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1
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Ganame S, Walter T, Durand A, Lièvre A, Tougeron D, Scoazec JY, Baudin E, Lepage C, Boussari O, Hadoux J. Proof of concept and design of an externally controlled trial for patients with gastro-enteropancreatic neuroendocrine carcinomas based on the randomized phase II BEVANEC trial. Eur J Cancer 2025:115450. [PMID: 40340189 DOI: 10.1016/j.ejca.2025.115450] [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: 12/06/2024] [Revised: 04/02/2025] [Accepted: 04/09/2025] [Indexed: 05/10/2025]
Abstract
AIM Randomized trials are very challenging to perform in rare cancers such as gastro-enteropancreatic neuroendocrine carcinomas. We hypothesized that the randomized BEVANEC trial of FOLFIRI + /- bevacizumab could have been designed with an external control arm (ECA) and led to similar results. METHODS For this proof of concept, BEVANEC-EMU was emulated as a prospective single experimental arm (EA) trial of FOLFIRI + bevacizumab (BEVANEC data) vs an ECA of FOLFIRI from real world data (RWD) with similar inclusion criteria and primary endpoints. RESULTS RWD characteristics were similar to those of BEVANEC. Missing data were observed for some patients in RWD (LDH, PAL and performance status). After weighting by the inverse of propensity-score, patient's characteristics were as well balanced between the ECA -n = 66) and the EA of BEVANEC-EMU (n = 59) as between the 2 randomized arm of BEVANEC trial. The 6-months OS rates were 61.1 % [95 %CI 48.9;76.5] in the EA and 53.4 % [95 %CI 42.2;67.6] in the ECA. In BEVANEC-EMU, the primary endpoint was met in both arms, as observed in the BEVANEC trial. The same conclusions were drawn when a hybrid ECA (generated by a mixture of RWD and prospective data from BEVANEC). A custom randomization algorithm which incrementally incorporate RWD into a prospective comparative externally controlled trial is described. CONCLUSIONS The BEVANEC trial could have been led as an externally-controlled trial. This proof of concept led to the design of REWENEC-01, a funded prospective comparative externally-controlled trial for the evaluation of an immunotherapy combination in association with FOLFIRI in GEP NEC patients.
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Affiliation(s)
- S Ganame
- FFCD Département Méthodologie & EPICAD U1231, INSERM, Dijon F-21079, France
| | - T Walter
- Service d'oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon F-69003, France
| | - A Durand
- Service d'oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon F-69003, France
| | - A Lièvre
- Service d'Hépato-gastro-entérologie, CHU de Rennes, Rennes F-35033, France
| | - D Tougeron
- Service d'Hépato-gastro-Entérologie, CHU de Poitiers, Poitiers F-8600, France
| | - J-Y Scoazec
- Service de Pathologie, Département de Biologie et Pathologie Médicale, Gustave Roussy, Villejuif F-94805, France; Université Paris Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France
| | - E Baudin
- Service d'Oncologie Endocrinienne, Département d'Imagerie, Gustave Roussy, Villejuif F-94805, France
| | - C Lepage
- Service d'Hépato-Gastro-Entérologie, CHU de Dijon & EPICAD U1231, INSERM, Dijon F-21079, France
| | - O Boussari
- FFCD Département Méthodologie & EPICAD U1231, INSERM, Dijon F-21079, France
| | - J Hadoux
- Service d'Oncologie Endocrinienne, Département d'Imagerie, Gustave Roussy, Villejuif F-94805, France.
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2
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Gao LL, Gao DN, Yuan HT, Chen WQ, Yang J, Peng JQ. Combining anti-PD-1 antibodies with surufatinib for gastrointestinal neuroendocrine carcinoma: Two cases report and review of literature. World J Clin Oncol 2025; 16:102297. [PMID: 40290678 PMCID: PMC12019270 DOI: 10.5306/wjco.v16.i4.102297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Gastrointestinal neuroendocrine carcinoma (GI NEC) has a low incidence rate and poor prognosis. Most patients already have metastatic disease when they are diagnosed. Platinum chemotherapy is the main means of treating metastatic GI NECs. There is a lack of effective treatment methods after chemotherapy failure. Therefore, Therefore, selecting appropriate posterior-line treatment programs to improve the prognosis of patients is urgently needed. CASE SUMMARY A 64-year-old female was diagnosed with stage IV NEC of the rectum due to abdominal pain and rectal bleeding. After multiline chemotherapy, the condition progressed, and the patient was treated with a combination of camrelizumab and surufatinib. The efficacy evaluation revealed partial remission (PR) and stable conditions, with the expression of the tumor marker neuron-specific enolase (NSE) returning to normal. The adverse reactions were controllable, and the overall condition was good, with weight gain achieved in the past four years. Another 51-year-old female experienced recurrence and metastasis of a duodenal NEC after surgery. After multiline chemotherapy, she received sintilimab combined with surufatinib. The curative effect fluctuated between PR and stability. During treatment, she recovered from immune-related diabetes and later died due to deterioration of her condition. During the treatment, the patient's NSE level returned to normal. CONCLUSION The combination of antiangiogenic targeted drugs and immunotherapy provides a new therapeutic approach for the treatment of metastatic GI-NECs.
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Affiliation(s)
- Lou-Lu Gao
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Dong-Ni Gao
- Department of Oncology, Shandong Public Health Clinical Center, Jinan 250100, Shandong Province, China
| | - Hong-Tu Yuan
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Wen-Qiang Chen
- Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jing Yang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Jie-Qiong Peng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
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3
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Yin L, Wang R, Ma X, Jiang K, Hu Y, Zhao X, Zhang L, Wang Z, Long T, Lu M, Li J, Sun Y. Exploring the expression of DLL3 in gastroenteropancreatic neuroendocrine neoplasms and its potential diagnostic value. Sci Rep 2025; 15:3287. [PMID: 39865119 PMCID: PMC11770191 DOI: 10.1038/s41598-025-86237-y] [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] [Received: 07/22/2024] [Accepted: 01/09/2025] [Indexed: 01/28/2025] Open
Abstract
Delta-like protein (DLL3) is a novel therapeutic target. DLL3 expression in gastroenteropancreatic neuroendocrine tumors (GEP-NECs) is poorly understood, complicating the distinction between well-differentiated neuroendocrine tumors G3 (NET G3) and poorly differentiated NEC. DLL3 immunohistochemistry (IHC) was performed on 248 primary GEP-NECs, correlating with clinicopathological parameters, NE markers, PD-L1, Ki67 index, and prognosis. Achaete-scute complex-like 1 (ASCL1) IHC was performed on some GEP-NECs. DLL3 IHC was conducted on 36 GEP-NETs, 29 gastric adenocarcinomas (GACs), and metastatic tumors (9 lymph node metastases and 19 distant metastases). DLL3 expression rates were 54.8% in GEP-NECs at the primary site, associated with small cell neuroendocrine carcinoma (SCNEC) (p < 0.001), chemotherapy before baseline (p = 0.015), and at least two NE markers (p = 0.048). DLL3 expression in metastatic GEP-NECs was similar to that of primary tumors. Expression rates in NET G1, NET G2, NET G3, and GACs were 0%, 0%, 15.8%, and 0%, respectively, highlighting DLL3 as a powerful tool for identifying poorly differentiated NEC. DLL3 expression was related to ASCL1 in GEP-NECs, especially in SCNEC. It was not correlated with progression-free survival (PFS) or overall survival(OS), regardless of cutoff value (1%, 50%, 75%). In conclusion, DLL3 targeted therapy may offer potential for the treatment of poorly differentiated NEC of the digestive system, although further studies are needed to validate its efficacy.
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Affiliation(s)
- L Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - R Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - K Jiang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Y Hu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - X Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - L Zhang
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - Z Wang
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - T Long
- Neukio Biotherapeutics, Shanghai, 200131, China
| | - M Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - J Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Y Sun
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Pathology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Hounschell CA, Higginbotham S, Al-Kasspooles M, Selby LV. Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management. Cancers (Basel) 2024; 16:3472. [PMID: 39456565 PMCID: PMC11506451 DOI: 10.3390/cancers16203472] [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: 09/18/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.
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Affiliation(s)
- Corey A. Hounschell
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
| | | | - Mazin Al-Kasspooles
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
| | - Luke V. Selby
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
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Bongiovanni A, Liverani C, Foca F, Bergamo F, Leo S, Pusceddu S, Gelsomino F, Brizzi MP, Di Meglio G, Spada F, Tamberi S, Lolli I, Cives M, Marconcini R, Pucci F, Berardi R, Antonuzzo L, Badalamenti G, Santini D, Recine F, Vanni S, Tebaldi M, Severi S, Rudnas B, Nanni O, Ranallo N, Crudi L, Calabrò L, Ibrahim T. A randomized phase II trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas. Eur J Cancer 2024; 208:114129. [PMID: 39002347 DOI: 10.1016/j.ejca.2024.114129] [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: 02/08/2024] [Revised: 05/10/2024] [Accepted: 05/18/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER NCT03387592.
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Affiliation(s)
- Alberto Bongiovanni
- Osteoncology and Rare Tumor Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Liverani
- Bioscience Laboratory, Preclinic and Osteoncology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
| | - Flavia Foca
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Francesca Bergamo
- Medical Oncology Unit 1, IOV-Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Silvana Leo
- Department of Medical Oncology, "Vito Fazzi" Hospital, Lecce, Italy
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, ENETS Center of Excellence, Milan, Italy
| | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, Modena, Italy
| | - Maria Pia Brizzi
- Department of Oncology, "San Luigi Gonzaga" University Hospital, University of Turin, Orbassano, Italy
| | | | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Stefano Tamberi
- Medical Oncology Unit, "Degli Infermi" Hospital, Faenza, Italy
| | - Ivan Lolli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS "Saverio De Bellis", Castellana Grotte, Italy
| | - Mauro Cives
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, Bari, Italy; Division of Medical Oncology, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, Bari, Italy
| | - Riccardo Marconcini
- Medical Oncology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Francesca Pucci
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Rossana Berardi
- Department of Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Giuseppe Badalamenti
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Daniele Santini
- Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy
| | - Federica Recine
- Medical Oncology Unit, Azienda Ospedaliera "San Giovanni Addolorata", Rome, Italy
| | - Silvia Vanni
- Bioscience Laboratory, Preclinic and Osteoncology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Michela Tebaldi
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Stefano Severi
- Nuclear Medicine and Radiometabolic Units, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Britt Rudnas
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Nicoletta Ranallo
- Osteoncology and Rare Tumor Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Laura Crudi
- Department of Oncology, University Hospital of Ferrara, Cona, Italy
| | - Luana Calabrò
- Oncology Pharmacy Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", 47014 Meldola, Italy; Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumor Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy; Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
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Corti F, Rossi RE, Cafaro P, Passarella G, Turla A, Pusceddu S, Coppa J, Oldani S, Guidi A, Longarini R, Cortinovis DL. Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:2025. [PMID: 38893145 PMCID: PMC11171242 DOI: 10.3390/cancers16112025] [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: 04/25/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.
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Affiliation(s)
- Francesca Corti
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Roberta Elisa Rossi
- Gastroenterology and Endoscopy Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy;
| | - Pietro Cafaro
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Gaia Passarella
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Antonella Turla
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Sara Pusceddu
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Jorgelina Coppa
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy;
| | - Simone Oldani
- Gastro-Entero-Pancreatic and Neuroendocrine Unit 1, Department of Medical Oncology, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy; (S.P.); (S.O.)
| | - Alessandro Guidi
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Raffaella Longarini
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
| | - Diego Luigi Cortinovis
- Medical Oncology Unit, Fondazione IRCCS San Gerardo dei Tintori, Via G.B. Pergolesi 33, 20900 Monza, Italy; (P.C.); (G.P.); (A.T.); (A.G.); (R.L.); (D.L.C.)
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7
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von Arx C, Della Vittoria Scarpati G, Cannella L, Clemente O, Marretta AL, Bracigliano A, Picozzi F, Iervolino D, Granata V, Modica R, Bianco A, Mocerino C, Di Mauro A, Pizzolorusso A, Di Sarno A, Ottaiano A, Tafuto S. A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial. ESMO Open 2024; 9:103003. [PMID: 38615472 PMCID: PMC11033066 DOI: 10.1016/j.esmoop.2024.103003] [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: 01/31/2024] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine carcinoma. These patients generally have poor performance status and low tolerance to combination therapy. In this trial, we aim to evaluate the efficacy and safety of temozolomide given every other week in patients with advanced platinum-pretreated NENs G3. PATIENTS AND METHODS This trial is an open-label, non-randomized, phase II trial. Patients with platinum-pretreated metastatic neuroendocrine carcinoma were treated with 75 mg/m2/day of temozolomide for 7 days, followed by 7 days of no treatment (regimen one week on/one week off). The primary endpoint was the overall response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and tolerability. This study is registered with ClinicalTrials.gov, NCT04122911. RESULTS From 2017 to 2020, 38 patients were enrolled. Among the patients with determined Ki67, 12 out of 36 (33.3%) had a Ki67 index <55% and the remaining 24 out of 36 (66.6%) had an index ≥55%. Overall response rate was 18% (7/38), including one complete response and six partial responses. The median PFS was 5.86 months [95% confidence interval (CI) 4.8 months-not applicable) and the median OS was 12.1 months (95% CI 5.6-20.4 months). The 1-year PFS rate was 37%. No statistically significant difference in median PFS [hazard ratio 1.3 (95% CI 0.6-2.8); P = 0.44] and median OS [hazard ratio 1.1 (95% CI 0.5-2.4); P = 0.77] was observed among patients with Ki67 <55% versus ≥55%. Only G1-G2 adverse events were registered, the most common being G1 nausea, diarrhea and abdominal pain. CONCLUSION One week on/one week off temozolomide shows promising activity in patients with poorly differentiated NEN. The good safety profile confirmed the possibility of using this scheme in patients with poor performance status.
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Affiliation(s)
- C von Arx
- Department of Breast and Thoracic Oncology, Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples.
| | - G Della Vittoria Scarpati
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
| | - L Cannella
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
| | - O Clemente
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
| | - A L Marretta
- Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, Caserta
| | - A Bracigliano
- Nuclear Medicine, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G. Pascale", Naples
| | - F Picozzi
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
| | - D Iervolino
- ISS Clinica di Domenico Iervolino, Palma Campania, Naples
| | - V Granata
- Radiology Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G. Pascale", Naples
| | - R Modica
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples
| | - A Bianco
- Medical Oncology Unit AORN Ospedale dei Colli, Naples
| | - C Mocerino
- Medical Oncology Unit AORN "A. Cardarelli", Naples
| | - A Di Mauro
- Pathology Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G. Pascale", Naples
| | - A Pizzolorusso
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
| | - A Di Sarno
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples
| | - A Ottaiano
- SSD Innovative Therapies for Abdominal Metastases, Abdominal Oncology, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy
| | - S Tafuto
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori - I.R.C.C.S. Fondazione "G.Pascale", Naples
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8
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Zhang P, Shi S, Xu J, Chen Z, Song L, Zhang X, Cheng Y, Zhang Y, Ye F, Li Z, Yin F, Ji D, Gao H, Li Y, Chen W, Yang M, Weng D, Wu C, Ma Y, Sheng W, Zhao Y, Yin X, Shen W, Su W, Shi M, Fan S, Tan P, Xu Q, Lu M, Shen L. Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial. Eur J Cancer 2024; 199:113539. [PMID: 38237373 DOI: 10.1016/j.ejca.2024.113539] [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: 11/09/2023] [Revised: 12/29/2023] [Accepted: 01/05/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS gov: NCT04169672.
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Affiliation(s)
- Panpan Zhang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Si Shi
- Department of Pancreatic Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Xuhui district, Shanghai, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center of Chinese PLA General Hospital, No.8 East Avenue, Fengtai District, Beijing, China
| | - Zhendong Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, No.678 Furong Road, Economic and Technological Development Zone, Hefei, Anhui, China
| | - Lijie Song
- First Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, Henan, China
| | - Xing Zhang
- Biotherapy Center, Sun Yat-sen University Cancer Center, No.651 East Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, No.1066 Jinghu Avenue, Gaoxin District, Changchun, Jilin,China
| | - Yanqiao Zhang
- Second Department of Gastroenterology, Harbin Medical University Cancer Hospital, No.150 Haping Road, Nangang District, Harbin, Heilongjiang, China
| | - Feng Ye
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Siming District, Xiamen, Fujian, China
| | - Zhiping Li
- Department of Abdominal Oncology, West China Hospital of Sichuan University, No.37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China
| | - Fei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, No.12 Jiankan Road, Shijiazhuang, Hebei, China
| | - Dongmei Ji
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Xuhui district, Shanghai, China
| | - Heli Gao
- Department of Pancreatic Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Xuhui district, Shanghai, China
| | - Yi Li
- Department of Gastrointestinal Oncology, The Fifth Medical Center of Chinese PLA General Hospital, No.8 East Avenue, Fengtai District, Beijing, China
| | - Wei Chen
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, No.678 Furong Road, Economic and Technological Development Zone, Hefei, Anhui, China
| | - Minjie Yang
- First Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, Henan, China
| | - Desheng Weng
- Biotherapy Center, Sun Yat-sen University Cancer Center, No.651 East Dongfeng Road, Yuexiu District, Guangzhou, Guangdong, China
| | - Chunjiao Wu
- Phase I Study Ward, Jilin Cancer Hospital, No.1066 Jinghu Avenue, Gaoxin District, Changchun, Jilin, China
| | - Yue Ma
- Second Department of Gastroenterology, Harbin Medical University Cancer Hospital, No.150 Haping Road, Nangang District, Harbin, Heilongjiang, China
| | - Wang Sheng
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, No.55 Zhenhai Road, Siming District, Xiamen, Fujian, China
| | - Yaqin Zhao
- Department of Abdominal Oncology, West China Hospital of Sichuan University, No.37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, China
| | - Xiaolei Yin
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, No.12 Jiankan Road, Shijiazhuang, Hebei, China
| | - Weina Shen
- Phase I Study Ward, Fudan University Shanghai Cancer Center, No.270 Dong'an Road, Xuhui district, Shanghai, China
| | - Weiguo Su
- HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Michael Shi
- Clinical & Regulatory Department, HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Songhua Fan
- Clinical & Regulatory Department, HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Panfeng Tan
- Clinical & Regulatory Department, HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Qian Xu
- Clinical & Regulatory Department, HUTCHMED Limited, Building 4, 720 Cailun Road, Pilot Free Trade Zone, Shanghai, China
| | - Ming Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
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9
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Yoshinami Y, Nishimura E, Hosokai T, Yamamoto S, Matsuda S, Nomura M, Kawakubo H, Kato K, Kitagawa Y. Rare malignant neoplasm of the esophagus: current status and future perspectives. Jpn J Clin Oncol 2024; 54:111-120. [PMID: 37861097 PMCID: PMC10849183 DOI: 10.1093/jjco/hyad144] [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: 06/14/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023] Open
Abstract
Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.
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Affiliation(s)
- Yuri Yoshinami
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Erica Nishimura
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Taisuke Hosokai
- Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Motoo Nomura
- Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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10
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Zi M, Ma Y, Chen J, Pang C, Li X, Yuan L, Liu Z, Yu P. Clinicopathological characteristics of gastric neuroendocrine neoplasms: A comprehensive analysis. Cancer Med 2024; 13:e7011. [PMID: 38457192 PMCID: PMC10922030 DOI: 10.1002/cam4.7011] [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] [Received: 09/25/2023] [Revised: 11/29/2023] [Accepted: 01/31/2024] [Indexed: 03/09/2024] Open
Abstract
OBJECTIVE This study aimed to explore the clinicopathological characteristics and prognostic implications of gastric neuroendocrine neoplasms (g-NENs). METHODS A retrospective enrollment of 142 patients diagnosed with g-NENs was conducted at Zhejiang Cancer Hospital between January 1, 2007 and December 31, 2021. The study compared essential clinicopathological features and survival rates. Additionally, the prognosis of gastric neuroendocrine carcinomas/mixed neuroendocrine-non-neuroendocrine neoplasms (g-NEC/MiNEN) were contrasted with those of gastric adenocarcinoma (GAC) and signet ring cell carcinoma (SRCC). RESULTS The study comprised a total of 142 g-NENs cases, with a male-to-female ratio of approximately 2:1. The 5-year survival rates for g-NEC and g-MiNEN were 26.7% and 35.2%, respectively. Corresponding 5-year survival rates for G1 and G2 were observed at 100% and 80.0%, respectively. g-NEC/MiNEN showed a significantly worse prognosis compared to g-NET (p < 0.001). g-NEC/MiNEN exhibited a poor prognosis compared to GAC (p < 0.001), and within poorly differentiated GAC, g-NEC/MiNEN demonstrated a worse prognosis (p = 0.007). Additionally, patients receiving postoperative adjuvant therapy exhibited notably prolonged overall survival (OS) in the case of g-NEC/MiNEN (p = 0.010). CONCLUSION In short, the prognosis of g-NEC/MiNEN was worse than that of g-NET, GAC and poorly differentiated GAC, but this group benefit from postoperative adjuvant therapy.
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Affiliation(s)
- Mengli Zi
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)HangzhouZhejiangChina
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
| | - Yubo Ma
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
- The Second Clinical Medical College of Zhejiang Chinese Medical UniversityHangzhouZhejiangChina
| | - Jinxia Chen
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)HangzhouZhejiangChina
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
| | - Chuhong Pang
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)HangzhouZhejiangChina
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
| | - Xiao Li
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
- The Second Clinical Medical College of Zhejiang Chinese Medical UniversityHangzhouZhejiangChina
| | - Li Yuan
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract CancerZhejiang Cancer HospitalHangzhouChina
- Zhejiang Key Lab of Prevention, Diagnosis and Therapy of Upper Gastrointestinal CancerZhejiang Cancer HospitalHangzhouChina
| | - Zhuo Liu
- Department of Colorectum surgeryZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
| | - Pengfei Yu
- Department of Gastric surgery, Zhejiang Cancer HospitalHangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
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11
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Stumpo S, Formelli MG, Persano I, Parlagreco E, Lauricella E, Rodriquenz MG, Guerrera LP, Zurlo IV, Campana D, Brizzi MP, Cives M, La Salvia A, Lamberti G. Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives. J Clin Med 2023; 12:7715. [PMID: 38137784 PMCID: PMC10743506 DOI: 10.3390/jcm12247715] [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: 11/04/2023] [Revised: 12/07/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.
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Affiliation(s)
- Sara Stumpo
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum–University of Bologna, Via Zamboni 33, 40126 Bologna, Italy; (S.S.); (M.G.F.); (D.C.); (G.L.)
| | - Maria Giovanna Formelli
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum–University of Bologna, Via Zamboni 33, 40126 Bologna, Italy; (S.S.); (M.G.F.); (D.C.); (G.L.)
| | - Irene Persano
- Medical Oncology, AO S. Croce e Carle, 12100 Cuneo, Italy; (I.P.); (E.P.)
| | - Elena Parlagreco
- Medical Oncology, AO S. Croce e Carle, 12100 Cuneo, Italy; (I.P.); (E.P.)
| | - Eleonora Lauricella
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, 70124 Bari, Italy; (E.L.); (M.C.)
| | - Maria Grazia Rodriquenz
- Oncology Unit, Ospedale IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Luigi Pio Guerrera
- Division of Medical Oncology, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy;
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori, IRCCS-Fondazione “G. Pascale”, 80131 Naples, Italy
| | | | - Davide Campana
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum–University of Bologna, Via Zamboni 33, 40126 Bologna, Italy; (S.S.); (M.G.F.); (D.C.); (G.L.)
- Medical Oncology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via P. Albertoni 15, 40138 Bologna, Italy
| | - Maria Pia Brizzi
- Department of Oncology, A.O.U. San Luigi Gonzaga Hospital, 10043 Orbassano, Italy;
| | - Mauro Cives
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, 70124 Bari, Italy; (E.L.); (M.C.)
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70121 Bari, Italy
| | - Anna La Salvia
- National Center for Drug Research and Evaluation, National Institute of Health (ISS), 00161 Rome, Italy
| | - Giuseppe Lamberti
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum–University of Bologna, Via Zamboni 33, 40126 Bologna, Italy; (S.S.); (M.G.F.); (D.C.); (G.L.)
- Medical Oncology Unit, Vito Fazzi Hospital, 73100 Lecce, Italy;
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12
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Weaver JMJ, Hubner RA, Valle JW, McNamara MG. Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma. Cancers (Basel) 2023; 15:4951. [PMID: 37894318 PMCID: PMC10604995 DOI: 10.3390/cancers15204951] [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: 06/09/2023] [Revised: 10/02/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
Extra-pulmonary poorly differentiated neuroendocrine carcinoma is rare, and evidence for treatment has been limited. In this article, the evidence behind the cytotoxic chemotherapy choices used for metastatic or unresectable EP-PD-NEC is reviewed. In the first-line setting, etoposide and platinum chemotherapy or irinotecan and platinum have been demonstrated to be equivalent in a large phase III trial. Questions remain regarding the optimal number of cycles, mode of delivery, and the precise definition of platinum resistance in this setting. In the second-line setting, FOLFIRI has emerged as an option, with randomized phase 2 trials demonstrating modest, but significant, response rates. Beyond this, data are extremely limited, and several regimens have been used. Heterogeneity in biological behaviour is a major barrier to optimal EP-PD-NEC management. Available data support the potential role of the Ki-67 index as a predictive biomarker for chemotherapy response. A more personalised approach to management in future studies will be essential, and comprehensive multi-omic approaches are required to understand tumour somatic genetic changes in relation to their effects on the surrounding microenvironment.
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Affiliation(s)
- Jamie M. J. Weaver
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
| | - Juan W. Valle
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Mairead G. McNamara
- The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; (J.M.J.W.); (R.A.H.); (J.W.V.)
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
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13
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Andreatos N, McGarrah PW, Sonbol MB, Starr JS, Capdevila J, Sorbye H, Halfdanarson TR. Managing Metastatic Extrapulmonary Neuroendocrine Carcinoma After First-Line Treatment. Curr Oncol Rep 2023; 25:1127-1139. [PMID: 37606874 DOI: 10.1007/s11912-023-01438-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 08/23/2023]
Abstract
PURPOSE OF REVIEW Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space. RECENT FINDINGS After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.
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Affiliation(s)
- Nikolaos Andreatos
- Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Patrick W McGarrah
- Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | | | - Jason S Starr
- Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA
| | - Jaume Capdevila
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
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14
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Castillón JC, Gordoa TA, Bayonas AC, Carretero AC, García-Carbonero R, Pulido EG, Fonseca PJ, Lete AL, Huerta AS, Plazas JG. SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022). Clin Transl Oncol 2023; 25:2692-2706. [PMID: 37204633 PMCID: PMC10425298 DOI: 10.1007/s12094-023-03205-6] [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: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/20/2023]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.
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Affiliation(s)
- Jaume Capdevila Castillón
- Servicio de Oncología Médica, Hospital Universitario Vall D’Hebron, Ps Vall d’Hebron, 119-129, 08035 Barcelona, Spain
| | - Teresa Alonso Gordoa
- Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | | | | | | | - Paula Jiménez Fonseca
- Servicio de Oncología Médica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Angela Lamarca Lete
- Servicio de Oncología Médica, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - Angel Segura Huerta
- Servicio de Oncología Médica, Hospital Universitari I Politècnic la Fe, Valencia, Spain
| | - Javier Gallego Plazas
- Servicio de Oncología Médica, Hospital General Universitario de Elche, Alicante, Spain
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15
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Ooki A, Osumi H, Fukuda K, Yamaguchi K. Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma. Cancer Metastasis Rev 2023; 42:1021-1054. [PMID: 37422534 PMCID: PMC10584733 DOI: 10.1007/s10555-023-10121-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/16/2023] [Indexed: 07/10/2023]
Abstract
Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koshiro Fukuda
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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16
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Riechelmann RP, Taboada RG, de Jesus VHF, Iglesia M, Trikalinos NA. Therapy Sequencing in Patients With Advanced Neuroendocrine Neoplasms. Am Soc Clin Oncol Educ Book 2023; 43:e389278. [PMID: 37257140 DOI: 10.1200/edbk_389278] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Neuroendocrine neoplasms (NENs) comprise a beautifully complicated, exciting landscape of histologies and clinical behaviors. However, the nuanced complexity of low- and high-grade variants can easily overwhelm both patients and providers. In this chapter, we review the ever-expanding literature on both functioning and nonfunctioning small bowel and pancreatic NENs, touching on somatostatin analogs, hepatic-directed therapies, small molecules, radiopharmaceuticals, immunotherapy, cytotoxic chemotherapy, and new promising agents. Furthermore, we suggest some strategies to address the most challenging scenarios seen in clinical practice, including sequencing of agents, treatment of carcinoid syndrome, and options for well-differentiated high-grade disease.
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Affiliation(s)
| | - Rodrigo G Taboada
- Department of Clinical Oncology, A.C.Camargo Cancer Center, Sao Paulo, Brazil
| | | | - Michael Iglesia
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
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17
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Robinson MD, Livesey D, Hubner RA, Valle JW, McNamara MG. Future therapeutic strategies in the treatment of extrapulmonary neuroendocrine carcinoma: a review. Ther Adv Med Oncol 2023; 15:17588359231156870. [PMID: 36872945 PMCID: PMC9983111 DOI: 10.1177/17588359231156870] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/27/2023] [Indexed: 03/06/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are rare malignancies arising most commonly in the gastrointestinal and bronchopulmonary systems. Neuroendocrine carcinomas (NECs) are a subgroup of NENs characterised by aggressive tumour biology, poor differentiation and dismal prognosis. Most NEC primary lesions arise in the pulmonary system. However, a small proportion arise outside of the lung and are termed extrapulmonary (EP)-, poorly differentiated (PD)-NECs. Patients with local or locoregional disease may benefit from surgical excision; however, this is often not an option, due to late presentation. To date, treatment has mirrored that of small-cell lung cancer, with platinum-etoposide forming the basis of first-line treatment. There is a lack of consensus in relation to the most effective second-line treatment option. Low incidence, an absence of representative preclinical models and a lack of understanding of the tumour microenvironment all present challenges to drug development in this disease group. However, progress made in elucidating the mutational landscape of EP-PD-NEC and the observations made in several clinical trials are paving the way towards improving outcomes for these patients. The optimisation and strategic delivery of chemotherapeutic interventions according to tumour characteristics and the utilisation of targeted and immune therapies in clinical studies have yielded mixed results. Targeted therapies that complement specific genetic aberrations are under investigation, including AURKA inhibitors in those with MYCN amplifications, BRAF inhibitors in those with BRAFV600E mutations and EGFR suppression, and Ataxia Telangiectasia and Rad3-related inhibitors in patients with ATM mutations. Immune checkpoint inhibitors (ICIs) have conferred promising results in several clinical trials, particularly with dual ICIs and in combination with targeted therapy or chemotherapy. However, further prospective investigations are required to elucidate the impact of programmed cell death ligand 1 expression, tumour mutational burden and microsatellite instability on response. This review aims to explore the most recent developments in the treatment of EP-PD-NEC and contribute towards the requirement for clinical guidance founded on prospective evidence.
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Affiliation(s)
- Matthew D. Robinson
- Division of Cancer Sciences, School of Medical
Sciences, Faculty of Biology Medicine and Health, The University of
Manchester, Manchester, UK
| | - Daniel Livesey
- The Christie Library, School of Oncology, The
Christie NHS Foundation Trust, Manchester, UK
| | - Richard A. Hubner
- Division of Cancer Sciences, School of Medical
Sciences, Faculty of Biology Medicine and Health, The University of
Manchester, Manchester, UK
- Department of Medical Oncology, ENETS Centre of
Excellence, The Christie NHS Foundation Trust, Manchester, UK
| | - Juan W. Valle
- Division of Cancer Sciences, School of Medical
Sciences, Faculty of Biology Medicine and Health, The University of
Manchester, Manchester, UK
- Department of Medical Oncology, ENETS Centre of
Excellence, The Christie NHS Foundation Trust, Manchester, UK
| | - Mairéad G. McNamara
- Division of Cancer Sciences, School of Medical
Sciences, Faculty of Biology Medicine and Health, The University of
Manchester, Manchester M20 4BX, UK
- Department of Medical Oncology, ENETS Centre of
Excellence, The Christie NHS Foundation Trust, Wilmslow Road, Manchester,
M20 4BX, UK
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18
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Kong G, Boehm E, Prall O, Murray WK, Tothill RW, Michael M. Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN). Curr Oncol Rep 2023; 25:465-478. [PMID: 36826704 PMCID: PMC10110720 DOI: 10.1007/s11912-023-01381-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE OF REVIEW Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.
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Affiliation(s)
- Grace Kong
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia. .,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
| | - Emma Boehm
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.,Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Owen Prall
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - William K Murray
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Richard W Tothill
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.,Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Michael Michael
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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19
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Symons R, Daly D, Gandy R, Goldstein D, Aghmesheh M. Progress in the Treatment of Small Intestine Cancer. Curr Treat Options Oncol 2023; 24:241-261. [PMID: 36826686 DOI: 10.1007/s11864-023-01058-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 02/25/2023]
Abstract
OPINION STATEMENT Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.
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Affiliation(s)
- Rebecca Symons
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia
| | - Daniel Daly
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - Robert Gandy
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - David Goldstein
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.,University of New South Wales, Randwick, NSW, Australia
| | - Morteza Aghmesheh
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, High St, Randwick, Sydney, NSW, 2031, Australia.
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20
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Mohamed A, Wu S, Hamid M, Mahipal A, Cjakrabarti S, Bajor D, Selfridge JE, Asa SL. Management of Appendix Neuroendocrine Neoplasms: Insights on the Current Guidelines. Cancers (Basel) 2022; 15:295. [PMID: 36612291 PMCID: PMC9818268 DOI: 10.3390/cancers15010295] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/19/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5-1% of intestinal neoplasms; they are found in 0.3-0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.
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Affiliation(s)
- Amr Mohamed
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sulin Wu
- Department of Internal Medicine, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
- Department of Medical Genetics, Center for Human Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mohamed Hamid
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Amit Mahipal
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sakti Cjakrabarti
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - David Bajor
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - J. Eva Selfridge
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sylvia L. Asa
- Department of Pathology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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21
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Arrivi G, Verrico M, Roberto M, Barchiesi G, Faggiano A, Marchetti P, Mazzuca F, Tomao S. Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs): A Systematic Review and Pooled Analysis. Cancer Manag Res 2022; 14:3507-3523. [PMID: 36575665 PMCID: PMC9790144 DOI: 10.2147/cmar.s372776] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022] Open
Abstract
Background Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs). Methods We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs. Results A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%). Conclusion This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.
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Affiliation(s)
- Giulia Arrivi
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Monica Verrico
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Michela Roberto
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Giacomo Barchiesi
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Antongiulio Faggiano
- Department of Clinical and Molecular Medicine, Endocrinology Unit, Sant ‘Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Paolo Marchetti
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
- Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Federica Mazzuca
- Department of Clinical and Molecular Medicine, Oncology Unit, Sant’ Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Medical Oncology Unit A, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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22
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Yao J, Bergsland E, Aggarwal R, Aparicio A, Beltran H, Crabtree JS, Hann CL, Ibrahim T, Byers LA, Sasano H, Umejiego J, Pavel M. DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms. Oncologist 2022; 27:940-951. [PMID: 35983951 PMCID: PMC9632312 DOI: 10.1093/oncolo/oyac161] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/01/2022] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis. METHODS This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs. DISCUSSION DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN. CONCLUSIONS Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.
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Affiliation(s)
- James Yao
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Emily Bergsland
- Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Rahul Aggarwal
- Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
| | - Ana Aparicio
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Himisha Beltran
- Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Judy S Crabtree
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Christine L Hann
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Toni Ibrahim
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCSS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Lauren A Byers
- Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | | | - Marianne Pavel
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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23
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Hadoux J, Walter T, Kanaan C, Hescot S, Hautefeuille V, Perrier M, Tauveron I, Laboureau S, Do Cao C, Petorin C, Blanchet O, Faron M, Leteurtre E, Rousselet MC, Joubert Zakeyh J, Marchal A, Chatelain D, Beaulaton C, Hervieu V, Lombard-Bohas C, Ducreux M, Scoazec JY, Baudin E. Second-line treatment and prognostic factors in neuroendocrine carcinoma: the RBNEC study. Endocr Relat Cancer 2022; 29:569-580. [PMID: 35920609 DOI: 10.1530/erc-22-0102] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/29/2022] [Indexed: 11/08/2022]
Abstract
Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an 'adenocarcinoma-like' or a 'neuroendocrine-like' 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum-etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum-etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.
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Affiliation(s)
- Julien Hadoux
- Oncologie Endocrinienne, Département d'Imagerie, Gustave Roussy, Villejuif, France
| | - Thomas Walter
- Service d'Oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France
| | - Christina Kanaan
- Service de Pathologie, Département de Biologie et Pathologie Médicale, Gustave Roussy, Villejuif, France
| | | | - Vincent Hautefeuille
- Service d'Hépato-gastro-entérologie et Cancérologie Digestive, CHU Amiens Picardie, Amiens, France
| | - Marine Perrier
- Département d'Hépato-gastro-entérologie, CHU de Reims, Reims, France
| | - Igor Tauveron
- Service d'Endocrinologie, Diabétologie et Maladies Métaboliques, CHU Clermont-Ferrand, Clermont-Ferrand, France
- Laboratoire GReD, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Sandrine Laboureau
- Département d'Endocrinologie-Diabétologie-Nutrition, CHU d'Angers, Angers Cedex 9, France
| | | | - Caroline Petorin
- CHU Clermont-Ferrand, Service de Chirurgie Digestive et Hépatobiliaire, Clermont-Ferrand, France
| | | | - Matthieu Faron
- Département de Chirurgie, Gustave Roussy, Villejuif, France
| | - Emmanuelle Leteurtre
- CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277, Lille, France
| | | | | | - Aude Marchal
- Service d'Anatomo-Pathologie, CHU Reims, Reims, France
| | | | | | - Valérie Hervieu
- Service d'Anatomo-Pathologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France
| | - Catherine Lombard-Bohas
- Service d'Oncologie, ENETS Centre of Excellence, Hospices Civils de Lyon et Université de Lyon, Lyon, France
| | - Michel Ducreux
- Service d'Oncologie Digestive, Département de Médecine, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Jean-Yves Scoazec
- Service de Pathologie, Département de Biologie et Pathologie Médicale, Gustave Roussy, Villejuif, France
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Eric Baudin
- Oncologie Endocrinienne, Département d'Imagerie, Gustave Roussy, Villejuif, France
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Jia R, Li Y, Xu N, Jiang HP, Zhao CH, Liu RR, Shi Y, Zhang YY, Wang SY, Zhou H, Xu JM. Sintilimab in Patients with Previously Treated Metastatic Neuroendocrine Neoplasms. Oncologist 2022; 27:e625-e632. [PMID: 35647908 PMCID: PMC9355821 DOI: 10.1093/oncolo/oyac097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 04/07/2022] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) are a group of diseases that show high heterogeneity but have limited treatment options. This phase I study evaluated the safety and efficacy of sintilimab, anti-PD-1 monoclonal antibody, in treating advanced NENs. METHODS We prospectively enrolled patients pathologically diagnosed with NENs after standard treatment failure. Neuroendocrine neoplasms were classified into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine cancers (NECs). Every patient received sintilimab, and response was assessed every 9 weeks. RESULTS Twenty-four patients with a median age of 57.0 years were enrolled from November 2016 to 2017. The median Ki-67 index was 60%. Five patients had NET, 1 had NET G3, 17 had NEC, and 1 had mixed adenocarcinoma-neuroendocrine carcinoma. The most common primary tumor sites were the pancreas and gastrointestinal tract in 7 and 10 patients, respectively. In phase Ia trial, 2 patients received sintilimab 1 mg/kg every 2 weeks, one received 3 mg/kg every 2 weeks, and 21 patients enrolled in the phase Ib trial received 200 mg every 3 weeks. The objective response rate was 20.8% in all enrolled patients and 27.8% in NEC patients. The median progression-free survival was 2.2 and 2.1 months in patients with NET and NEC, respectively. The median OS was not applicable (NA) and 10.8 months (95% CI, 4.3, NA) with NET and NEC, respectively. The duration of response (DOR) was not reached, with a median follow-up time of 20.7 months. Treatment-related adverse events (TRAE) occurred in 17 (70.8%) patients. The most frequent TRAE was thyroid dysfunction (41.7%), and a grade 3 pulmonary infection occurred in 1 patient. The programmed cell death 1-ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) rate was 18.8% (3 out of 16) and the expression of PD-L1 did not correlate with response. CONCLUSION Sintilimab was well-tolerated and showed encouraging response in NECs. CLINICALTRIALS.GOV IDENTIFIER NCT02937116.
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Affiliation(s)
- Ru Jia
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Yi Li
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Nong Xu
- Department of Oncology, The First Affiliated Hospital of the Medical School of Zhejiang University, Hangzhou, People’s Republic of China
| | - Hai-Ping Jiang
- Department of Oncology, The First Affiliated Hospital of the Medical School of Zhejiang University, Hangzhou, People’s Republic of China
| | - Chuan-Hua Zhao
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Rong-Rui Liu
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Yue Shi
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Yao-Yue Zhang
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Shu-Yan Wang
- Medical Science and Strategy Oncology, Innovent Biologics, Inc., Suzhou, People’s Republic of China
| | - Hui Zhou
- Medical Science and Strategy Oncology, Innovent Biologics, Inc., Suzhou, People’s Republic of China
| | - Jian-Ming Xu
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
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Chan D, Rodriguez-Freixinos V, Doherty M, Wasson K, Iscoe N, Raskin W, Hallet J, Myrehaug S, Law C, Thawer A, Nguyen K, Singh S. Avelumab in unresectable/metastatic, progressive, grade 2–3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials. Eur J Cancer 2022; 169:74-81. [DOI: 10.1016/j.ejca.2022.03.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/07/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
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RUNDC3A regulates SNAP25-mediated chemotherapy resistance by binding AKT in gastric neuroendocrine carcinoma (GNEC). Cell Death Dis 2022; 8:296. [PMID: 35752613 PMCID: PMC9233710 DOI: 10.1038/s41420-022-01084-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 06/06/2022] [Accepted: 06/08/2022] [Indexed: 11/26/2022]
Abstract
Gastric neuroendocrine carcinoma (GNEC) is a common type of neuroendocrine carcinoma (NEC) with a poor prognosis and limited therapeutic options. The underlying mechanisms of chemoresistance in patients with GNEC and those with NEC are largely unknown, and thus, reliable biomarkers and therapeutic targets that could improve treatment outcomes in patients with NECs are lacking. The aim of this study was to identify specific targets and investigate their roles in GNEC progression and treatment resistance. Differentially expressed genes (DEGs) were identified in GNEC specimens and were further analysed by focusing on their roles in chemoresistance. Gene Ontology (GO) and pathway enrichment analyses of GNEC DEGs revealed that synapse-related function was the most prominent cellular function perturbed in GNEC. SNAP25 was identified as the target gene involved in most of the enriched pathways. In vitro and in vivo experiments showed that SNAP25 plays a role in proliferation and chemoresistance in GNEC cell lines. AKT has been identified as a downstream target, and SNAP25 binds to AKT protein and promotes AKT protein half-life. Further analysis of other types of NEC as well as small cell lung cancer, which resembles NEC on a molecular level, has identified RUNDC3A as an upstream molecule that regulates SNAP25 expression and the associated phenotypes that could enhance chemoresistance in NECs. Our results show that SNAP25 expression in GNEC is mediated by RUNDC3A and promotes GNEC progression and chemoresistance via posttranslational modification of AKT. Thus, our results suggest that the RUNDC3A/SNAP25/Akt axis could be a potential therapeutic target in GNEC.
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Luecke S, Fottner C, Lahner H, Jann H, Zolnowski D, Quietzsch D, Grabowski P, Cremer B, Maasberg S, Pape UF, Mueller HH, Gress TM, Rinke A. Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice. Cancers (Basel) 2022; 14:2718. [PMID: 35681701 PMCID: PMC9179270 DOI: 10.3390/cancers14112718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Neuroendocrine neoplasia grade 3 (NEN G3) represents a rare and heterogeneous cancer type with a poor prognosis. The aim of our study was to analyze real-world data from the German NET Registry with a focus on therapeutic and prognostic aspects. METHODS NEN G3 patients were identified within the German NET Registry. Demographic data and data on treatments and outcomes were retrieved. Univariate analyses were performed using the Kaplan-Meier-method. Multivariate analysis was performed using a Cox proportional hazard model. RESULTS Of 445 included patients, 318 (71.5%) were diagnosed at stage IV. Well-differentiated morphology (NET G3) was described in 31.7%, 60% of cases were classified as neuroendocrine carcinoma (NEC), and the median Ki67 value was 50%. First-line treatment comprised chemotherapy in 43.8%, with differences in the choice of regimen with regard to NET or NEC, and surgery in 41.6% of patients. Median overall survival for the entire cohort was 31 months. Stage, performance status and Ki67 were significant prognostic factors in multivariate analysis. CONCLUSIONS The survival data of our national registry compare favorably to population-based data, probably mainly because of a relatively low median Ki67 of 50%. Nevertheless, the best first- and second-line approaches for specific subgroups remain unclear, and an international effort to fill these gaps is needed.
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Affiliation(s)
- Simone Luecke
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
| | - Christian Fottner
- Department of Internal Medicine I, Endocrinology, University Hospital Mainz, 55131 Mainz, Germany;
| | - Harald Lahner
- Department of Endocrinology and Metabolism, University Hospital of Essen, 45147 Essen, Germany;
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Campus Virchow Klinikum, University Medicine Charité, 10117 Berlin, Germany;
| | | | - Detlef Quietzsch
- Praxis Dr. med. habil. Diener, 09376 Oelsnitz/Erzgebirge, Germany;
| | - Patricia Grabowski
- Klinikum Havelhöhe, Campus Virchow Klinikum, Institute of Medical Immunology, MVZ Oncology, University Medicine Charité, 10117 Berlin, Germany;
| | - Birgit Cremer
- Department of Oncology, University Hospital of Cologne, 50923 Cologne, Germany;
| | - Sebastian Maasberg
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (S.M.); (U.-F.P.)
| | - Ulrich-Frank Pape
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, 20099 Hamburg, Germany; (S.M.); (U.-F.P.)
| | - Hans-Helge Mueller
- Institute of Medical Biometry and Epidemiology, Philipps University Marburg, 35037 Marburg, Germany;
| | - Thomas Matthias Gress
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
| | - Anja Rinke
- UKGM Marburg, Department of Gastroenterology, Philipps University Marburg, 35037 Marburg, Germany; (S.L.); (T.M.G.)
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Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC). Cancers (Basel) 2022; 14:cancers14112695. [PMID: 35681675 PMCID: PMC9179548 DOI: 10.3390/cancers14112695] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/10/2022] [Accepted: 05/24/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Extrapulmonary neuroendocrine carcinomas (EP-NEC) are a group of tumors which are often metastatic and characterized by poor outcomes. Platinum-etoposide chemotherapy is the current front-line therapy for metastatic EP-NEC, and has been adapted from small cell lung cancer. There are limited treatment options for patients with platinum-resistant EP-NEC, with no current established second-line standard of care. Recently, there has been mixed evidence for the role of immunotherapy in EP-NEC, with limited existing prospective data. In this multicenter retrospective analysis, we compared outcomes between patients with refractory EP-NEC who received single, dual immune check point inhibitors (ICPIs) and cytotoxic chemotherapy in the second-line setting. This real world experience suggests that utilizing ipilimumab and nivolumab in patients with second-line pretreated EP-NEC may be more effective than other existing treatment options. Abstract Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.
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Li YL, Cheng ZX, Yu FH, Tian C, Tan HY. Advances in medical treatment for pancreatic neuroendocrine neoplasms. World J Gastroenterol 2022; 28:2163-2175. [PMID: 35721885 PMCID: PMC9157622 DOI: 10.3748/wjg.v28.i20.2163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/31/2021] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years. For patients with locally advanced or distant metastatic PanNENs, systemic treatment options vary due to the different differentiations, grades and stages. The available options for systemic therapy include somatostatin analogs, mole-cularly targeted agents, cytotoxic chemotherapeutic agents, immune checkpoint inhibitors, and peptide receptor radionuclide therapy. In addition, the development of novel molecularly targeted agents is currently in progress. The sequence of selection between different chemotherapy regimens has been of great interest, and resistance to chemotherapeutic agents is the major limitation in their clinical application. Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents. Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors, and greater therapeutic efficacy may be achieved by emerging radio-labeled peptides. Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity, dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy. Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments. In the future, the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.
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Affiliation(s)
- Yuan-Liang Li
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zi-Xuan Cheng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Fu-Huan Yu
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chao Tian
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Huang-Ying Tan
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
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Bardasi C, Spallanzani A, Benatti S, Spada F, Laffi A, Antonuzzo L, Lavacchi D, Marconcini R, Ferrari M, Rimini M, Caputo F, Santini C, Cerma K, Casadei-Gardini A, Andrikou K, Salati M, Bertolini F, Fontana A, Dominici M, Luppi G, Gelsomino F. Irinotecan-based chemotherapy in extrapulmonary neuroendocrine carcinomas: survival and safety data from a multicentric Italian experience. Endocrine 2021; 74:707-713. [PMID: 34231124 DOI: 10.1007/s12020-021-02813-y] [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: 12/29/2020] [Accepted: 06/22/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE Neuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs. METHODS Patients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS Thirty-four patients, 16 males, and 18 females, median age of 59 years (range 32-77), with metastatic NEC were included. Twenty-seven patients had Ki-67 ≥ 55% and four patients Ki-67 of <55% (for three patients data were not available). The median number of treatment cycles of the IRI-based regimen was 7.5 (range 1-16). Six partial responses (17.6%) and 9 stable diseases (26.5%) were observed, with a disease control rate of 44.1%. Median PFS and OS were 4.4 and 5.9 months, respectively. Neutropenia, anemia, and nausea were the only G3-G4 toxicities reported. CONCLUSIONS Despite the relatively small sample size, IRI-based therapy demonstrated to be a valid option for patients with pretreated extrapulmonary NEC.
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Affiliation(s)
- Camilla Bardasi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Stefania Benatti
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Daniele Lavacchi
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | | | - Marco Ferrari
- Unit of Medical Oncology, Pisa University Hospital, Pisa, Italy
| | - Margherita Rimini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Francesco Caputo
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Chiara Santini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Krisida Cerma
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- Department of Medical Oncology, University Vita-Salute, San Raffaele Hospital, IRCCS, Milan, Italy
| | - Kalliopi Andrikou
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Massimiliano Salati
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Federica Bertolini
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Annalisa Fontana
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Gabriele Luppi
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.
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Chan DL, Bergsland EK, Chan JA, Gadgil R, Halfdanarson TR, Hornbacker K, Kelly V, Kunz PL, McGarrah PW, Raj NP, Reidy DL, Thawer A, Whitman J, Wu L, Becker C, Singh S. Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review. Oncologist 2021; 26:950-955. [PMID: 34342086 PMCID: PMC8571741 DOI: 10.1002/onco.13923] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/13/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. MATERIALS AND METHODS A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. RESULTS One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). CONCLUSION This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. IMPLICATIONS FOR PRACTICE Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.
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Affiliation(s)
- David L. Chan
- Odette Cancer Centre, Sunnybrook Health Sciences CentreTorontoCanada
- Northern Clinical School, University of SydneyCamperdownAustralia
| | - Emily K. Bergsland
- Helen Diller Family Comprehensive Cancer Centre, University of California San FranciscoSan FranciscoCaliforniaUSA
| | | | | | | | - Kathleen Hornbacker
- School of Medicine, Stanford University School of MedicinePalo AltoCaliforniaUSA
| | - Virginia Kelly
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Pamela L. Kunz
- School of Medicine, Stanford University School of MedicinePalo AltoCaliforniaUSA
| | | | - Nitya P. Raj
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Diane L. Reidy
- Memorial Sloan Kettering Cancer CenterNew YorkNew YorkUSA
| | - Alia Thawer
- Odette Cancer Centre, Sunnybrook Health Sciences CentreTorontoCanada
| | - Julia Whitman
- Helen Diller Family Comprehensive Cancer Centre, University of California San FranciscoSan FranciscoCaliforniaUSA
| | - Linda Wu
- New York Presbyterian‐Weill Cornell Medical CenterNew YorkNew YorkUSA
| | - Christoph Becker
- School of Medicine, Stanford University School of MedicinePalo AltoCaliforniaUSA
| | - Simron Singh
- Odette Cancer Centre, Sunnybrook Health Sciences CentreTorontoCanada
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Espinosa-Olarte P, La Salvia A, Riesco-Martinez MC, Anton-Pascual B, Garcia-Carbonero R. Chemotherapy in NEN: still has a role? Rev Endocr Metab Disord 2021; 22:595-614. [PMID: 33843007 PMCID: PMC8346445 DOI: 10.1007/s11154-021-09638-0] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/07/2023]
Abstract
Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor differentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well differentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and 177Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms.
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Affiliation(s)
- Paula Espinosa-Olarte
- Oncology Department, Hospital Universitario, 12 de Octubre, Imas12, UCM, Madrid, Spain
| | - Anna La Salvia
- Oncology Department, Hospital Universitario, 12 de Octubre, Imas12, UCM, Madrid, Spain
| | | | - Beatriz Anton-Pascual
- Oncology Department, Hospital Universitario, 12 de Octubre, Imas12, UCM, Madrid, Spain
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Corbett V, Arnold S, Anthony L, Chauhan A. Management of Large Cell Neuroendocrine Carcinoma. Front Oncol 2021; 11:653162. [PMID: 34513663 PMCID: PMC8432609 DOI: 10.3389/fonc.2021.653162] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 07/12/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease. METHODS We performed a PubMed search for "Large cell neuroendocrine carcinoma" and "High grade neuroendocrine carcinoma." All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC. RESULTS Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential. DISCUSSION LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.
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Affiliation(s)
- Virginia Corbett
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Susanne Arnold
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Lowell Anthony
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
| | - Aman Chauhan
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
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Wang X, Shi YF, Duan JH, Wang C, Tan HY. S-1 plus temozolomide as second-line treatment for neuroendocrine carcinoma of the breast: A case report. World J Clin Cases 2021; 9:7146-7153. [PMID: 34540971 PMCID: PMC8409205 DOI: 10.12998/wjcc.v9.i24.7146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/27/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Neuroendocrine carcinoma of the breast (NECB) is a rare type of malignant tumor. Due to the rarity of NECB, the relevant literature mostly comprises case reports. Available data on treatment options for NECB are very limited. CASE SUMMARY A 62-year-old woman presented to our hospital in October 2016 for intermittent vomiting and diarrhea and masses in the liver found on abdominal computed tomography (CT) imaging. She was diagnosed in July 2012 with neuroendocrine carcinoma of the right breast in local hospital. The patient initially presented with a painful lesion of the right breast. She then undergone surgical resection and adjuvant chemotherapy with pirarubicin and paclitaxel for four cycles as well as endocrine therapy. She was regularly followed every 3 mo after surgery. Enhanced abdominal CT imaging at our hospital revealed multiple suspicious masses in the liver with the largest lesion measuring 8.4 cm × 6.3 cm. Chest CT revealed masses in the anterior chest wall and lung. Core needle biopsy of the lesion revealed liver metastases of NECB. A bone scan showed right second anterior rib metastases. Upper endoscopy and colonoscopy did not provide any evidence of another possible primary tumor. She stopped receiving endocrine therapy and then received etoposide and cisplatin (EP) chemotherapy as a first-line treatment regimen for six cycles at our hospital after liver, bone, and lung metastases. On October 2017, the chemotherapy regimen was changed to S-1 (40 mg twice daily, days 1-14) combined with temozolomide (200 mg once daily, days 10-14) (STEM) every 21 d as a second-line treatment regimen due to disease progression. Progression-free survival (PFS) and adverse effects after treatment were analyzed, and the efficacy of the STEM regimen was assessed using RECIST version 1.1. This patient achieved a partial response after using the STEM regimen, with a PFS of 23 mo. Adverse effects included only grade 1 digestive tract reactions with no need for a reduction in chemotherapy. CONCLUSION This case report suggests that the STEM regimen may be effective and well tolerated as the second-line treatment for advanced NECB. STEM is still highly effective in patients who show disease progression with the EP regimen. More evidence is needed to prove the validity of STEM.
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Affiliation(s)
- Xin Wang
- Beijing University of Chinese Medicine; Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jiang-Hui Duan
- Department of Radiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Chao Wang
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Huang-Ying Tan
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, China
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Prantesh J, Dorth J, Asa SL, Mohamed A. Nasopharyngeal neuroendocrine neoplasms: Systematic review of the literature and case presentation. J Neuroendocrinol 2021; 33:e13005. [PMID: 34342078 DOI: 10.1111/jne.13005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/20/2021] [Accepted: 06/15/2021] [Indexed: 01/04/2023]
Abstract
Most of neuroendocrine neoplasms (NENs) are located in the gastrointestinal tract and lung, and they are rarely found on the upper aero-digestive tract, which limit the current literature about nasopharyngeal NENs. This systemic review will summarize the clinical, pathological features and optimal diagnosis and management of different types of nasopharyngeal NENs (NP NENs). In-addition, we herein report an EBV negative TP53-mutated/ Rb-wild type nasopharyngeal neuroendocrine carcinoma (NEC) in a young man in which touch preparation cytology studies were integral to establishing a definitive diagnosis. To our knowledge, only very few cases of primary neuroendocrine carcinoma of the nasopharynx have been reported in the literature and the reports of these cases have not included detailed description of different types and how to optimally diagnose and manage them. In this abstract, we also highlighted the evidence about the safety of using growth factors in patients with sickle cell anemia who are receiving cytotoxic chemotherapy.
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Affiliation(s)
- Jain Prantesh
- Department of Medicine, Division of Hematology and Medical Oncology, Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | - Jennifer Dorth
- Department of Radiation Oncology, Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | - Sylvia L Asa
- Department of Pathology, Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | - Amr Mohamed
- Department of Medicine, Division of Hematology and Medical Oncology, Seidman Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
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Shah MH, Goldner WS, Benson AB, Bergsland E, Blaszkowsky LS, Brock P, Chan J, Das S, Dickson PV, Fanta P, Giordano T, Halfdanarson TR, Halperin D, He J, Heaney A, Heslin MJ, Kandeel F, Kardan A, Khan SA, Kuvshinoff BW, Lieu C, Miller K, Pillarisetty VG, Reidy D, Salgado SA, Shaheen S, Soares HP, Soulen MC, Strosberg JR, Sussman CR, Trikalinos NA, Uboha NA, Vijayvergia N, Wong T, Lynn B, Hochstetler C. Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:839-868. [PMID: 34340212 DOI: 10.6004/jnccn.2021.0032] [Citation(s) in RCA: 312] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.
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Affiliation(s)
- Manisha H Shah
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | - Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | - Pamela Brock
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Paxton V Dickson
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | | | | | | | - Jin He
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | - Arash Kardan
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | | | | | | | | | | | | | | | | | | | - Nikolaos A Trikalinos
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | - Beth Lynn
- National Comprehensive Cancer Network
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Neuroendocrine Carcinomas of the Digestive Tract: What Is New? Cancers (Basel) 2021; 13:cancers13153766. [PMID: 34359666 PMCID: PMC8345167 DOI: 10.3390/cancers13153766] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/21/2021] [Accepted: 07/24/2021] [Indexed: 12/12/2022] Open
Abstract
Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.
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Lim KH, Opyrchal M, Acharya A, Boice N, Wu N, Gao F, Webster J, Lockhart AC, Waqar SN, Govindan R, Morgensztern D, Picus J, Tan BR, Baggstrom MQ, Maher CA, Wang-Gillam A. Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies. Eur J Cancer 2021; 154:102-110. [PMID: 34256279 DOI: 10.1016/j.ejca.2021.06.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/22/2021] [Accepted: 06/03/2021] [Indexed: 01/04/2023]
Abstract
AIM Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). METHOD This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. RESULTS In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. CONCLUSIONS The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01677559.
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Affiliation(s)
- Kian-Huat Lim
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Mateusz Opyrchal
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Abhi Acharya
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Nick Boice
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Ningying Wu
- Siteman Cancer Center Biostatistics Core, Division of Public Health Sciences, Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, US
| | - Feng Gao
- Siteman Cancer Center Biostatistics Core, Division of Public Health Sciences, Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, US
| | - Jace Webster
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Albert C Lockhart
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Saiama N Waqar
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Ramaswamy Govindan
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Daniel Morgensztern
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Joel Picus
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Benjamin R Tan
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Maria Q Baggstrom
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Christopher A Maher
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US
| | - Andrea Wang-Gillam
- Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, US.
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Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol 2021; 33:378-385. [PMID: 33973550 DOI: 10.1097/cco.0000000000000740] [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
PURPOSE OF REVIEW Neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies whose natural evolution may be defined according to various prognostic factors, including localization of the primitive tumour, hormone secretory status, histological grade, tumour burden, tumour growth rate, expression of somatostatin receptors and fluorodeoxyglucose-avidity. The treatment of these tumours in an advanced setting is based on relatively little robust data. RECENT FINDINGS A recent pathological classification introduced a new category of high-grade but well differentiated neuroendocrine tumours (NET G3), with markedly different behaviour from neuroendocrine carcinomas (NECs). Yet, the optimal treatment of those tumours is still uncertain. Advances are needed in molecular subtyping of NENs to understand better their heterogeneity and inform personalized therapies. SUMMARY The current review summarizes the current knowledge, indicates some exciting future directions and outlines the most interesting ongoing clinical trials likely to impact current practice.
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Affiliation(s)
- Christiane Jungels
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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Hadoux J, Afchain P, Walter T, Tougeron D, Hautefeuille V, Monterymard C, Lorgis V, Thuillier F, Baudin E, Scoazec JY, Lepage C, Desgrippes R. FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin. Dig Liver Dis 2021; 53:824-829. [PMID: 33994125 DOI: 10.1016/j.dld.2021.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen. METHODS The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled. MAIN INCLUSION CRITERIA ARE NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.
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Affiliation(s)
- Julien Hadoux
- Endocrine oncology, Imaging department, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif F-94805, France.
| | - Pauline Afchain
- Department of Oncology, Saint Antoine Hospital, Paris, France
| | - Thomas Walter
- Department of Oncology, ENETS Centre of Excellence, Hospices Civils de Lyon and Lyon University, Lyon, France
| | - David Tougeron
- Department of Hepato-gastroenterology, Poitiers University Hospital; University of Poitiers, Poitiers, France
| | - Vincent Hautefeuille
- Department of Hepato-gastroenterology, Amiens University Hospital, Amiens, France
| | - Carole Monterymard
- FFCD EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Dijon, France
| | - Véronique Lorgis
- Department of Oncology, Cancerology institut of Bourgogne GRReCC, Dijon, France
| | | | - Eric Baudin
- Endocrine oncology, Imaging department, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif F-94805, France
| | - Jean Yves Scoazec
- Pathology, Biopathology department, Gustave Roussy, Villejuif, F-94805, France
| | - Côme Lepage
- FFCD EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Dijon, France; Department of digestive oncology University hospital Dijon, University of Burgundy and Franche Comté, Dijon, France
| | - Romain Desgrippes
- Hepato-gastroenterology department, Centre Hospitalier de Saint-Malo, Saint-Malo F-35403, France
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Abstract
OPINION STATEMENT Treatment recommendations for advanced gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are based on uncontrolled, mainly retrospective data. Chemotherapy can offer palliative relief, but long-lasting complete responses or cures are rare. The European Neuroendocrine Tumour Society (ENETS) and European Society for Medical Oncology (ESMO) recommend platinum-based chemotherapy as first-line treatment. This has been the golden standard since the late 1980s and has been evaluated in mostly retrospective clinical studies. However, progression is inevitable for most patients. Unfortunately, data on effective second-line treatment options are scant, and ENETS and ESMO recommendations propose fluorouracil- or temozolomide-based chemotherapy schedules. As such, there is a huge unmet need for improved care. Improved knowledge on GEP-NEC biology may provide a pathway towards more effective interventions including chemotherapy, targeted gene therapy, peptide receptor radionuclide therapy, as well as immune checkpoint inhibitors. The review summarises this current state of the art as well as the most promising developments for systemic therapy in GEP-NEC patients.
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Pellat A, Cottereau AS, Palmieri LJ, Soyer P, Marchese U, Brezault C, Coriat R. Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions. Cancers (Basel) 2021; 13:2448. [PMID: 34070035 PMCID: PMC8158108 DOI: 10.3390/cancers13102448] [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: 04/28/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 02/06/2023] Open
Abstract
Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.
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Affiliation(s)
- Anna Pellat
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Anne Ségolène Cottereau
- Department of Nuclear Medicine, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Lola-Jade Palmieri
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Philippe Soyer
- Department of Radiology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Ugo Marchese
- Department of Surgery, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France;
| | - Catherine Brezault
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
| | - Romain Coriat
- Department of Gastroenterology and Digestive Oncology, Hôpital Cochin, AP-HP, 27 rue du Faubourg Saint Jacques, Université de Paris, 75014 Paris, France; (L.-J.P.); (C.B.); (R.C.)
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Liu AJ, Ueberroth BE, McGarrah PW, Buckner Petty SA, Kendi AT, Starr J, Hobday TJ, Halfdanarson TR, Sonbol MB. Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors. Oncologist 2021; 26:383-388. [PMID: 33496040 PMCID: PMC8100548 DOI: 10.1002/onco.13686] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/12/2021] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. MATERIALS AND METHODS This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). RESULTS Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. CONCLUSION Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. IMPLICATIONS FOR PRACTICE High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.
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Affiliation(s)
- Alex J. Liu
- Mayo Clinic Internal Medicine ResidencyPhoenixArizonaUSA
| | | | | | | | | | - Jason Starr
- Mayo Clinic Cancer CenterJacksonvilleFloridaUSA
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Apostolidis L, Dal Buono A, Merola E, Jann H, Jäger D, Wiedenmann B, Winkler EC, Pavel M. Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3). Cancers (Basel) 2021; 13:1936. [DOI: - apostolidis l, dal buono a, merola e, et al.multicenter analysis of treatment outcomes for systemic therapy in well differentiated grade 3 neuroendocrine tumors (net g3).cancers (basel).2021 apr 16;13(8):1936.doi: 10.3390/cancers13081936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
Abstract
Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months; p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.
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Affiliation(s)
- Leonidas Apostolidis
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Arianna Dal Buono
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
| | - Elettra Merola
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
| | - Dirk Jäger
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Bertram Wiedenmann
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
| | - Eva Caroline Winkler
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Marianne Pavel
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
- Department of Medicine 1, Division of Endocrinology, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
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Apostolidis L, Dal Buono A, Merola E, Jann H, Jäger D, Wiedenmann B, Winkler EC, Pavel M. Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3). Cancers (Basel) 2021; 13:1936. [PMID: 33923759 PMCID: PMC8073753 DOI: 10.3390/cancers13081936] [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: 03/02/2021] [Revised: 03/28/2021] [Accepted: 04/14/2021] [Indexed: 01/27/2023] Open
Abstract
Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months; p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.
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Affiliation(s)
- Leonidas Apostolidis
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (D.J.); (E.C.W.)
| | - Arianna Dal Buono
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany; (A.D.B.); (E.M.); (H.J.); (B.W.); (M.P.)
| | - Elettra Merola
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany; (A.D.B.); (E.M.); (H.J.); (B.W.); (M.P.)
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany; (A.D.B.); (E.M.); (H.J.); (B.W.); (M.P.)
| | - Dirk Jäger
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (D.J.); (E.C.W.)
| | - Bertram Wiedenmann
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany; (A.D.B.); (E.M.); (H.J.); (B.W.); (M.P.)
| | - Eva Caroline Winkler
- National Center for Tumor Diseases (NCT) Heidelberg, Department of Medical Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (D.J.); (E.C.W.)
| | - Marianne Pavel
- Department of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany; (A.D.B.); (E.M.); (H.J.); (B.W.); (M.P.)
- Department of Medicine 1, Division of Endocrinology, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany
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Feola T, Centello R, Sesti F, Puliani G, Verrico M, Di Vito V, Di Gioia C, Bagni O, Lenzi A, Isidori AM, Giannetta E, Faggiano A. Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review. Cancers (Basel) 2021; 13:1247. [PMID: 33809007 PMCID: PMC7999788 DOI: 10.3390/cancers13061247] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/01/2021] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Highly proliferative (G3) neuroendocrine neoplasms are divided into well differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), based on the morphological appearance. This systematic review aims to evaluate the clinicopathological features and the treatment response of the NEC subgroup with a Ki67 labeling index (LI) < 55%. METHODS A literature search was performed using MEDLINE, Cochrane Library, and Scopus between December 2019 and April 2020, last update in October 2020. We included studies reporting data on the clinicopathological characteristics, survival, and/or therapy efficacy of patients with NECs, in which the Ki67 LI was specified. RESULTS 8 papers were included, on a total of 268 NEC affected patients. NECs with a Ki67 LI < 55% have been reported in patients of both sexes, mainly of sixth decade, pancreatic origin, and large-cell morphology. The prevalent treatment choice was chemotherapy, followed by surgery and, in only one study, peptide receptor radionuclide therapy. The subgroup of patients with NEC with a Ki67 LI < 55% showed longer overall survival and progression free survival and higher response rates than the subgroup of patients with a tumor with higher Ki67 LI (≥55%). CONCLUSIONS NECs are heterogeneous tumors. The subgroup with a Ki67 LI < 55% has a better prognosis and should be treated and monitored differently from NECs with a Ki67 LI ≥ 55%.
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Affiliation(s)
- Tiziana Feola
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
- Neuroendocrinology, Neuromed Institute, IRCCS, 86077 Pozzilli (IS), Italy
| | - Roberta Centello
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Franz Sesti
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Giulia Puliani
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
- Oncological Endocrinology Unit, Regina Elena National Cancer Institute, IRCCS, 00144 Rome, Italy
| | - Monica Verrico
- Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, 00161 Rome, Italy; (M.V.); (C.D.G.)
| | - Valentina Di Vito
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Cira Di Gioia
- Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, 00161 Rome, Italy; (M.V.); (C.D.G.)
| | - Oreste Bagni
- Radiology Unit, “Santa Maria Goretti” Hospital, 04100 Latina, Italy;
| | - Andrea Lenzi
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Andrea M. Isidori
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Elisa Giannetta
- Department of Experimental Medicine, “Sapienza” University of Rome, 00161 Rome, Italy; (T.F.); (R.C.); (F.S.); (G.P.); (V.D.V.); (A.L.); (A.M.I.); (E.G.)
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy
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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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Fang L, Arvind D, Dowlati A, Mohamed A. Role of immunotherapy in gastro-enteropancreatic neuroendocrine neoplasms (gep-nens): Current advances and future directions. J Neuroendocrinol 2021; 33:e12943. [PMID: 33724586 DOI: 10.1111/jne.12943] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 12/20/2022]
Abstract
Neuroendocrine neoplasms (NENs) are heterogeneous tumours originating from neuroendocrine cells (Pearse & Polak, Gut, 1971, 12,783). They were once considered as rare tumours, although their annual incidence has increased significantly and now exceeds seven cases in 100 000 in the USA (Dasari, et al., JAMA oncology, 2017, 3, 1335). They are a group of highly diverse neoplasms and can be classified into the spectrum of well-differentiated neuroendocrine tumours to poorly differentiated neuroendocrine carcinomas. This is entirely based on the tumour differentiation and grade (low, intermediate, high), which is determined by the Ki-67/mitotic index. The lower grades (G1/2) of the well-differentiated group are characterised by a relative indolent clinical course and the ability to secrete a variety of peptide hormones (Kloppel, Visceral medicine, 2017, 33, 324). Higher grades and poorly differentiated tumours tend to be more aggressive and have limited therapeutic options (Sorbye et al., Neuroendocrinology, 2019, 108, 54). In the modern era of immuno-oncology, immune checkpoint inhibitors (ICPIs) that target programmed cell death 1 (pembrolizumab, nivolumab), programmed cell death-ligand1 (avelumab, atezolizumab and durvalumab) or cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) have revolutionised the management of many solid tumours. In patients with gastro-enteropancreatic (GEP)-NENs, there is a limited data regarding the role of ICPIs either as a single agent or in combination regimens. Here, we review the current advances for ICPIs and where they fit in the management of GEP-NENs.
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Affiliation(s)
- Liu Fang
- Department of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Dasari Arvind
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Afshin Dowlati
- Department of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Amr Mohamed
- Department of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA
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Özdirik B, Jann H, Bischoff P, Fehrenbach U, Tacke F, Roderburg C, Wiedenmann B. PD-L1 - inhibitors in neuroendocrine neoplasia: Results from a real-life study. Medicine (Baltimore) 2021; 100:e23835. [PMID: 33429744 PMCID: PMC7793325 DOI: 10.1097/md.0000000000023835] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 11/19/2020] [Indexed: 01/05/2023] Open
Abstract
Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN.
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Affiliation(s)
- Burcin Özdirik
- Charité – University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Henning Jann
- Charité – University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Philip Bischoff
- Charité – University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology
| | - Uli Fehrenbach
- Charité – University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Radiology, Berlin, Germany
| | - Frank Tacke
- Charité – University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Christoph Roderburg
- Charité – University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Bertram Wiedenmann
- Charité – University Medicine Berlin, Department of Hepatology & Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
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Betella N, Smiroldo V, Baldelli R, Lania A. Treatment of NETs from Rare Origin. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:211-229. [DOI: 10.1007/978-3-030-72830-4_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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