Hepatic arterial embolization in patients with neuroendocrine tumors

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[6‐8]. 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[12‐17]. 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.

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].

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.