Abstract
Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.
Keywords Neuroendocrine, liver metastasis, surgery, ablation, embolization
Introduction
Neuroendocrine neoplasms (NEN) represent a group of heterogeneous tumors that most frequently (70-75%) involve the gastro-entero-pancreatic (GEP) organs [1]. The majority of NENs are well differentiated (WD-NENs) and their biological behavior is determined by their proliferation capacity (grading G), based on the Ki67 proliferation index (Ki67 % LI). Grade 1 (G1 Ki67 LI ≤2%), and G2 (3-20%) neuroendocrine tumors (NETs) generally show less aggressive behavior, exhibiting prolonged survival even in the context of metastatic disease; a subset of WD-NENs have Ki67 LI >20% (G3NETs) [2]. Poorly differentiated GEP-NENs are designated as neuroendocrine carcinomas (NEC) and exhibit aggressive behavior leading to a poor outcome. Most NENs are non-functioning, while approximately 20-30% present with symptoms related to the secretion of bioactive compounds (peptides, amines) leading to distinct clinical syndromes [3].
Surgical resection represents the ideal therapeutic modality for tumor eradication and a potential “cure” for NENs. However, as most of these neoplasms present late with disseminated disease, resulting from asymptomatic presentation and/or the presence of non-specific symptoms, radical surgery is commonly reserved only for a small proportion of patients [1,2]. Even so, survival for all NENs has improved over time, including metastatic GEP-NENs, possibly reflecting improvements in classification systems and therapies applied [4].
A significant proportion of patients with NENs will commonly be diagnosed with synchronous neuroendocrine liver metastases (NELM), or will develop them metachronously during the course of their disease [5,6]. The exact incidence of NELM remains poorly determined and is reported to range from 27-90% [2,7,8]. This can be partly attributed to hepatic lesions being erroneously reported as distant metastases, rather than NELM specifically, and also to referral biases [6]. Approximately 50% of patients with pancreatic NENs (panNEN) and 60-75% of patients with small intestinal NENs (SI-NENs) either present with synchronous NELM or develop metachronous NELM [8-10]. In contrast, patients with gastric, appendiceal and rectal NEN primaries are less likely to develop NELM, whereas 5-10% of patients will be diagnosed with NELM of unknown primary [6,11]. The presence of NELM is a major predictor of adverse long-term outcomes [5,12], while available treatment options vary, depending on the extent of hepatic involvement and patients’ performance status. A number of liver tumor burden classification systems have been developed; one of the most commonly used was proposed by Frilling
Figure 1 Proposed types of neuroendocrine liver metastases distribution [13]
Following accurate identification of the extent of metastatic disease, thorough discussion in the context of a multidisciplinary board is paramount and is expected to outline the available and most suitable treatment options, as with other malignant conditions [14,15]. These tailored-to-the-patient treatment options can be applied sequentially or combined, highlighting the critical need for coordination between all subspecialties involved. As previously mentioned, patients with NELM frequently present with an extensive tumor load, whilst treating the patient in a manner that acknowledges the often relatively indolent nature of NEN progression should be the goal of treatment [16]. The selection of treatment options is adjusted accordingly, based on patient performance status, associated comorbidities, meticulous tumor staging, and assessment of prognostic factors [17].
Although liver surgery is the only therapeutic approach with curative intent, it is not unequivocally clear whether it prolongs overall survival (OS) in patients with NELM, as conflicting reports have been published and no randomized studies have been performed [18-23]. Nevertheless, complete hepatic resection (R0) is only feasible in approximately 10-25% of all NELM patients, as many exhibit bilobar liver involvement [2,13], whereas a significant proportion of NELM may elude detection on preoperative imaging [24,25]. Furthermore, surgical resection with curative intent is not indicated in patients with poorly differentiated tumors, extensive disease, existing comorbidities and/or frailty making surgery unsafe [2].
The application of local, non-surgical liver-targeted treatment modalities (local ablation, transarterial hepatic embolization [TAE] or chemo-embolization [TACE], radio-embolization [RE] and peptide receptor radionuclide therapy [PRRT]) is largely dependent on local expertise, and on the extent and location of hepatic involvement [2].
These treatment options are frequently considered in the context of multimodal management for WD-NENs with progressive, unresectable NELM and/or hormonal syndromes refractory to conventional medical treatment. If hepatic resection and/or minimally invasive techniques targeting NELM are not feasible, or in cases of extrahepatic metastatic spread, systemic treatment is then clinically indicated (Fig. 2).
Figure 2 Treatment algorithm for well-differentiated (G1/G2) neuroendocrine liver metastases
TACE, transarterial chemoembolization; TAE, transarterial embolization; RE, radio-embolization; PPRT, peptide receptor radionuclide therapy, OLT, orthotopic liver transplantation; SA, somatostatin analogues; panNEN, pancreatic neuroendocrine neoplasm; IFNa, interferon alpha; SI-NEN, small intestine neuroendocrine neoplasm; PVE, portal vein embolization; PVL, portal vein ligation; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy
In cases of bulky disease, locoregional options may also be indicated in the early stages for down-staging. Notably, systemic therapies for NENs act on all metastatic sites and are not liver-specific [3].
The present review aims to address the currently available treatment options targeting patients with NELM mainly of GEP origin, elucidating the role of liver surgery and that of minimally-invasive liver-targeted therapeutic modalities, in the context of multidisciplinary team management.
Surgical treatment options
Isolated surgical resection
Patients with WD-NENs and resectable NELM with an adequate future liver remnant (FLR) of at least 30% are considered eligible for curative-intent resection [10]. Although multiple studies over the past decades have demonstrated that patients who undergo complete resection of NELM have better outcomes, opinions are divided as to whether these favorable outcomes illustrate the true therapeutic effect of the approach, or are rather the result of selection and immortal time biases (Table 1) [8,26-35].
Table 1 Results of surgical resection in patients with liver metastases from neuroendocrine neoplasms (NENs)
A first large systematic review of 29 studies aimed to evaluate the safety and efficacy of hepatectomy for patients with NELMs, as well as to identify prognostic factors for survival [26]. The authors showed that liver resections for these patients were safe, with a median overall perioperative mortality of 0% and a median morbidity rate of 23%. Microscopically confirmed complete (R0) resection was achieved in 63% of patients (range 38-100%). The reported median 5-year OS rates for patients undergoing isolated liver resections and a combination of resection and ablation were 70% and 71.5%, respectively. Notably, a 95% median rate of symptom relief was also found. Lastly, with regard to prognostic variables, poor differentiation and extrahepatic extent of disease were confirmed as independent negative prognostic factors for OS [26].
A recent meta-analysis of 1108 patients with NELM from GEP-NENs confirmed favorable survival outcomes by liver surgery compared to chemotherapy (odds ratio [OR] 0.05, 95% confidence interval [CI] 0.01-0.21; P<0.0001), embolization (OR 0.18, 95%CI 0.05-0.61; P=0.006), and no NELM resection (OR 0.15, 95%CI 0.05-0.42; P=0.0003) [36]. These findings were in agreement with a previous systematic review and meta-analysis, which evaluated survival outcomes of patients with NELM from panNENs alone [37]. In that study, patients who underwent liver surgery for NELM had median 1-, 3- and 5-year OS rates of 92.69%, 76.93% and 67.54%, respectively, all superior to the equivalent OS rates of the non-resection groups (77.31%, 40.94%, and 26.6%, respectively; all P<0.001). The authors also showed that, regardless of the functional or non-functional nature of the primary panNET, patients who underwent resection had a higher chance of experiencing associated symptom relief, including hormonal and mechanical symptoms (OR 2.49, 95%CI 1.03-6.04; P=0.04). It should be taken into account, though, that all these outcomes are derived from partly heterogeneous, retrospective, non-randomized trials and thus their outcomes are subject to multiple biases.
Staged resections for extensive disease
As a result of advances in surgical techniques, staged resections of complex and extensive primary or metastatic hepatic disease, traditionally considered unresectable, are currently feasible and have been demonstrated to be safe and effective in selected patients [38-41]. Such procedures can be performed in the context of a multimodal approach for patients whose FLR was initially deemed insufficient. These may include initially portal vein embolization (PVE) and subsequent extended liver resection, 1st stage limited resection with concurrent portal vein ligation (PVL), and 2nd stage completion or hepatectomy or associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).
The Clichy group published their experience with 2-stage hepatectomies for NEN patients with synchronous bilobar NELM and initially insufficient FLR [38]. In the 1st stage patients underwent metastatic clearance of FLR alone (13%), or simultaneous metastatic clearance of FLR and synchronous resection (87%) of NEN primary and contralateral PVL, followed by a 2-month interval of monitoring and, in the absence of disease progression, performance of completion hepatectomy. Only 4% of patients did not proceed to a 2nd stage procedure because of disease progression; R0 resection was achieved in 75% of patients. Perioperative morbidity and mortality were 21% and 0%, respectively. With a median follow up of 64 months, the 2-, 5-, and 8-year OS rates were 94%, 94% and 85% respectively, whilst 2-, 5-, and 8-year disease-free survival (DFS) rates were 85%, 50% and 26%, respectively. The outcomes of this study, however, should be interpreted with caution, as the patients were highly selected; they were young, slim, with limited or no comorbidities, as well as having well-differentiated tumors. However, when such a selection process is applied good long-term outcomes may be achievable. Importantly, a 2-month observation period was adopted, illustrating the need for selecting patients with less aggressive biological tumor behavior. Moreover, the outcomes from the ALPPS registry were recently published, concerning patients with an extensive liver tumor burden not amenable to conventional resection [41]. The primary NEN site in these patients included the small bowel (43%), pancreas (33%), duodenum (5%), lung (5%), ovary (5%), and unknown (10%), whereas all grades were represented, although most were G1 and G2 tumors. Notably, the vast majority of patients (95%) presented with type II bilobar NELM (Fig. 1). All patients successfully underwent stage I and stage II procedures, whilst overall and major morbidity (grade ≥3b Dindo-Clavien) after stage 2 were 52% and 28%, respectively [42]. One late death was noted after a stage 2 procedure. During a median follow up of 28 months, 1- and 2-year OS rates were both 95.2%, while 1- and 2-year DFS was 73.2% and 41.8%, respectively. Based on their outcomes, the authors consider G3 NENs as a contraindication for performing ALPPS, while they recommend the performance of a preoperative liver biopsy to rule out any discrepancy in Ki67 expression between primary and NELM tumors, which could lead to futile resection of high-risk patients with a low expected survival benefit [41].
Simultaneous primary and NELM resection
Contrary to simultaneous resections for other tumors, such as colorectal cancer (CRC) and CRC liver metastases (CRCLM) [43,44], the safety and efficacy of such an approach in the case of primary NEN and synchronous NELM have not been extensively addressed and clinical data are limited [22,45,46]. Additionally, whether resections in these patients should be performed in 1 or 2 stages remains ill-determined, as no relevant comparative studies have been published, whereas such prospective randomization of patients is highly improbable at this stage.
In a small case series from Germany, 7 of 19 patients with panNENs who presented with synchronous NELM underwent simultaneous resections; 3 of them underwent R0, one R1 and 3 R2 resections [46]. During a median follow up of 30.5 months, the survival of patients who underwent simultaneous resection was significantly better than that of 12 patients who did not (P=0.026). Furthermore, the Memorial Sloan-Kettering group reported outcomes from 36 patients with different NEN primaries who underwent simultaneous resection of primary and NELM tumors [45]. Overall, postoperative morbidity and 90-day mortality were 42% and 3%, respectively. Six of 16 patients had a postoperative complication grade ≥3 according to Dindo-Clavien. R0, R1 and R2 rates of 36%, 31% and 33% were achieved, with 1- and 5-year OS rates of 94% and 69%, respectively. The authors concluded that synchronous resections are safe and feasible with acceptable long-term outcomes; however, patient selection is of paramount importance. In a recent series, short- and long-term outcomes following simultaneous resection of SI-NENs and NELM were assessed [22]. Thirty-four patients underwent simultaneous resections whilst 10 had unresectable NELM. Overall and major morbidity (grade ≥3 Dindo-Clavien) were 28% and 11%, respectively, whereas no perioperative deaths were reported. Three-, 5- and 10-year OS rates in patients with unresectable NELM were 34%, 33% and 33%, respectively and were demonstrated to be significantly lower than the equivalent of those who successfully underwent simultaneous resections (93%, 89% and 66%, respectively; P=0.0008) [22].
Despite emerging evidence that simultaneous resections are safe in terms of morbidity and perioperative mortality, as well as effective in achieving complete resection and adequate long-term survival, the exact subset of patients who may benefit from such an approach remains undetermined. Notably, patients deemed eligible to undergo such resections, besides being generally fit and without severe comorbidities, should be highly selected with regard to liver involvement (type I or limited bilobar NELM) and thus should not require extensive or complex liver resections, similarly to simultaneous resections for other indications [47].
Debulking surgery
Cytoreductive or debulking surgery has been proposed as an alternative palliative approach to locoregional liver-directed modalities, either for patients with uncontrollable functional NENs or for those with non-functional NENs and stable disease for an interval of 6 months, with symptomatology attributed to tumor burden [2,48]. Cytoreductive surgery may include surgical resection, radiofrequency ablation (RFA), cryoablation or a combination, with the aim of removing 70-90% of NELM load and thus relieving associated NELM-related symptoms [18]. The potentially beneficial role of this approach was explored in the early 90s by the Mayo Clinic group [49]; the indications for gross surgical resection were symptomatic endocrinopathy and symptomatology caused by the primary tumor in 80% and 20% of the included patients, respectively, and a 50% relief of symptoms was reported following cytoreduction. A number of studies, however, with limited numbers of patients, have evaluated the survival benefit of debulking surgery and have shown that achieving acceptable long-term outcomes with such an approach is feasible in selected patients [18,50-52]. An international multicenter study, which included 179 patients who underwent R2/cytoreductive surgery mainly for symptomatic disease (74.9%), showed a median 5-year OS of 60.7% months [51]. Even though these patients more commonly had multiple negative prognostic factors, such as synchronous disease, bilateral NELM and lymph node metastasis, reasonable long-term outcomes were achieved. However, the contemporary literature provides no evidence from randomized trials to support the role of palliative cytoreductive surgery in non-resectable NELM of GEP origin [18].
The threshold for liver debulking of NELM has been a matter of debate. With the aim of increasing the number of patients eligible for such procedure, a number of studies have evaluated whether achieving less than the standard 90% tumor debulking is adequate [23,52,53]. In a series of panNENs and SI-NENs, one group showed that >70% of NELM reduction was associated with significantly higher OS and progression-free survival (PFS) [23]. Another group that adopted a 70% threshold for patients with carcinoid NELM demonstrated a 5-year disease-specific survival of 90% [53]. The authors showed that the percentage of NELM resected (≥70%) was not independently prognostic for survival. Applying the 70% cytoreduction threshold in NELMs from pancreatic origin, a 5-year OS rate of 81% was achieved, whilst no significant differences in patient outcomes were evident, based on NELM percentage cytoreduction [53].
Liver transplantation
In view of the well-established and effective role of orthotopic liver transplantation (OLT) in the treatment of hepatobiliary malignancies in the context of cirrhosis, increased interest has been focused on expanding its use in the management of highly selected patients with unresectable NELM [54]. Several single- and multicenter, and registry studies have published in the last 15 years on the implementation of OLT for patients with unresectable NELM; however, they have yielded conflicting results. Notably, there is a remarkable heterogeneity of patient numbers, patient cohorts and selection criteria, which in turn is reflected in 5-year OS ranging from 30% to almost 100%, and a 5-year DFS ranging from 10-90% [55-65].
Multivariate analysis of NEN patients undergoing OLT by the European liver transplant registry (ELTR) since 2000 identified hepatomegaly, age more than 45 years, and any amount of resection concurrent with OLT as predictors of a poor outcome [58]. Owing to conflicting data on the implications of the Ki67% LI, a meta-analysis of the 4 largest OLT series in NENs has been conducted and provides evidence regarding the prognostic value of the Ki67 LI with respect to survival and recurrence. Indeed, only 17% of patients with Ki67% LI <2% were free from recurrence at 3 years, compared to 52% of patients with Ki67% LI >2% [66]. However, the probability of escaping NELM recurrence despite maximal radicality is close to zero after more than 5 years.
A number of selection criteria for OLT emerged over the past 2 decades (Table 2) [2,67]. The aim of more strict patient selection is to offer a “curative” treatment that translates into the best possible survival outcome, rather than just a palliative option [59]. The Milan group compared the outcomes of 42 highly selected patients who fulfilled their criteria and subsequently underwent OLT to those of 46 who received other treatments according to non-transplant strategies [59]. During a long-term follow up of over 10 years, OLT patients presented significantly better OS compared to non-OLT patients at 5 and 10 years, with 97.2% vs. 50.9% and 88.9% vs. 22.4%, respectively (P<0.001) [59].
Table 2 Selection criteria for consideration for OLT for NELM
A recent study identified SI-NEN patients who satisfied the Milan criteria but underwent multimodal treatment instead, according to standardized clinical protocols as per ENETS guidelines, with none of the included patients being referred for OLT. Strikingly, for patients who fulfilled the Milan criteria and received standardized multimodal treatment, the 5-year OS was 97% [68]. It is noteworthy that, using strict selection criteria and contemporary methods of NELM assessment, there is a substantial risk of underestimating the extent of the liver tumor burden and at the same time over-selecting G1 patients, who might exhibit prime results following OLT, but most probably do not need it [24,69]. Nevertheless, given that the worldwide donor pool is relatively small, the use of already limited deceased donor grafts for patients with expanded novel indications remains equivocal [70]. Special reference should finally be made to the use of live donor liver transplantation (LDLT), which has been advocated as an effective alternative approach for these patients, primarily providing encouraging outcomes and secondarily overcoming the ethical challenge of providing grafts to patients with more novel indications, such as NELM [54,70].
Surgery for recurrent NELM
Recurrent disease is commonly encountered in patients following surgical resection of their NELM at as high a rate as 65-90%, largely depending on the origin of the NEN primary and the NELM tumor load (Table 1) [2,71,72]. Although studies have shown that repeat liver resections for recurrent primary or secondary liver lesions are safe and feasible in selected patients with limited hepatic involvement [73-75], data on the outcomes of such an approach for recurrent NELM (rNELM) are limited [71,72]. A retrospective, international multicenter study, which evaluated patients with recurrent disease following curative-intent liver surgery for NELM, showed a 65.7% intrahepatic-only recurrence rate. Patients with liver-only recurrence were more commonly those with non-functional primaries of GEP origin, moderately differentiated, initially diagnosed with synchronous disease, having undergone R1 resections, ≥50% liver involvement and those who underwent concurrent intraoperative tumor ablation [71]. Repeat liver resection was feasible in 43.8% of patients with rNELM, demonstrating that patients who underwent surgery in the whole cohort had better 10-year OS compared to those receiving intra-arterial therapies, somatostatin analogs or chemotherapy (P=0.001) [71]. A more recent study from Japan analyzed data from 33 patients who initially underwent resection for NELM, 85% of whom presented with rNELM [72]. Sixteen patients (48.4%) with rNELM underwent repeat liver resection and their 5-year OS was significantly higher than those who did not (78.6% vs. 35.4%, P<0.001).
From these data it appears that roughly 45% of patients with rNELM are amenable to repeat liver resection, whilst survival of these patients was equal or longer compared to those undergoing primary liver resection. One could therefore argue that, in order to maximize the percentage of patients with recurrent disease who reach surgery, more intense follow-up planning should be implemented in patients at higher risk for recurrence, including cross-sectional and functional imaging strategies, to identify and accurately define recurrent disease at an earlier stage and potentially offer repeat surgery if feasible.
Non-surgical liver-targeted treatments
Ablative techniques (RFA and other ablative techniques)
RFA is a localized thermal treatment technique designed to induce tumor destruction by heating the tumor tissue to temperatures that exceed 60°C, achieving coagulative necrosis [76,77]. RFA is performed either percutaneously under imaging guidance (computed tomography [CT] or ultrasonography), or intraoperatively in combination with hepatic resection using either open or laparoscopic approaches. It is generally indicated for limited NELM <5 cm in size when surgery is contraindicated, or in combination with liver resection in cases of bilobar extension to limit the extent of hepatectomy. On the other hand, RFA is usually contraindicated for NELM around vital structures in the liver hilum, superficial NELM, or if the patient has had a previous Whipple procedure [78]. Cross-sectional imaging with CT or magnetic resonance imaging is commonly applied post-treatment to determine complete tumor necrosis [79]. In several studies, RFA has been confirmed as a relatively safe and well-tolerated procedure with a wide range of patient outcomes in terms of OS and PFS [80-82]. Importantly, apart from RFA’s complementary role to liver surgery, special attention should be given to its role in NEN cytoreduction and control of hormonal syndromes. RFA can also be effectively combined with surgical resection in an effort to preserve the highest possible percentage of hepatic parenchyma. Studies assessing outcomes from patients undergoing resection and concomitant ablation of NELM have documented equally good long-term outcomes [83-85]. Reported complications after RFA include portal vein thrombosis, hemoperitoneum, viscus perforation, bile leak, liver abscess, pneumothorax and pleural effusions [78,82]. Furthermore, RFA mandates a high level of operator experience in the use of conventional ultrasound- and CT-navigation in order to achieve precise 3D alignment of probes and subsequently create adequately overlapping ablation areas. In that setting, stereotactic RFA as an emerging alternative approach allows for optimal 3D ablation planning and achievement of optimal configuration of the RFA probes, thus creating multiple overlapping coagulation volumes, especially in larger tumors (>5 cm) [86].
Microwave ablation (MWA) has also been confirmed as an effective and relatively safe, minimally invasive technique in hepatocellular carcinomas and colorectal LM [87]. MWA is able to achieve prime results compared to RFA, i.e., larger ablation zones and less heat-sink effect [88,89]. Recently, MWA has been utilized in NELM management with promising results, as an alternative or supplement to hepatic resection, with high local efficiency, modest toxicity and favorable short-term local tumor control rates compared to RFA [90,91]. Combined treatments of intraoperative MWA and surgical resection represent interesting strategies that allow complete parenchyma-sparing approaches for otherwise unresectable NELM, potentially in the setting of a 2-staged hemi-hepatectomy.
TAE and TACE
A characteristic feature of NELM is their hypervascularity and enhanced arterial rather than portal blood supply. TAE by intravascular delivery of embolic agents through selective catheterization of the hepatic artery has been developed to induce tumor ischemia and necrosis. As embolization reduces the blood flow to the targeted NELM, TACE can also be applied, favoring a higher local drug concentration and retention by NELM [92-94]. Cytotoxics used with TACE include either doxorubicin or streptozotocin in mixtures with lipiodol [95]. In contrast to patients selected for RFA/MWA, TAE/TACE is mostly indicated for patients with multiple non-resectable NELM and a more advanced liver tumor burden [2]. Intra-arterial embolization techniques are generally contraindicated in the presence of portal vein thrombosis, hepatic insufficiency or bilio-enteric anastomosis. NEN patient outcomes on TAE or TACE are presented in Supplementary Table 1. However, the available literature on these techniques is derived from mostly underpowered retrospective studies with certain biases, including heterogeneity in embolization methodology. Symptom regression, tumor response rate according to Response Evaluation Criteria in Solid Tumors (RECIST), and survival outcomes after TAE/TACE varied greatly in the included studies, precluding the drawing of any safe conclusions. No available evidence exists that one trans-arterial technique is superior to the other in terms of anti-tumor efficacy; however, TAE may be rather safer than TACE [96,97]. Further comparative prospective studies are warranted to determine whether TAE/TACE potentially offer an advantage over surgical cytoreduction and/or PRRT in terms of PFS and preservation of health-related quality of life.
With regards to staged resections for extensive disease, preoperative PVE has been proposed to induce compensatory hypertrophy of the contralateral FLR, as previously discussed. Interestingly, in the setting of unilobar hepatocellular carcinoma, sequential selective TACE and PVE before major liver resection have been applied to increase the rate of FLR hypertrophy, resulting in a high rate of complete tumor necrosis associated with longer recurrence-free survival [98]. However, the role of the preoperative combination of TACE and PVE in NELM has not yet been assessed. Furthermore, the clinical utility of combinations of embolization and systemic NEN therapies remains to be explored.
Regarding the safety profile of TAE/TACE, post-embolization syndrome with abdominal pain, nausea, fever, hypertension, leukocytosis, thrombocytopenia, hypertransaminasemia, and an increase in lactate dehydrogenase have been reported in up to 90% of treated patients [79,99]. Other complications include liver necrosis, renal insufficiency, liver abscess and ischemic complications of the stomach and the gallbladder.
RE
RE is based on the percutaneous transarterial administration of micro-sized embolic particles connected with a radioisotope, commonly Yttrium-90 microspheres (Thera-Sphere) or resin (SIR-Spheres). RE may target multiple NELM [92]. This technique aims at delivering therapeutic radiation to NELM, while sparing normal parenchyma. Like TAE and TACE, RE is generally indicated in patients with NELM not amenable to hepatic resection as per ENETS guidelines [2]. Symptom control, tumor response rates and survival outcomes after RE varied significantly in relevant studies, with comparable figures to TAE/TACE administration; although RE seems to have a favorable safety profile more studies are needed on long-term toxicities and overall RE tolerability [2,100,101]. In particular, abdominal pain, nausea, fever and fatigue may occur in the short term, whereas hepatotoxicity and radiation- gastritis and pneumonitis may complicate RE administration later on in the disease course [102,103].
Importantly, in selected cases, liver resection may be possible post RE, as depicted in a recent study of NELM and other malignancies [104]. Therefore, it may be prudent to reconsider hepatectomy in patients undergoing transarterial embolization modalities. It should be noted that postoperative complications following major and extended liver resections in this setting need to be thorougly considered in surgical planning.
PRRT
PRRT is a therapeutic approach that uses β-emission radiation to induce tumor necrosis. PRRT agents for NELM consist of a chelator attached to a somatostatin receptor (SSTR) ligand, such as [Tyr3] octreotide or [Tyr3]octreotate, and a radionuclide, such as Yttrium-90 (90Y) or Lutetium-177 (177Lu) [105].
The most important indications for PRRT include lower-grade NELM and extra-hepatic metastases (grades 1 and 2) with sufficient SSTR expression on diagnostic SSTR scintigraphy in patients with adequate renal function and bone marrow reserves [106]. In addition, dual tracer using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/CT and SSTR scintigraphy may provide important information for patient selection for PRRT in the heterogeneous complex high-grade disease group of G3 NEN and NECs [107].
PRRT, irrespective of the radionuclide or peptide used, seems to be an effective therapy for NENs, as exhibited in several retrospective studies and prospective trials, where the tumor response rate ranged between 74% and 100% for 177Lu-DOTATATE and 90Y-DOTATOC. Favorable PFS and OS figures have also been demonstrated. Patient outcomes from NEN studies on PRRT are presented in Supplementary Table 2. Importantly, the efficacy and safety of PRRT in the management of metastatic SI-NENs with progressive disease was confirmed in the NETTER-1 randomized controlled trial [108]. Although in most studies assessment of the treatment response occurred at all sites, many patients had undergone resection of the primary and the liver was the dominant site of metastases assessed by RECIST criteria. Although no randomized PRRT trial has been conducted in pancreatic and lung NENs as yet, the efficacy of PRRT in these subsets of NENs has been confirmed in retrospective studies with real-world data, also in the setting of patients heavily pretreated with chemotherapy [109-111].
In addition, resection of the primary tumor followed by PRRT has been safely proposed as an upfront strategy for the treatment of G1–G2 PanNENs with diffuse unresectable NELM, because it seems to enhance the response to PRRT and to improve PFS significantly [112]. Accordingly, combining PRRT and RE has been suggested in NEN patients with bulky NELM or those with a predominant liver tumor burden and extrahepatic disease, since PRRT results in a limited response in bulky NELM compared to a miliary metastatic pattern [113]. Despite concerns about cumulative hepatotoxicity, RE following PPRT was a safe sequence as a salvage option, with RE-induced liver disease occurring only rarely [113-115].
PRRT agents’ toxicity profiles are generally modest, but can sometimes include life-threatening events of myelotoxicity, hepatic and renal failure [106,116]. Although the risk of therapy-related myeloid neoplasm after PRRT is small, close monitoring is warranted to identify such patients early in the disease course when hematologic abnormalities persist [117].
Ongoing trials
Several ongoing trials are aiming to elucidate the optimal management for patients with non-operable NELM. The LUTIA trial (NCT03590119) is a multicenter, interventional, block randomized, phase 2 clinical trial in which patients with NELM were randomized to administration of 177Lu-dotatate between the right or left hepatic artery. Selective intra-arterial administration of 177Lu-dotatate will potentially allow for intra-patient comparison between intra-arterial administration (one lobe) vs. intravenous (IV) “administration” (contralateral lobe). Another trial (NCT02724540) is recruiting patients with unresectable NELM and randomizing them to bland embolization, TACE, and embolization by drug-eluting beads, aiming to estimate the duration of hepatic PFS in each arm. Another multicenter trial from the US (NCT03724409) is recruiting patients with NELM deriving from SI-NENs, not amenable to other therapies (surgery, ablation), which have progressed after treatment with octreotide/lanreotide and/or other treatments, and randomizing them to several different [90]Y-DOTATOC dosages administered intra-arterially to the liver. The NCT03457948 trial is a four-arm, open-label non-randomized pilot study recruiting biomarker non-selected patients with NELM from G1/G2 NEN initially treated with pembrolizumab. Patients with up to 6 liver lesions (maximum 4 cm) will be treated with RFA or cryoablation, patients with up to 75% involvement of hepatic parenchyma and largest lesion up to 5 cm will be treated with subsegmental embolization, while patients with up to 75% involvement and largest lesion larger than 5 cm will receive subsegmental Yttrium-90 RE. Finally, study NCT0388306 is a prospective trial recruiting patients with unresectable NELM to evaluate the safety and effectiveness of TACE using CalliSpheres drug-eluting beads with oxaliplatin (DEBOXA). In addition, the COMPET trial (NCT03049189), a phase 3 study of the efficacy and safety of 177Lu-edotreotide PRRT in NELM from GEP origin, the phase 2 EVACEL trial (NCT01678664) of everolimus after TACE for NELM, the phase 2 OCCLURANDOM study (NCT02230176) of 177Lutetium-octreotate PRRT randomized versus sunitinib in NELM of pancreatic origin, and the phase 1 NCT03724409 trial of selective intra-arterial injection of PRRT for NELM are all eagerly anticipated.
Concluding remarks
Surgical resection remains the cornerstone in the management of selected patients with NELM whenever feasible. The combination of advances in surgical techniques and improvements in patient selection during the past decades has remarkably transformed relevant long-term outcomes. Complex liver surgery for primary or recurrent NELMs is currentlsy widely performed, equally safely and effectively for patients with extensive disease previously deemed unresectable, whilst OLT, under strict criteria, represents a potentially curative treatment option rather than a palliative option.
Interventional radiology liver-targeted modalities for NELM can be used alone or in combination with liver-directed surgical techniques and generally precede systemic treatments in patients with liver-dominant metastatic NEN disease, as indicated per patient. Apart from control of hormonal syndromes with reduced treatment-related toxicities, special attention should be given to the potential use of these techniques as neoadjuvant cytoreduction and bridging to liver surgery for NEN patients with NELM previously deemed inoperable. In addition, in the setting of recurrent NELM necessitating repeated treatments not amenable to re-resection, these minimally invasive techniques may offer a safe alternative.
Prospective clinical trials in more homogeneous cohorts of NEN patients are warranted to further elucidate the optimal sequencing of these treatment modalities and their potential combination with systemic agents. Finally, combinations of sequencing and imaging data are expected to allow for a better tumor characterization and therefore improved selection of the appropriate treatment protocol on an individual patient basis.