1
|
Arrivi G, Fazio N, Tafuto S, Falconi M, Carnaghi C, Campana D, Rinzivillo M, Panzuto F. The efficacy of streptozotocin in managing pancreatic neuroendocrine neoplasms - A systematic review. Cancer Treat Rev 2025; 134:102899. [PMID: 39954330 DOI: 10.1016/j.ctrv.2025.102899] [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: 10/31/2024] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/17/2025]
Abstract
Pancreatic neuroendocrine tumors (pan-NETs) represent a highly heterogeneous and complex pathology, with therapeutic management and prognosis influenced by several biological and clinical characteristics. Chemotherapy, including regimens based on capecitabine and temozolomide (CAPTEM) or the combination of streptozotocin and 5-fluorouracil (STZ-5FU), is indicated for rapidly growing, symptomatic, or high-burden disease requiring swift cytoreduction. Historical studies provide scientific evidence for the STZ-5FU regimen, often retrospective and frequently analyzing small series. Despite these limitations, the efficacy of this treatment is well-established, and it is included in all guidelines as a therapeutic option. This systematic review aims to gather scientific evidence on using STZ-based chemotherapy to assess its real impact in managing well-differentiated metastatic or unresectable pan-NETs.
Collapse
Affiliation(s)
- Giulia Arrivi
- Oncology Unit Department of Clinical and Molecular Medicine Sapienza University of Rome Sant'Andrea University Hospital ENETS Center of Excellence Rome Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS Milan IT Italy
| | - Salvatore Tafuto
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori, IRCCS Fondazione "G. Pascale", Naples 80131, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" San Raffaele University, Milan, Italy
| | - Carlo Carnaghi
- Medical Oncology Unit, Humanitas Istituto Clinico Catanese, Misterbianco, Catania 95045, Italy
| | - Davide Campana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Maria Rinzivillo
- Digestive Disease Unit, Department of Surgical-Medical Sciences and Translational Medicine, Sapienza University of Rome, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Department of Surgical-Medical Sciences and Translational Medicine, Sapienza University of Rome, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy.
| |
Collapse
|
2
|
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.
Collapse
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.)
| |
Collapse
|
3
|
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. CLINICALTRIALS GOV IDENTIFIER NCT03387592.
Collapse
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
| |
Collapse
|
4
|
Zhang XB, Fan YB, Jing R, Getu MA, Chen WY, Zhang W, Dong HX, Dakal TC, Hayat A, Cai HJ, Ashrafizadeh M, Abd El-Aty AM, Hacimuftuoglu A, Liu P, Li TF, Sethi G, Ahn KS, Ertas YN, Chen MJ, Ji JS, Ma L, Gong P. Gastroenteropancreatic neuroendocrine neoplasms: current development, challenges, and clinical perspectives. Mil Med Res 2024; 11:35. [PMID: 38835066 DOI: 10.1186/s40779-024-00535-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 05/07/2024] [Indexed: 06/06/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are highly heterogeneous and potentially malignant tumors arising from secretory cells of the neuroendocrine system. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are the most common subtype of NENs. Historically, GEP-NENs have been regarded as infrequent and slow-growing malignancies; however, recent data have demonstrated that the worldwide prevalence and incidence of GEP-NENs have increased exponentially over the last three decades. In addition, an increasing number of studies have proven that GEP-NENs result in a limited life expectancy. These findings suggested that the natural biology of GEP-NENs is more aggressive than commonly assumed. Therefore, there is an urgent need for advanced researches focusing on the diagnosis and management of patients with GEP-NENs. In this review, we have summarized the limitations and recent advancements in our comprehension of the epidemiology, clinical presentations, pathology, molecular biology, diagnosis, and treatment of GEP-NETs to identify factors contributing to delays in diagnosis and timely treatment of these patients.
Collapse
Affiliation(s)
- Xian-Bin Zhang
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Yi-Bao Fan
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Rui Jing
- Department of Radiology, Second Hospital of Shandong University, Jinan, Shandong, 250000, China
| | - Mikiyas Amare Getu
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Wan-Ying Chen
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Wei Zhang
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Hong-Xia Dong
- Department of Gastroenterology, General Hospital of Chinese PLA, Beijing, 100853, China
| | - Tikam Chand Dakal
- Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India
| | - Akhtar Hayat
- Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Lahore, 54000, Pakistan
| | - Hua-Jun Cai
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Milad Ashrafizadeh
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Ahmet Hacimuftuoglu
- Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Peng Liu
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
| | - Tian-Feng Li
- Reproductive Medicine Center, Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong, 518055, China
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Yavuz Nuri Ertas
- ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, 38039, Türkiye
- Department of Biomedical Engineering, Erciyes University, Kayseri, 38280, Türkiye
- UNAM-National Nanotechnology Research Center, Bilkent University, Ankara, 06800, Türkiye
| | - Min-Jiang Chen
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China
| | - Jian-Song Ji
- Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China
| | - Li Ma
- Department of Epidemiology, Dalian Medical University, Dalian, Liaoning, 116044, China
| | - Peng Gong
- Department of General SurgeryInstitute of Precision Diagnosis and Treatment of Digestive System Tumors and Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China.
| |
Collapse
|
5
|
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.
Collapse
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.)
| |
Collapse
|
6
|
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.
Collapse
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
| |
Collapse
|
7
|
Díaz-López S, Jiménez-Castro J, Robles-Barraza CE, Ayala-de Miguel C, Chaves-Conde M. Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract. World J Gastrointest Oncol 2024; 16:1166-1179. [PMID: 38660639 PMCID: PMC11037054 DOI: 10.4251/wjgo.v16.i4.1166] [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: 12/06/2023] [Revised: 01/17/2024] [Accepted: 02/18/2024] [Indexed: 04/10/2024] Open
Abstract
Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are a heterogeneous group of malignant neoplasms that can settle in the gastroenteropancreatic tract. They are composed of a neuroendocrine (NE) and a non-NE component in at least 30% of each tumour. The non-NE component can include different histological combinations of glandular, squamous, mucinous and sarcomatoid phenotypes, and one or both of the components can be low-or high grade malignant. Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion, and the lack of specific clinical trials is the main reason why their management is difficult. The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data. It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that, due to their low incidence, will require long recruitment periods.
Collapse
Affiliation(s)
- Sebastián Díaz-López
- Medical Oncology Department, Hospital Universitario Valme, Seville 41014, Andalucía, Spain
| | | | | | - Carlos Ayala-de Miguel
- Medical Oncology Department, Hospital Universitario Valme, Seville 41014, Andalucía, Spain
| | - Manuel Chaves-Conde
- Medical Oncology Department, Hospital Universitario Valme, Seville 41014, Andalucía, Spain
| |
Collapse
|
8
|
Jurkiewicz K, Miciak M, Kaliszewski K. Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) - Current literature review of diagnostics and therapy. What has changed in the management? POLISH JOURNAL OF SURGERY 2024; 96:58-66. [PMID: 39138986 DOI: 10.5604/01.3001.0054.4169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2024]
Abstract
<b>Introduction:</b> Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are malignancies originating from cells of the diffuse endocrine system. They are rare and localize in the upper and lower parts of the gastrointestinal tract and in the pancreas. Despite such a varied location, GEP-NENs are considered a common group of neoplasms due to the fact of their similar morphology and ability to secrete peptide hormones and biologically active amines. They are associated with clinical manifestations specific to the substances produced by a particular neoplasm. The classification of GEP-NENs is constantly systematized and updated based on their differentiation and grading. The development of available diagnostic and treatment methods for these tumors has made significant progress over the past 10 years and is still ongoing.<b>Aim:</b> In the following paper, we review the diagnostics and treatment of GEP-NENs, taking into account the latest molecular, immunological, or gene-based methods. Imaging methods using markers for receptors allow for high diagnostic sensitivity<b>Methods:</b> Medical databases were searched for the latest information. The authors also sought confirmation of the content of a particular publication in another publications, so as to present the most reliable information possible.<b>Results:</b> Research results revealed that the diagnostics and treatment of GEP-NENs have significantly advanced in recent years. Surgical interventions, especially minimally invasive techniques, have shown efficacy in treating GEP-NENs, with specific therapies such as somatostatin analogs, chemotherapy, and peptide receptor radionuclide therapy demonstrating promising outcomes. The evolution of diagnostic methods, including imaging techniques and biomarker testing, has contributed to improved patient care and prognosis.<b>Conclusions:</b> The increasing incidence of GEP-NENs is attributed to enhanced diagnostic capabilities rather than a rise in population prevalence. The study emphasizes the importance of ongoing research to identify specific markers for early detection and targeted therapies to further enhance the effectiveness of treating these rare and heterogeneous malignancies. The findings suggest a positive trajectory in the management of GEP-NENs, with future prospects focused on personalized and targeted treatment approaches.
Collapse
Affiliation(s)
- Krzysztof Jurkiewicz
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Poland
| | - Michał Miciak
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Poland
| | - Krzysztof Kaliszewski
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Poland
| |
Collapse
|
9
|
Beyer GV, Hueser S, Li R, Manika D, Lee M, Chan CHF, Howe JR, Ear PH. Gastroenteropancreatic neuroendocrine carcinoma tumor spheroid drug screen reveals vulnerability to tyrosyl-DNA phosphodiesterase 1 inhibitors. Surgery 2024; 175:605-612. [PMID: 37914572 PMCID: PMC10872605 DOI: 10.1016/j.surg.2023.08.044] [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: 05/16/2023] [Revised: 07/26/2023] [Accepted: 08/08/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine carcinomas are rare neoplasms with no effective treatments and poor prognosis. Few reliable preclinical models exist for the study of gastroenteropancreatic neuroendocrine carcinomas, limiting investigation of novel treatments. We used tumor spheroids from our recently established gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models to systematically screen for compounds with diverse structures to identify potential new categories of therapeutic agents that can target gastroenteropancreatic neuroendocrine carcinomas. METHODS Tumor spheroids were derived from our NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma patient-derived xenograft models. Gastroenteropancreatic neuroendocrine carcinoma spheroids were screened against a library of 885 compounds from the National Cancer Institute Diversity Set VII collection. Cell viability was measured via AlamarBlue assay. After identification of potential therapeutic compounds, synergy screening of a selected group with temozolomide and doxorubicin was performed, and these combinations were further analyzed for γH2AX and phosphorylated-ERK proteins. RESULTS We identified 16 compounds that inhibit over 75% of gastroenteropancreatic neuroendocrine carcinoma spheroid survival. Seven are inhibitors of tyrosyl-DNA phosphodiesterase 1, a DNA repair enzyme working closely with the topoisomerase I complex. When combined with temozolomide or doxorubicin, the tyrosyl-DNA phosphodiesterase 1 inhibitor cytarabine increased the cytotoxic effects of these drugs on NEC1452 cells which was further evidenced by increasing γH2AX and decreasing phosphorylated-ERK in combination treatment compared to temozolomide alone. CONCLUSION Both NEC913 and NEC1452 gastroenteropancreatic neuroendocrine carcinoma spheroid lines are useful preclinical models for drug testing. Our library screen revealed these gastroenteropancreatic neuroendocrine carcinoma spheroids are highly sensitive to a novel class of anti-cancer drugs that target nuclear genome stability.
Collapse
Affiliation(s)
- Gabriella V Beyer
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Sophia Hueser
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Rachel Li
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Deeraj Manika
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Minhyuk Lee
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Carlos H F Chan
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA
| | - James R Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA
| | - Po Hien Ear
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA.
| |
Collapse
|
10
|
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.
Collapse
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;
| |
Collapse
|
11
|
Morken S, Langer SW, Sundlöv A, Vestermark LW, Ladekarl M, Hjortland GO, Svensson JB, Tabaksblat EM, Haslerud TM, Assmus J, Detlefsen S, Couvelard A, Perren A, Sorbye H. Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms. Br J Cancer 2023; 129:1930-1939. [PMID: 37872405 PMCID: PMC10703888 DOI: 10.1038/s41416-023-02462-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/22/2023] [Accepted: 10/04/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NTC02248012).
Collapse
Affiliation(s)
- Siren Morken
- Department of Oncology, Haukeland University Hospital, Bergen, Norway.
| | - Seppo W Langer
- Department of Oncology, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Anna Sundlöv
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | | | - Morten Ladekarl
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
- Department of Oncology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | - Johanna B Svensson
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Torjan Magne Haslerud
- Department of Radiology and Nuclear Medicine, Haukeland University Hospital, Bergen, Norway
| | - Jörg Assmus
- Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | | | - Aurel Perren
- Institute of Tissue medicine and Pathology, University of Bern, Bern, Switzerland
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| |
Collapse
|
12
|
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.
Collapse
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
| |
Collapse
|
13
|
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.
Collapse
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
| | | |
Collapse
|
14
|
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.
Collapse
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
| |
Collapse
|
15
|
Banerjee J, Ranjan RP, Alam MT, Deshmukh S, Tripathi PP, Gandhi S, Banerjee S. Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics. Pathol Res Pract 2023; 248:154720. [PMID: 37542862 DOI: 10.1016/j.prp.2023.154720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/22/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.
Collapse
Affiliation(s)
- Juni Banerjee
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India.
| | - Ramya P Ranjan
- National Institute of Animal Biotechnology (NIAB), Gachibowli, Hyderabad, Telangana 500032, India
| | - Md Tanjim Alam
- CSIR-Indian Institute of Chemical Biology (IICB), 4, Raja S. C. Mullick Road, Kolkata 700032, India; IICB-Translational Research Unit of Excellence(IICB-TRUE), Kolkata 700091, India
| | - Sanika Deshmukh
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India
| | - Prem Prakash Tripathi
- CSIR-Indian Institute of Chemical Biology (IICB), 4, Raja S. C. Mullick Road, Kolkata 700032, India; IICB-Translational Research Unit of Excellence(IICB-TRUE), Kolkata 700091, India.
| | - Sonu Gandhi
- National Institute of Animal Biotechnology (NIAB), Gachibowli, Hyderabad, Telangana 500032, India.
| | - Shuvomoy Banerjee
- Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382426, India.
| |
Collapse
|
16
|
Le BK, McGarrah P, Paciorek A, Mohamed A, Apolo AB, Chan DL, Reidy-Lagunes D, Hauser H, Rivero JD, Whitman J, Batty K, Zhang L, Raj N, Le T, Bergsland E, Halfdanarson TR. Urinary Neuroendocrine Neoplasms Treated in the "Modern Era": A Multicenter Retrospective Review. Clin Genitourin Cancer 2023; 21:403-414.e5. [PMID: 37031047 PMCID: PMC11296333 DOI: 10.1016/j.clgc.2023.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/15/2023] [Indexed: 03/19/2023]
Abstract
BACKGROUND Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy. PATIENTS AND METHODS A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology. RESULTS A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n = 24), kidney 10% (n = 23), ureter 95% (n = 1), urethra 54% (n = 2), and others 90% (n = 3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary). CONCLUSION This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs.
Collapse
Affiliation(s)
- Bryan Khuong Le
- Department of Medicine, University of California, San Francisco, CA
| | | | - Alan Paciorek
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Amr Mohamed
- UH Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Andrea B Apolo
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David L Chan
- Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, New South Wales, Australia
| | - Diane Reidy-Lagunes
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Haley Hauser
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Jaydira D Rivero
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Kathleen Batty
- Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, New South Wales, Australia
| | - Li Zhang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - Nitya Raj
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Tiffany Le
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Emily Bergsland
- Department of Medicine, University of California, San Francisco, CA.
| | | |
Collapse
|
17
|
Yeung HM, Sreekrishnanilayam K, Meeker C, Deng M, Agrawal S, Abdullah H, Vijayvergia N. Comparative Outcomes of Second-line Topoisomerase-I Inhibitor Therapies on Neuroendocrine Carcinoma. J Gastrointest Cancer 2023; 54:73-79. [PMID: 35006522 PMCID: PMC9271131 DOI: 10.1007/s12029-021-00800-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2021] [Indexed: 10/19/2022]
Abstract
INTRODUCTION This investigation aims to assess the outcomes for second-line therapies to treat extrapulmonary neuroendocrine carcinoma (EP-NEC) after first-line platinum-based chemotherapy. METHODS With IRB approval, we conducted a retrospective study of EP-NEC patients that progressed on first-line platinum chemotherapy from 2008 to 2018. Demographic data and treatment-related characteristics were collected and represented as descriptive statistics. The primary endpoints include overall survival (OS) and progression-free survival (PFS). OS and PFS were estimated and stratified by site of primary (gastroenteropancreatic [GEP] versus non-GEP) and type of second-line therapy (irino/topotecan versus others). Log-rank test and Kaplan-Meier curves were used to compare survival distributions between groups. RESULTS Forty-seven patients met eligibility, with median age 65 (range 31-82), 62% male, and 83% White; 22 were GEP and 25 were non-GEP primary. Thirty patients (63.8%) received second-line therapy where 11 received irinotecan/topotecan (ir/to), while 19 received other agents (temozolomide, other platinum agents, gemcitabine, paclitaxel, pembrolizumab, and sunitinib). The median OS was 10.3 months in the ir/to group versus 13.4 months for other therapies, p = 0.10. The median PFS for ir/to therapy compared to other therapies was 2.0 months versus 1.8 months, respectively, p = 0.72. The OS and PFS with and without ir/to were not significantly different by the primary site (p = 0.61 and p = 0.21). DISCUSSION/CONCLUSION Many EP-NEC patients undergo second-line therapies. Interestingly, outcomes for ir/to-containing second-line therapies were not statistically different from other agents, regardless of the site of primary. With approval of new second-line therapies for small cell lung cancer, further research in therapeutic options is needed for this aggressive disease.
Collapse
Affiliation(s)
- Ho-Man Yeung
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
| | | | - Caitlin Meeker
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Mengying Deng
- Bioinformatics and Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Sonali Agrawal
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Haaris Abdullah
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Namrata Vijayvergia
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| |
Collapse
|
18
|
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: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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.
Collapse
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
| |
Collapse
|
19
|
Gubbi S, Vijayvergia N, Yu JQ, Klubo-Gwiezdzinska J, Koch CA. Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors. Horm Metab Res 2022; 54:795-812. [PMID: 35878617 PMCID: PMC9731788 DOI: 10.1055/a-1908-7790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.
Collapse
Affiliation(s)
- Sriram Gubbi
- Endocrinology, National Institutes of Health Clinical Center, Bethesda,
United States
| | | | - Jian Q Yu
- Nuclear Medicine, Fox Chase Cancer Center, Philadelphia, United
States
| | - Joanna Klubo-Gwiezdzinska
- National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, United States
| | - Christian A. Koch
- Medicine/Endocrinology, The University of Tennessee Health
Science Center, Memphis, United States
- Medicine, Fox Chase Cancer Center, Philadelphia, United
States
- Correspondence Prof. Christian A. Koch, FACP,
MACE Fox Chase Cancer
CenterMedicine, 333 Cottman
AvePhiladelphia19111-2497United
States215 728 2713
| |
Collapse
|
20
|
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.
Collapse
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
| |
Collapse
|
21
|
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.
Collapse
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.)
| | | |
Collapse
|
22
|
Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors. J Clin Med 2022; 11:jcm11092358. [PMID: 35566487 PMCID: PMC9104547 DOI: 10.3390/jcm11092358] [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: 03/16/2022] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 11/28/2022] Open
Abstract
Introduction: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. Patients and methods: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). Results: 45.5% female, median age 60 years (range, 27–84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90–98), 3-year OS = 84.3 (CI: 78–90) and 5-year OS = 77.5 (CI: 70–85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. Conclusions: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.
Collapse
|
23
|
Kurita Y, Hara K, Kobayashi N, Kuwahara T, Mizuno N, Okuno N, Haba S, Yagi S, Hasegawa S, Sato T, Hosono K, Endo I, Shimizu Y, Niwa Y, Utsunomiya D, Inaba Y, Nakajima A, Kubota K, Ichikawa Y. Detection rate of endoscopic ultrasound and computed tomography in diagnosing pancreatic neuroendocrine neoplasms including small lesions: a multicenter study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:950-959. [PMID: 35362661 DOI: 10.1002/jhbp.1144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/15/2022] [Accepted: 02/07/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND/PURPOSE The detection ability and role of different imaging modalities to detect pancreatic neuroendocrine neoplasms (PNENs) including small lesions is unclear. This study aimed to compare the ability of endoscopic ultrasound (EUS) and computed tomography (CT) to detect PNENs. METHODS Data of patients who underwent EUS and contrast-enhanced CT and were diagnosed with PNENs were analyzed. The detection rates of pancreatic lesions with EUS and CT based on tumor size and influencing factors were investigated. RESULTS For 256 PNEN lesions, the detection rate of EUS was better than that of CT (94.5% vs. 86.3%; p < 0.001). EUS was significantly superior to CT for PNENs ≤ 5 mm (58.3% vs 16.7%; p = 0.006) and 5-10 mm (97.7% vs 79.5%; p = 0.008). There was no significant difference in the detection rate between EUS and CT for PNENs > 10 mm (98.4% vs 96.4%; p = 0.375). Size (≤ 5 mm) and insulinoma were independent factors associated with poor EUS and CT detection rates. CONCLUSIONS EUS exhibited better detection ability than CT, with an excellent detection rate for PNENs > 5 mm, except for insulinomas. CT could detect PNENs > 10 mm, which are amenable to treatment.
Collapse
Affiliation(s)
- Yusuke Kurita
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.,Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | | | | | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | - Nozomi Okuno
- Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | - Shin Haba
- Department of Gastroenterology, Aichi Cancer Center, Nagoya, Japan
| | - Shin Yagi
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Sho Hasegawa
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Takamitsu Sato
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Kunihiro Hosono
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | - Yasumasa Niwa
- Department of Endoscopy, Aichi Cancer Center, Nagoya, Japan
| | | | - Yoshitaka Inaba
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center, Nagoya, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Kensuke Kubota
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Yasushi Ichikawa
- Department of Oncology, Yokohama City University, Yokohama, Japan
| |
Collapse
|
24
|
Inaba Y, Hijioka S, Iwama I, Asai T, Miyamura H, Chatani S, Hasegawa T, Murata S, Kato M, Sato Y, Yamaura H, Onaya H, Shimizu J, Hara K. Clinical usefulness of Somatostatin Receptor Scintigraphy in the Diagnosis of Neuroendocrine Neoplasms. ASIA OCEANIA JOURNAL OF NUCLEAR MEDICINE & BIOLOGY 2022; 10:1-13. [PMID: 35083344 PMCID: PMC8742849 DOI: 10.22038/aojnmb.2021.56254.1390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/03/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES We investigated the detectability of somatostatin receptor scintigraphy (SRS) for neuroendocrine neoplasms (NEN). METHODS From January 2016 to October 2020, 125 SRS examinations using indium-111 pentetreotide performed for patients with NEN lesions were retrospectively evaluated. The detection rate of NEN lesions was determined according to histopathological classification by primary site and by organ. RESULTS At least one NEN lesion was detected in 73% (91/125) with a positive Krenning score of ≥2 in SRS. The detection of abdominal NENs (gastrointestinal tract, 38; pancreas, 62; and others, 14) was 89% (49/55) for neuroendocrine tumor (NET)-grade (G) 1, 78% (32/41) for NET-G2, 66% (2/3) for NET-G3, 31% (4/13) for neuroendocrine carcinoma (NEC), 100% (1/1) for mixed neuroendocrine-non-neuroendocrine neoplasm, and 0% (0/1) for non-classified NEN. That of thoracic NENs was 33% (2/6) for typical carcinoid tumor and 40% (2/5) for atypical carcinoid tumor. For a total of 226 organ lesions, hepatic lesions were 76% (58/76); pancreatic lesions, 61% (31/51); lymph node lesions, 77% (27/35); bone lesions, 83% (20/24); duodenal lesions, 82% (9/11); and other lesions, 41% (11/27). CONCLUSION The detectability of SRS for NEN in Japan was verified at a center, and its usefulness was confirmed.
Collapse
Affiliation(s)
- Yoshitaka Inaba
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Susumu Hijioka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Isanori Iwama
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Tsubasa Asai
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Hiroki Miyamura
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Shohei Chatani
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Takaaki Hasegawa
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Shinichi Murata
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Mina Kato
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Yozo Sato
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Hidekazu Yamaura
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Hiroaki Onaya
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Junichi Shimizu
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Kazuo Hara
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| |
Collapse
|
25
|
Araujo-Castro M, Pascual-Corrales E, Molina-Cerrillo J, Moreno Mata N, Alonso-Gordoa T. Bronchial Carcinoids: From Molecular Background to Treatment Approach. Cancers (Basel) 2022; 14:520. [PMID: 35158788 PMCID: PMC8833538 DOI: 10.3390/cancers14030520] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/05/2023] Open
Abstract
A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.
Collapse
Affiliation(s)
- Marta Araujo-Castro
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
| | - Eider Pascual-Corrales
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
| | - Javier Molina-Cerrillo
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Nicolás Moreno Mata
- Thoracic Surgery Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
| | - Teresa Alonso-Gordoa
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| |
Collapse
|
26
|
Nagel I, Herrmann K, Lahner H, Rischpler C, Weber F. Combined medical therapy, nuclear medicine therapy and other therapies in metastatic neuroendocrine tumor. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00156-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|
27
|
Li S, Niu M, Deng W, Li N, Wei C, Zhang C, Luo S. Efficacy of Chemotherapy versus Transcatheter Arterial Chemoembolization in Patients with Advanced Primary Hepatic Neuroendocrine Carcinoma and an Analysis of the Prognostic Factors: A Retrospective Study. Cancer Manag Res 2021; 13:9085-9093. [PMID: 34916851 PMCID: PMC8671721 DOI: 10.2147/cmar.s343572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
Background Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare liver tumor, and there is no clear therapeutic recommendation for patients with advanced PHNEC. This study aims to compare the efficacy of platinum-based chemotherapy (etoposide combined with cisplatin/carboplatin, EP/EC) and transcatheter arterial chemoembolization (TACE) in patients with advanced PHNEC, and to evaluate the relevant prognostic factors. Patients and Methods The clinical data of 41 patients with advanced PHNEC from June 2014 to October 2019 were retrospectively reviewed. Results At a median follow-up time of 13.9 months, the median overall survival (OS) was 14.8 months in the EP/EC group and 12.2 months in the TACE group (P = 0.040). The median progression-free survival (PFS) was 4.4 months and 2.7 months in the EP/EC group and the TACE group, respectively (P = 0.005). No significant differences in the overall response rate and disease control rate were observed between the EP/EC group and the TACE group (26.1% vs 11.1%, P = 0.429; 73.9% vs 44.4%, P = 0.055, respectively). A univariate analysis indicated that the Eastern Cooperative Oncology Group performance status (ECOG PS), Ki-67, tumor number, and treatment options were prognostic factors for OS. A multivariate analysis further showed that ECOG PS (P < 0.001), Ki-67 (P = 0.003), and treatment options (P = 0.022) were independent prognostic factors for OS. Conclusion Ki-67, ECOG PS, and treatment options were the independent prognostic factors for OS in patients with advanced PHNEC. EP/EC may be a better choice for patients with advanced PHNEC.
Collapse
Affiliation(s)
- Shuyi Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People's Republic of China
| | - Wenying Deng
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| | - Ning Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| | - Chen Wei
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| | - Chi Zhang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| | - Suxia Luo
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, Henan Province, People's Republic of China
| |
Collapse
|
28
|
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.
Collapse
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.
| |
Collapse
|
29
|
Ciobanu OA, Martin S, Fica S. Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review). Exp Ther Med 2021; 22:1479. [PMID: 34765020 PMCID: PMC8576627 DOI: 10.3892/etm.2021.10914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.
Collapse
Affiliation(s)
- Oana Alexandra Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Sorina Martin
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| |
Collapse
|
30
|
Kang NW, Tan KT, Li CF, Kuo YH. Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden. Curr Oncol 2021; 28:4587-4596. [PMID: 34898561 PMCID: PMC8628778 DOI: 10.3390/curroncol28060388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/06/2021] [Accepted: 11/07/2021] [Indexed: 01/05/2023] Open
Abstract
Poorly differentiated pancreatic neuroendocrine carcinomas (NECs) are rare and aggressive malignancies with rapid disease progression and early widespread metastasis. Given histology similarity, they are commonly treated with platinum-based chemotherapy as small cell lung cancer (SCLC). However, no standard treatment has been established for recurrent or progressive disease. We present an Asian patient with recurrent poorly differentiated pancreatic NEC after curative surgery and adjuvant chemotherapy with cisplatin and etoposide. The tumor mutational burden (TMB) was high. The patient received chemotherapy combined with maintenance immunotherapy with nivolumab and achieved promising and durable response, suggesting TMB could be a biomarker to identify NEC patients for immune checkpoint inhibitor (ICI) treatment.
Collapse
Affiliation(s)
- Nai-Wen Kang
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan;
| | | | - Chien-Feng Li
- Department of Medical Research, Chi-Mei Medical Center, Tainan 71004, Taiwan;
- National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan
| | - Yu-Hsuan Kuo
- Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan;
- College of Pharmacy and Science, Chia Nan University, Tainan 71710, Taiwan
- Correspondence:
| |
Collapse
|
31
|
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.
Collapse
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
| | | |
Collapse
|
32
|
Nakano-Tateno T, Satou M, Inoshita N, van Landeghem FKH, Easaw J, Mehta V, Tateno T, Chik CL. Effects of CAPTEM (Capecitabine and Temozolomide) on a Corticotroph Carcinoma and an Aggressive Corticotroph Tumor. Endocr Pathol 2021; 32:418-426. [PMID: 32833164 DOI: 10.1007/s12022-020-09647-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 01/16/2023]
Abstract
Corticotroph carcinomas and aggressive corticotroph tumors can be resistant to conventional therapy, including surgery, radiotherapy, and medical treatment. Recent evidence suggests that temozolomide (an oral alkylating agent) administered with capecitabine (pro-drug of 5-fluorouracil) may improve progression-free survival in patients with high-risk corticotroph tumors and carcinomas. This led to the use of capecitabine and temozolomide (CAPTEM) in two patients, one with a corticotroph carcinoma and the other with an aggressive corticotroph tumor, as well the in vitro analysis of capecitabine and 5-fluorouracil on cell growth and hormone production. Both patients had previous surgical and radiation therapy. The first patient developed leptomeningeal spread 2 years after his radiation treatment. He had 12 cycles of CAPTEM, which resulted in tumor control associated with clinical and radiological improvement. Twenty-seven months later, CAPTEM was restarted for disease recurrence with ongoing tumor response. The second patient had a rapid tumor regrowth 2 years after his third surgical resection. He was treated with 12 cycles of CAPTEM, which led to tumor shrinkage with no tumor regrowth 22 months after cessation of therapy. Experiments using mouse ACTH-producing pituitary tumor AtT20 cells demonstrated that treatment with 5-fluorouracil in combination with temozolomide had an additive effect in reducing cell viability and ACTH production in the culture medium. Our patients and experimental data in AtT20 cells support CAPTEM as a potential treatment option for aggressive corticotroph tumors and carcinomas. However, a prospective clinical trial is required to determine whether CAPTEM is superior to temozolomide in the treatment of these tumors.
Collapse
Affiliation(s)
- Tae Nakano-Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 9-112 Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada
| | - Motoyasu Satou
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 9-112 Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada
- Department of Biochemistry, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi, 321-0293, Japan
| | - Naoko Inoshita
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho Itabashi City, Tokyo, 173-0015, Japan
| | - Frank K H van Landeghem
- Department of Laboratory Medicine & Pathology, University of Alberta, 5B4.17 Walter Mackenzie Health Sciences Centre, 8440-112 Street, Edmonton, Alberta, T6G 2B7, Canada
| | - Jay Easaw
- Cross Cancer Institute, University of Alberta, 11560 University Ave, Edmonton, Alberta, T6G 1Z2, Canada
| | - Vivek Mehta
- Division of Neurosurgery, Department of Surgery, University of Alberta, 2D, Walter Mackenzie Health Sciences Centre, 8440 -112, Edmonton, Alberta, T6G 2B7, Canada
| | - Toru Tateno
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 9-112 Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada
| | - Constance L Chik
- Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, 9-112 Clinical Sciences Building, Edmonton, Alberta, T6G 2G3, Canada.
| |
Collapse
|
33
|
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.
Collapse
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
| |
Collapse
|
34
|
Mansfield AS, Hong DS, Hann CL, Farago AF, Beltran H, Waqar SN, Hendifar AE, Anthony LB, Taylor MH, Bryce AH, Tagawa ST, Lewis K, Niu J, Chung CH, Cleary JM, Rossi M, Ludwig C, Valenzuela R, Luo Y, Aggarwal R. A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors. NPJ Precis Oncol 2021; 5:74. [PMID: 34354225 PMCID: PMC8342450 DOI: 10.1038/s41698-021-00214-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 07/14/2021] [Indexed: 11/10/2022] Open
Abstract
Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.
Collapse
Affiliation(s)
| | - David S Hong
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christine L Hann
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | | | | | - Saiama N Waqar
- Washington University School of Medicine, St. Louis, MO, USA
| | | | - Lowell B Anthony
- University of Kentucky Chandler Medical Center, Lexington, KY, USA
| | - Matthew H Taylor
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA
| | | | | | - Karl Lewis
- University of Colorado Denver, Aurora, CO, USA
| | - Jiaxin Niu
- Banner MD Anderson Cancer Center, Gilbert, AZ, USA
| | | | | | | | | | | | - Yan Luo
- AbbVie, Inc, North Chicago, IL, USA
| | - Rahul Aggarwal
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
| |
Collapse
|
35
|
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.
Collapse
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
| |
Collapse
|
36
|
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.
Collapse
|
37
|
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.
Collapse
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.
| |
Collapse
|
38
|
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.
Collapse
Affiliation(s)
- Christiane Jungels
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | | |
Collapse
|
39
|
Janson ET, Knigge U, Dam G, Federspiel B, Grønbaek H, Stålberg P, Langer SW, Kjaer A, Arola J, Schalin-Jäntti C, Sundin A, Welin S, Thiis-Evensen E, Sorbye H. Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. ACTA ONCOLOGICA (STOCKHOLM, SWEDEN) 2021; 60:931-941. [PMID: 33999752 DOI: 10.1080/0284186x.2021.1921262] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. AIM These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.
Collapse
Affiliation(s)
- Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology Uppsala University, Uppsala, Sweden*
| | - Ulrich Knigge
- Departments of Surgery C and Endocrinology PE, Faculty of Health Science, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark*
| | - Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark*
| | - Birgitte Federspiel
- Department of Pathology, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark*
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark*
| | - Peter Stålberg
- Department of Surgical Sciences, Endocrine Surgery, Uppsala University, Uppsala, Sweden*
| | - Seppo W. Langer
- Department of Oncology, Rigshospitalet, Copenhagen, Denmark*
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark*
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark*
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark*
| | - Johanna Arola
- Department of Pathology, HUSLAB, Helsinki University and Helsinki University Central Hospital, Helsinki, Finland
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anders Sundin
- Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden*
| | - Staffan Welin
- Department of Medical Sciences, Endocrine Oncology Uppsala University, Uppsala, Sweden*
| | - Espen Thiis-Evensen
- Department for Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway*
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| |
Collapse
|
40
|
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.
Collapse
|
41
|
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.
Collapse
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.)
| |
Collapse
|
42
|
Bongiovanni A, Maiorano BA, Azzali I, Liverani C, Bocchini M, Fausti V, Di Menna G, Grassi I, Sansovini M, Riva N, Ibrahim T. Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2021; 14:476. [PMID: 34067837 PMCID: PMC8155858 DOI: 10.3390/ph14050476] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/11/2021] [Indexed: 01/14/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6-15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28-56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6-5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8-21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.
Collapse
Affiliation(s)
- Alberto Bongiovanni
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| | - Brigida Anna Maiorano
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
- Oncology Unit, Foundation Casa Sollievo della Sofferenza IRCCS, 71013 San Giovanni Rotondo, Italy
| | - Irene Azzali
- Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Chiara Liverani
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| | - Martine Bocchini
- Immunotherapy, Cell Therapy and Biobank (ITCB), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Valentina Fausti
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| | - Giandomenico Di Menna
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| | - Ilaria Grassi
- Nuclear Medicine Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.); (M.S.)
| | - Maddalena Sansovini
- Nuclear Medicine Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.); (M.S.)
| | - Nada Riva
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (B.A.M.); (C.L.); (V.F.); (G.D.M.); (N.R.); (T.I.)
| |
Collapse
|
43
|
Kobayashi N, Takeda Y, Okubo N, Suzuki A, Tokuhisa M, Hiroshima Y, Ichikawa Y. Phase II study of temozolomide monotherapy in patients with extrapulmonary neuroendocrine carcinoma. Cancer Sci 2021; 112:1936-1942. [PMID: 33453146 PMCID: PMC8088944 DOI: 10.1111/cas.14811] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/12/2021] [Accepted: 01/12/2021] [Indexed: 12/28/2022] Open
Abstract
Extrapulmonary neuroendocrine carcinoma (EPNEC) is a lethal disease with a poor prognosis. Platinum-based chemotherapy is used as the standard first-line treatment for unresectable EPNEC. Several retrospective studies have reported the results of the utilization of temozolomide (TMZ) as a drug for the second-line treatment for EPNEC. Patients with unresectable EPNEC that were resistant to platinum-based combination chemotherapy were recruited for a prospective phase II study of TMZ monotherapy. A 200 mg/m2 dose of TMZ was given from day 1 to day 5, every 4 weeks. Response rate (RR) was evaluated as the primary end-point. The presence of O6 -methylguanine DNA methyltransferase (MGMT) in EPNEC patients was also evaluated as exploratory research. Thirteen patients were enrolled in this study. Primary lesions were pancreas (n = 3), stomach (n = 3), duodenum (n = 1), colon (n = 1), gallbladder (n = 1), liver (n = 1), uterus (n = 1), bladder (n = 1), and primary unknown (n = 1). Each case was defined as pathological poorly differentiated neuroendocrine carcinoma from surgically resected and/or biopsied specimens. The median Ki-67 labeling index was 60% (range, 22%-90%). The RR was 15.4%, progression-free survival was 1.8 months (95% confidence interval [CI], 1.0-2.7), overall survival (OS) was 7.8 months (95% CI, 6.0-9.5), and OS from first-line treatment was 19.2 months (95% CI, 15.1-23.3). No grade 3 or 4 hematological toxicity had occurred and there was one case of grade 3 nausea. One case presented MGMT deficiency and this case showed partial response. Temozolomide monotherapy is a feasible, modestly effective, and safe treatment for patients with unresectable EPNEC following platinum-based chemotherapy, especially those with MGMT deficiency.
Collapse
Affiliation(s)
| | - Yuma Takeda
- Oncology DivisionYokohama City University HospitalYokohamaJapan
| | - Naoki Okubo
- Oncology DivisionYokohama City University HospitalYokohamaJapan
| | - Akihiro Suzuki
- Oncology DivisionYokohama City University HospitalYokohamaJapan
| | | | | | | |
Collapse
|
44
|
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: 22] [Impact Index Per Article: 5.5] [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.
Collapse
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
| |
Collapse
|
45
|
Spada F, Maisonneuve P, Fumagalli C, Marconcini R, Gelsomino F, Antonuzzo L, Campana D, Puliafito I, Rossi G, Faviana P, Messerini L, Barberis M, Fazio N. Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: an Italian multicenter real-world analysis. Endocrine 2021; 72:268-278. [PMID: 32700133 DOI: 10.1007/s12020-020-02421-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 07/09/2020] [Indexed: 01/05/2023]
Abstract
PURPOSE Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. METHODS Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. RESULTS From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. CONCLUSIONS This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.
Collapse
Affiliation(s)
- Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Caterina Fumagalli
- Histopathology and Molecular Diagnostics Unit, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Riccardo Marconcini
- Department of Oncology 2, Santa Chiara Hospital, Via Roma 67, 56100, Pisa, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital, Via del Pozzo 70, 41100, Modena, Italy
| | - Lorenzo Antonuzzo
- Medical Oncology 1, AOU Careggi Hospital, Viale Pieraccini 17, 50139, Firenze, Italy
| | - Davide Campana
- Scienze Mediche e Chirurgiche, Azienda Ospedaliero-Universitaria, Policlinico Sant'Orsola-Malpighi, Bologna, Italy
| | - Ivana Puliafito
- Oncologia Medica, Istituto Oncologico del Mediterraneo (IOM), Via Penninazzo 7, 95029, Viagrande, Italy
| | - Giulio Rossi
- Anatomia Patologica, Azienda USL Romagna, Ospedale S. Maria delle Croci, Viale Randi 5, 48121, Ravenna, Italy
| | - Pinuccia Faviana
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Paradisa 2, 56126, Pisa, Italy
| | - Luca Messerini
- Division of Human Pathology, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, 50139, Firenze, Italy
| | - Massimo Barberis
- Histopathology and Molecular Diagnostics Unit, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Via Ripamonti 435, 20141, Milan, Italy.
| |
Collapse
|
46
|
A Patient with an Ileocecal MiNEN and a Synchronous Squamous Non-Small-Cell Lung Cancer: Case Report and Review of the Literature. Case Rep Oncol Med 2021; 2021:8896254. [PMID: 33859853 PMCID: PMC8026310 DOI: 10.1155/2021/8896254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/17/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare tumors composed of two different histological components, one of which is of a neuroendocrine origin. Given its suggested underdiagnosis and consequent low prevalence, no clear diagnostic and treatment guidelines are available, and treatment usually follows regimens similar to that of the most aggressive component. On the other hand, multiple primary tumors (MPTs) are also rare neoplastic entities that usually confer a challenge regarding treatment options, for a regimen that comprises both the primary and the synchronous/metachronous malignancy should be used. Here, we discuss the challenging diagnostic and therapeutic management of a patient with an ileocecal MiNEN that presented along with a synchronous squamous non-small-cell lung cancer (SQ-NSCLC). The patient presented with intestinal obstruction symptoms for which he underwent an emergency resection of the ileocecal MiNEN. An initial CT scan showed an additional lung mass later identified as an SQ-NSCLC after bronchoscopy biopsy analysis. Given the rapid hepatic metastatic progression, palliative platinum-based chemotherapy was initiated, with an adequate response of the local and metastatic lesions of the MiNEN, but suggested platinum resistance and progression of the pulmonary neoplasm. Second-line treatment with pembrolizumab directed for the SQ-NSCLC was initiated; however, it was stopped after immune-mediated toxicities developed. A third-line chemotherapy scheme with carboplatin/gemcitabine was initiated, but central nervous system (CNS) progression developed, with the patient dying 11 months after initial diagnosis.
Collapse
|
47
|
Apostolidis L, Schrader J, Jann H, Rinke A, Krug S. Leptomeningeal Carcinomatosis: A Clinical Dilemma in Neuroendocrine Neoplasms. BIOLOGY 2021; 10:biology10040277. [PMID: 33800581 PMCID: PMC8066280 DOI: 10.3390/biology10040277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/21/2021] [Accepted: 03/26/2021] [Indexed: 11/16/2022]
Abstract
Central nervous system (CNS) involvement by paraneoplastic syndromes, brain metastases, or leptomeningeal carcinomatosis (LC) in patients with neuroendocrine neoplasms (NEN) has only been described in individual case reports. We evaluated patients with LC in four neuroendocrine tumor (NET) centers (Halle/Saale, Hamburg, Heidelberg, and Marburg) and characterized them clinically. In the study, 17 patients with a LC were defined with respect to diagnosis, clinic, and therapy. The prognosis of a LC is very poor, with 10 months in median overall survival (mOS). This is reflected by an even worse course in neuroendocrine carcinoma (NEC) G3 Ki-67 >55%, with a mOS of 2 months. Motor and sensory deficits together with vigilance abnormalities were common symptoms. In most cases, targeted radiation or temozolomide therapy was used against the LC. LC appears to be similarly devastating to brain metastases in NEN patients. Therefore, the indication for CNS imaging should be discussed in certain cases.
Collapse
Affiliation(s)
- Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany;
| | - Jörg Schrader
- I. Medical Department—Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Henning Jann
- Department of Gastroenterology and Hepatology, Charité—University Medical Center Berlin, Campus Virchow Klinikum and Charité Mitte, Augustenburger Platz 1, 13353 Berlin, Germany;
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, University Hospital Marburg, Baldinger Strasse, 35043 Marburg, Germany
- Correspondence: (A.R.); (S.K.); Tel.: +49-0345-557-2661 (S.K.); Fax: +49-0345-557-2253 (S.K.)
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin-Luther University Halle/Wittenberg, Ernst-Grube-Straße 40, 06120 Halle, Germany
- Correspondence: (A.R.); (S.K.); Tel.: +49-0345-557-2661 (S.K.); Fax: +49-0345-557-2253 (S.K.)
| |
Collapse
|
48
|
Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis. Biosci Rep 2021; 40:222307. [PMID: 32141507 PMCID: PMC7098124 DOI: 10.1042/bsr20194127] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/28/2020] [Accepted: 03/01/2020] [Indexed: 12/28/2022] Open
Abstract
Background: O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs. Methods: We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein. Results: Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04–8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups. Conclusion: Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.
Collapse
|
49
|
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%.
Collapse
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
| |
Collapse
|
50
|
Xu JL, Guo Y. Clinical characteristics and survival of extrapulmonary small cell carcinoma in 11 different primary tumor sites in the United States, 1975-2016. Curr Med Res Opin 2021; 37:71-81. [PMID: 33135938 DOI: 10.1080/03007995.2020.1846024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Few studies have investigated extrapulmonary small cell carcinoma (EPSCC) in a systematic way. This study is to analyze EPSCC in 11 tumor sites from different aspects in the United States (1975-2016). METHODS In total 4397 patients diagnosed with EPSCC in 11 primary tumor locations were selected from the Surveillance, Epidemiology and End Results (SEER) database. The incidence of EPSCC in the last decade, and the 1, 3 and 5 year survival rates of each tumor site were also roughly calculated. Prognostic factors of EPSCC were investigated by Cox regression analysis. RESULTS Statistically, the incidence of EPSCC was on the rise over the past 30 years. Of its 11 primary tumor sites, bladder was the most frequently affected while the stomach and kidney were rarely affected. Males were more susceptible to EPSCC than females. Married patients were more commonly afflicted by EPSCC, but had longer survival. Cases were most intensive in California and an increased trend had been observed. The 5 year overall survival (OS) rate ranged from 2.0% to 42.5% in patients with EPSCC in 11 tumor sites (p < .001). The OS was better for EPSCC in the breast and cervix. However, tumor sites in the colon, esophagus, pancreas, rectum and stomach were all associated with worse survival. Characteristics and prognosis of EPSCC in different tumor sites were statistically significant (p < .001). Age, gender, marital status, stage, surgery, radiotherapy and chemotherapy were equally significant factors of survival of EPSCC patients (p < .05). CONCLUSION There was an increasing trend of EPSCC incidence. The survival of EPSCC in different tumor sites was significantly different. Tumor locations, age, gender, marital status, stage, surgery, radiotherapy and chemotherapy were all important factors of survival. This study has implications for EPSCC prevention and treatment.
Collapse
Affiliation(s)
- Ji-Li Xu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, P.R. China
| | - Yong Guo
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, P.R. China
| |
Collapse
|