
- Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province
| | - Liwei Wang
- Department of Oncology, Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai
| | - Ou Wang
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Yu Wang
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Xiaoping Xing
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
| | - Ling Xue
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Yang Yang
- Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai
| | - Chunhui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing
| | - Xiongzeng Zhu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yupei Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing
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