Open Access

Hepatic arterial embolization in patients with neuroendocrine tumors

  • Michela Del Prete1,
  • Francesco Fiore2,
  • Roberta Modica1,
  • Vincenzo Marotta1,
  • Francesca Marciello1,
  • Valeria Ramundo1,
  • Antonella Di Sarno3,
  • Annachiara Carratù1,
  • Chiara de Luca di Roseto1,
  • Salvatore Tafuto4,
  • Fabiana Tatangelo5,
  • Robero Baldelli6,
  • Annamaria Colao1,
  • Antongiulio Faggiano1Email author and
  • on the behalf of the Multidisciplinary Group for NeuroEndocrine Tumors of Naples
Contributed equally
Journal of Experimental & Clinical Cancer Research201433:43

https://doi.org/10.1186/1756-9966-33-43

Received: 6 March 2014

Accepted: 5 May 2014

Published: 19 May 2014

Abstract

Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.

TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases.

Keywords

Embolization Chemoembolization Liver metastases Neuroendocrine tumor

Introduction

Neuroendocrine neoplasms (NEN)s represent a heterogeneous group of neoplasms with distinct morphological and biological manifestations. According to the 2010 WHO classification, NENs are divided into: well differentiated neuroendocrine neoplasm (NEN) G1 (mitotic count <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index), NEN G2 (mitotic count 2–20 per 10 HPF and/or 3–20% Ki67 index), and poorly differentiated high grade malignant neoplasm (NEC) G3 (mitotic count >20 per 10 116 HPF and/or >20% Ki67 index)[1]. Most common sites of origin are the gastrointestinal tract and the bronchopulmonary system. With a global incidence of approximately 5-7 cases per 100,000 per yr, gastroenteropancreatic NEN represents the second most frequent digestive cancer[2, 3]. Metastatic involvement of the liver typically develops in about 46–93% of NEN patients[4, 5]. In 12.9% of these patients, metastases are already detectable at the time of initial tumor diagnosis and 5-10% of them present with metastases and primary of unknown origin. Up to 75% of patients with small bowel NEN and 30-85% of those with pancreatic NEN present with liver metastases either at initial evaluation or during the course of their disease[68]. Presence and extension of liver metastases are considered important prognostic factors for NENs as they may significantly impair the patient’s quality of life because of either tumor bulk or hormonal hypersecretion. Liver metastases can result in a gradual replacement of liver parenchyma resulting in a progressive deficit of function until death, thus decreasing long term survival. Treatment of liver metastases can be curative or palliative. An effective treatment has to result in control of tumor growth and systemic hormonal effect, improvement of quality of life and increase of survival[9]. The treatment of liver metastases should take into account the natural history of the disease, the degree of liver involvement and the severity of related symptoms. The first line treatment of liver metastases is surgery and it can be curative for NEN G1/G2 or palliative. Complete resection (R0/R1) is associated with better long-term survival and quality of life. Resection of NEC G3 is not recommended, but may be considered in individual cases with isolated resecable metastases. Debulking resections (reduction of tumor mass >90%, resection of metastases and lymphnodes) can exceptionally be justified in palliative situations and incompleted debulking surgery (R2) has limited indication especially in functioning tumors[10]. However, only 10-20% of patients are eligible for either palliative or curative surgical resection. Liver transplantation is a potentially curative approach but limited to extremely selected patients and in experienced centers; moreover risk of recurrence persists in the transplantated liver[11].

For patients with multiple site metastases, systemic therapies are required to control tumor growth and clinical symptoms. They include chemotherapy (with streptozotocin or other agents), biotherapy with somatostatin analogs and/or alpha interferon and therapy with new agents targeting specific molecular pathways[1217]. In most of NEN patients with liver metastases, minimally invasive, loco-regional approaches are adopted in place of surgery. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation. Newly developed locoregional ablative procedures are under evaluation. TAE is based on selective infusion of particles in the branch (segmental or subsegmental) of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. TACE differs from TAE for the administration of a chemotherapeutic agent (anthracyclines such as Doxorubicin or Epirobicin) mixed with Lipiodol (fat-soluble contrast-medium with high concentration of Iodine; Lipiodol R), into the hepatic artery followed by the administration of embolizing agents (75-150 μm). In TAE treatment, Lipiodol administration (50%) is followed by the administration of embolizing agents (75-150 μm) without the administration of chemotherapeutic agents. Eligible patients for these procedures include NEN patients in metastatic phase, with predominant liver disease, which is judjed not resectable by surgery[18, 19]. Although both techniques have been widely adopted, it remains debatable if the addition of cytotoxic drugs to embolization material increases the effectiveness of bland embolization alone, particularly when performed selectively[20, 21]. This review will focus on TAE in NEN patients with liver metastases.

Clinical, biochemical, instrumental characterization of NEN patients before TAE

Clinical work-up has to establish if the tumor is associated with a functioning endocrine syndrome which can result also in life-threatening conditions. Carcinoid syndrome is the most frequent functioning endocrine syndrome predominantly associated with the presence of liver metastases (60%). Regardless from endocrine symptoms, tumor mass-related symptoms need to be carefully evaluated, highlighting in particular the patient performance status, hepatic function and degree of liver involvement by the tumor, as liver metastases are often multilocular and bilateral[22]. Plasma chromogranin A (CgA) should be measured in all cases in order to have a potential sensitive marker, helpful for tumor monitoring and follow-up. However false-positive CgA false positive need to be carefully excluded[23, 24]. The 24 h urinary 5-hydroxyindolacetic acid (5-HIAA) is an additional sensitive marker in NENs with carcinoid syndrome[25]. Other helpful NEN markers related to the specific syndrome are insulin, gastrin, glucagons or vasoactive intestinal polypeptide, to be evaluated according to the clinical picture[26, 27].

Contrast-enhanced abdominal ultrasound and multidetector-row computed tomography (CT) are the standard initial imaging procedures. Advanced CT protocols and fusioning CT - positron emission tomography (PET) showed a sensitivity of 94–100%[28, 29]. As an alternative to CT, magnetic resonance imaging (MRI), using gadolinium as liver-specific contrast agents, is recommended for routine staging, assessment of disease progression and monitoring of the therapy[30]. Functional imaging is mainly based on the [111-In-diethylene-triamine-penta-acetic-acid (DTPA)-D-Phe1]-octreotide (Octreoscan). Nowadays this technique has been replaced in several centers with 68Ga-radilabelled PET[3133]. The diagnostic work-up of liver metastases should encompass tissue acquisition for histopathological and immunohistochemistry examination, since staging of NEN depends on markers of proliferation, such as Ki-67 and mitotic index and evaluation of vascular and neural invasiveness. Tumor staging predicts the prognosis and tailors the therapeutic strategy, particularly in patients who are not candidates for complete resection[34].

Embolization procedures

Hepatic arterial embolization using a percutaneous Seldinger technique under radiological control was developed for metastatic endocrine tumors in the early 1970s. Indications for TAE generally include unresectability with symptoms related to tumor bulk, excessive hormone production, and rapid progression of liver disease. TAE has been shown to improve biophysical markers, palliate symptoms and reduce tumor burden at the radiological evaluation[20, 35]. Neuroendocrine liver metastase are higly vascular and receive their blood supply from the hepatic artery (>90%), while normal liver receives 75-80% of its blood supply from the portal vein. TAE aims to create tumor ischemia embolizing the tumor feeding hepatic arterial branches[36]. Tumor ischemia has already been demonstrated useful in primary hepatocellular carcinoma, and now it finds indication for treatment of neuroendocrine liver metastases. In TACE procedure, tumor tissue ischemia is caused by both the chemotherapy activity and arterial embolization.

Different protocols have been used in TAE and embolizing agents are lipiodol, gel foam particles, polyvinyl alcohol (PVA) particles or microspheres[37]. Eligibility requirements included intact liver and renal function (bilirubin <2 mg/dL, serum creatinine level <2 mg/dL). Absolute contraindications were main portal vein occlusion and poor liver function. Other contraindications are: bilirubin greater than 2 mg/dL, hepatic tumor burden greater than 75%, specific contraindications to angiography such as allergy o contrast medium, fever and/or septic state, renal insufficiency, peripheral vascular disease, coagulopathies[38]. All patients were admitted to the hospital prior to the procedure and started intravenous hydration. Prior to embolization, a celiac angiogram was performed to identify the hepatic vasculature and ensure patency of the portal vein. Superior mesenteric artery angiogram was performed if needed to evaluate for accessory or replaced hepatic arteries supplying the liver. Embolization was performed until the selected vessel demonstrates complete or near complete stasis of flow. Usually the liver lobe with the bulkiest disease was embolized first. After embolization, patients were monitored in the hospital and discharged only after their liver enzymes had peaked. All patients were prophylactically administered antibiotics for one week in order to prevent abscess formation. Intravenous narcotics were typically administered for pain control. In case of recurrence or progression, TAE procedure can be performed several times[39]. When proximal embolization of tumor-feeding arteries in hepatic metastases was performed major effectiveness is remarked. Individual embolizations were spaced approximately 4 weeks apart and the majority of patients completed their embolizations in 2 or 3 times[9, 40, 41].

Efficacy

Many reviews have been published on loco-regional ablative treatments of liver metastases of NENs. Several studies have been reported on TACE, while only few studies on TAE. This review focuses on TAE performance and safety in patients with liver metastases of NENs. It has to be highlighted that many authors did not report data on clinical response to TAE or reported these data as indirect consequence of decrease of tumour markers.

As a whole, 896 patients with NEN and liver metastases have been treated for a total of 979 TAE procedures. Median survival rates ranged from 10 to 80 months[9, 21, 35, 39, 4252], but in the most of studies it was between 35 and 60 months (Table 1). Survival was reported to be correlated to objective tumor response. Progression free survival ranged from 0 to 60 months. Objective tumour response, including partial and complete response, was 50% as average (range, 2-100%). If we consider both tumour response and stabilization of tumor growth, the rate of patients who received a benefit from TAE was about 40%[9, 21, 35, 39, 4252] (Table 1). Clinical response was about 56% (range, 9-100%). As far as biochemical response is concerned, TAE was reported to be effective in reducing biochemical markers in >50% of patients with NEN. In NEN patients with carcinoid syndrome, major decreases in 5-HIAA levels (>50% decrease as compared to baseline) occured in a range of 11-100%[9, 35, 39, 4244, 51, 5357] (Table 2).
Table 1

Tumour response and survival rate in patients treated with Transarterial Embolization (TAE)

Paper

Number and type of NEN

Number of TAEs

TR

OS

Loewe et al. 2003[7]

23 carcinoids

75 TAE

4 (18%) CR, 12 (55%) PR, 6 (27%) PD (22 pts evaluable)

69 months

Gupta et al. 2003[18]

69 carcinoids

Carcinoids:

Carcinoids: 46 (67%) PR, 6 (8.5%) MR, 11 (16%) SD, 6 (8.5%) PD

18 months

 

54 PNENs

42 TAE/27 TACE

PNEN: 19 (35%) PR, 1 (2%) MR, 32 (59%) SD, 2 (4%) PD

 
 

PNENs:

 
 

32 TAE/22 TACE

 

Carrasco et al. 1986[32]

25 carcinoids

25 TAE

20 (87%) CR, 1 (5%) PD

11 months

 

(23 evaluable)

 

Strosberg et al. 2006[36]

59 carcinoids

161 TAE

23 pts evaluable: 11 (48%) PR, 12 (52%) SD

36 months

 

20 PNENs

 
 

5 unspecified NENs

 

Hanssen et al. 1989[39]

19 carcinoids (7 evaluable)

7 TAE

7 (100%) PR

12 months

Wangberg et al. 1996[40]

64 carcinoids

40 TAE

---

60 months

Eriksson et al. 1998[41]

29 carcinoids

55 TAE

Carcinoids: 18 (62%) CR, 9 (31%) SD, 2 (7%) PD

80 months (carcinoids)

 

12 PNENs

 

PNEN: 6 (67%) CR, 1 (11%) SD, 2 (22%) PD

20 months (PNEN)

Brown et al. 1999[42]

21 carcinoids

63 TAE

---

60 months

 

14 PNENs

 

Chamberlain et al. 2000[43]

41 carcinoids

59 TAE

33 pts evaluable: 19 (58%) SD

NR

 

44 PNENs

 

Ruutiainen et al. 2007[44]

67 unspecified NENs

23 TAE/44 TACE

(100%) CR

36 months

 

(219 procedures)

(35%) CR

 

Ho et al. 2007[45]

31 carcinoids

7 TAE/86 TACE

33 pts evaluable:

48 months

 

15 PNEN

 

Carcinoids: 5 (23%) PR, 5 (23%) MR, 7 (31%) SD, 5 (23%) PD*

 
 

PNEN: 2 (18%) PR, 3 (27%) MR, 5 (46%) SD, 1 (9%) PD*

 

Kamat et al. 2008[46]

60 unspecified NENs

33 TAE/27 TACE

12 (25%) PR, 6 (12%) MR, 22 (46%) SD, 8 (17%) PD*

9.3 months

 

(123 procedures)

48 pts evaluable

 

Pitt et al. 2008[47]

100 unspecified NENs

106 TAE/123 TACE

---

32.4 months

Sward et al. 2009[48]

107 carcinoids

213 TAE

---

56 months

Fiore et al. 2014[50]

12 PNENs

38 TAE/37 TACE

17 pts evaluable:

60 months

 

16 NENs ileum

 

12 (70%) CR, 5 (30%) PR

 
 

2 NENs colon

 

Legend = PNEN: NEN pancreas, TR: tumor response, OS: overall survival, PR: partial response, CR: complete response, MR: minor response, SD: stable disease, PD: progressive disease, NR: not reached, *cumulative results.

Table 2

Symptomatic and biochemical response in patients treated with TAE

Paper

Number and type of NEN

Number of TAEs

BR

SR (endocrine symptoms)

SR (aspecific symptoms)

Loewe et al. 2003[7]

23 small-bowel NENs

75

13 pts evaluable: 8 (61%) PR, 5 (39%) MR

9 pts evaluable:

- - -

 

Abdominal pain 5 (56%) PR

 
 

Diarrhea 2 (22%) CR

 
 

Flushing 2 (22%) CR

 

Gupta et al. 2003[18]

69 carcinoids

Carcinoids:

- - -

- - -

- - -

 

42 TAE/27 TACE

 
 

54 PNENs

PNENs:

 
 

32 TAE/22 TACE

 

Carrasco et al. 1986[32]

25 carcinoids

25

18 (72%) CR

- - -

20 (87%) CR

Strosberg et al. 2006[36]

59 carcinoids

161

35 pts evaluable:

Flushing and/or diarrhea 21 (48%) CR

9 (20%) CR

 

20 PNENs

 

28 (80%) CR

Abdominal pain 11 (25%) CR

(44 pts evaluable)

 

5 unspecified NENs

 

4 (11%) MR

Hypoglicemia 3 (7%) CR

 
 

3 (9%) no response

(44 pts evaluable)

 

Hanssen et al. 1989[39]

19 carcinoids (7 pts evaluable)

7

7 (100%) PR

Diarrhea and/or flushing: 7 (100%) CR

- - -

Wangberg et al. 1996[40]

64 carcinoids

40

40 (100%) PR

- - -

40 (100%) PR

 

(40 pts evaluable)

 

Eriksson et al. 1998[41]

29 carcinoids

55

Carcinoids: 12 (41%) PR, 8 (28%) MR, 9 (31%) no response

- - -

11 carcinoid (38%) CR

 

12 PNENs

 

PNEN: 6 (50%) PR, 2 (16%) MR, 4 (34%) no response

 

6 PNEN (50%) CR

Brown et al. 1999[42]

21 carcinoids

63

- - -

- - -

46 (96%) PR

 

14 PNENs

(48 evaluable)

 

(48 TAE evaluable)

Chamberlain et al. 2000[43]

41 carcinoids

59

- - -

33 pts evaluable

31 (94%) PR

 

26 non functional PNENs

 

Hormonal and/or pain symptoms

 
 

18 functional PNENs

 

31 (94%) PR

 

Ruutiainen et al. 2007[44]

67 unspecified NENs

23 TAE/44 TACE (219 procedures)

- - -

- - -

- - -

Ho et al. 2007[45]

46 NENs

7TAE/86 TACE

- - -

- - -

27 pts evaluable

 

(31 carcinoids; 15 PNEN)

 

21 (78%) PR

Kamat et al. 2008[46]

60 unspecified NENs

33 TAE/27 TACE

- - -

- - -

20 pts evaluable

 

(123 procedures)

 

13 (65%) PR

Pitt et al. 2008[47]

100 unspecified NENs

106TAE/123TACE

- - -

- - -

35 pts evaluable: 29 TAE (83%) PR

 

35 pts evaluable: 32 TACE (86%) PR

Sward et al. 2009[48]

107 carcinoids

213

37 pts evaluable:

Diarrhea and/or flushing 76 (71%) CR

76 (71%)

 

CgA: 19 (51%) CR

 
 

54 pts evaluable:

 
 

5HIAA: 26 (48%) CR

 

Fiore et al. 22014[50]

12 PNENs

38 TAE/37 TACE

- - -

- - -

19 pts evaluable

 

16 NENs ileum

 

(64%) PR*

 

2 NENs colon

 

Legend = PNEN: NEN pancreas, BR: biochemical response, SR: symptomatic response, PR: partial response, CR: complete response, MR: minor response.

*Cumulative results.

The first study reporting on TAE treatment in patients with liver metastases from NEN was published by Carrasco et al.[35]. A response to TAE was observed in 95% of patients with malignat liver metastases from carcinoids, with a median response duration of 11 months. Tumour response was subsequently confirmed in all studies performed on TAE and the rate of patients responsive to treatment (objective response plus stability) was always about or more than 80% and the median reponse duration was about 36 months[9, 21, 39, 4749, 52] (Table 1).

In the Carrasco study, a symptomatic response occurred in 87% of patients and correlated with size decrease of liver lesions. In the Fiore study a symptomatic response occurred in 64% of patients who had an uncontrolled endocrine syndrome[52]. Furthermore, a decrease in urine 5-HIAA concentrations of about 41% as average has been reported[35]. A similar o greater effect on 5-HIAA was confirmed in subsequent studies[9, 35, 39, 42, 43, 51, 52] (Table 2). When combined with somatostatin analogs or interferon therapy, TAE was found to be still more effective in reducing 5-HIAA and controlling carcinoid syndrome[42, 43] (Table 2). The biochemical response to repeated TAE cycles was similar to that observed after the first cycle. Finally, the biochemical response was also found to be correlated with survival[51] (Table 2).

Some studies reported a comparison between carcinoid tumors (according to old classifications of NEN) and pancreatic NENs. Eriksson et al. reported a median survival of 80 months in patients with midgut carcinoid tumors and 20 months in those with pancreatic NENs[42] (Table 1). Similar difference was reported in the Gupta study where progression free survival as well as tumor response rate were higher in carcinoids than in pNENs[21]. On the contrary, no difference in overall survival, progression free survival and objective response was reported by Ho et al.[48] (Table 1).

On the other hand, symptomatic response and duration of the response were similar for patients with carcinoid tumors and pancreatic NEN[21, 35, 4246, 48, 51, 52] (Table 2). In general, the duration of response was longer in patients treated for hormonal symptoms with or without pain, while it was shorter when the indication was pain alone[45] (Table 2).

Safety

TAE was found to be a quite safe procedure. Range of TAE-related death was from 2 to 13 patients, with a total of 50 deaths. Adverse events such as ischemia of biliary tree, post-embolization syndrome may occur. Complications were observed in a total of 125 patients (14%) of all 896 patients with NENs, but it is not always clarified wether adverse events and toxicity occurred after TAE and/or TACE (Table 3). Post-embolization syndrome includes abdominal pain, nausea, fevers, hypertension, thrombocytopenia, leukocytosis, transient increase in liver enzymes (predominantly transaminases) and LDH which generally comes down within a few days to 2-3 weeks. Increased bilirubin levels have also been noted. Ischemia of the biliary tree has also been rarely reported and moderate elevation of alkaline phosphatase. When some devices were considered to keep the patient well hydrated and in supportive care, post-embolization syndrome resulted to be less frequent[4, 44]. As a whole, TAE may be considered a quite safe procedure, given the high number of procedures carried out (979) and the low number of deaths (50 patients: 6%) and complications (125 patients: 14%) (Table 3).
Table 3

Safety of TAE

Paper

Number and type of NEN

Number of TAE

Complications

Death

Loewe et al. 2003[7]

23 small-bowel NENs

75

Decreased body weight 1 (1%)

2 (8%)

 

Leg pain 1 (1%)

 

Gupta et al. 2003[18]

69 carcinoids

Carcinoids:

Serious adverse events 19 (15%)*

1 (1%)

 

54 PNENs

42 TAE/27 TACE

 
 

PNENs:

 
 

32 TAE/22 TACE

 

Carrasco et al. 1986[32]

25 carcinoids

25

- - -

2 (8%)

 

(23 evaluable)

 

Strosberg et al. 2006[36]

59 carcinoids

161

- - -

2 (2%)

 

20 PNENs

 
 

5 unspecified NENs

 

Hanssen et al. 1989[39]

19 carcinoids

7

- - -

- - -

 

(7 evaluable)

 

Wangberg et al. 1996[40]

64 carcinoids

40

- - -

Increased risk of cardiovascular deaths (not specified)

Eriksson et al. 1998[41]

29 carcinoids

55

Unspecified severe complications 6 (10%)

13 (31%)

 

12 PNENs

 

Brown et al. 1999[42]

21 carcinoids

63

Unspecified severe complications 11 (17%)

4 (6%)

 

14 PNENs

 

Chamberlain et al. 2000[43]

41 carcinoids

59

- - -

4 (6%)

 

26 non functional PNENs

 
 

18 functional PNENs

 

Ruutiainen et al. 2007[44]

67 unspecified NENs

23 TAE/44 TACE

Unspecified toxicity 34 (50%)*

(1) 1.4%*

 

(219 procedures)

 

Ho et al. 2007[45]

46 NENs

7 TAE/86 TACE

Unspecified complications 9 (10%)*

4 (4.3%)

 

(31 carcinoids; 15 PNEN)

 

Kamat et al. 2008[46]

60 unspecified NENs

33 TAE/27 TACE

Unspecified complications 21 (35%)*

12 (20%)

 

(123 procedures)

 

Pitt et al. 2008[47]

100 unspecified NENs

106TAE/123TACE

Liver abscesses, ileus, groin hematoma, hypotension 7 (13%) TAE hematoma, acute renal failure, and a biloma 3 (6%) TACE

3 (3%)*

Sward et al. 2009[48]

107 carcinoids

213

Liver abscess 4 (4%)

2 (2%)

 

Mild pancreatitis 1 (1%)

 
 

Accidental occlusions of the common hepatic artery 2 (2%)

 

Fiore et al. 2014[50]

12 PNENs

38 TAE/37 TACE

Post-embolization syndrome 6 (40%) TAE

0%

 

16 NENs ileum

 

Post-embolization syndrome 8 (60%) TACE

 
 

2 NENs colon

 

*Cumulative results.

Conclusions

TAE appears to be an optimal treatment approach for inoperable liver metastases from NENs, for higher metastatic load, for management of symptoms alone and in association with interferon or somatostatin analogues, suggesting a prolonged 5-yr survival and local tumor control and for survival improvement[42, 43, 45, 51]. Tumor response as well as survival, but not clinical and biochemical response, appear to be better for patients with carcinoid than pancreatic NENs.

TAE is considered a safe procedure. The low number of complications during and/or after TAE procedures can be easily and quickly treated, while the small number of deaths further confirms the safety of this technique. Moreover the deaths are often associated with adverse effects not related to TAE, but with the chemotherapeutic agents used for TACE. It is essential that TAE is performed by highly qualified and specialized team. Finally, the presence of extra-hepatic metastases or unresected primary tumor should not limit the use of TAE[48] since the liver function plays the most important role in the survival of these patients.

On the other hand, TAE should be avoided in patients with massive tumor burden and severely compromised liver function, poor performance status, sepsis, carcinoid heart disease and other risk factors for treatment related mortality (Table 4). In these cases less aggressive TAE, repeated if needed, can be effective, while decreasing the risk for procedure related mortality[49, 50].
Table 4

Indications and contraindications of TAE in patients with NENs

Indications

Contraindications

- NEN tumor functioning or not

- Massive tumor burden

- Highly vascularised liver metastases

- Severely compromised liver function

- Liver metastases >3 in number and or >3 cm in size

- Poor performance status

- Sepsis

- Patients with tumor mass-related symptoms and/or carcinoid syndrome

- Carcinoid heart disease and other risk factors for treatment related mortality

Future randomized, prospective clinical trials comparing safety, efficacy and lorng term outcomes of different treatment approaches for liver metastases in NEN patients with comparable disease, should better define the role of TAE. In conclusion, available data suggest TAE as a safe therapeutic option in patiens with liver metastases from NENs, effective for controlling tumor progression and improving mass and endocrine symptoms, while increasing long term survival. In order to minimize risk related procedure TAE should be performed in a multidisciplinary setting and in experienced NEN centers. Finally, the choice of TAE instead of TACE, PRRT, chemotherapy or biotherapy should be performed in a multidisciplinary setting and in experienced NEN centers, according to patient and tumor characteristics.

Notes

Abbreviations

NENs: 

Neuroendocrine neoplasms

TAE: 

Trans-arterial embolization

TACE: 

Trans-arterial chemoembolization

CgA: 

Chromogranin A

5-HIAA: 

Urinary 5-hydroxyindoleacetic acid

CT: 

Computed tomography

PET: 

Positron emission tomography

MRI: 

Magnetic resonance imaging

Octreoscan: 

[111-In-diethylene-triamine-penta-acetic-acid (DTPA)-D-Phe1]-octreotide

DOTA: 

Tricarboxy-methyl-1-yl-acetyl-D-Phe1

DOTATOC: 

Try3–octreotide

DOTANOC: 

DOTA-1-Nal3-octreotide

PVA: 

Polyvinyl alcohol

PNEN: 

Neuroendocrine neoplasm of pancreas

TR: 

Tumor response

OS: 

Overall survival

PR: 

Partial response

CR: 

Complete response

MR: 

Minor response

SD: 

Stable disease

PD: 

Progressive disease

BR: 

Biochemical response

SR: 

Symptomatic response.

Declarations

Acknowledgement

We are extremely grateful to all subjects who took part in these studies and the research teams who collected the data.

Role of funding source

This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Authors’ Affiliations

(1)
Divisione di Endocrinologia, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II
(2)
Divisione di Radiologia Interventistica, Dipartimento di Diagnostica per Immagini, Terapia Radiante e Metabolica, "Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS
(3)
Interventional Unit Ultrasound A.O. Dei Colli
(4)
Divisione di Oncologia Medica Addominale, Dipartimento di Oncologia Addominale, "Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS
(5)
Divisione di Anatomia Patologica e Citopatologia, Dipartimento di Patologia diagnostica e di Laboratorio, "Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS
(6)
Divisione di Endocrinologia, Istituto Nazionale Tumori

References

  1. Bosman FT: World Health Organization, and International Agency for Research on Cancer. WHO classification of tumours of the digestive system, World Health Organization classification of tumours. 2010, Lyon: International Agency for Research on Cancer, 417-4Google Scholar
  2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB: 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. 10.1200/JCO.2007.15.4377.View ArticlePubMedGoogle Scholar
  3. Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD, Knowledge NETwork: Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Canc. 2013, 21 (3): R153-R163.View ArticleGoogle Scholar
  4. Touzios JG, Kiely JM, Pitt SC, Rilling WS, Quebbeman EJ, Wilson SD, Pitt HA: Neuroendocrine hepatic metastases: does aggressive management improve survival?. Ann Surg. 2005, 241 (5): 776-783. 10.1097/01.sla.0000161981.58631.ab. discussion 783-5PubMed CentralView ArticlePubMedGoogle Scholar
  5. Hemminki K, Li X: Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer. 2001, 92 (8): 2204-2210. 10.1002/1097-0142(20011015)92:8<2204::AID-CNCR1564>3.0.CO;2-R.View ArticlePubMedGoogle Scholar
  6. Modlin IM, Lye KD, Kidd M: A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003, 97 (4): 934-959. 10.1002/cncr.11105.View ArticlePubMedGoogle Scholar
  7. Oberg K, Eriksson B: Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005, 19 (5): 753-781. 10.1016/j.bpg.2005.06.002.View ArticlePubMedGoogle Scholar
  8. Norheim I, Oberg K, Theodorsson-Norheim E, Lindgren PG, Lundqvist G, Magnusson A, Wide L, Wilander E: Malignant carcinoid tumors. An analysis of 103 patients with regard to tumor localization, hormone production, and survival. Ann Surg. 1987, 206 (2): 115-125. 10.1097/00000658-198708000-00001.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Loewe C, Schindl M, Cejna M, Niederle B, Lammer J, Thurnher S: Permanent transarterial embolization of neuroendocrine metastases of the liver using cyanoacrylate and lipiodol: assessment of mid- and long-term results. AJR Am J Roentgenol. 2003, 180 (5): 1379-1384. 10.2214/ajr.180.5.1801379.View ArticlePubMedGoogle Scholar
  10. Pavel M, Baudin E, Couvelard A, Krenning E, Öberg K, Steinmüller T, Anlauf M, Wiedenmann B, Salazar R, Barcelona Consensus Conference participants: ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology. 2012, 95 (2): 157-176. 10.1159/000335597.View ArticlePubMedGoogle Scholar
  11. Blonski WC, Reddy KR, Shaked A, Siegelman E, Metz DC: Liver transplantation for metastatic neuroendocrine tumor: a case report and review of the literature. World J Gastroenterol. 2005, 11 (48): 7676-7683.PubMedGoogle Scholar
  12. Oberg K, Norheim I, Lundqvist G, Wide L: Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin–alone or in combination with 5-FU. Acta Oncol. 1987, 26 (6): 429-432. 10.3109/02841868709113712.View ArticlePubMedGoogle Scholar
  13. Oberg K: Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Ann Oncol. 2001, 12 (Suppl 2): S111-S114. 10.1093/annonc/12.suppl_2.S111.View ArticlePubMedGoogle Scholar
  14. Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, Jürgensen R, Stein K, Schäfer H, Bruns C, Dennler HJ: Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. 1996, 38 (3): 430-438. 10.1136/gut.38.3.430.PubMed CentralView ArticlePubMedGoogle Scholar
  15. Strosberg JR, Nasir A, Hodul P, Kvols L: Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Canc Res. 2008, 2 (3): 113-125.Google Scholar
  16. Kulke MH: Gastrointestinal neuroendocrine tumors: a role for targeted therapies?. Endocr Relat Canc. 2007, 14 (2): 207-219. 10.1677/ERC-06-0061.View ArticleGoogle Scholar
  17. Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011, 364 (6): 501-513. 10.1056/NEJMoa1003825.View ArticlePubMedGoogle Scholar
  18. Allison DJ, Modlin IM, Jenkins WJ: Treatment of carcinoid liver metastases by hepatic-artery embolisation. Lancet. 1977, 2 (8052–8053): 1323-1325.View ArticlePubMedGoogle Scholar
  19. Ajani JA, Carrasco CH, Charnsangavej C, Samaan NA, Levin B, Wallace S: Islet cell tumors metastatic to the liver: effective palliation by sequential hepatic artery embolization. Ann Intern Med. 1988, 108 (3): 340-344. 10.7326/0003-4819-108-3-340.View ArticlePubMedGoogle Scholar
  20. Madoff DC, Gupta S, Ahrar K, Murthy R, Yao JC: Update on the management of neuroendocrine hepatic metastases. J Vasc Interv Radiol. 2006, 17 (8): 1235-1249. 10.1097/01.RVI.0000232177.57950.71. quiz 1250View ArticlePubMedGoogle Scholar
  21. Gupta S, Yao JC, Ahrar K, Wallace MJ, Morello FA, Madoff DC, Murthy R, Hicks ME, Ajani JA: 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. 10.1097/00130404-200307000-00008.View ArticlePubMedGoogle Scholar
  22. Pelage JP, Soyer P, Boudiaf M, Brocheriou-Spelle I, Dufresne AC, Coumbaras J, Rymer R: Carcinoid tumors of the abdomen: CT features. Abdom Imaging. 1999, 24 (3): 240-245. 10.1007/s002619900488.View ArticlePubMedGoogle Scholar
  23. Marotta V, Nuzzo V, Ferrara T, Zuccoli A, Masone M, Nocerino L, Del Prete M, Marciello F, Ramundo V, Lombardi G, Vitale M, Colao A, Faggiano A: Limitations of Chromogranin A in clinical practice. Biomarkers. 2012, 17 (2): 186-191. 10.3109/1354750X.2012.654511.View ArticlePubMedGoogle Scholar
  24. Oberg K, Stridsberg M: Chromogranins as diagnostic and prognostic markers in neuroendocrine tumours. Adv Exp Med Biol. 2000, 482: 329-337.View ArticlePubMedGoogle Scholar
  25. Carling RS, Degg TJ, Allen KR, Bax ND, Barth JH: Evaluation of whole blood serotonin and plasma and urine 5-hydroxyindole acetic acid in diagnosis of carcinoid disease. Ann Clin Biochem. 2002, 39 (Pt 6): 577-582.View ArticlePubMedGoogle Scholar
  26. Lamberts SW, Hofland LJ, Nobels FR: Neuroendocrine tumor markers. Front Neuroendocrinol. 2001, 22 (4): 309-339. 10.1006/frne.2001.0218.View ArticlePubMedGoogle Scholar
  27. Ferolla P, Faggiano A, Mansueto G, Avenia N, Cantelmi MG, Giovenali P, Del Basso De Caro ML, Milone F, Scarpelli G, Masone S, Santeusanio F, Lombardi G, Angeletti G, Colao A: The biological characterization of neuroendocrine tumors: the role of neuroendocrine markers. J Endocrinol Invest. 2008, 31 (3): 277-286. 10.1007/BF03345602.View ArticlePubMedGoogle Scholar
  28. Panzuto F, Falconi M, Nasoni S, Angeletti S, Moretti A, Bezzi M, Gualdi G, Polettini E, Sciuto R, Festa A, Scopinaro F, Corleto VD, Bordi C, Pederzoli P, Delle Fave G: Staging of digestive endocrine tumours using helical computed tomography and somatostatin receptor scintigraphy. Ann Oncol. 2003, 14 (4): 586-591. 10.1093/annonc/mdg160.View ArticlePubMedGoogle Scholar
  29. Seemann MD: Detection of metastases from gastrointestinal neuroendocrine tumors: prospective comparison of 18 F-TOCA PET, triple-phase CT, and PET/CT. Technol Canc Res Treat. 2007, 6 (3): 213-220.View ArticleGoogle Scholar
  30. Dromain C, de Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, Ducreux M, Duvillard P, Elias D, Schlumberger M, Sigal R, Baudin E: Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol. 2005, 23 (1): 70-78. 10.1200/JCO.2005.01.013.View ArticlePubMedGoogle Scholar
  31. Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS, Mäcke HR: Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000, 27 (3): 273-282. 10.1007/s002590050034.View ArticlePubMedGoogle Scholar
  32. Al-Nahhas A, Win Z, Szyszko T, Singh A, Nanni C, Fanti S, Rubello D: Gallium-68 PET: a new frontier in receptor cancer imaging. Anticancer Res. 2007, 27 (6B): 4087-4094.PubMedGoogle Scholar
  33. Lopci E, Nanni C, Rampin L, Rubello D, Fanti S: Clinical applications of 68Ga-DOTANOC in neuroendocrine tumours. Minerva Endocrinol. 2008, 33 (3): 277-281.PubMedGoogle Scholar
  34. Nicholson SA, Ryan MR: A review of cytologic findings in neuroendocrine carcinomas including carcinoid tumors with histologic correlation. Cancer. 2000, 90 (3): 148-161. 10.1002/1097-0142(20000625)90:3<148::AID-CNCR3>3.0.CO;2-9.View ArticlePubMedGoogle Scholar
  35. Carrasco CH, Charnsangavej C, Ajani J, Samaan NA, Richli W, Wallace S: The carcinoid syndrome: palliation by hepatic artery embolization. AJR Am J Roentgenol. 1986, 147 (1): 149-154. 10.2214/ajr.147.1.149.View ArticlePubMedGoogle Scholar
  36. Venook AP: Embolization and chemoembolization therapy for neuroendocrine tumors. Curr Opin Oncol. 1999, 11 (1): 38-41. 10.1097/00001622-199901000-00009.View ArticlePubMedGoogle Scholar
  37. Strosberg JR, Cheema A, Kvols LK: A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract. Cancer Control. 2011, 18 (2): 127-137.PubMedGoogle Scholar
  38. Yao KA, Talamonti MS, Nemcek A, Angelos P, Chrisman H, Skarda J, Benson AB, Rao S, Joehl RJ: Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery. 2001, 130 (4): 677-682. 10.1067/msy.2001.117377. discussion 682-5View ArticlePubMedGoogle Scholar
  39. Strosberg JR, Choi J, Cantor AB, Kvols LK: Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors. Cancer Control. 2006, 13 (1): 72-78.PubMedGoogle Scholar
  40. Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Madoff DC, McRae SE, Hicks ME, Rao S, Vauthey JN, Ajani JA, Yao JC: Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer. 2005, 104 (8): 1590-1602. 10.1002/cncr.21389.View ArticlePubMedGoogle Scholar
  41. Schell SR, Camp ER, Caridi JG, Hawkins IF: Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg. 2002, 6 (5): 664-670. 10.1016/S1091-255X(02)00044-6.View ArticlePubMedGoogle Scholar
  42. Hanssen LE, Schrumpf E, Kolbenstvedt AN, Tausjø J, Dolva LO: Treatment of malignant metastatic midgut carcinoid tumours with recombinant human alpha2b interferon with or without prior hepatic artery embolization. Scand J Gastroenterol. 1989, 24 (7): 787-795. 10.3109/00365528909089215.View ArticlePubMedGoogle Scholar
  43. Wangberg B, Westberg G, Tylén U, Tisell L, Jansson S, Nilsson O, Johansson V, Scherstén T, Ahlman H: Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg. 1996, 20 (7): 892-899. 10.1007/s002689900136. discussion 899View ArticlePubMedGoogle Scholar
  44. Eriksson BK, Larsson EG, Skogseid BM, Löfberg AM, Lörelius LE, Oberg KE: Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. Cancer. 1998, 83 (11): 2293-2301. 10.1002/(SICI)1097-0142(19981201)83:11<2293::AID-CNCR8>3.0.CO;2-E.View ArticlePubMedGoogle Scholar
  45. Brown KT, Koh BY, Brody LA, Getrajdman GI, Susman J, Fong Y, Blumgart LH: Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Interv Radiol. 1999, 10 (4): 397-403. 10.1016/S1051-0443(99)70055-2.View ArticlePubMedGoogle Scholar
  46. Chamberlain RS, Canes D, Brown KT, Saltz L, Jarnagin W, Fong Y, Blumgart LH: Hepatic neuroendocrine metastases: does intervention alter outcomes?. J Am Coll Surg. 2000, 190 (4): 432-445. 10.1016/S1072-7515(00)00222-2.View ArticlePubMedGoogle Scholar
  47. Ruutiainen AT, Soulen MC, Tuite CM, Clark TW, Mondschein JI, Stavropoulos SW, Trerotola SO: Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol. 2007, 18 (7): 847-855. 10.1016/j.jvir.2007.04.018.View ArticlePubMedGoogle Scholar
  48. Ho AS, Picus J, Darcy MD, Tan B, Gould JE, Pilgram TK, Brown DB: Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol. 2007, 188 (5): 1201-1207. 10.2214/AJR.06.0933.View ArticlePubMedGoogle Scholar
  49. Kamat PP, Gupta S, Ensor JE, Murthy R, Ahrar K, Madoff DC, Wallace MJ, Hicks ME: Hepatic arterial embolization and chemoembolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol. 2008, 31 (2): 299-307. 10.1007/s00270-007-9186-3.View ArticlePubMedGoogle Scholar
  50. Pitt SC, Knuth J, Keily JM, McDermott JC, Weber SM, Chen H, Rilling WS, Quebbeman EJ, Agarwal DM, Pitt HA: Hepatic neuroendocrine metastases: chemo- or bland embolization?. J Gastrointest Surg. 2008, 12 (11): 1951-1960. 10.1007/s11605-008-0640-6.PubMed CentralView ArticlePubMedGoogle Scholar
  51. Sward C, Johanson V, Nieveen van Dijkum E, Jansson S, Nilsson O, Wängberg B, Ahlman H, Kölby L: Prolonged survival after hepatic artery embolization in patients with midgut carcinoid syndrome. Br J Surg. 2009, 96 (5): 517-521. 10.1002/bjs.6587.View ArticlePubMedGoogle Scholar
  52. Fiore F, Del Prete M, Franco R, Marotta V, Ramundo V, Marciello F, Di Sarno A, Carratù AC, de Luca di Roseto C, Colao A, Faggiano A: Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocrine. 2014, [Epub ahead of print]Google Scholar
  53. Perez EA, Koniaris LG, Snell SE, Gutierrez JC, Sumner WE, Lee DJ, Hodgson NC, Livingstone AS, Franceschi D: 7201 carcinoids: increasing incidence overall and disproportionate mortality in the elderly. World J Surg. 2007, 31 (5): 1022-1030. 10.1007/s00268-005-0774-6.View ArticlePubMedGoogle Scholar
  54. Dominguez S, Denys A, Madeira I, Hammel P, Vilgrain V, Menu Y, Bernades P, Ruszniewski P: Hepatic arterial chemoembolization with streptozotocin in patients with metastatic digestive endocrine tumours. Eur J Gastroenterol Hepatol. 2000, 12 (2): 151-157. 10.1097/00042737-200012020-00004.View ArticlePubMedGoogle Scholar
  55. Casadei R, Tomassetti P, Rossi C, la Donna M, Migliori M, Marrano D: Treatment of metastatic glucagonoma to the liver: case report and literature review. Ital J Gastroenterol Hepatol. 1999, 31 (4): 308-312.PubMedGoogle Scholar
  56. Lee SM, Forbes A, Williams R: Metastatic islet cell tumour with clinical manifestations of insulin and glucagon excess: successful treatment by hepatic artery embolization and chemotherapy. Eur J Surg Oncol. 1988, 14 (3): 265-268.PubMedGoogle Scholar
  57. Ruszniewski P, Rougier P, Roche A, Legmann P, Sibert A, Hochlaf S, Ychou M, Mignon M: Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. A prospective phase II study in 24 patients. Cancer. 1993, 71 (8): 2624-2630. 10.1002/1097-0142(19930415)71:8<2624::AID-CNCR2820710830>3.0.CO;2-B.View ArticlePubMedGoogle Scholar

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