Nonsurgical Strategies in Patients With NET Liver Metastases: A Protocol of Four Systematic Reviews
Background: Patients diagnosed with neuroendocrine tumors (NETs) with hepatic metastases generally have a worse prognosis as compared with patients with nonmetastasized NETs. Due to tumor location and distant metastases, a surgical approach is often not possible and nonsurgical therapeutic strategies may apply.
Objective: The aim of these systematic reviews is to evaluate the role of nonsurgical therapy options for patients with nonresectable liver metastases of NETs.
Methods: An objective group of librarians will provide an electronic search strategy to examine the MEDLINE, EMBASE, and The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials [CENTRAL]) databases. There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective, and retrospective comparative cohort, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes.
Results: This study is ongoing and presents a protocol of four systematic reviews to assess the role of nonsurgical treatment options in patients with neuroendocrine liver metastases.
Conclusions: These systematic reviews, performed according to this protocol, will assess the value of noninvasive therapy options for patients with nonresectable liver metastases of NETs in combination with invasive techniques, such as percutaneous liver-directed techniques and local ablation techniques.
Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO):
CRD42012002657; http://www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2657 (Archived by WebCite at http://www.webcitation.org/6NDlYi37O);
CRD42012002658; http://www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2658 (Archived by WebCite at http://www.webcitation.org/6NDlfWSuD);
CRD42012002659; www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2659 (Arichived by Webcite at http://www.webcitation.org/6NDlmWAFM); and
CRD42012002660; http://www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2660 (Archived by WebCite at http://www.webcitation.org/6NDmnylzp).
JMIR Res Protoc 2014;3(1):e9)
- neuroendocrine tumor; NET; liver resection; adjuvant; neoadjuvant; liver transplantation; primary NET; systematic review
Neuroendocrine tumors (NET) arise from neuroendocrine cells and are a heterogeneous group of neoplasms [- ]. NETs originate from a wide range of anatomic sites, which are mainly located in the gastroenteropancreatic system (60%) and the bronchopulmonary system (>25%) [ , ]. With an incidence of 5.25 per 100,000 each year in the United States, NETs are considered to be rare tumors [ ].
Patients with NET liver metastases either complain of abdominal pain due to the mass effect of the tumor or excessive hormone production leading to the carcinoid syndrome, which consists of diarrhea, cutaneous flushing, various hemodynamic alterations, and wheezing [, ]. Moreover, up to 75% of patients with NETs (including midgut or hindgut origin) present with liver metastasis at the time of diagnosis [ ].
A 5-year survival rate of 22% for patients with NET liver metastases has been described . Surgical approach shows a benefit concerning overall survival as compared with the nonsurgical approach; however, curative surgery is only applicable in 10% of the patients [ ]. Therefore, noninvasive alternatives, such as local ablation techniques, percutaneous liver-directed techniques (chemoembolization, bland embolization, and selective internal radiation therapy), peptide receptor radionuclide technique, chemotherapy, targeted therapy, and biotherapy are of great importance and their value has to be determined.
Local Ablative Techniques
Mechanistically, local ablative techniques such as cryotherapy, radiofrequency ablation (RFA), and percutaneous alcohol injection (PEI) rely on the cytotoxic effects of chemicals and induce nonphysiologic temperatures into the hepatic tissue [, ]. Therefore, tumor location and extension in the liver influences the choice of treatment modality [ ].
Percutaneous Liver-Directed Techniques
Treatment modalities involved in percutaneous liver-directed techniques, include bland embolization (BE), transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT). The principle of BE consists of inducing regional ischemia to the tumor. In TACE, chemotherapeutic substances are locally applied causing a cytotoxic effect. Due to the local embolization the intratumoral concentration of the cytostatic is as much as 20 times higher using TACE than in systemically applied chemotherapy . In addition, systemic side effects can be minimized and cytotoxicity can be maximized [ ]. SIRT uses intracorporal radiation through microspheres made of glass (Thera-Spheres) or of resins (SIR-Spheres). These microspheres are loaded with radioactive Yttrium-90 [ ]. By virtue of their size, the microspheres obliterate the vessels and irradiate the tumor with a high radiation dose. The adjacent healthy tissue receives minimal dosage [ ]. Unfortunately, these treatment modalities are difficult to compare due to the small number of patients and to heterogeneous inclusion criteria (eg, tumor staging, primary tumor location, etc). [ ].
Peptide Receptor Radionuclide Therapy
Peptide receptor radionuclide therapy (PRRT), a combination of a somatostatin analog with a radioligand, a beta-emitter, is used to detect and treat NETs expressing somatostatin receptors. After systemic injection, the radioligand is internalized into the cells and transported to the lysosomes. The effect on tumor cell proliferation is based on the radiotoxicity of the radionuclide in the deoxyribonucleic acid of the target cell . However, radionuclides should be applied cautiously since side effects, such as bone marrow toxicity, hepatic insufficiency, myelodysplastic syndrome, renal insufficiency, or hematological toxicity might occur. Secondary malignancies such as leukemia are rare, but may also occur [ - ]. Functional imaging (ie, octreoscan or gallium 68 Positron Emission Tomography [PET]) is required to identify the subgroup of patients eligible for PRRT [ , ].
The role of systemic chemotherapy for NETs with liver metastases has been discussed vigorously. In a prospective study, Moertel et al  evaluated streptozotocin as a chemotherapeutic monotherapy and found a significant response; however, the benefit was strongly limited by the renal and hematologic toxicity of streptozotocin, and therefore is not an acceptable treatment option. Studies combining streptozotocin with other agents have been conducted with the aim to decrease the dosage of streptozotocin, and thus reduce its toxicity [ ]. For the therapy of metastatic pancreatic NETs, Kouvaraki et al [ ] reported that a combined multidrug chemotherapy with fluorouracil, doxorubicin, and streptozotocin showed an acceptable response rate of 39% with responders having both increased progression-free survival and overall survival. However, patients with metastatic midgut NETs treated with this multidrug chemotherapy regimen showed the same survival rates as interferon-based therapy concepts [ ]. Since poorly differentiated (G3) gastrointestinal NETs behave like lung neuroendocrine carcinomas (small-cell carcinomas) a platin-based chemotherapy is discussed [ ].
Targeted therapy includes multikinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and monoclonal antibodies, which interact with various molecular pathways . Sunitinib, an orally applied multikinase inhibitor, targets vascular endothelial growth factor (VEGF) receptors as well as platelet-derived growth factor receptors, which are often expressed in NETs [ , ]. Everolimus, an mTOR inhibitor, has also shown antitumor activity [ ]. Bevacizumab, a monoclonal antibody against VEGF, inhibits angiogenesis in tumors and seems to reduce tumor perfusion [ , ].
Biotherapy, using interferon-α and somatostatin analogues such as octreotide and lanreotide, prevents the synthesis of the polypeptide hormones and biogenic amines produced by functional NETs. This provides relief from endocrine symptoms associated with the carcinoid syndrome in 80% of patients [- ]. The Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Antiproliferative Efficacy of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors reports treatment with octreotide (long-acting release) essentially delays the period to tumor progression in patients with both functionally active and inactive metastatic midgut NETs compared with the placebo-treated group. However, survival analysis could not be performed due to a small number of observed deaths [ ].
The aim of these four systematic reviews is to determine evidence for the noninvasive treatment options in terms of symptom relief and tumor control in patients with nonresectable liver metastases of NETs.
The following four systematic reviews dealing with the nonsurgical treatment options of neuroendocrine liver metastases attempt to address the following questions represented in.
Our research results will be reported in accordance with the standards of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).
The eligibility criteria for inclusion as well as for exclusion of studies are illustrated in- . Furthermore, the count and reason of exclusion will be revealed in a flow diagram, which will comply with the PRISMA Statement 2009 ( ) [ ]. The study types that will be included are randomized controlled trials (RCTs), prospective and retrospective comparative cohort studies, noncomparative cohort studies, case-control-studies, and case series.
These studies will provide the basis for the qualitative synthesis of this systematic review. Single-cohort studies will be collected in a separate database and will only be used for descriptive purposes. No publication date or language restrictions will apply.
The electronic search strategy to scan the databases and detect all relevant articles was developed by the librarians of the Medical Library Careum (University of Zurich, Switzerland). The search will be performed on the MEDLINE, EMBASE, and The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Cochrane Central Register of Controlled Trials [CENTRAL]) databases. An endnote file, comprising all identified titles and, if accessible, the corresponding abstracts will be prepared for the investigators. Supplementary publications will be found by manual search or by reviewing reference lists. Two independent review group members will peruse titles and/or abstracts from studies, which were identified using the search profile. Afterwards, the entire text of these potentially eligible studies will be re-examined for eligibility. Any uncertainties will be discussed and resolved with a third member. A specially created Web-based, predetermined protocol will be used to extract data from the included studies for the study quality expertise and synthesis of medical findings.
The data extraction parameters, include manuscript title, name of journal, first author's name, publication year, total number of patients, number of patients in the chemotherapy/biotherapy/targeted therapy group, number of patients in the nontreatment group, name of used substances, age (mean, standard deviation, median), male to female ratio, progression-free survival, overall survival, quality of life (containing side effects), study design, and targeting objective 1-5. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to grade the quality (level) of evidence and the strength of recommendations .
We will prepare a narrative synthesis of the findings from the included studies. A quantitative synthesis will be used if the included studies are sufficiently homogenous. We anticipate that there will be a limited scope for meta-analysis of a relatively large number of studies because of the range of outcomes measured across the small number of existing trials (such tumors are rare). Nevertheless, where studies have used the same type of intervention and comparator, with the same outcome measure, we will pool the results using a random-effects meta-analysis. We calculate a 95% CI and two-sided P values for each outcome.
This study is ongoing and presents a protocol of four systematic reviews to assess the role of nonsurgical treatment options in patients with neuroendocrine liver metastases. Both noninvasive as well as invasive methods, such as percutaneous liver-directed techniques and local ablation techniques will be investigated.
Several nonsurgical treatment options for neuroendocrine liver metastases have been reported. However, there is a lack of consensual data on the subject. These four systematic reviews described in this protocol aim to clarify the role of nonsurgical therapy modalities in patients with nonresectable NETs liver metastases. The systematic reviews will serve as a basis for developing clinical practice guidelines.
We would like to thank Martina Gosteli and her colleagues for their excellent support.
All authors were involved in editing the manuscript and approved the final text of the manuscript.
Conflicts of Interest
- Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011 Mar;30 Suppl 1:3-7. [CrossRef] [Medline]
- Vogl TJ, Nour-Eldin N, Zangos S, Grünwald F, Bojunga J, Trojan J, et al. Regionale interventionelle Behandlungsverfahren von Lebermetastasen neuroendokriner Tumoren: Embolisation (TAE), Chemoembolisation (TACE) und selektive interne Radiotherapie (SIRT). Viszeralmedizin 2010;26(4):269-275. [CrossRef]
- Frilling A. Management of neuroendocrine liver metastases according to the type of manifestation. Regulatory Peptides 2010;164(1):8. [CrossRef]
- Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26(18):3063-3072. [CrossRef] [Medline]
- Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97(4):934-959 [FREE Full text] [CrossRef] [Medline]
- Drougas JG, Anthony LB, Blair TK, Lopez RR, Wright JK, Chapman WC, et al. Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors. Am J Surg 1998;175(5):408-412. [Medline]
- Gupta S, Yao JC, Ahrar K, Wallace MJ, Morello FA, Madoff DC, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J 2003;9(4):261-267. [Medline]
- Steinmüller T, Kianmanesh R, Falconi M, Scarpa A, Taal B, Kwekkeboom DJ, Frascati Consensus Conference participants. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008;87(1):47-62. [CrossRef] [Medline]
- Mayo SC, de Jong MC, Bloomston M, Pulitano C, Clary BM, Reddy SK, et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann Surg Oncol 2011;18(13):3657-3665. [CrossRef] [Medline]
- Atwell TD, Charboneau JW, Que FG, Rubin J, Lewis BD, Nagorney DM, et al. Treatment of neuroendocrine cancer metastatic to the liver: the role of ablative techniques. Cardiovasc Intervent Radiol 2005;28(4):409-421. [CrossRef] [Medline]
- Siperstein AE, Berber E. Cryoablation, percutaneous alcohol injection, and radiofrequency ablation for treatment of neuroendocrine liver metastases. World J Surg 2001;25(6):693-696. [Medline]
- Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013;24(1):152-160 [FREE Full text] [CrossRef] [Medline]
- Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007;142(1):10-19. [CrossRef] [Medline]
- Knox CD, Anderson CD, Lamps LW, Adkins RB, Pinson CW. Long-term survival after resection for primary hepatic carcinoid tumor. Ann Surg Oncol 2003;10(10):1171-1175. [Medline]
- Auernhammer CJ, Göke B. Therapeutic strategies for advanced neuroendocrine carcinomas of jejunum/ileum and pancreatic origin. Gut 2011;60(7):1009-1021. [CrossRef] [Medline]
- Slooter GD, Mearadji A, Breeman WA, Marquet RL, de Jong M, Krenning EP, et al. Somatostatin receptor imaging, therapy and new strategies in patients with neuroendocrine tumors. Br J Surg 2001;88(1):31-40. [CrossRef] [Medline]
- Basuroy R, Srirajaskanthan R, Ramage JK. A multimodal approach to the management of neuroendocrine tumor liver metastases. Int J Hepatol 2012;2012:819193 [FREE Full text] [CrossRef] [Medline]
- Gulenchyn KY, Yao X, Asa SL, Singh S, Law C. Radionuclide therapy in neuroendocrine tumors: a systematic review. Clin Oncol (R Coll Radiol) 2012;24(4):294-308. [CrossRef] [Medline]
- Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med 2005;46 Suppl 1:62S-66S [FREE Full text] [Medline]
- Ezziddin S, Lohmar J, Yong-Hing CJ, Sabet A, Ahmadzadehfar H, Kukuk G, et al. Does the pretherapeutic tumor SUV in 68Ga DOTATOC PET predict the absorbed dose of 177Lu octreotate? Clin Nucl Med 2012;37(6):e141-e147. [CrossRef] [Medline]
- Chougnet CN, Leboulleux S, Caramella C, Lumbroso J, Borget I, Déandreis D, et al. Frequency and characterization of gastro-entero-pancreatic neuroendocrine tumor patients with high-grade of uptake at somatostatin receptor scintigraphy. Endocr Relat Cancer 2013;20(2):229-239. [CrossRef] [Medline]
- Moertel CG, Hanley JA, Johnson LA. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980;303(21):1189-1194. [CrossRef] [Medline]
- Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979;2(4):327-334. [Medline]
- Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004;22(23):4762-4771. [CrossRef] [Medline]
- Dahan L, Bonnetain F, Rougier P, Raoul JL, Gamelin E, Etienne PL, Fédération Francophone de Cancérologie Digestive (FFCD), Digestive Tumors Group of the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC). Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710. Endocr Relat Cancer 2009;16(4):1351-1361 [FREE Full text] [CrossRef] [Medline]
- Walter T, Brixi-Benmansour H, Lombard-Bohas C, Cadiot G. New treatment strategies in advanced neuroendocrine tumors. Dig Liver Dis 2012;44(2):95-105. [CrossRef] [Medline]
- Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26(20):3403-3410. [CrossRef] [Medline]
- Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364(6):501-513. [CrossRef] [Medline]
- Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, RAD001 in Advanced Neuroendocrine Tumors‚ Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364(6):514-523. [CrossRef] [Medline]
- Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007;49(2):186-193. [CrossRef] [Medline]
- Stathopoulos GP, Papadopoulos G, Koutantos J. Long-term survival of patients with carcinoid tumor and liver metastases. J BUON 2009;14(4):609-611. [Medline]
- Oberg KE. The management of neuroendocrine tumors: current and future medical therapy options. Clin Oncol (R Coll Radiol) 2012;24(4):282-293. [CrossRef] [Medline]
- Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumors. Br J Surg 2003;90(6):687-693. [CrossRef] [Medline]
- Madeira I, Terris B, Voss M, Denys A, Sauvanet A, Flejou JF, et al. Prognostic factors in patients with endocrine tumors of the duodenopancreatic area. Gut 1998;43(3):422-427 [FREE Full text] [Medline]
- Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27(28):4656-4663. [CrossRef] [Medline]
- Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010;8(5):336-341. [CrossRef] [Medline]
- Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 Apr 26;336(7650):924-926 [FREE Full text] [CrossRef] [Medline]
|BE: bland embolization|
|CENTRAL: Cochrane Central Register of Controlled Trials|
|GRADE: The Grading of Recommendations Assessment, Development and Evaluation|
|mTOR: mammalian target of rapamycin|
|NET: neuroendocrine tumors|
|PET: Positron Emission Tomography|
|PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses|
|PRRT: peptide receptor radionuclide therapy|
|R0, R1, R2: resection margin (R0: tumor free; R1: microscopic lesion; R2: macroscopic lesion)|
|RCT: randomized controlled trial|
|RFA: radio frequency ablation|
|SIRT: selective internal radiation therapy|
|TACE: transarterial chemoembolization|
|VEGF: vascular endothelial growth factor (receptor)|
Edited by G Eysenbach; submitted 20.08.13; peer-reviewed by R Rossi; comments to author 30.09.13; revised version received 07.11.13; accepted 18.01.14; published 07.03.14
©Perparim Limani, Christoph Tschuor, Laura Gort, Bettina Balmer, Alexander Gu, Christos Ceresa, Dimitri Aristotle Raptis, Mickael Lesurtel, Milo Puhan, Stefan Breitenstein. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.03.2014.
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