|
1
|
Palaniappan V, Li CH, Frilling A, Clift AK. Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review. J Pers Med 2023; 13:1428. [PMID: 37888039 PMCID: PMC10607978 DOI: 10.3390/jpm13101428] [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: 08/18/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023] Open
Abstract
Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting.
Collapse
Affiliation(s)
| | - Chun Hei Li
- St George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UK
| | - Andrea Frilling
- Department of Surgery & Cancer, Imperial College London, London SW7 2BX, UK
| | - Ashley Kieran Clift
- Department of Surgery & Cancer, Imperial College London, London SW7 2BX, UK
- Cancer Research UK Oxford Centre, University of Oxford, Oxford OX1 2JD, UK
| |
Collapse
|
|
2
|
Moeckli B, Ivanics T, Claasen M, Toso C, Sapisochin G. Recent developments and ongoing trials in transplant oncology. Liver Int 2020; 40:2326-2344. [PMID: 33021344 DOI: 10.1111/liv.14621] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/17/2020] [Accepted: 07/21/2020] [Indexed: 12/17/2022]
Abstract
Over the past two decades since the introduction of the Milan criteria, the field of transplant oncology has undergone a rapid development with a rising proportion of liver transplantations being performed for oncological indications. For many patients with liver tumours, transplantation represents the only chance for cure. However, many challenges remain, such as the adequate patient selection, management of post-transplant recurrence and refinement of neoadjuvant treatment protocols. This review provides an overview of the current state of the art of liver transplantation for oncological indications such as hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastasis and metastatic neuroendocrine tumours. We also summarize the ongoing research and explore future trends. Clinical trials are currently studying new diagnostic modalities, innovative pharmacological treatments, novel surgical techniques, downstaging regimens and new indications for liver transplantation. These emerging results will continue to shape the field of transplant oncology and provide us with the necessary tools to better select, treat and follow patients with liver tumours qualifying for liver transplantation.
Collapse
Affiliation(s)
- Beat Moeckli
- Department of Visceral and Transplantation Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Marco Claasen
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Christian Toso
- Department of Visceral and Transplantation Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada.,Division of General Surgery, University Health Network, Toronto, ON, Canada
| |
Collapse
|
|
3
|
Semrau S, Agaimy A, Pavel M, Lubgan D, Schmidt D, Cavallaro A, Golcher H, Grützmann R, Fietkau R. Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: a case report. J Med Case Rep 2019; 13:82. [PMID: 30902067 PMCID: PMC6431024 DOI: 10.1186/s13256-019-1995-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/23/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation. CASE PRESENTATION A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years. CONCLUSIONS Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
Collapse
Affiliation(s)
- S Semrau
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, 91054, Erlangen, Germany.
| | - A Agaimy
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Krankenhausstraße 8-10, 91054, Erlangen, Germany
| | - M Pavel
- Department of Medicine, Division of Endocrinology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - D Lubgan
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, 91054, Erlangen, Germany
| | - D Schmidt
- Clinic of Nuclear Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany
| | - A Cavallaro
- Institute of Radiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Maximiliansplatz 1, 91054, Erlangen, Germany
| | - H Golcher
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Maximiliansplatz 1, 91054, Erlangen, Germany
| | - R Grützmann
- Department of Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Maximiliansplatz 1, 91054, Erlangen, Germany
| | - R Fietkau
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsstraße 27, 91054, Erlangen, Germany
| |
Collapse
|
|
4
|
Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis. J Clin Med 2019; 8:jcm8030403. [PMID: 30909512 PMCID: PMC6462926 DOI: 10.3390/jcm8030403] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/14/2022] Open
Abstract
Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR .05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible.
Collapse
|
|
5
|
Moris D, Tsilimigras DI, Ntanasis-Stathopoulos I, Beal EW, Felekouras E, Vernadakis S, Fung JJ, Pawlik TM. Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review. Surgery 2017. [PMID: 28624178 DOI: 10.1016/j.surg.2017.05.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
6
|
Valadares LJ, Costa Junior W, Ribeiro HSC, Diniz AL, Coimbra FJF, Herman P. Resection of liver metastasis from neuroendocrine tumors: evaluation of results and prognostic factors. Rev Col Bras Cir 2017; 42:25-31. [PMID: 25992697 DOI: 10.1590/0100-69912015001006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 04/20/2014] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVES to determine the prognostic factors that may impact on morbidity and mortality and survival of patients undergoing surgical treatment of liver metastases from neuroendocrine tumors. METHODS We studied 22 patients undergoing liver resection for metastases from neuroendocrine tumors between 1997 and 2007. Epidemiological and clinical data were correlated with morbidity and mortality and overall and disease-free survivals. RESULTS twelve patients were male and ten female, with a mean age of 48.5 years. Bilobar disease was present in 17 patients (77.3%). In ten patients (45.5%) the primary tumor originated in the pancreas, terminal ileum in eight, duodenum in two, rectum in one and jejunum in one. Complete surgical resection (R0) was achieved in 59.1% of patients. Eight patients (36.3%) developed complications in the immediate postoperative period, one of them dying from septicemia. All patients undergoing re-hepatectomy and/or two-stage hepatectomy had complications in the postoperative period. The overall survival at one and five years was 77.3% and 44.2%. The disease-free survival at five years was 13.6%. The primary pancreatic neuroendocrine tumor (p = 0.006) was associated with reduced overall survival. Patients with number of metastatic nodules < 10 (p = 0.03) and asymptomatic at diagnosis (p = 0.015) had higher disease-free survival. CONCLUSION liver metastases originating from pancreatic neuroendocrine tumors proved to be a negative prognostic factor. Symptomatic patients with multiple metastatic nodules showed a significant reduction in disease-free survival.
Collapse
Affiliation(s)
| | | | | | - Alessandro L Diniz
- Department of Abdominal Surgery, Hospital A. C. Camargo, São Paulo, Brazil
| | - Felipe J F Coimbra
- Department of Abdominal Surgery, Hospital A. C. Camargo, São Paulo, Brazil
| | - Paulo Herman
- Department of Gastroenterology, Faculty of Medicine, Universidade de São Paulo, São Paulo, Brazil
| |
Collapse
|
|
7
|
Vennarecci G, Mascianà G, de Werra E, Guglielmo N, Levi Sandri GB, Coluzzi M, Ettorre GM. Rectal Carcinoid Tumor With Liver Metastases Treated by Local Excision and Orthotopic Liver Transplant With Long-term Follow-up. EXP CLIN TRANSPLANT 2017; 16:506-510. [PMID: 28350289 DOI: 10.6002/ect.2016.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In patients affected by unresectable liver metastases from neuroendocrine tumor, liver transplant represents currently the only realistic chance for cure. The first attempt to establish selection criteria for liver transplant in patients affected by neuroendocrine tumor liver metastases was made by Mazzaferro and associates in 2007. We report the case of a 46-year-old man who came to our institution in 2006 with right upper quadrant abdominal pain. Diagnosis of rectal neuroendocrine tumor with bilobar liver nodules was made; the patient underwent transanal local resection. A liver biopsy confirmed the metastatic nature of the hepatic lesion, showing a low-grade neuroendocrine tumor (G1, proliferation index Ki-67 <2%). The patient underwent 2 sessions of transarterial chemoembolization that resulted in stable disease. Afterward, the patient underwent a liver transplant, using the piggyback technique without a venous-venous bypass. His postoperative course was uneventful. The patient has been disease-free for 3 years. Posttransplant treatment has played a key role in increasing the overall survival of the patient and assuring him a good quality of life. He died 9 years (102 mo) after liver transplant.
Collapse
Affiliation(s)
- Giovanni Vennarecci
- Department of Surgical Oncology and Liver Transplantation, San Camillo Hospital, POIT San Camillo-INMI Lazzaro Spallanzani, Rome, Italy
| | | | | | | | | | | | | |
Collapse
|
|
8
|
Jin K, Xu J, Chen J, Chen M, Chen R, Chen Y, Chen Z, Cheng B, Chi Y, Feng ST, Fu D, Hou B, Huang D, Huang H, Huang Q, Li J, Li Y, Liang H, Lin R, Liu A, Liu J, Liu X, Lu M, Luo J, Mai G, Ni Q, Qiu M, Shao C, Shen B, Sheng W, Sun J, Tan C, Tan H, Tang Q, Tang Y, Tian X, Tong D, Wang X, Wang J, Wang J, Wang W, Wang W, Wang Y, Wu Z, Xue L, Yan Q, Yang N, Yang Y, Yang Z, Yin X, Yuan C, Zeng S, Zhang R, Yu X. Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET). Int J Oncol 2016; 49:1991-2000. [PMID: 27826620 DOI: 10.3892/ijo.2016.3711] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.
Collapse
Affiliation(s)
- Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University, Shanghai, P.R. China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University, Shanghai, P.R. China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Rufu Chen
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Ye Chen
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Zhiyu Chen
- Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, P.R. China
| | - Bin Cheng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Yihebali Chi
- Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China
| | - Baohua Hou
- Department of General Surgery, Guangdong General Hospital, Guangzhou, Guangdong, P.R. China
| | - Dan Huang
- Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, P.R. China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Qiang Huang
- Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui, P.R. China
| | - Jie Li
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Beijing Cancer Hospital, Beijing, P.R. China
| | - Ying Li
- Department of Radiology, Peking University Cancer Hospital, Beijing, P.R. China
| | - Houjie Liang
- Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Rong Lin
- Department of Gastroenterology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - An'an Liu
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Jixi Liu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Xubao Liu
- Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Beijing Cancer Hospital, Beijing, P.R. China
| | - Jie Luo
- Department of Pathology, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Gang Mai
- Department of Hepatobiliopancreatic Surgery, The People's Hospital of Deyang, Chengdu, Sichuan, P.R. China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University, Shanghai, P.R. China
| | - Meng Qiu
- Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Chenghao Shao
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Baiyong Shen
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Weiqi Sheng
- Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, P.R. China
| | - Jian Sun
- Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Chunlu Tan
- Department of Hepatobiliopancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Huangying Tan
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Qiyun Tang
- Department of Gastroenterology, Jiangsu People's Hospital, Nanjing, Jiangsu, P.R. China
| | - Yingmei Tang
- Department of Gastroenterology, The Second Affliated Hospital of Kunming Medical University, Yunnan Research Center for Liver Diseases, Kunming, Yunnan, P.R. China
| | - Xiaodong Tian
- Department of General Surgery, Peking University First Hospital, Beijing, P.R. China
| | - Danian Tong
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, P.R. China
| | - Xiaohong Wang
- Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, P.R. China
| | - Jian Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Wei Wang
- Department of Surgery, Huadong Hospital, Fudan University, Shanghai, P.R. China
| | - Wei Wang
- Department of Gastric and Pancreatic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, P.R. China
| | - Yu Wang
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou Guangdong, P.R. China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Ling Xue
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Qiang Yan
- Department of Hepatobiliopancreatic Surgery, Huzhou Central Hospital, Huzhou, Zhejiang, P.R. China
| | - Ning Yang
- Hepatobiliary Surgery Department V, Eastern Hepatobiliary Surgery Hospital, Shanghai, P.R. China
| | - Yinmo Yang
- Department of General Surgery, Peking University First Hospital, Beijing, P.R. China
| | - Zhiying Yang
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, P.R. China
| | - Xiaoyi Yin
- Department of Biliary-Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China
| | - Chunhui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing, P.R. China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Renchao Zhang
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, P.R. China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Pancreatic Cancer Institute, Fudan University; Shanghai, P.R. China
| |
Collapse
|
|
9
|
Sher LS, Levi DM, Wecsler JS, Lo M, Petrovic LM, Groshen S, Ji L, Uso TD, Tector AJ, Hamilton AS, Marsh JW, Schwartz ME. Liver transplantation for metastatic neuroendocrine tumors: Outcomes and prognostic variables. J Surg Oncol 2015; 112:125-32. [PMID: 26171686 DOI: 10.1002/jso.23973] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 06/13/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Patient selection for liver transplantation for metastatic neuroendocrine tumors remains a topic of debate. There is no established MELD exception, making it difficult to obtain donor organs. METHODS A multicenter database was created assessing outcomes for liver and multivisceral transplantation for metastatic neuroendocrine tumors and identifying prognostic factors for survival. Demographic, transplant, primary tumor site and management, pathology, recurrent disease and survival data were collected and analyzed. Survival probabilities were calculated using the Kaplan-Meier method. RESULTS Analysis included 85 patients who underwent liver transplantation November 1988-January 2012 at 28 centers. One, three, and five-year patient survival rates were 83%, 60%, and 52%, respectively; 40 of 85 patients died, with 20 of 40 deaths due to recurrent disease. In univariate analyses, the following were predictors of poor prognosis: large vessel invasion (P < 0.001), extent of extrahepatic resection at liver transplant (P = 0.007), and tumor differentiation (P = 0.003). In multivariable analysis, predictors of poor overall survival included large vessel invasion (P = 0.001), and extent of extrahepatic resection at liver transplant (P = 0.015). CONCLUSION In the absence of poor prognostic factors, metastatic neuroendocrine tumor is an acceptable indication for liver transplantation. Identification of favorable prognostic factors should allow assignment of a MELD exception similar to hepatocellular carcinoma.
Collapse
Affiliation(s)
- Linda S Sher
- Department of Surgery, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - David M Levi
- Department of Surgery, Carolinas Medical Center, Charlotte, North Carolina
| | - Julie S Wecsler
- Department of Surgery, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Mary Lo
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Lydia M Petrovic
- Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Susan Groshen
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Lingyun Ji
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - Teresa Diago Uso
- Department of General Surgery and Transplant Center, Cleveland Clinic, Cleveland, Ohio
| | - A Joseph Tector
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ann S Hamilton
- Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California
| | - J Wallis Marsh
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Myron E Schwartz
- Department of Surgery, Recanati/Miller Transplantation Institute Icahn School of Medicine at Mount Sinai, New York, New York
| |
Collapse
|
|
10
|
Lesurtel M, Nagorney DM, Mazzaferro V, Jensen RT, Poston GJ. When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations. HPB (Oxford) 2015; 17:17-22. [PMID: 24636662 PMCID: PMC4266436 DOI: 10.1111/hpb.12225] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 12/27/2013] [Indexed: 12/12/2022]
Abstract
AIM To determine the benefits and risks of hepatic resection versus non-resectional liver-directed treatments in patients with potentially resectable neuroendocrine liver metastases. METHODS A systematic review identified 1594 reports which alluded to a possible liver resection for neuroendocrine tumour metastases, of which 38 reports (all retrospective), comprising 3425 patients, were relevant. RESULTS Thirty studies reported resection alone, and 16 studies reported overall survival (OS). Only two studies addressed quality-of-life (QoL) issues. Five-year overall survival was reported at 41-100%, whereas 5-year progression-free survival (PFS) was 5-54%. We identified no robust evidence that a liver resection was superior to any other liver-directed therapies in improving OS or PFS. There was no evidence to support the use of a R2 resection (debulking), with or without tumour ablation, to improve either OS or QoL. There was little evidence to guide sequencing of surgery for patients presenting in Stage IV with resectable disease, and none to support a resection of asymptomatic primary tumours in the presence of non-resectable liver metastases. CONCLUSION Low-level recommendations are offered to assist in the management of patients with neuroendocrine liver metastases, along with recommendations for future studies.
Collapse
Affiliation(s)
- Mickaël Lesurtel
- Department of Surgery, Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital ZurichZurich, Switzerland
| | - David M Nagorney
- Department of Surgery, Mayo Clinic College of MedicineRochester, MN, USA
| | | | - Robert T Jensen
- Digestive Diseases Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, NIHBethesda, MD, USA
| | - Graeme J Poston
- Department of Surgery, Aintree University HospitalLiverpool, UK
| |
Collapse
|
|
11
|
Bacchetti S, Pasqual EM, Bertozzi S, Londero AP, Risaliti A. Curative versus palliative surgical resection of liver metastases in patients with neuroendocrine tumors: a meta-analysis of observational studies. Gland Surg 2014; 3:243-51. [PMID: 25493256 DOI: 10.3978/j.issn.2227-684x.2014.02.05] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/24/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND The role of surgical therapy in patients with liver metastases from neuroendocrine tumors (NETs) is unclear. In this study, the results obtained with curative or palliative resection, by reviewing recent literature and performing a meta-analysis, were examined. MATERIALS AND METHODS A systematic review and meta-analysis of observational studies published between January 1990 and October 2013 were performed. Studies that evaluated the different survival between patients treated by curative or palliative surgical resection of hepatic metastases from NETs were considered. The collected studies were evaluated for heterogeneity, publication bias, and quality. To calculate the pooled hazard ratio (HR) estimate and the 95% confidence interval (95% CI), a fixed-effects model was applied. RESULTS After the literature search, 2,546 studies were found and, among 38 potentially eligible studies, 3 were considered. We did not find a significant longer survival in patients treated with curative surgical resection of hepatic metastases when compared to palliative hepatic resection HR 0.40 (95% CI: 0.14-1.11). In one study, palliative resection of hepatic metastases significantly increased survival when compared to embolization. CONCLUSIONS Curative and also palliative surgery of NETs liver metastases may improve survival outcome. However, further randomized clinical trials are needed to elucidate this argument.
Collapse
Affiliation(s)
- Stefano Bacchetti
- 1 Department of Surgery, 2 University of Udine, AOU "Santa Maria della Misericordia", Udine, Italy
| | - Enrico Maria Pasqual
- 1 Department of Surgery, 2 University of Udine, AOU "Santa Maria della Misericordia", Udine, Italy
| | - Serena Bertozzi
- 1 Department of Surgery, 2 University of Udine, AOU "Santa Maria della Misericordia", Udine, Italy
| | - Ambrogio P Londero
- 1 Department of Surgery, 2 University of Udine, AOU "Santa Maria della Misericordia", Udine, Italy
| | - Andrea Risaliti
- 1 Department of Surgery, 2 University of Udine, AOU "Santa Maria della Misericordia", Udine, Italy
| |
Collapse
|
|
12
|
Singh S, Dey C, Kennecke H, Kocha W, Maroun J, Metrakos P, Mukhtar T, Pasieka J, Rayson D, Rowsell C, Sideris L, Wong R, Law C. Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group. Ann Surg Oncol 2014; 22:2685-99. [PMID: 25366583 DOI: 10.1245/s10434-014-4145-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Indexed: 12/29/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare heterogeneous tumors that have been steadily increasing in both incidence and prevalence during the past few decades. Pancreatic NETs are categorized as functional (F) or nonfunctional (NF) based on their ability to secrete hormones that elicit clinically relevant symptoms. Specialized diagnostic tests are required for diagnosis. Treatment options are diverse and include surgical resection, intraarterial hepatic therapy, and peptide receptor radionuclide therapy (PRRT). Systemic therapy options include targeted agents as well as chemotherapy when indicated. Diagnosis and management should occur through a collaborative team of health care practitioners well-experienced in managing pNETs. Recent advances in pNET treatment options have led to the development of the Canadian consensus document described in this report. The discussion includes the epidemiology, classification, pathology, clinical presentation and prognosis, imaging and laboratory testing, medical and surgical management, and recommended treatment algorithms for pancreatic neuroendocrine cancers.
Collapse
Affiliation(s)
- Simron Singh
- Department of Medicine, Odette Cancer Centre - Sunnybrook Hospital, University of Toronto, Toronto, ON, Canada,
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Saeed A, Buell JF, Kandil E. Surgical treatment of liver metastases in patients with neuroendocrine tumors. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:6. [PMID: 25332951 DOI: 10.3978/j.issn.2305-5839.2013.01.08] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 01/31/2013] [Indexed: 12/21/2022]
Abstract
Liver metastases occur in 75% to 80% of patients with neuroendocrine tumors (NETs), and are considered significant adverse prognostic indicators. Management of NETs liver metastases is challenging and requires aggressive therapy. Currently, there are many therapeutic options for metastatic NETs. However, there is considerable controversy regarding the optimal management. Although complete surgical resection remains the optimal therapy, a variety of other minimally invasive surgical and medical options are available, this includes thermal ablative techniques (e.g., radiofrequency ablation, microwave ablation, cryotherapy), embolization using transcatheter embolization, chemoembolization, or radioembolization, and medical therapy (e.g., chemotherapy, biotherapy with somatostatin analogues and interferon). Currently there is no evidence-based data directly comparing surgical versus alternative liver-directed treatment options. An aggressive surgical approach, coupled with additional liver-directed procedures is often recommended as it extends the overall survival. Optimal patient care should be directed by a multidisciplinary team to assure that all treatment options are explored for decision-making while treating this aggressive disease.
Collapse
Affiliation(s)
- Ahmad Saeed
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Joseph F Buell
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Emad Kandil
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| |
Collapse
|
|
14
|
Partelli S, Maurizi A, Tamburrino D, Baldoni A, Polenta V, Crippa S, Falconi M. GEP-NETS update: a review on surgery of gastro-entero-pancreatic neuroendocrine tumors. Eur J Endocrinol 2014; 171:R153-62. [PMID: 24920289 DOI: 10.1530/eje-14-0173] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence of neuroendocrine tumors (NETs) has increased in the last decades. Surgical treatment encompasses a panel of approaches ranging from conservative procedures to extended surgical resection. Tumor size and localization usually represent the main drivers in the choice of the most appropriate surgical resection. In the presence of small (<2 cm) and asymptomatic nonfunctioning NETs, a conservative treatment is usually recommended. For localized NETs measuring above 2 cm, surgical resection represents the cornerstone in the management of these tumors. As they are relatively biologically indolent, an extended resection is often justified also in the presence of advanced NETs. Surgical options for NET liver metastases range from limited resection up to liver transplantation. Surgical choices for metastatic NETs need to consider the extent of disease, the grade of tumor, and the presence of extra-abdominal disease. Any surgical procedures should always be balanced with the benefit of survival or relieving symptoms and patients' comorbidities.
Collapse
Affiliation(s)
- Stefano Partelli
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Angela Maurizi
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Domenico Tamburrino
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Andrea Baldoni
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Vanessa Polenta
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Stefano Crippa
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| | - Massimo Falconi
- Pancreatic Surgery UnitUniversità Politecnica delle Marche, Via Conca, 71, 60126 Ancona, ItalyDepartment of SurgeryUniversity of Verona, Verona, Italy
| |
Collapse
|
|
15
|
Birnbaum DJ, Turrini O, Vigano L, Russolillo N, Autret A, Moutardier V, Capussotti L, Le Treut YP, Delpero JR, Hardwigsen J. Surgical management of advanced pancreatic neuroendocrine tumors: short-term and long-term results from an international multi-institutional study. Ann Surg Oncol 2014; 22:1000-7. [PMID: 25190116 DOI: 10.1245/s10434-014-4016-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND The role of extended resections in the management of advanced pancreatic neuroendocrine tumors (PNETs) is not well defined. METHODS Between 1995 and 2012, 134 patients with PNET underwent isolated (isoPNET group: 91 patients) or extended pancreatic resection (synchronous liver metastases and/or adjacent organs) (advPNET group: 43 patients). RESULTS The associated resections included 27 hepatectomies, 9 vascular resections, 12 colectomies, 10 gastrectomies, 4 nephrectomies, 4 adrenalectomies, and 3 duodenojejunal resections. R0 was achieved in 41 patients (95%) in the advPNET. The rates of T3-T4 (73 vs 16%; p < .0001) and N+ (35 vs 13%; p = .007) were higher in the advPNET group. Mortality (5 vs 2%) and major morbidity (21 vs 19%) rates were similar between the 2 groups. The 5-year overall survival (OS) of the series was 87% in the isoPNET group and 66% in the advPNET group (p = .006). Only patients with both locally advanced disease and liver metastases showed worse survival (p = .0003). The advPNET group developed recurrence earlier [disease-free survival (DFS) at 5 years: 26 vs 81%; p < .001]. In univariate analysis, negative prognostic factors of survival were: poor degree of differentiation (p < .001), liver metastasis (p = .011), NE carcinoma (p < .001), and resection of adjacent organs (p = .013). The multivariate analysis did not highlight any factor that influenced OS. In multivariate analysis independent DFS factors were a poor degree of differentiation (p = .03) and the European Neuroendocrine Tumor Society stage (p = .01). CONCLUSIONS An aggressive surgical approach for locally advanced or metastatic tumors is safe and offers long-term survival.
Collapse
|
|
16
|
Alistar A, Sung M, Kim M, Holcombe RF. Clinical pathways for pancreatic neuroendocrine tumors. J Gastrointest Cancer 2013; 43:532-40. [PMID: 22661335 DOI: 10.1007/s12029-012-9397-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (PNETs) represent a group of diseases that pose diagnostic and therapeutic challenges due to their clinical and pathological heterogeneity as well as the limited number of patients available for clinical trials. Over the last couple of decades, a major progress in understanding tumor biology led to the discovery of new potential targets for the medical treatment of these tumors. DISCUSSION There are numerous novel targeted agents in various stages of preclinical and clinical development that offer considerable promise as monotherapy or combination therapy for PNETs. The question of whether traditional clinical research methods are appropriate for the development of novel, targeted anticancer agents has been the subject of many discussions. Major challenges include identifying a valid target, the most effective agent within a target class, the right subset of population to benefit from the drug, and the most appropriate setting to use the drug. As new agents emerge, oncologists are faced with making clinical decisions sometimes before having a high level of evidence. In this review, we attempt to address some of the management steps involved in treating patients with pancreatic neuroendocrine tumors, particularly well to moderately differentiated tumors. The purpose of this review is to offer a therapeutic sequence including surgery, liver-directed therapy, chemotherapy, and targeted therapy for this disease.
Collapse
Affiliation(s)
- Angela Alistar
- Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
| | | | | | | |
Collapse
|
|
17
|
Coan KE, Gray RJ, Schlinkert RT, Pockaj BA, Wasif N. Metastatic carcinoid tumors--are we making the cut? Am J Surg 2013; 205:642-6. [PMID: 23414634 DOI: 10.1016/j.amjsurg.2012.05.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Accepted: 05/16/2012] [Indexed: 10/27/2022]
Abstract
BACKGROUND Although controversial, surgical resection for metastatic carcinoid tumors (MCTs) can potentially prolong survival. METHODS Patients with MCTs were identified from the Surveillance, Epidemiology and End Results database. Patients undergoing surgery were compared to unresected patients. RESULTS Surgery was performed in 33% of patients. Predictors of surgery included age <50 years (odds ratio [OR], 2.4), low grade (OR, 3.1), and the appendix (OR, 36.2) or small intestine (OR, 27.2) as the primary site. Predictors of adverse survival included high grade (hazard ratio, 2.4) and no surgery (hazard ratio, 2.5) or surgery on only primary or distant disease (hazard ratio, 1.5) compared with surgery for both. Survival at 5 years was 5% with no surgery, 28% with surgery on either site, and 46% with surgery at both sites (P < .001). CONCLUSIONS Surgery for MCTs is more common in younger patients, those with low-grade disease, and those with small bowel or appendiceal primary tumors. Although selection bias cannot be excluded, these data lend support to "debulking" for MCT.
Collapse
Affiliation(s)
- Kathryn E Coan
- Department of Surgery, Mayo Clinic, Phoenix, AZ 85054, USA
| | | | | | | | | |
Collapse
|
|
18
|
Haugvik SP, Labori KJ, Edwin B, Mathisen Ø, Gladhaug IP. Surgical treatment of sporadic pancreatic neuroendocrine tumors: a state of the art review. ScientificWorldJournal 2012; 2012:357475. [PMID: 23304085 PMCID: PMC3523601 DOI: 10.1100/2012/357475] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 11/25/2012] [Indexed: 02/07/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms. They are clinically diverse and divided into functioning and nonfunctioning disease, depending on their ability to produce symptoms due to hormone production. Surgical resection is the only curative treatment and remains the cornerstone therapy for this patient group, even in patients with advanced disease. Over the last decade there has been a noticeable trend towards more aggressive surgery as well as more minimally invasive surgery in patients with PNETs. This has resulted in improved long-term survival in patients with locally advanced and metastatic disease treated aggressively, as well as shorter hospital stays and comparable long-term outcomes in patients with limited disease treated minimally invasively. There are still controversies related to issues of surgical treatment of PNETs, such as to what extent enucleation, lymph node sampling, and vascular reconstruction are beneficial for the oncologic outcome. Histopathologic tumor classification is of high clinical importance for treatment planning and prognostic evaluation of patients with PNETs. A constant challenge, which relates to the treatment of PNETs, is the lack of an internationally accepted histopathological classification system. This paper reviews current issues on the surgical treatment of sporadic PNETs with specific focus on surgical approaches and tumor classification.
Collapse
Affiliation(s)
- Sven-Petter Haugvik
- Department of Hepato-Pancreato-Biliary Surgery, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
| | | | | | | | | |
Collapse
|
|
19
|
Treatment of liver metastases in patients with digestive neuroendocrine tumors. J Gastrointest Surg 2012; 16:1981-92. [PMID: 22829240 DOI: 10.1007/s11605-012-1951-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 06/24/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver metastases are a strong prognostic indicator in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). Therapeutic options for metastatic NETs are expanding and not mutually exclusive. AIMS This paper reviews the literature relating to multidisciplinary approach towards GEP-NET metastases, to highlight advances in knowledge regarding these tumors, and to understand the interdisciplinary management of individual patients. METHODS A PubMed search was performed for English-language publications from 1995 through 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for GEP-NET-related liver metastases were selected. RESULTS There is considerable controversy regarding the optimal management of GEP-NET metastases. Although radical surgery still remains the gold standard, a variety of other therapeutic options are available for metastatic GEP-NETs, including loco-regional chemotherapy/radiotherapy, radioembolization, systemic peptide receptor radionuclide therapy, biotherapy, and chemotherapy. In selected patients, liver transplantation should also be considered. Systemic somatostatin analogues and/or interferon show anti-proliferative effects, representing an appropriate first-line treatment for most patients. In advanced metastatic NETs, recent options include targeted therapies (i.e., everolimus and sunitinib). CONCLUSIONS It is evident that multidisciplinary care and multimodality treatments remain the cornerstone of management of NET patients. Since NETs often show a more indolent behavior compared to other malignancies, physicians should aim to preserve a satisfactory quality of life for the patient by personalizing the therapeutic approach according to the tumor's features and prognostic factors.
Collapse
|
|
20
|
Frilling A, Akerström G, Falconi M, Pavel M, Ramos J, Kidd M, Modlin IM. Neuroendocrine tumor disease: an evolving landscape. Endocr Relat Cancer 2012; 19:R163-85. [PMID: 22645227 DOI: 10.1530/erc-12-0024] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.
Collapse
Affiliation(s)
- Andrea Frilling
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, UK
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surg Oncol 2012; 21:e131-41. [PMID: 22658833 DOI: 10.1016/j.suronc.2012.05.001] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Revised: 04/26/2012] [Accepted: 05/03/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Neuroendocrine tumours (NET) most commonly metastasize to the liver. Hepatic resection of NET hepatic metastases (NETHM) has been shown to improve symptomology and survival. METHODS A systematic review of clinical studies before September 2010 was performed to examine the efficacy of hepatic resection for NETHM. As a secondary end-point, the impact of treatment on safety and symptomology were determined and prognostic variables were identified. The quality of each study was also assessed using predefined criteria incorporating 9 characteristics. Clinical outcome was synthesized through a narrative review with full tabulation of results of all included studies. RESULTS Twenty-nine included reported survival outcomes with a median 3-, 5- and 10-year overall survival of 83% (range, 63-100%), 70.5% (range, 31-100%), and 42% (range, 0-100%), respectively. The median progression-free survival (PFS) was 21 months (range, 13-46 months) and median 1-,3-,5- and 10-year PFS of 63% (range, 50-80 %), 32% (range, 24-69%), 29% (range, 6-66%) and 1% (range, 0-11%), respectively. Poor histologic grade, extra-hepatic disease and a macroscopically incomplete resection were associated with a poor prognosis. Studies reported a median rate of symptomatic relief from surgery in 95% of patients (range, 50-100%). CONCLUSION Hepatic resection for NETHM provides symptomatic benefit and is associated with favourable survival outcomes although the majority of patients invariably develop disease progression.
Collapse
Affiliation(s)
- Akshat Saxena
- Hepatobiliary and Surgical Oncology Unit, University of New South Wales, Department of Surgery, St George Hospital, Q1 Kogarah NSW 2217, Sydney, Australia
| | | | | | | | | |
Collapse
|
|
22
|
Gu P, Wu J, Newman E, Muggia F. Treatment of liver metastases in patients with neuroendocrine tumors of gastroesophageal and pancreatic origin. Int J Hepatol 2012; 2012:131659. [PMID: 22518318 PMCID: PMC3299245 DOI: 10.1155/2012/131659] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 11/16/2011] [Accepted: 12/04/2011] [Indexed: 12/23/2022] Open
Abstract
Well-to-moderately differentiated neuroendocrine tumors of gastroesophageal and pancreatic origin (GEP-NETs) with liver metastasis are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. Surgical resection of hepatic metastases or hepatic artery embolization may be beneficial in patients with hepatic-predominant metastatic disease. Patients with "carcinoid" syndrome and syndromes associated with functional pancreatic NET (PNET) can be effectively treated with somatostatin analogs. On the other hand, the efficacy of systemic chemotherapy for these patients is limited. A placebo-controlled, double-blind, prospective, and randomized study showed that octreotide LAR improves progression-free survival in patients with advanced midgut functional "carcinoids." In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, octreotide LAR, sunitinib, or everolimus are now considered as first-line therapeutic options in patients with advanced NET. Future studies will likely further define the role of these agents in patients with carcinoid liver metastasis and pancreatic NET liver metastasis.
Collapse
Affiliation(s)
- Ping Gu
- Department of Hematology and Medical Oncology, NYU Cancer Institute, New York, NY 10016, USA
| | - Jennifer Wu
- Department of Hematology and Medical Oncology, NYU Cancer Institute, New York, NY 10016, USA
| | - Elliot Newman
- Department of General Surgery, NYU Medical Center New York, NY 10016, USA
| | - Franco Muggia
- Department of Medical Oncology, NYU Cancer Institute, New York, NY 10016, USA
| |
Collapse
|
|
23
|
Surgical treatment of liver metastases in neuroendocrine neoplasms. Int J Hepatol 2012; 2012:782672. [PMID: 22319653 PMCID: PMC3272813 DOI: 10.1155/2012/782672] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 10/07/2011] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a distinctive entity, and nearly 10% of patients already have liver metastases at presentation. The management of neuroendocrine liver metastases (NEN-LM) is complex with differing patterns of metastatic presentation. An aggressive approach should be used to resect the primary tumor, to remove regional lymph nodes, and to resect or treat appropriate distant metastases (including liver tumors). Despite having an indolent course, NENs have a significantly reduced survival when liver metastases are untreated. Though a wide range of therapies are now available with a multimodal approach to the treatment, surgical treatment offers the only chance for a significant survival prolongation and/or improvement of symptoms and quality of life. A review of the existing surgical modalities for NEN-LM is discussed in this paper.
Collapse
|
|
24
|
Abstract
Management of Neuroendocrine liver metastases (NELM) is challenging. The presence of NELM worsens survival outcome and almost 10% of all liver metastases are neuroendocrine in origin. There is no firm consensus on the optimal treatment strategy for NELM. A systematic search of the PubMed database was performed from 1995-2010, to collate the current evidence and formulate a sound management algorithm. There are 22 case series with a total of 793 patients who had undergone surgery for NELM. The overall survival ranges from 46-86% at 5 years, 35-79% at 10 years, and the median survival ranges from 52-123 months. After successful cytoreductive surgery, the mean duration of symptom reduction is between 16-26 months, and the 5-year recurrence/progression rate ranges from 59-76%. Five studies evaluated the efficacy of a combination cytoreductive strategy reporting survival rate of ranging from 83% at 3 years to 50% at 10 years. To date, there is no level 1 evidence comparing surgery versus other liver-directed treatment options for NELM. An aggressive surgical approach, including combination with additional liver-directed procedures is recommended as it leads to long-term survival, significant long-term palliation, and a good quality of life. A multidisciplinary approach should be established as the platform for decision making.
Collapse
|
|
25
|
Khan MS, Caplin ME. Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2011; 18 Suppl 1:S53-74. [PMID: 22005115 DOI: 10.1530/erc-10-0271] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Patients with neuroendocrine tumours (NETs) are best managed in a specialist centre as part of a multidisciplinary team comprising gastroenterologists, oncologists, endocrinologists, gastrointestinal and hepatopancreaticobiliary surgeons, pathologists, nuclear medicine physicians and technicians, radiologists, specialist nurses, pharmacists, biochemists and dieticians. This should ideally be led by a clinician with experience and interest in NETs. Although the number of medical treatments and clinical trials has increased in the decade, there is still a lack of prospective randomised trials; thus, management is mainly based on limited often single-centre studies, although there are now formal guidelines based on consensus expert opinion. We have outlined the current optimal management of patients with NETs. We have reviewed therapeutic options including surgery, somatostatin analogues and other biotherapies and peptide receptor-targeted therapy. We have discussed the challenge in managing hepatic metastases including hepatic artery embolisation, ablation and orthotopic liver transplant. In addition, we have briefly reviewed the emerging therapies such as the mammalian target of rapamycin and angiogenic inhibitors and the newer somatostatin analogues.
Collapse
Affiliation(s)
- Mohid S Khan
- Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital, London NW3 2QG, UK
| | | |
Collapse
|
|
26
|
Palesty JA, Al-Kasspooles M, Gibbs JF. Patient selection for surgical management of primary and metastatic liver cancers: current perspectives. Semin Intervent Radiol 2011; 23:13-20. [PMID: 21326716 DOI: 10.1055/s-2006-939837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The surgical management of liver malignancies remains a mainstay in the treatment of such patients, and has benefited from dramatic advancements over the last two decades. Improvements in surgical technique, better understanding of hepatic anatomy, and improvement in anesthesiological supportive care has resulted in a decline in perioperative morbidity and operative mortality. Proper patient selection for surgical and nonsurgical treatment currently employs a multidisciplinary approach in our institution. This review will focus on the surgical treatment options for both primary and secondary liver cancers.
Collapse
Affiliation(s)
- J Alexander Palesty
- Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York
| | | | | |
Collapse
|
|
27
|
Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. J Hematol Oncol 2011; 4:29. [PMID: 21672194 PMCID: PMC3128039 DOI: 10.1186/1756-8722-4-29] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 06/14/2011] [Indexed: 01/02/2023] Open
Abstract
Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise, with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET.
Collapse
|
|
28
|
Fiebiger W, Olszewski U, Ulsperger E, Geissler K, Hamilton G. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Transl Oncol 2011; 13:43-9. [PMID: 21239354 DOI: 10.1007/s12094-011-0615-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.
Collapse
Affiliation(s)
- Wolfgang Fiebiger
- Department of Internal Medicine I, Division of Oncology, St. Poelten Hospital, St. Poelten, Austria
| | | | | | | | | |
Collapse
|
|
29
|
Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: a survival-based analysis. Transplantation 2011; 91:575-82. [PMID: 21200365 DOI: 10.1097/tp.0b013e3182081312] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Liver transplantation (LT) has been accepted as a treatment in selected cases of neuroendocrine tumors (NETs) with hepatic metastases. PATIENTS AND METHODS A systematic review of the literature was conducted to evaluate long-term patient survival in the instances of LT for pancreatic NET. Univariate and multivariate regression analyses and survival analysis were performed. RESULTS Fifty-three clinical studies were screened. Data from 20 studies encompassing 89 transplanted patients were included in the study. Most primary tumors were endocrine pancreatic tumors (n=69), with gastrinomas representing the most frequent diagnosis (n=21). There were 61 functioning pancreatic NET. Simultaneous LT and pancreatic NET resections were performed in 45 instances. Cumulative 1-, 3-, and 5-year survival was 71%, 55%, and 44%, respectively, with a calculated mean survival of 54.45±6.31 months. Vasoactive intestinal peptide (VIPomas) had the best overall survival. Recurrence-free survival at 1, 3, and 5 years was 84%, 47%, and 47%, respectively. Recipient age more than or equal to 55 years (P=0.0242) and simultaneous LT-pancreatic resection (P=0.0132) were found to be significant predictors of worse survival by both univariate and multivariate Cox proportional hazard analyses. A scoring system was developed, with prognostic points assigned as follows: age more than or equal to 55 years:age less than 55 years=1:0 points and simultaneous LT-pancreatic resection:LT alone=1:0 points. This stratification delineated three separate population samples corresponding to patients with scores of 0, 1, and 2, respectively. The calculated 5-year survival for scores 0, 1, and 2 was 61%, 40%, and 0%, respectively (P=0.0023). CONCLUSIONS Despite the limitations of this retrospective analysis, good results can be achieved even for pancreatic NET primaries if the above-proposed scoring system is applied.
Collapse
|
|
30
|
Lillegard JB, Fisher JE, Mckenzie TJ, Que FG, Farnell MB, Kendrick ML, Donohue JH, Reid-Lombardo K, Schaff HV, Connolly HM, Nagorney DM. Hepatic resection for the carcinoid syndrome in patients with severe carcinoid heart disease: does valve replacement permit safe hepatic resection? J Am Coll Surg 2011; 213:130-6; discussion 136-8. [PMID: 21493110 DOI: 10.1016/j.jamcollsurg.2011.03.029] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 03/10/2011] [Accepted: 03/14/2011] [Indexed: 10/18/2022]
Abstract
BACKGROUND Hepatic resection of metastatic carcinoid cancer can prolong survival and control symptomatic endocrinopathy. Decompensated carcinoid heart disease (CHD) can develop in some patients with metastatic carcinoid cancers, which can preclude operation for resectable hepatic metastases. We hypothesized that outcomes after hepatic resection for patients with the carcinoid syndrome after valve replacement for CHD would be similar to carcinoid patients without CHD. STUDY DESIGN We compared the survival and symptom control after hepatic resection for patients undergoing valve replacement for CHD to carcinoid patients without CHD matched for age, sex, and extent of hepatectomy. RESULTS Fourteen patients with earlier valve replacement for CHD were compared with 28 carcinoid patients without CHD. All patients had hepatic resection for metastatic carcinoid disease and carcinoid syndrome. Mean age, sex distribution, and extent of hepatectomy (major hepatectomy, 78%) was similar between groups. Mean interval from valve replacement to hepatectomy was 101 days. There was no operative mortality. Major operative morbidity, inclusive of operative blood loss and cardiorespiratory events, occurred in 28.5% and 14.2% for CHD and non-CHD groups, respectively (p = 0.16). Symptom-free survival for CHD and non-CHD groups was 69% and 81% at 1 year (p = 0.22) and 61% and 44% (p = 0.17) at 5 years, respectively. Octreotide-free survival after hepatectomy 69% and 84% (p = 0.15) at 1 year and 62% and 52% (p = 0.29) 5 years, respectively. Overall survival CHD and non-CHD groups 100% at 1 year and 100% and 70% (p = 0.002) 5 years. CONCLUSIONS Valve replacement for severe CHD is safe and hepatic resection is associated with similar outcomes as patients without CHD undergoing hepatic resection for carcinoid syndrome. Identifying resectable hepatic metastases from carcinoids in patients with severe CHD should prompt valve replacement and interval hepatic resection.
Collapse
Affiliation(s)
- Joseph B Lillegard
- Division of Gastroenterologic and General Surgery, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
de Herder WW, Mazzaferro V, Tavecchio L, Wiedenmann B. Multidisciplinary approach for the treatment of neuroendocrine tumors. TUMORI JOURNAL 2011; 96:833-46. [PMID: 21302641 DOI: 10.1177/030089161009600537] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Wouter W de Herder
- Department of Internal Medicine, Section of Endocrinology Erasmus MC, Rotterdam, The Netherlands
| | | | | | | |
Collapse
|
|
32
|
Fendrich V, Bartsch DK. Surgical treatment of gastrointestinal neuroendocrine tumors. Langenbecks Arch Surg 2011; 396:299-311. [PMID: 21279821 DOI: 10.1007/s00423-011-0741-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Accepted: 01/17/2011] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are uncommon but clinically challenging and fascinating tumors. GEP-NETs present as either functional or as nonfunctional tumors. Functional tumors are commonly associated with a specific hormonal syndrome directly related to a hormone secreted by the tumor, like gastrinomas with a Zollinger-Ellison syndrome or carcinoid syndrome in patients with neuroendocrine tumors (NET) of the ileum. Nonfunctional tumors do not secrete a hormone resulting in a clinical syndrome. METHODS The natural course of GEP-NETs is highly variable. Small, benign neoplasms such as 90% of all insulinomas or gastric endocrine tumors type 1 are readily curable by surgical resection; however, most other GEP-NETs have a much less favorable prognosis. Patients with completely resected tumors generally have a good prognosis, and an aggressive surgical approach in patients with advanced disease may also prolong survival. CONCLUSIONS This review focuses on the current standards of surgical treatment of gastric endocrine tumors, NETs of the pancreas (PNET) and NETs of the ileum. Although the evidence level is low in many instances due to the lack of randomized controlled trials, important treatment recommendations can be given.
Collapse
Affiliation(s)
- Volker Fendrich
- Department of Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany.
| | | |
Collapse
|
|
33
|
Fendrich V, Michl P, Habbe N, Bartsch DK. Liver-specific therapies for metastases of neuroendocrine pancreatic tumors. World J Hepatol 2010; 2:367-73. [PMID: 21160945 PMCID: PMC2998945 DOI: 10.4254/wjh.v2.i10.367] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Revised: 10/05/2010] [Accepted: 10/12/2010] [Indexed: 02/06/2023] Open
Abstract
The presence or development of liver metastases in patients with neuroendocrine pancreatic tumors is the most important prognostic factor. Liver resection, transplantation and many different therapeutic approaches are discussed in this special review.
Collapse
Affiliation(s)
- Volker Fendrich
- Volker Fendrich, Nils Habbe, Detlef Klaus Bartsch, Department of Surgery, Philipps-University, Marburg D-35043, Germany
| | | | | | | |
Collapse
|
|
34
|
Frilling A, Sotiropoulos GC, Li J, Kornasiewicz O, Plöckinger U. Multimodal management of neuroendocrine liver metastases. HPB (Oxford) 2010; 12:361-79. [PMID: 20662787 PMCID: PMC3028577 DOI: 10.1111/j.1477-2574.2010.00175.x] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The incidence of neuroendocrine tumours (NET) has increased over the past three decades. Hepatic metastases which occur in up to 75% of NET patients significantly worsen their prognosis. New imaging techniques with increasing sensitivity enabling tumour detection at an early stage have been developed. The treatment encompasses a panel of surgical and non-surgical modalities. METHODS This article reviews the published literature related to management of hepatic neuroendocrine metastases. RESULTS Abdominal computer tomography, magnetic resonance tomography and somatostatin receptor scintigraphy are widely accepted imaging modalities. Hepatic resection is the only potentially curative treatment. Liver transplantation is justified in highly selected patients. Liver-directed interventional techniques and locally ablative measures offer effective palliation. Promising novel therapeutic options offering targeted approaches are under evaluation. CONCLUSIONS The treatment of neuroendocrine liver metastases still needs to be standardized. Management in centres of expertise should be strongly encouraged in order to enable a multidisciplinary approach and personalized treatment. Development of molecular prognostic factors to select treatment according to patient risk should be attempted.
Collapse
Affiliation(s)
- Andrea Frilling
- Department of Surgery and Cancer, Imperial College London, Hammersmith HospitalLondon, UK
| | | | - Jun Li
- Department of General, Visceral and Transplantation Surgery, University Hospital TübingenTübingen
| | - Oskar Kornasiewicz
- Department of Surgery and Cancer, Imperial College London, Hammersmith HospitalLondon, UK
| | - Ursula Plöckinger
- Interdisciplinary Centre for Metabolism: Endocrinology, Diabetes and Metabolism, Campus Virchow-Klinikum, Charité-Universitaetsmedizin BerlinBerlin, Germany
| |
Collapse
|
|
35
|
Asymptomatic somatostatinoma of the pancreatic head: Report of a case. Surg Today 2010; 40:569-73. [DOI: 10.1007/s00595-008-4089-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2008] [Accepted: 09/18/2008] [Indexed: 10/19/2022]
|
|
36
|
Abstract
Endocrine tumors comprise a heterogeneous group of rare neoplasms. Liver metastatic endocrine tumors (MET) are amenable to various therapeutic modalities including liver transplantation (LT). However, LT for MET remains controversial because of the lack of clear selection criteria. The purpose of this study based on thorough perusal of English and French literature since 1989 was to identify prognostic factors and propose recommendations for selecting patients most likely to benefit LT for primary and secondary endocrine tumors.
Collapse
Affiliation(s)
- Emilie Gregoire
- Department of Digestive Surgery and Liver Transplantation, Hôpital de La Conception, and Université de la Mediterranée, Marseille, France
| | | |
Collapse
|
|
37
|
Bonaccorsi-Riani E, Apestegui C, Jouret-Mourin A, Sempoux C, Goffette P, Ciccarelli O, Borbath I, Hubert C, Gigot JF, Hassoun Z, Lerut J. Liver transplantation and neuroendocrine tumors: lessons from a single centre experience and from the literature review. Transpl Int 2010; 23:668-78. [PMID: 20478000 DOI: 10.1111/j.1432-2277.2010.01086.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumor (NET) metastases represent at this moment the only accepted indication of liver transplantation (LT) for liver secondaries. Between 1984-2007, nine (1.1%) of 824 adult LTs were performed because of NET. There were five well differentiated functioning NETs (four carcinoids and one gastrinoma), three well differentiated non functioning NETs and one poorly differentiated NET. Indications for LT were an invalidating unresectable tumor (4x), and/or a diffuse tumor localization (3x) and/or a refractory hormonal syndrome (5x). Median post-LT patient survival is 60.9 months (range 4.8-119). One-, 3- and 5-year actuarial survival rates are 88%, 77% and 33%; 1, 3 and 5 years disease free survival rates are 67%, 33% and 11%. Due to a more rigorous selection procedure, results improved since 2000; three out of five patients are alive disease-free at 78, 84 and 96 months. Review of these series together with a review of the literature reveals that results of LT for this oncological condition can be improved using better selection criteria, adapted immunosuppression and neo- and adjuvant surgical as well as medical treatment. LT should be considered earlier in the therapeutic algorithm of selected NET patients as it is the only therapy that can offer a cure.
Collapse
Affiliation(s)
- Eliano Bonaccorsi-Riani
- Starzl Unit of Abdominal Transplantation, University Hospitals St Luc, Université catholique de Louvain, Brussels, Belgium
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Boleslawski E, Dharancy S, Truant S, Pruvot FR. Surgical management of liver metastases from gastrointestinal endocrine tumors. ACTA ACUST UNITED AC 2010; 34:274-82. [PMID: 20347242 DOI: 10.1016/j.gcb.2010.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2009] [Revised: 01/27/2010] [Accepted: 02/02/2010] [Indexed: 02/07/2023]
Abstract
Liver metastases from endocrine tumors can reduce 5-year survival from 90% to 40% and, in cases of functional gastrointestinal endocrine tumors, lead to a carcinoid syndrome. Complete resection of cancerous disease should be considered in all cases. Indeed, after hepatectomy, prolonged survival (41-86% at five years) can be achieved, with low rates of surgery-related mortality (0-6.7%). Extended liver resection is required in most cases. Percutaneous portal embolization increases the volumetric feasibility of resection, and sequential hepatectomy techniques enable a two-stage resection of both bilobar metastases and the primary tumor. For carcinoid syndrome that does not respond to medical therapy, incomplete resection of liver metastases, by reducing tumor volume, may be indicated to reduce symptoms and halt the progression of carcinoid heart disease. In cases of non-resectable liver metastases in selected patients, liver transplantation can lead to 5-year survival rates as high as 77%.
Collapse
Affiliation(s)
- E Boleslawski
- Service de Chirurgie Digestive et de Transplantation, Hôpital Huriez, CHRU de Lille, rue Michel-Polonovski, 59037 Lille cedex, France.
| | | | | | | |
Collapse
|
|
39
|
Abstract
The indolent nature of neuroendocrine tumors and their proclivity to be hormonally active warrant aggressive treatment for advanced stage disease with hepatic metastases. Cytoreduction has been associated with improved symptom control as well as prolonged survival compared with those treated with medical therapy. The primary modalities of cytoreduction employed are resection, ablation, and embolization. In particular, radiofrequency ablation has been utilized with good results and minimal morbidity for treating patients with advanced neuroendocrine disease.
Collapse
Affiliation(s)
- Shishir K Maithel
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | | |
Collapse
|
|
40
|
Abstract
It is clear that a properly performed initial operation is the key to success in the management of a patient with ZES. However, reoperation is frequently a consideration in the management of patients with ZES because high rates of persistent and recurrent disease are manifest even with modern imaging and surgical approaches. In carefully selected patients, reoperation can result in durable biochemical cure and improved survival and should be considered. A thorough knowledge of the natural history of the sporadic form of ZES and ZES in the context of MEN-1, patterns of presentation, and sites of metastases are necessary to achieve the best outcome in patients with this unusual disease.
Collapse
Affiliation(s)
- Stephen R Grobmyer
- Division of Surgical Oncology, Department of Surgery, University of Florida, 1600 SW Archer Road, Room 6165, P.O. Box 100109, Gainesville, FL 32610, USA.
| | | |
Collapse
|
|
41
|
Abstract
Neuroendocrine malignancies encompass a variety of tumors that differ considerably in origin, hormonal activity, and biological behavior. Because of their rarity most therapeutic recommendations have been based on limited evidence from small retrospective series observing miscellaneous patient cohorts. Only in recent years proposals for TNM and histological grading systems have been elaborated that allow further stratification of patients suffering from these tumors. Especially patients with well and moderately differentiated neuroendocrine malignancies benefit from resection of liver metastases, improving the 5-year survival rate from <50% to 80%. Orthotopic liver transplantation can likewise improve survival in carefully selected patients. New developments in imaging modalities, intensive care treatment, and in liver surgery itself have broadened the selection of potentially resectable tumors.
Collapse
|
|
42
|
Fendrich V, Waldmann J, Bartsch DK, Langer P. Surgical management of pancreatic endocrine tumors. Nat Rev Clin Oncol 2009; 6:419-28. [DOI: 10.1038/nrclinonc.2009.82] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
43
|
Frilling A, Li J, Malamutmann E, Schmid KW, Bockisch A, Broelsch CE. Treatment of liver metastases from neuroendocrine tumours in relation to the extent of hepatic disease. Br J Surg 2009; 96:175-84. [PMID: 19160361 DOI: 10.1002/bjs.6468] [Citation(s) in RCA: 166] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatic surgery is presumed to improve survival of patients with liver metastases (LM) from neuroendocrine tumours (NET). This study identified LM-specific variables that could be used as additional selection criteria for aggressive treatment. METHODS A novel classification of LM from NET was established based on their localization and presentation. RESULTS From 1992 to 2006, 119 patients underwent staging and treatment of LM. Three growth types of LM were identified radiologically: single metastasis (type I), isolated metastatic bulk accompanied by smaller deposits (type II) and disseminated metastatic spread (type III). The three groups differed significantly in terms of chronological presentation of LM, hormonal symptoms, Ki-67 index, 5-hydroxyindoleacetic acid and chromogranin A levels, lymph node involvement, presence of bone metastases and treatment options. The 3-, 5- and 10-year disease-specific survival rates for the entire cohort were 76.4, 63.9 and 46.5 per cent respectively. There were significant differences in survival between the three groups: 5- and 10-year rates were both 100 per cent for type I, 84 and 75 per cent respectively for type II, and 51 and 29 per cent for type III. CONCLUSION The localization and biological features of LM from NET defines therapeutic management and is predictive of outcome.
Collapse
Affiliation(s)
- A Frilling
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
| | | | | | | | | | | |
Collapse
|
|
44
|
Maire F, Hammel P, Kianmanesh R, Hentic O, Couvelard A, Rebours V, Zappa M, Raymond E, Sauvanet A, Louvet C, Lévy P, Belghiti J, Ruszniewski P. Is adjuvant therapy with streptozotocin and 5-fluorouracil useful after resection of liver metastases from digestive endocrine tumors? Surgery 2008; 145:69-75. [PMID: 19081477 DOI: 10.1016/j.surg.2008.08.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/06/2008] [Accepted: 08/07/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND In patients with digestive endocrine tumors (DET) and liver metastases (LM) surgical resection is the only curative treatment. However, 5-year recurrence occurs in 50-80% of patients in the literature. The effect of adjuvant chemotherapy (CT) on relapse-free survival (RFS) and overall survival (OS) is unknown. AIM To assess the safety and the efficacy of systemic adjuvant CT with streptozotocin and 5-fluorouracil (5-FU) following LM resection in patients with DET. PATIENTS AND METHODS Between 1996 and 2006, 52 consecutive patients (23 males, median age 54 years [21-69]) underwent surgery for LM of well-differentiated DET in our center. The primary tumor was resected. After R0 resection of LM, patients were considered for adjuvant CT if the primary tumor was pancreatic, if LM was >or=10, or if the patient was <50 years old, in patients with other primary tumors. Twenty-nine patients received adjuvant CT and 23 were in the observation group. Adjuvant CT included 4 postoperative courses of i.v. streptozotocin-5-FU (500 and 400 mg/m(2), respectively, daily for 5 days every 42 days). RFS, OS and toxicity were evaluated. Log rank and chi-square analysis were used to identify prognostic factors. RESULTS Median post-operative follow-up was 47 months (4-162). In the adjuvant CT group, all patients except one received the 4 cycles. Two patients had grade 3-4 toxicity, including 1 febrile neutropenia resulting in death. Recurrence occurred in 43% and 65% of patients in the observation and adjuvant CT groups, respectively. RFS at 3 and 5 years was 51% and 38% in the observation group and 40% and 20% in the adjuvant CT group, respectively (P = .36). In univariate analysis, the significant prognostic factors associated with RFS were the number of LM (>or=10) and synchronous LM. Administration of adjuvant CT was not correlated with RFS. OS at 3 and 5 years was 90% and 76% in the observation group and 96% and 96% in the adjuvant CT group, respectively (P = .58). CONCLUSION RFS in patients receiving adjuvant CT was similar to that reported in the observation group and in historical cohorts without adjuvant CT. Thus, administration of streptozotocin-5-FU cannot be recommended in this indication.
Collapse
Affiliation(s)
- Frédérique Maire
- Pôle des Maladies de l'Appareil digestif, Service de Gastroentérologie-Pancréatologie, Hôpital Beaujon, Clichy, France.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
OBJECTIVE We present the first reported case of primary carcinoid tumour of the nasal septum. METHOD Case report of our experience of a carcinoid tumour of the nasal septum. We discuss our clinical, radiological and pathological findings. RESULT An 83-year-old woman presented with a history of left-sided nasal blockage. Clinical examination showed a unilateral, left-sided nasal polyp. Further imaging and histological analysis confirmed this to be a carcinoid tumour. Carcinoid tumours outside the gastrointestinal tract are rare. There have been reports of carcinoid tumours in the head and neck region, but no published cases occurring in the nasal septum. Our management involved wide surgical resection with regular follow up to monitor for recurrence and for the development of carcinoid syndrome. Four years from initial presentation, the patient remained free of the primary tumour and had displayed no signs or symptoms suggestive of carcinoid syndrome. CONCLUSION To the authors' best knowledge, and after searching the world literature, the presented case represents the first report of primary carcinoid tumour of the nasal septum. Despite its rarity, this tumour should be considered as part of the differential diagnosis, as timely recognition and intervention are critical for successful treatment.
Collapse
|
|
46
|
Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Ann Surg 2008; 247:659-65. [PMID: 18362629 DOI: 10.1097/sla.0b013e31816a7061] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE We describe the early and distant results of a 2-step surgical strategy that enables complete resection in selected patients with primary digestive endocrine tumors (DET) and synchronous bilobar liver metastases (LM). BACKGROUND Frequent synchronous and bilobar liver involvement limits indications of surgery in LM from DET. STUDY DESIGN From 1996 to 2004, of 41 patients with synchronous bilobar LM from DET, 23 (56%) were selected for 2-step surgery. The first step included resection of the primary tumor and limited (nonanatomic) resection of left LM (segments 1-4) associated with a right portal vein ligation. After 8 weeks, following hypertrophy of the cleared left liver, a right or extended right hepatectomy was planned. RESULTS At the first step, all primary tumors (bowel = 12, distal pancreas = 10, rectal = 1) were resected and LM were resected in 20 patients (87%). One patient did not have second-step due to tumor progression. The second step (n = 19; 83%) was performed after a median interval of 8 weeks (range, 6-13) and a 54 +/- 21% mean left liver hypertrophy rate. Postoperatively, 4 (17%) and 4 (21%) patients developed nonlethal complications and the median hospital stay was 11 (range, 7-26) and 13 (range, 9-17) days after the first and the second step, respectively. The median number of resected LM was 4 (range, 1-9) and 7 (range, 4-17), respectively. With a median follow-up of 64 months (range, 6-122), of the 19 patients who had complete 2-step surgery, all except one are alive. The 2-, 5-, and 8-year Kaplan-Meier overall and disease-free survival rates were 94%, 94%, 79% and 85%, and 50% and 26%, respectively. CONCLUSIONS This 2-step surgery approach enables complete resection with no mortality, acceptable morbidity, and good long-term survival in selected patients with synchronous bilobar LM from DET.
Collapse
|
|
47
|
Multimodal cytoreduction for carcinoid liver metastases: analysis of a case series with highly advanced disease. Eur Surg 2008. [DOI: 10.1007/s10353-008-0395-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
|
|
48
|
Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors metastatic to the liver: how to select patients for liver transplantation? J Hepatol 2007; 47:460-6. [PMID: 17697723 DOI: 10.1016/j.jhep.2007.07.004] [Citation(s) in RCA: 206] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Vincenzo Mazzaferro
- Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Istituto Nazionale Tumori Fondazione IRCCS, Via Venezian 1, Milan 20133, Italy.
| | | | | |
Collapse
|
|
49
|
Abstract
The liver is the most common site of metastatic disease from both gastrointestinal and extra-intestinal malignancies. Historically, only a minority of patients with colorectal liver metastases were candidates for resection. However, over the past several decades, liver resection has evolved as a safe and potentially curative treatment for hepatic colorectal metastases. The development of active chemotherapy and molecular targeted therapies, together with newer modalities like radiofrequency ablation, have expanded the indications for hepatic resection and improved survival. Selected patients with isolated liver metastases from neuroendocrine tumors, germ cell cancers, ocular melanoma, gastrointestinal stromal tumors (GIST), and breast cancer also may be considered for hepatic surgery.
Collapse
Affiliation(s)
- Boris Kuvshinoff
- Department of Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | |
Collapse
|
|
50
|
Frilling A, Weber F, Cicinnati V, Broelsch C. Role of radiolabeled octreotide therapy in patients with metastatic neuroendocrine neoplasms. Expert Rev Endocrinol Metab 2007; 2:517-527. [PMID: 30290419 DOI: 10.1586/17446651.2.4.517] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Peptide receptor radionuclide therapy is a new therapeutic modality for patients with nonresectable neuroendocrine tumors. The technique is based on the unique ability of these tumors to express cell membrane-specific peptide receptors that can be targeted with radiolabeled somatostatin analogues. A high level of uptake on somatostatin receptor scintigraphy is a prerequisite for effective treatment. The efficacy of this method has been proven in several clinical trials. In a substantial number of patients, an improvement of life quality has been achieved in addition to a marked morphologic and biochemical tumor response. Serious side effects are rarely observed. Attention must be paid to kidney protection during the treatment. The present review summarizes the clinical experience with the treatment of advanced neuroendocrine tumors with radiolabeled somatostatin analogues and focuses on patient selection and the appropriate timing of the therapy. Finally, it emphasizes treatment-related issues that deserve attention in the future.
Collapse
Affiliation(s)
- Andrea Frilling
- a Professor of Surgery; Vice chairman, University Hospital Essen, Department of General, Visceral, and Transplantation Surgery, Hufelandstr. 55, 45122 Essen, Germany.
| | - Frank Weber
- b Resident, University Hospital Essen, Department of General, Visceral, and Transplantation Surgery, Hufelandstr. 55, 45122 Essen, Germany.
| | - Vito Cicinnati
- c Resident, University Hospital Essen, Department of General, Visceral, and Transplantation Surgery, Hufelandstr. 55, 45122 Essen, Germany.
| | - Christoph Broelsch
- d Professor; Chairman, University Hospital Essen, Department of General, Visceral, and Transplantation Surgery, Hufelandstr. 55, 45122 Essen, Germany.
| |
Collapse
|