Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy. Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. This article describes intra-arterial hepatic-directed therapies for metastases from NETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors.
Key points
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Intra-arterial therapies for unresectable liver metastases from neuroendocrine primary tumors are supported by level 2a medical evidence (National Cancer Institute) regarding symptom control and imaging response.
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There is insufficient medical evidence showing which intra-arterial therapy (transarterial embolization [TAE], transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) provides the highest response rate, progression-free survival, or overall survival.
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TARE produces less toxicity and has similar efficacy to TAE and TACE.
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Intra-arterial therapies are an important aspect of managing metastases from neuroendocrine tumor liver disease in all stages of disease, including asymptomatic, first-line, salvage, and palliation scenarios.
Introduction
Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. The liver is the most common site of metastatic dissemination from NETs and this occurs in from 10% to 65% of cases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy.
Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. Less than 10% of patients with small bowel and colon NETs experience what is referred to as carcinoid syndrome, the symptoms of which are episodic flushing, bronchoconstriction (wheezing), diarrhea, and eventually heart valve dysfunction. Disease progression differs widely but the overall median survival is 75 months. With metastatic disease, 5-year survival rates are less than 20%. In patients with advanced, unresectable liver metastases the treatment challenge is directed toward palliating symptoms and slowing down or stabilizing tumor growth.
Metastases from NETs (mNETs) to the liver represent a significant clinical entity, and multiple treatment modalities have been used, engaging multidisciplinary teams of gastroenterologists, diagnostic radiologists, oncologists, surgeons, and interventional radiologists. Management modalities used in patients with unresectable metastatic disease, described in other articles of this issue, include systemic chemotherapy, somatostatin analogues, cryotherapy, radiofrequency ablation, peptide receptor radiation therapy, percutaneous alcohol injection, and hepatic transplantation.
This article describes intra-arterial hepatic-directed therapies for mNETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors.
Introduction
Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. The liver is the most common site of metastatic dissemination from NETs and this occurs in from 10% to 65% of cases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy.
Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. Less than 10% of patients with small bowel and colon NETs experience what is referred to as carcinoid syndrome, the symptoms of which are episodic flushing, bronchoconstriction (wheezing), diarrhea, and eventually heart valve dysfunction. Disease progression differs widely but the overall median survival is 75 months. With metastatic disease, 5-year survival rates are less than 20%. In patients with advanced, unresectable liver metastases the treatment challenge is directed toward palliating symptoms and slowing down or stabilizing tumor growth.
Metastases from NETs (mNETs) to the liver represent a significant clinical entity, and multiple treatment modalities have been used, engaging multidisciplinary teams of gastroenterologists, diagnostic radiologists, oncologists, surgeons, and interventional radiologists. Management modalities used in patients with unresectable metastatic disease, described in other articles of this issue, include systemic chemotherapy, somatostatin analogues, cryotherapy, radiofrequency ablation, peptide receptor radiation therapy, percutaneous alcohol injection, and hepatic transplantation.
This article describes intra-arterial hepatic-directed therapies for mNETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors.
Hepatic anatomy and rationale for intra-arterial therapies
The unique double vascular supply of the liver, through the portal vein and the hepatic artery, and the predominantly arterial irrigation of liver tumors are the basis for intra-arterial therapies. Three types of hepatic arterial embolization techniques are currently in use: transarterial embolization (TAE); transarterial chemoembolization (TACE), which includes using drug-eluting beads (DEBs); and radioactive microsphere release into arteries. Radioactive microsphere release is also known as radioembolization, transarterial radioembolization (TARE), and selective internal radiation therapy (SIRT). TARE is a form of brachytherapy in which intra-arterially injected microspheres loaded with yttrium 90 ( 90 Y) serve as sealed sources for internal radiation via a near-pure beta-decay isotope with limited tissue penetrance in the range of 2 to 3 mm.
A well-established body of literature has described the process of tumoral angiogenesis occurring exclusively from the hepatic arterial supply. Circulation from the portal vein does not provide a significant contribution to tumor perfusion. Catheter-based hepatic arterial administration of therapy therefore results in a preferential deposition of a drug/particle into the tumor vasculature, which minimizes liver parenchymal exposure. Carrier-based delivery of chemotherapeutics is achieved via either the infusion of a lipiodol/water-based emulsion or via statically charged DEBs.
Intra-arterial therapies review
The various facets of intra-arterial therapies are discussed here, including their mechanisms of action, patient eligibility factors, and common toxicities arising from liver treatment, as well as therapy response evaluations and retreatment factors.
Mechanisms of Action
Arterial embolization, or TAE, is the general term for the procedure by which a catheter is inserted into an artery percutaneously, eventually directly accessing the hepatic artery. Contrast is subsequently injected via the catheter to verify its position relative to the vascular distribution of the target tumor. Contrast is frequently used during and after delivery of the therapeutic agent to monitor progress of treatment and verify completion of intended effect (ie, stasis or pruning of tumor arteries).
Transarterial embolization
In hepatic transarterial (bland) embolization, catheterization is typically followed by the injection of 50 μm of polyvinyl alcohol (PVA) particles, with or without ethiodized oil. No chemotherapeutic agents are used. The PVA particles physically occlude blood flow through the selected hepatic artery, thereby inducing ischemic injury; if stasis remains unachieved, then larger PVA particles of 200 to 500 μm can be used. Hypoxia is the goal of TAE with subsequent ischemic tumor cell death.
Transarterial chemoembolization
TACE follows the same principles as TAE, but an intra-arterial chemotherapeutic agent is added at the time of embolization. TACE has the potential to result in intratumoral drug concentrations more than 20 times greater than those afforded by the systemic administration of the same drug. In addition, TACE affords the potential clinical benefit of tumor ischemia following embolization. Drugs that are commonly used for this purpose include doxorubicin, irinotecan, mitomycin C, and streptozocin.
Overall, TACE embraces different procedures that share 2 different aims: (1) to increase the exposure of tumor cells to cytotoxic agents, and (2) to induce ischemic necrosis. This aim is usually accomplished by the sequential intra-arterial injection of chemotherapeutic agents and embolizing particles. The wide variety of drug vehicles, cytotoxic agents, and embolizing particles has introduced numerous variations worldwide and no standard protocol has been uniformly adopted. Centers have different choices regarding type and/or dose of the anticancer agents used, use of lipiodol as a vehicle, embolizing material, selectivity of catheter positioning, embolization end points, and schedule and/or interval of retreatment.
Although the most popular technique used in conventional TACE has been the administration of an anticancer-in-lipiodol emulsion followed by embolic agents, bland embolization is still preferred in some centers, and TACE with drug-eluting particles (DEB-TACE) has replaced conventional regimens in others.
Transarterial chemoembolization using drug-eluting beads
The concept of DEB-TACE is to intra-arterially inject embolizing particles that have been loaded in vitro with cytotoxic agents and slowly release them into the tumor environment. These beads are composed of either a sulfonate-modified PVA hydrogel (DC-Beads, Biocompatibles, Surrey, United Kingdom) or a sodium acrylate and vinyl alcohol copolymer (HepaSphere, BioSphere Medical, Inc, Rockland, MA). DEB-TACE provides a way of performing TACE in a more standardized way and has shown that when the optimal patients are selected, the beneficial effect of TACE can challenge that of percutaneous ablation.
The 2 most common DEB platforms are based on PVA (DC/LC Bead, BTG, UK Ltd) and acryl-amine polymer (AAP; Quadrasphere, Merit Medical, South Jordan, UT) substrates that possess static charge. This charge allows oppositely charged molecules to bind and release via ion exchange. For PVA, the ionic interaction occurs between the positively charged chemotherapy, typically doxorubicin or an irinotecan (IRI) salt, and the negatively charged sulfonic acid group. In AAP, the drug binds to carboxylate groups. When DEBs are loaded with IRI, the procedure, platform, and technique are collectively termed DEBIRI. Dose intensity of IRI varies widely in the literature, with a reported dose range of 50 to 200 mg of IRI loaded onto 2 to 4 mL of DEBs.
DEBs possess a pharmacologic advantage by offering simultaneous embolization and sustained release of the drug to the tumor. Some studies have shown that the pharmacokinetics of chemotherapy delivery trend toward controlled release in some configurations of DEB. However, DEBs have a significant cost compared with non–DEB-TACE. More importantly, the drugs currently used in DEBs have not been specifically proved to be active against mNETs.
Radioembolization (transarterial radioembolization)
TARE comprises those procedures in which intra-arterially injected radioactive microspheres are used for internal radiation treatment. There are 2 types of commercially available radioactive microspheres: a ceramic/glass composition (TheraSphere, BTG International Ltd, London, United Kingdom) and resin polymer microsphere (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia). Both use 90 Y as the radiation-emitting isotope. 90 Y is a pure beta emitter with half-life of 64.2 hours (94% of the energy is emitted in the first 11 days) and average tissue penetration of 2.5 mm (isolation for radiation protection is not needed after implantation). Because of their small size (25–45 μm), they produce no significant ischemic effect, as opposed to the greater than 100-μm particles used in TACE. To avoid misplacement of particles in extrahepatic territories, a thorough angiographic evaluation is performed 1 to 2 weeks before treatment to detect and eventually occlude aberrant vessels arising from hepatic arteries that may feed the gastrointestinal tract, and to measure the hepatopulmonary shunting using technetium-99m–labeled macroaggregated albumin.
TACE and TARE should not be considered competing therapies, but complementary tools. For many patients, their individual tumor and normal liver characteristics are such that they are candidates for either TACE/TAE or TARE. There are potential advantages and disadvantages with each approach. Overall, TARE does not have the two main contraindications for use that limit use of TACE, mainly limited use in bulky disease and portal vein thrombosis, but still have a good liver function.
Fundamentally, embolic therapy is designed to exploit and preferentially deposit therapeutic particles into the blood vessels feeding the tumor. In the setting of TARE, this technique is justified because the preferential deposition of radiation into the tumor vascular bed results in targeted delivery of therapy and cell killing by radiation not ischemia. In contrast, given the mechanism of action and metabolism associated with DEBIRI, trials indicate that the metabolism or conversion into its active metabolite occurs within the normal hepatic parenchyma, not the tumor. Therefore embolic effects may predominate in TACE/DEB-TACE approaches, whereas ischemia is not a factor in radiation-mediated TARE tumor cell kill. Hypoxia is a critically important inhibitor of radiation effectiveness and thus is actively avoided.
Patient Selection Factors: Eligibility
Indications for eligibility include nonoperative candidates with symptomatic or asymptomatic tumors, with dominant metastatic burden in the liver. Contraindications include main portal vein thrombosis (TAE/TACE), bilirubin level greater than 2 mg/dL, inability to adequately prevent significant extrahepatic deposition of therapeutic agents, and contraindications to angiography.
Transarterial embolization/transarterial chemoembolization: classic and drug-eluting beads
To be selected for TAE or TACE, patients generally must meet the criteria discussed earlier with additional contraindications to treatment that include pregnancy, myelosuppression, and renal failure.
Radioembolization (transarterial radioembolization)
Patients can only be considered for TARE if they have sufficiently compensated liver function with main factors of normal or near-normal serum total bilirubin level (<2 mg/dL), no coagulopathy, and if they have minimal ascites and no hepatic encephalopathy. Patients are included or excluded by well-established and accepted parameters regarding liver reserve and vascular access. Vascular issues of import include the ability to isolate the liver arterial tree from gastric and small bowel branches. Also excluded for safety reasons are patients with arteriovenous fistulas in tumors that allow a high percentage of microspheres to pass through the liver capillary bed to the lung vascular bed. Controversy exists as to what percentage of shunting excludes patients from TARE, which is based on a few case reports involving hepatocellular carcinoma tumors. A guideline from both manufacturers of TARE microspheres has limited the total lung absorbed dose of radiation to 30 Gy (instruction documents, SirSphere and TheraSphere). Subsequent reports have called this dose level in lungs into question. No patient with mNET has been reported to have experienced pneumonitis or severe pulmonary side effects. Absolute contraindications have been: pregnant women, heavily previously irradiated liver volumes, and predicted normal liver volume remaining after TARE to be less than 700 cm 3 .
Common Toxicities of Liver Treatment by Intra-arterial Therapy
Toxicities resulting most often from the use of TAE, TACE, and TARE are similar but have some significant and important different entities based on the mechanisms of action.
Transarterial embolization/classic transarterial chemoembolization and drug-eluting beads transarterial chemoembolization
Posttreatment side effects reported from TAE, TACE, or both may include nausea, vomiting, abdominal pain, diarrhea, weight loss, fever, hepatorenal syndrome, sepsis, transient myelosuppression, as well as the more rare complications of anasarca, cortical blindness, necrotizing cholecystitis, pancreatitis, and hepatic abscess ( Table 1 ). Commonly referred to as postembolization syndrome after TAE/TACE, up to 40% of patients remain as inpatients on the day of treatment, for an average of 3 days to receive intravenous medications for pain, nausea, and dehydration. Once it resolves, it does not recur and has been described as an ischemic phenomenon.
| Study | N | Device Used | Toxicity |
|---|---|---|---|
| Dong | 123 | TACE | Abdominal pain (44%), diarrhea (30%), weight loss (22%) |
| de Baere | 20 | TACE with doxorubicin-eluting beads | Nausea (61%), fever (36%) |
| Vogl | 48 | TACE with mitomycin C | Nausea and vomiting (27.8%), abdominal pain (11.1%) |
| TACE with mitomycin C + gemcitabine | Nausea and vomiting (16.7%), abdominal pain (10%) | ||
| Loewe | 23 | Bland embolization | Not reported |
| Eriksson | 41 | Bland embolization | Postembolization syndrome (all), nausea (33%), fever (7 patients), median hospitalization: 12 d |
| Pitt | 100 | Bland vs TACE | Bland: 7 of 51, (3 liver abscesses, 1 groin hematoma, 2 ileus, 1 hypotension) TACE: none |
| Ruutiainen | 67 | Bland vs TACE | Grade 3 or worse toxicity in 25% of TACE and 22% of bland TACE (≥grade 3): pain (3), nausea (1), GGT/ALP (4), AST (1), infection (1) Bland (≥grade 3): GGT/ALP (3), AST (1), cardiac (1) |
| Gupta | 49 | TACE vs bland | Serious adverse events in 19 patients (8.5%), hepatorenal syndrome (7), sepsis (6), transient myelosuppression (1), anasarca (1), cortical blindness (1), necrotizing cholecystitis (1), hepatic abscess (2), overall complications in TACE, 20%; bland, 12% |
| Maire | 26 | TACE vs bland | TACE: postembolization syndrome (10), carcinoid crisis (2), acute liver failure (1), neutropenia (2) Bland: postembolization syndrome (10), carcinoid crisis (0), acute liver failure (2), neutropenia (0) |
| Guiu | 120 NET 88 HCC | DEB-TACE in HCC (cirrhotic) and NETs (noncirrhotic) | Liver biliary injury occurred in 64 of 208 patients. Occurrence associated with DEB-TACE P <.001 irrespective of tumor type |
| Ruszniewski | 23 | TACE | Bleeding peptic ulcer (1), oligoanuric renal failure (1), abdominal pain (50%), fever (6 patients), nausea and vomiting (5) |
Doxorubicin has shown a narrow window of activity with significant toxicities, including liver failure, in its use with colorectal metastases in animal models. In colorectal metastases, when this toxicity profile is considered with the well-documented resistance of colorectal metastases to doxorubicin, its application in intra-arterial and liver-directed therapies of NETs is unsubstantiated and may potentially be harmful. Guiu and colleagues reported on consecutive patients treated with DEBs (irinotecan) and evaluated each for liver or biliary injuries as seen on MRI or computed tomography (CT) scans. A total of 120 patients with mNETs and 88 patients with hepatocellular carcinoma were studied. Liver/biliary injury followed 17.2% (82 of 476) of sessions in 30.8% (64 of 208) of patients. The occurrence of liver/biliary injury was associated with DEBs (odds ratio [OR], 6.63; P <.001) not dependent on the tumor type. Biloma/parenchymal infarct was strongly associated with both DEBs (OR, 9.78; P = .002) and mNET histology (OR, 8.13; P = .04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase ( P = .005, P = .005, P = .012, and P = .006, respectively).
Fiore and colleagues retrospectively investigated 30 patients with gastroenteropancreatic NETs with liver metastases. Seventeen patients underwent TAE and 13 patients underwent TACE. These investigators concluded that although TAE and TACE are both effective in patients with mNETs, TAE is preferred to TACE in light of its similar antitumor effects and slightly better toxicity profile. The choice of TAE versus TACE continues to be controversial without definitive medical evidence and is therefore driven by institutional experience and preference.
Radioembolization (transarterial radioembolization)
Patients are evaluated at least during the 6th and 12th weeks after TARE treatment, with some patients needing more frequent evaluations ( Table 2 ). During follow-up visits, laboratory data are obtained, including liver function tests; tumor markers if levels are increased before treatment; abdominal imaging with CT, MRI, or PET/OctreoScan; and a physical examination with recent history taken for side effects. After 12 weeks, patients resume a routine schedule of laboratory tests and imaging at 3-month intervals. Acute toxicities are most often mild abdominal pain lasting from day 1 to day 3, and rarely needing narcotics to control discomfort. Nausea and emesis are typically mild and controlled with antiemetics. Fatigue can last up to 14 days after treatment. Serious injuries are rare, with gastric or duodenal ulcer formation in 2% to 5% and radioembolization-induced liver disease occurring in less than 1% of all patients.
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