Chemoembolization Beyond Hepatocellular Carcinoma: What Tumors Can We Treat and When?

Abstract

Liver metastases are the most common malignancy found in the liver and are 20 to 40 times more common than primary hepatic tumors, including hepatocellular carcinoma. Patients with liver metastases often present with advanced disease and are not eligible for curative-intent surgery or ablative techniques. The unique hepatic arterial blood supply of liver metastases allows interventional radiologists to target these tumors with transarterial therapies. Transarterial chemoembolization (TACE) has been studied in the treatment of liver metastases originating from a variety of primary malignancies and has demonstrated benefits in terms of hepatic progression-free survival, overall survival, and symptomatic relief, among other benefits. Depending on the primary tumor from which they originate, liver metastases may have different indications for TACE, may utilize different TACE regimens and techniques, and may result in different post-procedural outcomes. This review offers an overview of TACE techniques and specific considerations in the treatment of liver metastases, provides an in-depth review of TACE in the treatment of liver metastases originating from colorectal cancer, neuroendocrine tumor, and uveal melanoma, which represent some of the many tumors beyond hepatocellular carcinoma that can be treated by TACE, and summarizes data regarding when one should consider TACE in their treatment algorithms.

Keywords

transarterial chemoembolization - drug-eluting beads - liver metastases - colorectal cancer - neuroendocrine tumor - interventional radiology

Malignant hepatic tumors, whether of primary hepatocellular origin or secondary metastatic disease, primarily receive their blood supply from the hepatic artery, whereas normal liver parenchyma receives the majority of its blood supply from the portal vein.[1] This unique feature of hepatic malignancies allows for targeted transarterial therapies. Transarterial chemoembolization (TACE), in which the arterial blood supply of a tumor is selectively catheterized for delivery of a chemotherapeutic emulsion followed by embolization with a particulate embolic agent, was first described in the early 1980s for the treatment of hepatocellular carcinoma (HCC).[2] Today, TACE plays a central role in HCC management as a result of decades of evidence supporting its use, including level 1 randomized controlled trial data demonstrating superiority of TACE compared with best supportive care.[3] [4] [5] While TACE has its origins in HCC treatment, its use quickly expanded beyond HCC to the treatment of liver metastases, which are 20 to 40 times more common than primary hepatic tumors and represent the most common form of malignancy found in the liver.[6] Patients with hepatic metastases often present with advanced disease and are not eligible for curative-intent surgery due to tumor burden, disease location, and/or inadequate healthy remnant liver tissue. Locoregional therapies such as TACE play an important role in the treatment algorithms for patients with hepatic metastases, whether it be to facilitate potential curative-intent surgery, provide disease control, help improve cancer-associated symptoms, or achieve other palliative-intent treatment goals.

TACE has been studied in the treatment of liver metastases originating from a variety of primary malignancies, including colorectal cancer (CRC), neuroendocrine tumor (NET), uveal melanoma (UM), and many others. Liver metastases from different types of primary tumors have differing prognoses as well as unique surgical, interventional, and systemic treatment options, among several other important distinctions, making a “one-size-fits-all” approach to incorporating TACE into the treatment of liver metastases impossible. Rather, an understanding of the evidence for TACE that is specific to the primary tumor type and familiarity with the management guidelines for that type of cancer are necessary. Additionally, the concurrent development of other interventional technologies, such as ablation, and other transcatheter techniques, such as transarterial radioembolization, make determining whether to offer TACE over another treatment modality a nuanced disease-specific and patient-specific decision. Such decisions should be made using all available evidence and incorporate patient- and institution-related factors. Having a multidisciplinary approach to treatment that includes discussion at tumor boards with active participation of the interventional radiologist helps provide the best evidence-based treatments for patients.[7]

The goal of this article is to aid interventional radiologists in the decision-making process by providing a brief overview of the common TACE techniques employed in the treatment of liver metastases, reviewing the evidence supporting TACE in the treatment of liver metastases originating from differing primary malignancies for which TACE is performed, and discussing the differing indications, technical factors, and outcomes that are unique to some of these malignancies.

TACE Mechanism, Technique, and Considerations

TACE exploits the dual blood supply of the liver to selectively deliver chemotherapeutic and embolic agents to intrahepatic tumors via hepatic arteries, while preferentially sparing, and thereby limiting toxicity to, the normal liver parenchyma, which receives the majority of its blood supply from the portal vein. Conventional transarterial chemoembolization (cTACE) consists of delivery of two sequential components: (1) an emulsion of one or more chemotherapy drugs with lipiodol (Guerbet, Aulnay, France), an oil-based contrast agent consisting of the iodized fatty acids of poppy seed oil, and (2) a particulate embolic agent, such as polyvinyl alcohol (PVA), gelatin sponge, or Trisacryl gelatin microspheres.[8] The purpose of lipiodol is multi-fold: it serves as a contrast agent, a vehicle for drug delivery, and as a temporary embolic agent. Lipiodol has been shown to be selectively taken up by and retained within hypervascular liver metastases, where it permeates through the feeding arteries of the tumor (arterial inflow), through the peribiliary capillary plexus, and into the terminal portal sinusoids (portal outflow), exerting a microembolic effect in these areas.[9] [10] [11] When delivered in the form of an emulsion with chemotherapy, high concentrations of chemotherapy are trapped within the microvascular bed of the tumor where the emulsion resides. If delivery of the emulsion is not followed by embolization with a larger particulate embolic agent, the chemotherapeutic emulsion will wash out of the tumor vascular bed in less than an hour.[12] In addition to inducing tumor ischemia, subsequent embolization performed with a particulate embolic agent prevents washout of the emulsion—by “closing the door” that is the inflow artery via embolization, the emulsion is retained within the tumor vasculature for a prolonged time. Studies have demonstrated improved pharmacokinetics, increased rates of tumor necrosis, and better survival when the lipiodol-drug emulsion is followed by particle embolization, noting these studies were primarily performed in the treatment of HCC.[13] [14] [15] The synergistic effect of local deposition of chemotherapeutic agents at several times their lethal dose and arterial ischemia (provided by both the microembolic lipiodol and macroembolic particulate embolic agent) serves as the basis for TACE.

There is an extensive literature regarding TACE technique, a full description of which is beyond this scope of this review. In general, a water-in-oil emulsion is favored, with the volume of the aqueous solution (the chemotherapeutic mixture) lower than that of the oily lipiodol. The solutions are vigorously mixed via a three-way stopcock with at least 20 pumping exchanges, the first of which should inject the chemotherapeutic mixture into the oil, which will favor a water-in-oil emulsion rather than the other way around.[16] The emulsion is then delivered under continuous fluoroscopic monitoring until the vascular bed is saturated and very distal/peripheral stasis is achieved. Following this, particulate embolization is performed. The use of gelatin sponge particles allows for complete vessel recanalization within a few weeks, preserving the vessel for subsequent TACE or other transarterial therapies.[17] Non-resorbable calibrated microparticles, such as PVA and Trisacryl gelatin microspheres, allow for a more controlled embolization but may result in permanent occlusion of arteries. Ideal particle size has been debated. Many studies use microparticles on the order of 100 to 300 μm. Smaller diameter particles have been shown to be effective; however, concerns exist regarding potential shunting and increased rates of ischemia-associated biliary injury.[18] [19] Fluoroscopic endpoints include complete stasis up to the catheter tip when performing super-selective TACE and a “pruned tree” or “tree-in-winter” appearance when treating less selectively, representing occlusion of smaller tumor-feeding arteries with preservation of flow in segmental and major lobar arteries. For a more detailed review of TACE techniques, the reader is referred to references focused on this topic.[8] [12] [19] [20]

Chemotherapeutic Agents

There is no standardized chemotherapy emulsion employed when performing TACE for the treatment of liver metastases. The most common single-agent TACE emulsion used in the treatment of HCC utilizes drugs in the anthracycline group, including doxorubicin or epirubicin, although single-agent platinum regimens using cisplatin have also been studied.[21] [22] The most common combination-drug emulsions include cisplatin, doxorubicin, and mitomycin C.[23] This is accompanied by evidence demonstrating a higher response rate, lower incidence of tumor progression, and fewer required treatments with combination-drug emulsions compared with single-agent emulsions.[24] [25] One may consider removal of the nephrotoxic agent cisplatin in those with advanced chronic kidney disease, minimizing risks of renal toxicity from limited systemic release of the drug. A different chemotherapeutic emulsion may be employed when treating UM metastases with TACE, consisting of single-agent carmustine, or 1,2-bis (2-chloroethyl)-1-nitrosurea (BCNU), an alkylating agent typically used in brain cancer and hematopoietic malignancies.[26] Evidence for its use in UM will be discussed in subsequent sections.

Drug-Eluting Beads

While the use of a chemotherapy emulsion in conventional TACE is effective, there is still some systemic release of chemotherapy due to emulsion instability and washout. Additionally, significant variation in cTACE technique exists among interventionalists.[23] Drug-eluting bead TACE (DEB-TACE), which utilizes permanent embolic microspheres to which chemotherapeutic agents are chemically bound, seeks to further limit the systemic release of chemotherapy and provide for a more uniform, reproducible treatment as compared with cTACE.[27] The goals of DEB-TACE are similar to cTACE: synergistically induce local tumor ischemia and deposit high local concentrations of chemotherapy. DEBs are typically loaded with a single chemotherapeutic agent, such as doxorubicin, epirubicin, or irinotecan, depending on the primary origin of the liver metastases being treated.[28] Drug-eluting beads loaded with doxorubicin (DEBDOX) have been primarily studied in the treatment of HCC, as well as a variety of liver metastases including NET, while drug-eluting beads loaded with irinotecan (DEBIRI) are more commonly used in the treatment of CRC metastases. Randomized clinical trials have not demonstrated any clear advantage in the use of DEB-TACE compared with cTACE or “bland” transarterial embolization (TAE) without chemotherapy in the treatment of HCC.[29] [30] [31] Some studies have cautioned interventionalists against DEB-TACE due to increased risk of biliary injury. Mechanistically, DEB-TACE results in the most concentrated chemotherapy release at the level of the peribiliary capillary plexus, where the doxorubicin in DEBDOX may cause local coagulative necrosis, with resulting reports of significantly higher incidence of biliary injury with DEBDOX in the treatment of NET metastases and HCC when compared with cTACE and TAE.[32] [33] [34] Increased rates of biliary injury with DEBIRI-TACE in the treatment of CRC metastases have not been reported. While reasons for this are unclear, it is noted that irinotecan is a prodrug, and requires metabolization by the liver into its active metabolite, and is therefore not immediately lethal in its delivered form, whereas doxorubicin is.[35] Overall, data regarding DEB-TACE in the treatment of liver metastases are heterogenous, primary-tumor specific, and dependent on the bound drug, with evidence for the use of DEB-TACE discussed in subsequent sections.

Specific Considerations for TACE in the Treatment of Liver Metastases

Tumor Vascularity

Tumor vascularity plays a significant role in the effectiveness of TACE. Hypervascular tumors will have a high propensity to take up the lipiodol emulsion and be more sensitive to embolization of their extensive blood supply, whereas a hypovascular tumor may not stain well with the lipiodol emulsion and be less affected by embolization. Studies have demonstrated poorer response, decreased survival, and early recurrence following TACE of hypovascular tumors compared with hypervascular tumors, primarily in the setting of HCC, where tumor vascularity has been found to be an independent predictor of tumor response after TACE.[36] [37] Similar findings have demonstrated in other tumor types, such as cholangiocarcinoma, as well.[38] Yttrium-90 transarterial radioembolization (TARE), which relies on radiation-induced cell death rather than induction of local tumor ischemia, has not demonstrated such reliance on tumor vascularity, and may be favored by some in the treatment of hypovascular lesions.[39] Liver metastases can demonstrate a range of vascularity, with NETs, melanoma, renal cell carcinoma, and thyroid carcinoma metastases typically considered hypervascular, whereas metastases from colorectal, breast, and lung malignancies are typically considered hypovascular.[40] While treatment decisions should not be based on vascularity alone, one should be cognizant of the role tumor vascularity plays in transarterial therapies and the different degrees of vascularity that liver metastases may demonstrate.

Bile Duct Injury

While HCC is most typically encountered in those with cirrhosis and advanced liver disease, liver metastases are often encountered in those with otherwise normal liver function. This results in unique physiology that puts those undergoing TACE for liver metastases at increased risk of ischemic biliary injury as compared with those undergoing treatment of HCC in the setting of cirrhosis.[19] The intrahepatic bile ducts do not have the dual blood supply that the surrounding liver parenchyma relies upon after TACE; rather, the bile ducts receive their blood supply exclusively from the hepatic artery via the peribiliary capillary plexus.[41] The intrahepatic bile ducts are therefore prone to ischemic injury following TACE, with potential bile duct necrosis and biloma formation as a result. It is thought that those with cirrhosis have bile ducts that are less susceptible to ischemic injury than those without cirrhosis due to hypertrophy of the peribiliary capillary plexus that occurs over time in the cirrhotic liver, providing increased capacity for collateralization, thus protecting the biliary tree from TACE's ischemic insult.[19] [41] [42] No such collateral network exists in those with liver metastases in otherwise healthy livers. Multiple studies have demonstrated increased rates of biliary complications in those undergoing TACE of liver metastases compared with HCC. Sakamoto et al demonstrated a significantly higher incidence of biloma formation in those with metastatic tumors (9.6%) compared with those with HCC (3.3%).[41] Yu et al found an overall incidence of bile duct injury of 11.3%, with a higher incidence in those with metastatic disease, as well as decreased incidence in those undergoing treatment of HCC with more advanced liver disease (3% for Childs-Pugh class B/C compared with 16% in Childs-Pugh class A).[43] Similarly, higher rates of bile duct injury have been reported in those undergoing DEB-TACE for liver metastases as compared with HCC, as will be discussed in the subsequent discussion of DEB-TACE in the treatment of NET metastases. As a result, many authors have suggested that DEB-TACE should be performed with caution in those without cirrhosis.[32] [33] [34] When treating liver metastases with TACE, whether cTACE or DEB-TACE, interventionalists should consider this increased risk of biliary injury in their treatment strategy, their discussion of consent and potential complications with patients, and in their post-procedural evaluation of patients.

Colorectal Cancer Liver Metastases

Colorectal cancer is the 3rd most common malignancy worldwide, with ∼2 million new cases per year, and represents ∼10% of all new cancer diagnoses.[44]

Fifteen percent of patients diagnosed with CRC present with synchronous liver metastases and 30 to 60% will develop liver metastases at some point in their disease course, with liver metastases contributing to patient death in ∼50% of patients.[45] Results of surgical resection to completely remove liver metastases are durable, with 5-year overall survival (OS) upward of 50%; however, the majority of patients are not eligible for resection upon presentation.[46] Recent advances in systemic therapies have improved survival for those with inoperable liver metastases, although are associated with the expected side-effects of systemic therapy, and eventually some tumors may develop multi-drug resistance and progress.[47] Transarterial therapies offer a targeted approach to CRC liver metastases, with applications including use in downstaging initially inoperable disease to surgical resection or ablation candidacy, as an alternative to systemic therapy in those either not tolerating such therapies or demonstrating progression, or in combination with systemic therapies. The evidence for use of cTACE and DEB-TACE utilizing DEBIRI (DEBIRI-TACE) is reviewed here.

Conventional TACE for CRC Liver Metastases

There are no large studies evaluating conventional TACE as a first-line treatment for CRC metastases, either alone or in combination with systemic therapy, and most trials evaluating cTACE have been performed in patients who have been heavily pretreated with systemic therapies.[48] The majority of existing studies are retrospective, with heterogenous treatment regimens and outcomes. Early, smaller studies regarding cTACE in the treatment of CRC metastases, including two small prospective phase II trials, demonstrated response rates ranging from 23 to 82%, noting significant heterogeneity in the definition of response. In the phase II trials, the mean OS ranged from 9 to 10 months after first cTACE and 29 months after initial diagnosis of liver metastases (reported in one of two trials).[49] [50] [51] In a retrospective study of 121 patients, Albert et al described the outcomes of a cTACE regimen including doxorubicin, cisplatin, and mitomycin C followed by embolization with PVA.[52] Of those who completed their TACE treatment cycles, 2% demonstrated partial response, 41% demonstrated stable disease, and 57% demonstrated progression. Median OS was 9 months after first cTACE and 27 months after initial diagnosis of liver metastases, similar to aforementioned trials. Subgroup analysis according to the number of prior lines of systemic therapy demonstrated improved survival when cTACE was performed after first- or second-line systemic therapy as compared with the third to fifth lines of therapy, with 1-year survival after cTACE of ∼40% in those with ≤2 prior lines of therapy compared with 12% in those with ≥3 prior to cTACE.[52] Additionally, this study is one of the few to include patients with limited extrahepatic disease. Additional small studies including patients with extrahepatic disease demonstrated median OS of 8 to 14 months.[53] [54] Given outcomes were similar to studies that excluded those with extra-hepatic disease, some authors have suggested that limited extrahepatic disease is not a strict contraindication to liver-directed therapy (LDT).

A large prospective trial including 463 patients sought to determine whether different TACE drug regimens resulted in different outcomes, evaluating mitomycin C, mitomycin C with gemcitabine, and mitomycin C with irinotecan. No statistically significant differences were found between these regimens. Overall, 15% of patients demonstrated a partial response, 48% stable disease, and 37% disease progression after cTACE, with median OS of 14 months after first cTACE and 28 months after initial diagnosis of liver metastases.[55] Gruber-Rouh et al reported the largest retrospective series with long-term follow-up, in which 564 patients with unresectable and chemo-refractory CRC metastases underwent nearly 3,400 cTACE procedures (mean of 6 TACEs per patient) with various chemotherapy emulsion regimens, depending on what prior systemic chemotherapy the patient had received. Clinical indication for cTACE (neoadjuvant, palliative, symptom treatment) and initial tumor response were statistically significant factors in survival. An overall response rate of 65% was reported, with 1-, 2-, and 3-year survival after TACE of 62, 28, and 7%, respectively. Median survival after initial cTACE was 14 months.[56] In a follow-up study, the same group described differences in those undergoing cTACE for palliative intent (n = 233) as compared with those undergoing neoadjuvant-intent treatment prior to ablation (n = 219).[57] Of those undergoing neoadjuvant therapy, 116 patients (54%) were eligible for ablation prior to cTACE, while the remaining 103 patients (46%) were downstaged to candidacy as a result of cTACE. The authors acknowledge inherent differences between the two study groups, noting the neoadjuvant group had limited tumor burden compared with the palliative cohort. Those undergoing neoadjuvant cTACE demonstrated a significantly longer OS and progression-free survival (PFS) of 26 and 11 months, respectively, compared with the palliative group, where OS and PFS were 13 months and 6 months, respectively. Tumor number, location, and mean size were significant prognostic factors for OS and PFS in the neoadjuvant group. While it is difficult to draw conclusions on the comparison of these two differing patient groups, the study importantly suggests that cTACE may be of benefit in conjunction with other therapies, such as percutaneous ablation, and allow for downstaging of tumors so that they may undergo ablation. Smaller studies have reported on the combination of cTACE and ablation, including a phase II trial of 25 patients with either three metastatic lesions measuring ≤3 cm or a single lesion ≤5 cm treated with cTACE followed by radiofrequency ablation. The results demonstrated high rates of local tumor control and a median OS of 48 months. Results of other studies have not been as robust.[58] [59]

Overall, data regarding cTACE for colorectal liver metastases demonstrate that cTACE is feasible and similarly effective with different chemotherapy emulsion regimens, but may not significantly improve OS, especially when utilized later in the disease process after multiple lines of systemic therapy have already been exhausted. However, prospective trials comparing cTACE with other treatment options in the same line of therapy (e.g., cTACE vs. first- or second-line systemic therapy) are lacking. Conventional TACE appears to be more efficacious when used after only one or two lines of systemic therapy have been given. It may also be useful in combination with thermal ablation, whether used as a downstaging mechanism or as a synergistic therapy.

DEB-TACE Utilizing DEBIRI (DEBIRI-TACE) for CRC Liver Metastases

DEB-TACE has largely superseded cTACE as the intra-arterial chemotherapy-based treatment of choice for CRC metastases. The reason for this is likely multifactorial—cTACE has not demonstrated substantial benefit in this patient population and irinotecan, already a common systemic agent in the treatment of CRC, can be utilized in DEBIRI-TACE, making this version of DEB a particularly attractive option. As a result, multiple phase II trials, as well as a phase III trial, have been performed using DEBIRI-TACE, and trials have evaluated the use of DEBIRI-TACE earlier in patient's treatment regimens, including use of DEBIRI-TACE as a first-line therapy.[60]

There have been numerous single-arm trials, including phase II trials, and retrospective studies evaluating DEBIRI-TACE without a comparison group and without specific combination with a systemic chemotherapy. In 2011, Martin et al described the outcomes of 55 patients with unresectable and chemotherapy-refractory CRC metastases as part of a multicenter treatment registry.[61] Response rates were 66% at 6 months and 75% at 12 months, with median OS of 19 months and PFS of 11 months, noting 30% of the cohort was receiving simultaneous systemic chemotherapy. In the same year, Aliberti et al reported an OS of 25 months and PFS of 8 months in 82 patients, all of who had undergone at least two prior lines of systemic therapy, as part of a prospective two-institution study.[62] In 2015, Stutz et al described outcomes in 27 heavily pretreated patients, 40% of whom had extrahepatic metastases, with a median OS of 5.5 months.[63] Those with better performance status and fewer prior lines of therapy appeared to do better; however, the small cohort size limited meaningful analysis. More recent studies have evaluated DEBIRI-TACE technique and factors associated with outcomes. In 2020, Boeken et al evaluated whether bead size affected patient outcomes, comparing 70 to 150 μm beads and 100 to 300 μm beads in 84 patients undergoing DEBIRI-TACE while also on systemic chemotherapy.[64] No significant difference was found between groups, with those undergoing treatment with the smaller beads and larger beads demonstrating a PFS of 8 and 7 months, respectively. A slightly increased OS was seen in those treated with smaller beads (15 vs. 13 months, p = 0.04); however, this was attributed to post-TACE treatment regimen differences between groups. A trend toward higher treatment-related toxicity was seen in those treated with smaller beads (37%) as compared with larger beads (17%). In a small study evaluating DEBIRI-TACE in those who had right-sided versus left-sided primary tumors, Seidl et al reported median OS of 33 months and PFS of 6 months in those with left-sided tumors versus OS of 17 months and PFS of 4 months in those with right-sided tumors.[65] While no evaluation of the statistical significance of this result was reported, it is in line with known differences in treatment outcomes between right- and left-sided tumors.[66]

Several studies have specifically evaluated DEBIRI-TACE in combination with systemic therapies. Iezzi et al performed a phase II single-center study of DEBIRI-TACE with concurrent gemcitabine.[67] Twenty patients who had failed at least two prior lines of systemic therapy were included (>50% failed three prior lines of therapy), with an objective response rate of 60%, median PFS of 4 months, and OS of 7 months, comparable to other salvage therapies. In the first randomized controlled trial to evaluate DEBIRI-TACE in combination with an oxaliplatin-containing systemic regimen, Martin et al compared those undergoing DEBIRI-TACE + FOLFOX to those undergoing treatment with FOLFOX alone. Notably, patients were naive to systemic chemotherapy.[60] Patients also received treatment with bevacizumab in both groups, as decided by the treating oncologist, with 70% of those in the combination group and 90% of those in the systemic-only group receiving concurrent bevacizumab. Overall response rate in the combination group versus the systemic-only group was 76 versus 60% at 6 months, respectively (p = 0.05). A trend toward longer PFS was seen in the combination group (15 months) compared with the systemic-only group (8 months), despite the combination group having more patients with extrahepatic metastases and poorer performance status, although the difference was not significant (p = 0.18). There was a significant difference in liver PFS favoring the combination group (17 vs. 12 months, p = 0.05). Additionally, significantly more patients in the combination group were downstaged to resection (35 vs. 16%, p = 0.05). Overall, this study demonstrated that DEBIRI-TACE in combination with systemic therapy as a first-line treatment may lead to improved response rates and increased hepatic progression-free survival (HPFS) in unresectable patients, while possibly downstaging more patients to resection compared with FOLFOX alone. Notably, no OS data were reported in this study. Five years after this study, Pernot et al performed a phase II study evaluating a similar group: patients undergoing DEBIRI-TACE in combination with FOLFOX as first-line therapy.[68] Fifty-seven patients underwent four courses of DEBIRI-TACE, consisting of either four courses of alternating lobar treatments or two combined bilobar treatments. Due to increased toxicity in those undergoing bilobar treatments identified at interim analysis, this approach was halted, and subsequent patients underwent alternating lobar treatments. The prespecified endpoint of a >75% PFS at 9 months was not met. PFS at 9 months was 54% PFS. An objective response rate of 73% was observed, along with an OS of 11 months and PFS of 37 months. Approximately one-third of patients were downstaged to undergo surgery or ablation. This result was similar to that in the study by Martin et al, in which 35% of those receiving combination therapy were downstaged.[60] Fiorenti et al described a different combination therapy, DEBIRI-TACE followed by bevacizumab (started 15 days after DEBIRI-TACE), allowing patients to self-randomize between the combination group and a DEBIRI-TACE-only group after an explanation of both therapies.[69] Thirty patients were enrolled with 13 in the combination arm and 17 in the DEBIRI-TACE-only arm. The addition of bevacizumab appeared to improve outcomes, with the combination group demonstrating an improved response rate (77 vs. 19%, p < 0.01), median OS (12 vs. 6 months, p < 0.01), and median PFS (6 vs. 4 months, p < 0.01) compared with the DEBIRI-TACE-only group. Notably, the combination group in this study had outcomes similar to other studies of DEBIRI-TACE only, while the DEBIRI-TACE-only group had below average outcomes. While the reasons for this were unclear, it may be attributed to patients in this study being heavily pre-treated with systemic therapy. In 2022, Lu et al described a retrospective of patients undergoing DEBIRI-TACE with regorafenib, a multi-target tyrosine kinase inhibitor currently used as a third-line systemic therapy in CRC treatment. This combination therapy group was compared with those who underwent DEBIRI-TACE alone.[70] Compared with the DEBIRI-TACE alone group, the combination group demonstrated significantly improved overall response rates (57 vs. 33%), median OS (18 vs. 11 months), and median PFS (9 vs. 5 months), suggesting DEBIRI-TACE in combination with regorafenib may be considered as a third-line therapy.

In 2012, Fiorentini et al published a phase III prospective multi-institutional double-arm trial evaluating the role of DEBIRI-TACE versus FOLFIRI in CRC. The study included 74 patients who were heavily pre-treated with systemic therapies, with those enrolled failing two (n = 45) or three (n = 29) prior lines of therapy. Those undergoing DEBIRI-TACE demonstrated a median OS of 22 months and PFS of 7 months, significantly greater than the median OS of 15 months and PFS of 4 months in the FOLFIRI arm. While this study demonstrated benefits in the use of DEBIRI-TACE as compared with FOLFIRI, the study was planned in 2005, after which the standard of care for systemic therapy in CRC metastases saw numerous changes, with other regimens (FOLFOX) and new combination regimens including bevacizumab and cetuximab playing a large role in earlier lines of treatment, somewhat limiting the applicability of the results of this study by the time it was published.

DEBIRI-TACE has also been specifically assessed in the neoadjuvant and down-staging setting. A prospective multi-institution registry of 55 patients who underwent DEBIRI-TACE for unresectable liver metastases demonstrated that 20% of patients were able to be downstaged or achieve disease stability to allow for resection and/or ablation.[71] In the PARAGON-II study, Jones et al reported results in a truly neoadjuvant setting, describing single-session DEBIRI-TACE in 40 patients who were already eligible for resection at the time of study inclusion.[72] TACE was performed at a median of 30 days before surgery. The majority (76%) of resected lesions demonstrated either major or complete pathologic responses. Median OS survival after surgery was 51 months, comparable to systemic neoadjuvant therapies.

When Should Chemoembolization of Liver Metastases from Colorectal Cancer Be considered?

When the interventional radiologist is presented with a patient with CRC liver metastases for whom percutaneous intra-arterial therapies are being considered, options include cTACE, DEBIRI-TACE, and TARE. There are limited data on the efficacy of TAE. While the aforementioned evidence for cTACE and DEBIRI-TACE is heterogenous, the data regarding DEBIRI-TACE are more robust and better established, including multiple phase II trials, a randomized phase III trial, and additional studies regarding use within different lines of therapy and in combination with systemic therapies. As a result, DEBIRI-TACE has largely replaced cTACE in the treatment of CRC liver metastases. The question then becomes, DEBIRI-TACE or TARE?

TARE has been studied in phase II and phase III trials as both first-line therapy and salvage treatment for CRC liver metastases. While a complete review of the data behind TARE is beyond this scope of this review, notable studies include the SIRFLOX, FOXFIRE, and FOXFIRE global phase III trials, which evaluated TARE + FOLFOX versus FOLFOX alone as first-line therapy.[73] [74] In summary, while those who underwent TARE demonstrated improved radiologic response rates and improved HPFS, no significant difference in OS was seen. While TARE did not demonstrate improvement in survival in the first-line setting, some survival benefit has been demonstrated in combination with second- or third-line chemotherapy and as salvage therapy in chemorefractory patients.[75] [76] [77] [78] [79] [80] [81] TARE can also be used to induce contralateral lobe hypertrophy after unilateral treatment in those under consideration for hepatic resection with insufficient remnant liver volume.[82] In 2017, TARE was included in the NCCN guidelines with the category 2a recommendation for use as second-line therapy in those with liver-predominant metastases resistant or refractory to other therapies. The 2023 NCCN guidelines state, “Consensus amongst panel members is that arterially directed catheter therapy and, in particular, yttrium-90 microsphere selective internal radiation is an option in highly selected patients with chemotherapy-resistant/-refractory disease and with predominant hepatic metastases.”[83]

While meta-analyses have demonstrated equivocal differences between TACE and TARE in the treatment of CRC metastases, given the above evidence and recommendations, TARE is typically considered before DEBIRI-TACE when deciding among the two, although this is dependent on physician and institutional practices and expertise.[84] [85] [86] Treatment with DEBIRI-TACE is more definitely indicated if there is a contraindication to TARE or if the patient progresses after TARE. Consideration of either is typically occurring as part of second-line therapy or beyond in those with unresectable disease that are not candidates for ablation.

Neuroendocrine Tumor Liver Metastases

Neuroendocrine tumors represent neoplasms that arise from neuroendocrine cells throughout the body, with common primary tumor sites including the gastrointestinal tract, pancreas, and bronchi, among other organs.[87] [88] [89] The incidence of NETs has been on the rise, possibly due to increased awareness and improved diagnostic capabilities.[87] [88] [89] Their presentation, symptomatology, and clinical course vary significantly based on several factors, including primary site, histologic grade and stage, functionality, and the presence of metastases. NETs have a predilection for metastasizing to the liver, with nearly a third of patients presenting with liver metastases at the time of diagnosis, and greater than 50% of those with gastrointestinal NETs developing liver metastases over the course of their disease.[88] [90] [91] Development of hepatic metastases portends a worse prognosis, with associated 5-year survival rates reported between 30 and 50%.[87] [92] Disease behavior and prognosis also correlates with tumor grade, with higher grade tumors demonstrating progressively worse OS.[89] The grading system for gastroenteropancreatic NETs is based on histologic determination of the Ki-67 proliferation index and mitotic count, with grade 1 NETs demonstrating a Ki-67 <3% and mitotic count <2 per 10 high power fields (HPFs), grade 2 NETs demonstrating a Ki-67 between 3 and 20% and mitotic count between 2 and 20 per HPF, and grade 3 NETs demonstrating a Ki-67 >20% and mitotic count of >20 per HPF.[93] NETs are typically well-differentiated tumors; however, some grade 3 tumors may be found to be poorly differentiated upon evaluation of cellular morphology, and are then diagnosed as neuroendocrine carcinomas.

NETs can secrete various hormones, which may result in associated hormone syndromes, including carcinoid syndrome, which is characterized by attacks of flushing, abdominal cramping, diarrhea, bronchospasm, and hypotension. Carcinoid syndrome is most commonly seen in those with gastrointestinal NETs, with symptoms arising after the development of liver metastases. This is because NET metastases within the liver will circumvent the “first pass” hepatic inactivation of hormonal substances, resulting in hormones produced by NET liver metastases entering the systemic circulation. The hepatic inactivation process was previously preventing hormones produced by the primary GI NET, which enter the portal circulation to the liver, from reaching systemic circulation in meaningful concentrations.[94] Carcinoid syndrome may significantly affect a patient's quality of life and result in long-term complications, including carcinoid heart syndrome related to fibrotic degeneration of the right-sided cardiac valves.[95]

In addition to the association of NET liver metastases with decreased OS and aforementioned carcinoid syndrome, metastases may cause bulk symptoms related to their size and can result in liver dysfunction as the hepatic parenchyma is replaced by tumor burden.[96] [97] The treatment of NET liver metastases requires a multidisciplinary team consisting of medical oncologists, surgical oncologists, interventional radiologists, and other subspecialty physicians. Goals of treatment may include tumor bulk reduction, palliation of symptoms related to carcinoid syndrome, and potential downstaging for surgery.[86] Somatostatin analogs (SSAs) are typically employed prior to LDTs, with the PROMID and CLARINET studies demonstrating SSA's cytostatic effect on tumor growth, with improved PFS compared with control groups.[98] [99] Surgical resection is the only curative therapy for NET liver metastases; however, most patients are unresectable at presentation due to their hepatic disease burden, with curative-intent surgery performed in only a small subset of patients. Cytoreductive surgery may also be performed if between 70 and 90% of the metastatic disease burden can be resected.[100] Thermal ablation may also be considered; however, it is similarly limited due to the extensive multifocal location of liver metastases typical of NETs. Systemic chemotherapies, targeted agents such as everolimus, and peptide receptor radionuclide therapy (PRRT) are used in those with extrahepatic disease, especially if the disease burden is non-liver dominant. Transarterial LDT is often the therapy of choice for liver-dominant NET metastases, with conventional TACE representing the mainstay of interventional treatments.

Indications for Liver-Directed Therapy in NETs

In general, transarterial LDT should be considered in patients with liver-dominant, unresectable metastases that are symptomatic, whether due to tumor bulk (pain, early satiety) or hormone production (carcinoid syndrome and/or heart disease), and when disease is progressing despite medical therapy. NCCN guidelines specifically recommend embolization for patients when liver metastases are (1) symptomatic on an SSA or following another form of systemic therapy, (2) progressive on an SSA or following another form of systemic therapy, and (3) when presenting with bulky liver disease, at which time embolization may be used as a debulking therapy without waiting for progression ([Fig. 1]).[101] One additional area in which transarterial LDT may be employed is in combination with PRRT to reduce the size of large hepatic lesions, which may act as a sink for PRRT, resulting in poor PRRT distribution to extrahepatic metastatic disease.[102]

Fig. 1 Indications, response rates, and response durability for transarterial chemoembolization of neuroendocrine tumor liver metastases. Response rates and response durability represent estimated ranges of median response rates and HPFS based on available studies. HPFS, hepatic progression-free survival. Figure 1 created with Biorender.com.

The life expectancy of those with NET is typically longer than those with other types of cancer treated with transarterial LDT. It is therefore not unusual for patients to undergo multiple “cycles” of embolization in their lifetime, with a cycle of embolization performed whenever it is clinically indicated. A cycle of embolization may consist of two to three separate embolization sessions performed ∼4 weeks apart to ultimately treat all known liver metastases.[103] Typically, the left and right hepatic lobes are treated in separate sessions, and occasionally the right-hepatic lobe treatment will be split further, separating treatment of the anterior and posterior divisions into two sessions. Decisions regarding this typically depend on the patient's tumor burden, hepatic function, and tolerance of post-embolization syndrome, among others. Each “cycle” may be effective in controlling symptoms and metastatic burden for a time and repeated as necessary. Maintenance of the patient's functional healthy liver is of paramount importance in these treatment decisions, such that future liver-directed and systemic treatment options are preserved.[102]

Conventional TACE for NET Liver Metastases

Conventional TACE has been performed for the treatment of NET liver metastases since the early 1990s.[104] [105] [106] [107] Conventional TACE in this population has typically consisted of typical doxorubicin containing chemotherapy emulsions, as described earlier. Some groups have reported good outcomes with streptozotocin as well, noting streptozotocin-TACE requires treatment under general anesthesia due to pain associated with its administration, limiting its use.[108] [109] [110] Given the goals of treatment for NETs are different from other cancers and include control of hormonal symptoms and disease control (rather than cure), results in this population are typically described in multiple ways. In addition to typical survival data (OS, PFS, etc.), meaningful data often include symptomatic response, biochemical response, and morphologic/radiologic response.[111] Complete responses are generally rare due to the large hepatic tumor burden typically present at the time of referral for transarterial therapy, and are reported in less than 5% of patients.[96]

Multiple systematic reviews and other descriptions of pooled data have evaluated the numerous studies describing cTACE outcomes in this population.[111] [112] [113] The large majority of included studies are retrospective. Reported symptomatic response rates after TACE have typically ranged between 60 and 95% (although have been described as low as 0% and as high as 100%).[103] [107] [108] [112] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] A systematic review by Yang et al reported a median symptomatic clinical response rate of 88.5%, which incorporated data from 18 studies.[112] Biochemical response rates are slightly lower and reported in fewer studies, with a median biochemical response of 73% (range: 13–100%) based on data from 11 studies.[107] [112] [118] [120] [121] [122] [125] [126] [127] Radiologic response rates at 3 months have ranged from 10 to 90%.[103] [107] [108] [112] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] Yang et al included 21 studies in their analysis of radiologic response rates and demonstrated a median objective response rate of 58%, as well as a median of 22% reporting disease stability.[112] Dermine et al reported a median objective response rate of 49% and median partial response rate of 27% in an analysis that included nearly 20 studies, although this included some studies focused on TAE.[113] In summary, TACE has demonstrated its greatest effect in controlling symptoms, with median symptomatic response rates approaching 90%, while it is able to induce a biochemical response in a median of ∼75% of patients. TACE results in a less reliable morphologic/radiologic response compared with its ability to produce symptomatic relief, with a median of ∼50 to 60% of patients demonstrating an objective radiologic response, although another 20 to 30% of patients will demonstrate stable disease on imaging after TACE ([Fig. 1]). This ultimately results in disease control in 80 to 90% of patients.

The durability of the aforementioned treatment responses and effect on survival is variable. Symptomatic responses have been reported in the range of 10 to 55 months, with multiple studies demonstrating responses of 10 to 20 months.[107] [111] [119] [122] Radiologic responses have been reported between 6 and 60 months.[111] Median HPFS has been reported between 8 and 30 months, with a pooled median of ∼18 months in one review that included predominantly TACE studies, although with some studies utilizing TAE.[96] [108] [111] [121] [130] Median OS has been described between 25 and 64 months, with a pooled median OS of 35 months in the aforementioned review that included predominantly TACE studies. Five-year survival rates after TACE are reported between 50 and 80%.[96] [103] [108] [109] [121] [130] [131] [132] In their description of 15-year monocentric experience treating 202 patients, Touloupas et al reported a median time to hepatic progression of 19 months and a median OS of 64 months. They also reported a unique statistic relevant to those who may undergo multiple cycles of TACE: time to untreatable progression with TACE. Time to untreatable progression with TACE was 26 months, with inability to continue to treat with TACE due to hepatic progression in 34%, combined hepatic and extrahepatic progression in 18%, isolated extrahepatic progression in 16%, and arterial or biliary damage in 6%.[103]

Prognostic Factors for Liver-Directed Therapy for Metastatic NET

The above statistics must be considered in the context of their heterogenous NET patient populations, as they are not stratified for known prognostic factors such as tumor grade or disease burden. Multiple studies have been performed evaluating prognostic factors and variables affecting outcomes of TACE in the treatment of NET liver metastases. Gupta et al evaluated 69 patients with non-pancreatic NETs and 54 patients with pancreatic NETs who underwent embolization.[128] Compared with those with pancreatic NETs, those with non-pancreatic NETs had better response rates (67 vs. 35%, p < 0.01), longer PFS (23 vs. 16 months, p = 0.046), and longer OS (34 vs. 23 months, p = 0.01). For those with non-pancreatic NETs, male gender was the only identified predictor of poor outcome. Among the pancreatic NET group, univariate analysis demonstrated worse outcomes if patients had an intact primary tumor, >75% liver involvement by metastases, or extrahepatic disease, with only the presence of bone metastases remaining as a significant predictor on multivariate analysis. Hur et al similarly evaluated those with non-pancreatic (n = 24) and pancreatic NETs (n = 22) after TACE and found similar PFS (17 vs. 15 months, p = 0.4) and a trend towards longer OS in those with non-pancreatic NETs (55 vs. 28 months, p = 0.375), noting a small sample size in this study.[131] On univariate and multivariate analysis, significantly decreased OS was seen in those with enterobiliary communication, >20% hepatic tumor burden, and the presence of extrahepatic metastases, with hazard ratios of 4.6, 2.7, and 5.1, respectively. Touloupas et al found tumor grade, degree of liver involvement, and age predictive of worsened OS, while SSA administration correlated with improved OS.[103] This study also found a correlation between OS and best morphologic response as measured by RECIST and mRECIST criteria, with a median OS that was twice as long in mRECIST responders (81 months) versus non-responders (40 months). In a multicenter retrospective study of prognostic factors for HPFS and OS in 155 patients, Chen et al demonstrated higher tumor grade and tumor burden to be prognostic of shorter HPFS and OS.[130] Following embolization, those with G1 tumors had a median HPFS of 19 months and median OS of 125 months, G2 tumors had a median HPFS of 12 months and median OS of 24 months, and G3 tumors had a median HPFS of 5 months and median OS of 9 months ([Fig. 1]). While these data include patients who underwent TACE, TARE, and TAE, no differences in HPFS or OS were seen among these different embolization techniques after propensity score-weighted analysis.

Additional studies have taken a focused approach to the evaluation of specific prognostic factors. Arrese et al specifically evaluated the presence of extrahepatic disease and its effect on outcomes.[115] Those with and without extrahepatic disease had similar biochemical and radiographic responses after TACE; however, a greater symptomatic response was seen in those with extrahepatic disease (79 vs. 60%, p = 0.01). Median OS was 28 months in those with extrahepatic disease versus 62 months in those with liver-only metastases (p = 0.001). Given a median survival of >2 years after TACE in those with extrahepatic disease and meaningful symptomatic responses, the authors concluded that TACE should be considered in such patients despite their extrahepatic disease burden, especially for those with carcinoid symptoms. Others have come to similar conclusions regarding the use of TACE in those with extrahepatic disease.[132] Studies of various laboratory values have demonstrated prognostic abilities. Increased chromogranin A and pancreastatin (a split product of chromogranin A) values; markers of hepatocyte dysfunction, including increased alkaline phosphatase and elevated prothrombin time; evidence of malnutrition as demonstrated by low serum albumin; and neutrophil:lymphocyte ratio >4 have all correlated with worse outcomes after embolization.[108] [114] [115] [116] [133] [134] Imaging markers have also demonstrated prognostic value. Luo et al evaluated pre-TACE multiparametric MRI and found tumor volume of the dominant lesion and volumetric enhancement values during the arterial and venous phases of imaging to be prognostic of both HPFS and OS.[135] Those with a dominant lesion volume greater than 73 cm³ had worse OS (HR: 2.7, 95% CI: 1.45) and HPFS (HR: 2.3, 95% CI: 1.4), while those with greater arterial and venous enhancement had improved outcomes. Arterial phase enhancement has proven to be prognostic of improved outcomes in other studies as well, consistent with the theory that the more hypervascular a tumor is, the better it will respond to TACE.[109]

TACE versus TAE for NET Metastases

It should be noted that data comparing TACE and TAE in the treatment of NET liver metastases are inconclusive, and whether TACE offers any significant advantages over TAE in the NET population remains controversial. A small prospective study including 14 patients who underwent TAE and 12 patients who underwent TACE demonstrated no differences between the two groups, with similar 2-year PFS rates and similar toxicities.[136] Ruutiainen et al retrospectively compared 67 patients who underwent TAE or TACE and found a trend toward improved symptom control, time to progression, and survival in those who underwent TACE; however, none of these differences were statistically significant.[124] Toxicities were also similar between the two groups. Pitt et al compared 100 patients undergoing TAE or TACE and found no differences in morbidity, mortality, symptomatic response, or OS.[123] One study demonstrated an improved radiologic response in those with pancreatic NET liver metastases who underwent TAE compared with TACE, although no corresponding significant difference in survival was seen between the two groups.[128] A smaller retrospective study by Fiore et al also demonstrated similar outcomes between the two groups, although with decreased occurrence of post-embolization syndrome in the TAE group (41%) compared with the TACE group (61%).[137] Meta-analyses have demonstrated no difference in OS or PFS between the two techniques.[138] The results of a large prospective trial to comparing embolization techniques in the treatment of NET liver metastases, the RETNET trial, are forthcoming.[139]

DEB-TACE Utilizing DEBDOX for NET Liver Metastases

Numerous studies have evaluated DEB-TACE for the treatment of NET liver metastases. Studies of DEB-TACE in this population have focused on DEBDOX. While some studies have demonstrated similar effectiveness of DEB-TACE to cTACE in terms of response rates, others have demonstrated superiority of cTACE, and multiple studies have raised concerns of increased incidence of hepatic and biliary injury associated with the use of DEB-TACE in the NET population, inciting much debate regarding the use of DEB-TACE in this population.[33] [34] [125] [129] [139] [140] [141] [142] [143] [144]

In 2008, De Baere et al published results of their initial experience with DEB-TACE in 20 NET patients, with an 80% initial response rate and disease control in nearly half of patients at median follow-up of 15 months.[125] Twenty-five percent of included patients were found to have peripheral liver necrosis on 1-month CT follow-up. Five years later, the same group retrospectively reviewed 120 patients with NETs (and 88 patients with HCC) who underwent DEB-TACE or cTACE.[34] They found the occurrence of liver/biliary injury to be associated with DEB-TACE with an odds ratio of 6.63 (p < 0.001), with biloma/parenchymal infarct independently associated with both DEB-TACE (OR = 9.78, p = 0.002) and NETs (OR = 8.13, p = 0.04). The incidence of biliary complications in this study was 30%. The authors subsequently recommended caution when using DEB-TACE in non-cirrhotics. Another retrospective study performed by Joskin et al evaluated liver necrosis after cTACE and DEB-TACE in NET liver metastases, and demonstrated increased liver necrosis in those treated with DEBs >300 μm in size compared with DEBs <300 μm in size (OR: 19.95, p < 0.01), suggesting DEB particle size may play a role in hepatobiliary complications.[140] Increased liver necrosis was also seen with DEBs >300 μm compared with cTACE (OR: 35.20, p < 0.001). While the relationship between increased DEB size and liver necrosis may seem counterintuitive, as it has been suggested that smaller particle size may lead to increased hepatobiliary necrosis by some authors, the increased rates of liver necrosis seen with larger particle sizes in DEBs, particularly DEBDOX, may be attributed to the location of doxorubicin delivery rather than the level at which particle-induced ischemia is ocurring.[19] [140] [145] The authors postulated that beads >300 μm did not travel distally into tumor tissue, but rather remained within more proximal healthy liver parenchyma, exposing non-tumoral tissue, including the biliary tree, to the cytotoxic doxorubicin.[140]

Other retrospective studies have not reported as significant of complications associated with DEB-TACE, but have reported superiority of cTACE in certain measures of treatment effectiveness. Makary et al have published two studies regarding DEB-TACE in NET liver metastases, with less worrisome findings regarding increased complication rates. A 2016 study compared 177 TACE treatments, 78 with cTACE and 99 with DEB-TACE.[129] No significant differences were noted between the two populations in terms of lesion size, distribution, and the presence of carcinoid syndrome. A higher symptomatic response rate of 47% was identified in the cTACE group compared with 30% in the DEB-TACE group (p < 0.05). No difference was observed in biochemical or radiologic responses. Higher category C–E complications were seen in the DEB-TACE group (11.1 vs. 3.8%), although this difference was not significant. This was followed up with a larger, 5-year single-institute experience published by the same group including 287 patients with NET liver metastases treated with DEB-TACE.[141] Complete and partial responses after DEB-TACE were seen in 21 and 46% of patients, respectively, comparable to other embolization techniques. OS was 80% at 1 year, 49% at 3 years, and 14% at 5 years. This study demonstrated an overall low rate of adverse events and toxicity, with a major complication rate of 2.4%. It is notable that these two studies reported use of 100 μm DEBs, again noting the previously described study by Joskin et al suggesting fewer complications with DEBs <300 μm. A large retrospective analysis comparing cTACE, DEB-TACE, and TARE performed by Do Minh et al in 2017 included 192 patients with NETs and found significant survival benefits in the cTACE group compared with both DEB-TACE and TARE, demonstrating the superiority of cTACE in this population.[142] Median OS in those undergoing cTACE was 33.8 months, significantly longer than the 21.7 months in those treated with DEB-TACE (p < 0.01). Five-year survival was 28.2 versus 10.3% in these two groups, respectively. HPFS was also longer in the cTACE group at 20.1 months compared with 14.6 months, although this difference was not significant (p = 0.14). Adverse event rates were similar between the groups.

Two prospective studies have evaluated the use of DEB-TACE in NET liver metastases. In 2013, Bhagat et al found a high incidence of biliary injury in a single-arm phase II study of DEB-TACE in patients with NET liver metastases at interim analysis, with biloma development in >50% of patients, some of which required drainage for related abscess development.[33] This resulted in a protocol change and ultimately closure of the study. A prospective, multicenter randomized controlled trial seeking to determine the optimal embolization technique for NET liver metastases (RETNET) began enrolling patients in 2018, with a primary endpoint of HPFS and secondary endpoints including overall PFS, duration of symptom control, and rate of adverse events, among others.[139] Three arms were included: cTACE, DEB-TACE, and TAE. The protocol included closure of a treatment arm if there was a >20% rate of significant adverse events at interim analysis. Due to a 40% major complication rate seen in the DEB-TACE arm at interim analysis, this arm was closed early. The remaining two arms of the study have finished enrollment and results are pending at the time of this publication.[143]

Overall, studies have suggested cTACE may have benefits in terms of symptom control, OS, and potentially HPFS compared with DEB-TACE. While some retrospective studies have demonstrated similar toxicity profiles among the two, others have demonstrated significant association of DEB-TACE with hepatobiliary complications. Both prospective studies evaluating DEB-TACE in NETs identified excessive complication rates associated with the technique. As a result, NCCN guidelines state “drug-eluting embolics are associated with increased hepatobiliary toxicity in the NET population, and are not recommended.”[101] In summary, DEB-TACE utilizing DEBDOX is not recommended for use in NET liver metastases based on current evidence, and cTACE remains the chemoembolization technique of choice in these patients.

When Should Chemoembolization of NET Liver Metastases Be Considered?

When presented with a patient with unresectable liver-only or liver-dominant metastatic NET, options include systemic therapies and transarterial LDT. If a patient has not undergone a trial of SSAs, this should be considered prior to any transarterial LDT, as many patients will have symptomatic relief and experience control of tumor burden with SSA treatment, at least for a time. Embolization should be considered if a patient cannot tolerate SSAs, or demonstrates recurrent symptoms or progression of disease despite medical management. Early embolization can also be considered if a patient's tumor burden is so extensive that significant debulking is necessary or if the severity of their symptoms is such that initiation of SSAs may not result in fast enough symptom relief. Given the aforementioned risks of DEB-TACE in this population, treatment with DEB-TACE is typically not considered. Conventional TACE and TAE may be considered equivalent based on current evidence, and this decision will be based primarily on institutional and operator's preference. Therefore, in the NET population, the question that must be answered is whether to choose cTACE/TAE or TARE.

Some studies have demonstrated a benefit of TACE over TARE in the neuroendocrine population. A 2021 meta-analysis of TACE versus TARE found the treatments to have comparable effectiveness in terms of symptom control and HPFS. OS was significantly longer in the TACE group (OR: 1.9, 95% CI: 1.2–3.2, p = 0.01).[146] No apparent differences in baseline characteristics that might contribute to this difference were identified. In an analysis of 192 patients, Do Minh et al demonstrated both an improved median OS (34 vs. 23 months, p = 0.03) and HPFS (22 vs. 11 months, p = 0.03) in those who underwent TACE compared with TARE.[142] Egger et al evaluated 248 patients from two institutions and found long-term outcomes between TACE and TARE to be comparable, although the disease-control rate on first posttreatment imaging was higher in the TACE group.[147] TARE is also being evaluated in combination with systemic therapies for NETs, specifically in combination with the radiosensitizing chemotherapeutic agents capecitabine and temozolomide (CAPTEM), a regimen already in use within the NET population.[148] A part of this protocol, patients with liver-dominant grade 2 metastatic NET are started on CAPTEM, with cycles consisting of 14 days of CAPTEM on days 10 and 14, followed by a 14-day medication break before starting the next 4-week cycle. Pre-TARE simulation arteriography is performed during the initial CAPTEM cycle, with subsequent TARE performed on day 7 of the second CAPTEM cycle. For those being treated for bilobar disease, a second TARE is performed on day 7 of the third or fourth CAPTEM cycle. Initial safety and feasibility data from 19 patients showed the protocol to be safe, with expected toxicities of CAPTEM and TARE, and demonstrated promising results. The overall response rate was 74% in the liver and 55% for extrahepatic disease. PFS at 3 years was 67% and HPFS was 74%.[148] These results lead to a larger phase 2 multicenter trial, which is ongoing (NCT04339036).

While overall results between TACE/TAE and TARE are generally considered comparable, additional factors related to the relative longevity of NET patients and side effects of treatment must also be considered.[149] Three retrospective studies have been published regarding the risk of radiation-induced hepatotoxicity in those with NET liver metastases undergoing TARE.[149] [150] [151] Su et al described outcomes in 54 patients who underwent TARE with a mean of 4.1 years of follow-up.[151] In those who received whole-liver TARE (n = 39), 56% demonstrated cirrhosis-like liver morphology, 41% had ascites, and 15% had varices. These findings were identified to a lesser extent in those who underwent unilobar TARE. While the majority of patients were clinically asymptomatic, some developed clinical signs of hepatic decompensation without a cause of hepatotoxicity other than TARE. Tomozawa et al found that patients who underwent bilobar TARE had significantly increased liver function tests which were sustained for years after TARE. Imaging findings of cirrhosis-like morphology and portal hypertension were present in ∼30% of those who underwent bilobar TARE.[150] They similarly found bilobar treatment to have a higher association with long-term toxicity and portal hypertension than unilobar TARE. Finally, Currie et al compared chronic hepatotoxicity in those who underwent TACE versus TARE.[149] Chronic hepatotoxicity was found in 22% of those who underwent TACE and consisted primarily of subclinical abnormalities in laboratory markers of hepatic function, while 29% of those who underwent TARE demonstrated chronic hepatotoxicity, primarily in the form of clinical hepatic decompensation. The authors concluded that the long-term hepatotoxic effects of TARE were more severe than those of TACE. As a result of these studies, the NCCN guidelines for LDT have a statement regarding late radioembolization-induced chronic hepatotoxicity, noting it is of particular concern among those who undergo bilobar TARE.[101] Despite these risks, TARE has a better early side-effect profile and results in significantly less infectious risks, including risk of developing a liver abscess, in those who have undergone prior biliary instrumentation or surgical biliary anastomosis (Whipple, hepaticojejunostomy, choledochojejunostomy, etc.) compared with TACE.[101] [152] [153]

Given the effectiveness of TACE/TAE compared with TARE, the fact that TACE/TAE cycles can be repeated numerous times over the course of a patient's disease, and the better long-term safety profile of TACE/TAE compared with TARE, TACE/TAE is typically the first-line transarterial LDT employed in the treatment of NET liver metastases. If a patient has a durable response to their first cycle of TACE/TAE, and remains a candidate for TACE/TAE at the time repeat treatment is indicated, TACE/TAE should be repeated. If a patient does not have a durable response to TACE/TAE, a change in embolization strategy to TARE may be considered. Additionally, TARE may be considered as first-line therapy embolotherapy in those who cannot tolerate post-embolization syndrome, in those with prior biliary instrumentation or surgery, and potentially as part of synergistic combination therapies. When performing TARE, a unilobar or segmental treatment should be considered, sparing at least some of the liver the effects of radiation. A staged TACE/TAE may be considered in these other segments if a whole-liver treatment is desired.

Uveal Melanoma Metastases

Although rare, UM is the most common primary intraocular malignancy in adults, representing 3 to 5% of all melanomas.[154] Metastases are rarely seen at initial presentation; however, 50% of patients will eventually go on to develop metastases. Unfortunately systemic therapies have low efficacy in reducing the risk of extra-ocular disease development.[155] [156] The liver is the most common site of metastases, occurring in 70 to 90% of cases. It is the only site of metastases in ∼50% of cases.[157] [158] The prognosis of UM is generally favorable if the disease is confined to the eye; however, the development of extraocular metastatic disease is associated with a median survival of ∼13 months.[158] [159] Unfortunately, the vast majority of metastatic UM patients present with extensive hepatic involvement that is not amenable to resection.[160] [161] Additionally, the biological behavior of UM is distinctively different from cutaneous melanoma.[162] Systemic therapies typically effective for metastatic cutaneous melanoma have demonstrated poor results in the treatment of metastatic UM.[163] [164] There is no current FDA-approved treatment for metastatic UM.[165] The most recent NCCN guidelines recommend enrollment in a clinical trial as the preferred treatment option over existing systemic therapies, LDTs, and other options. No specific recommendation is made for those with liver-only or liver-dominant metastases.[166] Given the poor survival (ranging 2–9 months) of patients with untreated hepatic metastases, and the fact that a patient's prognosis is typically dependent on control of intrahepatic tumor burden and maintenance of hepatic function, numerous forms of LDT have been employed in attempts to treat UM liver metastases.[26] [167] [168] [169]

Comparative studies of those with metastatic UM undergoing systemic therapy, LDT, or combined systemic and LDT have demonstrated benefit of LDT, with median OS of 26 months in those who underwent LDT compared with 9 months in those who underwent systemic therapy only. Notably, LDT was the only treatment found to significantly improve OS.[170] In the description of a long-term single-center experience in treating UM metastases over 47 years, Seedor et al demonstrated similar benefits of LDT in terms of OS. Patients treated prior to 1993 typically received systemic therapy only, while nearly all patients treated after 1998 received LDT with or without systemic therapy.[165] Median time from diagnosis of metastases to death was 5 months prior to 1993, while those treated after 1998 had a median time from metastatic diagnosis to death of greater than 14 months. Meta-analyses have also suggested that patients undergoing LDT have improved PFS and OS.[169] LDTs for the palliative treatment of UM liver metastases have included various TACE techniques, with the most common being cTACE, BCNU-TACE, and DEB-TACE. BCNU-TACE utilizes the lipophilic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).

Conventional TACE for Uveal Melanoma Hepatic Metastasis

cTACE has been used to treat UM liver metastases for nearly four decades. Initially described by Carrasco et al, cTACE consisting of cisplatin and polyvinyl sponge was successfully performed in two patients with UM liver metastases.[171] Subsequently, this group summarized their experience in 30 patients reporting an overall response rate of 46%.[172] The median OS was 11 months, noting the median OS was 14 months in the responder group versus 6 months in the non-responder group.

There have since been multiple studies, both retrospective and prospective, investigating the effectiveness of cTACE with various chemotherapy agents, including cisplatin, carboplatin, mitomycin C, doxorubicin, and fotemustine, among other agents ([Table 1]). In general, cTACE is well-tolerated but variably effective, noting significant differences in reported overall response rates, ranging from 0 to 57%, as well as median OS, ranging from 5 to 29 months.[172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] Some of this heterogeneity in outcomes is due to differences in study design, end-point definition, and patient characteristics. For example, in a dose escalation study of cisplatin for chemoembolization, nearly 40% of patients received a dose below what would eventually be determined to be the optimal dose, and this underdosing may have contributed to the suboptimal response rate of 16%.[173] Similarly, the extent of tumor involvement varied significantly among studies, with some focusing on treatment of limited hepatic tumor burden and others including patients with >50% metastatic involvement of the liver.[174] [177] [178] The degree of hepatic involvement by metastases has been shown to correlate with outcomes. One study showed hepatic involvement <25% was associated with a significantly longer median OS than those with >25% hepatic involvement (17 vs. 11 months, p = 0.02).[177] Additional prognostic factors include angiographic pattern and lactate dehydrogenase (LDH) levels. Dayani et al demonstrated that patients with an infiltrative angiographic pattern of disease did worse than those with a nodular angiographic patter, with a mean OS of 4 months in the infiltrative group compared with 13 months in the nodular group (p < 0.001).[175] [176] Baseline LDH levels below two-times the normal limit have correlated with significantly longer survival after cTACE. One study demonstrated PFS and OS to be more than doubled for patients in a low-LDH group compared with a high-LDH group.[178] Gupta et al found that >75% liver involvement by metastases and high LDH levels were both associated with short OS after cTACE.[179]

Table 1 Summarized study data for conventional transarterial chemoembolization in the management of metastatic uveal melanoma to the liver

Study	Year	Patient number	Technique	Median survival	Response rate
Mavligit et al[172]	1988	30	Cisplatin with polyvinyl sponge	11 mo	46%
Agarwala et al[173]	2004	19	Cisplatin with and without polyvinyl sponge	8.5 mo	16%
Vogl et al[174]	2007	12	Mitomycin C and microspheres	21 mo	31%
Sharma et al[175]	2008	20	Cisplatin, doxorubicin, mitomycin C, and gelatin sponge or PVA particles	9 mo	0%
Dayani et al[176]	2009	21	Cisplatin, doxorubicin, mitomycin C, and gelatin sponge or PVA particles	7.6 mo[a]	n/a
Huppert et al[177]	2010	14	Cisplatin or carboplatin and PVA particle	11.5 mo	57%
Schuster et al[178]	2010	25	Fotemustine or cisplatin with starch microspheres	5 mo	16%
Gupta et al[179]	2010	125	Mostly cisplatin with gelatin sponge or PVA particles	6.7 mo	27%
Edelhauser et al[180]	2012	21	Fotemustine with PVA particles	29 mo[a]	14%
Duran et al[181]	2014	15	Doxorubicin, mitomycin C with PVA microspheres	5.6 mo	27%
Shibayama et al[182]	2017	29	Cisplatin with gelatin sponge	23 mo	21%

^a Mean survival.

While many of the aforementioned studies have demonstrated a small survival benefit when treating UM liver metastases with cTACE, other groups have found little success in doing so. In 1995, Sato et al reported a median survival of ≤7 months and a 0% response rate after cTACE, resulting in their abandoning of this technique for other types of transarterial therapies, including BCNU-TACE.[26] [183]

BCNU-TACE for Uveal Melanoma Hepatic Metastasis

BCNU was trialed as a chemoembolic agent because it is lipophilic and dissolves well in lipiodol, resulting in retention in the hepatic parenchyma after TACE, with rates of hepatic extraction greater than six times that of cisplatin, which is lipophobic.[184] There have been several studies investigating the safety and effectiveness of BCNU-TACE in managing metastatic UM. In a phase II study evaluating BCNU-TACE, Patel et al described the outcomes of 24 patients who underwent BCNU-TACE with 100 mg BCNU in emulsion with lipiodol followed by gelatin sponge embolization. Most patients had < 50% hepatic involvement by metastases and those with bilobar disease were treated with staged unilobar treatments.[184] The overall response rate was 21% and the median OS was 5 months. Those with >50% hepatic involvement had a median OS of 2 months. The poor median survival was thought to be secondary to inclusion of patients with bilobar disease who did not live long enough to undergo treatment of the second lobe due to rapid progression of disease. When these patients were excluded, the median OS increased to 7 months.[184] Gonsalves et al subsequently described treating 50 treatment-naive patients, all of whom had >50% hepatic involvement by metastases with over 271 BCNU-TACE sessions.[185] The dose of BCNU in the chemoembolic emulsion was double of that used in the study of Patel et al. The overall response rate was 6%, with the majority of patients demonstrating stable disease (66%). The median OS was 7 months, greater than the reported 2-month median OS of patients with similar degrees of liver involvement in the aforementioned study by Patel et al, and greater than that reported for cTACE by Schuster et al (median OS of 5 months).[178] [184] An ongoing phase II trial (NCT04728633) is recruiting patients to undergo BCNU-TACE with an increased BCNU dose (300 mg BCNU) with gelfoam embolization.

DEB-TACE for Uveal Melanoma Hepatic Metastasis

There have been multiple studies examining the safety and efficacy of DEB-TACE in the treatment of UM liver metastases, the majority of which have employed DEBIRI-TACE. A phase II study of DEBIRI-TACE included 10 patients, all of who had at least a partial response to treatment.[186] At a median follow-up of 6.5 months, 80% of the patients were alive. No severe toxicities were reported. In a separate study, Venturini et al treated five patients with limited hepatic disease (two to five lesions) with DEBIRI-TACE, with ORR of 60%.[187] Again, no significant toxicities were reported. Valpione et al conducted a retrospective study examining the efficacy of DEBIRI-TACE versus systemic chemotherapy in 160 metastatic UM patients. Fifty-eight patients received DEBIRI-TACE as part of first-line therapy, while the remainder received systemic chemotherapy only. Notably, 49 out of 58 DEBIRI-TACE patients also received systemic fotemustine for extrahepatic metastases or as consolidating treatment.[188] DEBIRI-TACE conferred a survival benefit, with a median survival of 16 months compared with 12 months in the systemic therapy alone group (p = 0.05). The survival benefit was most pronounced in patients with >50% hepatic involvement (HR = 0.17, 95% CI: 0.04–0.64, p = 0.009). While it was difficult to definitively discern the true effect of DEBIRI-TACE given the high percentage of concurrent systemic chemotherapy, findings suggested DEBIRI-TACE was well-tolerated in patients with extensive hepatic involvement and likely contributed to improved patient survival. In a similar retrospective study by Carling et al, comparison was again made between DEBIRI-TACE and systemic chemotherapy.[189] Half of patients in the DEBIRI-TACE group also obtained concurrent systemic therapy. Median OS was 15 months in the DEBIRI-TACE group versus 7 months in the chemotherapy-only group, although this difference was not statistically significant (p = 0.13). High rates of major complications were observed after DEBIRI-TACE (64%) compared with other studies. Complications appeared unrelated to systemic irinotecan toxicity, and may have been related to baseline hepatic dysfunction and extensive liver involvement by tumor. This highlights the challenging nature of treating patients with extensive UM liver metastases.

DEB-TACE utilizing DEBDOX has also been evaluated in this patient population.[190] The largest experience included 19 patients with bulky UM liver metastases who were initially treated with two separate lobar treatments of DEBDOX-TACE, with subsequent transarterial treatments consisting of BCNU-TACE.[191] The ORR was 16% and approximately half of patients demonstrated stable disease. Median survival was 9 months. The treatment seemed to be well-tolerated, although the authors noted high rates of biliary injury early in their experience, and subsequently utilized an earlier angiographic endpoint of slow antegrade flow (rather than stasis as well as administration of intra-arterial steroids to reduce inflammation and avoid biliary injury).[26]

When Should Chemoembolization of Liver Metastases from Uveal Melanoma Be Considered?

The described TACE techniques improve patient outcomes, but OS unfortunately remains measured in terms of months. Comparative data regarding TACE and other therapies are lacking. One of the larger comparative studies included 201 patients who underwent systemic chemotherapy (various chemotherapy agents), hepatic artery infusion (HAI), and cTACE. The overall response rates in the chemotherapy, HAI, and cTACE groups were 5.6, 15.8, and 36.4%, respectively. The median survival was significantly longer in the cTACE group compared with those treated with systemic chemotherapy (15 vs. 5 months, p = 0.003).[192] While TACE continues to play a large role in the treatment of UM liver metastases, alternative embolization techniques have also gained traction.

TARE has been evaluated in multiple small retrospective studies and in a phase II trial. Retrospective studies were performed primarily in populations who were heavily pre-treated, with some studies using an yttrium-90 dose reduction strategy as a result. Median PFS has been reported between 1 and 6 months, and OS between 3 and 12 months.[193] [194] [195] [196] Those with lower tumor burden generally had better outcomes, with patients who had <25% tumor involvement demonstrating at least double the OS and PFS than those with >25% in one study.[193] In 2019, Gonsalves et al published results of a phase II trial in which 48 patients with <50% hepatic tumor burden underwent TARE.[197] Half of the treatment population was treatment-naive and half had been previously treated with immunoembolization (IE). Median OS was ∼19 months in both groups. Median PFS was 8 months in those who underwent TARE as first-line intra-arterial therapy and 5 months in those who underwent TARE after IE. The authors concluded that TARE was effective as either first- or second-line intra-arterial therapy.[197] More recently, an ongoing phase II trial comparing TARE to cTACE with cisplatin and degradable starch microspheres reported interim results. The report included 40 patients (20 in each arm), with 5% overall response rates in both arms, a 95% rate of stable disease in the TARE arm, and an 85% rate of stable disease in the cTACE arm. Baseline disease burden was not reported. Median PFS was 5 months in the TARE arm and 2 months in the cTACE arm (p = 0.037) at a median follow-up of 14 months.[198]

IE utilizing granulocyte-macrophage colony-stimulating factor (GM-CSF) emulsified in lipiodol has also demonstrated efficacy in the treatment of UM liver metastases. IE has been compared with BCNU-TACE, with IE demonstrating both an improved median PFS (12 vs. 5 months, p = 0.001) and OS (20 vs. 10 months, p = 0.005).[199] A randomized phase II trial has been completed comparing IE to TAE, noting this study was primarily designed to evaluate immunologic outcomes. IE did induce a more robust inflammatory response and post-procedural interleukin-1 and interleukin-8 levels were significant predictors of PFS. Median OS was not significantly different, measuring 22 months in the IE group and 17 months in the TAE group.

The numerous embolotherapies used in the treatment of UM liver metastases, including cTACE, DEB-TACE, BCNU-TACE, TARE, and IE, may complicate treatment decisions. The frequent need for multiple cycles of transarterial LDT also raises questions regarding the optimal sequencing of treatments. Management of these patients requires a multidisciplinary team and one may consider referral to or consultation with a center specializing in the treatment of UM liver metastases to provide patients with clinical trial options and optimal therapy. One such center typically uses either IE or radioembolization as first-line intra-arterial therapy in those with limited hepatic tumor burden (<50% hepatic involvement).[26] [86] Patients with excessive hepatic tumor burden or bulky tumors typically undergo some form of TACE as first-line intra-arterial therapy. Patients may undergo multiple cycles of embolotherapy and switch between different types of embolotherapy as salvage therapy in the setting of progression.

TACE for Other Cancers Metastatic to the Liver

The three described cancers—CRC, NET, and UM—provide excellent examples of how the role of TACE in the treatment of liver metastases can significantly differ among different types of primary tumors. While these three examples were chosen for discussion, they obviously do not represent all the types of metastatic tumors to the liver that may be treated with TACE, a description of which would be beyond the scope of any one review. Liver metastases from some cancers, such as breast cancer and renal cell carcinoma, have followed a trajectory similar to CRC metastases, where there are some data suggesting TARE may be more effective than TACE. For example, pooled data regarding the treatment of breast cancer liver metastases demonstrated improved disease control by RECIST criteria in those who underwent TARE (78%) compared with TACE (58%). This finding is supported by a single-center retrospective review comparing the two techniques, which also demonstrated a trend toward improved survival with TARE.[200] [201] Regarding renal cell carcinoma liver metastases, studies of TACE have demonstrated objective response rates of 14% and median OS of 8 months, while TARE has demonstrated an ORR of 83% and median OS of 23 months.[202] [203] However, as with many tumors metastatic to the liver undergoing TACE, TARE, or other LDT, these data primarily come from small, single-center, retrospective studies or pooled data from numerous, often heterogenous, retrospective studies. For other liver metastases, such as those from sarcoma, TACE remains the primary form of liver-directed embolotherapy.[204] Many other liver metastases, such as those from lung cancer, thyroid cancer, and other solid organ tumors, may be treated by TACE, although there is little evidence to guide decisions regarding which type of embolotherapy may result in the best patient outcomes. There is a relevant need for additional clinical trials to help determine how liver-directed transarterial therapies, such as TACE, should be integrated into oncologic treatment algorithms.

Conclusion

Interventional radiologists play an enormous role in the treatment of hepatic malignancy, with TACE representing one of many options in an interventional radiologist's armamentarium. While TACE continues to play a dominant role in the treatment of HCC, its role in the treatment of hepatic metastases is dependent on the primary tumor type and several other factors. For some hepatic metastases, such as those from NET, conventional TACE remains a first-line intra-arterial therapy. For others, such as CRC metastases, TARE is typically considered as first-line intra-arterial therapy, followed by DEBIRI-TACE. Alternative regimens, such as BCNU-TACE, are considered for UM metastases. Treatment decisions for the above types of hepatic metastases, as well as others, are informed not only by the available evidence for their use, but by patient performance status, ability to tolerate post-embolization syndrome, discussion with a multidisciplinary treatment team, local expertise, and an informed discussion with the patient. Given the ever-changing landscape of oncologic treatments and interventional options, it is important for interventionalists to remain informed regarding the evidence for locoregional therapies including TACE specific to each cancer they treat to provide the best oncologic care and outcomes to their patients.

Conflicts of Interest

None declared.

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Article published online:
14 March 2024