Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference

Objectives: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity.A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management.Methods: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system.Results: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. Conclusions: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

# Introduction
The development of liver metastases from neuroendocrine tumours (NETs) originating in the foregut, midgut or hindgut represents a significant and frequent clinical occurrence, which negatively impacts prognosis. The management of patients with liver metastases can include surgical, medical, radiological and nuclear medicine interventions. [bib_ref] ENETS Consensus Guidelines for the management of patients with liver and other..., Pavel [/bib_ref] This broad range of possible treatments, each of which has therapeutic potential for different indications, necessitates evidence-based recommendations for the optimal management of these patients. A multidisciplinary [bib_ref] Chemoembolization and bland embolization of neuroendocrine tumour metastases to the liver, Ruutiainen [/bib_ref] individual workgroup sessions that covered a variety of topics from diagnosis to treatment. Each workgroup was comprised of recognized experts in its particular subject matter. Prior to the conference, questions were sent to the members of each workgroup to allow for deliberation and the development of statements on the workgroup topic. During the conference, a spokesperson for each workgroup presented the panel's recommendations and statements to the attendees and the conference jury. Feedback on this exchange was given to the workgroup and was considered prior to the development of the final results presented in this report. A summary of this conference has been published recently. [bib_ref] Recommendations for management of patients with neuroendocrine liver metastases, Frilling [/bib_ref] For patients who are not candidates for surgery, selective hepatic transarterial embolization (TAE), transarterial chemoembolization (TACE) or radioembolization (RE) with yttrium-90 microspheres can produce objective responses, decrease tumour markers and control symptoms. However, none of these techniques has been shown to have clear superiority over the others in a randomized controlled trial (RCT). The authors of this manuscript were tasked with developing recommendations on the use of angiographic liver-directed techniques, including TAE, TACE and RE, in relation to surgery, percutaneous liver tumour ablation and systemic therapies.

# Materials and methods
Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed. These were presented to a multidisciplinary jury of peers for thorough discussion in order to achieve consensus recommendations. The authors were asked to consider the following questions related to percutaneous arterial liver techniques (TAE, TACE and RE) in patients with nonresectable NET liver metastases in conducting their review.and the GRADE (grading of recommendations assessment, development and evaluation) system. [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref] Each of the papers selected for consideration were assigned both an NCI and a GRADE score. In addition, individual factors derived from the GRADE system were used to estimate the strength of the recommendations for each treatment modality (TAE, TACE and RE). For the purposes of report evaluation by the working group, the scoring system shown in [fig_ref] Table 1: Conversions of the National Cancer Institute [/fig_ref] was used. The NCI Levels of Evidence evaluate both the strength of the study design and the strength of the study endpoints. The GRADE system considers four factors to determine the strength of a recommendation: (i) the balance between desirable and undesirable affects; (ii) the quality of the evidence; (iii) values and preferences, and, finally, (iv) costs. The quality of evidence is given a 'grade' of A, B, C or D; thus high-quality papers receive a GRADE score of A. The strength of the recommendation for or against an intervention is scored as 1 if it is strong and 2 if it is weak.

# Results
A total of 18 reports met the workgroup's stringent criteria and were reviewed by the present authors. These included 11 reports on TAE or TACE, [bib_ref] Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumours with..., De Baere [/bib_ref] [bib_ref] Hepatic artery chemoembolization for the treatment of liver metastases from neuroendocrine tumours:..., Dong [/bib_ref] [bib_ref] Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumours, Eriksson [/bib_ref] [bib_ref] Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic..., Gupta [/bib_ref] [bib_ref] Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and..., Loewe [/bib_ref] [bib_ref] Hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from..., Maire [/bib_ref] [bib_ref] Hepatic neuroendocrine metastases: chemo-or bland embolization?, Pitt [/bib_ref] [bib_ref] Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumours. A..., Ruszniewski [/bib_ref] [bib_ref] Chemoembolization and bland embolization of neuroendocrine tumour metastases to the liver, Ruutiainen [/bib_ref] [bib_ref] Liver metastases of neuroendocrine tumours: treatment with hepatic HPB HPB, Vogl [/bib_ref] and seven on RE. [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref] [bib_ref] Radioembolization for neuroendocrine liver metastases: safety, imaging, and longterm outcomes, Memon [/bib_ref] [bib_ref] Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumour..., Saxena [/bib_ref] Radioembolization studies are outlined in [fig_ref] Table 2: Outcomes of studies of radioembolization in patients with liver metastases from neuroendocrine... [/fig_ref]. These included four studies on the use of salvage therapy in refractory disease and three studies conducted in mixed cohorts of patients treated with RE as either first-line treatment or in refractory disease. Four of these reports were retrospective studies. Studies on TAE and TACE are outlined in [fig_ref] Table 3: Outcomes of studies of transarterial embolization [/fig_ref]. [fig_ref] Table 4: Summary of statements of GRADE quality and strength [/fig_ref] shows GRADE factor scoring comparisons for TAE/TACE and RE.
Do these techniques improve outcomes (PFS, OS, QoL) in comparison with partial (R2) surgical resection? Because data from prospective, randomized, placebo-controlled studies are lacking, the authors were unable to make a definitive statement about the superiority of percutaneous arterial liver techniques over R2 resection; neither is there sufficient evidence to indicate the use of one technique over another in terms of PFS or OS. There is some evidence to suggest that RE provides for improved QoL in comparison with TAE and TACE. The review of this literature suggests that tumour dissemination and tract seeding are not caused by the use of arterial therapies, but by direct puncture from ablation or biopsy (GRADE B1).
The consensus was to recommend that comparative studies should be conducted to adequately determine whether percutaneous arterial liver techniques offer an advantage over R2 resection (in terms of PFS, OS and QoL). These comparative effectiveness studies should include measures of costs, complications, QoL and hospital resource utilization. Other studies should compare the use of embolization techniques with that of systemic agents, and explore the utility of combinations of embolization and systemic therapy. Higher-level evidence is required before any strong recommendation on the use of embolotherapy and surgery can be made. Which of these techniques achieves the best outcome (PFS, OS, QoL)? No studies directly comparing the three forms of embolotherapy were discovered, nor were any found in a search of Clinicaltrials.gov (December 2012). This is surprising because the controversy over the relative superiority of TAE and TACE is longstanding, yet no properly conducted prospective comparison study has been performed. The inherent complexities of liver embolotherapy may represent a major barrier to investigations into the outcomes of non-radioactive arterial therapies and to enquiries into the use of these therapies in comparison with RE. Therefore, no statement on which arterial therapy offers the best PFS and OS can be made. Kalinowski et al. completed the only QoL study in liver embolotherapy of NETs, but their study investigated only RE and included a small sample. [bib_ref] Selective internal radiotherapy with yttrium-90 microspheres for hepatic metastatic neuroendocrine tumours: a..., Kalinowski [/bib_ref] However, this report, [bib_ref] Selective internal radiotherapy with yttrium-90 microspheres for hepatic metastatic neuroendocrine tumours: a..., Kalinowski [/bib_ref] coupled with other prospective and retrospective studies, [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref] [bib_ref] Radioembolization for neuroendocrine liver metastases: safety, imaging, and longterm outcomes, Memon [/bib_ref] [bib_ref] Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumour..., Saxena [/bib_ref] suggests the acute toxicity profile of RE is lower than those of TAE or TACE.
Do these techniques improve outcomes in combination with systemic treatment (such as PRRT, chemotherapy, targeted therapy, biotherapy) in comparison with percutaneous liver techniques alone? No prospective or retrospective series reported the concurrent use of embolotherapy with PRRT, targeted systemic agents or biotherapy. However, two RE studies involved i.v. 5-fluorouracil (5-FU) with yttrium-90. [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref] Their results suggested somewhat higher response rates and similar toxicity to that of RE alone, but both were single-arm studies with small treatment groups. No TAE/TACE studies reported the use of systemic therapy concurrently with liver embolotherapy. There are no comparator trials of percutaneous liver tumour ablation and arterial embolotherapy in hepatic metastases from NETs and therefore no statement or recommendation can be provided.
What is the incidence of tumour dissemination during the use of TAE, TACE or RE, evident on imaging or biopsy during follow-up? Tumour dissemination via the direct puncture of tumour with tract seeding is not a feature of arterial therapies. There are no reports of such occurrences in the literature. The femoral artery is the only site of percutaneous entry and thus no direct contact with the tumour occurs. Conversely, locally ablative techniques and biopsies have known potential to allow tumour dissemination.

## Consensus recommendations
It is clear that higher levels of evidence are needed to refine and optimize the treatment of NET liver metastases. The panel suggests the following points should be used as a framework for future research collaborations and for the insertion of RE into an accepted treatment algorithm [fig_ref] Figure 2: Proposed treatment approach in liver-only metastases from neuroendocrine tumours [/fig_ref].
1 Studies that compare the outcomes of the respective intraarterial approaches should be performed. Given the disparity in post-embolization syndrome symptoms between embolotherapy and RE, these studies should include prospective QoL measures. 2 Studies of surgical resection in comparison with intra-arterial therapy in select patient groups should be undertaken. These should investigate local control rates, but should also compare costs, complication rates, types of complication, QoL, and outpatient versus inpatient resource utilization. 3 Studies investigating the outcomes of intra-arterial therapy with and without the concurrent use of systemic agents (including biologic agents) should be conducted. 4 Studies of the outcomes of intra-arterial therapy in comparison with those of the use of systemic agents should be conducted in a similar fashion to that outlined in item 2.

# Discussion
Neuroendocrine tumours are uncommon but are clinically challenging tumours that occur at an annual incidence of one per 100 000 people. The current ability to produce consensus guidelines is limited by the heterogeneity of the disease itself and of the clinical studies recruiting patients with the disease. However, the development of liver metastases is the factor with the worst prognosis for patients with this disease and thus it is imperative that some statements derived from the evidence base must be attempted to guide clinicians in managing patients with liver metastases from NETs. Pavel and colleagues recently published a report on consensus guidelines for the management of liver and other distant metastases from neuroendocrine neoplasms. [bib_ref] ENETS Consensus Guidelines for the management of patients with liver and other..., Pavel [/bib_ref] The scope of the report is wide and touches on a great variety of topics, which include general management options for liver metastases. However, the current working group's charge differs in that the present authors were tasked with providing Although surgical resection for metastatic NETs involving the liver is advocated by some, no prospective randomized clinical trials have compared the outcomes of this treatment modality with those in a control group or with those of other forms of therapy. In particular, there are limited data on which patients should be selected for surgery. Survival data are difficult to analyse because details on the completeness of resection, variable indications for debulking or 'palliative resection' are inadequate, and follow-up criteria are inconsistent. Complete resection (R0) rates are often low and disease-free and overall survival rates can vary widely. Despite this, 5-year survival rates of 46-86% have been reported and, in general, patients in whom hepatic resection is achievable have a better median survival and 5-year survival than those with unresectable hepatic disease. [bib_ref] Treatment of liver metastases from neuroendocrine tumours in relation to the extent..., Frilling [/bib_ref] Surgery has been postulated as the only treatment to offer potential for cure, 1 and favourable prognostic factors include grade 1 or 2 tumours, no evidence of nonresectable extrahepatic disease, the ability to achieve an R0 resection and the absence of carcinoid heart disease. Surgery has been shown to have a beneficial effect in alleviating symptoms related to the hypersecretion of serotonin or other mediators. [bib_ref] Hepatic surgery for metastases from neuroendocrine tumours, Sarmiento [/bib_ref] Local ablation techniques have been used as sole treatments (performed either percutaneously or laparoscopically) or in combination with surgical resection. Histological proof of the complete destruction of tumour foci is difficult to obtain and local liver recurrence is common. Preferably, metastatic deposits should measure <5 cm in diameter, although rarely larger lesions can be targeted. Radiofrequency ablation and microwave ablation are currently the most favoured techniques and 5-year OS rates of up to 53% have been reported. 2 Improvements in symptom control have also been documented. [bib_ref] Laparoscopic radiofrequency ablation of neuroendocrine liver metastases, Berber [/bib_ref] [bib_ref] Surgery and radiofrequency ablation for treatment of liver metastases from midgut and..., Eriksson [/bib_ref] Arterially directed interventional strategies provide several diverse options in the treatment of neuroendocrine liver metastases because they represent means of delivering different modalities of treatment which range from arterial embolization to cause the local ischaemia of the tumour, to the local delivery of high doses of chemotherapy to the tumour and to selective internal radiotherapy (SIRT) using yttrium-90 microspheres delivered via the arterial route. The principal clinical aims of these techniques are the reduction of hormonal symptoms in patients with functionally active tumours and the control of tumour growth and symptoms arising from tumour size.
The basis for all of the endovascular procedures discussed herein is the discovery that neuroendocrine metastases are usually highly vascular and that these metastases draw their blood supplies predominantly from the hepatic artery rather than the portal vein, whereas normal liver tissue acquires 70-80% of its blood supply from the portal vein. [bib_ref] Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and..., Vogl [/bib_ref] An historical angle on this discovery is provided in a recent article focusing on the pathological changes resulting from SIRT. [bib_ref] Anatomical basis and histopathological changes resulting from selective internal radiotherapy for liver..., Wang [/bib_ref] Traditionally, transarterial therapy for liver metastases from NETs consists of TAE or TACE. In TAE, embolization is usually performed using lipiodol, gel foam parti-cles, polyvinyl alcohol (PVA) foam or bland microspheres. If the artery supplying the tumour can be superselectively embolized, the clinical benefit to be derived by devascularizing the tumour can be achieved with a lower likelihood that a collateral blood supply will form rapidly. In clinical cases of revascularization, TAE or TACE can often be repeated.
Transarterial chemoembolization follows the same principles as TAE, but the intra-arterial administration of a chemotherapeutic agent is added at the time of embolization. This technique has the potential to result in intra-tumoral concentrations of the drug that are over 20 times greater than those afforded by the systemic administration of the same drug, 31 plus the potential clinical benefit of tumour ischaemia as a result of embolization. Drugs that are commonly used for this purpose include doxorubicin, melphalan and streptozocin.
Selective internal radiotherapy with yttrium-90 microspheres is a technique that has been developed to target multiple sites of disease within the liver as a form of arterially delivered brachytherapy. By contrast with surgical resection and radiofrequency ablation or other forms of local ablation, the number and sites of liver metastases do not limit its use. The technique of SIRT involves an outpatient procedure in which a transfemoral catheterization is performed and millions of radioactive microspheres (15-20 million if resin; 1-8 million if glass) are selectively released into the hepatic arterial supply under fluoroscopic guidance. This treatment preferentially delivers a high dose of radiation to the liver tumour while sparing much of the normal liver.
Bearing in mind the heterogeneity of this disease and the difficulty of defining cohorts of patients with the same pathological classification of disease, rates of symptomatic response to TAE, TACE and SIRT in the studies reviewed in the present paper would appear to be 39-95% within a time period of 1-18 months from treatment. In other words, the majority of patients do experience improvements in hormonal syndromes and the symptoms caused by the disease burden. The clinical side-effects of the procedures include fever, leukocytosis, abdominal pain and elevated liver enzyme levels. More severe complications include pleural effusion, bowel ischaemia, hepatic infarction, liver abscess and radiation-induced liver disease (SIRT only, significantly <2% of cases treated). As the occurrence of severe side-effects is uncommon, most patients who are offered intra-arterial therapies for symptom relief consent to treatment and appreciate some degree of clinical benefit.
In advocating for greater research into the use and outcomes of intra-arterial therapies for metastatic NET carcinomas, the present group emphasizes the importance of applying robust entry criteria (which should include a central histology review of all cases), of optimizing recruitment by conducting multicentre trials and ensuring adequate quality assurance of treatment across participating centres, and of considering the evolution of the standard of care during the recruitment and follow-up phases of clinical trials. For relatively rare tumours such as NETs, there may be value in planning for combined analyses of the outcomes of several trials in order to facilitate greater statistical power. For example, FOXFIRE and SIRFLOX are both randomized multicentre trials with participating centres in Australia, New Zealand, Europe and the USA, which have evaluated the addition of yttrium-90 resin microspheres to first-line chemotherapy in patients with nonresectable liver metastases from colorectal cancer (P. Gibbs et al. 2014, unpublished data). [bib_ref] Study protocol: FOXFIRE: an open-label, randomized, phase III trial of 5-fluorouracil, oxaliplatin..., Dutton [/bib_ref] Both trials use similar chemotherapy delivery regimens with regard to the sequencing of drugs and the intra-arterial treatment intervention. Discussion between the respective development groups of the two trials led to the formulation of similar protocols and treatment paradigms in order to facilitate sufficient power for the prospective combined analysis of OS (P. Gibbs et al. 2014, unpublished data). [bib_ref] Study protocol: FOXFIRE: an open-label, randomized, phase III trial of 5-fluorouracil, oxaliplatin..., Dutton [/bib_ref] There are ongoing controversies over the feasibility of OS studies (treatment crossover) as well as the clinical correlation between imaging responses and the manifestation of symptoms in metastases from NETs. Accordingly, the use of QoL becomes of significant interest. Although its use is still controversial, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-GINET21 tool would strengthen any study of metastases from NETs and should be considered an essential component of prospective trials. The incorporation of such a tool is relevant not only to patients with mild symptoms (flushing), but also to those afflicted by the more severe and debilitating symptoms (diarrhoea, shortness of breath). [bib_ref] Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumours..., Khan [/bib_ref] [bib_ref] Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of..., Yadegarfar [/bib_ref] These are currently being studied in prospective settings (NCT00815620, NCT00454376). Overall survival cannot be used as in other cancers because life expectancy is long and multiple treatment lines are available. Quality of life is not sensitive enough and is not affected by treatment in most RCTs. Symptomatic response, including hormone-related symptoms, is observed in 80-90% of patients, and radiological response according to RECIST (response evaluation criteria in solid tumours) in 30-50%. Although no clear correlation between these two parameters has yet been established, radiological response is almost always associated with the alleviation of symptoms.
It is fortunate that multiple treatment options for the liverdirected therapy of hepatic metastases from NETs are available. It is now the responsibility of this field to learn the optimal ways of employing local therapies to achieve the best possible QoL in patients, sustainable resource utilization, and enhanced sequencing of treatment with new systemic and biologic agents that show encouraging promise in the treatment of liver metastases from NETs.

## Conflicts of interest
[fig] Figure 2: Proposed treatment approach in liver-only metastases from neuroendocrine tumours. LITT, laser-induced thermotherapy; LMs, liver metastases; RE, radioembolization; RFA, radiofrequency ablation; TAE, transarterial embolization; TACE, transarterial chemoembolization; Authors. HPB published by John Wiley & Sons Ltd on behalf of the International Hepato-Pancreato-Biliary Association specific and detailed opinion focused on embolotherapy of liver metastases. [/fig]
[table] Table 1: Conversions of the National Cancer Institute (NCI) and GRADE (grading of recommendations assessment, development and evaluation) scoring systems 4,5 used by the present working group HPB published by John Wiley & Sons Ltd on behalf of the International Hepato-Pancreato-Biliary Association [/table]
[table] Table 2: Outcomes of studies of radioembolization in patients with liver metastases from neuroendocrine tumours EASL, European Association for the Study of the Liver; WHO, World Health Organization. HPB published by John Wiley & Sons Ltd on behalf of the International Hepato-Pancreato-Biliary Association [/table]
[table] Table 3: Outcomes of studies of transarterial embolization (TAE) and transarterial chemoembolization (TACE) in patients with liver metastases from neuroendocrine tumours (NETs) [/table]
[table] Table 4: Summary of statements of GRADE quality and strength [/table]